Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2OC(S)=[N:9][N:8]=2)C=CC=CC=1.[C:13]([OH:21])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-:22].[Na+]>O>[O:22]1[CH:1]=[C:7]([C:19]2[C:14]([C:13]([OH:21])=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:8]=[N:9]1
Reactant: Sc1nnc(-c2ccccc2)o1
Reactant: O=C(O)c1ccccc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccccc1-c1conn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of men- phenyl-1,3,4-oxadiazole-2-thiol and a benzoic acid in water was added NaOH. After stirring at RT for 16 h, the reaction mixture's pH was adjusted to 2 upon addition of aqueous solution of HCI (10%). The precipitate was collected by filtration. The solid was dissolved in acetone and purified by MPLC (30-70% ethyl acetate in hexanes) to afford the corresponding oxadiazol-benzoic acid.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[CH3:11]O>>[ClH:1].[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: CO
Reactant: NCCCCCC(=O)O
Agent: Cl
Product: COC(=O)CCCCCN
Reaction time: 3 h
Yield: 99 %

Procedure:
Hydrogen chloride (gas) was added to a solution of 20.0 g (152 mmol) of 6-aminocaproic acid in 250 ml of methanol via rapid bubbling for 2-3 minutes. The mixture was stirred at 15°-25° C. for 3 hours and then concentrated to afford 27.5 g of the product as a white solid (99%):
Reaction SMILES: [CH3:1][O:2][N:3]([CH2:8][CH2:9][CH2:10][P:11](=[O:18])([O:15]CC)[O:12]CC)C(OC)=O.C(O)(=O)C.Cl.N1C=CC=CC=1>C(O)C>[CH3:1][O:2][NH:3][CH2:8][CH2:9][CH2:10][P:11](=[O:12])([OH:18])[OH:15]
Reactant: CCOP(=O)(CCCN(OC)C(=O)OC)OCC
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CONCCCP(=O)(O)O
Yield: 63.6 %

Procedure:
A mixture of diethyl 3-(N-methoxy-N-methoxycarbonylamino)propylphosphonate (4.0 g), acetic acid (20 ml) and conc. hydrochloric acid (20 ml) was refluxed for 15 hours. The resultant mixture was concentrated under reduced pressure to give a residue, which was dissolved in ethanol (15 ml). The solution was neutralized with pyridine to give crystals, which were separated by filtration, washed with a small volume of ethanol and dried to give crystalline 3-(N-methoxyamino)propylphosphonic acid (1.52 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[NH3:23]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[NH2:23][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: N
Reactant: CC(C)(C)n1cc(C(=O)c2cncc(Br)c2)c2cncnc21
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CC(C)(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Temperature: 140 °C
Reaction time: 17 h
Yield: 49 %

Procedure:
Copper sulfate pentahydrate (55 mg, 0.24 mmol) was added to (5-bromopyridin-3-yl)(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (292 mg, 0.81 mmol) (see Preparation 30) and concentrated ammonia solution (20 mL). The mixture was heated in a sealed vessel at 140° C. for 17 hours. The reaction mixture was evaporated in vacuo and the residue was stirred in aqueous hydrochloric acid (10 mL, 2M) at room temperature for 17 hours. The reaction mixture was basified to pH 9 using saturated aqueous sodium carbonate then extracted with DCM (3×20 mL). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to afford the title compound as a white solid in 49% yield, 240 mg.
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[C:5]([N+:27]([O-])=O)=[C:6]([C:16]([NH:18][CH:19]2[CH:24]3[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]3)[CH2:20]2)=[O:17])[C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]=2[CH:15]=1>CN(C)C=O.[Fe]>[ClH:3].[NH2:27][C:5]1[C:4]([Cl:3])=[CH:15][C:8]2[N:9]([CH3:14])[C:10](=[O:13])[CH2:11][O:12][C:7]=2[C:6]=1[C:16]([NH:18][CH:19]1[CH:24]2[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]2)[CH2:20]1)=[O:17]
Reactant: CN1C(=O)COc2c1cc(Cl)c([N+](=O)[O-])c2C(=O)NC1CN2CCC1CC2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN1C(=O)COc2c1cc(Cl)c(N)c2C(=O)NC1CN2CCC1CC2
Product: Cl

