Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:39][O:40][CH2:41][CH:42]([NH:44][C:45](=[O:53])[CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[CH3:43]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:50]3[CH2:51][CH2:52][N:47]([CH2:46][C:45]([NH:44][CH:42]([CH3:43])[CH2:41][O:40][CH3:39])=[O:53])[CH2:48][CH2:49]3)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: COCC(C)NC(=O)CN1CCNCC1
Agent: Cl
Product: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC(C)COC)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-(2-methoxy-1-methyl-ethyl)-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12e) and N-(2-methoxy-1-methylethyl)-2-piperazin-1-yl-acetamide (example 15) in an analogous manner as described in example 25. LR-MS: 719.4 [(M+H)+]
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([NH:17][NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)C>[C:19]([N:18]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[NH:17][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)N(Cc1ccccc1)NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
Benzyl bromide (0.9 g), 1-benzoyl-2-t-butyl hydrazine (1 g) and triethylamine (0.52 g) were warmed in dimethylformamide (50 ml) at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with diethylether (100 ml) and washed three times with 25 ml of water. The organic layer was dried over magnesium sulfate, filtered and the solvent removed in vacuo to afford the product as a white solid. The product was chromatographed on silica gel (G:70 to 230 mesh) using methylene chloride as eluant to afford a 75% yield of a white solid: m.p. 147-149.
Reaction SMILES: [C:1]1([NH:7]/[C:8](=[CH:13]/[C:14]([O:16]C)=O)/[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.O>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[O:16]=[C:14]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13]1
Reactant: COC(=O)/C=C(/Nc1ccccc1)C(=O)OC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(=O)c2ccccc2[nH]1
Temperature: 250 °C
Yield: 4.3 %

Procedure:
A mixture of the compound prepared in Example 271 (0.980 g) in Dowtherm A (trade mark; 1 mL) was heated at 250° C. for 15 minutes. The mixture was cooled to room temperature and shaken between dichloromethane and water. The organic layer was dried, concentrated in vacuo and purified by column chromatography on silica gel (1-5% methanol in dichloromethane) to obtain the title compound (0.036 g) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12]Br.[Cl:14][C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[CH3:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][NH:21][C:19]1[CH:18]=[CH:17][C:16]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:23]=2[CH3:32])=[C:15]([Cl:14])[CH:20]=1
Reactant: Cc1cc(C(F)(F)F)ccc1-c1ccc(N)cc1Cl
Reactant: FC(F)(F)c1ccc(CBr)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)ccc1-c1ccc(NCc2ccc(C(F)(F)F)cc2Br)cc1Cl
Temperature: 80 °C

Procedure:
2-Bromo-1-(bromomethyl)-4-(trifluoromethyl)benzene, prepared as described in Example 1 (2.5 g, 7.9 mmol), 2-chloro-2′-methyl-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-amine, prepared as described in Example 2 (2.5 g, 8.7 mmol), and K2CO3 (1.6 g, 11.8 mmol) were diluted with DMF (20 mL) and heated to 80° C. After 3 h the resulting mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=[CH:14][C:13]=2[NH2:26])=[N:8][C:7]=1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)=[O:5])[CH3:2].[CH:34](OCC)(OCC)OCC>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:12]3[CH:17]=[C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:15]=[CH:14][C:13]=3[N:26]=[CH:34]2)=[N:8][C:7]=1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)=[O:5])[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)c1sc(Nc2cc(OCc3ccccc3)ccc2N)nc1-c1cccc(Cl)c1
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(-n2cnc3ccc(OCc4ccccc4)cc32)nc1-c1cccc(Cl)c1

