Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[N:4]([C:8]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:5]=[CH:6][N:7]=1)=[O:2].[CH2:19](O)[CH2:20][OH:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1.[OH-].[Na+]>>[O:2]1[CH2:19][CH2:20][O:21][CH:1]1[CH:3]1[NH:7][CH2:6][CH2:5][N:4]1[C:8]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: OCCO
Reactant: N#Cc1ccc([N+](=O)[O-])cc1-n1ccnc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: N#Cc1ccc([N+](=O)[O-])cc1N1CCNC1C1OCCO1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
Into a round bottom flask equipped with a Dean Stark trap, 2-(2-formyl-imidazol-1-yl)-4-nitro-benzonitrile (10.48 g, 0.04327 mol), 1,2-ethanediol (15.0 mL, 0.269 mol), p-toluenesulfonic acid monohydrate (8.23 g, 0.0433 mol), and benzene (150 mL, 1.7 mol) were added. The reaction was heated to reflux for 6 hours. The reaction was cooled to room temperature. 1N NaOH was added to adjust the pH to 10. The reaction was partitioned with water and EtOAc. The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with EtOAc. The solvent was removed under vacuum. The product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 5% methanol). The collected fractions afforded 2-(2-[1,3]dioxolan-2-yl-imidazolidin-1-yl)-4-nitro-benzonitrile as a yellow solid (8.20 g, 66%). 1H-NMR (DMSO-D6, 400 MHz): δ8.53 (d, 1H), 8.42 (s, 1H), 8.35 (d, 1H), 7.65 (s, 1H), 7.14 (s, 1H), 5.82 (s, 1H), 3.65 (bs, 2H), 3.45 (bs, 2H).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][C:11]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1>C1COCC1>[CH3:10][C:11]1[CH:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:28]=[CH:27][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21]3=[N:26][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:22]3[CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1cc(C(F)(F)F)ccc1Oc1ccc(-c2cccnc2N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)ccc1Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 284 mg) in THF (dry) (25 mL) was added 2-chloroethanesulfonyl chloride (0.448 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(2-methyl-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-amine (489 mg) in THF (dry) (40 ml) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was quenched with water at 0° C. Water, EtOAc and THF were added and the extracted is organic layer was washed with brine. Silica-gel was added to the organic layer and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) and washed with IPE to give the title compound (390 mg) as a white solid. A part of this was recrystallized from MeCN/IPE.
Reaction SMILES: COCCOC.Br[C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1B(O)O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1ccccc1Br
Reactant: CC(C)(C)OC(=O)NCc1cnccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)c1ccccc1-c1ccncc1CNC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
20 ml of 1,2-dimethoxyethane were aerated with argon, and 230 mg (0.2 mmol) of Pd(PPh3)4 and 0.86 g (4 mmol) of methyl 2-bromobenzoate were added. After 10 min, 1.51 g (6 mmol) of 3-(tert-butoxycarbonylaminomethyl)pyridine-4-boronic acid and finally 4 ml of a 2M sodium carbonate solution were added. The mixture was heated to reflux under argon for 13 h, diluted with dichloromethane after cooling and washed with water. The organic phase was dried, concentrated and purified by chromatography on silica gel. 1.15 g (84%) of a viscous pale yellow oil were obtained. MS (ES+): m/z=343 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[N+](C1C=CC(S(O[C@H:36]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]2)(=O)=O)=CC=1)([O-])=O.[F-].[Cs+].CN(C)C=O>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][C@@H:40]3[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (prepared as described in the starting materials used in Example 22; 4.0 g, 12.5 mmol) was mixed with tert-butyl (3S)-3-[(4-nitrophenyl)sulfonyloxy]pyrrolidine-1-carboxylate (4.7 g, 12.6 mmol) and cesium fluoride (5.7 g, 7.5 mmol). Dry N,N-dimethylformamide (60 ml) was then added and the mixture stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water, 50% aqueous brine then brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (98/2). The fractions containing the expected product were combined and evaporated to give 4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yloxy]-7-methoxyquinazoline as a dry foam (2.35 g, 38%); 1H NMR Spectrum: (DMSO d6) 1.39 (s, 9H); 2.10-2.30 (m, 2H); 3.35-3.50 (m, 3H); 3.64-3.71 (m, 1H); 3.92 (s, 3H); 5.12 (m, 1H); 7.21 (s, 1H); 7.23-7.27 (m, 1H); 7.44-7.55 (m, 2H); 7.80 (s, 1H); 8.37 (s, 1H); 9.61 (s, 1H); Mass Spectrum: (M+H)+ 489.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH2:14](I)[CH3:15].O>CN(C=O)C>[CH2:14]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1)[CH3:15]
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ccc2c(C=O)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.7 %