Procedure:
To a solution of 12 ml of 0.78N aqueous ammonium chloride and 5 ml of dimethylformamide with heating at 85° C. is added 4.8 g of powdery iron under stirring and then a solution of 8.0 g of 6-chloro-3,4-dihydro-4-methyl-7-nitro-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide in 40 ml of dimethylformamide is added over 10 minutes. The mixture is stirred at 80°-90° C. for an hour and filtered with suction through cellite under heating. The solvent is distilled off and to the residue is added 10 ml of cold water. The crystals are collected by filtration and washed with cold water and recrystallized from ethanol-water to give 7-amino-6-chloro-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide hydrochloride, melting above 320° C. 1 -NMR(DMSO):δ(ppm)=1.40-2.30 and 2.76-4.50(each m), 3.22(s, 3H), 4.70(s,2H), 5.28(s,2H), 7.18(s,1H), 8.74(d,1H)
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[C:15]([O:21][CH3:22])=[CH:14][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:5].Cl.[H][H]>CCO.[Pd]>[NH2:18][C:16]1[C:15]([O:21][CH3:22])=[CH:14][C:3]([C:4]([NH:6][CH:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)=[O:5])=[C:2]([F:1])[CH:17]=1
Reactant: [H][H]
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1N
Yield: 100.4 %

Procedure:
To a solution of 2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)-4-nitrobenzamide (55 g, 177 mmol) in EtOH (450 mL) was added 10% Pd/C (11 g), followed by 4.4 mL of concentrated HCl. The reaction mixture was hydrogenated using a hydrogen balloon for 22 h. The solution was filtered through celite and concentrated to a minimum volume, after which solid was filtered, washed with ether. The filtrate concentrated again and trituated with EtOH and repeated several times to get out more products. The solid was combined and further dried to give total 50 g of product as light yellow powder (>98%). 1H NMR (400 MHz, DMSO-d6) δ 1.64-2.02 (m, 4H) 2.61 (s, 3H) 2.90 (t, J=11.0 Hz, 2H) 3.24 (m, 2H) 3.72-3.81 (m, 3H) 3.84-4.03 (m, 1H) 5.60 (s, 2H) 6.29-6.50 (m, 1H) 7.01 (d, J=6.8 Hz, 1H) 7.69 (dd, J=7.3, 4.8 Hz, 1H). [M+H] calc'd for C14H20FN3O2, 282. found 282.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]2>>[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([NH:6][C:25]([C:20]1[NH:21][C:22]2[C:18]([CH:19]=1)=[CH:17][C:16]([Cl:15])=[CH:24][CH:23]=2)=[O:26])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
L-Phenylalanine methyl ester hydrochloride (77.0 mmol) and 5-chloro-1 H-indole-2-carboxylic acid (77 mmol) were coupled according to procedure A (0-25° C.) and the product purified by chromatography on silica gel in 10 and 20% ethyl acetate-hexanes giving the title substance as an off-white solid (22.12 g, 81%): mp 156-157° C.; HPLC (60/40) 9.5 minutes (98%); PBMS 357/359 (MH+, 100%).
Reaction SMILES: COC[N:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([C:15]3[CH:19]=[CH:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29]C5CCCCO5)=[CH:22][N:21]=4)[N:16]=3)[CH3:14])=[CH:12][C:7]=2[S:6][C:5]1=[O:36].FC(F)(F)C(O)=O.C1COCC1.[OH-].[NH4+]>CCOC(C)=O>[OH:29][CH2:28][CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([N:17]2[CH:18]=[CH:19][C:15]([CH:13]([C:11]3[CH:10]=[CH:9][C:8]4[NH:4][C:5](=[O:36])[S:6][C:7]=4[CH:12]=3)[CH3:14])=[N:16]2)=[N:21][CH:22]=1
Reactant: COCn1c(=O)sc2cc(C(C)c3ccn(-c4ccc(OCCOC5CCCCO5)cn4)n3)ccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(c1ccc2[nH]c(=O)sc2c1)c1ccn(-c2ccc(OCCO)cn2)n1
Temperature: 72 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Dissolve 3-(methoxymethyl)-6-{1-[1-(5-{2-(tetrahydro-2H-pyran-2-yloxy)ethoxy}pyridine-2-yl)-1H-pyrazol-3-yl]ethyl}-3H-1,3-benzothiazol-2-one (140 mg, 274.18 μmoles) in trifluoroacetic acid (0.05 M; 73 mmoles; 5.5 mL) and heat at reflux (˜72° C.) under N2 for 2 hr. (orange color observed after about 10 min. and at 70° C.). Cool the reaction to room temperature and concentrate under reduced pressure. Dissolve the residue in THF (0.05 M; 67 mmoles, 5.5 mL), add 28% ammonium hydroxide (0.2 M; 9.9 mmoles; 1.4 mL), and stir at room temperature for ˜1 hr. Dilute with EtOAc (100 ml), wash with brine, dry over sodium sulfate, filter and concentrate. Purify by liquid chromatography on a 25 g silica gel column, eluting with a gradient of 60-80% EtOAc in hexanes to give 6-(1-{1-[5-(2-hydroxy-ethoxy)-pyridin-2-yl]-1H-pyrazol-3-yl}-ethyl)-3H-1,3-benzothiazol-2-one as a white foam (80 mg; 209 μmoles; 76% yield). LCMS (Low) rt 1.8 min., M+1=383.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[CH:5]=[C:6]([O:8][CH2:9][CH2:10][F:11])[CH:7]=1.[BH4-].[Na+].C(OCC)C.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([O:8][CH2:9][CH2:10][F:11])[CH:7]=1)[NH2:12]
Reactant: O=[N+]([O-])c1cc(Br)cc(OCCF)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Nc1cc(Br)cc(OCCF)c1
Temperature: 25 °C

