Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].Br[CH2:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][C:16]2[N:26]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:19]3[N:20]=[C:21]([C:24]#[N:25])[N:22]=[CH:23][C:18]=3[CH:17]=2)=[CH:13][CH:12]=1.C(Cl)Cl.CO>CN(C=O)C.CCOC(C)=O>[CH3:29][C:28]([CH3:30])([CH3:31])[CH2:27][N:26]1[C:19]2[N:20]=[C:21]([C:24]#[N:25])[N:22]=[CH:23][C:18]=2[CH:17]=[C:16]1[CH2:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)=[CH:33][CH:32]=1
Reactant: CCN1CCNCC1
Reactant: CC(C)(C)Cn1c(Cc2ccc(CBr)cc2)cc2cnc(C#N)nc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN1CCN(Cc2ccc(Cc3cc4cnc(C#N)nc4n3CC(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
1-Ethyl-piperazine (1.1 mmol) and 6-(4-bromomethyl-benzyl)-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.35 mmol) are dissolved in DMF (3 ml) and stirred at room temperature for 3 h. After the reaction mixture is diluted with AcOEt, the organic layer is washed with brine, dried over magnesium sulfate and filtrated. The solvent is evaporated and the residue is purified by chromatography on silica gel using 2% MeOH in CH2Cl2 and 7% MeOH in CH2Cl2. The solvent of the latter effluent is removed by evaporation and dried in vacuo to afford crystals. yield 81.8%, Rf=0.34 (CH2Cl2:MeOH=9:1).
Reaction SMILES: Cl[CH2:2][O:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][N:5]=1.[CH3:10][NH:11][CH2:12][CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:17][CH:16]=1.C([O-])(O)=O.[Na+].O>CN(C=O)C>[CH3:2][O:3][C:4]1[N:5]=[CH:6][N:7]=[C:8]([N:11]([CH3:10])[CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH2:19][CH:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: ClCOc1ccncn1
Reactant: CNCCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N(C)CCOc2ccc(CC3SC(=O)NC3=O)cc2)ncn1
Temperature: 100 °C

Procedure:
A starting mixture consisting of 2.9 g (0.02 mol) 4-chloromethoxypyrimidine and 5.6 g (0.02 mol) 5-[4-(2-methylaminoethoxy)-benzyl]-thiazolidine-2,4-dione in 60 ml DMF and in the presence of 17 g NaHCO3 is heated at 100° C. for 24 h. Once the reaction completed, the mixture is poured onto 600 ml water and it is extracted with 4×200 ml AcOEt.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[CH2:25]([C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:28]=1[C:29](O)=[O:30])[CH3:26]>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:29]([C:28]1[C:32]([CH3:36])=[CH:33][CH:34]=[CH:35][C:27]=1[CH2:25][CH3:26])=[O:30]
Reactant: CCc1cccc(C)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Product: CCc1cccc(C)c1C(=O)N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)OC
Yield: 46 %

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[(2-ethyl-6-methylphenyl)carbonyl]-L-phenylalanine methyl ester was prepared in 46% yield from 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 2-ethyl-6-methylbenzoic acid using the general procedure described in example 3. HR MS: Obs. mass, 513.1359. Calcd. mass, 513.1348 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][OH:26])[CH:19]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:30][O:31][CH2:32]Cl>CN(C)C=O>[C:1]([O:5][C:6](=[O:27])[N:7]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][OH:26])[CH:19]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:30][O:31][CH3:32])([CH3:3])([CH3:2])[CH3:4]
Reactant: COCCl
Reactant: CC(C)(C)OC(=O)N(CCc1ccccc1O)Cc1cccc(CCO)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccccc1CCN(Cc1cccc(CCO)c1)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
A solution of [3-(2-hydroxy-ethyl)-benzyl]-[2-(2-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (123 mg) in anhydrous N,N-dimethylformamide (2 mL) was treated with sodium hydride (14 mg of 60% grade reagent) and the mixture stirred under nitrogen for 10 minutes. A solution of chloromethyl methyl ether (29 mg) in anhydrous N,N-dimethylformamide (0.5 mL) was added dropwise followed by stirring at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous brine, the organic layer was separated, dried and the solvent evaporated under reduced pressure to yield the sub-titled compound (110 mg).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].O>C1COCC1>[OH:2][CH2:1][C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(-c2ccc(-c3cccs3)s2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc(-c3cccs3)s2)s1
Temperature: 25 °C
Yield: 97 %

