Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:31](=[O:32])[N:30]([CH3:33])[C:12]2[N:13]([CH3:29])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=O)[CH2:21][C:22](=O)[CH2:23][O:24][CH2:25][CH3:26])=[CH:16][CH:15]=3.C(O)(=O)C(O)=O.[CH2:40]([NH:42][NH2:43])[CH3:41]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:31](=[O:32])[N:30]([CH3:33])[C:12]2[N:13]([CH3:29])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:42]([CH2:40][CH3:41])[N:43]=[C:22]([CH2:23][O:24][CH2:25][CH3:26])[CH:21]=1)=[CH:16][CH:15]=3
Reactant: CCOCC(=O)CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Reactant: CCNN
Agent: O=C(O)C(=O)O
Product: CCOCc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n(CC)n1

Procedure:
The process is carried out as in Example 37 above, with the compound from Example 80A, 1-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-4-ethoxybutane-1,3-dione and ethylhydrazine oxalate.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C@@H:10]2[CH2:14][C@H:13]([S:15]CC3C=CC(OC)=CC=3)[CH2:12][N:11]2[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:26])=[O:9])[CH2:4]1.FC(F)(F)C(O)=O.[F:46][C:47]([F:53])([F:52])[S:48]([OH:51])(=[O:50])=[O:49]>C1(OC)C=CC=CC=1>[F:46][C:47]([F:53])([F:52])[S:48]([OH:51])(=[O:50])=[O:49].[CH3:1][N:2]([CH3:38])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C@@H:10]2[CH2:14][C@H:13]([SH:15])[CH2:12][N:11]2[C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)=[O:26])=[O:9])[CH2:4]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@@H](N(C)C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CN(C)[C@@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.56 g of (2S,4S)-2-[(3R)-3-dimethylamino-1-pyrrolidinylcarbonyl]-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (1) above] were suspended in 5.1 ml of anisole, and 25.5 ml of trifluoroacetic acid and 0.83 ml of trifluoromethanesulfonic acid were added, whilst ice-cooling, to the resulting suspension. The mixture was then stirred at room temperature for 3 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, 1,2-dichloroethane was added to the residue, and excess acid was removed by azeotropic distillation. The residue was decanted using hexane and then triturated with diethyl ether, after which the mixture was decanted and dried by evaporation under reduced pressure to give 3.65 g of the title compound as a powdery product.
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:28]=[CH:27][C:12]([O:13][CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[NH:17]1[CH2:16][CH2:15][CH:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([C:3]3([C:1]#[N:2])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]3)=[CH:28][CH:27]=2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C3(C#N)CCOCC3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(c2ccc(OC3CCNCC3)cc2)CCOCC1
Temperature: 25 °C

Procedure:
tert-Butyl 4-[4-(4-cyanotetrahydro-2H-pyran-4-yl)phenoxy]-1-piperidinecarboxylate (720 mg) was dissolved in dichloromethane (50 ml) at 0° C. TFA (10 ml) was added and the mixture stirred whilst warming to room temperature over 2 hours. The reaction mixture was then concentrated in vacuo, and partitioned between dichloromethane (80 ml) and 0.5M NaOH (50 ml). The dichlorormethane solution was dried over Na2SO4 and evaporated to give 4-[4-(4-piperidinyloxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile as a colorless oil which crystallized on standing (500 mg, 94%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[C:5](=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[NH:6][C:7](=[O:17])[CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.I([O-])(=O)(=O)=[O:25].[Na+].CC(C)=O>O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[C:5](=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[NH:6][C:7](=[O:17])[CH2:8][S:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:25]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)CSCc1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc(Cl)cc1NC(=O)CS(=O)Cc1ccccc1

