Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10](S(C)(=O)=O)[C:9]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:8]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CS(C1N=C(N2CCCC2)C(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2Cl)N=1)(=O)=O.C([Li])CCC.[OH:66][C:67]1[CH:68]=[N:69][CH:70]=[CH:71][CH:72]=1>>[N:1]1([C:6]2[N:11]=[C:10]([O:66][C:67]3[CH:68]=[N:69][CH:70]=[CH:71][CH:72]=3)[C:9]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:8]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1cccnc1
Reactant: CS(=O)(=O)c1nc(N2CCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(N2CCCC2)n1
Agent: [Li]CCCC
Product: Clc1ccc(-c2c(Oc3cccnc3)nc(N3CCCC3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-(N-pyrrolidinyl)-4-methylsulfonyl-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (HRf product from Example 36, Step A (50 mg, 0.10 mmol) was reacted with 2 equivalents each of n-butyl lithium and 3-hydroxypyridine by the procedure described in Reference Example 6 and 7 to afford the title compound: HPLC/MS: m/e=497 (M++1); Rt=3.84 min. 1H-NMR 400 MHz (CDCl3): δ 1.91-2.00 (m, 4H), 3.23-3.35 (s, 2H), 3.55-3.62 (s, 2H), 7.08-7.21 (m, 6H), 7.35-7.39 (m, 2H), 7.56-7.58 (m, 1H), 8.48 (d, J=6 Hz, 1H), 8.58 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:12]([N:14]([CH2:22][CH3:23])[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)[CH3:13].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:21][C:18]2[CH:17]=[CH:16][C:15]([N:14]([CH2:22][CH3:23])[CH2:12][CH3:13])=[CH:20][CH:19]=2)[N:10]=1
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(Nc2nc(Cl)ccc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2,6-dichloronicotinamide (1 g, 5.24 mmol) and N1,N1-diethylbenzene-1,4-diamine (2.150 g, 13.09 mmol) in THF (50 mL) was added lithium bis(trimethylsilyl)amide (26.2 mL, 26.2 mmol) drop-wise at first then portion-wise at −78° C. The reaction mixture was stirred at rt for 30 min. The ice bath was removed and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with water, extracted twice with ethyl acetate, and the combined organic layers were washed with water and concentrated. The residue was purified by MPLC (ISCO, hexane/ethyl acetate, 120 g silica gel column) to give 6-chloro-2-(4-(diethylamino)phenylamino)nicotinamide. LCMS: (M+H)+=319.10. 1H NMR (400 MHz, CDCl3) δ ppm 10.44 (1H, s), 7.56 (1H, d, J=7.91 Hz), 7.47 (2H, d, J=9.23 Hz), 6.69 (2H, d, J=9.23 Hz), 6.55 (1H, d, J=7.91 Hz), 5.73 (2H, br. s.), 3.33 (4H, q, J=7.03 Hz), 1.15 (6H, t, J=7.03 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[NH:5][CH3:6].N1C=CC=CC=1.[CH2:17]=[C:18]1[O:22][C:20](=[O:21])[CH2:19]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[N:5]([CH3:6])[C:20](=[O:21])[CH2:19][C:18]([CH3:17])=[O:22]
Reactant: C=C1CC(=O)O1
Reactant: CNc1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)N(C)c1ccc(Cl)c(Cl)c1

Procedure:
Dissolved in toluene were 3.5 g (0.02 mole) of 3,4-dichloro-N-methylaniline and a catalytic amount of pyridine, followed by a dropwise addition of 1.9 g (0.022 mole) of diketene at 50° C. After completion of the the dropwise addition, the resultant mixture was heated under reflux for 3 hours. The reaction mixture was cooled, and its organic layer was then washed with water, water, a 10% aqueous solution of hydrochloric acid and a 5% aqueous solution of sodium hydrogencarbonate in order. The thus-washed organic solution was dried and concentrated to obtain 3',4'-dichloro-N-methylacetoacetoanilide.
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[CH3:15][NH:16][C:17]1[C:30]2[C:29](=O)[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:32])[C:21]=2[C:20]([Br:33])=[CH:19][CH:18]=1>>[C:6]([C:5]1[C:4](=[O:14])[N:16]([CH3:15])[C:17]2[CH:18]=[CH:19][C:20]([Br:33])=[C:21]3[C:22](=[O:32])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[C:29]=1[C:30]=23)(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CNc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Product: Cn1c(=O)c(C(=O)c2ccccc2)c2c3c(c(Br)ccc31)C(=O)c1ccccc1-2

