Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[C-:19]#[N:20].[K+]>CN(C)C=O>[C:19]([C:11]1[N:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:14]=[CH:13][N:12]=1)#[N:20]
Reactant: CS(=O)(=O)c1nccc(-c2cccc(C#N)c2)n1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2ccnc(C#N)n2)c1
Reaction time: 4 h

Procedure:
A mixture of 4-(3-cyanophenyl)-2-methylsulfonylpyrimidine and potassium cyanide in N,N-dimethylformamide is stirred for 4 hours at 100°. The reaction mixture is concentrated by evaporation, distilled water is added thereto and the whole is extracted with methylene chloride. The organic phase is dried and concentrated by evaporation to give the title compound.
Reaction SMILES: [OH-].[Na+].[C:3]([CH2:5][C:6]([O:8]C)=[O:7])#[N:4].[CH2:10]1[O:20][C:19]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][C:12]=2[O:11]1.Cl>>[C:3]([C:5](=[CH:15][C:14]1[CH:17]=[CH:18][C:19]2[O:20][CH2:10][O:11][C:12]=2[CH:13]=1)[C:6]([OH:8])=[O:7])#[N:4]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COC(=O)CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#CC(=Cc1ccc2c(c1)OCO2)C(=O)O
Temperature: 95 °C
Reaction time: 16 h

Procedure:
To an aqueous solution containing 14.20 g of sodium hydroxide and 33.75 g of methyl cyanoacetate, 30.32 g of 3,4-(methylenedioxy)benzaldehyde was added, followed by stirring at 95° C. for 16 hours. After completion of the reaction, an aqueous diluted hydrochloric acid solution was added to obtain a pale yellow solid. The resultant solid was recrystallized from ethanol to obtain a crystal having a melting point of 233° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=O.[NH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:7]
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: NCCN1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Nc1ccc(C(=O)NCCN2CCOCC2)cc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.9 %

Procedure:
3,4-Diaminobenzoic acid (5 g, 32.9 mmol), 4-(2-aminoethyl)morpholine (5.2 mL, 39.4 mmol), triethylamine (9.2 mL, 66 mmol), and DMAP (0.40 g, 3.3 mmol) were combined in dry DMF (80 mL) at 0° C. EDC (9.45 g, 49.3 mmol) was added, and the reaction stirred for 24 h at r.t. Concentration in vacuo and purification by silica gel chromatograpy (10% MeOH(CH2Cl2 with 0.2% NH4OH) gave 2.6 g (31%) of 3,4-diamino-N-(2-morpholin-4-yl-ethyl)-benzamide as a light brown solid. 1H NMR (300 MHz, DMSO-d6) δ 7.72 (t, 1H, J=5.4 Hz), 7.02 (d, 1H, J=1.8 Hz), 6.92 (dd, 1H, J=8.1, 1.8 Hz), 6.46 (d, 1H, J=8.1 Hz), 4.89 (br s, 2H), 4.51 (br s, 2H), 3.55 (t, 4H, J=4.8 Hz), 3.29 (q, 2H, J=7.2 Hz), 2.36-2.43 (m, 6H).
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[CH:17]1[C:29]2[CH:28]([CH2:30][O:31][C:32]([NH:34][C@@H:35]([CH2:39][C:40]([O:42][CH2:43][CH:44]=[CH2:45])=[O:41])[C:36]([OH:38])=[O:37])=[O:33])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1>ClCCl>[CH:26]1[C:27]2[CH:28]([CH2:30][O:31][C:32]([NH:34][C@@H:35]([CH2:39][C:40]([O:42][CH2:43][CH:44]=[CH2:45])=[O:41])[C:36]([O:38][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([CH3:7])[CH3:6])=[O:37])=[O:33])[C:29]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]=2[CH:23]=[CH:24][CH:25]=1
Reactant: C=CCOC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC(C)(OC(=N)C(Cl)(Cl)Cl)c1ccccc1
Solvent: ClCCl
Product: C=CCOC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
2-Phenylpropan-2-yl 2,2,2-trichloroacetimidate separately synthesized by a conventional method (2.17 g, 7.74 mmol) was added to a solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(allyloxy)-4-oxobutanoic acid (Compound 106) (1.80 g, 4.55 mmol) in dichloromethane (40 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→65/35) to afford 4-allyl 1-(2-phenylpropan-2-yl) (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)succinate (Compound 107) (2.17 g, 93%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(N(CC)CC)C.[CH3:20][O:21][C:22]1[CH:42]=[CH:41][C:25]([CH2:26][O:27][C:28](ON=C(C2C=CC=CC=2)C#N)=[O:29])=[CH:24][CH:23]=1>O.O1CCOCC1.[Cl-].[Na+]>[CH3:20][O:21][C:22]1[CH:42]=[CH:41][C:25]([CH2:26][O:27][C:28]([NH:1][CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[O:29])=[CH:24][CH:23]=1
Reactant: COc1ccc(COC(=O)ON=C(C#N)c2ccccc2)cc1
Reactant: NCCc1c[nH]c2ccccc12
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)NCCc2c[nH]c3ccccc23)cc1
Reaction time: 0.12 h
Yield: 81 %