Procedure:
2 g (5.7 mmol) of N-(benzylthio)acetyl-4-chloro-anthranilic acid methyl ester and 3.66 g (17.1 mmol) of sodium metaperiodate are dissolved in 12 ml of water and 48 ml of acetone and the resulting solution is stirred at reflux for 6 hours. The reaction mixture is allowed to cool, filtered and concentrated by evaporation. Chromatography of the crude product on silica gel with hexane/ethyl acetate yields N-(benzylsulfinyl)acetyl-4-chloro-anthranilic acid methyl ester in the form of a yellow oil interspersed with crystals.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:21])[CH2:12][CH:13]2[C:17](=[O:18])[O:16]C(C)(C)[O:14]2)=[C:6]([O:22][CH3:23])[CH:5]=1)[CH:2]=[CH2:3].Cl>C1COCC1>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:21])[CH2:12][CH:13]([OH:14])[C:17]([OH:18])=[O:16])=[C:6]([O:22][CH3:23])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(OC(=O)CC2OC(C)(C)OC2=O)c(OC)c1
Agent: Cl
Solvent: C1CCOC1
Product: C=CCc1ccc(OC(=O)CC(O)C(=O)O)c(OC)c1
Reaction time: 8 h
Yield: 107 %

Procedure:
To a solution of (2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-yl)-acetic acid 4-allyl-2-methoxy-phenyl ester (35.0 g, 0.10 mol) in THF (350 mL) was added 1N hydrochloric acid (350 mL) at room temperature (25° C.) and the mixture was stirred at same temperature over a period of 8 h. The solvent was evaporated to half volume, saturated with sodium chloride and the product was extracted with ethyl acetate (2×850 mL). The organic layer was dried over sodium sulphate and concentrated to obtain off-white solid (30.0 g, 98%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 42 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-methoxybenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 42%. Melting point: 202-205° C. (Ethyl acetate-hexane)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[N+:15]([C:11]1[C:2]([Br:1])=[C:3]2[C:8](=[CH:9][C:10]=1[Br:12])[NH:7][C:6](=[O:13])[C:5](=[O:14])[NH:4]2)([O-:17])=[O:16]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(Br)cc(Br)c2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(Br)c([N+](=O)[O-])c(Br)c2[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
The method of Cheeseman, supra. was adapted. 5,7-Dibromo-1,4-dihydroquinoxaline-2,3-dione (74 mg, 0.23 mMol) was dissolved in concentrated H2SO4 (1 mL) at 0° C. for 30 mins., and then KNO3 (28 mg, 0.27 mMol, Baker) was added to this solution. The mixture was stirred at 0° C. for 3 h and then at room temperature for 30 h. It was poured into ice water (8 g) and the precipitate was collected by filtration, was dissolved into iN KOH (5 mL), and the red precipitate was removed by filtration. The solution then was acidified to pH=2 with 4N HCl to obtain a cream precipitate, which was collected by filtration, then was dried in the air at 50° C. for 4 h, affording the pure 6-nitro-5,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (71 mg, 84.5%), as a yellow powder; mp: 318°-20° C. (dec.). IR (KBr, cm-1): 3468, 3131, 3062, 2931, 1712, 1593, 1537. NMR (1H, DMSO-d6): δ7.392 (s, 1H), 11.566 (s, H), 12.274 (s, 1H). HRMS: calcd. for C8H3N3O4Br2 m/z: 362.8489, found: 62.8478.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:27]=[CH:28][CH:29]=2)[CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[OH:39][C:40]1[C:45]([Cl:46])=[CH:44][C:43]([Cl:47])=[CH:42][C:41]=1[S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[Cl:46][C:45]1[C:40]([OH:39])=[C:41]([S:48]([N:11]([CH2:10][C:9]2[CH:27]=[CH:28][CH:29]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:31][CH:30]=3)[CH:8]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=2)(=[O:50])=[O:49])[CH:42]=[C:43]([Cl:47])[CH:44]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: CCCCCCCCc1ccc(CNCc2cccc(Oc3ccc(F)cc3)c2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCc1ccc(CN(Cc2cccc(Oc3ccc(F)cc3)c2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.3 %

