Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[S:23][C:22]([CH3:24])=[N:21][C:20]=3[CH3:25])[CH:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1)=[O:4].[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>>[CH3:24][C:22]1[S:23][C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)=[CH:7][CH:8]=3)[N:18]=2)=[C:20]([CH3:25])[N:21]=1
Reactant: c1c[nH]cn1
Reactant: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)CCl)cc3)n2)s1
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)Cn4ccnc4)cc3)n2)s1

Procedure:
By treatment of 2-chloro-N-{4-[4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-phenyl}-acetamide with 1H-imidazole. 1H-NMR (DMSO-D6) δ: 2.61 (s, 3H, CH3), 2.63 (s, 3H, CH3), 4.86 (s, 2H, CH2), 6.88 (s, 1H, Aryl-H), 7.04 (d, 1H, J=5.9 Hz, pyrimidinyl-H), 7.15 (s, 1H, Aryl-H), 7.50 (d, 2H, J=7.8 Hz, Ph-H), 7.62 (s, 1H, Aryl-H), 7.68 (d, 2H, J=7.8 Hz, Ph-H), 8.48 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 9.60 (s, 1H, NH), 10.18 (brs, 1H, NH). MS (ESI+) m/z 406.02 [M+H]+ (C20H19N7OS requires 405.48).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([OH:16])=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:46][C:47]([CH2:49]O)=[O:48].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:46][C:47](=[O:48])[CH3:49])=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2O)cc1
Reactant: CC(=O)CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 47.2 %

Procedure:
A solution of 2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (378 mg, 1 mmol), Ph3P (524 mg, 2 mmol) and acetol (74 mg, 1 mmol) in THF (25 mL) at room temperature was treated dropwise with a solution of DIAD (0.4 mL, 2 mmol) in THF (5 mL). The mixture was stirred at room temperature for 6 hours and concentrated in vacuo. The residue was chromatographed (silica gel, 1:1 hexanes-ethyl acetate) to provide the desired product (yield: 205 mg, 48%). mp 169-170° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.08 (s, 3H), 3.30 (s, 3H), 5.30 (s, 2H), 7.48 (m, 1H), 7.62 (q, J=10 Hz, 1H), 7.75 (m, 1H), 7.94 (d, J=9 Hz, 2H), 8.05 (d, J=9 Hz, 2H), 8.21 (s, 1H); MS (APCI+) m/z 435 (M+H)+, (APCI−) m/z 469 (M+Cl)−; Anal. calc. for C20H16F2N2O5S.0.75H2O: C, 53.62; H, 3.93; N, 6.25. Found: C, 53.26; H, 3.61; N, 6.08.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([O:21][CH3:22])=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=2)[CH:3]=1.[CH:23]1([CH:26]=O)[CH2:25][CH2:24]1.[BH3-]C#N.[Na+]>CO.CC(O)=O>[CH:23]1([CH2:26][NH:1][C:2]2[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]3[CH:11]=[CH:12][C:13]([O:21][CH3:22])=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=3)[CH:3]=2)[CH2:25][CH2:24]1
Reactant: O=CC1CC1
Reactant: COc1ccc(-c2cc(N)c(=O)n(C)c2)cc1NS(C)(=O)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(NCC3CC3)c(=O)n(C)c2)cc1NS(C)(=O)=O
Temperature: 30 °C
Yield: 13.2 %

Procedure:
To a solution of compound from Example 109 (64.6 mg, 0.2 mmol) in MeOH (3 mL) and AcOH (0.3 mL) was added cyclopropanecarbaldehyde (14.0 mg, 0.2 mmol) dropwise with stirring at 30° C. NaBH3CN (24.5 mg, 0.4 mol) was added in portions at 30° C. The reaction mixture was stirred for 2 h at 30° C. It was then quenched with saturated aqueous NH4Cl (5 mL), extracted with EtOAc (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to give the title compound (10.0 mg, 13.2%) as a light green solid. 1H NMR (Methanol-d4 400 MHz): δ 7.55 (d, J=2.4 Hz, 1H), 7.36 (dd, J=8.4, 2.4 Hz, 1H), 7.16-7.07 (m, 2H), 6.61 (d, J=2.4 Hz, 1H), 3.94 (s, 3H), 3.66 (s, 3H), 3.05 (s, 2H), 2.95 (s, 3H), 1.21-1.14 (m, 1H), 0.64-0.56 (m, 2H), 0.35-0.28 (m, 2H). LCMS (M+H)+ 378.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](OBr)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[OH-].[K+].CC(C)CC(O)C>>[CH2:21]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: CCCCCCCCCCCCOBr
Reactant: O=Cc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)CC(C)O
Product: CCCCCCCCCCCCOc1ccc(C=O)cc1
Yield: 77.4 %

