Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[O:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1>CCOC(C)=O>[I:8][C:5]1[CH:6]=[CH:7][C:2]([NH:17][CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)=[N:3][CH:4]=1
Reactant: Clc1ccc(I)cn1
Reactant: NCCN1CCOCC1
Solvent: CCOC(C)=O
Product: Ic1ccc(NCCN2CCOCC2)nc1
Reaction time: 0.5 h

Procedure:
2-Chloro-5-iodopyridine (2.21 g, 9.25 mmol) was dissolved in 2-morpholinoethanamine (10 mL) and placed in the microwave for 30 min. at about 180° C. The reaction mixture was diluted with 100 mL EtOAc, washed with 50 mL saturated, aqueous NaHCO3, and dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained. MS (ES+): 334 (M+H)+.
Reaction SMILES: NN.C1(=O)[N:7]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:19][CH:18]3[CH:13]([CH2:14][C:15]4[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=4[CH2:17]3)[CH2:12]2)C(=O)C2=CC=CC=C12>C(O)C>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:19][CH:18]2[CH:13]([CH2:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[CH2:17]2)[CH2:12]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CC2Cc3ccccc3CC2C1
Agent: NN
Solvent: CCO
Product: NCCCN1CC2Cc3ccccc3CC2C1
Temperature: 25 °C

Procedure:
Hydrazine (42 mg, 1.31 mmol) was added to a solution of 2-(3-Phthalimido-n-prop-1-yl)-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole (200 mg, 0.65 mmol) in 5 mL of ethanol, and the mixture was refluxed for 20 hours, over which time a white solid had precipitated. The mixture was cooled to room temperature, the solid was removed by filtration, and the filtrate was concentrated in-vacuo. The residue was suspended in chloroform, and the solids were removed by filtration. The filtrate was concentrated in-vacuo to 90 mg of a yellow oil as product. NMR (300 MHz, CDCl3) δ 7.16-7.08 (m, 4H), 3.39-3.32 (m, 2H), 3.04-2.98 (m, 6H), 2.80-2.61 (m, 4H), 2.08-2.05 (m, 2H), 1.90-1.79 (m, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:19][C:20]1[CH:25]=[C:24](F)[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28]>CN(C=O)C>[F:19][C:20]1[CH:25]=[C:24]([CH:4]([C:3]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28]
Reactant: CCOC(=O)CC(=O)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 7.3 %

Procedure:
Sodium hydride (17.8 g, 445 mmol) was added portionwise to a solution of benzyl ethyl malonate (98.9, 445 mmol) in dry DMF (280 ml) and stirred for 10 minutes. Cooled to 10° C. over 30 minutes. 2,4-difluoro-1-nitrobenzene (48.9 ml, 445 mmol) was added and stirred at room temperature for 16 hours. The reaction mixture was quenched with 2N hydrochloric acid (150 ml) to pH 3-4 then extracted ×2 with ether. The combined organics washed with 2× water and brine, dried over magnesium sulphate and evaporated to a yellow oil. Purified by chromatography on silica gel eluting with 5% ethyl acetate in hexane to give the title compound as a yellow oil (11.66, 32.3 mmol). LC/MS: Rt=3.39, [MH]− 360.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:14]2[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:14]2[CH2:15][NH:16][CH2:17]2)[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(=C(c2cc(F)cc(F)c2)C(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=C1CNC1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 210 mg (0.623 mmol) of tert-butyl 3-[1-(3,5-difluorophenyl)-2,2-dimethylpropylidene]azetidine-1-carboxylate in 1 mL of CH2Cl2, was added 1.5 mL of TFA followed by stirring for 1 h at rt. The reaction mixture was concentrated and washed with ether to afford the title compound as white solid; Mass Spectrum: m/e=238 (M+1).
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.S(=O)(=O)(O)O.Cl[C:53]1[N:58]=[C:57]([C:59]2[CH:60]=[N:61][CH:62]=[C:63]([Cl:65])[CH:64]=2)[C:56]2[N:66]([CH2:69][C@H:70]3[CH2:75][CH2:74][C@H:73]([CH3:76])[CH2:72][CH2:71]3)[CH:67]=[N:68][C:55]=2[CH:54]=1.[CH3:77][N:78](C)C(=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[C-]#N.[Zn+2].[C-]#N.[Zn]>[Cl:65][C:63]1[CH:64]=[C:59]([C:57]2[C:56]3[N:66]([CH2:69][C@H:70]4[CH2:71][CH2:72][C@H:73]([CH3:76])[CH2:74][CH2:75]4)[CH:67]=[N:68][C:55]=3[CH:54]=[C:53]([C:77]#[N:78])[N:58]=2)[CH:60]=[N:61][CH:62]=1
Reactant: CC(=O)N(C)C
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(Cl)nc(-c4cncc(Cl)c4)c32)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Product: C[C@H]1CC[C@H](Cn2cnc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 80 °C

