Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](Cl)=[O:8])[C:4]([CH3:10])=[N:3]1.[F:11][C:12]1[CH:13]=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH2:26])[CH:15]=[C:16]([F:19])[C:17]=1[F:18]>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:13]=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH:26][C:7]([C:5]2[C:4]([CH3:10])=[N:3][N:2]([CH3:1])[CH:6]=2)=[O:8])[CH:15]=[C:16]([F:19])[C:17]=1[F:18]
Reactant: Cc1nn(C)cc1C(=O)Cl
Reactant: Nc1ccccc1-c1cc(F)c(F)c(F)c1
Solvent: Cc1ccccc1
Product: Cc1nn(C)cc1C(=O)Nc1ccccc1-c1cc(F)c(F)c(F)c1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
79.1 g (0.494 mol, 99% pure) of 1,3-dimethyl-1H-pyrazole-4-carbonyl chloride were dissolved at 25° C. in 257.2 g of toluene. The solution was evacuated to 400 mbar and heated to 85° C. Subsequently, within 3 hours, 483.0 g (0.489 mol, 23% strength) of toluenic 3′,4′,5′-trifluorobiphenyl-2-ylamine solution were metered in and the reaction mixture was stirred for a further 1 hour. After venting and cooling to 70° C., the mixture was cooled to 20° C. with a cooling ramp of 5° C./h and stirred overnight. Subsequently, the mixture was cooled to 0° C., and the solids were filtered off, washed with cold toluene and dried at 80° C. under reduced pressure. The yield (without further processing of the mother liquor) was 155.4 g (92%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:14])=[O:13])[C:6]=1[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1.[H-].[Na+].CN(C=O)C.Cl[C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][N:39]=1>C1COCC1>[C:26]1([CH3:29])[CH:27]=[CH:28][C:23]([C:6]2[C:7]([NH:11][S:12]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:13])=[O:14])=[N:8][CH:9]=[N:10][C:5]=2[O:4][CH2:3][CH2:2][O:1][C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][N:39]=2)=[CH:24][CH:25]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)C=Cc3ccccc3)ncnc2OCCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(NS(=O)(=O)C=Cc3ccccc3)ncnc2OCCOc2ccc(C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.1 %

Procedure:
2-Phenyl-ethenesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (150 mg) was dissolved in THF (10 ml) and sodium hydride (45 mg; 55-65% in mineral oil) was added. The mixture was stirred for 15 min at rt., followed by the addition of DMF (2 ml) and 2-chloro-5-trifluoromethyl-pyridine (146 mg) and heating to 75° C. for 5 h. Then the reaction mixture was evaporated to dryness and water (15 ml) and citric acid was added. The precipitated product was filtered off, washed with water and dried. 2-Phenyl-ethenesulfonic acid {5-p-tolyl-6-[2-(5-trifluoromethyl-pyridin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-amide (130 mg) could be obtained as a white powder. tR=5.92 (LC); [M+H]+=557.38 (ES+).
Reaction SMILES: C[O-].[Na+].[F:4][CH:5]([F:8])[C:6]#[N:7].Cl.[CH3:10][O:11][C:12](=[O:17])[CH:13]([CH2:15][OH:16])N>CO>[F:4][CH:5]([F:8])[C:6]1[O:16][CH2:15][CH:13]([C:12]([O:11][CH3:10])=[O:17])[N:7]=1
Reactant: COC(=O)C(N)CO
Reactant: N#CC(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1COC(C(F)F)=N1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a cooled (0° C.) solution of sodium methoxide (25 wt % solution in methanol; 0.230 mL, 1.032 mmol) and MeOH (20 mL) was added dropwise difluoroacetonitrile (0.690 mL, 10.03 mmol) while maintaining an internal temperature of <1° C. After 20 min DL-serine methyl ester hydrochloride (1.55 g, 9.96 mmol) was added followed by MeOH (20 mL) and the reaction was allowed to warm to rt overnight. Subsequently, the reaction was heated to 55° C. for 5 h. The reaction was cooled to rt and partitioned between DCM/water. The aqueous layer was extracted with DCM (3×) and the combined organic layers were washed with water and dried over MgSO4. The filtrate was concentrated in vacuo to give 1.59 g (89%) of a light-brown oil. MS m/z=180 [M+H]+. Calculated for C6H7F2NO3:179.
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)[C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18]C)=[O:17])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[OH-].[Li+]>CO.O>[CH2:36]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([N:23]2[CH2:24][CH2:25][N:26]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:27][CH2:28]2)[C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([OH:18])=[O:17])=[CH:10][CH:11]=1)=[O:5])[CH3:37]
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(C(=O)OC)c2)N2CCN(Cc3ccccc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(C(=O)O)c2)N2CCN(Cc3ccccc3)CC2)cc1