Procedure:
100 g of 4-hydroxy-benzaldehyde are reacted with 224.5 g of dodecyloxybromide along with 56.7 g of anhydrous KOH (85%) in 11 of 4-methyl-2-hydroxy-pentane. The mixture is then heated to reflux and maintained at reflux for 7 hours. The cooled reaction mixture is filtered to eliminate salts and distilled in a claisen equipment. 184 g (yield 77%) of a clear oil are collected at 178-181° C. and 0.5 mbar, which slowly crystallises on standing at room temperature.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@@H:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[C:2]1([CH3:8])[CH:3]=[CH:4][CH:5]=[C:6]([O:7][C@H:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31])[CH:1]=1
Reactant: Cc1cccc(O)c1
Reactant: COC(=O)[C@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@@H](C)Oc1cccc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of the m-cresol (1.0 g, 9.2 mmol) in anhydrous THF (15 mL) at 0° C. under argon protection was added triphenylphosphine (2.55 g, 9.7 mmol), followed by addition of the (S)-methyl 2-hydroxypropanoate (926 μL, 9.7 mmol). Then diisopropylazodicarboxylate (DIAD) (2.85 mL, 13.8 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted by ethyl acetate, washed with a 0.5 N HCl solution, a saturated solution of NaHCO3, and brine, dried on MgSO4, and concentrated. The obtained oil was purified by flash chromatography (Hexane/Ethyl acetate 0˜50%) to afford a colorless oil (820 mg, 46%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(OCC)(=O)C>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a solution of tert-butyl (1S,2S)-2-hydroxycyclohexylcarbamate (1.30 g, 6.04 mmol), 4-nitrobenzoic acid (1.11 g, 6.64 mmol), triphenylphosphine (1.74 g, 6.64 mmol) in THF (30 mL) was added diethylazo dicarboxylate (1.05 ml, 6.64 mmol) and the resulting solution was stirred at ambient temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried and concentrated to give an orange oil that was purified by column chromatography (hexanes/ethyl acetate, 8:1) to give (1R,2S)-2-(tert-butoxycarbonylamino)cyclohexyl 4-nitrobenzoate (1.95 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:26][CH3:27])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][NH:20][CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16].[C:28](Cl)(=[O:30])[CH3:29].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:28]([N:20]1[CH2:21][C@H:22]([O:23][CH2:24][CH3:25])[C@H:18]([NH:17][C:12]2[C:11]([CH2:26][CH3:27])=[N:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:14]([CH2:15][CH3:16])[N:13]=2)[CH2:19]1)(=[O:30])[CH3:29]
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of 5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine (105 mg) in methylene chloride (5 ml) under N2 was added acetyl chloride (0.027 ml). The reaction mixture stirred for 30 min and was poured into saturated sodium bicarbonate (20 ml), extracted methylene chloride (2×20 ml), dried MgSO4, filtered and concentrated. MPLC chromatography was run on a biotage 25 S column with 60% ethyl acetate/heptane to provide the title compound as an oil (79 mg, 69%): 1H NMR (400 MHz, CDCl3) δ) 7.50, 7.34–7.26, 5.30, 5.12, 4.81, 4.19, 4.01, 3.87–3.67, 3.61–3.37, 2.72, 2.48, 1.33–1.26, 1.14; HRMS (FAB) calcd for C22H28Cl2N4O2+H 451.1667, found 451.1667.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.O.[NH2:14][NH2:15]>O1CCCC1>[NH:14]([C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1)[NH2:15]
Reactant: NN
Reactant: CCOC(=O)c1sc(Br)nc1C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1sc(NN)nc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 137.4 %