Procedure:
In an oven-dried, nitrogen cooled flask were placed palladium(II) acetate (438 mg, 1.95 mmol) and (R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (1.22 g, 1.95 mmol). N,N-dimethylacetamide (98 mL) was added, and the flask was degassed for three minutes with nitrogen (sparge). Sulfuric acid (0.104 mL, 1.95 mmol) was added, and the flask was degassed for three minutes with nitrogen (sparge). The flask was sealed and heated to 80° C. for 30 minutes. The mixture was cooled to room temperature and added to a separate nitrogen purged flask containing 6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (7.33 g, 19.5 mmol), zinc cyanide (1.15 g, 9.77 mmol), and zinc (128 mg, 1.95 mmol). The flask was purged with nitrogen for five minutes, then sealed and heated to 100° C. for 3.5 hours. The reaction mixture was cooled to room temperature, filtered, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C20H20ClN5 [M+H]+ 366. found 366.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([CH3:10])[C:7](O)=[O:8]>>[CH3:5][C:6]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([CH3:10])[C:7]([Cl:3])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C(=O)O)N1C(=O)c2ccccc2C1=O
Product: CC(C)(C(=O)Cl)N1C(=O)c2ccccc2C1=O
Yield: 98.3 %

Procedure:
Thionyl chloride (750 ml, 10.28 mol) was added to 2-methyl-2-phthalimidopropanoic acid (385 g, 1.65 mol) and the mixture refluxed under nitrogen for 3 hours. Excess thionyl chloride was removed under reduced pressure to yield a solid. The solid was washed with diethyl ether (2×250 ml) to yield the title compound as a white crystalline solid (408.2 g, 98%).
Reaction SMILES: [ClH:1].S1[CH2:6][CH:5]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10]2)C2C=CC=CC1=2.S(OCCCC1[C:42]2[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:43]=2[O:44][CH:45]=1)(C1C=CC(C)=CC=1)(=O)=O.COC1C(N2CCNCC2)=NC=CC=1>>[ClH:1].[F:50][C:48]1[CH:49]=[CH:42][C:43]2[O:44][CH:45]=[C:6]([CH2:5][CH2:7][CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15]4[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:11][CH2:10]3)[C:46]=2[CH:47]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2coc3ccc(F)cc23)cc1
Reactant: COc1cccnc1N1CCN(CCC2CSc3ccccc32)CC1
Agent: COc1cccnc1N1CCNCC1
Agent: Cl
Product: COc1cccnc1N1CCN(CCCc2coc3ccc(F)cc23)CC1

Procedure:
The title compound was prepared (0.93 g, 74%, mp 182°-184° C.) in a manner analogous to the preparation of 1-[2-(2,3-dihydrobenzo[b]thien-3-yl)ethyl]-4-(3-methoxy-2-pyridinyl)piperazine hydrochloride (Example 17) by the reaction of 5-fluoro-3-benzo[b]furanpropanol tosylate with 1-(3-methoxy-2-pyridinyl)piperazine.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][S:4][N:3]=1.C1(=O)[N:11](CCCBr)[C:10](=O)[C:9]2=CC=CC=[C:8]12>>[NH2:11][CH2:10][CH2:9][CH2:8][NH:1][C:2]1[N:6]=[CH:5][S:4][N:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Nc1ncsn1
Product: NCCCNc1ncsn1

Procedure:
Reaction of 3-amino-1,2,4-thiadiazole with 3-phthalimidopropyl bromide and hydrazinolysis of the product gives 3-(3-aminopropylamino)-1,2,4-thiadiazole and from this intermediate N-cyano-N'-methyl-N"-[3-(3-(1,2,4-thiadiazolyl)amino)propyl]-guanidine is prepared.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)(C)(C)C.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>ClCCl>[OH:33][C:31]([C:30]([F:35])([F:34])[F:29])=[O:32].[CH2:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH2:7][C:6]([OH:28])=[O:5])=[CH:16][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)CN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Reaction time: 4 h
Yield: 94 %

