Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:15])=[N:11][N:10]=1.Cl[C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][CH:17]2[CH2:18][CH2:19][N:20]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=3)[CH2:21][CH2:22]2)=[O:15])=[N:11][N:10]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: O=C(NC1CCNCC1)c1nnc(Nc2ccccc2F)o1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(N2CCC(NC(=O)c3nnc(Nc4ccccc4F)o3)CC2)nc1
Reaction time: 0.17 h
Yield: 2.5 %

Procedure:
A solution of 5-[(2-fluorophenyl)amino]-N-piperidin-4-yl-1,3,4-oxadiazole-2-carboxamide (Intermediate 101) (200 mg, 0.66 mmol) and 6-chloronicotinamide (103 mg, 0.66 mmol) in dry DMF (4 mL) was heated in the microwave at 125° C. for 20 minutes and then for a further 10 minutes at 135° C. The mixture was filtered and purified by preparative HPLC to give the title compound (7 mg, 2.5%) as a solid; 1H NMR δ 1.55-1.65 (2H, m), 1.83-1.86 (2H, m), 2.99 (2H, t), 4.04-4.12 (1H, m), 4.42-4.46 (2H, m), 6.87 (1H, d), 7.11 (2H, m), 7.21-7.30 (2H, m), 7.72 (1H, s), 7.94-8.03 (2H, m), 8.62 (1H, d), 8.99 (1H, d), 10.61 (1H, s); MS m/e MH+ 426.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[C:8]([C:10]1[CH:14]=[CH:13][NH:12][CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](I)[CH3:26]>CN(C)C=O>[CH2:25]([N:12]1[CH:13]=[CH:14][C:10]([C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([OH:18])=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)=[CH:11]1)[CH3:26]
Reactant: CC(C)(C)c1cc(C(=O)c2cc[nH]c2)cc(C(C)(C)C)c1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1
Reaction time: 0.5 h

Procedure:
2 G (6.6 mmol) of 3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole were added to a cooled, stirred suspension of 0.70 g of sodium hydride (50% in mineral oil) in 50 ml of anhydrous dimethylformamide under nitrogen. After 30 minutes at room temperature, 0.7 ml of ethyl iodide was added, and stirring at room temperature was continued for an additional 2 hours. The reaction mixture was poured over a 10% HCl--ice mixture, then extracted three times with 250 ml ethyl acetate. The organic layer was washed five times with 200 ml water, dried and evaporated to dryness. The residue was purified by chromatography on alumina (3% water, 100 g) eluting with hexane:ethyl acetate (9:1). Crystallization from methylene chloride-hexane gave 1.11 g of N-ethyl-3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole (mp 73°-75° C.).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[C:4]([CH3:18])=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]#[N:34]>CC(C)=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:32][C:33]#[N:34])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[C:4]([CH3:18])=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#CCBr
Reactant: Cc1c(-c2ccccc2)n(C)c2ccc(-c3ccc(O)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(-c2ccccc2)n(C)c2ccc(-c3ccc(OCC#N)cc3)cc12
Yield: 91.2 %

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(1,3-dimethyl-2-phenyl-1H-indol-5-yl)-phenol (0.353 g, 1.126 mmol) was reacted with K2CO3 (0.189 g, 1.352 mmol) and bromoacetonitrile (0.162 g, 1.352 mmol) in acetone (15 ml) to give the desired product (0.362 g, 1.027 mmol, 91%) as a white solid, mp 177-179° C. 1H NMR (DMSO-d6) δ 2.25 (s, 3H), 3.61 (s, 3H), 5.21 (s, 2H), 7.15 (d, J=8.7 Hz, 2H), 7.45-7.52 (m, 5H), 7.55 (t, J=7.5 Hz, 2H), 7.72 (d, J=8.9 Hz, 2H), 7.78 (s, 1H); [EI], m/z 352 (M)+.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[NH:14]1[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1>CC(O)C>[OH:1][CH:2]([CH2:3][N:14]1[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1)[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(OCC2CO2)cc1
Reactant: C1CSCCN1
Solvent: CC(C)O
Product: N#Cc1ccc(OCC(O)CN2CCSCC2)cc1