Procedure:
To a mixture of N-(3-(4-fluorophenoxy)benzyl)-1-(4-octylphenyl)methanamine (100 mg, 0.238 mmol, 1.0 eq) in DCM (10 mL) was added triethylamine (72 mg, 0.72 mmol, 3.0 eq) followed by 2-hydroxy-3,5-dichlorobenzenesulfonyl chloride (62 mg, 0.238 mmol, 1.0 eq). After stirring at ambient temperature for 4 h, the reaction mixture was diluted with 100 mL DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude residue was purified by preparative HPLC to afford the title compound (25 mg, 16%). 1H NMR (400 MHz, CD3OD) δ 7.64-7.63 (d, 1H), 7.55-7.54 (d, 1H), 7.21 (m, 1H), 7.19-7.11 (m, 2H), 7.09-7.02 (m, 4H), 6.95-6.91 (m, 2H), 6.88-6.86 (d, 1H), 6.80-6.78 (d, 1H), 6.68 (s, 1H), 4.43-4.40 (d, 4H), 3.35-3.30 (m, 6H), 2.55-2.51 (t, 2H), 1.57-1.56 (t, 3H), 1.3 (s, 10H), 0.87-0.91 (t, 3H). MS (ESI): 644.0 (M−H)−.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[C:17]([NH:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:44]2[CH2:45][CH2:46][CH:41]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:42][CH2:43]2)=[O:14])=[CH:10][C:9]=1[C:17]([NH:19][C:20]1[CH:21]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: c1ccc(CC2CCNCC2)cc1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C(=O)N2CCC(Cc3ccccc3)CC2)ccc1Cc1ccccc1
Yield: 76.7 %

Procedure:
Using 4-benzyl-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid and 4-benzylpiperidine as the raw materials, the same operation as the example 84(3) gave the title compound.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[NH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].BrBr>C(O)(=O)C>[CH3:1][NH:2][C:3]1[S:4][C:7]2[C:8]([C:9]([OH:11])=[O:10])=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1
Reactant: CN=C=S
Reactant: Nc1cccc(C(=O)O)c1
Agent: BrBr
Solvent: CC(=O)O
Product: CNc1nc2cccc(C(=O)O)c2s1
Temperature: 95 °C
Yield: 97 %

Procedure:
A solution of 39.2 g of methyl isothiocyanate and 50 g of 100% acetic acid is added dropwise to a suspension of 70 g of 3-amino-benzoic acid and 250 g of 100% acetic acid at 75-80° C. in the course of 50 minutes. A solution from which 3-(N′-methylthioureido)-benzoic acid slowly precipitates out in crystalline form is temporarily formed. After the mixture has been allowed to react completely for 2 hours, it is cooled to 50° and a solution of 81.5 g of bromine and 50 g of 100% acetic acid is added dropwise at 45-50° C. in the course of 2 hours. The mixture is then heated to 90-100° C. in the course of 2 hours and allowed to react completely for 2 hours, until the release of gas has ended. After 160 g of acetic acid have been distilled oft at 75-80° C. under reduced pressure, 200 g of water have been added to the residue, 67 g of 30% sodium hydroxide solution have been added dropwise, the mixture has been filtered with suction at 75-80° C. and the residue has been washed with water, 73 g of product of melting point >330° C. are obtained. HPLC analysis shows a content of 97% of the title compound, in addition to 0.7% of isomeric 2-methylamino-benzothiazole-5-carboxylic acid. Yield: 68% of theory.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH3:20])[N:3]=1.[C:21]1([S:27]([OH:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Na].O>CN(C=O)C>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([S:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:29])=[O:28])=[N:3][C:4]([CH3:20])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc2c(Cl)nc(C)c(-c3ccccc3)c2c1
Reactant: O=S(O)c1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(S(=O)(=O)c3ccccc3)nc(C)c(-c3ccccc3)c2c1