Procedure:
[(S)-2-(4-Benzyl-phenoxymethyl)-pyrrolidin-1-yl]-acetic acid tert-butyl ester (30 mg, 0.079 mmol) was added to a solution of trifluoroacetic acid and dichloromethane (1:3, 4 mL). The reaction was run at room temperature for 4 h. The Mixture was concentrated to dryness and dried in a vacuum over at 50° C. The residue was triturated with diethyl ether and dried to obtain the title product (24.1 mg, 0.074 mmol, 94% yield) was confirmed by LCMS: m/z 325.41 (free amine), found 325 (M); 1H NMR (400 MHz, DMSO-d6) δ 1.78-1.83 (m, 1H), 1.96-2.05 (m, 2H), 2.19-2.25 (m, 1H), 3.31 (s, 1H), 3.68 (s, 1H), 3.88 (s, 2H), 3.98 (s, 1H), 4.18-4.34 (m, 4H), 6.88-6.90 (d, J=8.8, 2H), 7.17-7.21 (m, 5H), 7.26-7.29 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[O:14].C(CN)O.Cl>O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:18]2[NH:12][C:13](=[O:14])[NH:15][C:16]2=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CNC(=O)N1
Agent: Cl
Solvent: NCCO
Solvent: O
Product: O=C1NC(=O)C(=Cc2ccc([N+](=O)[O-])cc2)N1

Procedure:
A mixture of p-nitrobenzaldehyde (2.510 g.) and hydantoin (1.671 g., 1 molar ratio) in water (15 ml) was heated to 70°. Monoethanolamine (1.53 g., 1.5 molar ratio) was added and the mixture was stirred magnetically and heated at 90°-92° (bath temperature) for 4 1/4 hours. The mixture was cooled in an ice-bath and acidified with HCl. After refrigeration overnight the mixture was filtered, washed with water and dried at 55°/10 mm. The title compound was obtained as a brown solid (3.258 g.), m.p. 252°-253° decomp.
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[Br:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[C:33]([Cl:39])[CH:32]=1>>[Br:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[C:2]([CH3:4])[CH3:3])=[C:33]([Cl:39])[CH:32]=1
Reactant: O=Cc1ccc(Br)cc1Cl
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Product: CC(C)=Cc1ccc(Br)cc1Cl

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 23 (23d) using isopropyltriphenylphosphonium iodide (5.4 g, 12.6 mmol), potassium t-butoxide (1.5 g, 13.5 mmol) and 4-bromo-2-chlorobenzaldehyde (2.0 g, 9.0 mmol) that was obtained in Example 24 (24f). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 6:94) as the eluent to afford the title compound (2.1 g) in a yield of 94% as a colourless oily product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[CH2:22][NH:23][C:24]3[N:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][N:25]=3)=[O:15])=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[CH2:22][NH:23][C:24]3[N:25]=[CH:26][C:27]([CH:30]([OH:32])[CH3:31])=[CH:28][N:29]=3)=[O:15])=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1cnc(NC[C@@H]2CCCCN2C(=O)c2nn(C)cc2-c2ccc(F)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)c1cnc(NC[C@@H]2CCCCN2C(=O)c2nn(C)cc2-c2ccc(F)cc2)nc1
Reaction time: 8 h