Procedure:
To a suspension of 0.70 g (4.7 mmol) of tryptamine in 2.5 mL of deionized water and 0.65 mL (4.7 mmol) of triethylamine in a round bottom flask, equipped with an argon inlet, was added 1.45 g (4.7 mmol) of 2-(4-methoxybenzyloxycarbonyloxyimino)-2-phenylacetonitrile (MoZ-ON, Aldrich) in 5 mL of dioxane. During the first 5-10 minutes of stirring, the mixture became clear. This mixture was stirred for an additional 6 hours and diluted with 150 mL of saturated sodium chloride solution and extracted with 2×50 mL of ethyl acetate. The organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using hexane:ethyl acetate (1:1) as an eluent to yield (81%) N-(p-Methoxybenzyloxycarbonyl)tryptamine as white solid, mp. 108°-109° C.
Reaction SMILES: N(OCCC(C)C)=O.CS[S:11][CH3:12].[Br:13][C:14]1[CH:15]=[CH:16][C:17]([N:21]2[C:25]([CH3:26])=[N:24][N:23]=[N:22]2)=[C:18](N)[CH:19]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:21]2[C:25]([CH3:26])=[N:24][N:23]=[N:22]2)=[C:16]([S:11][CH3:12])[CH:15]=1
Reactant: Cc1nnnn1-c1ccc(Br)cc1N
Reactant: CSSC
Agent: CC(C)CCON=O
Product: CSc1cc(Br)ccc1-n1nnnc1C
Temperature: 85 °C
Yield: 140.3 %

Procedure:
A solution of isoamyl nitrite (402 μL, 3 mmol) in dimethyl disulfide (2 mL, 22 mmol) at 25° C. was slowly treated with 5-bromo-2-(5-methyl-tetrazol-1-yl)-phenylamine (0.51 g, 2 mmol). The reaction was exothermic with gas evolution. The resulting brown reaction mixture was heated to 80-90° C. for 2 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was cooled to 25° C. and then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (50 mL). The organic layer was washed successively with a 1N aqueous hydrochloric acid solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 6/1 to 5/1 hexanes/ethyl acetate) afforded 1-(4-bromo-2-methylsulfanyl-phenyl)-5-methyl-1H-tetrazole (0.8 g) as a brown solid that was used without further purification and characterization.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2.OS(O)(=O)=O>>[Br:6][C:7]1[CH:16]=[CH:15][C:14]([N+:1]([O-:4])=[O:2])=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2
Reactant: Brc1cccc2ncccc12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc(Br)c2cccnc12
Yield: 92.2 %

Procedure:
KNO3 (1.58 g, 15.6 mmol) was added portionwise to a solution of 5-bromoquinoline (2.0 g, 12.0 mmol) conc.H2SO4 (7.5 ml) at 0° C. and the mixture was stirred at room temperature for 16 h. The mixture was poured onto ice and the resulting solid was extracted into DCM. The organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to give the title compound (2.8 g, 92%) which was used in the next step without further purification.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH2:8]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:8]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[C:5]1/[C:4](=[O:6])[NH:3][C:2](=[O:7])[S:1]/1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C1CSC(=O)N1
Reactant: CCCCCCCCCCOCCCCC=O
Product: CCCCCCCCCCOCCCC/C=C1\SC(=O)NC1=O

Procedure:
TZD1c was prepared according to General Procedure A presented hereinabove, using 2,4-thiazolidinedione and 5-(decyloxy)pentanal as reactants.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4[C:32]4[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[C:34]([CH2:40][CH2:41][C:42]([O:44]C)=[O:43])[CH:33]=4)[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[OH-].[Li+].OO>C1COCC1.O.[O-]S([O-])=O.[Na+].[Na+]>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[CH:24][C:23]=4[C:32]4[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[C:34]([CH2:40][CH2:41][C:42]([OH:44])=[O:43])[CH:33]=4)[CH2:20][CH2:21][C@@H:14]23)[CH:4]=[C:3]([C:2]([F:1])([F:47])[F:46])[CH:8]=1
Reactant: COC(=O)CCc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2[C@@H]2CC[C@H]3[C@@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)OC(=O)N23)c1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CCC(=O)O)cc1-c1ccc(C(F)(F)F)cc1[C@@H]1CC[C@H]2[C@@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)OC(=O)N12
Temperature: 25 °C
Yield: 46.7 %