Procedure:
To a solution of 1-chloro-6-methoxy-3-methyl-4-phenylisoquinoline (0.24 g) in 20 mL DMF was added benzenesulfinic acid, sodium salt dihydrate (0.60 g). The reaction was heated at 120 C overnight, then poured into water and extracted with EtOAc (3×). The combined organic solutions were washed with water (1×) and brine (1×), dried (Na2SO4) and concentrated. To a solution of the residue in 20 mL DMF was added benzenesulfinic acid, sodium salt dihydrate (0.74 g). The reaction was heated at 160 C overnight, then poured into water and extracted with EtOAc (3×). The combined organic solutions were washed with water (1×) and brine (1×), dried (Na2SO4) and concentrated. The residue was recrystallized from ethyl ether/hexanes, then further purified by flash chromatography (5% to 30% EtOAc/hexanes). A second recrystallization from ethyl ether/hexanes gave the titled compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[CH3:9][NH:10][NH2:11].NN>C(O)C>[CH3:9][NH:10][N:11]=[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2]
Reactant: CNN
Reactant: N#Cc1ccccn1
Agent: NN
Solvent: CCO
Product: CNN=C(N)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
This compound was prepared by a modification of a reported procedure (J. Het Chem. 1975, 12, 855): A 2-L, 3-necked round bottom flask was charged with 2-cyanopyridine (40 g, 0.384 mol), methylhydrazine (93.7 g, 5.3 equiv, 2.035 mol), and ethanol (200 mL). The reaction was stirred under N2, overnight at room temperature. An additional equiv of hydrazine was added (6.3 equiv cumulative total in reaction mixture) and stirred for an additional 2–3 h at room temperature. The EtOH and excess hydrazine were distilled off in vacuo to afford a yellow crystalline solid. The yellow solid was triturated with benzene, affording a slurry of white crystals. The crystals were filtered, washed with a minimal amount of benzene and dried overnight in a vacuum oven at 50° C. The reaction yielded 41.33 g (71.6%) of the product as white crystals. 1H NMR (300 MHz, CDCl3): δ 2.97 (s, 3H), 4.02 (br s, 1H), 5.30 (br s, 1H), 7.20 (m, 1H), 7.66 (m, 1H), 8.08 (m, 1H), 8.45 (m, 1H). MS (APCI) calcd for C7H10N4: 150.09, found (M+H+): 151.3
Reaction SMILES: [NH:1]([C:14]([CH3:16])=[O:15])[C@@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:39]([O:43][C:44]([C:46]1[C:54]2[CH2:53][CH2:52][O:51][CH:50]([CH2:55][NH2:56])[C:49]=2[S:48][C:47]=1[NH2:57])=[O:45])([CH3:42])([CH3:41])[CH3:40].C(N(CC)C(C)C)(C)C>ClCCl>[C:39]([O:43][C:44]([C:46]1[C:54]2[CH2:53][CH2:52][O:51][CH:50]([CH2:55][NH:56][C:11](=[O:13])[CH:2]([NH:1][C:14](=[O:15])[CH3:16])[CH2:3][C:4]3[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=3)[C:49]=2[S:48][C:47]=1[NH2:57])=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN
Reactant: CC(=O)N[C@H](Cc1ccc(O)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC(Cc1ccc(O)cc1)C(=O)NCC1OCCc2c1sc(N)c2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.1 %

Procedure:
To a mixture of Ac-D-Tyr-OH (235 mg, 1.05 mmol) dissolved in dichloromethane (10 ml) was added 1-hydroxybenzotriazole (0.14 g, 1.05 mmol), 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (0.20 g, 1.05 mmol) and the reaction mixture was stirred for 15 min at room temperature. 2-Amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.3 g, 1.05 mmol) dissolved in dichloromethane (10 ml) was added followed by N,N-diisopropyl-ethylamine (0.18 ml, 1.05 mmol). The resulting reaction mixture was stirred for 18 h at room temperature, diluted with dichloromethane (15 ml) was washed with 10% aqueous citric acid (25 ml), saturated sodium hydrogencarbonate, dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel (40 g) using ethyl acetate as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 304 mg (59%) of 7-((2-acetylamino-3-(4-hydroxy-phenyl)propionylamino)methyl)-2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[CH:5]2.[OH2:12].[OH-].[Na+]>P(=O)(O)(O)O>[OH:12][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[CH:5]2
Reactant: Cn1ncc2cc(N)ccc21
Reactant: O
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cn1ncc2cc(O)ccc21
Temperature: 180 °C

