Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:9][C:10]([O:12][C@@H:13]([CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])=[O:11])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].C=O.[C:31](O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([C:3]1([NH:9][C:10]([O:12][C@@H:13]([CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:14]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[O:15])=[O:11])[CH2:8][CH2:7][N:6]([CH3:31])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)O[C@@H](CC2CCCCC2)C(=O)N2CCOCC2)CCNCC1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCC(C#N)(NC(=O)O[C@@H](CC2CCCCC2)C(=O)N2CCOCC2)CC1
Yield: 72 %

Procedure:
A sample of the free amine obtained from the previous step (40 mg, 0.102 mmol) is dissolved in MeOH (1 mL) and formaldehyde (6.06 mg, 0.202 mmol) is added as a solution in methanol (2 mL) with a single drop of acetic acid. Sodium cyanoborohydride (2.1 mg, 0.034 mmol) is added as a solid and the reaction is allowed to stir for half an hour. The solvent is removed in vacuo and the product is purified by preparative HPLC to afford the title material, 29.8 mg, 72% yield. HPLC-MS calculated for C21H34N4O4 (M+H+)407.3, found 407.3.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([OH:11])=O)=[CH:4]1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][CH:45]=1)[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[CH:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:25]=[C:24]([NH:23][C:9]([C:5]5[C:6]([CH3:8])=[CH:7][N:3]([CH2:1][CH3:2])[CH:4]=5)=[O:11])[CH:45]=[CH:44][CH:43]=4)=[CH:33][N:32]3[N:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: CCn1cc(C)c(C(=O)O)c1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: CCn1cc(C)c(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c1
Yield: 23.3 %

Procedure:
In the same manner as in Example 18-4 and using 1-ethyl-4-methyl-1H-pyrrole-3-carboxylic acid (198 mg, 1.29 mmol), tetrahydrofuran (7 mL), oxalyl chloride (169 μL, 1.94 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (67.0 mg, 23%) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]3[CH:13]=[C:12]([CH2:14][OH:15])[N:11]=[C:9]3[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.CN(C=O)C.O=[Mn]=O>[CH:14]([C:12]1[N:11]=[C:9]2[N:8]([CH:13]=1)[C:7]1[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=1[S:10]2)=[O:15]
Reactant: Cc1cccc2sc3nc(CO)cn3c12
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc2sc3nc(C=O)cn3c12

Procedure:
2-Formyl-5-methylimidazo[2,1-b]-benzthiazole was prepared according to the procedure outlined in Example 1, (Step 3). Starting from 5-methyl imidazo[2,1-b]-benzthiazole-2-methanol (2.0 g 9.1 mmol) in methylene chloride/DMF(300 mL: 50 mL) and active MnO2 (12 g, excess), 700 mg (35% Yield) of the aldehyde derivative was isolated as brown solid. (M+H) 217.
Reaction SMILES: [C:1]([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].[CH2:15]1[CH2:20][CH2:19][C:18]([CH2:25][NH2:26])([CH2:21][C:22]([OH:24])=[O:23])[CH2:17][CH2:16]1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(O)C>[CH3:2][C:1]([NH:26][CH2:25][C:18]1([CH2:21][C:22]([O-:24])=[O:23])[CH2:19][CH2:20][CH2:15][CH2:16][CH2:17]1)=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2+:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NCC1(CC(=O)O)CCCCC1
Reactant: C1CCNCC1
Reactant: CCOC(=O)C(C(C)=O)C(=O)OCC
Solvent: CCO
Product: C1CC[NH2+]CC1
Product: CCOC(=O)C(C(=O)OCC)=C(C)NCC1(CC(=O)[O-])CCCCC1