Procedure:
A mixture of the 2-(2-amino-5-benzyloxy-phenylamino)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester (VII.25) from previous step, 50 mL of acetic acid, 5 mL of triethyl orthoformate was heated to 50 degrees for 1 hour. The mixture was concentrated under reduced pressure and the residue taken up in 200 mL of dichloromethane. The mixture was washed with 100 mL saturated sodium bicarbonate. The aqueous layer was extracted twice with 100 mL of dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with diethyl ether to afford 3.5 g of 2-(6-benzyloxy-benzoimidazol-1-yl)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester (I.25a) as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]#N)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[BH4-].[Na+].[OH-].[K+].[CH:18]1(CBr)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.C(Cl)(Cl)Cl.O>[CH:18]1([CH2:12][S:11][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrCC1CCCCC1
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Nc1ccc(SCC2CCCCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 9.75 g (0.05 mole) of 2-nitro-4-thiocyanoaniline in 500 ml of absolute ethanol under nitrogen there is added 2.04 g (0.05 mole) of sodium borohydride in portions. The mixture is stirred at room temperature for 15 minutes and then refluxed for 15 minutes. The heating mantle is removed and 3.25 g (0.05 mole) of KOH in 15 ml of absolute ethanol is added. The mixture is stirred for 1 minute. A solution of 8.85 g (0.05 mole) of cyclohexylmethyl bromide in 15 ml of absolute ethanol is added and the mixture is stirred at room temperature for 15 minutes then refluxed for 1 hour. Equal amounts of water and CHCl3 are added until 2 layers are formed. The organic layer is separated, dried (MgSO4) and the solvent removed in vacuo. The residue is crystallized from ethyl ether to yield 8.3 g, m.p. 80°-82°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH2:7][C:3]2[CH:2]=[CH:10][C:6]([CH3:7])=[CH:5][CH:4]=2)[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(Cc2cc(Br)ccc2Cl)cc1

Procedure:
Synthesis was performed by a similar method as in Preparation Example 14 using 5-bromo-2-chlorobenzoic acid and toluene.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][N:21]([CH3:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1>ClCCl>[CH3:20][N:21]([CH3:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:11]2[CH2:10][CH2:9][CH:8]([CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:13][CH2:12]2)=[O:27])=[CH:24][CH:23]=1
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Solvent: ClCCl
Product: CN(C)c1ccc(C(=O)N2CCC(C(c3ccccc3)c3ccccc3)CC2)cc1
Reaction time: 24 h

Procedure:
To a solution of 150 parts of 4-(diphenylmethyl)piperidine and 99 parts of 4-(dimethylamino)benzoic acid in 4000 parts of dichloromethane is added a solution of 123 parts of N,N1 -methanetetraylbiscyclohexanamine in 1330 parts of dichloromethane. The resultant mixture is stirred for 6 hours, whereupon a further 25 parts of 4-(dimethylamino)benzoic acid and 30 parts of N,N1 -methanetetraylbiscyclohexanamine is introduced and stirring continued thereafter for 24 hours. The reaction mixture is then filtered, and the filtrate is stripped of solvent by vacuum distillation. The residue is taken up in ether; and the ether solution is consecutively washed with 5% hydrochloric acid, water, and 5% ammonium hydroxide, then dried over anhydrous potassium carbonate and finally stripped of solvent by vacuum distillation. The residue is recrystallized from a mixture of benzene and hexane to give 1-[4-(dimethylamino)benzoyl]-4-(diphenylmethyl)piperidine melting at 177°-179°.
Reaction SMILES: [C:1]1([CH:7]([NH:9][CH:10]([CH3:13])[CH2:11][OH:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[Cl:30]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:30][C:22]1[CH:23]=[C:24]([N:9]([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[CH:10]([CH3:13])[CH2:11][OH:12])[CH:25]=[CH:26][C:21]=1[F:20]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC(CO)NC(C)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(CO)N(c1ccc(F)c(Cl)c1)C(C)c1ccccc1
Reaction time: 24 h

Procedure:
2-[(1-phenylethyl)amino]propan-1-ol (5-5, 0.027 g, 0.151 mmol) in CH2Cl2 (1.0 mL) was treated with Cu(OAc)2 (0.041 g, 0.227 mmol), pyridine (0.024 mL, 0.302 mmol), and 4-fluoro-3-chloro-phenylboronic acid (0.026 g, 0.149 mmol). 4 A MS (20 mg) were added and the resulting solution stirred 24 h. Upon completion, the reaction mixture was filtered and the filtrate was purified by reverse phase liquid chromatography (Semi-prep YMC C-18 Column 5% CH3CN/H2O up to 95% CH3CN/H2O) to give 2-[(3-chloro-4-fluorophenyl)(1-phenylethyl)amino]propan-1-ol (5-6) as a brown oil. MS 308.3 found 308.8 (M+H+) required.
Reaction SMILES: [ClH:1].Cl.[N:3]1([C:8]2[CH:9]=[C:10]([C:14]3[O:15][C:16]4[CH:32]=[CH:31][C:30]([NH:33][C:34](=[NH:36])[CH3:35])=[CH:29][C:17]=4[C:18](=[O:28])[C:19]=3[O:20]CC3C=CC=CC=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.C(Cl)(Cl)[Cl:38].CO.N>>[ClH:38].[ClH:1].[N:3]1([C:8]2[CH:9]=[C:10]([C:14]3[O:15][C:16]4[CH:32]=[CH:31][C:30]([NH:33][C:34](=[NH:36])[CH3:35])=[CH:29][C:17]=4[C:18](=[O:28])[C:19]=3[OH:20])[CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: ClC(Cl)Cl
Reactant: CC(=N)Nc1ccc2oc(-c3cccc(-n4ccnc4)c3)c(OCc3ccccc3)c(=O)c2c1
Agent: Cl
Agent: N
Solvent: CO
Product: CC(=N)Nc1ccc2oc(-c3cccc(-n4ccnc4)c3)c(O)c(=O)c2c1
Yield: 90 %

