Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](Cl)=[O:39]>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[CH2:17][C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:38]([C:34]3[O:33][CH:37]=[CH:36][CH:35]=3)=[O:39])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2Cc3c(CNC(=O)c4ccco4)cccc3C2=O)C(=O)N1
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
1,8-Diazabicyclo[5,4,0]-undec-7-ene (0.8 g, 5.3 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) in acetonitrile (100 mL). The mixture was stirred for 30 minutes. 2-Furoyl chloride (0.4 g, 3.2 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with CH2Cl2 (60 mL) and 2N HCl (30 mL). The mixture was filtered, and the solid was slurried with ethanol (20 mL) to give furan-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.5 g, 58%) as a white solid: mp 219-221° C.; 1H NMR (DMSO-d6) δ 2.00-2.05 (m, 1H), 2.30-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.39-4.49 (m, 3H), 4.53 (d, J=17.3 Hz, 1H), 5.11-5.18 (dd, J=5.0 and 13.1 Hz, 1H, CH), 6.62-6.63 9m, 1H), 7.14 (d, J=3.4 Hz, 1H), 7.47-7.65 (m, 3H, Ar), 7.84 (s, 1H), 8.00 (t, J=5.8 Hz, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.59, 31.18, 38.72, 46.24, 51.58, 111.87, 113.69, 121.70, 128.32, 130.74, 131.61, 134.55, 140.11, 145.15, 147.61, 157.84, 168.05, 171.01, 172.85; Anal. calcd. for C19H17N3O5: C, 62.12; H, 4.66; N, 11.44. Found: C, 61.91; H, 4.64; N, 11.38.
Reaction SMILES: [CH:1]#[C:2][C:3]([NH2:6])([CH3:5])[CH3:4].C(N(CC)CC)C.[CH3:14][Si:15]([CH3:18])([CH3:17])Cl>O1CCCC1>[CH:1]#[C:2][C:3]([NH:6][Si:15]([CH3:18])([CH3:17])[CH3:14])([CH3:5])[CH3:4]
Reactant: C#CC(C)(C)N
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CC(C)(C)N[Si](C)(C)C
Reaction time: 1.5 h

Procedure:
In 5000 ml flask were combined 250 g of commercial HC≡CCMe2NH2, 581.8 g of triethylamine, and 1637.5 g of tetrahydrofuran solvent. The flask and contents were cooled at 17° and addition of 625.5 g of trimethylchlorosilane begun with rapid stirring under nitrogen. The addition was completed in 90 min, followed by stirring for 85 min. Analysis by gas chromatography (GC) showed a small amount of HC≡CCMe2NH2, which was converted to product by an additional 53.4 g of trimethylchlorosilane. Reaction mixture was pressure-filtered and the solids triturated with fresh tetrahydrofuran and refiltered. The organic solutions were combined and distilled, providing the desired product, HC≡CCMe2NHSiMe3, as a liquid boiling at 135° at atmospheric pressure. Its structure was confirmed by NMR analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:10]([OH:12])=O)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[C:10]2=[O:12])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(CCc2cccc(OC)c2)C(=O)O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CCc3cc(OC)ccc3C2=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.31 g (7.7 mmol) of 2-(4-methoxyphenyl)-4-(3-Methoxyphenyl)butyric acid was dissolved in 30 mL of CH2Cl2 and cooled to 0° C. To this solution was added 3.4 ml (23.1 mmol) of trifluoroacetic acid, the reaction was allowed to proceed for 30 minutes. The reaction was quenched by pouring into an aqueous solution of NaHCO3. The organic layer was separated, washed twice with NaHCO3 solution washed twice with brine, dried with Na2SO4, and evaporated to a solid. This yielded 1.5 g of the title compound as a tan amorphous solid.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:18]2[CH:19]=[CH:20][N:21]=[C:17]2[CH:16]=[CH:15][CH:14]=1)=O)(C)(C)C.[ClH:22].CO>C(Cl)Cl>[ClH:22].[ClH:22].[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:18]2[CH:19]=[CH:20][N:21]=[C:17]2[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCCNc1cccc2nccn12
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: NCCCNc1cccc2nccn12
Temperature: 25 °C
Reaction time: 20 h
Yield: 83 %

