Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:19][CH2:20]Cl)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:22]([N:29]([C@@:41]([CH3:68])([CH2:52][C:53]1[CH:58]=[CH:57][C:56]([OH:59])=[C:55]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH:54]=1)[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(#N)C.N12CCCN=C1CCCCC2>O>[CH2:22]([N:29]([C@@:41]([CH3:68])([CH2:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH2:20][O:19][P:1]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])=[C:55]([O:60][CH2:61][C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:54]=1)[C:42]([O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:43])[NH:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@](Cc1ccc(O)c(OCc2ccccc2)c1)(C(=O)OCc1ccccc1)N(Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: O=P(OCCl)(OCc1ccccc1)OCc1ccccc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@](Cc1ccc(OCOP(=O)(OCc2ccccc2)OCc2ccccc2)c(OCc2ccccc2)c1)(C(=O)OCc1ccccc1)N(Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 8 %

Procedure:
To a 100 mL round bottom flask were added dibenzyl (chloromethyl) phosphate (1.632 g, 4.99 mmol), (S)-benzyl 2-benzyl-2-(1-(benzyloxy)-3-(3-(benzyloxy)-4-hydroxyphenyl)-2-methyl-1-oxopropan-2-yl)hydrazinecarboxylate, Compound 2, (2.1 g, 3.33 mmol) and 25 mL acetonitrile. The mixture was cooled in an ice bath. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.745 mL, 4.99 mmol) was added, and the mixture was stirred in the ice bath for 30 minutes, then at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate twice. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The crude was purified first by flash chromatography using a 120 g silica column (0-50% ethyl acetate in heptanes), followed by RP-HPLC (60-100% acetonitrile in 0.1% TFA/water on Phenonemex C18 5 u column) to afford Compound 3 as a colorless oil (247 mg, 8%).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[O:19]=[C:20]([NH:35][C@@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1)[CH2:21][NH:22][C:23](=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][N:2]([CH3:18])[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([N:38]3[CH2:39][CH2:40][C@@H:36]([NH:35][C:20](=[O:19])[CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=4)[CH2:37]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Reactant: CN(C)C(=O)c1ccc(C2CCC(=O)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(C2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.7 %

Procedure:
100 mg (0.4 mmol) of N,N-dimethyl-4-(4-oxocyclohexyl)benzamide and 126 mg (0.4 mmol) of N-{2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}-3-(trifluoromethyl)benzamide were dissolved in 10 mL of methylene chloride. To the solution was added 170 mg (0.8 mmol) of sodium triacetoxyborohydride. The reaction mixture was stirred at room temperature for 2 h. Direct chromatography on silica gel gave the final desired product 45 mg (top spot on TLC and first peak on HPLC), yield: 22%. MS: 545 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:17](=[O:19])[CH3:18])[C:10]([OH:16])=[CH:11][CH:12]=2)[CH:7]=1.[H-].[Na+].[Br:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:17](=[O:19])[CH3:18])[C:10]([O:16][CH2:28][CH2:27][O:26][CH2:25][CH2:24][Br:23])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: COC(=O)COc1ccc2ccc(O)c(C(C)=O)c2c1
Reactant: BrCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2ccc(OCCOCCBr)c(C(C)=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
Under an argon atmosphere, 2 g of [[8-acetyl-7-hydroxy-2-naphthalenyl]oxy]acetic acid methyl ester was added to a suspension of 0.32 g of 60% sodium hydride in 30 ml of anhydrous dimethylformamide. The mixture was stirred at room temperature for 30 minutes and then 8.5 g of bis-(2-bromoethyl)ether was added and the mixture was stirred at room temperature for 20 hours. The solvent was removed and residual oil was purified by high pressure liquid chromatography using 7% ethyl acetate-toluene to yield 2.4 g (77%) of [[8-acetyl-7-[2-(2-bromoethoxy)ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1>>[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)=[CH:17][CH:18]=1
Reactant: Clc1ccnc2ccccc12
Reactant: O=C(O)c1cccc2cc(O)ccc12
Product: O=C(O)c1cccc2cc(Oc3ccnc4ccccc34)ccc12
Yield: 51.7 %

