Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC([NH:8][C:9](=[O:18])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=CC=1.[Cl-:19].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[CH:10][C:9](=[O:18])[NH:8]2
Reactant: O=C(C=Cc1ccccc1)Nc1ccc(Cl)cc1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: O=c1ccc2c(Cl)cccc2[nH]1
Temperature: 125 °C
Reaction time: 3 h

Procedure:
To a mixture of N-(4-chlorophenyl)cinnamamide (8.3 g), and chlorobenzene (60 ml) was added portionwise aluminum chloride (21.4 g) trader nitrogen at room temperature and the reaction mixture was slowly warmed up to 125° C. and kept at that temperature for 3 hours. The reaction mixture was cooled down and poured over 400 g of ice. The product crystallized out as a pink solid which was filtered and dried.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3](=O)[CH2:4][C:5](OCC)=[O:6].C(O)(=O)C.[CH3:16][NH:17][NH2:18]>C(OC)(C)(C)C>[CH3:16][N:17]1[C:5]([OH:6])=[CH:4][C:3]([CH:2]([F:11])[F:1])=[N:18]1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)C(F)F
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: Cn1nc(C(F)F)cc1O
Temperature: 5 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
166 g (1 mol) of ethyl difluoroacetoacetate are initially charged in 500 ml of methyl tert-butyl ether, and 60 g of acetic acid are added. After the mixture has been cooled to 5° C., 119 g of methylhydrazine are added in 40% aqueous solution. The mixture is stirred at 22° C. for a further 20 h. The phases are separated, and the organic phase is washed with 200 ml of water and dried over MgSO4. After the solvent has been removed under reduced pressure, 140 g of the product are obtained as a yellow solid with an m.p. of 133° C. and a purity of 96%. Yield 91%.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[Cl:6][C:7]1([C:10]([OH:20])([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH2:11][C:12]#[CH:13])[CH2:9][CH2:8]1.N.C(I)C>CCCCCC.O1CCCC1>[Cl:6][C:7]1([C:10]([OH:20])([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH2:11][C:12]#[C:13][CH2:1][CH3:2])[CH2:8][CH2:9]1
Reactant: [Li]CCCC
Reactant: C#CCC(O)(Cn1cncn1)C1(Cl)CC1
Agent: N
Solvent: C1CCOC1
Solvent: CCI
Solvent: CCCCCC
Product: CCC#CCC(O)(Cn1cncn1)C1(Cl)CC1
Reaction time: 1 h

Procedure:
89.7 ml (021 mol) of n-butyllithium in hexane are added at -40° C., with stirring and under a nitrogen atmosphere, to a solution of 22.5 g (0.1 mol) of 4-(1-chlorocyclopropyl)4hydroxy-5-(1,2,4-triazol-1-yl)1-pentine in 350 ml of liquid ammonia. After the end of the addition, stirring is continued initially at from -30° C. to -40° C. for 1 hour, and then a solution of 17.2 g (0.11 mol) of ethyl iodide in 20 ml of absolute tetrahydrofuran is added dropwise. The reaction mixture is subsequently stirred under ammonia reflux. For working up, the ammonia is evaporated off, ethyl acetate and water are added to the residue, and the organic phase is separated off, dried over sodium sulphate and concentrated under reduced pressure. This gives 25 g of a product which consists to the extent of 85.3% of 6-(1-chlorocyclopropyl)-6-hydroxy-7-(1,2,4-triazol-1-yl)-3-heptine. Recrystallization from ethanol gives 6-(1-chlorocyclopropyl)-6-hydroxy-7-(1,2,4triazol-1-yl)3-heptine in the form of a solid of melting point 83°-84° C. ##STR63##
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])/[CH:9]=[CH:10]/[C:11]1[CH:15]=[CH:14][NH:13][CH:12]=1)([CH3:6])([CH3:5])[CH3:4].[C:17]1([CH2:23][S:24](Cl)(=[O:26])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:3]([O:7][C:8](=[O:16])/[CH:9]=[CH:10]/[C:11]1[CH:15]=[CH:14][N:13]([S:24]([CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:26])=[O:25])[CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)Cc2ccccc2)c1

