Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](C)[C:6]=1[CH3:12])C.[OH:16][CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH2:24]CC#N>>[OH:16][CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH2:24][CH2:15][C:14]1[NH:3][C:4](=[O:13])[C:5]2[C:6]([CH:12]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: N#CCCCN1CCC[C@@H]1CO
Product: O=c1[nH]c(CCCN2CCC[C@@H]2CO)cc2ccccc12
Yield: 16.8 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-diethyl-2,3-dimethylbenzamide (5.0136 g) and (R)-4-(2-hydroxymethylpyrrolidin-1-yl)butyronitrile (2.2 g), (R)-3-[3-(2-hydroxymethylpyrrolidin-1-yl)propyl]-2H-isoquinolin-1-one (627.3 mg) was obtained. 1N aqueous HCl solution (2.4 ml) was added thereto in an acetone solvent, and the precipitated crystals were collected by filtration to give (R)-3-[3-(2-hydroxymethylpyrrolidin-1-yl)propyl]-2-isoquinolin-1-one hydrochloride (555.3 mg).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.C[Al](C)C.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@@:25]([OH:51])([CH2:45][N:46]1[CH:50]=[N:49][CH:48]=[N:47]1)[C@H:26]([S:28][C@@H:29]1[CH2:34][O:33][C@@H:32]([C:35]2[CH:44]=[CH:43][C:38]([C:39](OC)=[O:40])=[CH:37][CH:36]=2)[O:31][CH2:30]1)[CH3:27]>>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@@:25]([OH:51])([CH2:45][N:46]1[CH:50]=[N:49][CH:48]=[N:47]1)[C@H:26]([S:28][C@@H:29]1[CH2:34][O:33][C@@H:32]([C:35]2[CH:36]=[CH:37][C:38]([C:39]([NH:8][C:7]3[CH:9]=[CH:10][C:4]([S:3][C:2]([F:11])([F:1])[F:12])=[CH:5][CH:6]=3)=[O:40])=[CH:43][CH:44]=2)[O:31][CH2:30]1)[CH3:27]
Reactant: Nc1ccc(SC(F)(F)F)cc1
Reactant: COC(=O)c1ccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)cc1
Agent: C[Al](C)C
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(SC(F)(F)F)cc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(4), a reaction was carried out using commercially available 4-(trifluoromethylthio)aniline (230 mg, 1.2 mmol), trimethylaluminium (1.1 ml, 1.07M n-hexane solution, 1.2 mmol) and methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoate (150 mg, 0.30 mmol), obtained in Example 12(1), and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to afford the title compound (184 mg, yield 93%) as a colorless oil which was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:14][CH2:15][CH2:16][CH2:17]Br.C([O-])([O-])=O.[K+].[K+].[Cl:25][C:26]1[CH:27]=[N:28][NH:29][CH:30]=1>CN(C)C=O>[Cl:25][C:26]1[CH:27]=[N:28][N:29]([CH2:14][CH2:15][CH2:16][CH2:17][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:8]=[CH:9][CH:10]=[CH:11][N:12]=3)[CH2:2][CH2:3]2)[CH:30]=1
Reactant: Clc1cn[nH]c1
Reactant: BrCCCCBr
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cnn(CCCCN2CCN(c3ncccn3)CC2)c1

