Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[N:14]1[C:18](=[S:19])[N:17]([CH3:20])[N:16]=[C:15]1[C:21]([F:24])([F:23])[F:22]>Cl.O.[Fe]>[NH2:11][C:9]1[CH:8]=[CH:7][C:6]([N:14]2[C:18](=[S:19])[N:17]([CH3:20])[N:16]=[C:15]2[C:21]([F:23])([F:22])[F:24])=[C:5]([Cl:4])[CH:10]=1
Reactant: Cn1nc(C(F)(F)F)n(-c2ccc([N+](=O)[O-])cc2Cl)c1=S
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cn1nc(C(F)(F)F)n(-c2ccc(N)cc2Cl)c1=S
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.1 %

Procedure:
To a stirred mixture of 18.8 g (0.0337 mole) of iron powder in 400 ml of concentrated hydrochloric acid, 20 ml of water, and 300 ml of ethanol was added slowly 28.5 g of 4-(2-chloro-4-nitrophenyl)-3-trifluoromethyl-4,5-dihydro-1-methyl-1,2,4-triazol-5(1H)-thione. This mixture was heated at reflux for eight hours and then was cooled to room temperature and stirred for approximately 18 hours. The mixture was heated to reflux and was filtered hot. The filter cake was washed with methylene chloride. The wash and the filtrate were combined, and the solvents were removed by evaporation under reduced pressure, leaving a residue. This residue was purified by column chromatography on silica gel, eluting with diethyl ether to yield 23.4 g of 4-(4-amino-2-chlorophenyl)-3-trifluoromethyl-4,5-dihydro-1-methyl-1,2,4-triazol-5(1H)-thione as a solid, mp 145°-147° C., Compound 94 of Table 1. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([NH2:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[N:6]=1.C(N(C(C)C)CC)(C)C.[Cl:24][C:25]1[N:30]=[CH:29][N:28]2[N:31]=[CH:32][C:33]([C:34](Cl)=[O:35])=[C:27]2[CH:26]=1>ClCCl>[CH3:1][C:2]1[S:3][C:4]([NH:14][C:34]([C:33]2[CH:32]=[N:31][N:28]3[CH:27]=[CH:26][C:25]([Cl:24])=[N:30][C:29]=23)=[O:35])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[N:6]=1
Reactant: O=C(Cl)c1cnn2cnc(Cl)cc12
Reactant: Cc1nc(-c2ccccc2C)c(N)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccccc2C)c(NC(=O)c2cnn3ccc(Cl)nc23)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To an ice-cooled solution of 2-methyl-4-o-tolyl-thiazol-5-ylamine (55.0 mg, 0.27 mmol, 1.0 equiv) and diisopropylethylamine (52.0 mg, 0.41 mmol, 1.5 equiv) in dichloromethane (10 mL) was added a solution of 5-chloropyrazolo[1,5-c]pyrimidine-3-carbonyl chloride (58.0 mg, 0.27 mmol, 1.0 equiv) in dichloromethane (5 mL). The reaction mixture was warmed to ambient temperature and stirred overnight. The mixture was washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under vacuum. Purification by flash column chromatography on silica gel (gradient: 0 to 3% methanol in dichloromethane) afforded 74.0 mg (73%) of 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2-methyl-4-o-tolyl-thiazol-5-yl)-amide as a solid. LCMS (ESI) m+H=384.0 (mono chlorinated isotope pattern); 1H NMR (400 MHz, CDCl3) δ: 9.73 (s, 1H), 8.70 (s, 1H), 8.63 (d, 1H), 7.44-7.30 (m, 4H), 6.93 (d, 1H), 2.72 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]([O:14]C(C)(C)C)=O)=[CH:10][C:5]=2[CH2:4][O:3]1.[C:19](O)([C:21](F)(F)F)=O.C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C=O)C>[C:2]1(=[O:1])[C:6]2[CH:7]=[C:8]3[C:9](=[CH:10][C:5]=2[CH2:4][O:3]1)[CH2:11][C:12](=[O:14])[CH2:21][CH2:19]3
Reactant: CC(C)(C)OC(=O)Cc1ccc2c(c1)COC2=O