Procedure:
A solution of 4-(oxiranylmethoxy)benzonitrile (10 g, 56.8 mmol) and thiomorpholine (7 g, 67.8 mmol) in 2-propanol (100 ml) was stirred over night at room temperature. Solvent was evaporated. The oily residue was dissolved in hydrochloric acid (2M, 50 ml) and extracted twice with diethylether. The acid aqueous solution was treated with sodium carbonate solution. The basic-aqueous layer was extracted three times with methylene chloride. The combined organic layers were dried over magnesium sulphate and solvent was evaporated. The crude oil was crystallized from diisopropylether; methylene chloride (9:1). Yield of the title compound (8.85 g; 56%) as colourless crystals with mp. 94°-95° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][N:14]=2)[CH:11]=1)#[N:2].[Li+].[OH-].Cl>C1COCC1.CO>[C:1]([CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=2)[CH:11]=1)#[N:2]
Reactant: CCOC(=O)c1cnc2ccc(CCCC#N)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#CCCCc1ccc2ncc(C(=O)O)n2c1
Temperature: 50 °C

Procedure:
To a stirring solution of ethyl 6-(3-cyanopropyl)imidazo[1,2-a]pyridine-3-carboxylate (24w) (375 mg, 1.46 mmol) in THF:MeOH (4:1, 5 mL) was added 2N LiOH (500 μL). The reaction was heated at 50° C. for 45 minutes then cooled to room temperature and the pH was adjusted between 3-4 with 1N HCl. The solvent was partially concentrated and the remaining aqueous was lyophilized to yield 6-(3-cyanopropyl)imidazo[1,2-a]pyridine-3-carboxylic acid (25). 1H NMR (400 MHz, d6-DMSO) δ 9.21-9.19 (m, 1H), 8.45 (s, 1H), 7.85 (dd, J=0.8, 9.2 Hz, 1H), 7.70 (dd, J=1.6, 9.2 Hz, 1H), 2.82 (t, J=7.2 Hz, 2H), 2.55 (t, J=7.2 Hz, 2H), 1.97-1.90 (m, 2H). MS m/z 230.3 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3)=[CH:16][CH:15]=1)[N:8]([CH:28]([CH3:30])[CH3:29])[CH2:7][CH2:6]2>C(O)(=O)C.C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[N:8]([CH:28]([CH3:30])[CH3:29])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCN(C(C)C)C2Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN(C(C)C)C2Cc1ccc(O)cc1
Reaction time: 8 h
Yield: 90.8 %

Procedure:
A suspension of 6-methoxy-2-(methylethyl)-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.3 g, 0.75 mmol), palladium (10% wt) on activated carbon (0.06 g) and acetic acid (5 drops) in ethyl acetate (10 mL) was stirred under hydrogen overnight. The reaction was filtered and concentrated to provide the title compound (0.212 g, 91% yield): ES−MS (m/z) 312 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]([CH3:14])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C>[N:15]([CH2:2][CH2:3][CH2:4][N:5]([CH3:14])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cccc(N(C)CCCBr)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(N(C)CCCN=[N+]=[N-])c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Compound 15 (0.5 g, 1.94 mmol) was dissolved in anhydrous DMF (20 mL) and sodium azide (1.26 g, 19.43 mmol) was added, followed by stirring of the reaction mixture at 70° C. for 16 hours. The remaining procedure was followed as described for compound 16 to obtain compound 17. Yield: 0.340 g (80%). 1H NMR (500 MHz, CDCl3): δ 1.86 (tt, 2H, J=6.5, 13.5 Hz, Hc), 2.93 (s, 3H, NCH3, Ha), 3.36 (t, 2H, J=6.5 Hz, Hd), 3.40 (t, 2H, J=7.5 Hz, Hb), 3.79 (s, 3H, OMe), 6.20-6.25 (m, 1H, Hi), 6.26-6.30 (m, 1H, Hg), 6.33-6.38 (m, 1H, He), 7.10-7.18 (m, 1H, Hf); 13C NMR (125 MHz, CDCl3): δ 26.32 (Cc), 38.56 (Ca), 49.14 (Cd), 49.77 (Cb), 55.10 (OCH3), 98.90 (Ci), 101.16 (Ce), 105.39 (Cg), 129.91 (Cf), 150.47 (Cj), 160.81 (Ch). EI-MS: [M+H]+ C11H17N4O calcd 221.14, obsd 221.12.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C1COCC1.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[NH2:8]
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.2 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenyl)morpholine (15.0 g, 66 mmol) in THF (100 mL) was added Pd/C (3.0 g). The reaction mixture was stirred at rt under H2 for 12 h. The mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo to give the title compound as a white solid (11.55 g, 89%).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:34])[N:29]([CH3:33])[CH2:30][CH2:31]O)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:49]=[N+:50]=[N-:51])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>O1CCCC1>[Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:34])[N:29]([CH2:30][CH2:31][N:49]=[N+:50]=[N-:51])[CH3:33])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(CCO)C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN(CCN=[N+]=[N-])C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Yield: 100.8 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-{4-[N-methyl-N-(2-hydroxyethyl)carbamoyl]-1,3-thiazol-2-yl}azetidine (997.5 mg, 2.0 mmol) (obtained as described in Reference Example 58(1)) in tetrahydrofuran (50 ml) were added diphenylphosphoryl azide (0.65 ml, 3.02 mmol), triphenylphosphine (793 mg, 3.02 mmol), and a 40% solution of diethylazodicarboxylate in toluene (1.12 g, 3.04 mmol) in an ice bath under an atmosphere of nitrogen, and the mixture was stirred overnight under the same conditions. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using toluene:ethyl acetate (1:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-{4-[N-(2-azidoethyl)-N-methyl-carbamoyl]-1,3-thiazol-2-yl}azetidine (1.05 g, yield 100%) as a colorless and transparent syrup.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][CH2:6][NH:7][C:8](=O)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[K+].C(OCC)C>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:20](=[CH:21][CH:22]=1)[C:8]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[N:7][CH2:6][CH2:5]2
Reactant: O=C(NCCc1cccc(F)c1)c1ccc(C(F)(F)F)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Fc1ccc2c(c1)CCN=C2c1ccc(C(F)(F)F)cc1
Temperature: 170 °C
Reaction time: 0.08 h