Procedure:
Benzoylacetic acid ethyl ester is reacted with 1-methylamino-4-bromoanthraquinone in a solvent to obtain 1-benzoyl-6-bromo-2,7-dihydro-3-methyl-2,7-dioxo-3H-dibenzo[f,ij]isoquinoline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20]Br)[CH:15]=2)[CH:10]=[C:9]1[C:22]1[C:23]2[S:36][C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:34][C:24]=2[N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[CH:15]=2)[CH:10]=[C:9]1[C:22]1[C:23]2[S:36][C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:34][C:24]=2[N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(OCCCBr)cc3n2C(=O)OC(C)(C)C)c2sc(-c3ccccc3)cc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(OCCCN4CCCCC4)cc3n2C(=O)OC(C)(C)C)c2sc(-c3ccccc3)cc21
Temperature: 70 °C
Reaction time: 20 h

Procedure:
A mixture of 6-(3-bromo-propoxy)-2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester [300 mg, 0.460 mmol, Intermediate 50)], piperidine (60.2 mg, 0.707 mmol), potassium carbonate (191 mg, 1.38 mmol), potassium iodide (40.0 mg, 0.241 mmol), and anhydrous acetonitrile (5.0 mL) was heated at 70° C. with shaking at 200 rpm. After 20 hours, the reaction was cooled to ambient temperature, filtered, the insolubles washed three times with dichloromethane (5 mL), and the filtrate concentrated under reduced pressure to give a dark residue. The residue was chromatographed on silica, eluting with 10%-1 M ammonia in methanol/90% dichloromethane, to give 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-[3-(piperidin-1-yl)-propoxy]-indole-1-carboxylic acid tert-butyl ester (310 mg) as a brittle green foam: LC/MS: 657.3, (M+H), RT=3.92 minutes, 50% UV purity). A mixture of this material (300 mg), 4 M aqueous potassium carbonate (5.0 mL), tetrahydrofuran (5.0 mL) and methanol (5.0 mL) was heated at 60° C. for 2 hours. After cooling to room temperature, the solvent was removed in vacuo to give a solid. The crude solid was suspended in water (25 ml) and the mixture stirred at room temperature for 0.5 hours. The solid was collected by filtration and dried to give a grey solid. Trituration of the solid with 20% methanol/ether provided 2-(5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-(3-piperidin-1-yl-propoxy)-1H-indole [90.0 mg, 43%, Example 58] as a grey solid. TLC Rf 0.37 (silica, 14% 1 M ammonia in methanol/86% dichloromethane); LC/MS: 457.3 (M+H), RT=2.93 minutes; 1H NMR [300 Mhz, (CD3)2SO]: δ 13.30 (br s 1H), 11.39 (br s, 1H), 7.78 (d, J=7 Hz, 2H), 7.64 (s, 1H), 7.49-7.35 (m, 4H), 6.92 (s, 1H), 6.65 (d, J=8.5 Hz, 1H), 6.59 (s, 1H), 3.98 (t, J=6 Hz, 2H), 2.43-2.33 (m, 6H), 1.88 (m, 2H), 1.50-1.39 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CS[C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[N:23][C:21]=2[N:22]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[N:23][C:21]=2[N:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1nc2ncccc2o1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1nc2ncccc2o1

Procedure:
The title compound (0.7 g) was prepared from (RS)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.64 g) and 2-methylthio-4-azabenzoxazole Chu-Moyer et al J. Org. Chem. (1995), 60(17), 5721-5. (0.5 g) according to the method of D30.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[CH2:20]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][C:29]=1[C:37]([F:40])([F:39])[F:38])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:20]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][CH2:2]2)=[O:33])=[CH:30][C:29]=1[C:37]([F:38])([F:39])[F:40])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(OCc2ccccc2)c(C(F)(F)F)c1)N1CSc2ccccc21
Reaction time: 1.5 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (282 mg) and 37% formalin (0.19 mL) in the same manner as in Example 1 was dissolved in chloroform (6 mL), and triethylamine (0.62 mL) and 4-benzyloxy-3-trifluoromethylbenzoyl chloride were added to the solution, and then the mixture was stirred at mom temperature for 1.5 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to obtain the title compound (356 mg) as a pale yellow oily substance.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:9]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: OC1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1