Procedure:
A solution of 3-bromo-5-fluoroethoxynitrobenzene, as described above in Step D, (990 mg, 3.75 mmol) in tetrahydrofuran (22 mL) was added to a mixture of NaBH4/S3 (1.2 g) in tetrahydrofuran (15 mL) and the resulting mixture was placed in a 60° C. oil bath and heated overnight. The reaction was cooled to room temperature and concentrated using the rotary evaporator giving a yellow solid. Diethyl ether was added and 10% HCl until the pH was 1. The resulting mixture was filtered through celite and the layers were separated. The aqueous layer was washed with diethyl ether. The aqueous layer was made basic (pH>10) with diethyl ether present, the layers were separated and the aqueous layer was extracted with diethyl ether and ethyl acetate. The organic layers were combined and dried (MgSO4), filtered and concentrated in vacuo to give 3-bromo-5-fluoroethoxyaniline as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:31])[N:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][Br:30])=[CH:25][CH:24]=3)[N:21]=[C:8]2[N:7]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)[C:6]=1[CH3:42])=[O:4]>CN(C)C.C(O)C>[Br-:30].[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH:10]2[N:9]3[C:19](=[O:31])[N:20]([CH2:22][C:23]4[CH:24]=[CH:25][C:26]([CH2:29][N+:7]([CH3:32])([CH3:8])[CH3:6])=[CH:27][CH:28]=4)[N:21]=[C:8]3[N:7]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:40])([F:39])[F:41])[CH:33]=3)[C:6]([CH3:42])=[C:5]2[C:3]([O:2][CH3:1])=[O:4])=[CH:12][CH:13]=1)#[N:18]
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(Cc3ccc(CBr)cc3)c(=O)n2C1c1ccc(C#N)cc1
Agent: CN(C)C
Solvent: CCO
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(Cc3ccc(C[N+](C)(C)C)cc3)c(=O)n2C1c1ccc(C#N)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 111.1 %