Procedure:
A To a stirred solution of ethyl 2-bromo-4-methylthiazole-5-carboxylate (10.00 g, 40.00 mmol) in tetrahydrofuran (125 mL), was added hydrazine monohydrate (6.01 g, 120.0 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, concentrated in vacuo to dryness. The residue was purified by column chromatography to afford ethyl 2-hydrazinyl-4-methylthiazole-5-carboxylate as a white solid (11.06 g, 91%): 1H NMR (300 MHz, DMSO-d6) δ 5.02 (s, 2H), 4.13 (q, J=6.0 Hz, 2H), 2.33 (s, 3H), 1.18 (t, J=6.0 Hz, 3H); MS (ES+) m/z 202.2 (M+1).
Reaction SMILES: [CH2:1]([C:5]1([CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH3:22])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[C:11]=2[Cl:14])[C:6]1=O)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C.Cl.CCOC(C)=O>[CH2:1]([C:5]12[CH2:18][CH2:19][C:20](=[O:23])[C:21]([CH3:22])=[C:6]1[C:7]1[C:12](=[C:11]([Cl:14])[C:10]([O:15][CH3:16])=[CH:9][CH:8]=1)[CH2:13]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCC(=O)CC)Cc2c(ccc(OC)c2Cl)C1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCCC12CCC(=O)C(C)=C1c1ccc(OC)c(Cl)c1C2
Temperature: 90 °C
Reaction time: 48 h
Yield: 60.6 %

Procedure:
A solution of 2-butyl-4-chloro-5-methoxy-2-(3-oxo-pentyl)-1-indanone (250 mg, 0.74 mmol) in acetic acid (2 mL) was diluted with 6N aqueous HCl (2 mL). The resulting mixture was stirred and heated in an oil bath at 90° C. for 18 hours, then kept at room temperature for 2 days. The mixture was diluted with EtOAc (20 mL), washed with water (30 mL), 5% NaHCO3 (10 mL) and brine (5 mL), dried over MgSO4, filtered, and evaporated under vacuum to an oil (250 mg). The crude product was purified by preparative layer chromatography on three 0.1×20×20 silica gel GF plates, developing with 5% EtOAc in CH2Cl2, to afford 9a-butyl-8-chloro-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (143 mg).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]([NH2:26])([C:23](=[O:25])[NH2:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[C:27](Cl)(Cl)=[S:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][C:20]2([NH:26][C:27](=[S:28])[NH:24][C:23]2=[O:25])[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: S=C(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(N)=O)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=S)NC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
N,N-Diisopropylethylamine (1.67 ml, 9.84 mmol) was added to a solution of 4-amino-4-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.1 mmol) in THF (10 ml) at 0° C., and thiophosgene (0.376 ml, 4.9 mmol) was further added dropwise slowly. The reaction solution was warmed to room temperature and stirred overnight. A 10% aqueous citric acid solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layers were combined and dried over magnesium sulfate, and the solvent was then distilled off. The residue was purified by silica gel column chromatography to give 4-oxo-2-thioxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (944 mg, 81%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][CH:10]2[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1)#[CH:2].I[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1>>[C:19]1([CH3:23])[CH:20]=[CH:21][CH:22]=[C:17]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH:9]3[CH2:11][CH:10]3[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=2)[CH:18]=1
Reactant: Cc1cccc(I)c1
Reactant: C#Cc1ccc(C2CC2C(=O)OC)cc1
Product: COC(=O)C1CC1c1ccc(C#Cc2cccc(C)c2)cc1

Procedure:
The title compound was prepared from methyl 2-(4-ethynylphenyl)cyclopropanecarboxylate (80 mg, 0.40 mmol) and 1-iodo-3-methylbenzene (60 μL, 0.47 mmol) according to the general procedure IF to give 42 mg (36%) of a pale yellow solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:9): Rf=0.43 (EtOAc:PE, 1:4); 1H NMR (CDCl3) δ 7.43 (d, J=8.3 Hz, 2H), 7.37-7.30 (m, 2H), 7.23 (t, J=7.6 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 7.06 (d, J=8.2 Hz, 2H), 3.72 (s, 3H), 2.61-2.45 (m, 1H), 2.35 (s, 3H), 1.92 (ddd, J=8.5, 5.3, 4.3 Hz, 1H), 1.63 (dt, J=9.9, 5.0 Hz, 1H), 1.33 (ddd, J=8.4, 6.5, 4.7 Hz, 1H); 13C NMR (CDCl3) δ 173.6, 140.3, 138.0, 132.2, 131.7, 129.1, 128.6, 128.2, 126.2, 123.1, 121.5, 89.7, 88.8, 52.0, 26.2, 24.2, 21.2, 17.2; ESI-MS m/z 313.1 (M+Na+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:32]([C:36]1[CH:61]=[CH:60][C:39]([C:40]([NH:42][C@@H:43]([CH2:48][C:49]2[CH:54]=[CH:53][C:52](/[C:55](=[N:58]/[H])/[NH:56]O)=[CH:51][CH:50]=2)[C:44]([O:46][CH3:47])=[O:45])=[O:41])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>CN(C=O)C>[C:32]([C:36]1[CH:61]=[CH:60][C:39]([C:40]([NH:42][C@@H:43]([CH2:48][C:49]2[CH:50]=[CH:51][C:52]([C:55](=[NH:56])[NH:58][O:14][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:10][CH:11]=3)=[CH:53][CH:54]=2)[C:44]([O:46][CH3:47])=[O:45])=[O:41])=[CH:38][CH:37]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1
Reactant: [H]/N=C(\NO)c1ccc(C[C@H](NC(=O)c2ccc(C(C)(C)C)cc2)C(=O)OC)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(C(=O)ONC(=N)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Reaction time: 2 h