Procedure:
1-{2-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-pyrimidin-5-yl}-ethanone (0.2 g) was dissolved in methanol 20 ml) and sodium borohydride (0.4 g) added. The reaction was stirred overnight, water was added and stirring continued for 30 min. The reaction mixture was extracted with ethyl acetate (x3), the organic extracts combined, dried (MgSO4) and solvent removed at reduced pressure to give the title compound as a colourless foam.
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([C:45]2[CH:50]=[CH:49][C:48]([NH:51][C:52]3[N:57]=[C:56]([CH2:58][CH2:59][C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=4[CH:66]([CH3:70])[C:67]([O-])=[O:68])[C:55]([C:71]([F:74])([F:73])[F:72])=[CH:54][N:53]=3)=[CH:47][CH:46]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[Li+].C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[NH2:2][C:67](=[O:68])[CH:66]([C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=1[CH2:59][CH2:58][C:56]1[C:55]([C:71]([F:73])([F:74])[F:72])=[CH:54][N:53]=[C:52]([NH:51][C:48]2[CH:49]=[CH:50][C:45]([CH:42]3[CH2:43][CH2:44][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:40][CH2:41]3)=[CH:46][CH:47]=2)[N:57]=1)[CH3:70]
Reactant: On1nnc2ccccc21
Reactant: CC(C(=O)[O-])c1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-Hydroxybenzotriazole (21.1 mg, 0.156 mmol), EDCl (30.0 mg, 0.156 mmol) and N,N-diisopropylethylamine (54.5 μL, 0.313 mmol) were added to a solution of lithium 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)propanoate (I54) (0.086 g, 0.142 mmol) in dry THF (6 mL) and dry DMF (1 mL) under an atmosphere of nitrogen. Ammonium carbonate (54.6 mg, 0.569 mmol) was added in one portion to the stirred reaction mixture after 10 minutes. The reaction was left stirred at room temperature for 18 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (50 mL) then washed with saturated NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and dried over Na2SO4. After filtration the solvent was removed in vacuo to afford a pale yellow solid. The crude material was purified by column chromatography on silica gel (0-85% EtOAc in petroleum benzine 40-60° C.) to afford the title compound (I55) (65.2 mg, 77%) as a white foamy solid; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.51 (d, J=8.5 Hz, 2H), 7.47 (s, 1H), 7.40-7.36 (m, 1H), 7.30-7.17 (m, peaks obscured by CDCl3), 5.37 (s, 1H), 5.20 (s, 1H), 4.25 (b s, 2H), 4.01 (q, J=7.1 Hz, 1H), 3.17-3.02 (m, 4H), 2.80 (t, J=12.3 Hz, 2H), 2.64 (tt, J=12.3, 3.6 Hz, 1H), 1.83 (d, J=12.7 Hz, 2H), 1.67-1.59 (m, peaks obscured by water peak), 1.56 (d, J=7.2 Hz, 3H), 1.49 (s, 9H). LCMS Method C: rt 6.60 min; m/z 620 [M+Na]+, 598 [M+H]+, 542 [M-tButyl+2H]+, 498 [M-Boc+2H]+.
Reaction SMILES: CN(C)CCN(C)C.C([Li])CCC.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([SH:22])[CH:19]=[CH:20][CH:21]=1.CON(C)[C:26](=[O:35])[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>C1CCCCC1>[SH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[C:17]=1[C:26](=[O:35])[CH:27]=[CH:28][CH:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH2:34]1
Reactant: CON(C)C(=O)CCc1ccccc1
Reactant: COc1cccc(S)c1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCCCC1
Product: COc1cccc(S)c1C(=O)C=CC1C=CC=CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
To a solution of N,N,N′,N′-tetramethylethylenediamine (4.31 mL) in cyclohexane (50 ml) were added n-butyl lithium (2.46 mol/L n-hexane solution 12.2 mL) and 3-methoxythiophenol (2 g) successively under ice-cooling. The reaction mixture was stirred at room temperature overnight. To the reaction mixture was added N-methoxy-N-methyl-3-phenylpropionamide (2.76 g) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1-5/1) to give the title compound (1.2 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][C:16]1[C:17]([C:26]([F:29])([F:28])[F:27])=[N:18][N:19]([CH2:22][C:23](O)=[O:24])[C:20]=1[CH3:21].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:15][C:16]1[C:17]([C:26]([F:28])([F:27])[F:29])=[N:18][N:19]([CH2:22][C:23]([N:12]2[CH2:11][CH2:10][N:9]([C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:14][CH2:13]2)=[O:24])[C:20]=1[CH3:21]
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C)c(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)c1
Reaction time: 6 h