Procedure:
Intermediate 15 (105 mg, 0.16 mmol) was dissolved in a solution of 31% trimethylamine in ethanol. The reaction mixture was stirred at RT for 16 hours and then filtered. The solid was collected by filtration and dried in vacuo to yield the title compound as a white solid (62 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:26]([OH:28])=[O:27])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[I:29][CH2:30][CH2:31][CH2:32]O>CO.C(Cl)Cl>[I:29][CH2:30][CH2:31][CH2:32][O:27][C:26](=[O:28])[C@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:17][C:15](=[O:16])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: OCCCI
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: CO
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCCCI

Procedure:
Following General Procedure B and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (prepared by coupling N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylalanine (Aldrich) using General Procedure B) and 3-iodo-1-propanol (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.45 in 5% MeOH/methylene chloride) and the product was purified by preparative tlc using 5% MeOH/methylene chloride.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([O:7][C@H:8]2[CH2:12][CH2:11][C@@H:10]([O:13][Si](C(C)(C)C)(C)C)[CH2:9]2)=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)C>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][C:4]([O:7][C@H:8]2[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](Oc2ccc(-c3ccccc3)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O[C@@H]1CC[C@H](Oc2ccc(-c3ccccc3)cc2)C1
Yield: 100 %

Procedure:
(1R*,3S*)-[3-(Biphenyl-4-yloxy)-cyclopentyloxy]-tert-butyldimethylsilane (0.25 g, 0.67 mmol) was dissolved in 2 mL of THF and tetrabutylammonium fluoride (0.67 mL, 1M in THF) and stirred at room temperature for 2 hours. The solution was diluted with 15 mL of diethyl ether and washed with 1N HCl (2×15 mL). The organic layer was dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (silica gel, hexanes/ethyl acetate 3:1, Rf0.09) to give the product (100%). 1H-NMR (200.15 MHz, CDCl3): δ 7.58–7.26 (m, 7H), 6.95 (d, 2H, J=8.9), 4.92–4.84 (m, 1H), 4.40–4.38 (m, 1H), 2.18–1.92 (m, 7H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN(C)C=O.[BH4-].[Na+].[F:21][C:22]([F:26])([F:25])CBr>O>[N+:11]([C:3]1[CH:4]=[C:5]([S:8][CH2:9][C:22]([F:26])([F:25])[F:21])[CH:6]=[CH:7][C:2]=1[NH2:1])([O-:13])=[O:12]
Reactant: FC(F)(F)CBr
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(SCC(F)(F)F)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1 h

Procedure:
4.4 G. of 1-amino-2-nitro-4-thiocyanatobenzene in 10 ml. of dimethylformamide is treated under nitrogen with 0.85 g. of sodium borohydride in 10 ml. of DMF at not greater than 30° C. The mixture is stirred at 15° to 20° C for 1 hour, then treated with 5 g. of 1,1,1-trifluoro-2-bromoethane at 20° to 25° C. The mixture is heated to 100° C for 3 hours, cooled and diluted with water. The mixture is extracted with chloroform and the chloroform solution is dried over sodium sulfate. 2-Nitro-4-(2,2,2-trifluoroethylthio) aniline is obtained upon evaporation of the solution.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[S:13][C:12]([NH2:14])=[N:11][N:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1C=CC([NH:20][C:21](N)=[S:22])=N1>>[N:1]1([CH2:7][CH2:8][C:9]2[S:13][C:12]([NH:14][C:21]([NH2:20])=[S:22])=[N:11][N:10]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1nnc(CCN2CCOCC2)s1
Reactant: NC(=S)Nc1cc[nH]n1
Product: NC(=S)Nc1nnc(CCN2CCOCC2)s1

