Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH2:20][CH:21]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][CH:24]1[CH2:29][NH:28][CH2:27][CH2:26][N:25]1[C:30]1[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:23][CH:24]1[CH2:29][N:28]([CH2:21][CH2:20][CH2:19][C:9]2[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:27][CH2:26][N:25]1[C:30]1[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=1
Reactant: Cc1cccc(N2CCNCC2C)c1
Reactant: Cc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4cccc(C)c4)C(C)C3)nn2-c2ccccc2)cc1

Procedure:
112 mg (81%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80 mg, 0.276 mmol), 2-methyl-1-m-tolylpiperazine (53 mg, 0.276 mmol), DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)3 (175 mg, 0.828 mmol).
Reaction SMILES: [CH2:1]([N:6]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:7]([C@@H:9]1[NH:21][CH2:20][C:12]2[NH:13][C:14]3[C:19]([C:11]=2[CH2:10]1)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[C:27]1([CH3:36])[CH:32]=[CH:31][CH:30]=[C:29]([N:33]=[C:34]=[O:35])[CH:28]=1>O1CCCC1>[CH2:22]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]([C@@H:9]1[N:21]([C:34](=[O:35])[NH:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([CH3:36])[CH:28]=2)[CH2:20][C:12]2[NH:13][C:14]3[C:19]([C:11]=2[CH2:10]1)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:8])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CCCCCN(CCCCC)C(=O)[C@H]1Cc2c([nH]c3ccccc23)CN1
Solvent: C1CCOC1
Product: CCCCCN(CCCCC)C(=O)[C@H]1Cc2c([nH]c3ccccc23)CN1C(=O)Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
0.114 g (3R)-3-(N,N-dipentylcarbamoyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole is dissolved in 2 ml tetrahydrofuran and 42.7 mg of m-tolylisocyanate is added. The solution is stirred at room temperature for 1 hour, evaporated, and the residue triturated with hexane to give 0.119 g (3R)-3-(N,N-dipentylcarbamoyl)-2-(3-methylphenylcarbamoyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole, m.p. 154°-155° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:6][CH2:7][C:8]([F:12])([F:11])[CH2:9][NH2:10]>Br>[F:11][C:8]([F:12])([CH2:9][NH2:10])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3][CH2:2][NH2:1]
Reactant: Cc1ccc(S(=O)(=O)N(CCCN)CCC(F)(F)CN)cc1
Agent: Br
Product: NCCCNCCC(F)(F)CN
Temperature: 25 °C

Procedure:
The 1,8-diamino-4-p-toluenesulfonyl-7,7-difluoro-4-aza-octane so obtained is refluxed with 100 mL of 48% aqueous HBr for 20 hours. After cooling to room temperature, the solution is carefully extracted with ether (5×300 mL). After evaporation of the solvent, traces of free HBr are removed by stripping twice with water; on stripping with ethanol, the desired 7,7-difluoro-1,8-diamino-aza-octane crystallizes as the trihydrobromide. Digestion with acetone yields white crystals which are washed with acetone, a small amount of ethanol, and finally with ether: 12.85 g (95%).
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.[C:6]([OH:11])(=[O:10])/[CH:7]=[CH:8]/[CH3:9].[Cl:12][C:13]([Cl:17])([Cl:16])[CH2:14]O.S(=O)(=O)(O)O>O>[Cl:12][C:13]([Cl:17])([Cl:16])[CH2:14][O:10][C:6](=[O:11])/[CH:7]=[CH:8]/[CH3:9]
Reactant: C/C=C/C(=O)O
Reactant: OCC(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: C/C=C/C(=O)OCC(Cl)(Cl)Cl
Yield: 95 %