Procedure:
The mixture of 42.0 g of diphenylmethanol, 25.25 g of 4-hydroxypiperidine and 49.4 g of p-toluenesulfonic acid monohydrate is placed in a flask fitted with a thermometer and an air condensor. The reaction vessel is connected to a vacuum pump and heated to 155°-160° until the evolution of water ceases. Upon cooling, the glassy residue is partitioned between 500 ml of diethyl ether and 200 ml of 2 N aqueous sodium hydroxide, the ethereal solution is separated and washed with water and saturated aqueous sodium chloride, dried and evaporated, to yield the 4-diphenylmethoxy-piperidine melting at 56°; (its hydrochloride, prepared in isopropanol-diethyl ether, melts at 175°-177°).
Reaction SMILES: COC1C=C(NC2C3N(N=CN=3)C(C3C=NNC=3)=CN=2)C=CC=1C(NCC1C=NC(C)=CC=1)=O.Br[C:36]1[N:41]2[N:42]=[CH:43][N:44]=[C:40]2[C:39]([NH:45][C:46]2[CH:47]=[CH:48][C:49]([NH:52][C:53](=[O:61])[CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[N:50][CH:51]=2)=[N:38][CH:37]=1.[NH2:62][C:63]([C:65]1[S:66][CH:67]=[C:68](B(O)O)[CH:69]=1)=[O:64]>>[C:55]1([CH2:54][C:53]([NH:52][C:49]2[N:50]=[CH:51][C:46]([NH:45][C:39]3[C:40]4[N:41]([N:42]=[CH:43][N:44]=4)[C:36]([C:68]4[CH:69]=[C:65]([C:63]([NH2:62])=[O:64])[S:66][CH:67]=4)=[CH:37][N:38]=3)=[CH:47][CH:48]=2)=[O:61])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: NC(=O)c1cc(B(O)O)cs1
Reactant: O=C(Cc1ccccc1)Nc1ccc(Nc2ncc(Br)n3ncnc23)cn1
Agent: COc1cc(Nc2ncc(-c3cn[nH]c3)n3ncnc23)ccc1C(=O)NCc1ccc(C)nc1
Product: NC(=O)c1cc(-c2cnc(Nc3ccc(NC(=O)Cc4ccccc4)nc3)c3ncnn23)cs1

Procedure:
This compound may be prepared using methods as described for Compound 120, step 4, using N-[5-(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)-pyridin-2-yl]-2-phenylacetamide and 2-(aminocarbonyl)thiophene-4-boronic acid. LCMS: Rt 1.06 min (100%) m/z (ESI) 471 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[F:18])[CH2:7][CH2:6]1)=[O:4].ClC1C=CC(N2CCNCC2)=C(F)C=1.ClCC(Cl)=O.[N+:38]([C:41]1[CH:46]=[CH:45][C:44]([NH:47][C@H:48]2[CH2:53][CH2:52][C@H:51]([OH:54])[CH2:50][CH2:49]2)=[CH:43][C:42]=1[C:55]([F:58])([F:57])[F:56])([O-:40])=[O:39]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][O:54][C@H:51]3[CH2:52][CH2:53][C@H:48]([NH:47][C:44]4[CH:45]=[CH:46][C:41]([N+:38]([O-:40])=[O:39])=[C:42]([C:55]([F:56])([F:57])[F:58])[CH:43]=4)[CH2:49][CH2:50]3)[CH2:6][CH2:7]2)=[C:12]([F:18])[CH:13]=1
Reactant: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2F)CC1
Agent: Fc1cc(Cl)ccc1N1CCNCC1
Agent: O=C(Cl)CCl
Product: O=C(CO[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2ccc(Cl)cc2F)CC1