Procedure:
To a solution of 1H-indole-4-carbaldehyde (2.00 g, 13.8 mmol) in anhydrous DMF (6.5 mL) was added sodium hydride (827 mg of 60% dispersion in oil, 20.7 mmol). The mixture was stirred for 30 min at room temperature. Ethyl iodide (2.22 mL, 27.5 mmol) was then added and the reaction mixture was stirred for 12 h at room temperature. Water was added (100 mL) and the mixture was extracted with ethyl acetate (3×100 mL). Combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to an orange oil. Purification by column chromatography (silica gel, gradient elution of CH2Cl2 to 5% MeOH/CH2Cl2) gave the title compound (1-ethyl-1H-indole-4-carbaldehyde) (2.43 g, 99%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 10.19 (s, 1H), 7.88 (d, J=8.1 Hz, 1H), 7.68-7.64 (m, 2H), 7.37-7.32 (m, 1H), 7.08 (d, J=3.0, 1H), 4.28 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1.C1(C)C(S([CH2:20][N+:21]#[C-])(=O)=O)=CC=CC=1.CC(C)([O-])C.[K+]>C(COC)OC.C(O)C>[CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:20]#[N:21])[CH2:6][CH2:5]1
Reactant: COCC1CCC(=O)CC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: COCC1CCC(C#N)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (−10° C.) solution of EXAMPLE 374C (1.18 g) and toluenesulfonylmethyl isocyanide (2.268 g) in dimethoxyethane (3 mL) and absolute ethanol (0.1 mL) was added (in small portions) potassium tert-butoxide (2.235 g). The reaction mixture was continued to stir at <5° C. for 30 minutes, warmed to room temperature, heated at 35° C. for 30 minutes and then at room temperature for 2 hours. The reaction mixture was concentrated and the residue was dissolved in water-brine, and extracted with dichloromethane. The dichloromethane layer was purified by flash chromatography, and was eluted with 5% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([CH3:7])[CH3:6].[OH:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].C1CCN2C(=NCCC2)CC1>CC#N>[CH3:6][C:5]([CH3:7])=[CH:4][CH2:3][CH2:2][O:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CC(C)=CCCBr
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)=CCCONC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a solution of 5-bromo-2-methylpent-2-ene (1.33 mL, 10.0 mmol) in CH3CN (25 mL) was added tert-butyl hydroxycarbamate (2.0 g, 15.0 mmol) and DBU (4.5 mL, 30 mmol) at 0° C. and the reaction mixture stirred at r.t. for overnight. Quenched with saturated NH4Cl solution and extracted with brine. Combined organic layers washed with brine and dried over anhydrous Na2SO4, filtered and concentrated to provide yellow oil, which was purified by flash chromatography (50% EtOAc-hexane) to yield tert-butyl 4-methylpent-3-enyloxycarbamate (750 mg, 70%) as a viscous oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.40 (s, 9H) 1.54 (s., 3H) 1.61 (s., 3H) 2.21-2.31 (m, 2H) 3.70-3.78 (m, 2H) 5.02-5.10 (m, 1H). MS (ES) [M+H] calculated for C11H22NO3, 216.15; found 216.10.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OC)=O.CCCCCC.[C:43]([O:46]CC)(=[O:45])[CH3:44]>C(Cl)Cl>[C:43]([OH:46])(=[O:45])/[CH:44]=[CH:1]/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCOC(C)=O
Reactant: CCCCCCCC/C=C/C=O
Agent: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCCCC/C=C/C=C/C(=O)O
Reaction time: 2 h

Procedure:
To trans-2-undecenal (5.0 g) dissolved in methylene chloride (80 ml) was added (carbomethoxymethylene)-triphenylphosphorane (9.9 g), and the mixture was stirred for 2 hours. The reaction mixture was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans,trans-2,4-tridecadienoic acid (5.2 g). Potassium hydroxide (6.5 g) was dissolved in a mixed solvent of ethanol-water (1:1) (100 ml). The methyl ester of trans,trans-2,4-tridecadienoic acid (5.2 g) was added to the mixture, and the resulting mixture was stirred at 60° C. for 40 minutes. After the reaction mixture was cooled, it was adjusted to the weak acidic range of pH with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give trans,trans-2,4-tridecadienoic acid (4.4 g). To trans,trans-2,4-tridecadienoic acid dissolved in N,N-dimethylformamide (DMF, 50 ml) were added para-nitrophenol (3.0 g) and N,N'-dicyclohexylcarbodiimide (4.4 g), and the mixture was stirred for 12 hours. After precipitates obtained were removed by filtration and the solvent (DMF) was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1) to give the active ester of trans,trans-2,4-tridecadienoic acid (2.4 g). To the active ester (880 mg) dissolved in DMF (30 ml) were added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (800 mg) and triethylamine (2.0 ml). The mixture was stirred for 12 hours. After the solvent was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK281 in the yield of 380 mg.
Reaction SMILES: [CH:1]1([CH2:11][CH2:12]O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.[N:14]1([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[C@@H:1]1([CH2:11][CH2:12][N:17]2[CH2:18][CH2:19][N:14]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH2:15][CH2:16]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1
Reactant: NS(=O)(=O)c1ccc(N2CCNCC2)cc1
Reactant: OCCC1OCCc2ccccc21
Product: NS(=O)(=O)c1ccc(N2CCN(CC[C@H]3OCCc4ccccc43)CC2)cc1