Procedure:
The title compound (1.24 g, 52% yield) was prepared as a brown solid from 6-hydroxy-1-naphthoic acid (1.43 g, 7.6 mmol) and 4-chloroquinoline (1.49 g, 9.14 mmol) by an analogous procedure to that described in example 1. LC-MS (m/z) 316 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][N:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:2][CH2:3][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: COC(=O)c1ncccc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccnc1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
Heat a mixture of 3-methylpicolinic acid (1.0 g, 7.3 mmol), potassium carbonate (4.1 g, 29.7 mmol), and iodomethane (4.4 g, 31.0 mmol) in acetone (35 mL) overnight under reflux. Filter, wash the residue with EtOAc, and concentrate in vacuo. Pass through a short plug of silica gel eluting with hexane/EtOAc (1:1) to provide 2-methoxycarbonyl-3-methylpyridine as a pale yellow liquid (630 mg, 57%). To a solution of 2-methoxycarbonyl-3-methylpyridine in anhydrous THF (10 mL) at 0° C., add with stirring a solution of 1M lithium aluminum hydride in THF (5 mL, 5 mmol), and continue stirring for 30 min at 0° C. Allow the mixture to warm to ambient temperature and quench cautiously with 0.5M aqueous NaOH. Heat the mixture at 60° C. for 40 min, cool to ambient temperature, extract with EtOAc, dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (4:3) to give the desired intermediate (90 mg, 18%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=2)=[CH:5][CH:4]=1.CO.C1COCC1.[Li+].[OH-]>O>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1coc(-c2ccc(CO)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1coc(-c2ccc(CO)cc2)n1
Yield: 91 %

Procedure:
A solution of ethyl 2-[4-(hydroxymethyl)phenyl]-1,3-oxazole-4-carboxylate (2.5 g, 10.1 mmol) in 1:1 MeOH:THF was treated with 1.0 M LiOH:H2O and stirred at room temperature overnight and concentrated in in vacuo. The resulting residue was diluted with water, treated with 1.0 M HCl and filtered to afford the title product 91% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 219 (MH+).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:18]2[O:17][C:16]3[C:19]([CH:25]=O)=[C:20]([OH:24])[CH:21]=[C:22]([CH3:23])[C:15]=3[C:14](=[O:27])[O:13][C:12]=2[C:11]([CH3:28])=[C:10]([O:29][CH3:30])[CH:9]=1)=[O:7])[CH2:2][CH2:3]C.[S:31]([NH2:41])(=[O:40])([C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)=[O:32]>>[CH2:1]([O:5][C:6]([C:8]1[C:18]2[O:17][C:16]3[C:19]([CH2:25][NH:39][C:36]4[CH:35]=[CH:34][C:33]([S:31](=[O:40])(=[O:32])[NH2:41])=[CH:38][CH:37]=4)=[C:20]([OH:24])[CH:21]=[C:22]([CH3:23])[C:15]=3[C:14](=[O:27])[O:13][C:12]=2[C:11]([CH3:28])=[C:10]([O:29][CH3:30])[CH:9]=1)=[O:7])[CH2:2][CH3:3]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CCCCOC(=O)c1cc(OC)c(C)c2c1Oc1c(C=O)c(O)cc(C)c1C(=O)O2
Product: CCCOC(=O)c1cc(OC)c(C)c2c1Oc1c(CNc3ccc(S(N)(=O)=O)cc3)c(O)cc(C)c1C(=O)O2

Procedure:
This compound was prepared from the compound from Example 8 by means of a procedure similar to that used for Example 18 except replacing ethanolamine with sulphanilic amide.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([CH2:14][O:15][C:16]3[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=3)[NH2:19])=[N:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:23]([C:25]1([CH2:32][CH3:33])[CH2:30][C:29](=[O:31])[O:28][C:26]1=[O:27])[CH3:24]>N1C=CC=CC=1>[C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([CH2:14][O:15][C:16]3[CH:17]=[C:18]([NH:19][C:29](=[O:31])[CH2:30][C:25]([CH2:32][CH3:33])([CH2:23][CH3:24])[C:26]([OH:28])=[O:27])[CH:20]=[CH:21][CH:22]=3)=[N:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2ccc(COc3cccc(N)c3)nc2c1
Reactant: CCC1(CC)CC(=O)OC1=O
Solvent: c1ccncc1
Product: CCC(CC)(CC(=O)Nc1cccc(OCc2ccc3ccc(C(C)=O)cc3n2)c1)C(=O)O
Reaction time: 0.5 h