Procedure:
0.5 g of 5-formyl-2,2':5',2"-terthiophene was dissolved in 20 ml of THF and stirred at room temperature, followed by adding 0.034 g of NaBH4 and stirred for 2 hours. After the reduction was completed, 50 ml of water was added. The solution was then extracted with chloroform, dried over anhydrous Na2SO4, filtered and condensed. The yellowish powder was thus obtained and the melting point thereof was 151°-152° C. (yield was 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]2[C:9]3[CH2:10][CH2:11][C@@:12]4([CH2:21][CH3:22])[C:16]([C:8]=3[CH2:7][CH:6]([CH3:26])[C:5]=2[CH:4]=1)=[CH:15][CH2:14][C:13]14[O:20][CH2:19][CH2:18][O:17]1>C1C=CC=CC=1.[Pd].C([O-])([O-])=O.[Ca+2]>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]2[C:9]3[CH2:10][CH2:11][C@@:12]4([CH2:21][CH3:22])[C@H:16]([C:8]=3[CH2:7][CH:6]([CH3:26])[C:5]=2[CH:4]=1)[CH2:15][CH2:14][C:13]14[O:17][CH2:18][CH2:19][O:20]1
Reactant: CC[C@]12CCC3=C(CC(C)c4cc(OC)ccc43)C1=CCC21OCCO1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: c1ccccc1
Product: CC[C@]12CCC3=C(CC(C)c4cc(OC)ccc43)[C@@H]1CCC21OCCO1
Yield: 71.5 %

Procedure:
Monohydrogenate dl-3-methoxy-6-methyl-17,17-ethylenedioxy-13-ethylgona-1,3,5(10), 8,14-pentaene (15.3 g) in benzene (300 cc) in the presence of 2% Pd/CaCO3 (5.0 g). Filter, remove the benzene under reduced pressure and recrystallize from 95% ethanol (110 cc) to yield the dl-3-methoxy-6-methyl-17,17-ethylenedioxy-13-ethylgona-1,3,5(10),8-tetraene (11.0 g), m.p. 122°-124°, diamond shaped plates, λmax. EtOH 280 mμ (ε15,140).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][CH:5]1[C:9](=[O:10])[CH2:8][CH2:7][CH:6]1[CH:11](C(OC)=O)[C:12]([O:14][CH3:15])=[O:13].CN1C(=O)CCC1>O>[CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][CH:5]1[C:9](=[O:10])[CH2:8][CH2:7][CH:6]1[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(C(=O)OC)C1CCC(=O)C1CC(OC)OC
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)CC1CCC(=O)C1CC(OC)OC
Yield: 81 %

Procedure:
In a 3-neck 250 ml round bottom flask equipped with a short path distillation apparatus, a solution of 80.0 g of dimethyl [2-(2,2-dimethoxyethyl)-3-oxocyclopentyl]malonate and 63.0 g NMP was heated to 160° C. The solution was then charged with water until the reaction was complete. Upon completion of the reaction, distillation under vacuum (b.p.=140-145° C. at 1 mbar) of the reaction medium allowed to recover directly the purified title compound with a yield of 81%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[CH2:10]O.[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[CH2:10][N:16]1[C:12](=[O:22])[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15]1=[O:17]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCC1Cc2ccccc2O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CC1Cc2ccccc2O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 116.5 %

Procedure:
To a mixture of (2,3-dihydro-benzofuran-2-yl)-methanol (1.65 g, 11 mmol), phthalimide (3.24 g, 22 mmol), and triphenylphosphine (5.77 g, 22 mmol) in THF (40 mL) is added diethyl azodicarboxylate (3.46 mL, 22 mmol) at −10° C., and the mixture is allowed to warm to room temperature. After 20 h at rt, the mixture is concentrated in vacuo, and the residue is chromatographed on SiO2 (40% EtOAc in heptane) to afford 2-(2,3-dihydro-benzofuran-2-ylmethyl)-isoindole-1,3-dione (3.58 g). LCMS: RT=2.64 minutes; MS: 280 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:14]2[C:33]([CH:34]3[CH2:36][CH2:35]3)=[CH:32][C:17]3[C:18]([C:28]([NH:30][CH3:31])=[O:29])=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[O:20][C:16]=3[CH:15]=2)[S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][B:45]1[O:49]C(C)(C)C(C)(C)[O:46]1>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:14]2[C:33]([CH:34]3[CH2:36][CH2:35]3)=[CH:32][C:17]3[C:18]([C:28](=[O:29])[NH:30][CH3:31])=[C:19]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[O:20][C:16]=3[CH:15]=2)[S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH2:44][B:45]([OH:49])[OH:46]
Reactant: CC1(C)OB(CBr)OC1(C)C
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(O)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(OCB(O)O)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 65 °C
Yield: 59.6 %