Procedure:
In 200 ml. carbon tetrachloride are dissolved 0.5 mole (43.07 g.) crotonic acid and the equimolar amount of 2,2,2-trichloroethanol, 1 ml. concentrated sulphuric acid is added thereto and the reaction mixture is heated under reflux on a water separator until the theoretical amount of water (9 ml.) has separated off. Subsequently, the organic phase is shaken out twice with, in each case, 100 ml. aqueous 2N sodium hydrogen carbonate solution and twice with, in each case, 50 ml. of water, the organic phase is then dried with anhydrous magnesium sulphate and the solvent is distilled off in a vacuum. There is finally obtained the desired product (i) in the form of a bright yellow oil in a yield of 95% of theory. C6H7O2Cl3. (217.4791).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[N:9][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.BrC1C=CC(C(C2C=CC(S(C)(=O)=O)=CC=2)=O)=CC=1.[BH4-].[Na+]>C(O)(=O)C.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[NH:9][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CC(C)C)N=C(c1ccc(Br)cc1)c1ccc(S(C)(=O)=O)cc1
Agent: CS(=O)(=O)c1ccc(C(=O)c2ccc(Br)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(c1ccc(Br)cc1)c1ccc(S(C)(=O)=O)cc1

Procedure:
To a solution of a 1:1 mixture of methyl N-{(4-bromophenyl)[4-(methylsulfonyl)phenyl]methylene}leucinate and (4-bromophenyl)[4-(methylsulfonyl)phenyl]methanone from step 1 (185 mg, ˜0.2 mmol) in acetic acid/methanol (1:3, 4 mL) was added sodium borohydride (−400 mg) by portions every 30 min over 2 days (addition was stopped during the night) using a solid addition funnel. The reaction mixture was partitioned between EtOAc and water, the organic layer was dried over Na2SO4 and concentrated. The resulting mixture was purified by chromatography using EtOAc and hexane as eluant. Methyl N-{(4-bromophenyl)[4-(methylsulfonyl)phenyl]methyl}-L-leucinate was obtained as a colorless gum and (4-bromophenyl)[4-(methylsulfonyl)phenyl]methanol was obtained as a white solid.
Reaction SMILES: [C:1]([C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1)#[CH:2].[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13].[C-:14]1([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23](I)[CH:22]=2)[CH:18]=[CH:17][CH:16]=[CH:15]1.[CH-:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1.[Fe+2]>>[C-:3]1([C:1]#[C:2][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:20]#[C:19][C-:14]3[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:22]=2)[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13].[CH-:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1.[Fe+2:13]
Reactant: C#C[c-]1cccc1
Reactant: Ic1cccc(C#C[c-]2cccc2)c1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Product: C(#C[c-]1cccc1)c1cccc(C#C[c-]2cccc2)c1

Procedure:
Example 11 describes the procedure for producing 1,3-bis(ferrocenylethynyl) benzene 516. Ethynylferrocene 500 was reacted with 1,3-diiodobenzene 502 to form 1-(ferrocenylethynyl)-3-iodobenzene 504. Sufficient ethynylferrocene 500 was present such that the second step of the reaction immediately proceeded. 1-(Ferrocenylethynyl)-3-iodobenzene 504 reacted with ethynylferrocene 514 to form 1,3-bis(ferrocenylethynyl) benzene 516. The reaction procedure is shown in FIG. 5.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]([C:9]2[C:10]([CH3:19])=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=2)[C:14]([OH:16])=O)=[C:6]([CH3:8])[N:7]=1.C(CC1NC(C2C(C)=CC(C)=C(C=2)C(O)=O)=C(C)N=1)#N.Cl.[NH:41]1[CH2:44][CH:43]([C:45]2[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=2)[CH2:42]1.Cl.FC1(C2C=CC(C#N)=CC=2)CNC1>>[OH:1][CH2:2][C:3]1[NH:4][C:5]([C:9]2[C:10]([CH3:19])=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=2)[C:14]([N:41]2[CH2:44][CH:43]([C:45]3[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=3)[CH2:42]2)=[O:16])=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1cc(C)c(-c2[nH]c(CO)nc2C)cc1C(=O)O
Reactant: N#Cc1ccc(C2CNC2)cc1
Agent: Cc1cc(C)c(-c2[nH]c(CC#N)nc2C)cc1C(=O)O
Agent: Cl
Agent: N#Cc1ccc(C2(F)CNC2)cc1
Product: Cc1cc(C)c(-c2[nH]c(CO)nc2C)cc1C(=O)N1CC(c2ccc(C#N)cc2)C1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 222, except 5-(2-(hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 222.5) was used in place of 5-(2-(cyanomethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 222.6) and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) was used in place of 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4). m/z (ES+) 401 (M+H)+.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27]([OH:29])=[O:28])[CH2:23][CH2:22]1)[CH2:17][CH2:18][CH2:19][CH3:20].O[C:31]1[CH:36]=[CH:35][C:34]([S:37]([F:42])([F:41])([F:40])([F:39])[F:38])=[CH:33][CH:32]=1>C(Cl)Cl>[CH2:16]([C@H:21]1[CH2:22][CH2:23][C@H:24]([C:27]([O:29][C:31]2[CH:32]=[CH:33][C:34]([S:37]([F:40])([F:38])([F:42])([F:39])[F:41])=[CH:35][CH:36]=2)=[O:28])[CH2:25][CH2:26]1)[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: Oc1ccc(S(F)(F)(F)(F)F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](C(=O)Oc2ccc(S(F)(F)(F)(F)F)cc2)CC1