Procedure:
Prepared analogously to Example 5, starting from 2-[(3-(imidazol-1-yl)-phenyl]-3-benzyloxy-6-[(1-iminoethyl)amino]-4H-1-benzopyran-4-one dihydrochloride. Yield: 90%; m.p.: 281.0-281.5° C. TLC (80/20/2 Chloroform/Methanol/Ammonia) Rf: 0.32; Elem. anal.: C20H16N4O3.2HCl, Theory: C, 55.44; H, 4.19; N, 12.93. Found: C, 53.05; H, 4.34; N, 12.18. 1H-NMR (d6-DMSO): 11.83 (s broad, 1H), 10.30 (s, 1H), 9.75 (m, 2H), 8.73 (s broad, 1H), 8.46 (m, 2H), 8.38 (m, 1H), 8.07-7.75 (m, 6H), 2.41 (s, 3H).
Reaction SMILES: C([O:7][CH2:8][CH2:9][C@H:10]1[C@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[O:13][C:12]2([CH2:25][CH2:24][CH2:23][CH2:22]2)[O:11]1)(=O)C(C)(C)C.C(OCC[C@H]1[C@H](C2C=CC=CC=2Cl)OC(CC)(CC)O1)(=O)C(C)(C)C>>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C@@H:14]1[O:13][C:12]2([CH2:25][CH2:24][CH2:23][CH2:22]2)[O:11][C@H:10]1[CH2:9][CH2:8][OH:7]
Reactant: CC(C)(C)C(=O)OCC[C@@H]1OC2(CCCC2)O[C@H]1c1ccccc1Cl
Agent: CCC1(CC)O[C@@H](CCOC(=O)C(C)(C)C)[C@H](c2ccccc2Cl)O1
Product: OCC[C@@H]1OC2(CCCC2)O[C@H]1c1ccccc1Cl
Yield: 80 %

Procedure:
The substantially same method as described in Example 364 was conducted, except that 2-((2S,3S)-3-(2-chlorophenyl)-1,4-dioxaspiro[4.4]nonan-2-yl)ethyl pivalate (Preparation example 365) was used instead of that 2-((4S,5S)-2,2-diethyl-5-(2-chlorophenyl)-1,3-dioxolan-4-yl)ethyl pivalate (Preparation example 363), to obtain the title compound (0.4 g, 80˜95%)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([N+:48]([O-:50])=[O:49])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:45])=[O:46])=[C:40]([N+:48]([O-:50])=[O:49])[CH:39]=2)[C:35]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:37])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.5 %

Procedure:
A solution of triphenylphosphine (138 mg, 0.53 mmol) in methylene chloride (2 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (94 mg, 0.53 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (150 mg, 0.44 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C., where it was stirred for 25 min. The reaction mixture was then treated with 2-aminothiazole (97 mg, 0.97 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was directly purified by flash chromatography, (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate), to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-yl-propionamide (96 mg, 52%) as a pale yellow solid: mp 121-124° C.; FAB-HRMS m/e calcd for C18H21N3O5S2 (M+H)+ 424.1001, found 424.1000.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([NH2:11])=O)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)=O>>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]#[N:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(C(N)=O)cc(S(N)(=O)=O)c1Oc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCNc1cc(C#N)cc(S(N)(=O)=O)c1Oc1ccccc1
Temperature: 120 °C