Procedure:
To methyl 3-[2′-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]propanoate (20 mg, 0.03 mmol) in THF (2 mL) and water (0.5 mL) was added lithium hydroxide-monohydrate (6.21 mg, 0.148 mmol) and hydrogen peroxide (30%, 33.6 mg, 0.296 mmol). The reaction mixture was stirred at room temperature. Upon completion the reaction was diluted with water (10 mL), and solid Na2SO3 was added to quench hydrogen peroxide. The solution was acidified with aqueous HCl (1 M) and was partitioned with ethyl acetate (20 mL). The organic was dried over sodium sulfate, filtered and concentrated before purification by reverse phase HPLC to yield 3-[2′-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]propanoic acid (9 mg, 0.014 mmol). 1H NMR indicated that this compound exists as a pair of rotamers at a 3:1 ratio. 1H NMR (500 MHz, CDCl3) δ7.87 (s, 1H), 7.82 (s, 2H), 7.75 (s, 1H, minor rotamer), 7.73 (s, 1H, major rotamer) 7.6 (m, 1H) 6.9-7.4 (m, 4H), 6.08 (d, J=8.1 Hz, 1H, major rotamer), 5.15 (t, 1H, minor rotamer) 5.06 (t, J=8.2 Hz, 1H, major rotamer), 4.6 (m, 1H, major rotamer) 4.45 (m, 1H, minor rotamer), 4.98 (m, 1H, minor rotamer), 4.1 (m, 1H), 3.85 (s, 3H, minor rotamer), 3.69 (s, 3H, major rotamer), 2.4-3.1 (m, 4H), 0.9-1.9 (m, 4H). MS ESI calc'd. for C31H25F9NO5 [M+H]+ 662.2, found 662.3. RTA (95% HS): 128 nM
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=1)[C:5]([C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH3:12])=O.[ClH:21].[N:22]1([C:28](=[NH:30])[NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.CC(C)([O-])C.[K+]>C(O)C>[ClH:21].[CH3:12][C:8]1[O:9][CH:10]=[CH:11][C:7]=1[C:5]1[C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[CH:3][N:29]=[C:28]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:30]=1
Reactant: N=C(N)N1CCCCC1
Reactant: Cc1cc(C(=CN(C)C)C(=O)c2ccoc2C)ccn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1cc(-c2cnc(N3CCCCC3)nc2-c2ccoc2C)ccn1
Temperature: 25 °C
Yield: 30.7 %

Procedure:
A mixture of 3-(dimethylamino)-1-(2-methyl-3-f uranyl)-2-(2-methyl-4-pyridinyl)-2-propen-1-one (270 mg, 1 mmol) and 1-piperidinecarboximidamide hydrochloride (245 mg, 1.500 mmol) in ethanol (4 ml) was stirred at room temperature. Potassium tert-butoxide (224 mg, 2.000 mmol) was added and the mixture was heated at reflux for 90 minutes. After cooling to room temperature the solvent was evaporated and the residue was diluted with water and extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 30-100% ethyl acetate in isohexane. The resulting oil was dissolved in dichloromethane (2 ml) and was treated with hydrogen chloride (1M in diethyl ether, 1 ml). The solvent was evaporated and the residue co-evaporated with diethyl ether (×2). The residue was triturated with diethyl ether and the resulting solid was collected, washed with diethyl ether and dried to give the title compound as a pale yellow solid (114 mg, 31%). LC/MS [M+H]+=335. 1H NMR (400 MHz, d6-DMSO): δ 8.60 (2H, d), 8.55 (1H, s), 7.83 (1H, b), 7.58-7.54 (1H, m), 7.51 (1H, d), 6.03 (1H, d), 3.90-3.85 (4H, m), 2.67 (3H, s), 2.38 (3H, s), 1.70-1.53 (6H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](F)=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1>C1COCC1>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][C:18]=1[N+:23]([O-:25])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCOc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of (3-Hydroxy-propyl)-carbamic acid tert-butyl ester (11 mmoles, 1.88 ml) in THF (20 ml) was added to a suspension of sodium hydride 50% grade (23 mmoles, 1.058 g) in THF (20 ml) and stirred at 50° C for 1 hour. Following cooling to 0° C., 4-Chloro-1-fluoro-2-nitro-benzene was added and the mixture stirred at RT overnight. After quenching with water, the organic layer was separated and the aqueous layer was extracted several times with Ethyl acetate. The combined organic layers were washed with water then brine, and dried over sodium sulfate. The crude reaction was purified by flash chromatography to afford [3-(4-Chloro-2-nitro-phenoxy)-propyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[I:30])[CH2:5][C@H:6]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:7](=O)[NH:8][CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[NH4+:35]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C@H:6]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:7]2[NH:35][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][N:8]=2)[CH:27]=[CH:28][C:29]=1[I:30]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)c(Cl)c1)C(=O)NCC(=O)c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)c(Cl)c1)c1ncc(-c2ccccc2)[nH]1
Temperature: 120 °C
Yield: 67 %