Procedure:
To a suspension of 5-[3-(tert-butoxycarbonylamino)propylamino]imidazo[1,2-a]pyridine (1.742 g, 6 mmoles) in methylene chloride (40 ml) was added hydrogen chloride-methanol (6 ml) and the mixture was stirred at room temperature for 20 hours. After the solvent was distilled off, ethanol (15 ml) and ether (30 ml) were added to the residue. Then, the crystals precipitated were filtered off and washed in turn with ether and a small amount of ethanol to obtain 1.311 g of the desired product (83.0%, pale yellow crystals).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2].[CH3:13][Si:14](Cl)([CH3:16])[CH3:15]>>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([Si:14]([CH3:16])([CH3:15])[CH3:13])[C:5]=1[C:4]([NH:3][CH2:1][CH3:2])=[O:12]
Reactant: CCNC(=O)c1ccccc1Cl
Reactant: C[Si](C)(C)Cl
Product: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)C

Procedure:
The compound of Example f (2.2 g, 0.012 mol) was reacted with TMSCl (3.91 g, 0.036 mol) using General Method A. The title compound was recrystallized from ether/hexanes as a solid. m.p. 105-107° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[F:30][C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[C:41]([I:43])[CH:40]=[C:39]([OH:44])[CH:38]=2)[CH:34]=[CH:35][CH:36]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:44][C:39]2[CH:38]=[C:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=3)[CH:42]=[C:41]([I:43])[CH:40]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: Oc1cc(I)cc(-c2cccc(F)c2)c1
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Yield: 98.7 %

Procedure:
A similar procedure as described in Example 12, step 7 was used, starting from 4-[3-(6-bromo-hexyl)-2-(ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.67 g, 3.54 mmol) and 3′-fluoro-5-iodo-biphenyl-3-ol (1.01 g, 3.22 mmol) to obtain 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3′-fluoro-5-iodo-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid ethyl ester (2.24 g, 99%) as a light yellow oil: ES(+)-HRMS m/e calculated for C35H42FIO6 (M+Na)+ 727.1902, found 727.1902.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=1)=[O:8].[NH:26]1[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]1>>[Br:1][C:2]1[C:3]([N:26]2[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]2)=[N:4][CH:5]=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=1)=[O:8]
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)C(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described infashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-(perfluoroethoxy)phenyl)nicotinamide (Stage 220.2) and (R)-pyrrolidin-3-ol to afford an off-white crystalline solid. HPLC (Condition 4) tR=6.01 min, UPLC-MS (Condition 3) tR=1.17 min, m/z=496.2 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13](NC2C=CC(C3ON=CC=3)=CC=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[O:30]1[C:34]([C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)=[CH:33][N:32]=[CH:31]1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:39][C:38]2[CH:40]=[CH:41][C:35]([C:34]3[O:30][CH:31]=[N:32][CH:33]=3)=[CH:36][CH:37]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: Nc1ccc(-c2cnco2)cc1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2cnco2)cc1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 4-(oxazol-5-yl)aniline in step 1.
Reaction SMILES: [BH3-]C#N.[Na+].[CH2:5]([O:7][CH:8]([O:10][C:11]1[CH:19]=[CH:18][C:14]2[O:15][CH2:16][O:17][C:13]=2[C:12]=1[CH:20]=O)[CH3:9])[CH3:6].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(O)(=O)C>CC#N>[CH2:5]([O:7][CH:8]([O:10][C:11]1[CH:19]=[CH:18][C:14]2[O:15][CH2:16][O:17][C:13]=2[C:12]=1[CH2:20][N:26]1[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]1)[CH3:9])[CH3:6]
Reactant: CCOC(C)Oc1ccc2c(c1C=O)OCO2
Reactant: CN1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(C)Oc1ccc2c(c1CN1CCN(C)CC1)OCO2
Reaction time: 3 h
Yield: 74 %