Procedure:
A mixture of 10.6 g of dicyclohexylcarbodiimide and 40 ml of methylene chloride is added to a mixture of 9.1 g of trans-4-pentylcyclohexylcarboxylic acid, 11.2 g of p-hydroxyphenyl-sulfur pentafluoride and 100 ml of methylene chloride, and the combined mixture is heated at the boil for 6 hours. Working up in the customary manner gives 4-(trans-4-pentylcyclohexylcarbonyloxy)-phenyl-sulfur pentafluoride.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([C:8]([O:10][C@H:11]([CH3:29])[C@@H:12]([NH:21]C(OC(C)(C)C)=O)[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][C@H:11]([CH3:29])[C@@H:12]([NH2:21])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)=[O:9])=[CH:30][CH:31]=1)([O-:3])=[O:2]
Reactant: C[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@@H](NC(=O)OC(C)(C)C)c1ccc(F)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@@H](N)c1ccc(F)c(Cl)c1
Yield: 99.9 %

Procedure:
To a stirred solution of 332 (103 mg, 0.227 mmol) in DCM (2.2 mL) at RT under nitrogen was added TFA (1 mL). After 2 h the reaction was concentrated to dryness in a rotovap and high vacuum. The crude presumed TFA salt was redissolved in DCM (5 mL) and stirred rapidly with 10% aqueous Na2CO3 (5 mL). After 5 min the organics phase was separated, dried (MgSO4), filtered and concentrated to afford 80 mg (100%) of (1S,2R)-1-amino-1-(3-chloro-4-fluorophenyl)propan-2-yl 4-nitrobenzoate (334) as a yellow oil which was used without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[O:7][C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22]([O:29][NH2:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[CH2:22]([O:29][N:30]1[C:6]([C:13]([OH:15])=[O:14])=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[C:8]1=[O:7])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccccc1
Reactant: NOCc1ccccc1
Solvent: CCO
Product: O=C(O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1OCc1ccccc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 88.9 %

Procedure:
A mixture of 6-chloro-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid (300 mg), O-benzylhydroxylamine (620 mg) and ethanol (6.0 ml) was stirred at 90° C. for 12 hrs. in a sealed tube. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was washed with ethyl acetate/diethyl ether=1/10 to give the title compound (360 mg) as a colorless powder.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:29])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[C:14]([O:27][CH3:28])[CH:13]=2)[CH2:4][CH2:3]1>[C].[Pd].CO>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:29])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[C:14]([O:27][CH3:28])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCCCN(C)C
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCCCN(C)C

