Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:7])[CH2:5][SH:6])C.[H-].[Na+].[H][H].Cl[C:13]1[O:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1.BrC1OC(C2C=CC=CC=2)=C(C2C=CC=CC=2)N=1>CN(C=O)C>[C:18]1([C:16]2[N:17]=[C:13]([S:6][CH2:5][C:4]([OH:3])=[O:7])[O:14][C:15]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Clc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: CCOC(=O)CS
Reactant: [H][H]
Agent: Brc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CSc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 5 h

Procedure:
12 g. of thioglycolic acid ethyl ester is added to a suspension of 2.4 g. of NaH in 200 ml. of freshly distilled DMF, and the mixture is agitated until the evolution of hydrogen has ceased. Thereafter, 25.5 g. of 2-chloro-4,5-diphenyl-oxazole or 30 g. of 2-bromo-4,5-diphenyl-oxazole is added to the mixture. The latter is agitated for 5 hours at 80° and worked up as usual, thus obtaining the ethyl ester of 4,5-diphenyl-2-oxazolylmercaptoacetic acid, b.p. 207°-210°/0.1 mm.; m.p. 54°-56° (hexane).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH:5]1[CH2:10][CH2:9][CH:8]=[CH:7][CH:6]=1.[NH2:11][OH:12].Cl.NO.[OH-].[K+]>C(Cl)(Cl)Cl.O>[CH:6]12[CH2:5][CH2:10][CH:9]([CH:8]=[CH:7]1)[C:1](=[N:11][OH:12])[S:2]2
Reactant: C1=CCCC=C1
Reactant: S=C(Cl)Cl
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: ON=C1SC2C=CC1CC2
Reaction time: 0.75 h

Procedure:
Thiophosgene (296 g of 85% , 2.19 m) was added dropwise to a stirred solution of 167 g (2.08 m) of 1,3-cyclohexadiene in 500 ml of chloroform. The exothermic reaction caused the temperature to rise from 25° C. to 68° C. with refluxing of the solvent. After 45 minutes, the reaction mixture was cooled and added in portions over four hours to a stirred solution of hydroxylamine (prepared from 480 g (6.9 m) of hydroxylamine hydrochloride in 175 ml water by dropwise addition at 0° C. of a solution of 434 g of 89% potassium hydroxide (6.9 m) in 250 ml of water) at -15° C. After being stirred overnight, the reaction mixture was filtered and the filter cake washed with methylene chloride. The combined filtrate and washings were separated and the organic layer dried (MgSO4) and reduced in volume at about 20 Torr. After addition of carbon tetrachloride to the residue, distillation of solvent was continued at atmospheric pressure until a pot temperature of 75° C. was attained. The hot mixture was filtered. Cooling of the gave a solid which was recrystallized from carbon tetrachloride to yield 271 g of the title compound.
Reaction SMILES: C(O[C:6]([N:8]1[C:24]2C=[C:22]3[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]3)=[N:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=O)CCC.[CH3:25][I:26]>CO>[IH:26].[CH3:6][NH+:8]1[C:24]2[C:15]([N:16]=[C:17]3[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]3)=[CH:25][C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2
Reactant: CI
Reactant: CCCCOC(=O)n1c2ccccc2c2nc3ccccc3cc21
Solvent: CO
Product: C[NH+]1C2=c3ccccc3=NC2=Cc2ccccc21
Product: I
Temperature: 120 °C

Procedure:
A mixture of 10-butyloxycarbonylquindoline (100 mg, 0.31 mmol) from Example 10, methyl alcohol (5 mL) and methyl iodide (45 mL, 0.70 mmol) was heated in a bomb at 120° C. for 4 hours. After cooling, the resulting yellow precipitate (93 mg, 82.3%) was filtered, washed with ethanol, then washed with ether and hexane to afford 5-methylquindolinium hydroiodide identical to that obtained above in Example 3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([I:19])[S:18][C:11]=12)[NH2:5].[N:20]1[CH:25]=[CH:24][CH:23]=C[CH:21]=1.ClC(OC1C=CC=CC=1)=[O:28].C1(N)CC1>CN(C=O)C.O>[CH:25]1([NH:20][C:21]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[CH:16]=[C:17]([I:19])[S:18][C:11]=34)=[C:2]([F:1])[CH:3]=2)=[O:28])[CH2:23][CH2:24]1
Reactant: c1ccncc1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1)NC1CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 93.7 %