Procedure:
To a solution of INTERMEDIATE 8 (1.66 g, 3.3 mmol) in methanol (15 mL) and water (5 mL) was added lithium hydroxide (0.69 g, 16.5 mmol). After 5 hours at room temperature the methanol was removed and INTERMEDIATE 9 was precipitated from the aqueous solution by the addition of 2M hydrochloric acid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>O>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:22]3[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)cc2)on1
Reactant: Cc1ccc(B(O)O)cc1
Solvent: O
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3cc(C)no3)cc2)cc1
Reaction time: 24 h
Yield: 101.5 %

Procedure:
Nitrogen was bubbled through a biphasic mixture of ethanol (15 ml), toluene (15 ml) and 2M sodium carbonate solution (15 ml). N-(3-methyl-5-isoxazolyl)-4-bromobenzene sulfonamide (0.951 g, 3 mmol), 4-methylbenzeneboronic acid (0.56 g, 4 mmol) and tetrakistriphenylphosphine palladium (0) (300 mg) were added. The reaction mixture was kept at 80° C., under a N2 atmosphere for 24 h, with stirring, and was then diluted with water (50 ml) and extracted with ether (50 ml) to remove neutral impurities and excess 4-methylbenzeneboronic acid. The aqueous phase was neutralized to pH 2 using concentrated hydrochloric acid and the resultant solid was filtered. This was dried under vacuum and recrystallized using hexane/ethyl acetate giving N-(3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfonamide (1.0 g, 100% yield, m.p. 194-198° C.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.[CH2:19]([CH:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1)[CH2:20][CH2:21][CH2:22][CH3:23].O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)(=O)C>[CH3:18][C@@:12]1([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH:27]4[CH2:26][CH2:25][CH:24]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:29][CH2:28]4)[CH:3]=3)[CH:8]=2)[CH2:16][O:15][C:14](=[O:17])[NH:13]1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: CCCCCC1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCC1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Reaction time: 0.08 h
Yield: 68.4 %

Procedure:
(R)-4-(6-Hydroxnaphthalen-2-yl)-4-methyl-oxazolidin-2-one (Example 4, 0.3303 g, 0.001358 mol) was added to a capped 40 mL vial equipped with a magnetic stir bar. 4-Pentyl-cyclohexanol (0.277 g, 0.00163 mol) was added, followed by tetrahydrofuran (6.00 mL, 0.0740 mol). Triphenylphosphine polymer-bound (1.17 g, 0.00217 mol) was then added and the mixture was stirred for 5 minutes. Diisopropyl azodicarboxylate (0.428 mL, 0.00217 mol) was then added and the mixture was stirred for 48 hours at room temperature. The mixture was diluted in ethyl acetate, filtered through CELITE™, concentrated under vacuum and purified by flash chromatography (0-5% MeOH in dichloromethane) to give 0.3672 g of the title compound (68% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[F:18][C:19]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][C:22]([NH2:23])=[C:21]([O:29][CH3:30])[CH:20]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N.O>O1CCOCC1>[F:18][C:19]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][C:22]([NH:23][C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH3:17])[CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[C:21]([O:29][CH3:30])[CH:20]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Reactant: Cn1cc(-c2ccnc(Cl)n2)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 85 °C
Reaction time: 3 h
Yield: 118.5 %