Procedure:
To a mixture of 2- (1-piperazinyl)pyrimidine (32.8 g; 0.2 mol), 1,4-dibromobutane (47.5 g; 0.22 mol) and K2CO3 (69 g; 0.5 tool) in 400 ml of dimethylformamide is added 4 -chloropyrazole (20.5 g; 0.2 mol), and the mixture is held at the reflux for 17 hours. The reaction mixture is filtered hot and evaporated to dryness. The residue is dissolved in HCl, washed with CHCl3, rendered alkaline with dilute NaOH and extracted in basic medium with CHCl3. The organic phase is then dried and subsequently evaporated to dryness, and 61 g (95%) of 2-{4-[4-(4-chloro-1-pyrazolyl)butyl]-1-piperazinyl}pyrimidine are obtained.
Reaction SMILES: C=C[C@@H]1[C@@H]2C[C@H]([C@@H:11]([OH:22])[C:12]3C4C(=CC=CC=4)N=CC=3)N(CC2)C1.N1C=CC=CC=1.[CH3:29][NH:30][C:31]([C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:43]([C:45]3[N:46]=[CH:47][N:48]([C:50]([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[CH:49]=3)=[O:44])[CH:39]=2)[CH:34]=1)=[O:32].Cl.[O:70]1CC[CH2:72][CH2:71]1>C(OCC)(=O)C>[OH:44][C@@:43]([C:38]1[CH:37]=[CH:36][C:35]2[C:40](=[CH:41][CH:42]=[C:33]([C:31]([NH:30][CH3:29])=[O:32])[CH:34]=2)[CH:39]=1)([C:45]1[N:46]=[CH:47][N:48]([C:50]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:49]=1)[CH2:72][C:71]([O:22][CH2:11][CH3:12])=[O:70]
Reactant: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccccc12
Reactant: C1CCOC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@](O)(c1ccc2cc(C(=O)NC)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
Under argon atmosphere, 21.2 g (72 mmol, 1.25 equivalent) of (+)-cinchonine was added to 431 mL (0.23 mol) of the solution of ethyl bromozincacetate in tetrahydrofuran obtained in Example 43 at 0˜5° C. 18.6 mL (230 mmol, 4 equivalent) of pyridine was added dropwise at 0˜5° C. over 7 minutes. The mixture was stirred at 0˜5° C. for 20 minutes. A solution of 30 g (57.5 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide in 300 mL of THF was added dropwise at −42˜−40° C. over 30 minutes. The mixture was stirred at −45˜−40° C. for 1 hour. 430 mL of 1N hydrochloric acid was added dropwise, diluted with 430 mL of ethyl acetate, and the mixture was stirred at 20˜25° C. for 30 minutes. After the layers were separated, the organic layer was washed successively with 290 mL of 1N hydrochloric acid, 290 mL of water, 290 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 290 mL of an aqueous saturated sodium chloride solution. After washing and concentration under reduced pressure, to the concentration residue was added 90 mL of ethyl acetate, and this was warmed to 50° C. to dissolve it. The solution was stirred at 20˜25° C. for 1 hour. 90 mL of IPE was added, and the mixture was stirred at, 0˜5° C. for 2 hours. Crystals were filtered, and washed with 30 mL of IPE. After washing, vacuum drying (50° C.) to a constant weight afforded 29.2 g of ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate (yield 83%, enantiomer excess 93.5% ee).
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH3:3].[F:6][C:7]1[C:8]([CH2:17][CH2:18][CH3:19])=[C:9]([OH:16])[CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][CH3:15].FC(F)(F)S(O)(=O)=[O:23]>>[F:6][C:7]1[C:8]([CH2:17][CH2:18][CH3:19])=[C:9]([OH:16])[C:10]([CH2:1][CH2:2][CH3:3])=[CH:11][C:12]=1[C:13](=[O:23])[CH2:14][CH3:15]
Reactant: CCC(=O)O
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CCCc1ccc(O)c(CCC)c1F
Product: CCCc1cc(C(=O)CC)c(F)c(CCC)c1O

Procedure:
Propionic acid (9.07 g, 123 mmol) and 3-fluoro-2,4-dipropylphenol (9.60 g, 49.0 mmol) were mixed in trifluoromethanesulfonic acid (50 mL) as in Example 13, step 1. Purification by chramotography on silica gel using ethyl acetate:hexane (10:90) gave the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.C(O)C>[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: Nc1ccc(S)cc1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: Nc1ccc(Sc2ccnc3cc(C(F)(F)F)ccc23)cc1
Yield: 74.1 %

Procedure:
4-Chloro-7-trifluoromethylquinoline (0.043 moles, 10.0 g), 4-aminothiophenol (0.043 moles, 5.3 g) and 4-dimethylaminopyridine (0.04 moles, 4.9 g) were stirred in 250 ml ethanol for 3 days. The reaction mixture was filtered, concentrated, ethyl acetate added, washed with water and dried over sodium sulfate. The solution was concentrated and the product purified by HPLC over silica gel eluted with 25% ethyl acetate/hexane to yield 4-(4-aminophenylthio)-7-trifluoromethylquinoline 10.2 g, 74%. Mass Spec (FD) 320. Calculated for C16H11F3 N2S: C, 59.99; H, 3.46; N. 8.74. Found: C, 60.08; H, 3.49; N, 8.77.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[O:5][C:6]=1[CH3:7].C([O-])(=O)C.[NH4+:20]>>[CH3:1][C:2]1[CH:3]=[C:4]([OH:5])[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:20][C:6]=1[CH3:7]
Reactant: Cc1cc(C(=O)c2ccccc2)oc1C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: Cc1cc(O)c(-c2ccccc2)nc1C
Temperature: 250 °C
Reaction time: 10 h
Yield: 16079.1 %