Procedure:
tert-Butyl (1S)-1-(3-chloro-4-iodobenzyl)-2-oxo-2-[(2-oxo-2-phenylethyl)-amino]ethylcarbamate (3.1 g, 5.7 mmol) and ammonium acetate (30.0 g, 0.389 mol) were dissolved in DMF (50 mL). The solution was separated into 6 batches, and each batch was heated in the microwave at 120° C. for 30 minutes. The solution was diluted with ethyl acetate (600 mL) and washed with water (600 mL). After the organic layer was dried over sodium sulfate, the solution was concentrated. Purification by silica gel chromatography (20–40% ethyl acetate:hexanes) afforded product as a white solid (2.0 g, 67%). 1H NMR (400 MHz, CD3OD): δ 7.86–7.78 (m, 2H), 7.73–7.68 (m, 2H), 7.59–7.50 (m, 3H), 7.40–7.37 (m, 1H), 6.89–6.87 (m, 1H), 5.13–5.11 (m, 1H), 3.40–3.25 (m, 2H), 1.38 (s, 9H). LCMS found for C22H24ClIN3O2 (M+H)+: m/z=524.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[CH2:8]([S:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[C:18]([Cl:23])[N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>CN(C=O)C.CCOC(C)=O>[CH2:8]([S:15][C:16]1[N:21]=[C:20]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:19]=[C:18]([Cl:23])[N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1cc(Cl)nc(SCc2ccccc2)n1
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc(Cl)nc(SCc2ccccc2)n1
Reaction time: 1 h

Procedure:
To methane sulphonamide (1.47 g) in DMF (30 ml) was added 60% sodium hydride (0.59 g) at room temperature and stirred for 1 h. To this mixture was then added the subtitle product of step ii) and the mixture stirred at room temperature for 6 h. To the reaction mixture was added EtOAc (50 ml) and aqueous hydrochloric acid (50 ml, 1M). The organic layer was separated and washed with brine (20 ml), combined, dried (MgSO4) and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (20 to 50% EtOAc/iso-hexane) to afford the subtitle compound as a yellow oil. Yield: 1.60 g.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([S:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:16](Cl)(Cl)=[O:17].C1(C)C=CC=CC=1>>[F:1][C:2]1[CH:8]=[C:7]([S:9][C:10]([F:15])([F:14])[CH:11]([F:12])[F:13])[CH:6]=[CH:5][C:3]=1[N:4]=[C:16]=[O:17]
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(SC(F)(F)C(F)F)cc1F
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(SC(F)(F)C(F)F)cc1F

Procedure:
To 140 ml of 4% phosgen-toluene solution was added 3.6 g of 2-fluoro-4-(1,1,2,2-tetrafluoroethylthio)aniline, and the mixture was heated under reflux for 3 hours. After the conclusion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure to give 2-fluoro-4-(1,1,2,2-tetrafluoroethylthio)phenyl isocyanate as an oily material. The oily material was dissolved in 50 ml of xylene, and 1.5 g of 2,6-difluorobenzamide was added to the solution, followed by heating under reflux for 20 hours. After the conclusion of the reaction, the reaction mixture was cooled (0° C.), and the crystals which separated out were recovered by filtration, and further recrystallized from acetone to give N-(2,6-difluorobenzoyl)-N'-[2-fluoro-4-(1,1,2,2-tetrafluoroethylthio)phenyl]urea (Compound No. 1) as crystals having a m.p. of 177°-179° C. The resulting compound was found to show no decrease in melting point even when admixed with the authentic sample as obtained in Example 2.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[Cl:6][SiH:7]([Cl:9])[Cl:8]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:6][Si:7]([Cl:9])([Cl:8])[C:2]([CH2:3][CH:4]([Si:7]([Cl:9])([Cl:8])[Cl:6])[CH3:5])=[CH2:1]
Reactant: C1=CCC=C1
Reactant: Cl[SiH](Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: C=C(CC(C)[Si](Cl)(Cl)Cl)[Si](Cl)(Cl)Cl
Temperature: 180 °C
Yield: 8.8 %