Procedure:
Diethyl acetylmalonate (202 mg, 1 mmol), gabapentin (171 mg, 1 mmol), and piperidine (99 μL, 1 mmol) were mixed in anhydrous ethanol (10 mL). After heating under reflux for 16 h, the solvent was removed under reduced pressure to give the title compound with purity greater than 90%. 1H NMR (CDCl3, 400 MHz): δ 1.28 (t, J=7.2 Hz, 6H), 1.38-1.64 (m, 12H), 1.75 (m, 4H), 1.96 (s, 3H), 2.23 (s, 2H), 2.99 (m, 4H), 3.24 (d, J=5.2 Hz, 2H), 4.20 (q, J=7.2 Hz, 4H), 4.35 (s, br, 2H), 7.79 (t, J=5.2 Hz, 1H). MS (ESI) m/z 354.38 (M−H−).
Reaction SMILES: [C:1]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][NH2:30]>>[C:1]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:30][CH2:29][CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])=[CH:15][CH:14]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCC#Cc1ccc(C=O)cc1
Reactant: NCCc1ccccc1F
Product: CCCCCCCCCCC#Cc1ccc(CNCCc2ccccc2F)cc1

Procedure:
The same procedure as employed in the preparation of Example 394 (step b) but using 4-dodec-1-ynylbenzaldehyde and 2-(2-fluorophenyl)ethylamine gave the title compound as an oil. M+(LC/MS(ESI)): 394.4. HPLC (Condition A), Rt: 5.00 min (HPLC purity: 93.6%).
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11](S(O)(=O)=O)=[CH:10][CH:9]=1.Cl[CH2:20]Cl>>[CH3:4][C:3]1([CH3:5])[O:6][CH2:7][C:10](=[CH2:9])[C@@H:11]2[C@@H:20]([C@@H:8]([CH3:18])[CH2:13][CH2:12]2)[CH2:1][O:2]1
Reactant: COC(C)(C)OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: ClCCl
Product: C=C1COC(C)(C)OC[C@H]2[C@@H]1CC[C@@H]2C
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.7 %