Procedure:
1,4-Dioxane (585 mL) was added to a mixture of 3-(2-chloropyrimidin-4-yl)-1-methylindole (Intermediate 177, 50 g, 160.04 mmol), 4-fluoro-2-methoxy-5-nitro-aniline (38.03 g, 192.04 mmol) and p-toluenesulfonic acid monohydrate (37.09 g, 192.04 mmol) at r.t. The resulting mixture was stirred at 85° C. for 3 h. After cooling to r.t., the mixture was quenched with 23% aqueous ammonia (39.59 mL, 480.1 mmol) and water (195 mL, 510.1 mmol) and a solid precipitated. The resulting slurry was stirred at r.t. for 3-4 h. The solid was collected by filtration and dried at 50° C. in vacuo for 12 h to give the title compound (74.6 g, 85%) as yellow solid; 1H NMR (CDCl3): 4.01 (6H, s), 6.90 (1H, d), 7.37-7.48 (4H, m), 8.05-8.12 (2H, m), 8.43 (1H, s), 8.90 (1H, s), 9.34 (1H, s); m/z: ES+ MH+ 394.12.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][O:12][CH3:13])[CH:7]=[CH:8][CH:9]=1.[Cl:22][C:23]1[N:28]=[C:27](Cl)[C:26](=[O:30])[N:25]([CH2:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C:24]=1[CH3:42].C(N(CC)CC)C>C(OCC)(=O)C>[C:17]([O:16][C:15]([NH:14][CH:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:2][NH:1][C:27]1[C:26](=[O:30])[N:25]([CH2:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C:24]([CH3:42])=[C:23]([Cl:22])[N:28]=1)[CH2:11][O:12][CH3:13])=[O:21])([CH3:18])([CH3:20])[CH3:19]
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: COCC(NC(=O)OC(C)(C)C)c1cccc(CCN)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCC(NC(=O)OC(C)(C)C)c1cccc(CCNc2nc(Cl)c(C)n(CC(=O)OCc3ccccc3)c2=O)c1
Yield: 75.7 %

Procedure:
A mixture of tert-butyl (1R/S)-1-[3-(2-aminoethyl)phenyl]-2-methoxyethylcarbamate (preparation 121) (196 mg, 0.67 mmol), benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (182 mg, 0.56 mmol) and triethylamine (368 ml, 2.78 mmol) in ethyl acetate (5 ml) was heated under reflux for 18 hrs. The cooled mixture was washed with brine (15 ml), dried over MgSO4 and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (100:0 to 99:1) to afford the title compound as a colourless oil, (248 mg, 76%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[N+:12]([O-:14])=[O:13].[C:15]1(OB(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[N+:12]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:11]2)([O-:14])=[O:13]
Reactant: OB(O)Oc1ccccc1
Reactant: O=[N+]([O-])c1cccc2cc(Br)cnc12
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: CCOC(C)=O
Product: O=[N+]([O-])c1cccc2cc(-c3ccccc3)cnc12
Yield: 41.6 %

Procedure:
A mixture of 3-bromo-8-nitroquinoline (253 mg), phenylboric acid (159 mg), tetrakis(triphenylphosphine)palladium(0) (23 mg) and aqueous 2M sodium carbonate solution (2.5 ml) in 1,2-dimethoxyethane (3.5 ml) was refluxed for 4 hours. To the mixture was added phenylboric acid (122 mg), and the mixture was additionally refluxed for 3 hours. The resulting mixture, after diluted with ethyl acetate, was washed with aqueous 3° sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by chromatography on silica gel (n-hexane-ethyl acetate) and the obtained oil was crystallized from diethyl ether to give 8-nitro-3-phenylquinoline (104 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:7]=1[CH2:27]Br)=[O:5])[CH3:2].[CH2:29]([O:31][C:32](=[O:42])[CH2:33][NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH3:30]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[N:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:7]=1[CH2:27][N:34]([C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])[CH2:33][C:32]([O:31][CH2:29][CH3:30])=[O:42])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Br)c(-c2ccc(F)cc2)n(-c2ccc(OC)cc2)c1CBr
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c(Br)c(-c2ccc(F)cc2)n1-c1ccc(OC)cc1)C(=O)OC(C)(C)C

Procedure:
Prepared in analogy to that of Example 1(c) from 4-bromo-2-bromomethyl-5-(4-fluoro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrrole-3-carboxylic acid ethyl ester and tert-butoxycarbonylamino-acetic acid ethyl ester. The title compound, ESI MS (m/z): 655 (M+Na+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.[NH2:17][C:18]1[N:19]=[CH:20][NH:21][C:22]=1[C:23]#[N:24]>>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[CH:20]=[N:21][C:22]([C:23]#[N:24])=[C:18]3[N:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(=O)CC(=O)C(F)(F)F)c1
Reactant: N#Cc1[nH]cnc1N
Product: Cc1cccc(-c2cc(C(F)(F)F)n3cnc(C#N)c3n2)c1
Yield: 53.3 %