Procedure:
To 38 mg (0.20 mmol) of 1-(2,5-Dimethylphenyl)piperazine and 53 mg (0.22 mmol) of (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid in 1.6 mL of anhydrous dimethylformamide was added 62 mg (0.6 mmol) of triethylamine, followed by 84 mg (0.22 mmol) of O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU). After 6 hours, the reaction was partitioned between ethyl acetate and water, and the phases were separated. The aqueous phase was back-extracted once with ethyl acetate, and the combined ethyl acetate phases were washed once each with 0.5M pH=7 phosphate buffer, water, 1M NaOH, water, brine. The ethyl acetate phase was then dried over Na2SO4, filtered, and concentrated to a residue in vacuo. The residue was dissolved in a minimum volume of 5M HCl in isopropanol, and was precipitated by diluting the solution with ethyl acetate. The product was isolated by filtration to give a white solid: 1H NMR (DMSO-d6, 400 MHz) 7.07 (d 1H), 6.90 (s, 1H), 6.82 (d, 1H), 5.39 (s, 2H), 3.66 (m, 4H), 2.98 (m, 2H), 2.89 (m, 2H), 2.26 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H) ppm; MS (ES) M+H expected=415.1, found 415.1.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[C:9]([CH3:18])([CH3:17])[CH2:8][CH2:7]1.[C:20](Cl)(=[O:22])[CH3:21]>ClCCCl>[C:20]([C:13]1[C:12]([CH3:16])=[CH:11][C:10]2[C:9]([CH3:18])([CH3:17])[CH2:8][CH2:7][C:6]([CH3:19])([CH3:5])[C:15]=2[CH:14]=1)(=[O:22])[CH3:21]
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a suspension of aluminum chloride (0.96 g, 7.17 mmol) in 1 mL of 1,2-dichloroethane under argon at room temperature was added a solution of 1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalene 29 (1.2 g, 5.93 mmol) and acetyl chloride (0.51 g, 6.52 mmol) in 9 mL of 1,2-dichloroethane. The reaction mixture was stirred for 1 h and then was poured onto ice water and extracted with 40% ethyl acetate/hexane. The combined organic layers were washed with saturated aqueous NaHCO3 and brine. The solution was dried over anhydrous MgSO4, filtered through a plug of silica gel, and concentrated to afford a white solid 39 (1.45 g, 99%): m.p. 54°-57° C.; Rf 0.62 (10% ethyl acetate/hexane). The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.Cl>CCO.O1CCOCC1>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[S:3][C:4]3[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Clc1ccc2nc(Nc3ccc(Br)cc3)sc2c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a suspension of 2,6-dichlorobenzothiazole (2.52 g, 12.3 mmol) and 4-bromoaniline (2.12 g, 12.2 mmol) in EtOH (15 mL) was added 4 N HCl in dioxane (0.2 mL, 0.8 mmol). The reaction mixture was stirred at 140° C. in a microwave reactor for 1 h. After cooling to room temperature, the resulting suspension was filtered. The collected solid was washed with MeOH (10 mL), and dried in a 50° C. vacuum oven for 16 h to afford 3.28 g (80%) of the title compound as a white solid. HPLC/MS (method C): retention time=4.24 min, [M+H]+=339.0.
Reaction SMILES: O.[C:2](Cl)(=[O:7])[CH2:3][CH2:4][CH2:5][CH3:6].[CH3:9][NH:10][C:11](=[O:29])[CH2:12][NH:13][C:14](=[O:28])[C:15]1[C:20]([I:21])=[C:19]([NH2:22])[C:18]([I:23])=[C:17]([C:24]([OH:26])=[O:25])[C:16]=1[I:27].CNC(=O)[C@H](CC1C=CC=CC=1)NC(=O)C1C(I)=C(N)C(I)=C(C(O)=O)C=1I>CC(N(C)C)=O>[CH3:9][NH:10][C:11](=[O:29])[CH2:12][NH:13][C:14](=[O:28])[C:15]1[C:20]([I:21])=[C:19]([NH:22][C:2](=[O:7])[CH2:3][CH2:4][CH2:5][CH3:6])[C:18]([I:23])=[C:17]([C:24]([OH:26])=[O:25])[C:16]=1[I:27]
Reactant: CCCCC(=O)Cl
Reactant: CNC(=O)CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Agent: CNC(=O)[C@H](Cc1ccccc1)NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCCC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NCC(=O)NC)c1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under agitation and water cooling, 31.5 ml. of valeroyl chloride is added dropwise to 45.8 g. (0.073 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-glycine methylamide (IV a), m.p. 252°-253° C. (under decomposition), in 120 ml. of dimethylacetamide. After agitating the reaction mixture overnight at room temperature, the product is precipitated by adding water; then, the product is vacuum-filtered and purified by dissolving the corresponding sodium salt and separation of the free acid by the addition of a mineral acid.
Reaction SMILES: [NH2:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH:6]([CH2:7][OH:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[C:23]([N:31]=[C:32]=[S:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[C:23]([NH:31][C:32]([NH:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH:6]([CH2:7][OH:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1)=[S:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(N)(c2ccccc2F)C1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CO)C(NC(=S)NC(=O)c2ccccc2)(c2ccccc2F)C1
Temperature: 22 °C

Procedure:
To three separate reaction vessels, each containing racemic tert-butyl 3-amino-3-(2-fluorophenyl)-4-(hydroxymethyl)pyrrolidine-1-carboxylate (0.142 g, 4.58 mmol) and tetrahydrofuran (18 mL), is added benzoyl isothiocyanate (0.784 g, 4.80 mmol). The solutions are stirred at 22° C., and stirred for 15 hours. The solvent is removed under a stream of nitrogen, the residues combined, and concentrated to provide the crude title compound, which is used without further purification. ES/MS (m/e): 474 (M+H).