Procedure:
Starting materials: sodium hydride 60% (0.240 g), (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound D1) (1.01 g), α-toluenesulfonylchloride (1.19 g). Reaction conditions: −30° C., 30 min; 30° C., 2.5 hours.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]=O)[CH:38]=4)[C:33]([CH3:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[C@H:47]12[CH2:53][C@H:50]([NH:51][CH2:52]1)[CH2:49][N:48]2C(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C@H:47]12[CH2:53][C@H:50]([NH:51][CH2:52]1)[CH2:49][N:48]2[CH2:43][C:39]1[CH:38]=[C:37]([C:32]2[C:33]([CH3:36])=[CH:34][CH:35]=[C:30]([CH2:29][N:20]([CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:45][CH3:46])[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:24][CH2:25]3)=[O:22])[CH:31]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(C=O)c2)c1)C(=O)C1(C(N)=O)CC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(CN3C[C@@H]4C[C@H]3CN4)c2)c1)C(=O)C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
A mixture of N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide (55 mg, 0.088 mmol), tert-butyl (1S,4S)-(−)-2,5-diazabicyclo[2.2.1]Heptane-2-carboxylate (17.51 mg, 0.088 mmol), sodium triacetoxyborohydride (37.4 mg, 0.177 mmol) and acetic acid (6.07 μL, 0.106 mmol) in DCM (2 mL) was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were concentrated under vacuum to give the crude residue. It was re-dissolved in 25% TFA in DCM (2 mL) and stirred at room temperature for 2 h. Solvent was evaporated under a stream of nitrogen and then purified by reverse phase hplc with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 60% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined, washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-({3′-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylmethyl]-6-methyl-3-biphenylyl}methyl)-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamide as a solid (34 mg, 54.6%). LC-MS m/z 705 (M+H)+, 0.68 min (ret time).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[C:5]([CH2:7][CH2:8][NH:9][N:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:6]>C1C=CC=CC=1>[C:5]([CH2:7][CH2:8][N:9]([C:3](=[O:4])[NH:2][CH3:1])[N:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:6]
Reactant: N#CCCNN=Cc1ccccc1
Reactant: CN=C=O
Solvent: c1ccccc1
Product: CNC(=O)N(CCC#N)N=Cc1ccccc1

Procedure:
0.57 g (10-2 moles) of methyl isocyanate is added, at 25° C., to a solution of 10-2 moles of benzaldehyde (2-cyanoethyl)hydrazone in 30 ml of anhydrous benzene. The mixture is then heated to boiling temperature and left under reflux for 30 minutes. On cooling, the acylated compound crystallizes. It is filtered, drained and then recrystallized from a mixture of benzene and cyclohexane. Its melting point is 145° C. The reaction yield is 48%.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[CH2:12][S:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:13]=[C:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:24])=[C:20]([Cl:23])[CH:21]=2)[CH:16]([C:25](Cl)=[O:26])[CH2:15]1>C(N(CC)CC)C>[ClH:23].[N:1]1([CH2:6][C@@H:7]2[CH2:12][S:11][CH2:10][CH2:9][N:8]2[C:25]([C@@H:16]2[C:17]3[C:22](=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[C:14](=[O:13])[CH2:15]2)=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1CCN(C[C@@H]2CSCCN2)C1
Reactant: O=C1CC(C(=O)Cl)c2cc(Cl)c(Cl)cc21
Solvent: CCN(CC)CC
Product: Cl
Product: O=C1C[C@H](C(=O)N2CCSC[C@H]2CN2CCCC2)c2cc(Cl)c(Cl)cc21