Procedure:
A suspension of N-(3-fluorophenethyl)-4-(trifluoromethyl)benzamide (2.8 g, 8.9 mmol) and phosphoric pentoxide (0.6 g, 0.45 mmol) in polyphosphoric acid (62.0 g, 8.9 mmol) was heated at 170° C. for 75 min. The hot reaction mixture was poured into ice and KOH (20% W/V, 50 mL) was added followed by diethyl ether (100 mL) and stirred for 5 mins. Additional KOH was added until pH˜11.0 was achieved. Then, EtOAc (200 mL) was added and the mixture continued stirring at RT for an additional 5 min. and the ethyl acetate layer was separated. The aqueous layer was back-extracted with ethyl acetate (3×200 mL). The combined ethyl acetate layers were dried over anhydrous sodium sulfate, and concentrated under vacuum to provide 6-fluoro-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline as a yellow oil. MS (ESI pos. ion) m/z: 294 (M+H).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH2:6]([C:13]1[S:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:22](Cl)(=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.C(=S)=S>O>[CH2:6]([C:13]1[S:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[C:14]=1[C:22]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:31])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: c1ccc(Cc2cc3ccccc3s2)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: S=C=S
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)sc3ccccc23)cc1
Reaction time: 6 h
Yield: 81.8 %