Procedure:
To a solution of amine 268 (1.7 g, 3.98 mmol) in DMF (7 mL) was added pyridine (0.55 mL, 6.77 mmol) at RT and the resultant solution was stirred for 10 min under Ar atmosphere. Phenyl chloroformate (0.75 mL, 5.97 mmol) was added at 0° C. and the mixture was stirred at RT for 40 min. Cyclopropylamine (1.1 mL, 15.9 mmol) was added to the mixture, and the reaction mixture was warmed to 50° C. and stirred for 2 hours. The mixture was then cooled to RT then poured into water (150 mL) and stirred for 30 min. The precipitate was collected by filtration, washed with water and dried. The crude product was triturated with EtOActo afford title compound 269 (1.75 g, 86% yield) as a pale-violet solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.70 (br, 1H), 8.45 (d, J=5.4 Hz, 1H), 7.91 (s, 1H), 7.72 (dd, J=13.5, 2.4 Hz, 1H), 7.35 (t, J=9.0 Hz, 1H), 7.23 (m, 1H), 6.62 (d, J=5.4 Hz, 1H), 6.56 (br, 1H), 2.60-2.40 (m, 1H), 0.70-0.60 (m, 2H), 0.48-0.35 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1([CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[ClH:19].[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([N:23]3[CH2:22][CH2:21][N:20]([CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])[CH2:25][CH2:24]3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: OCCOCCN1CCNCC1
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCN(CCOCCO)CC3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 90 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride (70 mg, 0.220 mmol) is reacted with 2-(2-piperazin-1-yl-ethoxy)-ethanol (41.7 μL, 0.242 mmol) as described in Steps 5 and 6, Example 24 to give the title compound as an orange solid (90% yield). LC/MS: RT 2.03 min, m/e 456 (M+H); 1H NMR (δ, ppm): 11.89 (1H, s), 10.6 (1H, s), 7.69 (1H, d), 7.37 (1H, s), 7.34 (1H, d), 3.71-3.76 (4H, m), 3.60-3.64 (2H, m), 3.45-3.50 (4H, m), 3.32-3.31 (4H, m), 2.92-3.00 (2H, m), 2.41 (2H, q), 2.35 (3H, s), 1.10 (3H, t).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH:15]([C:17]([CH3:19])=[O:18])=[CH2:16].[CH3:20]CO>CC[O-].[Na+]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:9]([CH2:16][CH2:15][C:17](=[O:18])[CH3:19])[C:10]([O:12][CH2:13][CH3:20])=[O:11])=[O:14])=[CH:6][CH:7]=1
Reactant: CCO
Reactant: C=CC(C)=O
Reactant: COC(=O)CC(=O)c1ccc(C)cc1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(CCC(C)=O)C(=O)c1ccc(C)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of methyl 3-(4-methylphenyl)-3-oxopropanoate(2.28 g, 11.1 mmol) in EtOH(10 ml), NaOEt(11 mg, 0.16 mmol) was added and methyl vinyl ketone(2.0 g, 27.8 mmol) was added dropwise less than 25° C. After stirring the reaction mixture for 30 min. less than 25° C., the solvent was evaporated under reduced pressure. Dil.HCl aq. was added to the residue and extracted by EtOAc. The organic layer was washed with water and brine, dried over MgSO4. After removal of the solvent, the residue was purified by column chromatography on silica gel with n-hexane-AcOEt to afford 2.73 g of ethyl 2-((4-methylphenyl)carbonyl)-5-oxohexanoate as a pale yellow oil (y=89.0%). 1H-NMR(ppm, 300 MHz, CDCl3) δ 7.92(2H, d, J=8.0 Hz), 7.28(2H, d, J=8.0 Hz), 4.41(1H, t, J=7.0 Hz), 4.14(2H, q, J=6.9 Hz), 2.55-2.60(2H, m), 2.13(3H, s), 1.17(3H, t, J=6.9 Hz)
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.Cl.[CH3:11][NH:12][CH3:13].[CH2:14]=O.O.Cl>C(O)(C)C>[CH3:11][N:12]([CH3:14])[CH2:13][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1
Reactant: C=O
Reactant: c1cnc2[nH]ccc2c1
Reactant: CNC
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CN(C)Cc1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.4 %