Procedure:
Using 1.5 g of N-(trans-4-methylcyclohexyl)-4-(5-dimethylaminopentyloxy)-3-methoxycinnamamide (Example 135), 0.075 g of 10% palladium-carbon, and 100 ml of methanol, a reaction similar to that conducted in Example 147 was carried out. The product obtained was recrystallized from methylene chloride/ether, yielding 1.3 g of N-(trans-4-methylcyclohexyl)-3-[4-(5-dimethylaminopentyloxy)-3-methoxyphenyl]propionamide (a compound of the present invention) as light-greenish white crystal, which had had the following physiochemical properties:
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH:12]([C:15]1[C:20]([CH2:21][OH:22])=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:18]([CH:30]=[N:31][O:32][CH3:33])=[C:17]([CH:34]([CH3:36])[CH3:35])[N:16]=1)([CH3:14])[CH3:13]>C(Cl)Cl>[CH:12]([C:15]1[C:20]([CH:21]=[O:22])=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:18]([CH:30]=[N:31][O:32][CH3:33])=[C:17]([CH:34]([CH3:36])[CH3:35])[N:16]=1)([CH3:14])[CH3:13]
Reactant: CON=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CON=Cc1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.62 g (6.2 mmol) of neutral alumina and 1.3 g (6.1 mmol) of pyridinium chlorochromate are added to a solution of 1.05 g (3.05 mmol) of the compound from Example 2 in 50 ml of methylene chloride and the mixture is stirred at room temperature for 1 hour. It is filtered through kieselguhr and then washed with 200 ml of methylene chloride. The methylene chloride phase is concentrated in vacuo and the residue is chromatographed on a column (100 g of silica gel, 70-230 mesh, diameter 3.5 cm) using ethyl acetate/petroleum ether 1:9.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH:12][C:13]2[N:17]=[C:16]([NH2:18])[NH:15][N:14]=2)=[CH:4][C:3]=1[Cl:19].[CH:20]([S:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])=[O:24])([CH3:22])[CH3:21].C([O-])([O-])=O.[K+].[K+]>COCCOC.O1CCOCC1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:3]1[CH:4]=[C:5]([NH:12][C:13]2[N:17]=[C:16]([NH2:18])[NH:15][N:14]=2)[CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]=1[C:29]1[CH:28]=[CH:27][C:26]([S:23]([CH:20]([CH3:22])[CH3:21])(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: Nc1nc(Nc2cc(Cl)c(Br)c(C(F)(F)F)c2)n[nH]1
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)c1ccc(-c2c(Cl)cc(Nc3n[nH]c(N)n3)cc2C(F)(F)F)cc1
Temperature: 125 °C

Procedure:
A mixture of N3-(4-bromo-3-chloro-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 1 (150 mg, 421 μmol), 4-(isopropylsulfonyl)phenylboronic acid (240 mg, 1.05 mmol) and 3M K2CO3 (351 μl, 1.05 mmol) in DME (1 ml) and dioxane (1 ml) was degassed with argon and tetrakis(triphenylphosphine)palladium(0) (97.2 mg, 84.1 μmol) was added. The reaction mixture was heated in microwave at 125° C. for 3 hours, diluted with MeOH, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 3% to 7% MeOH in DCM). Further purification by super fluid chromatography afforded a white foam (32 mg, 16% yield) as desired product. MS +m/z: 460 (M+H)+
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:28]=[CH:27][C:11]([CH2:12][N:13]2[C:18]3[S:19][CH:20]=[C:21]([CH3:22])[C:17]=3[C:16]3=[N:23][CH:24]=[N:25][N:15]3[C:14]2=[O:26])=[CH:10][CH:9]=1.[C:29](=O)([O-])[O-:30].[K+].[K+]>CN(C)C=O>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][N:13]2[C:18]3[S:19][C:20]([CH:29]=[O:30])=[C:21]([CH3:22])[C:17]=3[C:16]3=[N:23][CH:24]=[N:25][N:15]3[C:14]2=[O:26])=[CH:27][CH:28]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3c(C)csc32)cc1
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)n3ncnc3c3c(C)c(C=O)sc32)cc1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 62.3 %