Procedure:
Tin tetrachloride (9.0 mL, 76.91 mmol) was added dropwise over a 25 minute period to a stirred solution of 2-benzyl-benzo[b]thiophene (14.87 g, 96.79 mmol), p-anisoyl chloride (11.75 g, 68.87 mmol) and carbon disulfide (75 mL) under a dry nitrogen atmosphere. After 6 hours, the reaction mixture was added to water and extracted with dichloromethane. The dichloromethane extract was washed with sat. aq. sodium bicarbonate and brine. The solvent was removed and the resultant solid was triturated with pet. ether to give the title compound as a white solid (20.2 g, 85%): mp 135-137° C.: NMR (CDCl3); δ 7.85 (dm, J=9 Hz, 2H), 7.73 (dm, 1H), 7.42 (dm, 1H), 7.18-7.30 (m, 7H), 6.93 (dm, J=9 Hz, 2H), 4.21 (s, 2H, CH2), 3.88 (s, 3H, CH3): IR (KBr, cm-1): 1650; MS (EI): 358 (100%, MI), 343 (15%), 327 (75%); Anal. Calc. for C23H18O2S: C, 77.07, H, 5.06, N, 0.00. Found: C, 76.91, H, 5.02, N, -0.12.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:19]1([CH:27]=O)[C:20]([CH:25]=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=1.C(O)(=O)C>ClCCl>[O:26]=[C:25]1[C:20]2[C:19](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27][N:1]1[CH:2]([C:7]1[CH:8]=[C:9]([O:17][CH3:18])[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COc1cc(C(N)CC(=O)O)cc(OC)c1OC
Reactant: O=Cc1ccccc1C=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
3-Amino-3-(3,4,5-trimethoxy-phenyl)-propionic acid (3.66 mmol, 1 eq), benzene-1,2-dicarbaldehyde (1 eq) and acetic acid (16 eq) are suspended in dichloromethane and refluxed for 2 h. The filtrate is concentrated in vacuo, dissolved in DCM and extracted with water. The organic phase is reduced under vacuum. The resulting oil is suspended in 1 M NaOH and stirred for 30 min at room temperature. The solution is washed with EtOAc and the aqueous phase is acidified with 1 M HCl (pH 2) and extracted with EtOAc. The organic phase is reduced under vacuum, dissolved in DCM and 3-(4-(hydrazinosulfonyl)phenyl)propionyl AM resin is added. The suspension is shaken at rt for 16 h. The filtrate is concentrated in vacuo, dissolved in DMSO and purified by prep. LC/MS (reversed phase). 3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionic acid is obtained as a clear colourless film (20% yield); ES-MS (MH+)=372.0; mp. 162-164° C.; 1H-NMR (DMSO-d6, 300 MHz): δ [ppm] 12.37 (br s, 1H), 7.69 (d, 1H, 7.6 Hz), 7.62-7.45 (m, 3H), 6.70 (s, 2H), 5.68 (t, 1H, 7.9 Hz); 4.53 (d, 1H, 17.9 Hz), 4.20 (d, 1H, 17.9 Hz), 3.76 (s, 6H), 3.63 (s, 3H), 3.14 (d, 2H, 7.9 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21](=[O:23])[NH2:22])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[S:33][CH:34]=[CH:35][N:36]=1)[CH3:29]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:24][C:25](=[O:27])[N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([NH2:22])=[O:23])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccccc2C(N)=O)cc1
Reactant: CCNCc1nccs1
Product: CCN(Cc1nccs1)C(=O)CN(c1ccccc1C(N)=O)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(2-carbamoyl-phenyl)-amino]-acetic acid with ethyl-thiazol-2-ylmethyl-amine
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][OH:8].[Br:9]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Br:9][C:4]1[S:3][C:2]([Cl:1])=[C:6]([CH2:7][OH:8])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1ccsc1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCc1cc(Br)sc1Cl
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a solution of 3.0 g of (2-chlorothiophen-3-yl)methanol in 60 mL of dimethylformamide was added 3.59 g of N-bromosuccinimide at room temperature, and stirred at this temperature for 2 hours. Adding 10 mL of 10% sodium thiosulfate, and the resultant solution was diluted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated, to afford 3.7 g of the title compound as a colorless oil.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]([C:24]([F:27])([F:26])[F:25])=[CH:7][N:6]=1)(=O)=O.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]2)=[CH:31][C:30]=1[CH3:48].C(O)(C(F)(F)F)=O>>[CH3:48][C:30]1[CH:31]=[C:32]([CH:35]2[CH2:36][CH2:37][NH:38][CH2:39][CH2:40]2)[CH:33]=[CH:34][C:29]=1[NH:28][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]([C:24]([F:27])([F:26])[F:25])=[CH:7][N:6]=1
Reactant: Cc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reactant: COC(=O)Cc1ccccc1CCc1nc(S(C)(=O)=O)ncc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2C)ncc1C(F)(F)F

Procedure:
A solution of methyl 2-(2-(2-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I15) (450 mg, 1.11 mmol), tert-butyl 4-(4-amino-3-methylphenyl)piperidine-1-carboxylate (I53) (390 mg, 1.34 mmol) and TFA (0.25 mL) in 2,2,2-TFE (3 mL) was heated at 120° C. under microwave irradiation for 30 minutes. The resulting mixture was adsorbed onto silica gel and chromatographed (0-50% MeOH/DCM) to give the titie compound (I54) (478 mg, 83%) as a viscous liquid; 1H NMR (400 MHz, CDCl3) δ 9.14 (bs, 1H), 8.76 (bs, 1H), 8.51 (s, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.21 (ddt, J=10.7, 7.4, 4.3 Hz, 4H), 7.15-7.06 (m, 1H), 3.65 (s, 2H), 3.60 (d, J=12.6 Hz, 2H), 3.49 (s, 3H), 3.15-3.02 (m, 6H), 2.87-2.71 (m, 1H), 2.32 (s, 3H), 2.07 (d, J=7.8 Hz, 4H). LCMS Method C: rt 5.24 min; m/z 513.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.Cl.[CH3:28][N:29]([CH2:31][C:32](Cl)=[O:33])[CH3:30].C(=O)([O-])O.[Na+]>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][N:12]([C:32](=[O:33])[CH2:31][N:29]([CH3:30])[CH3:28])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:6][CH:7]=1
Reactant: CN(C)CC(=O)Cl
Reactant: Clc1ccc(C2CNc3ccccc3S2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: CN(C)CC(=O)N1CC(c2ccc(Cl)cc2)Sc2ccccc21
Reaction time: 2.5 h
Yield: 165.5 %