Procedure:
Into a 3-neck round bottom flask was added Isopropyl alcohol (320.0 mL) followed by the addition of 1H-pyrrolo[2,3-b]pyridine 1 (7.10 g, 60.1 mmol), dimethylamine hydrochloride (5.4 g, 0.066 mol), and formaldehyde (2.0 g, 0.066 mol). The reaction mixture was stirred at room temperature for 12 hours, and then refluxed for 30 minutes. The suspension solution was evaporated to dryness in vacuo. To the residue was added water (60.0 mL, 3.33 mol) and concentrated hydrochloric acid (6.0 mL, 0.20 mol). The water layer was extracted with ether and the aqueous layer was neutralized with potassium carbonate. The aqueous layer was extracted with dichloromethane, dried over sodium sulfate and concentrated to give the compound, which was then further washed with ether and dried to afford compound 2 (7.1 g, yield=67.4%), as a white solid.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[C:11]([N+:32]([O-:34])=[O:33])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[F:20])[N:16]([C@@H:22]1[CH2:24][C@@H:23]1[F:25])[CH:15]=[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:13]2=[O:31].O.C(Cl)(Cl)Cl>CN(C)C=O>[F:20][C:19]1[C:18]([CH3:21])=[C:17]2[C:12]([C:13](=[O:31])[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:15][N:16]2[C@@H:22]2[CH2:24][C@@H:23]2[F:25])=[C:11]([N+:32]([O-:34])=[O:33])[CH:10]=1
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(F)c(N)c([N+](=O)[O-])c2c1=O
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(F)cc([N+](=O)[O-])c2c1=O
Temperature: 65 °C
Yield: 60.7 %

Procedure:
Isoamyl nitrite (2.56 ml, 19.1 mmol) was added to dimethylformamide (40 ml), and while stirring at 65° C., a solution, wherein ethyl 6-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-5-nitro-4-oxoquinoline-3-carboxylate (5.00 g, 13.6 mmol) was dissolved in dimethylformamide (60 ml), was added dropwise over a period of 3 hours. After completion of dripping, the reaction solution was stirred at 65° C. for 4 hours, allowed to cool, and then poured into water (500 ml). After extraction with chloroform (200 ml×3), the organic layers combined were washed with 1 mol/l hydrochloric acid (200 ml) and saturated saline solution (100 ml×2) in that order, and then dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and the residue obtained was applied to a silica gel chromatography to obtain 2.91 g (61%) of the title compound in the form of a white powder from a chloroform:methanol=30:1 eluate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[NH2:16][C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[N:21][CH:22]=1>>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:16][C:17]1[CH:22]=[N:21][C:20]([N:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)=[N:19][CH:18]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(N)cn2)CC1
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Yield: 44.7 %

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (300 mg, 1.06 mmol) was reacted with tert-butyl 4-(5-aminopyrimidin-2-yl)piperazine-1-carboxylate (495 mg, 1.59 mmol) to afford the desired product (250 mg, 44%) as a yellow solid: ESI MS m/z 527, [C24H27BrN6O3+H]+
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][O:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([CH2:36][C:37](O)=[O:38])[CH2:32][CH2:31]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH:24]([NH:27][C:37](=[O:38])[CH2:36][C@H:33]5[CH2:34][CH2:35][C@H:30]([O:29][CH3:28])[CH2:31][CH2:32]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: CO[C@H]1CC[C@H](CC(=O)O)CC1
Agent: Cl
Product: CO[C@H]1CC[C@H](CC(=O)NC2CCC(CCN3CCN(c4cccc5c4OCO5)CC3)CC2)CC1

Procedure:
The title compound, white solid (27.1 mg, 68.4%), MS (ISP) m/z=486.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and (trans-4-Methoxycyclohexyl)acetic acid (synthesized as described in W2009/013212 p. 73).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:17])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[Cl:18][C:19]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:20]=1[C:21]([N:23]=[C:24]=[O:25])=[O:22]>>[Cl:18][C:19]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:20]=1[C:21]([NH:23][C:24]([NH:17][C:3]1[C:2]([Cl:1])=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:14])[F:16])=[CH:9][CH:8]=2)[O:5][N:4]=1)=[O:25])=[O:22]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1noc(-c2ccc(C(F)(F)F)cc2)c1Cl

Procedure:
4-Chloro-5-(4-(trifluoromethyl)phenyl)-3-aminoisoxazole was reacted with 2,6-dichlorobenzoyl isocyanate to produce the desired product according to the teaching of Example 8. The identity of the product was confirmed by NMR, m.p.=237°-238° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.Br[CH:10]([CH2:18][CH3:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH:10]([CH2:18][CH3:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(Br)cc[nH]1
Reactant: CCC(Br)C(=O)OC(C)(C)C
Product: CCC(C(=O)OC(C)(C)C)n1ccc(Br)cc1=O