Procedure:
Phosphorus oxychloride (1.47 ml, 15.8 mmol) was added to N,N-dimethylformamide (13 ml) and the mixture was stirred for 20 minutes. 6-(4-Methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (1.29 g, 3.94 mmol) was added as a solid and the mixture was heated at 90° C. for 45 minutes. The mixture was cooled to room temperature and poured into a mixture of ice (30 mL) and potassium carbonate (5 g). After the ice had melted the pH was 8-9. The mixture was extracted with dichloromethane (3×30 mL) and the combined extracts were washed with brine (30 mL), dried (MgSO4) and concentrated under vacuum. The residue was purified by flash LC (20-100% ethyl acetate in hexanes) to afford the aldehyde (0.87 g, 62%) as a yellow powder. 1H NMR (400 MHz, CDCl3) δ 3.01 (s, 3H), 3.78 (s, 3H), 5.38 (s, 2H), 6.86-6.88 (m, 2H), 7.44-7.46 (m, 2H), 8.33 (s, 1H), 10.12 (s, 1H). LCMS (MH+, 355.0).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:23]3[CH:30]=[C:29]([CH2:31][CH3:32])[S:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:18][CH2:17]1)=[O:15])=O)(C)(C)C.Cl>CO>[CH2:31]([C:29]1[S:28][C:24]2[N:25]=[CH:26][N:27]=[C:22]([N:19]3[CH2:20][CH2:21][N:16]([C:14]([CH:9]4[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]4)=[O:15])[CH2:17][CH2:18]3)[C:23]=2[CH:30]=1)[CH3:32]
Reactant: CCc1cc2c(N3CCN(C(=O)C4CCCCN4C(=O)OC(C)(C)C)CC3)ncnc2s1
Agent: Cl
Solvent: CO
Product: CCc1cc2c(N3CCN(C(=O)C4CCCCN4)CC3)ncnc2s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
2-[4-(6-Ethyl-thieno[2,3-d]pyrimidin-4-yl)-piperazine-1-carbonyl]-piperidine-1-carboxylic acid tert-butyl ester (276.1 mg) was dissolved in methanol (1.00 mL) and HCl (4 M in dioxane, 1.00 mL) was added. After stirring at room temperature for 1.5 hours, the solvents were removed and the residue was desalted with MP-carbonate resin in methanol giving the desired free amine. Yield=100%, ES-MS: (M+H)+ 360
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@@H:5]([CH2:7][N:8]2[CH:12]=[C:11]([I:13])[CH:10]=[N:9]2)[CH2:4][O:3]1.[CH2:15]1COCC1.[Li+].CC([N-]C(C)C)C.C1CCCCC1.CI.[NH4+].[Cl-]>>[CH3:1][C:2]1([CH3:14])[O:6][C@@H:5]([CH2:7][N:8]2[C:12]([CH3:15])=[C:11]([I:13])[CH:10]=[N:9]2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@H](Cn2cc(I)cn2)O1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: CI
Product: Cc1c(I)cnn1C[C@H]1COC(C)(C)O1
Reaction time: 1 h

Procedure:
A solution of 1-{[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methyl}-4-iodo-1H-pyrazole (700 mg, 2.27 mmol) in THF (6 mL, 70 mmol) was cooled to −78° C., and 1.5 M of LDA in cyclohexane (4.5 mL, 6.8 mmol) was added. After stirring for 1 h, methyliodide (1.41 mL, 22.7 mmol) was added slowly, and the mixture was stirred at −78° C. for 1 h. Sat. NH4Cl was added to quench, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer purified via column chromatography, eluting with 5-10% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=323.06 (100) [MH+]. HPLC: tR=1.20 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>>[CH3:14][S:15]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:17])=[O:16]
Reactant: OCCOCCc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCOCCc1ccc(Cl)cc1
Yield: 92 %