Procedure:
2-[(1S, 2R, 3S)-2-(hydroxymethyl)-3-methylcyclopent-1-yl]-2-propen-1-ol (1.5 g, 0.0082 mol) obtained in Definite Example 46 was dissolved in 20 ml of dichloromethane and 10 ml of 2, 2-dimethoxypropane was added. Furthermore, 50 mg of p-toluenesulfonic acid was added, and the reaction mixture was stirred at room temperature for 24 hours. After 100 ml of dichloromethane was added, washing was carried out with a mixed aqueous solution of saturated sodium bicarbonate solution (20 ml) and saturated sodium chloride solution (20 ml), and this organic layer was dried by adding magnesium sulfate, and was filtered and then concentrated under a reduced pressure. The residual matter was purified by chromatography using silica gel, and the solvent of the fraction obtained from hexane:ether=8:2 eluent was distilled off. A colorless oily substance was thus obtained, i.e., (1R, 8S, 11S)-4, 4, 11-trimethyl-7-methylene-3, 5-dioxabicyclo[6. 3. 0]undecane (550 mg, yield=29.7%). This (1R, 8S, 11S)-4, 4, 11-trimethyl-7-methylene-3, 5-dioxabicyclo[6. 3. 0]undecane had the following physicochemical properties:
Reaction SMILES: C[C:2]([OH:13])([C:9]([O:11][CH3:12])=[O:10])C1C=CC=CC=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23](S(O)(=O)=O)=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:12][O:11][C:9](=[O:10])[C@@H:2]([O:13][CH:19]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH2:30][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C1=COCCC1
Reactant: COC(=O)C(C)(O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of L-phenyl lactic acid methyl ester (20.0 g, 111 mmol) in CH2Cl2 (300 mL) was treated with dihydropyran (9.32 g, 111 mmol) and p-toluenesulphonic acid (56 mg) and stirred at room temperature for 20 minutes. The reaction is quenched with 1 N NaOH and then washed with water, brine and dried over Na2SO4. The solution is filtered and the solvent removed under vacuum to give 28 grams of the THP protected alcohol as an oil. This was used without further purification.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[N:19]=[CH:18][C:17]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[CH:16][CH:15]=1.[N:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=1>C1COCC1>[F:13][C:14]1[N:19]=[CH:18][C:17]([C:20]2[S:21][C:22]([C:31]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)([OH:33])[CH3:32])=[CH:23][N:24]=2)=[CH:16][CH:15]=1
Reactant: Fc1ccc(-c2nccs2)cn1
Reactant: CC(=O)c1ccncc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(O)(c1ccncc1)c1cnc(-c2ccc(F)nc2)s1
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
To a solution of diisopropylamine (0.12 mL, 0.833 mmol) in dry THF (5 mL) was added n-BuLi in hexanes (1.6M, 0.7 mL, 1.111 mmol) slowly at −78° C. The mixture was stirred for 30 min, 2-(6-fluoropyridin-3-yl)thiazole (0.1 g, 0.555 mmol) in THF (5.0 mL) at −78° C. added, and the mixture stirred for 30 min. A solution of 1-(pyridin-4-yl)ethanone (0.09 mL, 0.833 mmol) in THF (5.0 mL) was added to reaction mixture, stirred for 2 hours at −78° C. The reaction mixture was quenched with saturated NH4Cl (50 mL) solution and extracted with EtOAc (3×50 mL). The organic layer was washed with water (2×50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by preparative TLC (3% methanol in dichloromethane) to obtain 1-(2-(6-fluoropyridin-3-yl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol as off-white solid (0.035 g, 22% yield) in 99.7% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.31 (s, 1H), 8.21 (d, 2H), 7.79 (d, 1H), 7.71 (d, 1H), 7.67 (s, 1H), 7.11 (s, 1H), 6.91 (d 2H), 1.83 (s, 3H); LC-MS m/z calculated for [M+H]+ 302.07, found 302.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:7]=1)#[CH:2].I[C:18]1[C:26]2[C:21](=[N:22][CH:23]=[C:24]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:25]=2[N:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)[N:20]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)[N:19]=1.O.C(OCC)(=O)C>C1COCC1.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>[CH3:54][O:53][C:50]1[CH:51]=[CH:52][C:47]([CH2:46][N:20]2[C:21]3=[N:22][CH:23]=[C:24]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:25]([N:27]4[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:29][CH2:28]4)=[C:26]3[C:18]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]([CH2:8][C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)[CH:7]=3)=[N:19]2)=[CH:48][CH:49]=1
Reactant: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Reactant: C#Cc1cnn(Cc2ccc(OC)cc2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(C#Cc3nn(Cc4ccc(OC)cc4)c4ncc(-c5ccccc5)c(N5CCN(C(=O)OC(C)(C)C)CC5)c34)cn2)cc1
Temperature: 40 °C
Reaction time: 18 h
Yield: 118 %

Procedure:
4-Ethynyl-1-(4-methoxybenzyl)-1H-pyrazole (0.068 g, 0.32 mmol) was added to a solution of tert-butyl 4-(3-iodo-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.10 g, 0.16 mmol), Cu(I)I (0.0015 g, 0.008 mmol), PdCl2(PPh3)2 (0.0056 g, 0.008 mmol) and TEA (0.11 ml, 0.80 mmol) in THF (10 mL) and stirred at 40° C. for 18 hours. Water (10 mL) and ethyl acetate (20 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by flash chromatography (hexane:ethyl acetate=5:1) to give tert-butyl 4-(1-(4-methoxybenzyl)-3-((1-(4-methoxybenzyl)-1H-pyrazol-4-yl)ethynyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.134 g, 95%) as a solid. LCMS (APCI+) m/z 710 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:10]([OH:12])=[O:11])[C:6]([SH:9])([CH3:8])[CH3:7])(=[O:3])[CH3:2].[CH3:13]CN(C(C)C)C(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].BrC[C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:35]=1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([S:47]([C:50]2[CH:54]=[C:53]([C:55](=[NH:57])[NH2:56])[S:52][C:51]=2[S:58][CH3:59])(=[O:49])=[O:48])[CH:42]=1)=[O:32]>CS(C)=O>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[C:1]([NH:4][CH:5]([C:6]([SH:9]([C:31](=[O:32])[NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:35]=1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([S:47]([C:50]2[CH:54]=[C:53]([C:55](=[NH:56])[NH2:57])[S:52][C:51]=2[S:58][CH3:59])(=[O:49])=[O:48])[CH:42]=1)[CH3:13])([CH3:7])[CH3:8])[C:10]([OH:12])=[O:11])(=[O:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CBr)c1
Reactant: CC(=O)N[C@H](C(=O)O)C(C)(C)S
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)[SH](C)C(C)(C)C(NC(C)=O)C(=O)O)c1