Procedure:
0.36 g of 3-(7-acetyl-2-quinolinylmethoxy)aniline and 0.385 g of 2,2-diethylsuccinic acid anhydride are stirred in 5 ml of pyridine for 72 hours at 20° and concentrated by evaporation. The residue is suspended in 5 ml of 2N aqueous hydrochloric acid, the suspension is stirred for 30 min. at 20° and filtered and the residue retained on the filter is dried in vacuo at 20°. The crude product obtained is chromatographed on 50 g of silica gel. The product-containing fractions (eluted with toluene/ethyl acetate 1:1 and with ethyl acetate) are combined and concentrated by evaporation and the evaporation residue is recrystallised from a CH2Cl2 /methanol/acetone mixture to give the title compound in the form of crystals of m.p. 164°. IR (Nujol): inter alia 3600-2100, 3350, 1675, 1600 cm-1.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:14](SC)[N:13]=[C:12]([S:25][CH3:26])[N:11]=1.[CH3:27][OH:28]>>[CH3:26][S:25][C:12]1[N:13]=[C:14]([O:28][CH3:27])[C:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=2[Cl:2])[N:11]=1
Reactant: CSc1nc(SC)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: CO
Agent: [Na]
Product: COc1nc(SC)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 5 h

Procedure:
To a round bottom flask fitted with a magnetic stir bar and small reflux condenser was added 0.25 mL methanol, sodium metal (23 mg, 1.0 mmol). The flask was flushed with nitrogen. When the sodium dissolved, 2,4-bis(methylthio)-5-[4-chlorophenyl]-6-[2,4-dichlorophenyl]-pyrimidine (Reference Example 4, 215 mg, 0.5 mmol) in 500 μL methanol was added by syringe. The methanol was removed under high vacuum and 2 mL scrupulously dried DMF (15X sieve and 3A sieve, respectively) added to the mixture. The mixture was stirred for 5 h, quenched in aqueous NH4Cl and immediately extracted with ether. Starting material and product were observed by LC. The organic layer was dried over MgSO4 and filtered. The solvent removed under reduced pressure. Flash column chromatography on silica gel (eluted with 98/2 hexanes/ethyl acetate) gave pure product and mixed starting material/product fraction. The title compound eluted by LC at Rt=4.62 min, m/e=313 (M++1). 1H-NMR 500 MHz (CDCl3): δ 2.64 (s, 3H), 4.05 (s, 3M), 7.08 (d, J=8 Hz, 2H), 7.13 (d, J=8 Hz, 1H), 7.19-7.24 (m, 3H), 7.34 (d, J=2 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[NH2:14][C:15]1[N:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[CH:17][N:16]=1>>[NH2:14][C:15]1[N:20]=[C:19]([C:21]([NH:11][CH2:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:12])([F:13])[F:1])[CH:5]=2)=[O:22])[CH:18]=[CH:17][N:16]=1
Reactant: NCc1cccc(OC(F)(F)F)c1
Reactant: Nc1nccc(C(=O)O)n1
Product: Nc1nccc(C(=O)NCc2cccc(OC(F)(F)F)c2)n1
Yield: 37 %

Procedure:
The title compound is prepared in 37% yield (82 mg, a white solid) from (3-(trifluoromethoxy)phenyl)methanamine (137 mg, 0.72 mmol) and 2-aminopyrimidine-4-carboxylic acid (100 mg, 0.72 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:29][C:30]([F:33])([F:32])[F:31]>C1COCC1>[F:31][C:30]([F:33])([F:32])[CH2:29][N:23]1[CH2:24][CH2:25][N:20]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[CH:11][C:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[CH:19]3)[CH2:21][CH2:22]1
Reactant: O=S(=O)(c1ccccc1)c1cnc2c(N3CCNCC3)cccc2c1
Reactant: FC(F)(F)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1cnc2c(N3CCN(CC(F)(F)F)CC3)cccc2c1
Temperature: 100 °C