Procedure:
A similar reaction to that of Example 1 was carried out by using 1.0 g of (3R)-3-(1-pyrrolidinyl)methylthiomorpholine, 2.0 ml of triethylamine and 3.0 g of 3-oxo-5,6-dichloro-1-indanecarboxylic acid chloride and the crude product was purified by column chromatography through silica gel using a 100:1 mixture of ethyl acetate and triethylamine as a mobile phase to give 0.82 g of the free basic form of the title compound from the less polar fractions. The product was treated with hydrogen chloride in a similar manner to the latter part of Example 1 to give 0.85 g of the title compound. m.p.: 257°-261° C. [α]D25 +26.8° (c=2.0, methanol)
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][C:9](=[N:12][N+:13]([O-:15])=[O:14])SC)=[CH:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[S:24][C:25]([CH2:28][NH2:29])=[CH:26][N:27]=1>C(#N)C>[Cl:22][C:23]1[S:24][C:25]([CH2:28][NH:29][C:9]([NH:8][CH2:7][C:4]2[S:3][C:2]([Cl:1])=[N:6][CH:5]=2)=[N:12][N+:13]([O-:15])=[O:14])=[CH:26][N:27]=1
Reactant: CSC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reactant: NCc1cnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])N=C(NCc1cnc(Cl)s1)NCc1cnc(Cl)s1
Reaction time: 1 h
Yield: 13.9 %