Procedure:
NaCNBH3 (6.4 g, 101.8 mmol) was added to a stirred solution of 5-(1-ethoxyethoxy)-4-formyl-1,3-benzodioxole (16.0 g, 67.2 mmol) and 1-methylpiperazine (20.2 g, 201.7 mmol) in CH3CN (150 ml). Acetic acid (10 ml) was added dropwise to the solution in one hour at room temperature, to keep the pH neutral (pH=7). After 3 hours of additional stirring, most of the CH3CN was evaporated in vacuo. Aqueous NaOH (2N, 300 ml) was added and the resulting mixture was extracted with diethyl ether (3 times). The combined ether extracts were washed with an aqueous solution of Na2CO3, dried over Na2SO4, filtered and evaporated to yield 26 g of a crude oil. This oil was purified by flash chromatography (eluent gradient; dichloromethane/methanol/25% aqueous ammonia=95/4.5/0.5 to 85/14/1 (v/v) to give 5-(1-ethoxyethoxy)-4-(4-methyl-piperazinylmethyl)-1,3-benzodioxole (16.0 g, 74% yield, compound No. 4) as a colorless oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:23]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[C:14]([C:24]#[N:25])=[C:13]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:12]=1.[H-].[Na+].C1C[O:37]CC1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:23]2[C:22](=[O:37])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[C:14]([C:24]#[N:25])=[C:13]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:12]=1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccc3ccccc3c2)c2c1-c1ccccc1C2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccc3ccccc3c2)c2c1-c1ccccc1C2=O
Temperature: 2.5 °C

Procedure:
A solution of 1-(naphthalen-2-yl)-3-(piperidin-1-yl)-9H-fluorene-4-carbonitrile (400 mg) in THF was added sodium hydride (39 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Yellow solid; mp 166-167° C.; ESIMS 415 (M++1); IR (KBr) 2218 (CN), 1712 cm−1 (CO); HRMS calcd. for C9H22N2O 414.1732. Found 414.1735.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4](=[N:6][OH:7])[CH3:5].F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1>CN(C=O)C.[Cl-].[Na+].O>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([O:7][N:6]=[C:4]([CH3:5])[CH3:3])=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: CC(C)=NO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=NOc1ccc([N+](=O)[O-])cc1
Reaction time: 0.75 h
Yield: 99.7 %

Procedure:
To a 0° C. slurry of sodium hydroxide (82 g, 2 mol) in DMF (1.5 L) was added acetone oxime (125 g, 1.7 mol). After stirring 45 min, 1-fluoro-4-nitrobenzene (218 g, 1.55 mol) was added over 45 min. After stirring at room temperature for 2.5 h, the reaction was poured into cold brine (4.5 L). The mixture was stirred at 0° C. for 2 h. The solid was collected by filtration, washed with water (4×1.5 L) and dried to provide 300 g (99%) of 2-propanone O-(4-nitrophenyl)oxime.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH3:6].II.[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14].Cl>CCOCC>[OH:9][C:10]1[CH:11]=[C:12]([CH:13]([OH:14])[CH2:3][CH2:4][CH2:5][CH3:6])[CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1cccc(O)c1
Reactant: CCCCBr
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CCCCC(O)c1cccc(O)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 221.9 %

Procedure:
A dried 1 L 3-neck flask equipped with a N2 inlet, reflux condenser, mechanical stirrer and a 500 ml drppping funnel was charged with 24.3 g (1.0 mol) of magnesium and 50 ml of anhydrous ether. To this was added 15 g (0.11 mol) of 1-bromobutane (Aldrich 23,988-7) and one crystal of iodine. The dropping funnel was charged with 122 g (0.89 mol) of 1-bromobutane and 100 ml. of anhydrous ether. After the contents of the reaction flask began to reflux, the flask was cooled with a water/ice bath and the 1-bromobutane solution was added at such a rate as to maintain a gentle reflux. After the addition was complete the reaction mixture was refluxed for one-half hour, then cooled to 0° C. in an ice/water bath. The dropping funnel was then charged with 38.0 g (0.311 mol) of 3-hydroxybenzaldehyde (Aldrich H 1,980-8) and 250 ml of anhydrous ether. This slurry was added over a 1 hour period. After the addition the reaction mixture was allowed to warm up to room temperature and was stirred overnight. The reaction mixture was neutralized with 900 ml of 5% aqueous HCl. The reaction mixture was extracted with 2×500 ml of ethyl acetate, the organic extracts combined, washed with 1L of water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate to yield 44.0 g (79%) of 1-(3-hydroxyphenyl)-1-pentanol, m.p. 120°-122° C.
Reaction SMILES: [CH2:1]([N:4]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]2[C@@H:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH2:21][N:20]([C@@H:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]3[CH2:36][C:37]([O:39]CC3C=CC=CC=3)=[O:38])[CH2:19]2)[CH2:13][CH2:12]1)[C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].[H][H]>CO.[Pd]>[CH2:1]([N:4]([CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][C@@H:18]2[C@@H:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH2:21][N:20]([C@@H:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]3[CH2:36][C:37]([OH:39])=[O:38])[CH2:19]2)[CH2:15][CH2:16]1)[C:5]1[N:6]=[CH:7][CH:8]=[CH:9][N:10]=1)[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: CCCN(c1ncccn1)C1CCN(C[C@H]2CN([C@@H]3CCCCC3CC(=O)OCc3ccccc3)C[C@@H]2c2cccc(F)c2)CC1
Agent: [Pd]
Solvent: CO
Product: CCCN(c1ncccn1)C1CCN(C[C@H]2CN([C@@H]3CCCCC3CC(=O)O)C[C@@H]2c2cccc(F)c2)CC1
Yield: 85.8 %