Procedure:
A solution of 3-phenylsulfonyl-8-piperazin-1-yl-quinoline (D12) (200 mg, 0.55 mmol) in dry THF (2 ml) was treated with sodium hydride (24 mg, 0.6 mmol, 60% oil dispersion), and 1-bromo-2,2,2-trifluoroethane (815 mg, 5 mmol). The mixture was heated to 100° C. for 4 days then cooled, evaporated and the residue subjected to purification by flash chromatography on silica gel (eluting with dichloromethane-methanol-aq. NH3) to give the free base form of the title compound. This was treated with 1M HCl in ether then crystallised from isopropanol to give the title compound (E8) as a yellow solid:
Reaction SMILES: [NH2:1]/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([Cl:18])[C:9]=1[NH:19]N.S(=O)(=O)(O)O>C(O)C>[NH2:5][C:4]1[N:19]([C:9]2[C:10]([Cl:18])=[CH:11][C:12]([C:14]([F:17])([F:15])[F:16])=[CH:13][C:8]=2[Cl:7])[N:1]=[C:2]([CH3:6])[CH:3]=1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: C/C(N)=C/C#N
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Aminocrotononitrile (5.0 g) was added to a stirred solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (15.0 g) in ethanol (100 ml), then the resulting solution treated with concentrated sulphuric acid (1.0 ml) to produce a white solid precipitate. The mixture was heated under reflux for 6 hours, allowed to cool and stirred for a further 18 hours at room temperature; this cycle was repeated, then more concentrated sulphuric acid (4 ml) added. The reaction mixture was heated at 60° C. for 8 hours, allowed to cool, stirred at room temperature for 18 hours and evaporated under reduced pressure. The resulting orange oil was partitioned between dichloromethane (100 ml) and water (100 ml), then the organic phase dried, allowed to stand at room temperature for 18 hours and filtered to remove some white solid material. The filtrate was evaporated under reduced pressure to give an orange oil which was triturated with hot hexane. On cooling, the hexane solution deposited a yellow oil which slowly crystallised to furnish the title compound as a white solid, m.p. 80-83° C. Found: C, 42.73; H, 2.62; N, 13.58. C11H8Cl2F3N3 requires 42.61; H, 2.60; N, 13.55%. δ(CDCl3): 2.25 (s,3H), 3.48 (br.s,2H), 5.52 (s,1H), 7.70 (s,2H). MS (thermospray): M/Z [M] 310.0; C11H8Cl2F3N3 requires 310.12.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[CH2:7](O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1CCCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH:2]([CH3:6])[C:3]([O:5][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(Br)C(=O)O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: CC(Br)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 104.5 %

Procedure:
A mixture of 2-bromopropanoic acid (15.3 g; 100 mmol), benzyl alcohol (13.0 g; 120 mmol) and p-toluenesulphonic acid monohydrate (50 mg) in cyclohexane (200 mL) was refluxed in a Dean-Stark apparatus for 19 h. The reaction mixture was cooled to ambient temperature, washed with saturated NaHCO3 solution (1×30 mL), water (1×30 mL) and saturated NaCl solution (1×30 mL). After drying (MgSO4), filtration, and evaporation, the residue was vacuum-distilled. 25.4 g (87%) product was obtained (colourless liquid, by 111-113° C./1.1 mm Hg).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[N:4]1)[CH3:2].[NH3:35]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([NH2:35])=[O:9])[C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[N:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)Cl)c(NS(=O)(=O)c2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Reactant: N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCn1cc(C(N)=O)c(NS(=O)(=O)c2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Reaction time: 16 h

Procedure:
To a solution of the title A compound, 1-ethyl-3-{4-[5-methyl-2-phenyl-oxazol-4-ylmethoxy]-benzenesulfonylamino}-1H-pyrazole-4-carbonyl chloride (0.15 g, 0.3 mmol) in DCM is added a saturated solution of ammonia (3 mL) in DCM at RT. The reaction mixture is stirred for 16 h. The reaction mixture is diluted with ethyl acetate, washed with water, dried and evaporated to give 1-ethyl-3-{4-[5-methyl-2-phenyl-oxazol-4-ylmethoxy]-benzene-sulfonylamino}-1H-pyrazole-4-carboxylic acid amide as a solid: MS [m/z] 481.5 [M-1]−.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17][CH2:18][CH3:19])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:20]>>[ClH:20].[CH2:18]([O:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:16]2)[CH3:19]
Reactant: CCOc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C2
Agent: Cl
Product: CCOc1ccc2c(c1)CNC2