Procedure:
The 2-[2-(4-chlorophenyl)ethoxy]ethanol obtained according to the preceding paragraph was sulfonylated with methanesulfonyl chloride in a manner analogous to that described in Example 1(c) to give 1.5 g (92%) of 2-[2-(4-chlorophenyl)ethoxy]ethyl methanesulfonate in the form of an oil which was homogeneous according to chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([C:8]1[N:9]=[C:10]([N:14](C(OC(C)(C)C)=O)CC2C=CC(OC)=CC=2)[S:11][C:12]=1[F:13])([CH3:7])[CH3:6])[CH3:2].C(O)(C(F)(F)F)=O>>[CH2:1]([O:3][C:4](=[O:31])[C:5]([C:8]1[N:9]=[C:10]([NH2:14])[S:11][C:12]=1[F:13])([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)c1nc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)sc1F
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(C)c1nc(N)sc1F
Yield: 97.8 %

Procedure:
The reaction was done by the same way as mentioned in the preparation 45, step-V using 2-{2-[tert-Butoxycarbonyl-(4-methoxy-benzyl)-amino]-5-fluoro-thiazol-4-yl}-2-methyl-propionic acid ethyl ester (0.5 g, 1.1 mmol) and TFA (5 mL) to afford 2-(2-Amino-5-fluoro-thiazol-4-yl)-2-methyl-propionic acid ethyl ester (0.25 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:31]2[CH2:32][CH2:33][CH:28]([C:24]3[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=3)[CH2:29][CH2:30]2)=[CH:4][CH:5]=1)(=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(C(=O)c4ccccc4)cc3)CC2)c1

Procedure:
Prepared by Procedure AJ and Scheme AV using [4-(bromomethyl)phenyl](phenyl)methanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 441.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3]([CH3:6])(=[O:5])=[O:4].C([Li])CCC.[F:13][C:14]1[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[C:16]([NH:24][CH3:25])[CH:15]=1>>[F:13][C:14]1[CH:23]=[CH:22][C:17]([C:18](=[O:19])[CH2:6][S:3](=[O:5])(=[O:4])[N:2]([CH3:7])[CH3:1])=[C:16]([NH:24][CH3:25])[CH:15]=1
Reactant: CN(C)S(C)(=O)=O
Reactant: CNc1cc(F)ccc1C(=O)OC
Agent: [Li]CCCC
Product: CNc1cc(F)ccc1C(=O)CS(=O)(=O)N(C)C

Procedure:
In a similar manner to that described in Example 12(a), N,N-dimethylmethanesulphonamide was reacted with n-butyl lithium and the product reacted with methyl 4-fluoro-2-methylaminobenzoate to give the novel compound 1-(4-fluoro-2-methylaminophenyl)-2-(N,N-dimethylsulphamoyl)ethanone, m.p. 120°-124°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])=[CH:11][C:10]([C:23]([F:26])([F:25])[F:24])=[N:9]2)=[CH:4][CH:3]=1.[CH3:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29].C([O-])([O-])=O.[K+].[K+]>>[CH3:27][S:28]([C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:19]([F:22])([F:20])[F:21])=[CH:11][C:10]([C:23]([F:25])([F:24])[F:26])=[N:9]3)=[CH:6][CH:7]=2)[CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1cc(-c2ccccc2C(F)(F)F)n(-c2ccc(Br)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3nc(C(F)(F)F)cc3-c3ccccc3C(F)(F)F)cc2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 76.5 %

Procedure:
A mixture of 1-(4-bromophenyl)-3-trifluoromethyl-5-(2-trifluoromethyl-phenyl)-1H-pyrazole (135 mg, 0.31 mmol), 3-methanesulfonyl-phenylboronic acid (74 mg, 0.37 mmol), K2CO3 (0.13 g, 0.93 mmol), Cl2Pd(dppf).DCM (24 mg, 10 mol %) and H2O (0.2 mL) in dioxane (2 mL) was sparged with Argon for 5 min and then heated at 80° C. as a sealed flask. After 16 h the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 0:100 to 40:60) to give the title compound (121 mg, 76%). 1H NMR (DMSO-d6): δ 8.15 (m, 1H), 8.03 (d, 1H), 7.91 (m, 2H), 7.83 (d, 2H), 7.71-7.76 (m, 3H), 7.66 (m, 1H), 7.40 (d, 2H), 7.18 (s, 1H); MS(ES): 511 [M+H]+.