Procedure:
N-Acetyl-penicillamine (3.0 mg, 0.0154 mmol, racemic) and DIEA (7 μL, 0.04 mmol) were dissolved in DMSO (223 μL) and then transferred to a solution of 2-bromo-N-[3′-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-biphenyl-2-yl]-acetamide trifluoroacetate (20 mM in DMSO, 230 μL, 0.0046 mmol, prepared from the title compound described in Example 249). The reaction was mixed on a shaker for 1 h at rt. Bromomethyl wang resin (16 mg, 1.47 mmol/gm) was added to scavenge the excess thiol. After 2 h of shaking, the resin was filtered and the filtrate was directly purified using RP-HPLC as previously described in Example 246, step b, to afford 1.5 mg (50%, single peak on analytical RP-HPLC) of the title compound as a glassy solid. ESI-MS (m/z): Calcd. for C28H32N4O6S4: 649.1 (M+H); found: 649.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH:24]=O)[CH3:19].[NH2:33][C:34]([NH2:36])=[O:35].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:24]([C:23]3[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]([OH:29])=[C:21]([O:20][CH2:18][CH3:19])[CH:22]=3)[NH:33][C:34](=[O:35])[NH:36][C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccc(Cl)c(Cl)c2)cc([N+](=O)[O-])c1O
Yield: 2.4 %

Procedure:
To a solution of 2-(3,4-dichlorophenyl)-1-phenylethanone (Intermediate 6) (400 mg, 1.5 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (317 mg, 1.5 mmol), and urea (207 mg, 4.5 mmol) in 20 mL of ethanol was added 0.2 mL of concentrated HCl, the mixture was stirred at reflux for 4 days. After the solvent was removed under reduced pressure, the residue was purified by HPLC (48-78% acetonitrile+0.1% trifluoroacetic acid in water, over 15 min.) and thin layer chromatography (PE:EtOAc=1:2) to give Compound 22 (17.8 mg, yield 2.4%). 1H NMR (CD3OD 400 MHz): δ 7.64 (s, 1H), 7.35-7.31 (m, 5H), 7.23-7.19 (m, 2H), 7.03 (s, 1H), 6.79 (d, J=8.0 Hz, 1H), 5.37 (s, 1H), 4.12 (m, 2H), 1.43 (t, J=6.8 Hz, 3H); MS (ESI): m/z 500.2 [M+1]+.
Reaction SMILES: C(N=C=NC(C)C)(C)C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:18]2[CH2:21][CH:20]([NH2:22])[CH2:19]2)=[CH:13][CH:12]=1.[C:30]1([S:36]([CH2:39][C:40](O)=[O:41])(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.OC1C2N=NNC=2C=CC=1>ClCCl.CN(C)C=O.CO>[C:30]1([S:36]([CH2:39][C:40]([NH:22][CH:20]2[CH2:19][N:18]([CH:17]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:14]3[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=3)[CH2:21]2)=[O:41])(=[O:37])=[O:38])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)CS(=O)(=O)c1ccccc1
Reactant: NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: O=C(CS(=O)(=O)c1ccccc1)NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reaction time: 17 h