Procedure:
A mixture of 6-(N-(3-chloro-4-hydroxyphenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (65.0 mg, 0.123 mmol), potassium carbonate (85.0 mg, 0.614 mmol), and 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.109 g, 0.492 mmol) in 4 mL of anhydrous MeCN in a sealed tube was heated to 65° C. with stirring. After 2 hours the mixture was cooled to RT, filtered to remove solids, and the filtrate concentrated to dryness at reduced pressure. The residue was subjected to RP-HPLC purification (C18, MeCN/water/0.1% formic acid) followed by lyophilization from MeCN/water to afford the title compound (43 mg, 60%) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40-8.47 (m, 1H) 8.20 (s, 1H) 8.05 (s, 2H) 7.97 (dd, J=8.7, 5.5 Hz, 2H) 7.65 (d, J=2.5 Hz, 1H) 7.53 (dd, J=8.9, 2.6 Hz, 1H) 7.40 (t, J=8.8 Hz, 2H) 7.14 (s, 1H) 7.00 (d, J=9.1 Hz, 1H) 3.73 (s, 2H) 3.32 (s, 3H) 2.82 (d, J=4.5 Hz, 3H) 2.20-2.35 (m, 1H) 0.90 (br. s., 3H) 0.45 (br. s., 1H). LCMS (m/z, ES+)=587 (M+H+).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8](OC)=[O:9])(=[O:4])=[O:3].[Cl-].[Cl-].[Ca+2].[BH4-].[Na+]>C1COCC1.CCO>[OH:9][CH2:8][C:7]1[CH:6]=[C:5]([S:2]([NH2:1])(=[O:3])=[O:4])[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1cccc(S(N)(=O)=O)c1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: NS(=O)(=O)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.3 %

Procedure:
To a solution of methyl 3-(aminosulfonyl)benzoate (520 mg, 2.4 mmol) in THF/EtOH (24 mL, 1:1), CaCl2 (533 mg, 4.8 mmol) and NaBH4 (363 mg, 9.6 mmol) were added in one portion respectively. The reaction mixture was stirred at room temperature for 6 hours, and then quenched with water. 1 M aqueous citric acid (8 mL) was added to the mixture and extracted with EtOAc (3×100 mL). The extracts were combined, washed with brine, and dried (Na2SO4). The solvent was evaporated to afford the product (307 mg, 68%) as a white solid. MS (ES+) m/z 210 [M+Na]+.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH:11]1[N:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14](=[O:24])[CH2:13][CH2:12]1>>[CH2:17]([O:16][N:15]1[CH:11]([N:1]2[CH2:9][CH2:8][N:7]([CH:11]3[N:15]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:14](=[O:24])[CH2:13][CH2:12]3)[CH2:6][CH2:5][N:4]([CH:11]3[N:15]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:14](=[O:24])[CH2:13][CH2:12]3)[CH2:3][CH2:2]2)[CH2:12][CH2:13][C:14]1=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C1CNCCNCCN1
Reactant: O=C1CCC(Br)N1OCc1ccccc1
Product: O=C1CCC(N2CCN(C3CCC(=O)N3OCc3ccccc3)CCN(C3CCC(=O)N3OCc3ccccc3)CC2)N1OCc1ccccc1

Procedure:
From 1,4,7-triazacyclononane (1.1.3), 5-bromo-1-benzyloxy-2-pyrrolidone (1.2.6.11) and base.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([NH:7][C@@H:8]([C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][C:14]([OH:22])([CH2:15]3)[CH2:13]1)[CH2:19]2)[C:9](O)=[O:10])=[O:6])[CH3:3].CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C.Cl.[C@H:39]12[CH2:44][C@H:43]1[CH2:42][C@@H:41]([C:45]([NH2:47])=[O:46])[NH:40]2.OC1C2N=NNC=2C=CC=1>C1COCC1>[CH3:3][C:2]([CH3:23])([O:4][C:5]([NH:7][C@@H:8]([C:12]12[CH2:19][CH:18]3[CH2:17][CH:16]([CH2:15][C:14]([OH:22])([CH2:20]3)[CH2:13]1)[CH2:21]2)[C:9]([N:40]1[C@H:41]([C:45]([NH2:47])=[O:46])[CH2:42][C@H:43]2[C@@H:39]1[CH2:44]2)=[O:10])=[O:6])[CH3:1]
Reactant: NC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1[C@H](C(N)=O)C[C@@H]2C[C@@H]21)C12CC3CC(CC(O)(C3)C1)C2
Temperature: -6 °C
Reaction time: 8 h