Procedure:
Prepared using General Procedure 5: To a solution of 4-(heptyloxy)benzoic acid (400.0 mg, 1.54 mmol) in anhydrous DMF (6 mL) were added HOBt (312.3 mg, 2.31 mmol) and EDC (442.75 mg, 2.31 mmol). After stirring for 2 h, (S,Z)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(N-hydroxycarbamimidoyl)phenyl)-propanoate, INT-2 (673.3 mg, 1.69 mmol) was added. The reaction mixture was stirred at RT for 2 h, partitioned between saturated aqueous NaHCO3 (15 mL) and EA (15 mL), and concentrated under reduced pressure to afford the intermediate (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(N-((4-(heptyloxy)benzoyl)oxy) carbamimidoyl)phenyl)propanoate. The intermediate was dissolved in DMF (10 mL) and heated to 100° C. for 18 h. The reaction mixture was cooled to RT and partitioned between EA (10 mL) and saturated aqueous NaHCO3 (50 mL). The organic layer was extracted with water (2×10 mL) and brine (10 mL). The organic layer was dried over MgSO4 and concentrated. The brown oil was purified by chromatography (EA/hexanes) to afford 710 mg (77%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)-propanoate as a white solid. LCMS-ESI (m/z) calculated for C36H43N3O5: 597.3; no m/z observed, tR=12.80 min (Method 2). 1H NMR (400 MHz, DMSO) δ 8.84 (d, J=8.0 Hz, 1H), 8.08 (t, J=17.2 Hz, 2H), 7.97 (dd, J=18.2, 8.5 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H), 7.50 (dd, J=18.6, 8.3 Hz, 4H), 7.18 (d, J=8.9 Hz, 2H), 4.85-4.63 (m, 1H), 4.09 (dd, J=13.8, 7.3 Hz, 2H), 3.67 (s, 3H), 3.24 (ddd, J=23.8, 15.7, 7.3 Hz, 4H), 2.08 (s, 4H), 1.74 (dd, J=14.1, 6.9 Hz, 2H), 1.42 (dd, J=13.6, 6.3 Hz, 2H), 1.30 (d, J=14.5 Hz, 9H), 0.88 (t, J=6.8 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 174.05, 170.87, 133.81, 165.14, 161.43, 153.21, 140.51, 129.70, 128.85, 128.78, 126.06, 125.84, 123.93, 123.39, 114.36, 114.25, 66.86, 52.66, 50.88, 34.32, 33.47, 30.06, 29.74, 27.33, 27.24, 24.23, 20.89, 12.80.
Reaction SMILES: I[C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1.[CH3:24][NH:25][C:26]1[N:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[N:27]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][NH:25][C:26]1[N:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:2]3[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][N:6]=[C:7]4[O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[CH:32]=2)[N:27]=1
Reactant: CNc1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Reactant: Cc1ccc2c(Oc3cccc(C(F)(F)F)c3)nccc2c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1ncc2cc(-c3c(C)ccc4c(Oc5cccc(C(F)(F)F)c5)nccc34)ccc2n1
Temperature: 150 °C