Procedure:
0.031 cm3 of diisopropylcarbodiimide, a solution of 30 mg of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ylamine in 0.5 cm3 of anhydrous dichloromethane, and 3 cm3 of anhydrous dichloromethane are added to a solution of 80.1 mg of benzenesulfonylacetic acid, 27 mg of hydroxybenzotriazole in solution in 0.5 cm3 of dimethylformamide under an inert argon atmosphere, at a temperature in the region of 23° C. After 17 hours at a temperature in the region of 23° C., the reaction mixture is loaded onto a 3-cm3 SPE cartridge containing 1 g of SCX phase preconditioned with methanol. After washing with twice 5 cm3 of methanol and then 4 cm3 of 0.1 N ammoniacal methanol, the expected product is eluted with 4 cm3 of 1 N ammoniacal methanol. The fraction containing the expected product is evaporated under an air stream at a temperature in the region of 45° C. and then dried under reduced pressure (1 mbar) at a temperature in the region of 40° C. 2-Benzenesulfonyl-N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}acetamide is thus obtained in the form of a white solid [1H NMR spectrum (500 MHz, CDCl3, δ in ppm): 2.96 (mt: 2H) 3.51 (mt: 2H); 4.00 (s: 2H); 4.34 (unresolved complex: 1H); 4.48 (mt: 1H); 7.10 (unresolved complex: 1H); from 7.20 to 7.45 (mt: 8H); 7.57 (t, J=8 Hz: 2H); 7.70 (t, J=8 Hz: 1H); 7.90 (d, J=8 Hz: 2H)].
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([NH:8][C:9]([NH:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C=NCc1ccccc1
Reactant: Nc1nccs1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: S=C(NCc1ccccc1)Nc1nccs1
Temperature: 100 °C
Yield: 46.1 %

Procedure:
A solution of benzyl isothiocyanate (1.5 g, 10 mmol) and 2-aminothiazole (1.0 g, 10 mmol) in N,N-dimethylformamide. (25 mL) was heated at 100° C. for 12 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized twice from ethyl acetate to provide 1.15 g (46%) of the title product:
Reaction SMILES: [CH3:1][I:2].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=1)=[O:9]>C1(C)C=CC=CC=1.CC(C)=O>[I-:2].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N+:11]=1[CH3:1])=[O:9]
Reactant: Cc1ccnc(C(=O)c2ccco2)c1
Reactant: CI
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc[n+](C)c(C(=O)c2ccco2)c1
Product: [I-]
Yield: 83.8 %