Reactant: O=C(O)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C1CCc2cc3c(cc2C1)COC3=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a flask charged with tert-butyl (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetate (375 mg, 2.0 mmol) was added TFA (10 mL). The mixture was allowed to sit at RT for half an hour. LC at that point indicated complete cleavage of the tert-butyl group. The volatiles were removed under reduced pressure. The residue was pumped under high vacuum for 15 minutes before DCM (20 mL) was added to the flask, followed by addition of oxalyl chloride (0.22 mL, 2.5 mmol) and a drop of DMF. The mixture was stirred at RT for 1 hour, and then cooled to 0° C. with an ice bath. Aluminum chloride (780 mg, 5.9 mmol) was added into the reaction. After stirring the solution for 10 minutes, ethylene was bubbled through the reaction with a needle. TLC showed consumption of all material within 1 hour. The crude reaction was dumped into ice, and extracted with DCM (100 mL×3). The extractions were combined, washed with brine, dried over sodium sulfate, adsorbed onto silica gel, and purified by MPLC. The solvent was removed under reduced pressure to afford 7,8-dihydronaphtho[2,3-c]furan-1,6(3H,5H)-dione,
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][CH:16]([F:18])[F:17])(=O)=O)=CC=1.[Br:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:34])=[C:24]([CH:33]=1)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:34])=[C:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:12][CH2:13][O:14][CH2:15][CH:16]([F:18])[F:17])=[CH:28][CH:27]=2)[CH:33]=1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)COCCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reaction time: 24 h
Yield: 92.2 %

Procedure:
2-(2,2-difluoroethoxy)ethyl 4-methylbenzenesulfonate (3 g, 10.7 mmol), 4-(5-bromo-2-chlorobenzyl)phenol (3.8 g, 12.8 mmol), and Cs2CO3 (8.7 g, 26.8 mmol) were suspended in DMF (8 mL) at 50° C. The mixture was stirred for 24 hours at this temperature. The mixture was diluted with water and the aqueous layer was extracted with PE two times. The combined organic layers were washed with brine, concentrated and purified by flash chromatography (PE/EtOAc=50:1) to obtain a yellow solid (4 g, yield 91.9%), which was used in the next step without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([S:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13](O)=[O:14])([CH3:9])[CH3:8].Cl.CN.[N:26]1C=CC=C[CH:27]=1>C(Cl)Cl.CN(C=O)C>[CH:7]([S:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13]([NH:26][CH3:27])=[O:14])([CH3:9])[CH3:8]
Reactant: CC(C)Sc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: c1ccncc1
Agent: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1cc([N+](=O)[O-])ccc1SC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
Oxalyl chloride (1.75 mL, 19.6 mmol) was added dropwise to a suspension of 16A (2.41 g, 10 mmol) in DCM (20 mL) containing DMF (2 drops) at 0° C. The reaction mixture was warmed to rt and stirred overnight. The reaction mixture was concentrated in vacuo and coevaporated twice with toluene. The residue was dissolved in DCM (25 mL) and added portionwise to a solution of methylamine hydrochloride (2.03 g, 30.1 mmol) and pyridine (8.1 mL, 100 mmol) in DCM (25 mL) at 0° C. The reaction mixture was stirred overnight at rt. The reaction mixture was concentrated in vacuo and the residue was triturated with water to give 16B (2.08 g, 82%) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CO.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH:26]=O.[BH3-]C#N.[Na+]>C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:26][C:25]2[CH:28]=[CH:29][C:30]([Cl:31])=[C:23]([Cl:22])[CH:24]=2)[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Clc1nc(NCCNCc2ccc(Cl)c(Cl)c2)c2ncn(C3CCCC3)c2n1
Reaction time: 0.5 h

Procedure:
281 mg of the product obtained in Stage 1 of Example 7, 4 ml of methanol, 0.2 ml of 3,4-dichloro-benzaldehyde and 0.2 ml of acetic acid are mixed together and the reaction medium is agitated for 2 hours and 30 minutes, 0.1 g of NaBH3CN is added and agitation is carried out at ambient temperature for 1 hour. After evaporating the solvent, the residue is chromatographed on silica eluting with CH2Cl2/methanol/ammonium hydroxide (95/0.5/0.33) and 278.4 mg of expected product is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[O:12])[N:7]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C:34](N3CC[C@H](O)C3)=[O:35])=[CH:29][CH:28]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:43][O:44][C:45](=[O:50])[C@H:46]([CH2:48][OH:49])[NH2:47]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:18][CH:19]=2)=[O:12])[N:7]([C:27]2[CH:28]=[CH:29][C:30]([CH2:33][C:34]([NH:47][C@H:46]([C:45]([O:44][CH3:43])=[O:50])[CH2:48][OH:49])=[O:35])=[CH:31][CH:32]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](N)CO
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(CC(=O)N3CC[C@H](O)C3)cc2)n1
Agent: Cl
Product: COC(=O)[C@H](CO)NC(=O)Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Yield: 62 %

Procedure:
The title compound was prepared in the same manner as described for N-[3-tert-butyl-1-(4-{2-[(3S)-3-hydroxypyrrolidin-1-yl]-2-oxoethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea, replacing (S)-3-pyrrolidinol with L-serine methyl ester hydrochloride. The desired product was purified by MPLC (EtOAc/hexane/MeOH) and obtained as a solid (150 mg) in 62% yield. A sample of this material was purified further by HPLC and the TFA salt isolated from HPLC was neutralized to provide the title compound. 1H-NMR (DMSO-d6) δ 9.12 (s, 1H), 8.50 (d, J=7.9 Hz, 1H) 8.40 (m, 3H), 7.50-7.38 (m, 6H), 7.07 (d, J=8.7 Hz, 2H), 6.85 (m, 2H), 6.34 (s, 1H), 5.10 (t, J=5.4 Hz, 1H), 4.35 (m, 1H), 3.72 (m, 1H), 3.61 (m, 6H), 1.27 (s, 9H); MS LC-MS [M+H]+=587.2, RT=2.27 min.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[S:16][CH:17]=[C:18]([CH2:20][O:21]C(=O)C)[N:19]=2)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[S:16][CH:17]=[C:18]([CH2:20][OH:21])[N:19]=2)=[N:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OCc1csc(Nc2ccc(Oc3ccccc3)cn2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCc1csc(Nc2ccc(Oc3ccccc3)cn2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
Acetic acid 2-(5-phenoxy-pyridine-2-ylamino)-thiazole-4-ylmethyl ester (0.44 mmol) is suspended in ethanol (1.5 ml) and 1 M NaOH (1.5 ml) is added. The solution is stirred at RT for 3 h. The reaction solution is diluted with water. The precipitate is filtered, washed with water and dried 16 h in vacuo at 40° C. “A10” is obtained as a beige powder in yield of 88%; mp. 130.0-131.0° C.; HPLC (method C): 1.64 min; LC-MS (method A): 1.430 min, 300.15 (M+H+); 1H-NMR (DMSO-d6, 400 MHz): δ [ppm] 11.221 (s, 1H), 8.102 (d, 1H, J=2.8 Hz), 7.515 (dd, 1H, J=8.9 Hz, J=2.8 Hz), 7.389-7.349 (m, 2H), 7.125-7.083 (m, 2H), 6.996-6.972 (s, 2H), 6.687 (s, 1H), 5.105 (t, 1H, J=5.3 Hz), 4.442 (d, 2H, J=5.3 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][O:5][CH2:6][CH:7]=1.CN1CCOCC1.[N+:15]([C:18]1[CH:27]=[CH:26][C:21]([O:22][C:23](Cl)=[O:24])=[CH:20][CH:19]=1)([O-:17])=[O:16]>C(Cl)Cl>[N+:15]([C:18]1[CH:27]=[CH:26][C:21]([O:22][C:23]([O:1][CH2:2][C:3]2[CH2:4][O:5][CH2:6][CH:7]=2)=[O:24])=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: OCC1=CCOC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(OCC1=CCOC1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To 65 mg (0.65 mmol) of the compound from Example 336D in methylene chloride was added 0.079 mL of 4-methylmorpholine and 144 mg (0.715 mmol) of p-nitrophenoxycarbonylchloride. The mixture was stirred for 2 hours, diluted with solvent, washed with saturated brine, and the solvent removed. The residue was chromatographed on a silica gel column, eluting with 20% and 30% ethyl acetate in hexane. The solvent was removed and the product dried to afford 0.115 g of the title product.