Procedure:
A mixture of 3-n-butylamino-4-phenoxy-5-sulfamylbenzamide (8.5 g) and phosphorus oxychloride (25 ml) is heated at 120° C. for 2 hours. The mixture is then evaporated in vacuo and the residue is triturated with ice-water (120 ml) to yield crude 3-n-butylamino-4-phenoxy-5-sulfamylbenzonitrile. After filtration, carefully washing with water, drying and recrystallization from methanol, it is obtained with a melting point of 217°-218° C.
Reaction SMILES: [F:1][C:2]1([C:5](=O)[CH3:6])[CH2:4][CH2:3]1.ClC1(C2C=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:14]([CH3:22])[N:13]=2)CC1>>[F:1][C:2]1([C:5]2[CH:6]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:14]([CH3:22])[N:13]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cc(C2(Cl)CC2)nn1C
Reactant: CC(=O)C1(F)CC1
Product: CCOC(=O)c1cc(C2(F)CC2)nn1C

Procedure:
Ethyl 3-(1-fluorocyclopropyl)-1-methyl-1H-pyrazole-5-carboxylate is prepared from 1-(1-fluorocyclopropyl)ethanone analogously to the process described in the synthesis of ethyl 3-(1-chlorocyclopropyl)-1-methyl-1H-pyrazole-5-carboxylate.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4](=NC)[CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].C([O-])([O-])=O.[K+].[K+].[C:18]([NH:26][NH2:27])(=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[CH3:2][N:3]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:26][N:27]=[C:4]1[CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9]
Reactant: NNC(=O)c1ccccc1
Reactant: C=CCCCC(=NC)NC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=CCCCc1nnc(-c2ccccc2)n1C
Yield: 0 %

Procedure:
To a solution of N,N′-dimethyl-5-hexenimidamide hydrochloride (3.1Mmol) in MeOH (20 ml) were added K2CO3 (3.1Mmol) and benzhydrazide (3.1Mmol). The solution was heated to reflux for 24 h. Volatiles were evaporated in vacuo, the crude dissolved in DCM, washed with water and dried over Na2SO4. After filtration and concentration to dryness in vacuo, the crude was purified by column chromatography (DCM:MeOH=98 to 2) to give 196 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.Cl[C:17]1[N:22]=[C:21]([C:23]2[C:24]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:46])[CH2:40][C:41]4[CH:45]=[CH:44][S:43][CH:42]=4)[CH:35]=[CH:36][CH:37]=3)=[N:25][N:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=23)[CH:20]=[CH:19][N:18]=1>CC(O)C.Cl.C(Cl)Cl>[F:14][C:11]([F:12])([F:13])[C:10]([NH:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:17]2[N:22]=[C:21]([C:23]3[C:24]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C:39](=[O:46])[CH2:40][C:41]5[CH:45]=[CH:44][S:43][CH:42]=5)[CH:33]=4)=[N:25][N:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=34)[CH:20]=[CH:19][N:18]=2)[CH:3]=1)=[O:15]
Reactant: O=C(Cc1ccsc1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1
Reactant: Nc1cccc(CNC(=O)C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C(Cc1ccsc1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(CNC(=O)C(F)(F)F)c3)n2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
A suspension of N-[(3-aminophenyl)methyl]-2,2,2-trifluoroacetamide (73 mg, 0.34 mmol) and N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(3-thienyl)acetamide (120 mg, 0.27 mmol) in i-PrOH (4 mL) was acidified with 3 drops of 12 N HCl and stirred at 80° C. overnight. After 16 h, the reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3, dried over Na2SO4, and adsorbed onto silica gel. The crude product was purified by column chromatography to generate the title compound in 53% yield. 1H NMR (400 MHz, d6-DMSO) δ 10.28 (s, 1H), 9.98 (t, 1H), 9.63 (s, 1H), 8.83 (d, J=6.9 Hz, 1H), 8.52 (d, J=9.0 Hz, 1H), 8.24 (d, J=5.1 Hz, 1H), 7.90 (s, 1H), 7.63 (s, 1H), 7.75 (d, J=9.0 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.47-7.49 (m, 2H), 7.42 (t, J=7.9 Hz, 1H), 7.32 (d, J=2.2 Hz, 1H), 7.26 (d, J=9.1 Hz, 1H), 7.22 (d, J=7.9 Hz, 1H), 7.08-7.13 (m, 2H), 6.85 (d, J=7.7 Hz, 1H), 6.51 (d, J=5.1 Hz, 1H), 4.35 (d, J=5.9 Hz, 2H), 3.66 (s, 2H). ES-LC/MS m/z=628 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([NH:22][NH2:23])=[O:21])[CH:4]=1.[CH:24](=O)[CH2:25][CH3:26].C(OCC)C.Cl>C(Cl)(Cl)Cl>[CH:24](=[N:23][NH:22][C:20](=[O:21])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[N:6]=1)[CH2:25][CH3:26]
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1
Reactant: CCC=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCC=NNC(=O)c1cc(OC)cc(Oc2cccc(C(F)(F)F)c2)n1