Procedure:
49.7 gr of methyl iodide dissolved in 43 ml of anhydrous toluene are added to a solution of 5.5 gr of 2-(2-furoyl)-4-methylpyridine in 35.5 ml of anhydrous acetone. The mixture is kept under reflux for ninety-six hours. Following this, it is cooled for twelve hours. 8.1 g (Yield: 84%) of 2-(2-furoyl)-1,4-dimethylpyridinium iodide (I) with a melting point of 190°-95° C. are removed by filtering. An analytical sample recrystallized from ethanol has a melting point of 202-3° C. Analysis calculated for C12H12NO2I: C: 43.78; H: 3.67; N: 4.25. Found: 43.76; H: 3.73; N: 4.50.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([CH2:14][OH:15])[C:12]([CH3:17])([CH3:16])[CH2:11][C:10]([CH3:19])([CH3:18])[CH:9]=2)=[CH:4][C:3]=1[CH3:20]>CS(C)=O.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([CH:14]=[O:15])[C:12]([CH3:16])([CH3:17])[CH2:11][C:10]([CH3:18])([CH3:19])[CH:9]=2)=[CH:4][C:3]=1[CH3:20]
Reactant: Cc1cc(C2=CC(C)(C)CC(C)(C)C2CO)ccc1F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(C2=CC(C)(C)CC(C)(C)C2C=O)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
Into a slurry of 61.4 g (0.222 mol) of 1-(4-fluoro-3-methylphenyl)-6-hydroxymethyl-3,3,5,5-tetramethylcyclohexene in 330 ml of DMSO and 194 ml of triethylamine is poured a solution of 106.0 g (0.666 mol) of sulfur trioxide pyridine complex in 330 ml of DMSO. The reaction mixture is then stirred for 30 min. Ice (660 g) is added and the reaction mixture is extracted twice with 300 ml of hexanes. The extracts are then backwashed thrice with 280 ml of 10% HCl, dried over anhydrous Na2SO4, filtered and concentrated in vacuo at 40° C. to yield 57.1 g (94%) of 2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethylcyclohex-2-enecarboxaldehyde suitable for use in the next step. A pure sample of 2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethylcyclohex-2-enecarboxaldehyde can be obtained via column chromatography on silica gel.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].O.ON1C2C=CC=CC=2N=N1.[CH3:31][C:32]([O:35][C:36](=[O:39])[CH2:37][NH2:38])([CH3:34])[CH3:33]>C(#N)C.O1CCCC1.O1CCCC1>[C:1]([NH:11][C@H:12]([C:17]([NH:38][CH2:37][C:36]([O:35][C:32]([CH3:34])([CH3:33])[CH3:31])=[O:39])=[O:19])[CH2:13][CH:14]([CH3:15])[CH3:16])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)CN
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a cold solution of 5.00 g of carbobenzoxy-L-leucine, 2.55 g of 1-hydroxybenzotriazole hydrate and 2.47 g of glycine 1,1-dimethylethyl ester in 100 ml of 1:1 acetonitrile/tetrahydrofuran is added dropwise a solution of 3.89 g of N,N-dicyclohexylcarbodiimide in 40 ml of tetrahydrofuran. The solution is stirred overnight allowing the ice bath to melt. The mixture is filtered and the solvent removed under reduced pressure. The residue is dissolved in ethyl acetate and washed with water, a 0.1M citric acid solution, a saturated sodium bicarbonate solution and then a saturated brine solution. After drying over magnesium sulfate, the solvent is removed under reduced pressure. The residue is chromatographed on silica gel eluting with 7:3 chloroform/ethyl acetate giving 6.68 g of an oil.
Reaction SMILES: Cl.[C:2]1([CH:8]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:9][N:10]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[C:30]=2[Cl:39])[CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:16](C)([CH3:26])C(C(C)C(O)=O)[CH:18]=[CH:19][CH:20]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:48](CC)CC.[CH2:53](OC([Cl:60])=O)[CH:54]([CH3:56])[CH3:55].[N-]=[N+]=[N-].[Na+]>O>[ClH:39].[ClH:60].[C:2]1([CH:8]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:9][N:10]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:26]([CH2:53][C:54]([CH3:56])([NH2:48])[CH3:55])[CH:16]=2)[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[C:30]=2[Cl:39])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C(=O)O)C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)C1(C)C
Reactant: CC(C)COC(=O)Cl
Reactant: CCN(CC)CC
Agent: Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: CC(C)(N)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A solution of N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-2,2-dimethyl-3-(3-aminopropoxy)phenylpropionic acid, hydrochloride (158 mg, 0.24 mmole) in 10 mL of Me2CO was treated with Et3N (56 mg, 0.55 mmole) and cooled in an ice bath. A solution of isobutylchloroformate (37 mg, 0.27 mmole) in 2 ml of Me2CO was added dropwise to the cold solution, and the reaction was stirred at 0° for 30 minutes. A solution of NaN3 (40 mg, 0.6 mmole) in 2 mL of H2O was added to the cold solution, and stirring was continued for 30 minutes. The reaction was diluted with H2O, and extracted with Et2O. The extracts were washed with H2O, and dried. The ethereal solution of the acyl azide was slowly added with stirring to 50 mL of refluxing toluene. After the addition, the toluene solution is stirred at 105° for 30 minutes, and all the solvents are removed. The residue is dissolved in 5 mL of dioxane, treated with 5 mL of 6N HCl and heated at 100° for 30 minutes. The reaction was cooled, diluted with H2O, made basic with aqueous NaOH and extracted with Et2O. The extracts were washed with H2O, dried, and the solvents removed. The residue was chromatographed on a silica gel column and the product was eluted with 10% MeOH in EtOAc. The chromatographed product was converted to the dihydrochloride salt in Et2O and isopropanol with 4N HCl in dioxane, and gave the titled product, 78 mg (55% yield). MS (ESI) 596 (MH+).