Reaction SMILES: [CH2:1]([O:9][C:10](=[CH:13]N(C)C)[CH:11]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.Cl.[C@H:19]1([C:28]([NH2:30])=[NH:29])[CH2:24][CH2:23][C@H:22]([C:25]([NH2:27])=[NH:26])[CH2:21][CH2:20]1.[Na]>C(O)C>[CH2:1]([O:9][C:10]1[CH:11]=[N:26][C:25]([C@H:22]2[CH2:21][CH2:20][C@H:19]([C:28]3[N:30]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:13][N:29]=3)[CH2:24][CH2:23]2)=[N:27][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: N=C(N)[C@H]1CC[C@H](C(=N)N)CC1
Reactant: CCCCCCCCOC(C=O)=CN(C)C
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCOc1cnc([C@H]2CC[C@H](c3ncc(OCCCCCCCC)cn3)CC2)nc1

Procedure:
2.27 g (9.96 mmol) of 2-octyloxy-3-dimethylaminoacrolein in 5 ml of ethanol and 1.0 g (4.15 mmol) of transcyclohexane-1,4-diamidine dihydrochloride are added dropwise at room temperature to 230 mg (9.96 mmol) of sodium, dissolved in 6.3 ml of ethanol, and the mixture is refluxed for 120 hours. After cooling, the reaction solution is adjusted to pH 3 using semiconcentrated HC1 and evaporated, and 30 ml of water are added to the residue. The aqueous solution is extracted several times with dichloromethane. The organic phases are combined, dried over magnesium sulfate and evaporated in vacuo. Chromatographic purification on silica gel and crystallization from hexane gives 380 mg (18%) of the end product. The product has the following phase sequence:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:5]=[C:4]([CH:15]2[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]2)[CH:3]=1.[CH3:26][C:27]1[NH:31][N:30]=[C:29]([NH2:32])[CH:28]=1.CCN(C(C)C)C(C)C.[I-].[Na+]>CN(C=O)C>[NH:17]1[CH2:16][CH:15]([C:4]2[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[Cl:14])[N:7]=[C:2]([NH:32][C:29]3[CH:28]=[C:27]([CH3:26])[NH:31][N:30]=3)[CH:3]=2)[CH2:18]1
Reactant: Cc1cc(N)n[nH]1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(Cl)nc(-c3ccccc3Cl)n2)C1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(C3CNC3)nc(-c3ccccc3Cl)n2)n[nH]1
Temperature: 120 °C
Reaction time: 0.75 h
Yield: 12.7 %

Procedure:
A mixture of tert-butyl 3-(6-chloro-2-(2-chlorophenyl)pyrimidin-4-yl)azetidine-1-carboxylate (280 mg, 0.74 mmol), 5-methyl-1H-pyrazol-3-amine (86 mg, 0.88 mmol), DIPEA (124 mg, 0.96 mmol) and sodium iodide (122 mg, 0.81 mmol) in DMF (5 mL) was heated at 120° C. overnight. The reaction mixture was concentrated and the residue partitioned between EtOAc and brine. After a further extraction with EtOAc, the combined organics were dried (MgSO4), filtered and concentrated. Purification was achieved by column chromatography (eluting with petroleum ether/ethyl acetate, 1/1). The residue was dissolved in TFA (1 mL) and DCM (3 mL) and stirred for 45 min and then concentrated. Purification by Gilson preparatory HPLC gave the azetidine as a white solid (32 mg, 13%). MS (ES+) m/e=341. 