Procedure:
A 2 L three-necked flask equipped with a thermometer, a mechanical stirrer and a gas inlet was charged with (S)-α[[(1,1-dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula VI) (50 grams, 153.8 mmol). THF (200 ml) was added and stirred to produce a clear solution. The solution was cooled to −6° C. in an acetone-dry ice-water bath. Methanesulfonyl chloride (Mes-Cl)(13.1 ml, 169 mmol, 1.1 equivalents) was then added as a single portion followed by diisopropylethylamine (94 ml, 539 mmol, 1.1 equivalents). The diisopropylethylamine was added slowly over a period of about 4 minutes to keep the internal temperature below 8° C. The reaction mixture was stirred at 0° C. until all acid was converted to mixed anhydride. (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride salt (32.5 grams, 200 mmol, 1.1 equivalents) and hydroxybenzotriazole (HOBT) (1.04 grams, 7.6 mmol, 0.05 equivalents) were then added in a single portion and the flask was removed from the cooling bath. The reaction mixture was stirred at room temperature for 2 hours and then left overnight at room temperature.
Reaction SMILES: CC1(C)C(C)(C)OB(C2CN(C(OC(C)(C)C)=O)CC=2)O1.[S:22]1[C:26]([NH:27][S:28]([N:31]2[CH2:40][CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][C:37]=3[C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][C:42]=3[C:51]3[CH2:52][N:53](C(OC(C)(C)C)=O)[CH2:54][CH:55]=3)[CH2:32]2)(=[O:30])=[O:29])=[N:25][CH:24]=[N:23]1.[ClH:63]>O1CCOCC1>[ClH:63].[NH:53]1[CH2:54][CH:55]=[C:51]([C:42]2[CH:43]=[C:44]([C:47]([F:50])([F:48])[F:49])[CH:45]=[CH:46][C:41]=2[C:37]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:38]=2[CH2:39][CH2:40][N:31]([S:28]([NH:27][C:26]2[S:22][N:23]=[CH:24][N:25]=2)(=[O:30])=[O:29])[CH2:32]3)[CH2:52]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2-c2cccc3c2CCN(S(=O)(=O)Nc2ncns2)C3)C1
Agent: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(Nc1ncns1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2C2=CCNC2)C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, except that tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate was used in place of (2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid and the resulting product, (tert-butyl 3-(2-(2-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate), was converted to the final product by treatment with 50 equivalents of HCl in dioxane. The reaction mixture was concentrated under a vacuum to provide 5-(2-(2,5-dihydro-1H-pyrrol-3-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride. [M+H]+=508.8 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.36 (br. s., 2H), 8.38 (s, 1H), 7.73-7.83 (m, 2H), 7.43 (d, J=7.8 Hz, 1H), 7.23-7.33 (m, 2H), 6.97-7.16 (m, 2H), 5.77 (br. s., 1H), 4.20-4.38 (m, 2H), 3.92 (br. s., 2H), 3.74 (br. s., 2H), 3.64 (t, J=6.7 Hz, 1H), 3.41 (t, J=6.3 Hz, 1H), 3.26-3.36 (m, 1H), 3.12-3.24 (m, 1H)
Reaction SMILES: [K].N1C=CN=C1.FC(F)(F)C(OCC)=O.[F:16][C:17]([N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)(F)[CH:18]([F:20])[F:19]>O1CCCC1>[F:16][C:17]([N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)=[C:18]([F:20])[F:19]
Reactant: FC(F)C(F)(F)n1ccnc1
Agent: CCOC(=O)C(F)(F)F
Agent: [K]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: FC(F)=C(F)n1ccnc1
Temperature: -78 °C
Yield: 13 %