Procedure:
(4,5-Dimethylfuran-2-yl)-phenyl-methanone (1 g) and ammonium acetate (910 mg) were placed in a sealed tube, and the mixture was stirred at 250° C. for 10 hr. The reaction solution was cooled to room temperature, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give 5,6-dimethyl-2-phenyl-pyridin-3-ol (160 g, yield 16%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1.[NH2:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:18]=2[N:19]=1.[C:25](N1C=CN=C1)(N1C=CN=C1)=S>C(Cl)CCl>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH3:25])[C:11]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:12][C:6]=2[CH:5]=1)=[O:13]
Reactant: Nc1nc2ccc(F)cc2s1
Reactant: CNc1ccc(C(=O)OC)cc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(F)cc3s1)n2C
Yield: 70.8 %

Procedure:
1-Methyl-2-(6-fluoro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (1.26 g) was prepared by following General Procedure D starting from 3-amino-4-methylamino-benzoic acid methyl ester (0.9 g), 2-amino-6-fluoro-benzo-thiazole (0.84 g), 1,1′-thiocarbonyldiimidazole (1.07 g), and EDC (1.15 g). LC/MS: m/z 358.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:24](COCC[Si](C)(C)C)[C:16]2[N:17]=[CH:18][C:19]3[N:20]([CH:21]=[N:22][CH:23]=3)[C:15]=2[CH:14]=1.C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:24][C:16]2[N:17]=[CH:18][C:19]3[N:20]([CH:21]=[N:22][CH:23]=3)[C:15]=2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c(ncc4cncn43)n1COCC[Si](C)(C)C)cn2C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cncn43)[nH]1)cn2C
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
7-(5-Methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.048 g, 0.11 mmol) in DMF (4 mL) was treated with ethylenediamine (0.22 mL, 3.3 mmol) and heated to about 85° C. for about 5 min. The solution was cooled and TBAF (1 M in THF, 0.11 mL, 0.11 mmol) was added. The solution was re-heated to about 85° C. for about 30 min. The mixture was cooled to ambient temperature and another portion of the TBAF (1 M in THF, 0.054 mL, 0.054 mmol) was added and heating was continued for about 1.5 h. The solution was cooled and the material was purified by preparative RP-HPLC (Table 2, Method 1). The product-containing fractions were concentrated to remove MeCN then basified with saturated aqueous NaHCO3 and extracted with EtOAc (2×10 mL). The combined organic solutions were dried over anhydrous MgSO4, filtered, and concentrated. Trituration of the solid with heptane (5 mL) then collection by filtration gave 7-(5-methoxy-1-methyl-1H-indol-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.028 g, 8%): LC/MS (Table 2, Method a) Rt=1.91 min; MS m/z: 318.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6 δ 12.18 (s, 1H), 8.77 (s, 1H), 8.59 (s, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.48 (d, J=2.3 Hz, 1H), 7.43 (d, J=8.9 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 6.92 (dd, J=8.90, 2.36 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[C:12]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)(=[O:16])/[CH:13]=[CH:14]/[CH3:15].[OH-].C([N+](CC)(CC)CC1C=CC=CC=1)C>>[CH:7](=[CH:15]/[CH:14]=[CH:13]/[C:12]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])[C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1
Reactant: C/C=C/C(=O)N1CCCCC1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [OH-]
Product: O=C(/C=C/C=Cc1ccc2c(c1)OCO2)N1CCCCC1