Procedure:
Following the general procedure of EXAMPLE 49 and making non-critical variations 2-(isochroman-1-yl)ethanol (LXXIX, (+)-enantiomer, 0.6045 g) and 4-(piperazin-1-yl)benzenesulfonamide (IV, 0.9824 g) are combined to give the title compound, mp 189-190°; MS (m/z) 401; [α]D +48 (c 0.877, DMF); IR (mineral oil) 1662, 1594, 1150, 1101, 614 cm-1.
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([NH:14]C(=O)C)=[N:11][C:10]=2[CH3:18])=[CH:5][CH:4]=1.Cl>CO.O>[F:19][CH:2]([F:1])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([NH2:14])=[N:11][C:10]=2[CH3:18])=[CH:5][CH:4]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(C(F)F)nc2)[nH]1
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1nc(N)[nH]c1-c1ccc(C(F)F)nc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 105 %

Procedure:
Dissolve N-[5-[6-(difluoromethyl)-3-pyridyl]-4-methyl-1H-imidazol-2-yl]acetamide (0.172 g, 0.65 mmol) in MeOH (5 mL) and water (5 mL). Heat the mixture to 60° C. Add hydrochloric acid (12 N, 5 mL, 60 mmol). Stir mixture for 2 hours at 60° C. Concentrate the mixture to a volume of about 10 mL. Adjust the pH of the aqueous solution to 8. Extract the resulting solution with EtOAc (2×20 mL). Dry the combined organic extracts over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure to give the title compound as a yellow oil (0.153 g, 100% crude yield). LCMS (m/z) 225 (M+1).
Reaction SMILES: CSC1C2C=C([CH:12]=[O:13])SC=2N=CN=1.[CH3:14][S:15][C:16]1[C:17]2[S:24][CH:23]=[CH:22][C:18]=2[N:19]=[CH:20][N:21]=1>>[CH3:14][S:15][C:16]1[C:17]2[S:24][C:23]([CH:12]=[O:13])=[CH:22][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: CSc1ncnc2ccsc12
Reactant: CSc1ncnc2sc(C=O)cc12
Product: CSc1ncnc2cc(C=O)sc12

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 15 but using 4-(methylthio)thieno[3,2-d]pyrimidine (intermediate 20) in place of 4-(methylthio)thieno[2,3-d]pyrimidine. Yellow solid (434 mg, 38%);
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21](N)=[O:22].N([O-])=[O:25].[Na+].O>S(=O)(=O)(O)O>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]([OH:22])=[O:25]
Reactant: NC(=O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl

Procedure:
3.5 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamide are dissolved in 15 ml of 90 % sulfuric acid and while stirring at 20° to 30° a solution of 0.7 g sodium nitrite in a little water is passed dropwise under the surface. Gentle heating is carried out until the evolution of gas is terminated and the mixture is then poured on to an ice and water mixture. 5-Chloro-3-p-chlorophenyl-1-phenylpyrazole-4-acetic acid is produced; F 179.5°-181°.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1>>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCOCC3)cn2)c1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCOCC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O

Procedure:
Following the procedures as described for 148c and starting with 400 mg of 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d and 302 mg of 5-bromo-1-methyl-3-(5-morpholinopyridin-2-ylamino)pyridin-2(1H)-one, 255d was obtained as a yellow solid (281 mg, 53%). MS: [M+H]+ 641
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1CCN.C(OCC)(=O)C>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[S:12]
Reactant: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Reactant: NCCc1ccccc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: S=C(NCCc1ccccc1Cl)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 40.5 %

Procedure:
A solution of 1-[(2-benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(2-chlorophenyl)ethylamine (0.81 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.67 g (40%) of the titled product as a white solid:
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[C:4]([N+:10]#[C-:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.[O:14]([C@H:21]1[CH2:26][CH2:25][C@H](N)[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(O)CCC>[O:14]([C@H:21]1[CH2:26][CH2:25][C@H:12]([N:2]2[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:10]=[CH:11]2)[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [C-]#[N+]C(=CN(C)C)C(=O)OCC
Reactant: N[C@H]1CC[C@H](Oc2ccccc2)CC1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn([C@H]2CC[C@H](Oc3ccccc3)CC2)cn1
Temperature: 150 °C
Reaction time: 3.25 h