Procedure:
Reaction of 1-(3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (230 mg, 1.0 mmol), prepared from commercially available 3-methyl-acetophenone according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (161 mg, 53%). MS (ISP) 302.9 [(M+H)+]; mp 202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[N:14]([CH:20]([F:22])[F:21])[C:13]2=[O:23])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH:28]1[CH:33]=CC=C[CH:29]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[N:14]([CH:20]([F:21])[F:22])[C:13]2=[O:23])=[CH:7][C:3]=1[C:4]([O:6][CH2:33][C:28]#[CH:29])=[O:5]
Reactant: c1ccccc1
Reactant: Cc1cc(=O)n(-c2cc(C(=O)O)c(Cl)cc2F)c(=O)n1C(F)F
Solvent: O=S(Cl)Cl
Product: C#CCOC(=O)c1cc(-n2c(=O)cc(C)n(C(F)F)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A suspension of 2.00 g of 2-chloro-5-[3-difluoromethyl-3,6-dihydro-2,6-dioxo-4-methyl -1(2H)-pyrimidinyl]-4-fluorobenzoic acid and 2.05 g of thionyl chloride in 25 ml of benzene is heated at reflux temperature for 20 hours. The clear solution is evaporated to dryness under reduced pressure at 50° C., the residue is dissolved in 20 ml of methylene chloride and subsequently stirred at room temperature for 3.5 hours with 5 ml of propargyl alcohol and 0.55 g of pyridine. The reaction mixture is evaporated to dryness under reduced pressure, the residue is dissolved in 100 ml of ethyl acetate and the solution is extracted three times with 100 ml of water each time. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness. The resinous residue is purified by chromatography on a silica gel column using diethyl ether/n-hexane (1:1) as the eluent. There is obtained propargyl 2-chloro-5-[3-difluoromethyl-3,6-dihydro-2,6-dioxo-4 -methyl -1(2H)-pyrimidinyl]-4-fluorobenzoate, 1H-NMR (CDCl3, 400 MHz): 7.94 ppm (d, 1H), 7.71 ppm (t, 1H), 7.39 ppm (d, 1H), 5.83 ppm (s, 1H), 4.91 ppm (d, 2H), 2.52 ppm (t, 1H), 2.50 ppm (m, 3H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]=[C:13]1[CH2:21][C:20]2[C:15](=[C:16]([S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[CH:18][CH:19]=2)[NH:14]1>C(Cl)(Cl)Cl>[O:12]=[C:13]1[CH2:21][C:20]2[C:15](=[C:16]([S:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:9])[CH:17]=[CH:18][CH:19]=2)[NH:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1Cc2cccc(Sc3ccccc3)c2N1
Solvent: ClC(Cl)Cl
Product: O=C1Cc2cccc(S(=O)c3ccccc3)c2N1

Procedure:
m-Chloroperbenzoic acid (purity: 85%, 0.76 g.) was added to a solution of 2-oxo-7-phenylthioindoline (0.9 g.) in chloroform (20 ml.) with stirring under ice cooling. The mixture was stirred at the same temperature for an hour. To the reaction mixture was added chloroform (50 ml.), and the solution was washed with a saturated aqueous solution of sodium bicarbonate and water, dried over magnesium sulfate and then evaporated. The resultant crystals (1.0 g.) were recrystallized from dioxane twice to give white prisms of the captioned compound (0.6 g.).
Reaction SMILES: [C:1]([CH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([OH:14])=O)[C:6]=2[CH2:5][CH2:4]1)#[N:2].S(Cl)([Cl:17])=O>>[C:1]([CH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([Cl:17])=[O:14])[C:6]=2[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1CCc2c(C(=O)O)cccc21
Reactant: O=S(Cl)Cl
Product: N#CC1CCc2c(C(=O)Cl)cccc21
Reaction time: 15 h

Procedure:
To 6.0 g. of 1-cyanoindan-4-carboxylic acid is added 96 ml. of thionyl chloride and the mixture is allowed to stand at room temperature for 15 hours. The excess thionyl chloride is removed under reduced pressure. To 1-cyanoindan-4-carbonyl chloride, which is thus obtained as the residue, are added 50 ml. of anisole, 50 ml. of methylene chloride and 6.0 g. of anhydrous aluminum chloride powder. The mixture is stirred at room temperature for 90 minutes. After cooling, the product is poured into ice-hydrochloric acid and extracted with ether. The extract is washed with 1N hydrochloric acid and a saturated aqueous solution of sodium chloride, followed by drying. The solvent is distilled under reduced pressure and the residue obtained is purified by chromatography on a column of silica gel (700 g. silica gel; eluted with chloroform). The procedure gives 4-(p-methoxybenzoyl)indan-1-carbonitrile as crystals melting at 109°-112°C.
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].C(=O)=O.[C:8]([N:12]=[N:13][C:14]([C:20]#[N:21])([CH2:16][CH2:17][CH2:18][OH:19])[CH3:15])([CH3:11])([CH3:10])[CH3:9]>>[Cl:3][C:1]([O:19][CH2:18][CH2:17][CH2:16][C:14]([N:13]=[N:12][C:8]([CH3:11])([CH3:9])[CH3:10])([C:20]#[N:21])[CH3:15])=[O:2]
Reactant: CC(C)(C)N=NC(C)(C#N)CCCO
Reactant: O=C(Cl)Cl
Agent: O=C=O
Product: CC(C)(C)N=NC(C)(C#N)CCCOC(=O)Cl
Reaction time: 2 h
Yield: 82 %