Procedure:
Prepared in analogy to Example A3(e) from 5-ethoxy-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Brown solid. MS (m/e): 164.4 ([M+H]+, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[OH:28][NH:29][C:30](=[NH:41])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([S:37](=[O:40])(=[O:39])[NH2:38])[CH:32]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[N:15]3[N:22]=[CH:23][C:24]([C:25]4[O:28][N:29]=[C:30]([C:31]5[CH:32]=[C:33]([S:37]([NH2:38])(=[O:39])=[O:40])[CH:34]=[CH:35][CH:36]=5)[N:41]=4)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4nc(-c5cccc(S(N)(=O)=O)c5)no4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) (195 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane) as a light yellow solid (190 mg, 67%). MS (EI) 568.1 [(M)+]; mp 270° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[CH:6]=[N:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH:21]=[CH2:22]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([CH2:22][CH:21]=[CH2:20])[C:7](=[O:13])[CH:6]=[N:5]2
Reactant: C=CCI
Reactant: O=c1cnc2cc(F)c(F)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)cnc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
A solution of 6,7-difluoro-2(1H)-quinoxalinone (0.57 g; 3.13 mmol) in dry DMF (10 ml) containing anhydrous potassium carbonate (1.3 g; 9.4 mmol) was treated with allyl iodide (0.31 ml; 3.45 mmol) and the mixture was stirred at rt for 2 h. The solvents were evaporated, water was added and the mixture was extracted (3×) with DCM. The extracts were dried and evaporated, and the residue was chromatographed on silica gel, eluting with 0-50% ethyl acetate/hexane to give the product (0.44 g, 63%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[C:6]([O:17][CH3:18])[CH:5]=1)[CH3:2].[C:19](OCC)(=O)[CH3:20]>[Pt]=O.C(O)C>[CH2:1]([N:3]1[C:4]2[CH:5]=[C:6]([O:17][CH3:18])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:8][C:9]=2[N:10]=[C:19]1[CH3:20])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCNc1cc(OC)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Product: CCn1c(C)nc2cc(C(F)(F)F)c(OC)cc21

Procedure:
A solution of 24.4g. (0.09 mole) of N-ethyl-3-methoxy-6-nitro-4-trifluoromethylaniline in 200 ml. of ethyl acetate, plus 100 ml. of ethanol, was hydrogenated in the presence of 0.2g. of platinum oxide at room temperature. The theoretical amount of hydrogen was absorbed in 19 hours of shaking at 60 psi. The catalyst was removed by filtration and the solvent evaporated at reduced pressure. The solid residue was dissolved in 200 ml. of absolute ethanol and 12.58g. (0.10 mole) of ethyl methylcarboximidate hydrochloride added. The mixture was stirred overnight at room temperature and the solvent removed at reduced pressure. Trituration of the brown residue with 200 ml. of chloroform, filtration, and evaporation of solvent from the filtrate left the crude residual product. Crystallization from hexane--CCl4 (3:1) gave 18.1g. (76%) of brown, shiny needles. Recrystallization from hexane gave the pure product, m.p. 127°-129.5°C. whose structure was confirmed by an nmr spectrum.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[Cl:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13]>ClC1C=CC=CC=1Cl>[Cl:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[N:13]1[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]1=[O:9]
Reactant: Nc1ccccc1Cl
Reactant: Cc1cc(O)cc(=O)o1
Solvent: Clc1ccccc1Cl
Product: Cc1cc(O)cc(=O)n1-c1ccccc1Cl
Temperature: 165 °C
Reaction time: 0.5 h
Yield: 27.8 %

Procedure:
To a mixture of 4-hydroxy-6-methyl-2H-pyran-2-one (10.0 g) and 1,2-dichlorobenzene (9.91 mL) was added 2-chloroaniline (10.1 g) over 10 min at 165° C., and the reaction mixture was stirred at 165° C. for 30 min, and cooled to room temperature. The resulting solid was collected by filtration, and washed with dichloromethane to give the title compound (5.19 g).
Reaction SMILES: [ClH:1].[NH:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[CH2:9][NH:10]C(=O)OC(C)(C)C)=[N:3]1>C(OCC)(=O)C>[ClH:1].[NH:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[CH2:9][NH2:10])=[N:3]1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1cc[nH]n1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCc1ccccc1-c1cc[nH]n1
Reaction time: 0.67 h

Procedure:
Hydrogen chloride gas was bubbled through a 0° C. solution of tert-butyl 2-(1H-pyrazol-3-yl)benzylcarbamate (60 mg, 0.220 mmol) in ethyl acetate (5 ml) for 2 min and stirred for 40 min. A precipitate formed, and the suspension was concentrated in vacuo to give 2-(1H-pyrazol-3-yl)-benzylamine hydrochloride salt; MS (ES+) M+1 174.1 for C10H11N3.