Procedure:
A solution of 2-(R)-(3-(S)-((4-(N-(prop-1-yl)-N-(pyrimid-2-yl)amino)-piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)cyclohexylacetic acid, benzyl ester (80 mg, 0.13 mmol) from Example 25 Step A, in 3.0 mL of MeOH was hydrogenated using 10% palladium on carbon (20 mg, 0.026 mmol) under one atmosphere of hydrogen gas. After TLC indicated the absence of the starting benzyl ester, the reaction was filtered through a 0.45 micron nylon membrane polypropylene filter and concentrated under reduced pressure to give 60 mg (80%) of the title compound as a white solid. HPLC (Zorbax SB-C8 column, 4.6 mm×7.5 cm, Gradient: 90 H2O:10 CH3CN to 0 H2O:100 CH3CN over 7.5 minutes then hold at 100 CH3CN:0 H2O for 45 seconds, 2.25 mL/min, 220 nm): Retention Time: 3.4 minutes. ESI-MS: 538.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 0.89-0.92 (t, J=7.4 Hz, 3H), 1.20-3.42 (25H), 3.87 (1H), 4.59 (1H), 6.42-6.43 (t, J=4.8 Hz, 1H), 6.91-6.95 (t, J=6.4 Hz, 1H), 7.03-7.09 (m, 2H), 7.24-7.31 (m, 1H), 8.24-8.25 (d, J=4.6 Hz, 2H).
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:10]([O-:13])(=[S:12])[CH3:11].[K+]>CN(C=O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2]([S:12][C:10](=[O:13])[CH3:11])([CH3:9])[CH3:8])[CH3:7]
Reactant: CC([O-])=S
Reactant: CCOC(=O)C(C)(C)Br
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)SC(C)=O
Reaction time: 16 h
Yield: 72.3 %

Procedure:
To a solution of ethyl α-bromoisobutyrate (62 g, 0.32 mol) in DMF (500 mL) at room temperature is added potassium thioacetate (72 g, 0.63 mol). The reaction is stirred for 16 h and then concentrated under reduced pressure. The residue is diluted with a 2M aqueous hydrochloric acid solution (500 mL) and extracted with ethyl acetate (3×500 mL). The organic fractions are combined, washed with brine (300 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with heptanes/dichloromethane provides 44 g of 2-acetylsulfanyl-2-methyl-propionic acid ethyl ester. Yield: 73%; m/z 191 [M+H]; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.18-1.30 (3 H, m), 1.57 (6 H, s), 2.27 (3 H, s), 4.19 (2 H, q, J=7.16 Hz)
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([N:15]1[C:24](=[O:25])[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:17])([CH3:14])[CH3:13]>C(Cl)Cl>[CH:12]([N:15]1[C:24](=[O:25])[C:23]2[C:18](=[N+:19]([O-:9])[CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:17])([CH3:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)N1C(=O)c2cccnc2C1=O
Solvent: ClCCl
Product: CC(C)N1C(=O)c2ccc[n+]([O-])c2C1=O
Reaction time: 2 h