Procedure:
Into a 50 ml autoclave were poured 10.6 g (100 mmol) of potassium salt of imidazole and tetrahydrofuran (30 ml), and the inside of the autoclave was cooled to −78° C., and evacuation and replacement of atmosphere in the autoclave with nitrogen gas were carried out three times. After the inside of a system was evacuated, TFE was introduced until the inside pressure of the system reached 0.1 MPa·G. Then the temperature of the reaction system was increased to 100° C., and TFE was further introduced to maintain the inside pressure of the reaction system at 0.3 to 0.5 MPa·G. Supply of TFE was stopped when the amount of TFE reached 1.1 equivalents (11 g=110 mmol) to the potassium salt of imidazole, and stirring was continued at 100° C. Fifteen hours after starting of the stirring, the inside of the reaction system was brought to room temperature, followed by evacuation to terminate the reaction. To this crude reaction product was added 2.84 g (20 mmol) of ethyl trifluoroacetate, and it was confirmed by a 19F-NMR analysis based on ethyl trifluoroacetate that 1-(1,1,2,2-tetrafluoroethyl)imidazole had been produced at yield of 13% and 1-(1,2,2-trifluoroethenyl)imidazole had been produced at yield of 56%. Also according to gas chromatography analysis, it was confirmed that the remaining imidazole was 14%.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].[CH3:50][C:51]1[CH:55]=[C:54]([CH:56]2[CH2:60][CH2:59][CH2:58][NH:57]2)[O:53][N:52]=1>>[C:28]([C:32]1[N:33]=[C:34]([N:57]2[CH2:58][CH2:59][CH2:60][CH:56]2[C:54]2[O:53][N:52]=[C:51]([CH3:50])[CH:55]=2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1cc(C2CCCN2)on1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: Cc1cc(C2CCCN2c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)on1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-methyl-5-(pyrrolidin-2-yl)isoxazole. MS(m/e): 452.4
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:6]=1)[CH3:2].Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9]([O:11][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(O)cc(Oc2ccc(C#N)cc2)c1
Reactant: BrCCc1ccccc1
Product: CCOC(=O)c1cc(OCCc2ccccc2)cc(Oc2ccc(C#N)cc2)c1
Yield: 69.5 %

Procedure:
Using 1.0 g (3.53 mmol) of 3-(4-cyano phenoxy)-5-hydroxy benzoic acid ethyl ester and (2-bromo-ethyl)-benzene (0.65 g, 3.53 mmol) and following the procedure of Example 42(b) afforded 0.95 g of the required product. 1H NMR (CDCl3): δ 1.35 (3H, t), 3.1 (2H, t), 4.2 (2H, t), 4.35 (2H, q), 6.78 (1H, t), 7.0 (2H, s), 7.22 (1H, m) 7.32 (5H, m), 7.42 (1H, m), 7.62 (2H, s).
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].S(Cl)([Cl:28])=O>>[CH2:1]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([Cl:28])=[O:25])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
After 1.2 g of 4'-n-nonyloxybiphenyl-4-carboxylic acid was heated together with an excess amount of thionyl chloride for 6 hours under a reflux condition, unaltered thionyl chloride was distilled off to obtain 1.25 g of 4'-n-nonyloxybiphenyl-4-carboxylic acid chloride.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:10].[CH3:11][C:12]([OH:29])([CH3:28])[CH2:13][N:14]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[N:15]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:17]2[CH:16]=[N:15][N:14]([CH2:13][C:12]([CH3:28])([OH:29])[CH3:11])[CH:18]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(I)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cnn(CC(C)(C)O)c2)cc(C)c1Br
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 2-bromo-5-iodo-1,3-dimethylbenzene (1.00 g), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (1.11 g), and 2 M aqueous Na2CO3 solution (4.0 mL) in N,N-dimethylformamide is purged with argon for 3 min. [1,1′-Bis(diphenylphosphino)-ferrocene]-dichloropalladium dichloromethane complex (85 mg) is added and the mixture is stirred at 60° C. for 3 h. After cooling to room temperature the mixture is diluted with water and ethyl acetate. The organic phase is washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is purified by HPLC on reversed phase to give the title compound. LC (method 11): tR=1.12 min; Mass spectrum (ESI+): m/z=323, 325 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=CC=CC=1)([O-])=O.[C:17]1(=O)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>CC1C=CC(C(C)C)=CC=1>[C:2]1([NH:1][C:25]2[C:26]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:22]=[CH:23][CH:24]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C1CCCc2ccccc21
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Cc1ccc(C(C)C)cc1
Product: c1ccc(Nc2cccc3ccccc23)cc1
Temperature: 185 °C

Procedure:
To a 200 ml, 3-necked round bottom flask equipped with a thermometer and a Dean-Stark apparatus filled with p-cymene and having a condenser are added 7.45 g (80 mmole) of aniline, 4.82 g (39 mmole) of nitrobenzene, 14.6 g (100 mmole) of 1-tetralone and 65 ml of p-cymene solvent. Also introduced were catalyst and various acid promoters as indicated in Table I. The reaction mixtures were heated at reflux (about 185° C.) for 5 hours while removing the evolving water. Thereafter, the mixture was cooled to room temperature, and the catalyst was filtered out using a Celite (trademark) diatomaceous earth filter. The reaction mixture was analyzed by gas-liquid phase chromatography (GLPC) against a PANA standard. The yields mentioned in Table I are based on conversion of tetralone to PANA.