1H NMR: (DMSO) 2.23 (3H, s), 4.05-4.28 (5H, m), 6.25 (1H, s), 7.11 (1H, s), 7.43-7.65 (3H, m), 7.78 (1H, d), 8.97 (1H, s), 9.61 (1H, s), 10.47 (1H, s).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=O)[C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14].Cl.[C:32]([O:36][C:37](=[O:44])[C@H:38]([CH2:40][CH:41]([CH3:43])[CH3:42])[NH2:39])([CH3:35])([CH3:34])[CH3:33].C([BH3-])#N.[Na+]>CO.O1CCCC1>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]([C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])=[O:14])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][NH:39][CH:38]([CH2:40][CH:41]([CH3:42])[CH3:43])[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:44]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCOC(=O)C(Cc1ccccc1C=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CC(NCc1ccccc1CC(C(=O)OCC[Si](C)(C)C)N1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
Dissolve 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(2-formyl-phenyl)-propionic acid, 2-trimethylsilanyl-ethyl ester (250 mg, 0.590 mmol) in methanol (15 mL) and treat with L-leucine tert-butyl ester hydrochloride (0.66 g, 3.0 mmol). Stir at room temperature for 2 hours with 3A molecular sieves, add sodium cyanoborohydride (0.6 mL of a 1.0M solution in tetrahydrofuran, 0.6 mmol), stir for 0.5 hours, add additional sodium cyanoborohydride (0.3 mL) and stir for 5 hours. Filter through filter aid, evaporate the solvent in vacuo and partition the residue between methylene chloride (100 mL) and saturated sodium hydrogen carbonate (40 mL). Dry (Na2SO4), evaporate the solvent in vacuo and purify by silica gel chromatography (5:1 hexane/ethyl acetate followed by 3:1 hexane/ethyl acetate) to give the title compound (221 mg, 63%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)[N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[NH2:24]>CCOC(C)=O>[CH3:31][O:30][C:26]1[CH:25]=[C:23]([NH:24][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[C:14](=[O:18])[CH2:13][CH2:12]4)[N:3]=2)[CH:22]=[C:21]([O:20][CH3:19])[C:27]=1[O:28][CH3:29]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C1CCc2cc(Oc3cncc(Cl)n3)ccc21
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3ccc4c(c3)CCC4=O)n2)cc(OC)c1OC
Yield: 20 %

Procedure:
Using Method EE with 2-chloro-6-(indanone-5-oxy)-pyrazine (200 mg, 0.77 mmol) and 3,4,5-trimethoxyaniline (169 mg, 0.92 mmol), and purification by column chromatography (AcOEt), the title compound was obtained (61 mg). Yield: 20%. 1H NMR (250 MHz, DMSO-d6) δ 2.68 (t, 2H, H3, J=5.6 Hz), 3.08 (t, 2H, H2, J=5.0 Hz), 3.39 (s, 6H, [CH3O]3+5), 3.55 (s, 3H, [CH3O]4), 6.77 (s, 2H, Harom2′+6′), 7.21 (dd, 1H, Harom 6, Jm=1.9 Hz, Jo=8.3 Hz), 7.40 (s, 1H, Harom 4), 7.68 (d, 1H, Harom 7, J=8.3 Hz), 7.84 (s, 1H, HPz 5), 8.02 (s, 1H, HPz 3), 9.62 (s, 1H, NH). m/z: 408.1 [(M+H)+, calcd for C22H21N3O5 407.1].