Procedure:
To a mixture of 1 g N-(2-chloro-5-thiazolylmethyl)-S-methyl-N'-nitroisothiourea, 560 mg potassium carbonate, 400 mg cuprous chloride and 12 ml acetonitrile was added 610 mg of 2-chloro-5-(aminomethyl)thiazole and the mixture was stirred for 1 hour under reflux. Thereafter, the reaction mixture was concentrated, then water was added to the resultant solids, followed by stirring thoroughly. Thereafter, the solids were collected by filtration and purified by column chromatography [eluent: dichloromethane-methanol (10:1)] to afford 191 mg of N,N'-bis(2-chloro-5-thiazolylmethyl)-N"-nitroguanidine (compound No.39) as a white powder, mp 217°-218° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH:3]([CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH2:9]1)[CH2:4][C:5]#[N:6].Cl.[NH2:27][OH:28].CCN(C(C)C)C(C)C>CCO>[F:25][C:2]([F:1])([F:24])[CH:3]([CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)[CH2:9]1)[CH2:4]/[C:5](=[N:27]/[OH:28])/[NH2:6]
Reactant: N#CCC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N/C(CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F)=N\O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
In a 50 mL round-bottomed flask, 4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butanenitrile (200 mg, 549 μmol) and hydroxylamine hydrochloride (37.9 mg, 549 μmol) were combined with EtOH (2 ml) to give a colorless suspension. DIEA (106 mg, 144 μl, 823 μmol) was added and the resulting mixture was stirred at 100° C. for 6 hr. The crude reaction mixture was concentrated in vacuo to give (Z)-4,4,4-trifluoro-N′-hydroxy-3-((3-(3-(trifluoromethyl)phenyl)-piperidin-1-yl)methyl)butanimidamide as a viscous oil. 85% pure by LC-MS. MH+=398.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12]([NH:14][C:15]1([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][C:30]2=[O:35])[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=2)[CH2:17][CH2:16]1)=[O:13])[CH3:10].[Br:36][C:37]1[CH:50]=[CH:49][C:40]2[CH:41]=[C:42]([S:45](Cl)(=[O:47])=[O:46])[CH2:43][O:44][C:39]=2[CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:36][C:37]1[CH:50]=[CH:49][C:40]2[CH:41]=[C:42]([S:45]([N:32]3[CH2:33][CH2:34][N:29]([CH2:28][C:15]4([NH:14][C:12]([O:11][CH2:9][CH3:10])=[O:13])[CH2:16][CH2:17][N:18]([C:21]5[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=5)[CH2:19][CH2:20]4)[C:30](=[O:35])[CH2:31]3)(=[O:46])=[O:47])[CH2:43][O:44][C:39]=2[CH:38]=1
Reactant: CCOC(=O)NC1(CN2CCNCC2=O)CCN(c2ccnc(C)c2)CC1
Reactant: O=S(=O)(Cl)C1=Cc2ccc(Br)cc2OC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NC1(CN2CCN(S(=O)(=O)C3=Cc4ccc(Br)cc4OC3)CC2=O)CCN(c2ccnc(C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
Triethylamine (253 mg) was added to a solution of 1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinone hydrochloride (258 mg) in dichloromethane (15 ml), 7-bromo-2H-benzopyran-3-sulfonyl chloride (233 mg) was added at 0° C., and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added an aqueous sodium carbonate solution, the mixture was extracted with dichloromethane, dried, concentrated, and purified by column chromatography (dichloromethane:10% aqueous ammonia-containing methanol=20:1) to obtain colorless amorphous 4-(7-bromo-2H-benzopyran-3-sulfonyl)-1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinone (169 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].[Li+].CC([N-]C(C)C)C.Br[CH2:27][C:28]([CH3:30])=[CH2:29]>C1COCC1>[CH3:29][C:28](=[CH2:27])[CH2:30][C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C=C(C)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)CC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-Boc-piperidine-4-carboxylic acid methyl ester (2.00 g, 8.22 mmol) in THF (40 mL) was cooled to −78° C. Under nitrogen, a 2.0 M THF solution of LDA (6.17 mL, 12.3 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 30 minutes before a solution of 3-bromo-2-methylpropene (1.60 g, 11.9 mmol) in THF (2 mL) was added. After the reaction was stirred for 1 hour at this temperature, a sample was taken for LC-MS analysis and it showed that the reaction was completed. The reaction was quenched by adding saturated ammonium chloride solution (5 mL) and the mixture was allowed to warm up to room temperature. The mixture was then extracted with EtOAc (50 mL twice). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrates were concentrated and the crude product was purified by column chromatography eluting with 0-30% ethyl acetate/hexane to give the title compound. LC-MS (IE, m/z): 242.21 [M−56+1]+.
Reaction SMILES: C([O:5][C:6](=[O:31])/[CH:7]=[CH:8]/[C:9]1[CH:30]=[N:29][C:12]2[NH:13][C:14](=[O:28])[CH2:15][N:16]([CH2:18][C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[O:20])[CH2:17][C:11]=2[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:40]>>[ClH:40].[CH3:27][N:24]1[CH2:23][CH2:22][N:21]([C:19](=[O:20])[CH2:18][N:16]2[CH2:17][C:11]3[CH:10]=[C:9](/[CH:8]=[CH:7]/[C:6]([OH:31])=[O:5])[CH:30]=[N:29][C:12]=3[NH:13][C:14](=[O:28])[CH2:15]2)[CH2:26][CH2:25]1
Reactant: CN1CCN(C(=O)CN2CC(=O)Nc3ncc(/C=C/C(=O)OC(C)(C)C)cc3C2)CC1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(C(=O)CN2CC(=O)Nc3ncc(/C=C/C(=O)O)cc3C2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A suspension of (E)-3-{4-[2-(4-Methyl-piperazin-1-yl)-2-oxo-ethyl]-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl}acrylic acid tert-butyl ester (1.12 g, 2.61 mmol) in CH2Cl2 (10 mL) was treated with TFA (10 mL). After stirring at room temperature for 35 min, the solution was concentrated in vacuo. The resulting oil was treated with anhydrous HCl (20 mL of a 4.0 M solution in dioxane, 80 mmol) and the resulting mixture was sonicated for 1 h. The mixture was diluted with Et2O (50 mL) and sonicated for 10 min. The solid was isolated by filtration, washed with Et2O and dried under vacuum at 50° C. for 4 h to give the title compound (1.72 g, quantitative) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 11.60 (br s, 1H), 11.09 (br s, 1H), 8.82 (s, 1H), 8.47 (s, 1H), 7.66 (d, J=19.9 Hz, 1H), 6.65 (d, J=16.1 Hz, 1H), 4.43-4.40 (m, 2H), 4.31 (br s, 2H), 3.95-3.91 (m, 1H), 3.84 (br s, 2H), 3.56 (s, 4H), 3.42 (br s, 2H), 3.23-2.97 (m, 2H), 2.76 (d, J=4.1 Hz, 3H); MS (ESI) m/e 374 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:13](=[S:18])(OCC)[S-].[K+].[ClH:20]>CN(C=O)C>[Cl:20][C:13]1[S:18][C:2]2[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Reactant: CCOC(=S)[S-]
Reactant: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2nc(Cl)sc2c1
Temperature: 130 °C
Yield: 99 %