Procedure:
5-Amino-1-methylindazole (1.56 g) in phosphoric acid (13 ml) containing water (3 ml) was heated to 180° C. for 18 hours, cooled to ambient temperature, poured into water (5 ml) then neutralised with aqueous sodium hydroxide. The solid that precipitated was filtered from solution, washed with cold water then sucked to dryness to give was hydrolysed to give 5-hydroxyl-1-methylindazole as a brown solid, (1.18 g).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:22][C:23](F)([F:32])[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.C(#N)C.[I-].[Na+]>C(OCC)(=O)C>[F:22][CH:23]([F:32])[O:24][C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:2]2[C:3]3[CH2:11][CH2:10][N:9]([C:12]4[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=4)[CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:30][CH:31]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: FC(F)(F)c1cccnc1N1CCc2c(Cl)ncnc2C1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: FC(F)Oc1ccc(Nc2ncnc3c2CCN(c2ncccc2C(F)(F)F)C3)cc1
Temperature: 150 °C

Procedure:
In a 5 mL microwave vial was combined 4-chloro-7-(3-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.113 g, 0.000356 mol), 4-(trifluoromethoxy)aniline (0.0964 mL, 0.000711 mol), acetonitrile (2 mL, 0.04 mol), and sodium iodide (0.00533 g, 0.0000356 mol). The mixture was heated at at 150° C. for 10 minutes and reduced in vacuo. The remaining solid was taken up in ethyl acetate (10 mL) and washed with saturated sodium bicarbonate (2×10 mL) and water (1×10 mL). The organic layer was dried over magnesium sulfate and reduced in vacuo to yield an off white solid. The mixture was purified by flash chromatography using an ethyl acetate:hexanes (0-50%) gradient to yield the desired product as an off white solid (0.052 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:31]=[O:32].O>O1CCCC1>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[C:10]([F:16])=[C:11]([C:12]([F:15])=[CH:13][CH:14]=1)[CH:31]=[O:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To dibenzyl-(2,4-difluoro-phenyl)-amine (52, 4.30 g, 13.9 mmol) in tetrahydrofuran (60 mL), under an atmosphere of nitrogen, cooled in a −78° C. acetone/dry ice bath, was added n-butyllithium (2.50 M in hexane, 6.1 mL, 15.3 mmol) slowly. The reaction was stirred for 1 hour, N,N-dimethylformamide (1.2 mL, 15.3 mmol) was added and the reaction was allowed to warm to room temperature for 1 hour. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane to provide the compound (53, 4.0 g, 85%). MS(ESI) [M+H+]+=337.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[C:11]1([N:17]=[C:18]=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOCC>[C:11]1([NH:17][C:18]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCCCCCCCCN
Reactant: O=C=Nc1ccccc1
Solvent: CCOCC
Product: NCCCCCCCCNC(=O)Nc1ccccc1

Procedure:
22 grams (0.139 moles) 1,8 diaminooctane in 300 cc ether was reacted with 7.0 gms (.059 mole) phenylisocyanate. The precipitate was filtered and washed with ether, yielding 10.9 gms. Recrystallized from dimethylformamide and recovered 7.8 gms having a melting point of 200°-217°C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[S:16][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:13][C:12]([C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[N:11]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[S:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:13][C:12]([C:26]([F:32])([F:31])[C:27]([F:28])([F:29])[F:30])=[N:11]1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccc(N3CCNCC3)s2)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)s2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.4 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[5-(piperazin-1-yl)-thiophen-2-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.07 mmol) prepared in Step 1, triethylamine (47.0 uL, 0.34 mmol) and methanesulfonyl chloride (11.6 mg, 0.10 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 15.0 mg of the titled compound as a yellow liquid.