Procedure:
To a solution of 2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (0.52 g) ad N,N-dimethylaniline (0.97 g) in methylene chloride (15 ml) is added dimethylaminoacetyl chloride hydrochloride (0.63 g) under ice cooling, and the mixture is stirred at the same temperature for 2.5 hours. To the reaction mixture is added aqueous sodium hydrogen carbonate solution, and is extracted with chloroform. The chloroform layer is washed, dried and distilled to remove the solvent. The residue is treated with hydrochloric acid and the resulting salt is recrystallized from ethanol-ether to give 2-(4-chlorophenyl)-4-(dimethylamino)acetyl-3,4-dihyro-2H-1,4-benzothiazine hydrochloride (0.63 g, yield 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:20]2[CH:23]=[CH:24][C:17]([Br:16])=[CH:18][CH:19]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Cl)cc1
Product: O=S(=O)(/C=C/c1ccc(Br)cc1)Cc1ccc(Cl)cc1
Yield: 92 %

Procedure:
A solution of 4-chlorobenzylsulfonyl acetic acid (0.01 mol) and 4-bromobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. The title compound was obtained in 92% yield.
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[C:13]2[C:5]([CH2:6][CH2:7][C:8]3([O:12]2)[CH2:11][CH2:10][CH2:9]3)=[CH:4][C:3]=1[OH:16].[CH3:17][C:18](=[CH:20][CH2:21][CH2:22]/[C:23](=[CH:25]/[CH2:26]O)/[CH3:24])[CH3:19].O>O1CCOCC1>[CH3:24][C:23]([CH2:22][CH2:21][CH:20]=[C:18]([CH3:19])[CH3:17])=[CH:25][CH2:26][C:4]1[C:3]([OH:16])=[C:2]([CH3:1])[C:14]([CH3:15])=[C:13]2[C:5]=1[CH2:6][CH2:7][C:8]1([O:12]2)[CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: Cc1c(O)cc2c(c1C)OC1(CCC1)CC2
Solvent: O
Solvent: C1COCCO1
Product: CC(C)=CCCC(C)=CCc1c(O)c(C)c(C)c2c1CCC1(CCC1)O2
Reaction time: 8 h

Procedure:
To a solution of 7,8-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol (0.5 g) in 20 mL of dioxane under argon, was added borontrifluoride-diethyl etherate (0.72 mL) followed by geraniol (0.4 mL) and the reaction was stirred overnight. After addition of water, the solution was extracted with EtOAc, washed with brine, dried over Na2SO4, and evaporated. The residue was purified on a silica column eluting with 1:8 EtOAc/hexane to give 5-(3,7-dimethylocta-2,6-dienyl)-7,8-dimethylspiro[chroman-2,1′-cyclobutan]-6-ol (104 mg ) as an amber oil. 1H-NMR (300 MHz, CDCl3) δ=1.65-1.99 (m, 10H), 2.01-2.28 (m, 17H), 2.74-2.79 (t, 2H), 3.35-3.37 (d, H), 4.78 (s, 1H), 5.10-5.12 (t, 1H), 5.17-5.21 (t, 1H) ppm. 13C-NMR (75 MHz, CDCl3) δ=11.93, 12.15, 12.61, 16.21, 17.80, 20.47, 25.55, 25.80, 26.45, 29.58, 34.05, 39.74, 76.23, 117.15, 121.87, 121.97, 122.48, 123.62, 123.89, 132.02, 138.03, 145.52, 145.89 ppm. MS (m/z)=354 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7]2
Reactant: Clc1cccc2cc[nH]c12
Reactant: Ic1ccccc1
Product: Clc1cccc2ccn(-c3ccccc3)c12

Procedure:
Prepared by Procedure C and Scheme O using 7-chloro-1H-indole and iodobenzene: ESMS m/e: 228.0 (M+H)+.