Procedure:
A mixture of 2-chloro-4-trifluoromethylaniline (15.0 g, 76.7 mmol) and potassium O-ethyl dithiocarbonate (29.5 g, 184.1 mmol) in 75 mL anhydrous DMF was heated at 130° C. overnight under a nitrogen atmosphere. The reaction mixture was cooled to rt, and then 1 N HCl solution (200 mL) was added with stirring to induce precipitation. After the mixture was stirred for 30 minutes, the solid precipitate was collected by filtration and rinsed with water. The filter cake was dissolved in 100 mL EtOAc, and the solution was dried over Na2SO4. EtOAc was removed by rotary evaporation, and the residue was dried in vacuo to afford the desired product as a white solid (18.0 g, 99%). 1H NMR (DMSO-d6) δ 14.00 (bs, 1 H), 8.20 (s, 1 H), 7.70 (d, 1 H), 7.40 (d, 1 H); GC-EIMS m/z 235 (M+).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:12]([NH:14][C:15]1([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH:25]2[OH:30])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:13].Br[C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[C:39]([F:42])([F:41])[F:40]>>[CH3:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:12]([NH:14][C:15]1([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][N:27]([C:34]3[CH:35]=[C:36]([F:38])[CH:37]=[CH:32][C:33]=3[C:39]([F:40])([F:41])[F:42])[CH2:26][C:25]2=[O:30])=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)=[O:13]
Reactant: Fc1ccc(C(F)(F)F)c(Br)c1
Reactant: Cc1c(C(=O)NC2(C(=O)NC3CCNCC3O)CCCCC2)oc2ccccc12
Agent: Cl
Product: Cc1c(C(=O)NC2(C(=O)NC3CCN(c4cc(F)ccc4C(F)(F)F)CC3=O)CCCCC2)oc2ccccc12

Procedure:
In accordance with the same procedure as in Example 85, except that 4-[N-[1-[N-(3-methyl-benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride was used instead of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride and 1-bromo-2-trifluoromethyl-5-fluorobenzene was used instead of 1-bromotoluene in Step 1 thereof, 128 mg of the titled compound was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:12])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(Cl)c(C=O)c(Cl)c1

Procedure:
Combine 2,6-dichloro-4-hydroxy-benzaldehyde (120 g, 628.24 mmol) and potassium carbonate (173.65 g, 1256.5 mmol) in 900 mL dimethylformamide and treat with iodomethane (107 g, 753.9 mmol). Stir the reaction at room temperature for 3 hours. Filter off solids and pour into 6 L of water. Filter solids, wash several times with water, air dry and dissolve in ethyl acetate. Wash with water, followed by brine then dry over sodium sulfate. Filter and concentrate under vacuum to ˜100 mL volume, at which point, solids start to crash out. Filter then concentrate down the filtrate to yield a second crop. Wash with hexane, combine all solids and vacuum dry to yield 112.3 g of off-white, solid: 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 6.90 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: C12(COC3C(Cl)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[C:24]12([CH2:34][O:35][C:36]3[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][C:37]=3[C:45]([F:48])([F:47])[F:46])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2.N1(S(N)(=O)=O)CCOCC1.[CH3:59][S:60]([NH2:63])(=[O:62])=[O:61]>>[C:24]12([CH2:34][O:35][C:36]3[CH:44]=[CH:43][C:39]([C:40]([NH:63][S:60]([CH3:59])(=[O:62])=[O:61])=[O:41])=[CH:38][C:37]=3[C:45]([F:48])([F:47])[F:46])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C(F)(F)F)c1
Agent: NS(=O)(=O)N1CCOCC1
Agent: O=C(O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: CS(=O)(=O)NC(=O)c1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C(F)(F)F)c1