Procedure:
1 mol of piperonal is reacted with 1.1 mols of crotonic acid piperidide in the presence of 0.09 mol of triethylbenzylammonium hydroxide in 100 parts by volume of one of the solvents indicated in Table 3 which follows, under the conditions described in Example 1 to give piperonylidenecrotonic acid piperidide. The yields achieved are likewise indicated in Table 3.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[Cl:7][S:8](O)(=[O:10])=[O:9].N#N.S(Cl)(Cl)=O>O>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([S:8]([Cl:7])(=[O:10])=[O:9])=[N:3]1
Reactant: Cn1cccn1
Reactant: O=S(=O)(O)Cl
Agent: N#N
Solvent: O
Solvent: O=S(Cl)Cl
Product: Cn1ccc(S(=O)(=O)Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The N-methylpyrazole sulfonyl chloride was prepared by adding N-methylpyrazole to chilled (0° C.) chlorosulfonic acid. The reaction mixture was allowed to warm to room temperature and then heated to 100° C. overnight under a stream of N2. The reaction mixture was then cooled to room temperature and chilled to 0° C. To this solution was added thionyl chloride (2.5 eq.) and the reaction was stirred at room temperature for 30 min., then warmed to 70° C. for two hours. The reaction was cooled to room temperature and then chilled in an ice bath. Water and ice were slowly added to the reaction mixture to precipitate a white solid which was collected by filtration. The desired sulfonyl chloride was washed with cold water and hexane.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].[CH:19](=[C:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:20][CH2:21][CH3:22]>CCCCCCC.CCOC(C)=O>[CH:19](=[C:23]1[CH2:28][CH2:27][N:26]([CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]2[C:10]3[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:17])[CH2:25][CH2:24]1)[CH2:20][CH2:21][CH3:22]
Reactant: COc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Reactant: CCCC=C1CCNCC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCC=C1CCN(C[C@@H](C)CN2C(=O)COc3ccc(OC)cc32)CC1
Yield: 87.5 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (111MF36) (0.612 g, 1.69 mmol) and 4-butylidenepiperidine (0.212 g, 1.5 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF39) (0.489 g, 77%). 1H NMR (CDCl3) d 6.90 (d, J=8.4 Hz, 1H), 6.73 (d, J=2.8 Hz, 1H), 6.50 (dd, J=8.4 Hz, J=2.8 Hz, 1H), 5.11 (t, J=7.6 Hz, 1H), 4.54 (q, J=14.4 Hz, 2H), 3.97-3.94 (d, J=6.8 Hz, 2H), 3.78 (s, 3H), 2.48-2.41 (m, 2H), 2.33-2.23 (m, 5H), 2.20-2.13 (m, 4H), 1.96 (q, J=7.4 Hz, 2H), 1.40-1.29 (m, 2H), 0.91-0.86 (m, 6H); 13C NMR (CDCl3) d 165.3, 155.5, 139.8, 136.5, 129.8, 122.5, 117.2, 107.0, 103.4, 68.1, 63.8, 56.5, 56.0, 55.7, 45.5, 36.2, 29.3, 29.2, 28.4, 23.3, 16.9, 13.9; HPLC-MS; (ammonium acetate) [M+H]+=373.3.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26].CO>C1COCC1.C(OCC)C>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([F:21])[CH:23]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4cccc(F)c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2 mmol) in THF (30 ml) was added 3-Fluorobenzoyl chloride (0.49 ml, 4 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo leaving a solid which was slurried in diethyl ether (20 ml) and filtered to give 0.69 g (96%) of product as an off-white solid: mp 260-262° C.; 1H NMR (DMSO-d6) d 11.00 (s, 1H), 10.39 (s, 1H), 8.53 (d, J=8.3 Hz, 1H), 7.94-7.50 (m, 6H), 5.15 (dd, J=5.6 and 12.7 Hz, 1H), 2.97-2.83 (m, 1H), 2.66-2.49 (m, 2H), 2.14-2.06 (m, 1H); 13C NMR (DMSO-d6) d 172.36, 169.36, 167.66, 166.39, 163.62, 136.03, 131.31, 131.12, 130.99, 126.60, 123.19, 123.15, 119.44, 119.11, 118.89, 118.42, 114.31, 113.94, 48.91, 30.77, 21.83; Anal. Calcd. For C20H14FN3O5: C, 60.76; H, 3.57; N, 10.63. Found: C, 60.88; H, 3.38; N, 10.51.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@H:14]([NH:15][C:16]([O:18][CH3:19])=[O:17])[C@@H:13]([CH3:20])[CH2:12][N:11]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[N:27](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.O1CCOCC1.CCN(C(C)C)C(C)C.C(OC(ON1C(=O)CCC1=O)=O)(C)(C)C>>[NH2:27][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:21]=1[N:11]1[CH2:12][C@H:13]([CH3:20])[C@H:14]([NH:15][C:16](=[O:17])[O:18][CH3:19])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10]1
Reactant: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@H]1NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2N)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A mixture of di-tert-butyl (4-{(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-4-[(methoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)imidodicarbonate (1.41 g, 2.43 mmol) and 4.0 M HCl in dioxane (40.0 mL, 1.60E2 mmol) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the solid was dried under high vacuum for 10 min. DCM (25.0 mL) was added to the residue, followed by DIPEA (1.94 g, 15.0 mmol) and 1-[(tert-butoxycarbonyl)oxy]pyrrolidine-2,5-dione (579 mg, 2.69 mmol). The mixture was then stirred room temperature for 16 h, then concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aq. Na2CO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (40 g, eluting with 100% EtOAc, then 10% MeOH in DCM with 1% Et3N) to give the sub-title compound as a yellow foamy solid (701 mg, 76%). LCMS calc. for C18H30N5O4 (M+H)+: m/z=380.2. Found: 380.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[C:5]#N.[OH-:15].[K+].[OH2:17]>C(O)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[C:5]([OH:17])=[O:15]
Reactant: COc1cc(C(F)(F)F)ccc1C#N
Reactant: O
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(C(F)(F)F)ccc1C(=O)O
Yield: 95 %