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH2:7][Si:8]([O:14][Si:15]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=2)([CH3:20])[C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:9])=[CH:4][CH:3]=1.Br[C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[C:36]#[N:37]>C1COCC1.CCOCC.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:36]([C:35]1[CH:34]=[C:33]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][Si:8]([O:14][Si:15]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:33]4[CH:40]=[CH:39][CH:38]=[C:35]([C:36]#[N:37])[CH:34]=4)=[CH:25][CH:24]=3)([CH3:20])[C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:9])=[CH:30][CH:31]=2)[CH:40]=[CH:39][CH:38]=1)#[N:37]
Reactant: CC(C)(C)[Si](C)(CCc1ccc(Br)cc1)O[Si](C)(CCc1ccc(Br)cc1)C(C)(C)C
Reactant: N#Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(CCc1ccc(-c2cccc(C#N)c2)cc1)O[Si](C)(CCc1ccc(-c2cccc(C#N)c2)cc1)C(C)(C)C
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
To a cooled (−78° C.) solution of 4-bromo-benzyl-(t-butyldimethylsilyl)-ether (2.73 g, 9 mmol) (reference example 10) in THF (40 mL) was added, dropwise, n-buLi (4.4 mL, 2.5M in hexanes). On complete addition, the resulting solution was stirred for 10 min then ZnCl2 (10 mL, 0.5M in THF) was added. The cold bath was removed and stirring continued for 10 min. To this solution was added a solution comprised of 3-bromo-benzonitrile (1.82 g, 10 mmol) (Aldrich), (Ph3P)4Pd (410 mg, 0.35 mmol) in THF (5 mL). The resulting mixture was heated to 65° C. and stirred at this temperature for 20 min. The reaction mixture was allowed to cool to room temperature then diluted with ether, washed, sequentially, with sat. ammonium chloride solution and brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography (eluting with 5% EtOAc in hexanes) to give 2.0 g of the title compound. 1H NMR (CDCl3) d 0.15 (s, 6H), 1.00 (s, 9H), 4.80 (s, 2H), 7.43 (d, J=8 Hz, 2H), 7.45-7.65 (m, 4H), 7.80 (m, 1H), 7.85 (bs, 1). MS (ion spray) m/z 324 (M+H)+.
Reaction SMILES: [I:1]I.[NH2:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([Cl:15])[CH:5]=1>C(O)C.S([O-])([O-])(=O)=O.[Ag+].[Ag+]>[NH2:3][C:4]1[C:14]([I:1])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([Cl:15])[CH:5]=1
Reactant: CCOC(=O)c1ccc(N)cc1Cl
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CCOC(=O)c1cc(I)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
An iodine solution in ethanol was admixed with silver(I) sulphate and ethyl 4-amino-2-chlorobenzoate and then stirred at room temperature for 45 min. The reaction mixture was filtered through a frit and the filtrate was concentrated under reduced pressure. The residue was slurried in EtOAc and admixed with dilute sodium hydrogencarbonate solution. Once everything had gone into solution, the aqueous phase was removed and sodium thiosulphate was dissolved therein. The organic phase was washed again with the aqueous phase, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated under reduced pressure. Column chromatography purification on silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 10% ethyl acetate to 33% ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.C([O:13][C:14]([C:16]1[S:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]2)=[N:19][N:20]=1)=O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:14]([C:16]2[S:17][C:18]([N:21]3[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[CH2:25][CH2:26]3)=[N:19][N:20]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(F)cc1
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Product: O=C(NCCc1ccc(F)cc1)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 2-(4-fluorophenyl)ethylamine in place of isoamylamine to react with 5[4-(2-trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid (0.098 g, yield 98%). 1H NMR (300 MHz, CDCl3) δ 7.74-7.71 (m, 1H), 7.64-7.52 (m, 2H), 7.34-7.32 (m, 1H), 7.17-7.05 (m, 3H), 6.99-6.94 (m, 2H), 4.09-4.02 (m, 1H), 3.9-3.82 (m, 1H), 3.76-3.61 (m, 4H), 3.54-3.51 (m, 2H), 3.35-3.31 (m, 2H), 2.86 (t, J=7.2 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 174.5, 167.6, 163.3, 160.0, 158.3, 155.6, 134.1, 133.9, 132.4, 130.2, 130.1, 129.7, 129.1, 126.9, 126.7, 126.8, 125.4, 121.8, 115.6, 115.3, 49.5, 48.9, 45.9, 40.9, 40.7, 34.9. MS (ES+) m/z 508 (M+1).