Procedure:
Ethyl 3-(dimethylamino)-2-isocyanoacrylate (0.70 g) and the compound (1.14 g) obtained in Step 2 of this Reference Example were dissolved in n-butanol (7.0 mL). Then, to the solution, triethylamine (0.70 mL) was added at room temperature, and the mixture was stirred at 150° C. for 3.25 hours. The reaction solution was concentrated and then purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=50/50-ethyl acetate) to obtain the title compound (0.28 g).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Mg]Br)=[CH:21][CH:20]=1>>[NH2:15][C:7]1[C:6]([C:4]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Product: CCSc1ncc(C(=O)c2ccc(OC)cc2)c(N)n1

Procedure:
The same procedure as described in Example 353 was used, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (Example 1) and 4-methoxyphenylmagnesium bromide (Aldrich) to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-4-methoxy-phenyl-methanone. MS (M+H)+, 290.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(N(CC)CC)C>CCO>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][N:22]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]2[C:14]([N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]2=[O:20])=[CH:15]1)[CH3:30]
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Reactant: CCOC(=O)CCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CCCn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate C) (996 mg, 2.95 mmol), ethyl 4-aminobutanoate hydrochloride (489 mg, 2.95 mmol) and triethylamine (0.823 ml, 5.91 mmol) were combined in EtOH (15 ml) and heated at reflux for 2.5 hours. The reaction mixture was cooled to RT and evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with water (1×) and brine (1×). The organic phase was dried over sodium sulphate and evaporated under reduced pressure to afford the title compound as an off-white solid;
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH:8]([O:12][CH2:13][C:14]([O:16]C)=O)[C:9](=[O:11])[CH3:10]>C(O)(C)(C)C.CCOCC>[CH3:7][CH:8]1[C:9](=[O:11])[CH2:10][C:14](=[O:16])[CH2:13][O:12]1
Reactant: COC(=O)COC(C)C(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: CC1OCC(=O)CC1=O

Procedure:
Potassium tert-butoxide in tert-butanol (1 M, 203 mL) and the product from Example 44B (15.5 g, 97 mmol) in ether (55 mL) were processed as described in Example 43C. The residue was purified on silica gel eluting with ethyl acetate:formic acid:water:hexane (200:1:1:200) provided the title compound. 1H NMR (CDCl3) δ 1.48 (d, 3H), 3.43 (d, 1H), 3.92 (d, 1H), 3.97 (q, 1H), 4.04 (d, 1H), 4.44 (d, 1H).
Reaction SMILES: N1(C2C=CC(C(C3C=CC=CC=3)=O)=CC=2)CCNCC1.CO[C:23]1[C:42]([O:43][CH3:44])=[CH:41][C:26]2[C:27]([OH:40])=[CH:28][C:29]3[C:30]([CH3:39])([CH3:38])[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=4[C:37]=3[C:25]=2[CH:24]=1.[NH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1.C([Li])CCC.Cl>CCCCCC.O1CCCC1>[N:45]1([C:23]2[C:42]([O:43][CH3:44])=[CH:41][C:26]3[C:27]([OH:40])=[CH:28][C:29]4[C:30]([CH3:38])([CH3:39])[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=5[C:37]=4[C:25]=3[CH:24]=2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: COc1cc2c(O)cc3c(c2cc1OC)-c1ccccc1C3(C)C
Reactant: C1CCNCC1
Agent: Cl
Agent: O=C(c1ccccc1)c1ccc(N2CCNCC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc2c(O)cc3c(c2cc1N1CCCCC1)-c1ccccc1C3(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an oven-dried 500 mL one-neck flask was added the product of Step 3, Example 1, of U.S. Pat. No. 6,296,785B1, 2,3-dimethoxy-7,7-dimethyl-7H-benzo[C]fluoren-5-ol (10 g) which is included herein as reference, piperidine (5.2 mL) and anhydrous tetrahydrofuran (150 mL). n-Butyl lithium in hexane solution (2.5M, 35 mL) was dropped to the mixture slowly. The reaction mixture was stirred at room temperature for 3 hours. The mixture was poured into cold aqueous hydrochloric acid (10%, 60 mL). The mixture was extracted with ethyl acetate (200 mL) and the recovered top layer was filtered through a silica gel plug. The desired product 2-piperidino-3-methoxy-7,7-dimethyl-7H-benzo[C]fluoren-5-ol (10 g) was obtained by recrystallization from solution in ethyl acetate/hexanes.