Procedure:
5-Iodo-6-methyl-1-(3-(trifluoromethyl)phenoxy)isoquinoline (0.170 g, 0.396 mmol), N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (0.124 g, 0.436 mmol), dichlorobis(triphenyl-phosphine)palladium (II) (0.0139 g, 0.0198 mmol), and sodium carbonate (0.0840 g, 0.792 mmol) were all placed in a clear microwave vial along with 5 ml of 9:1 DMF:water. The vial was capped and heated in a Personal Chemistry SmithSynthesizer to 150° C. for 10 minutes. The reaction was diluted with water and extracted with EtAOc. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 30-70% EtOAc in hexanes. The clean fractions were reduced in vacuo and the residue triturated with ether to give N-methyl-6-(6-methyl-1-(3-(trifluoromethyl)phenoxy)isoquinolin-5-yl)quinazolin-2-amine as a light yellow solid. MS (M+H)+ 461.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].Cl[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[O:8])[CH:9]=[CH:10][C:11]=1[O:12][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1)[CH3:2]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CCOc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOc1cc(C=O)ccc1Oc1ccc(C#N)cn1
Yield: 93.6 %

Procedure:
Using a method similar to Example 365, step 1, and using 3-ethoxy-4-hydroxy-benzaldehyde (3.00 g, 18.0 mmol), 6-chloro-nicotinonitrile (2.65 g, 18.0 mmol), and potassium carbonate (6.62 g, 45.2 mmol) in dimethylacetamide (90 mL), after 3 h at 100° C. (no purification) provides 4.52 g (93%) of the title compound as a yellow/white solid: mass spectrum (electrospray): m/z=269.0 (M+1); 1H NMR (CDCl3): 9.96 (s, 1H), 8.39 (d, 1H, J=2.0 Hz), 7.95 (dd, 1H, J=2.0, 8.3 Hz), 7.55-7.50 (m, 2H), 7.33 (d, 1H, J=7.8 Hz), 7.11 (d, 1H, J=9.3 Hz), 4.05 (q, 2H, J=6.8 Hz), 1.16 (t, 3H, J=6.8 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:11]2([C:15](=[O:16])[N:14]([OH:17])[C:13](=[O:18])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:24][C:25]#[N:26].C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:11]2([C:15](=[O:16])[N:14]([O:17][CH2:24][C:25]#[N:26])[C:13](=[O:18])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCCl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)N(O)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)N(OCC#N)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-tert-butyloxycarbonyl-2-hydroxy-2,8-diazaspiro[4,5]decane-1,3-dione (0.56 g) in dimethylformamide (5 ml) was added 88 mg of sodium hydride (60% in oil), and the mixture was stirred for one hour at room temperature. To the mixture was added chloroacetonitrile (140 μl). The whole mixture was stirred for 2 hours at room temperature, to which was added ethyl acetate (30 ml), followed by washing with a saturated aqueous solution of sodium hydrogencarbonate and then with a 10% aqueous solution of citric acid. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated off. The residue was recrystallized from ethyl acetate-diethyl ether to obtain 0.53 g of a colorless solid, m.p. 138° to 139° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[OH:14])[CH:2]=[CH2:3].Cl[Sn](Cl)(Cl)Cl.[I:20]I>ClCCl>[I:20][CH2:3][CH:2]1[CH2:1][C:4]2[CH:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=[CH:6][C:5]=2[O:14]1
Reactant: C=CCc1cc(C(F)(F)F)ccc1O
Reactant: II
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1ccc2c(c1)CC(CI)O2
Yield: 43.1 %

Procedure:
To a solution of 2-(prop-2-en-1-yl)-4-(trifluoromethyl)phenol (4 g, 20 mmol) in dichloromethane (50 ml) was added SnCl4 (2.6 g, 10.0 mmol, 0.5 eq) dropwise and iodine (5.03 g, 19.8 mmol, 1 eq) with stirring for 6 h at room temperature. The reaction mixture was diluted with dichloromethane (200 ml) and quenched by the addition of water (100 ml). The organic layer was separated and the pH value of the aqueous layer was adjusted to ˜8 with aqueous sodium bicarbonate. The aqueous layer was extracted further with dichloromethane (3×100 ml). The organic layers were combined, washed with aqueous Na2S2O4 (5%, 100 ml) to remove remaining iodine, dried over anhydrous magnesium sulfate, filtered, and then concentrated under vacuum. The crude material was purified by silica gel chromatography using 1% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford 2-(iodomethyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran as colorless oil (2.8 g, 43%); 1H NMR (300 MHz, CDCl3): δ 7.39 (d, J=5.7 Hz, 2H), 6.83 (d, J=8.7 Hz, 1H), 4.91-5.00 (m, 1H), 3.34-3.48 (m, 3H), 3.05-3.12 (m, 1H).