Procedure:
The titled compound is prepared from 5-(2-Morpholin-4-yl-ethyl)-[1,3,4]thiadiazol-2-ylamine (54b) following the procedure described for (1H-pyrazol-3-yl)-thiourea (35a)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14][S:15]([C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[CH:22]=1)(=[O:17])=[O:16].[C:30](Cl)(=[O:32])[CH3:31].N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C.Cl>[O:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[CH:22]=[C:18]1[S:15]([NH:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[S:6][CH2:5][C:4]1[CH:3]=[C:2]([NH:1][C:30](=[O:32])[CH3:31])[CH:29]=[CH:28][CH:27]=1)(=[O:17])=[O:16]
Reactant: Nc1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a solution of N-{2-[(3-aminobenzyl)sulfanyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide (440 mg, 0.90 mmol) in CH2Cl2 (10 ml) was added acetyl chloride (71 μl, 0.99 mmol), pyridine (180 μl, 2.25 mmol), and catalytic amount of DMAP. The reaction was stirred at room temperature for 2 hours, diluted with 1M HCl, and extracted with CH2Cl2. The organic layer was dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5-10% EtOAc in hexane) to yield the title compound (330 mg, 68%).
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([NH:7]/[N:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][CH:2]=1.[N+]([C:24]([CH2:51][CH2:52][CH2:53][CH3:54])=[CH:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][C:27]=1[C:39]([N:41]1[CH2:50][CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42]1)=[O:40])([O-])=O>>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:5][C:4]([N:7]2[C:24]([CH2:51][CH2:52][CH2:53][CH3:54])=[C:25]([C:26]3[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])=[CH:28][C:27]=3[C:39]([N:41]3[CH2:50][CH2:49][C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42]3)=[O:40])[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:8]2)=[CH:3][CH:2]=1
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Reactant: CCOC(=O)/C=N/Nc1ccc(-c2ccccc2)cc1
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1ccc(-c2ccccc2)cc1
Yield: 61.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223E, (E)-ethyl 2-(2-(biphenyl-4-yl)hydrazono)acetate (35 mg, 0.13 mmol) and tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (60 mg, 0.13 mmol) were converted to the title compound (55 mg, 62%) as a pale yellow solid. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.13 (dd, J=8, 2 Hz, 1H), 8.09-8.07 (m, 1H), 7.74-7.43 (m, 10H), 7.23-6.86 (m, 4H), 5.02-4.98 (m, 1H), 4.55-4.47 (m, 1H), 4.37-4.31 (m, 2H), 4.20-4.02 (m, 1H), 3.58-3.35 (m, 1H), 2.90-2.51 (m, 4H), 1.61 (s, 9H), 1.32 (t, J=8 Hz, 1.5H), 1.26 (t, J=8 Hz, 1.5H), 1.21-0.97 (m, 4H), 0.66-0.62 (m, 3H); MS (ESI+) m/z 684.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11](=O)[CH2:12][C:13]([O:15]CC)=O)[CH2:7][CH2:6]1)=[O:4].[NH2:19][C:20]1[CH:24]=[CH:23][NH:22][N:21]=1>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:12]=[C:13]([OH:15])[N:21]3[N:22]=[CH:23][CH:24]=[C:20]3[N:19]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: CCOC(=O)CC(=O)C1CCC(C(=O)OC)CC1
Reactant: Nc1cc[nH]n1
Solvent: ClCCl
Product: COC(=O)C1CCC(c2cc(O)n3nccc3n2)CC1
Temperature: 100 °C

Procedure:
4-(2-Ethoxycarbonyl-acetyl)-cyclohexanecarboxylic acid methyl ester (8.5 g) and 3-amino-1H-pyrazole (26.5 mmol, 2.2 g) were mixed and heated neat at 100° C. for 16 hours. The resulting residue is dissolved in dichloromethane (100 mL) and concentrated in vacuo to remove water formed during cyclization. This solid is taken forward without further purification. LC-MS: 403 [M+H].
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([CH2:11][CH3:12])[NH:5][N:4]=1)[CH3:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([C:6]1[C:7]([CH2:8][CH2:9][O:10][S:14]([CH3:13])(=[O:16])=[O:15])=[C:3]([CH2:1][CH3:2])[N:4]([S:14]([CH3:13])(=[O:16])=[O:15])[N:5]=1)[CH3:12]
Reactant: CCc1n[nH]c(CC)c1CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nn(S(C)(=O)=O)c(CC)c1CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.4 %