Procedure:
79.7 g of 55% strength 3-chloroperbenzoic acid are added to 22 g of N-isopropylpyridine-2,3-dicarboximide in 100 ml of methylene chloride in the course of 2 hours while refluxing and stirring, and stirring is continued for a further 2 hours. The reaction mixture is extracted three times with 10% strength sodium carbonate solution and then with water and saturated sodium chloride solution, dried, and evaporated down under reduced pressure. The residue is stirred with methyl tert-butyl ether, 11.2 g of the title compound of melting point 138°-142° C. being obtained.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][C:38]([F:41])([F:40])[F:39])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[F:41][C:38]([F:39])([F:40])[CH2:37][NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)NCC(F)(F)F)c1
Product: O=C(Nc1cccc(S(=O)(=O)NCC(F)(F)F)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-(2,2,2-trifluoroethyl)-benzenesulfonamide [synthesis: see part aniline derivatives] according to general procedure II. Yellow solid. MS (ISP) 592.0 [(M−H)−]; mp 257° C.
Reaction SMILES: [CH2:1]([O:5][N:6]=[C:7]([C:13](=O)[CH2:14]Cl)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][CH2:3][CH3:4].[NH2:17][C:18]([NH2:20])=[S:19].C([O-])(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[NH2:20][C:18]1[S:19][CH:14]=[C:13]([C:7](=[N:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:17]=1
Reactant: CCCCON=C(C(=O)CCl)C(=O)OCC
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCON=C(C(=O)OCC)c1csc(N)n1
Reaction time: 0.33 h
Yield: 63.8 %

Procedure:
A solution of ethyl 2-n-butoxyimino-4-chloro-3-oxobutyrate (syn isomer, 52.1 g.), thiourea (15.9 g.), sodium acetate 3 hydrate (18.4 g.), water (130 ml.) and ethanol (180 ml.) was stirred at 40° C. for 1.25 hours. The resultant solution was adjusted to pH 6.5 with an aqueous solution of sodium carbonate under ice cooling, and stirred for 20 minutes under ice cooling. The precipitates were collected by filtration, and washed with water and diisopropyl ether in turn to give ethyl 2-(2-aminothiazol-4-yl)-2-n-butoxyiminoacetate (syn isomer, 36.1 g.), mp 126° to 128° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.ClC1C=CC=C(C(OO)=[O:20])C=1.C1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[N+:3]([O-:20])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1cc2ccccc2cn1
Solvent: c1ccccc1
Solvent: ClCCl
Product: [O-][n+]1cc2ccccc2cc1Cl
Temperature: 25 °C
Reaction time: 60 h
Yield: 32.6 %

Procedure:
A mixture of 3-chloroisoquinoline (18.23 g), m-chloroperbenzoic acid (36.46 g) and benzene (180 ml) was stirred at ambient temperature for a period of 2.5 days. The mixture was diluted with dichloromethane and the resultant solution was washed several times with a aqueous 5% sodium bicarbonate solution and finally with water. The organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated to give a solid residue. The solid was recrystallised from ethyl acetate to give 3-chloroisoquinoline-2-oxide (6.53 g) as colourless crystals mp 147°-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([C:15]([N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH:27]4[CH2:29][CH2:28]4)[CH2:19][CH2:18]3)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5]([Cl:30])=[CH:4][C:3]=1[CH2:31][CH2:32][C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:69][CH2:70][C:71]([OH:73])=[O:72]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([C:15]([N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH:27]4[CH2:28][CH2:29]4)[CH2:19][CH2:18]3)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5]([Cl:30])=[CH:4][C:3]=1[CH2:31][CH2:32][C:33]([NH:69][CH2:70][C:71]([OH:73])=[O:72])=[O:34]
Reactant: O=C(O)CCc1cc(Cl)c(Oc2ncccc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Reactant: NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)CCc1cc(Cl)c(Oc2ncccc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Reaction time: 0.17 h
Yield: 16.1 %

Procedure:
To a solution of 3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-2-yloxy]-phenyl}-propionic acid (50 mg, 0.098 mmol, 1.0 equiv; Example 173) in anhydrous DMF (1 mL) was added HATU (44.5 mg, 0.12 mmol, 1.2 equiv; [CAS RN 148893-10-1]) and N-ethyldiisopropylamine (25 mg, 33 μL, 0.20 mmol, 2.0 equiv; [CAS RN 7087-68-5]). After stirring the reaction mixture for 10 min, glycine (8.1 mg, 0.11 mmol, 1.1 equiv; [CAS RN 56-40-6]) was added and stirring continued at rt over night. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 9 mg (16%) of the title compound as a light yellow oil. MS (ISP): 569.2 [M+H]+.