Procedure:
1-[4-(4-Chloro-2-fluoro-phenyl)-piperazin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared using a two-step synthesis. In the first step, 1-chloracetyl-4-(4-chloro-2-fluoro-phenyl)-piperazine (also known as 2-chloro-1-[4-(4-chloro-2-fluoro-phenyl)-piperazin-1-yl]-ethanone) was prepared from 1-(4-chloro-2-fluoro-phenyl)-piperazine and chloroacetyl chloride using the procedure illustrated in Example 4. In the second step, the 1-[4-(4-chloro-2-fluoro-phenyl)-piperazin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared from the 1-chloracetyl-4-(4-chloro-2-fluoro-phenyl)-piperazine and trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 5) using the procedure illustrated in Example 11. This afforded the product as a yellow solid (13% yield). The structure was confirmed using Protocol II-A. Calculated mass=559; observed mass=559; HPLC retention time=4.57 min.
Reaction SMILES: [CH2:1]([N:8]([CH3:29])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:25])([CH2:23][OH:24])[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11][C:10]=1[N+:26]([O-:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>O1CCCC1>[CH2:1]([N:8]([CH3:29])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:25])([CH2:23][O:24][S:38]([CH3:37])(=[O:40])=[O:39])[C:16]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:17])=[CH:11][C:10]=1[N+:26]([O-:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(Cc1ccccc1)c1ccc(C(C)(CO)C(=O)N2CCCC2)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)c1ccc(C(C)(COS(C)(=O)=O)C(=O)N2CCCC2)cc1[N+](=O)[O-]

Procedure:
A solution of 1.2 g (3.0 mmol) of 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-hydroxy-1-pyrrolidin-1-yl-propan-1-one in 20 ml of tetrahydrofuran was mixed with 1.3 ml of (9.3 mmol) of triethylamine at room temperature. Subsequently, 0.27 ml (3.5 mmol) of methanesulfonylchloride were dropped to the reaction mixture at 2-5° C. The formed precipitate was filtered after 2 hours at room temperature and the filtrate evaporated down. The raw product was further processed without purification.
Reaction SMILES: [C:1]([NH:9][C:10](=[CH:15][N:16]([CH3:18])C)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:20]1[CH:25]=[CH:24]C=[CH:22][CH:21]=1.Cl.O>C(O)(C)C>[C:1]([NH:9][C:10](=[CH:15][NH:16][C:18]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=CN(C)C)NC(=O)c1ccccc1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: COC(=O)C(=CNc1ccccc1)NC(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
10 g (39.5 mmol) of methyl 2-benzoylamino-3-dimethylaminoacrylate and 11.1 g (118 mmol) of aniline were dissolved at 40° C. in 200 ml of isopropanol. The solution was admixed with 3.6 ml (43.5 mmol) of concentrated hydrochloric acid within 5 minutes (min) and stirred for a further 10 min. 200 ml of deionized water were added, the suspension was cooled to 10° C. and the crystallized product was filtered off.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[CH3:14][N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH2:17][C:18](=[O:23])[CH2:19]2.Cl>CCCCCC.CCOCC>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:18]2([OH:23])[CH2:19][CH:20]3[N:15]([CH3:14])[CH:16]([CH2:22][CH2:21]3)[CH2:17]2)=[CH:8][CH:9]=1
Reactant: CN1C2CCC1CC(=O)C2
Reactant: Fc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CN1C2CCC1CC(O)(c1ccc(F)cc1)C2
Temperature: -45 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
A mixture of dry ether (600 ml) and 15% BuLi in hexane (500 ml) was cooled to -45° C. A solution of 4-bromo-1-fluorobenzene (145 g) in dry ether (350 ml) was added dropwise at -45° C. followed by stirring for 1 h. A solution of 8-methyl-8-azabicyclo[3,2,1]octan-3-one (85 g) in dry ether (400 ml) was added dropwise at -50° C. followed by stirring for 30 min, the temperature raising to -20° C. The reaction mixture was poured into 2M hydrochloric acid and the phases separated. The ether phase was extracted with 2M hydrochloric acid and the combined aqueous phases made alkaline with aqueous NaOH. Extraction with ethyl acetate, drying of the organic phase over magnesium sulfate and removal of solvent in vacuo, gave 3-(4-fluorophenyl)-3-hydroxy-8-methyl-8-azabicyclo[3,2,1]octane (96 g) as a solid, mp: 169° C.
Reaction SMILES: [CH:1](=[C:8]1/[C:9](=[O:14])[CH2:10][C:11](=[O:13])[NH:12]/1)\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(=[O:19])[CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>ClCCl>[CH:1](=[C:8]1/[C:9]([O:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:18])=[CH:10][C:11](=[O:13])[NH:12]/1)\[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(=O)Cl
Reactant: O=C1CC(=O)/C(=C/c2ccccc2)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)OC1=CC(=O)N/C1=C\c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 67.0 g of (Z)-5-benzylidene pyrrolidin-2,4-dione cooled to 0° C. in 670 ml of dichloromethane, 40.0 g of butyryl chloride and then 47.1 g of triethyl amine were added and the mixture was stirred another 5 minutes at 0° C. Then the mixture washed twice with 200 ml of 5 percent NaHCO3 solution each and then twice with 200 ml of 0.5M hydrochloric acid each. The aqueous phases were extracted separately with dichloromethane. The combined organic phases were dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue was recrystallized from 230 ml of toluene. The yield of the title compound was 67.25 g (73 percent of theory). The title compound had a melting point of 139.8° to 141.5° C. Other data concerning the title compound was:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([O:20][CH:21]([F:23])[F:22])[CH:19]=3)=[CH:12][C:11]([C:24](O)=[O:25])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:48]3[CH2:52][C:51](=[O:53])[NH:50][CH2:49]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([O:20][CH:21]([F:22])[F:23])[CH:19]=3)=[CH:12][C:11]([C:24]([N:48]3[CH2:52][C:51](=[O:53])[NH:50][CH2:49]3)=[O:25])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)c1cc(-c2cncc(OC(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cncc(OC(F)F)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1