Procedure:
To a solution of 2-(3,5-diethyl-1H-pyrazol-4-yl)-ethanol (0.8 g, 4.8 mmol) in methylene chloride (20 mL) was added methanesulfonyl chloride (0.92 mL, 12 mmol) and triethylamine (2.0 mL, 14 mmol). The mixture was stirred at room temperature for 16 h and was loaded directly on to a silica gel column and eluted (methylene chloride/heptane followed by ethyl acetate/methylene chloride) to provide methanesulfonic acid 2-(3,5-diethyl-1-methanesulfonyl-1H-pyrazol-4-yl)-ethyl ester (940 mg, 41% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[O:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[F:20][C:21]1[CH:44]=[CH:43][C:24]([C:25]([NH:27][C:28]2[S:29]C3C=CC=C(N4CCOCC4)C=3N=2)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:44]=[CH:43][C:24]([C:25]([NH:27][C:28]2[S:29][C:3]3[C:2]([N:16]4[CH2:17][CH2:18][CH2:19][O:13][CH2:14][CH2:15]4)=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[C:4]=3[N:10]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Reactant: C1CNCCOC1
Reactant: O=C(Nc1nc2c(N3CCOCC3)cccc2s1)c1ccc(F)cc1
Product: COc1ccc(N2CCCOCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
The title compound was prepared strarting from 4-bromo-1-methoxy-2-nitro-benzene and [1.4]Oxazepane as described for 4-fluoro-N-(4-morpholin-4-yl-benzothiazol-2-yl)-benzamide (Example 275) and obtained as a light yellow solid in about 10% overall yield, MS: m/e=402 (M+H+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[NH:8][C:7](=O)[N:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:4]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:7]1[N:8]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=1
Reactant: O=c1nc(-c2cccc(C(F)(F)F)c2)cc(C(F)(F)F)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(Cl)n2)c1

Procedure:
The title compound was prepared from 6-trifluoromethyl-4-(3-trifluoromethyl-phenyl)-1H-pyrimidin-2-one (7.85 g, 25.5 mmol) and phosphoroxychloride (85 mL) according to the general procedure I. Obtained as a yellow solid (5.33 g, 64%). MS (EI) 326.1 [(M)+]; mp 65° C.
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:13](O)(=[O:19])[CH2:14][CH2:15][C:16]([CH3:18])=O>CCCCOCCO>[CH3:18][C:16]12[C:5]3[NH:6][C:7]4[C:12]([C:4]=3[CH2:3][CH2:2][N:1]1[C:13](=[O:19])[CH2:14][CH2:15]2)=[CH:11][CH:10]=[CH:9][CH:8]=4
Reactant: CC(=O)CCC(=O)O
Reactant: NCCc1c[nH]c2ccccc12
Solvent: CCCCOCCO
Product: CC12CCC(=O)N1CCc1c2[nH]c2ccccc12

Procedure:
Tryptamine (112.15 g.), levulinic acid (97.6 g., 85.6 ml.) and butyl cellosolve (1 liter) are refluxed under nitrogen for 16 hours and the solvent is removed. The residue is successively washed with water, dilute aqueous sodium hydroxide, water, dilute aqueous hydrochloric acid, water and dried. Trituration of the crude product, decomposition at 252°-262°C., with methanol, and then with benzene, and drying provides 120.4 g. of the title compound, decomposition at 259°-263°C.; λmaxKBr 3.09, 6.01, 6.17, 13.38 μ.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[O:20][C:19](=[S:21])[NH:18][N:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[CH3:22]I>C1COCC1.CN(C=O)C>[CH3:3][O:4][CH2:5][O:6][C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[O:20][C:19]([S:21][CH3:22])=[N:18][N:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COCOc1cccc2oc(-c3n[nH]c(=S)o3)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCOc1cccc2oc(-c3nnc(SC)o3)cc12
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a suspension (40 ml) of sodium hydride (0.8 g) in THF was added dropwise a solution (30 ml) of 5-(4-(methoxymethyloxy)benzo(b)furan-2-yl)-2,3-dihydro-1,3,4-oxadiazole-2-thione (4.6 g) in DMF at room temperature, and the mixture was stirred for 40 min. To this reaction mixture was added dropwise methyl iodide at room temperature, and the mixture was further stirred for 1 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was evaporated under reduced pressure to give the title compound (2.5 g) as brown crystals.