Procedure:
348 mg (2.0 mmol) of 4-bromopyridin-2(1H)-one and 1.2 eq. of tert-butyl 2-bromobutanoate (racemate) were reacted according to General Method 4B at 120° C. After aqueous work-up, the desired product was reacted further as crude product. Yield: 608 mg (purity 82%, 79% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1n[nH]cc1-c1ccccn1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)c(Cl)c1
Product: Fc1ccc(-c2cc(C(F)(F)F)n3ncc(-c4ccccn4)c3n2)cc1Cl
Yield: 71 %

Procedure:
Reaction of 1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (269 mg, 1.0 mmol), prepared from commercially available 3-chloro-4-fluoro-acetophenone according to general procedure A, and 3-amino-4-(2-pyridinyl)-pyrazole [CAS No. 493038-87-2; prepared from 2-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (279 mg, 71%). MS (ISP) 393.1 [(M+H)+]; mp 197° C.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.CN([CH:35]=[O:36])C>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([CH:35]=[O:36])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CN(C)C=O
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (10.6 mg, 21.4 mmol) in THF (80 mL) under nitrogen atmosphere at −40° C. was added isopropylmagnesium chloride (25 mL, 50 mmol, 2 M in THF). The mixture was then warmed to 0° C. over 30 min and DMF (4 mL, 51 mmol) was added. The reaction mixture was stirred at room temperature overnight, quenched with saturated aqueous ammonium chloride, and followed by HCl (1 M) to pH ˜3. The mixture was extracted with ethyl acetate, dried, and concentrated to provide 4-chloro-N-(5-chloro-2-formyl-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide. MS: (M+H)/z=442.9.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C([O-])(O)=O.[Na+].CC(C)[CH2:20][C:21](=[O:23])C.ClCC(Cl)=O>O>[C:8]([C:6]1[C:5]([F:11])=[CH:4][C:3]2[O:12][CH2:20][C:21](=[O:23])[NH:1][C:2]=2[CH:7]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cc(N)c(O)cc1F
Reactant: CC(=O)CC(C)C
Agent: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)c1cc2c(cc1F)OCC(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a mixture of 1-(5-amino-2-fluoro-4-hydroxy-phenyl)-ethanone (13.2 g, 78 mmol), NaHCO3 (19.67 g, 234 mmol) in water (90 mL), and 4-methyl-2-pentanone (90 mL) at 0° C. was added 2-chloroacetyl chloride (13.22 g, 8.8 mL, 117 mmol) dropwise. After addition, the reaction mixture was stirred at ambient temperature for 0.5 h and then at 80° C. for 18 h. The mixture was cooled to ambient temperature and filtered to give 6-acetyl-7-fluoro-4H-benzo[1,4]oxazin-3-one as gray solid (12 g, 74%), which was used in next step directly without further purification. 1H NMR (DMSO-d6, 400 MHz): δ 10.90 (s 1H), 7.35 (d, J=7.6 Hz, 1H), 7.02 (d, J=11.6 Hz, 1H), 4.71 (s, 2H), 2.47 (d, J=4.8 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[F:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:21])[C:14]([OH:20])=[CH:15][N:16]2[CH3:19])=[CH:11][CH:10]=1.ClCCl>C(N(CC)CC)C>[CH3:1][CH:2]([S:4]([O:20][C:14]1[C:13](=[O:21])[C:12]2[C:17](=[CH:18][C:9]([F:8])=[CH:10][CH:11]=2)[N:16]([CH3:19])[CH:15]=1)(=[O:6])=[O:5])[CH3:3]
Reactant: Cn1cc(O)c(=O)c2ccc(F)cc21
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)Oc1cn(C)c2cc(F)ccc2c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Propanesulphonyl chloride (1.74 ml) was added to a stirred mixture of 7-fluoro-3-hydroxy-1-methyl-4quinolone (3.0 g), obtained as described in Example 3 a-f, triethylamine (4.35 ml) and dry dichloromethane (180 ml) and the mixture stirred at ambient temperature for 24 hours. Further quantities of 2-propanesulphonyl chloride (1.75 ml then 1 ml) and triethylamine (4.35 ml then 2.5 ml) were added after stirring for 24 hours and 48 hours respectively. After stirring for a further 24 hours, the mixture was filtered and the filter bed was washed with dichloromethane (30 ml). The combined filtrate and washing were washed with water (200 ml), saturated aqueous sodium bicarbonate (2×200 ml), then water (200 ml) and then dried over magnesium sulphate. The dichloromethane was removed by distillation to give a residue which was purified by flash chromatography on a silica gel column eluted with dichloromethane: industrial methylated spirit (19:1) followed by crystallisation from 2-propanol (25 ml) to give the novel compound 7-fluoro-1-methyl-4-oxo-1,4-dihydroquinol-3-yl 2-propanesulphonate, m.p. 130°-133°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[N+:25]([O-:27])=[O:26])[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c1cccc2[N+](=O)[O-]
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cccc([N+](=O)[O-])c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-nitro-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [OH:1]O.[CH3:3][O:4][C:5]1[C:6]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17](SC)=[N:18]3)=[CH:13][CH:12]=2)=[N:7][CH:8]=[CH:9][CH:10]=1.[OH-].[Na+].O>CO.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C>[CH3:3][O:4][C:5]1[C:6]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([OH:1])=[N:18]3)=[CH:13][CH:12]=2)=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: OO
Reactant: COc1cccnc1-c1ccc2cnc(SC)nn12
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COc1cccnc1-c1ccc2cnc(O)nn12
Temperature: 50 °C
Yield: 85.8 %