Procedure:
109 mg (0.28 mmol) of the compound of Example 65A is reacted analogously to the synthesis of the compound of Example 1 with 38 mg (0.31 mmol) of 4-imidazolinone-hydrochloride. 108 mg (84% of theory) of the title compound is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:20]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCCCSc1ccncc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCCSc1ccncc1)c1ccccc1
Yield: 34.3 %

Procedure:
To a solution of 1.00 g (5.49 mmol) of 4-(4-aminobutylthio)pyridine and 0.92 ml (6.60 mmol) of triethylamine in 30 ml of methylene chloride, 0.67 ml (5.77 mmol) of benzoylchloride was added with stirring under ice-cooling and the mixture was stirred at room temperature for 13 hours. The mixture was washed with saturated aqueous sodium bicarbonate and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent:ethyl acetate) to give 0.54 g of the desired compound (34.4% yield, colorless crystals), mp. 75°-77° C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1O[CH2:9]1)(=[O:5])[C:2]([CH3:4])=C.[CH3:11]OC1C=CC(O)=CC=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH3:11])(=[O:5])[CH:2]=[CH2:4]
Reactant: COc1ccc(O)cc1
Reactant: C=C(C)C(=O)OCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: C=CC(=O)OCCCC
Temperature: 25 °C

Procedure:
After the completion of the reaction, the solution was cooled to room temperature. To the solution, 10 g of glycidyl methacrylate, 0.33 g of p-methoxyphenol and 11.0 g of tetrabutylammonium bromide were added. The mixture was stirred until these added compounds dissolved completely. The solution thus obtained was heated to 80° C., and an addition reaction was allowed to take place for 16 hours between the carboxyl group in the copolymer and the epoxy group in the glycidyl methacrylate. Thereafter, the solution was cooled to room temperature to obtain an alkali soluble resin (A-2) in the form of resin solution.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][NH:17]3)=[C:13]([NH:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C(OCC)(=O)C.CO.[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][NH:17]3)=[C:13]([NH:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1ccc(Nc2nc(Nc3cccc([N+](=O)[O-])c3)nc3[nH]cnc23)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1ccc(Nc2nc(Nc3cccc(N)c3)nc3[nH]cnc23)cc1
Yield: 39.3 %

Procedure:
214 mg of the product of Example 24 are treated with 95 mg of platinum oxide (PtO2) in a mixture of 2.6 ml of ethyl acetate and 2.6 ml of methanol in the presence of hydrogen, H2. 78 mg of the expected product are thus obtained.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][CH2:15]Cl)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:17][O-:18].[Na+].O>CO>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:18][CH3:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCCOc1cccc2ccccc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCCCCOc1cccc2ccccc12

Procedure:
A solution of 4-(1-naphthyloxy)-butyl chloride (3.0 g) and sodium methoxide (1.5 g) in methanol (25 ml) was refluxed for 8 hours, then poured into water and the solution extracted with ether. The extract was dried and evaporated and the residue chromatographed on silica gel, eluting with 2:1 hexane ether, to produce the title compound as an oil.