Procedure:
4-methoxy-6-[3-(trifluoromethyl)phenoxy] picolinic acid hydrazide (0.5 g, 0.0015 mol) was mixed with propionaldehyde (0.27 g, 0.0015×3.1 mol), and further with a mixed solution of diethyl ether and chloroform and a small amount of concentrated hydrochloric acid. The resultant solution was heated and refluxed for about 8 hours. The obtained reaction solution was concentrated and then purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:12]=3)=[C:4]2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C.[CH:89]1([NH2:94])[CH2:93][CH2:92][CH2:91][CH2:90]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[NH:17]([C:13]1[N:12]=[C:11]([C:10]2[C:9]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[N:8][N:5]3[CH:6]=[CH:7][C:2]([NH:94][CH:89]4[CH2:93][CH2:92][CH2:91][CH2:90]4)=[CH:3][C:4]=23)[CH:16]=[CH:15][N:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC1CCCC1
Reactant: Fc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(Nc3ccccc3)n2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccc(-c2nn3ccc(NC4CCCC4)cc3c2-c2ccnc(Nc3ccccc3)n2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
To a solution of 4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-phenyl-2-pyrimidinamine (100 mg, 0.24 mmol) in cyclopentylamine (5 mL) was added successively racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (72 mg), cesium carbonate (200 mg), and palladium (II) acetate (16 mg). The resulting mixture was stirred at 100° C. for 24 hours, then additional racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (72 mg) and palladium (II) acetate (16 mg) were added and the reaction stirred at 100° C. for additional 24 hours, at which time the reaction was judged complete by thin layer chromatography. The solution was cooled to room temperature and ethyl acetate and water were added to the reaction mixture. The phases were separated, and the aqueous phase again extracted with ethyl acetate. The combined organic phases were dried (magnesium sulfate), filtered and concentrated. The resulting residue was purified by flash chromatography (1:1 hexanes:ethyl acetate) to give N-[3-(2-anilino-4-pyrimidinyl)-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]-N-cyclopentylamine (40 mg, 36%) as a solid. 1H NMR (CDCl3): δ 8.21 (d, 1H), 8.13 (d, 1H), 7.65 (m, 4H), 7.4–7.24 (m, 4H), 7.18 (t, 21H), 7.06 (t, 1H), 6.44 (d 1H), 6.30 (dd, 1H), 4.16 (d, 1H), 3.68 (m, 1H), 1.4–2.2 (m, 8H); 19F-NMR (CDCl3): δ−113.32; MS m/z 466 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([I:9])[C:3]=1[OH:10].[CH2:11](Br)[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([I:9])[C:3]=1[O:10][CH2:11][CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCC=Cc1ccccc1
Reactant: Cc1cc(Br)c(O)c(I)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Br)c(OCC=Cc2ccccc2)c(I)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 101.2 %

Procedure:
2-Bromo-4-methyl-6-iodophenol (7.82 gm, 25 mmol) and cinnamyl bromide (4.93 g, 25 mmol) were added to DMF (20 ml). Diisopropylethylamine (5.3 ml, 30.4 mmol) was added and the mixture heated to 60° C. for 15 minutes and then allowed stir for 16 hours at room temperature. The DMF was removed under vacuum, and 1M HCl was added until the residue was acidic. The mixture was extracted with ethyl acetate, and the combined organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 1-bromo-3-iodo-5-methyl-2-(3-phenylallyloxy)-benzene (10.86 g, 100% yield).
Reaction SMILES: Br.C[O:3][C:4]1[CH:5]=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1>>[NH:12]1[CH2:13][CH2:14][CH2:15][CH:10]([C:6]2[CH:5]=[C:4]([OH:3])[CH:9]=[CH:8][CH:7]=2)[CH2:11]1
Reactant: COc1cccc(C2CCCNC2)c1
Agent: Br
Product: Oc1cccc(C2CCCNC2)c1

Procedure:
HBr can be prepared from 3-(3-methoxyphenyl)piperidine as described in J. Med. Chem., 24 (1981) 1475.