Procedure:
As in Example 1, 1,3-cyclopentadiene (1.00 g, 15.13 mmol), trichlorosilane (8.19 g, 60.47 mmol) and tetrabutylphosphonium chloride (0.44 g, 1.49 mmol) were added in a 25 mL stainless steel tube under nitrogen atmosphere. After sealing the cylinder with a cap, the reactor was maintained at 180° C. for 10 hours. The resulting mixture was distilled to yield 0.45 g (yield: 9%) of 2,4-bis(trichlorosilyl)-1-pentene.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[CH2:14]([O:21][C:22]([NH:24][CH2:25][C@H:26]([NH:30][C:31]([O:33]C(C)(C)C)=O)[C:27]([OH:29])=[O:28])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(=O)O[C:41](=[O:42])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12>ClCCl.Cl.C1(C)C=CC=CC=1>[CH2:14]([O:21][C:22]([NH:24][CH2:25][C@H:26]([N:30]1[C:31](=[O:33])[C:39]2=[CH:47][CH:46]=[CH:45][CH:44]=[C:40]2[C:41]1=[O:42])[C:27]([OH:29])=[O:28])=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C1OC(=O)c2ccccc21
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(NC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of (2S)3-benzyloxycarbonylamino-2-tert-butoxycarbonylaminopropionic acid dicyclohexylamine salt (3 g, 5.8 mmol) in dichloromethane (200 ml) was washed four times with 1M HCl solution, dried (MgSO4) and concentrated. The resulting oil was dissolved in dry dichloromethane (35 ml), cooled to 0° C. and treated with trifluoroacetic acid (35 ml). This solution was stirred at 0° C. for 1.5 h then evaporated to dryness. Dichloromethane (50 ml) was added to the residue then removed under vacuum. This process repeated six times to afford a white solid. The white solid was suspended in toluene (50 ml), treated with powdered phthalic anhydride (940 mg, 6.35 mmol) and refluxed for 18 h. The resulting solution was concentrated to afford an oil which was purified by flash chromatography (2-10% methanol/dichloromethane) to afford 266, 2.01 g (94%) as a white powder: IR (KBr) 3600-2500br, 1776, 1714, 1530, 1469, 1455, 1392, 1263, 1131, 722; 1H NMR (CDCl3) δ 7.83 (2H, m), 7.72 (2H, m), 7.29 (5H, m), 5.41 (1H, m), 5.03 (2H, s), 3.90 (2H, m); MS (ES−), 367 (M−1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:19]1([CH2:25][CH:26]([CH3:29])[CH2:27]Cl)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([CH2:25][CH:26]([CH3:29])[CH2:27][O:1][C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[O:5][C:4](=[O:12])[C:3]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(CCl)CN1CCCCC1
Reactant: O=c1oc2c(c(O)c1-c1ccccc1)CCCC2
Product: CC(COc1c2c(oc(=O)c1-c1ccccc1)CCCC2)CN1CCCCC1
Yield: 82 %

Procedure:
Prepared according to the method of Example 13 by alkylation of 4-hydroxy-3-phenyl-5,6,7,8-tetrahydrocoumarin with 3-piperidino-2-methyl-1-chloropropane. A thick oil is obtained which cannot be crystallised. Yield 82%.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[F:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N(CC)CC)C>C(#N)C>[F:33][CH:34]1[CH2:39][CH2:38][N:37]([C:2]2[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:13][CH:12]=3)=[O:9])=[CH:4][CH:3]=2)[CH2:36][CH2:35]1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Br)nc3)cc2)CCN1C(=O)OC(C)(C)C
Reactant: FC1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(N4CCC(F)CC4)nc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 10 h
Yield: 103.1 %

Procedure:
A mixture of 1,1-dimethylethyl (2S)-4-({4-[[(6-bromo-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D108) (0.050 g, 0.0993 mmol), 4-fluoropiperidine (0.055 g, 0.397 mmol) and triethylamine (0.069 mL, 0.497 mmol) in acetonitrile (4 mL) was heated at 85° C. overnight then in a microwave at 140° C. for 10 h. Further portions of 4-fluoropiperidine (5 eq.) and triethylamine (5 eq.) were added and the reaction heated at 170° C. for 2 h. The reaction mixture was concentrated and the residue dissolved in DCM/water. The aqueous layer was further extracted with DCM (×3) and the combined organics were dried (Na2SO4) and concentrated to give the title compound as a yellow oil (0.0538 g). MS (ES): MH+ 526.2.