Procedure:
To 15 ml of liquid phosgene in a 50 ml round bottom flask, equipped with a thermometer, magnetic stirring bar, dry ice condenser and dropping funnel, was added 5 g. (0.0254 m) of 2-t-butylazo-2-cyano-5-hydroxypentane (from XIV) over 1 hour, holding the temperature at 0° C with an ice bath. After the addition was complete, the reaction was stirred an additional 11/2 hours, letting the temperature slowly rise to room temperature. The dry ice condenser was removed and the excess phosgene stripped off with a water aspirator. The chloroformate was taken up in pentane, dried over anhydrous Na2SO4, filtered and the pentane stripped off to give 5.4 g. (82% yield) of 4-t-butylazo-4-cyanopentyl chloroformate which assayed 92.4%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.Cl.[NH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:20][CH2:19]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)[CH2:20][CH2:19]2)=[O:14])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: CC(=O)c1ccc(OCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCC(=O)NC2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)cc1
Reaction time: 12 h
Yield: 29.2 %

Procedure:
(4-Acetylphenyloxy)acetic acid (2.0 g) and 4-amino-1-(3,4-dichlorobenzyl)piperidine dihydrochloride (3.4 g) were suspended in DMF (50 mL), and triethylamine (2.9 mL), EDC hydrochloride (2.4 g) and HOBt (1.9 g) were added to the suspension. The suspension was stirred for 12 hrs. The reaction mixture was washed with water and then saturated brine and dried, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to crystallize to give the title compound (1.3 g) as a white solid. melting point: 113° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:25]I>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][N:13]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH3:25])[N:20]=[CH:19]3)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3[nH]ncc3c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
To a stirred suspension of NaH (60%, 4 mg, 0.1 mmol) in DMF (0.5 mL) was added dropwise a solution of 4-(1H-Indazol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.100 g, 0.33 mmol) in DMF (1 mL). After stirring for 30 minutes, methyl iodide (0.026 g, 0.18 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours and then partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexanes:EtOAc, 2:1) to give 4-(1-Methyl-1H-indazol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.023 g, 22%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.87 (s, 1H), 7.32 (d, J=9.2 Hz, 1H), 7.20 (d, J=9.2 Hz, 1H), 7.12 (s, 1H), 4.04 (s, 3H), 3.62 (m, 4H), 3.09 (m, 4H), 1.50 (s, 9H). LCMS (APCI+) m/z 317 [M+H]+; Rt=3.31 minutes.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].[CH2:8](Br)[CH:9]=[CH2:10].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:10]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7])[CH:9]=[CH2:8]
Reactant: O=Cc1ncc[nH]1
Reactant: C=CCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCn1ccnc1C=O
Yield: 60.3 %

Procedure:
A solution of 2-imidazole carboxaldehyde (15.0 g, 156 mmol), allyl bromide (22.6 g, 187 mmol) and diisopropylethylamine (40.7 mL, 234 mmol) was stirred in N,N-dimethylformamide (500 mL) for 23 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (370 mL). The solution was washed once with a saturated solution of sodium carbonate (185 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×280 mL). The combined organic portions were dried with sodium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. The crude material was then purified by flash chromatography (99:1 CH2Cl2/methanol) to provide the desired compound (12.8 g, 60%) as yellow oil. 1H NMR (300 MHz, CDCl3, δ ppm) 5.04 (d, 2H, J=5.5 Hz), 5.11 (d, 1H, J=17.5 Hz), 5.25 (d, 1H, J=10.0 Hz), 5.90-6.05 (m, 1H), 7.16 (s, 1H), 7.30 (s, 1H), 9.81 (s, 1H); 13C NMR (75MHz, CDCl3, δ ppm) 49.77, 118.61, 126.00, 131.74, 132.39, 143.17, 182.05.