Procedure:
Sodium Tungstate Dihydrate (23.0 mg, 0.0698 mmol) and 50% Hydrogen Peroxide (50:50, Hydrogen peroxide:Water, 0.150 mL, 2.64 mmol) were added to 7-(3-Methoxy-pyridin-2-yl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.190 g, 0.698 mmol) in Methanol (10.0 mL) and Acetic acid (0.400 mL, 7.04 mmol). The mixture was stirred at 50° C. Formation of the sulfoxide was evident, followed by formation of the sulfone. After o.n., a 1:1 mixture of sulfoxide:sulfone was present. Additional 50% Hydrogen Peroxide (50:50, Hydrogen peroxide:Water, 0.150 mL, 2.64 mmol) was added. Further heating gave a ˜2:1 mixture. Aqueous workup (10% Na2S2O3, NaHCO3, water) and extract with DCM. The crude sulfone:sulfoxide mixture was hydrolyzed by dissolving in Tetrahydrofuran (6.0 mL) and adding 5.0 M of Sodium hydroxide in Water (0.500 mL, 2.50 mmol), then heating at 50° C. for 6 h. Work up by acidifying with Acetic acid to pH 5-6. Partition between DCM and water, extract with DCM using MeOH to solubilize the ppt that forms during extraction. Dry and conc. in vacuo to afford 7-(3-Methoxy-pyridin-2-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (145 mg, 85%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15]Br)[CH3:12]>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:15][CH:14]([O:17][CH2:18][CH3:19])[O:13][CH2:11][CH3:12])[CH:5]=1
Reactant: Oc1cccc(Br)c1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(COc1cccc(Br)c1)OCC
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (2.77 g, 115.6 mmol) in DMF (100 mL) at 0° C. was added a solution of 3-bromophenol 6-1 in DMF (40 mL) over 40 min. After the addition was complete, the solution was stirred for an additional 30 min. The solution was then treated with neat bromoacetaldehyde diethyl acetal (17.36 g, 115.6 mmol). The solution was heated at 100° C. for 8 h, cooled to room temperature, and extracted with Et2O (3×200 mL). The combined organic extracts were washed with 10% aq. NaOH (100 mL) and brine (100 mL), dried over MgSO4, filtered and concentrated to give 6-2 as a yellow oil.
Reaction SMILES: [I-:1].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([Cl:10])[C:7]([CH2:11]Cl)=[CH:6][N:5]=1>CC(C)=O>[Cl:3][C:4]1[N:9]=[C:8]([Cl:10])[C:7]([CH2:11][I:1])=[CH:6][N:5]=1
Reactant: [I-]
Reactant: ClCc1cnc(Cl)nc1Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: Clc1ncc(CI)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 500-mL, round-bottom flask equipped with a magnetic stirrer, condenser, and nitrogen-inlet bubbler was charged with sodium iodide (38.5 g, 256.9 mmol) (Aldrich) and acetone (300 mL). After a clear solution was obtained, 2,4-dichloro-5-(chloromethyl)pyrimidine (50.0 g, 253.2 mmol) (from Example 1b supra) was added in one portion. After stirring at room temperature for 20 minutes, the mixture was heated to reflux for 15 minutes. NMR analysis indicated 98% conversion. After cooling to room temperature, the resulting precipitate (sodium chloride) was removed by filtration through a medium-sintered glass funnel and washed with acetone. The combined filtrate and washes were concentrated to a weight of ca. 75 g. The resulting concentrated solution of 2,4-dichloro-5-(iodomethyl)pyrimidine in acetone was diluted with toluene (20 mL). After concentration to a weight of ca.85 g in order to remove the residual acetone, this concentrated solution of 2,4-dichloro-5-(iodomethyl)pyrimidine in toluene was used directly in the next step.