Procedure:
Following the procedure as described in Example 98 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid with 4-(adamantan-1-ylmethoxy)-3-(trifluoromethyl)benzoic acid and morpholine-4-sulfonamide with methanesulfonamide, the title compound was obtained as a colorless solid (0.11 g, 51%): 1H NMR (300 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.25-8.19 (m, 2H), 7.37 (d, J=8.8 Hz, 1H), 3.77 (s, 2H), 3.37 (s, 3H), 1.99 (br s, 3H), 1.75-1.63 (m, 12H); MS (ES−) m/z 430.3 (M−1); MS (ES+) m/z 432.2 (M+1).
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]([O:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[C:18]([C:31]([O-:33])=[O:32])[N:19]2[C:22]([O:24]CCC(C)(C)C)=[O:23])=[CH:15][CH:14]=1)=[O:11])([CH3:6])[CH3:5].CO.O>C1COCC1>[CH3:3][C:4]([O:24][C:22]([N:19]1[C:20]2[C:16](=[CH:15][CH:14]=[C:13]([NH:12][C:10](=[O:11])[CH2:9][CH2:8][O:7][C:4]([CH3:3])([CH3:6])[CH3:5])[CH:21]=2)[CH:17]=[C:18]1[C:31]([OH:33])=[O:32])=[O:23])([CH3:6])[CH3:5]
Reactant: CC(C)(C)CCOC(=O)n1c(C(=O)[O-])cc2ccc(NC(=O)CCOC(C)(C)C)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OCCC(=O)Nc1ccc2cc(C(=O)O)n(C(=O)OC(C)(C)C)c2c1
Temperature: 50 °C
Yield: 162.7 %

Procedure:
Lithium hydroxide (0.037 g, 1.55 mmol) was added to a solution of 1-(1,1-dimethylethyl)2-ethyl 6-({3-[(1,1-dimethylethyl)oxy]propanoyl}amino)-1H-indole-1,2-dicarboxylate (0.067 g, 0.155 mmol) in THF:methanol:water/3:1:1 (3 mL). The mixture was heated at 50° C. for 1 hr. The solvent was evaporated and the residue was dissolved in water, acidified with 1N aqueous HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give the title compound (0.051 g, 108%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.40 (br. s., 1H), 9.82 (s, 1H), 7.94 (s, 1H), 7.44 (d, 1H), 7.04 (d, 1H), 6.85 (s, 1H), 3.57 (t, 2H), 2.33-2.48 (m, 2H), 1.09 (s, 9H). ES MS: m/z 305 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])[CH2:19][CH3:20]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:28]([C:25]1[CH:26]=[CH:27][C:22]([C:18]([CH3:17])([CH3:21])[CH2:19][CH3:20])=[CH:23][CH:24]=1)(=[O:30])=[O:29])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CCC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-phenyl-methanone and 123 mg of 4-(1,1-dimethyl-propyl)-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 0.56 (t, 3H, J=7.2 Hz), 1.18 (s, 6H), 1.54 (q, 2H, J=7.2 Hz), 7.25 (d, 2H, J=8.4 Hz), 7.34 (d, 1H, J=2.8 Hz), 7.40 (m, 4H), 7.45 (dd, 1H, J=8.8 Hz, 2.0 Hz), 7.56-7.62 (m, 3H, 7.78 (d, 1H, J=8.8 Hz), 9.95 (s, 1H). MS: m/z 442.0 (M++1).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Cl:6].[CH3:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)=[O:10]>C(O)C.C(OCC)C>[Cl:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[CH3:8])=[CH:12][CH:13]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: OC(CCl)CCCl
Solvent: CCO
Solvent: CCOCC
Product: CC(=O)c1ccc(OCC(O)CCCl)cc1

Procedure:
Utilizing the procedure of Preparation 16, 1,4-dichloro-2-butanol was reacted with 4-hydroxyacetophenone to give cream colored solid, m.p. 75°-77° C. Recrystallizing solvent was a mixture of ethanol-diethyl ether.