Procedure:
To a solution of 2-methoxy-4-(trifluoromethyl)benzonitrile (Description 94; 19 g, 94.4 mmol) in ethanol (150 ml) was added a solution of potassium hydroxide (26.43 g; 472 mmol) in water (100 ml) and the resulting mixture heated at reflux overnight. The mixture was cooled and the ethanol removed by evaporation, the remaining aqueous phase was extracted with diethyl ether then acidified with 5N HCl. The acidic aqueous phase was then extracted with EtOAc (3×200 ml) and the combined organic layers washed with water, sat NaCl, dried over Na2SO4, filtered and evaporated to give the title compound (19.91 g, 95%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Br:18]Br.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Br:18][C:7]1[CH:6]=[C:5]([CH:8]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1]
Reactant: BrBr
Reactant: CCOC(=O)C(CC(C)C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(CC(C)C)c1ccc(O)c(Br)c1

Procedure:
To a stirred solution of ethyl 2-(4-hydroxyphenyl)-4-methylpentanoate E-9 (15 g, 63.55 mmol) in 100 ml of glacial acetic acid at 0° C., slowly added bromine (20.26 g, 64.14 mol) and stirred at same temperature for 2.5 h. After completion the reaction, the reaction mixture was poured into water and neutralized with saturated sodium carbonate solution and extracted with ethyl acetate (300 ml×3). The organic layer was washed with water, saturated sodium bicarbonate solution and brine. The organic layer was then distilled off to yield product ethyl 2-(3-bromo-4-hydroxyphenyl)-4-methylpentanoate. Yield: (16 g, 80%). 1H NMR (CDCl3): δ 7.20 (m 2H), 6.80 (d, J=7.9 Hz, 1H), 4.90 (bs, 1H), 4.15 (q, 2H), 3.60 (t, 1H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00 (m, 6H). Mass: (315, M+1,100%).
Reaction SMILES: [C:1]([CH:3]1[CH2:5][NH:4]1)#[N:2].[C:6]1([S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[C:6]1([S:12]([NH:15][C:16]([N:4]2[CH2:5][CH:3]2[C:1]#[N:2])=[O:17])(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: N#CC1CN1
Solvent: Cc1ccccc1
Product: N#CC1CN1C(=O)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
0.82 g. 2-Cyanoaziridine are dissolved in 8 ml. toluene and, while cooling with ice, 2 g. phenylsulphonyl isocyanate, dissolved in 10 ml. toluene, are added dropwise thereto. After further stirring the reaction mixture for 45 minutes at ambient temperature, the precipitated crystals are filtered off with suction, washed with diethyl ether and dried in a vacuum. There is thus obtained 1.45 g. (53% of theory) 1-(N-phenylsulphonyl-carbamoyl)2-cyanoaziridine in the form of white crystals; m.p. 103°-108° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6](Br)[CH:5]=1.[CH3:12][N:13]1[C:17]([CH3:18])=[C:16](B2OC(C)(C)C(C)(C)O2)[C:15]([CH3:28])=[N:14]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:16]1[C:15]([CH3:28])=[N:14][N:13]([CH3:12])[C:17]=1[CH3:18]
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1ccnc(Br)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccncc1-c1c(C)nn(C)c1C
Temperature: 80 °C
Yield: 40.2 %

Procedure:
To a microwave reactor tube was added 2-bromo-isonicotinic acid methyl ester (150 mg, 0.69 mmol), 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (197 mg, 0.83 mmol) and Pd2(PtBu3)2(14 mg, 0.028 mmol) and 1,4-dioxane (2 mL). The mixture was degassed and then 2M aqueous K3PO4 (0.46 mL, 1.4 mmol) was added. The mixture was heated in a microwave reactor at 80° C. for 1 hour. The cooled mixture was partitioned between CHCl3 and water. The organic layer was isolated and the product purified by SiO2 chromatography (0-15% MeOH in EtOAc) to give 2-(1,3,5-trimethyl-1H-pyrazol-4-yl-isonicotinic acid methyl ester (68 mg, 21%) as a yellow gum. MS(ESI) m/z 246 [M+H]+.