Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][C:8]([F:23])=[CH:7][N:6]=1.C(N(C(C)C)C(C)C)C.[CH3:38][O:39][C:40](=[O:50])[C:41]1[CH:46]=[CH:45][C:44]([C:47](Cl)=[O:48])=[CH:43][CH:42]=1>CN(C=O)C>[CH3:38][O:39][C:40](=[O:50])[C:41]1[CH:46]=[CH:45][C:44]([C:47]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]([C:11]([C:10]3[C:5]([O:4][C:3]4[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:2]=4[Cl:1])=[N:6][CH:7]=[C:8]([F:23])[CH:9]=3)=[O:12])[CH2:14][CH2:15]2)=[O:48])=[CH:43][CH:42]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: O=C(c1cc(F)cnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C(=O)N2CCN(C(=O)c3cc(F)cnc3Oc3cc(Cl)ccc3Cl)c3ccccc32)cc1
Temperature: 120 °C
Yield: 10.8 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-5-fluoro-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (52.3 mg, 0.125 mmol, 1.0 equiv; Example 147) in anhydrous DMF (1 mL) was added N-ethyldiisopropylamine (65 mg, 85 μL, 0.5 mmol, 4.0 equiv; [CAS RN 7087-68-5]) and 4-chlorocarbonyl-benzoic acid methyl ester (29.8 mg, 0.15 mmol, 1.2 equiv; [CAS RN 7377-26-6]). The reaction mixture was heated by microwave irradiation to 120° C. for 15 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 7.8 mg (11%) of the title compound as a white powder. MS (ISP): 580.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH:5](O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13].[C:19]([O:23][CH3:24])(=[O:22])[CH2:20][SH:21]>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])[S:21][CH2:20][C:19]([O:23][CH3:24])=[O:22]
Reactant: COc1ccccc1C(O)c1ccccc1OC
Reactant: COC(=O)CS
Product: COC(=O)CSC(c1ccccc1OC)c1ccccc1OC
Reaction time: 18 h
Yield: 72 %

Procedure:
Following the procedure of Example 4, 2,2'-dimethoxybenzhydrol, synthesized in accordance with M. L. Hoefle, et. al. in J. Med. Chem. 34, 7 (1971)] is reacted with methyl thioglycolate for 3 hours at 50°-60° C. followed by 18 hours at room temperature. Chromatography on silica gel, eluting with a gradient of 10% ethyl acetate in hexane to 20% ethyl acetate in hexane, followed by additional chromatography, eluting with a gradient of 5% ethyl acetate in hexane to 10% ethyl acetate in hexane, gives methyl [[bis-(2-methoxyphenyl)methyl]thio]acetate as a white solid in 72% yield: melting point 65°-67° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](O)([C:23]2[CH:28]=[CH:27][C:26]([C:29]([NH:31]C(C)(C)C)=O)=[CH:25][CH:24]=2)[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>S(Cl)(Cl)=O>[CH2:1]([N:8]1[C:12]([C:13]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:31])=[CH:25][CH:24]=2)=[CH:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)NC(=O)c1ccc(C(O)(CCCc2ccccc2)c2cncn2Cc2ccccc2)cc1
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(C(=CCCc2ccccc2)c2cncn2Cc2ccccc2)cc1

Procedure:
1,95 g of 1-benzyl-5-[1-hydroxy-4-phenyl-1-(4-tert-butylaminocarbonylphenyl)butyl]-1H-imidazole is refluxed 2 hours in 40 ml of thionyl chloride.
Reaction SMILES: [CH3:1][C:2](=[CH:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][C:2](=[CH:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3](=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=CSc1ccccc1)C(=O)Nc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=CSc1ccccc1)C(=Nc1ccccc1)Sc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.5 %

Procedure:
Toluene (4 mL) was added to a mixture of 2-methyl-N-phenyl-3-(phenylthio)acrylamide (0.80 g) and phosphorus pentachloride (0.62 g), and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure. To the concentrate was added DMF (35 mL), and then, phenylmercaptan sodium salt (793 mg) was added portionwise thereto. The mixture was stirred at room temperature for 2 hours. To the reaction mixture was added tert-butyl methyl ether, and then a 1 N aqueous sodium hydroxide solution was added, thereby the solution was separated. The organic layer was washed with water three times, dried and then concentrated. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain phenyl 2-methyl-N-phenyl-3-(phenylthio)thioacrylimidate (0.4 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([Li])CCC.[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1>CCCCCC>[OH:24][C:21]1([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1
Reactant: Brc1cnc2ccccc2c1
Reactant: CN1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CN1CCC(O)(c2cnc3ccccc3c2)CC1
Yield: 53.84 %

Procedure:
95.01 g of 3-bromoquinoline were treated with 200 ml of a 2.5M solution of butyllithium in hexane and 51.62 g of 1-methylpiperid-4-one in accordance with the procedure described in Stage A of Example 1, in order to obtain the expected product.
Reaction SMILES: Cl.Cl.Cl.[C:4]1([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][C:14]([C:20]4[N:21]=[C:22]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[N:23]5[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[C:24]=45)=[CH:15][CH:16]=3)[N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(N(CC)CC)C.CN(C=O)C>[NH2:29][C:25]1[C:24]2[N:23]([C:22]([CH:30]3[CH2:35][CH2:34][N:33]([C:36](=[O:38])[CH3:37])[CH2:32][CH2:31]3)=[N:21][C:20]=2[C:14]2[CH:13]=[C:12]3[C:17]([CH:18]=[CH:19][C:10]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)=[N:11]3)=[CH:16][CH:15]=2)[CH:28]=[CH:27][N:26]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nccn2c(C3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Reaction time: 1 h

Procedure:
1-(2-Phenyl-quinolin-7-yl)-3-piperidin-4-yl-imidazo[1,5-a]pyrazin-8-ylamine-tris HCl salt (59.0 mg, 0.1 mmol) was dissolved in triethylamine (1.0 mL) and DMF (0.5 mL). Acetic anhydride (12.0 μL, 0.1 mmol) was added and the reaction was stirred for 1 h. The reaction was concentrated in vacuo and purified by silica gel chromatography (Jones Flashmaster, 2 g/12 mL cartridge, eluting with 2% 7N NH3 in methanol/CH2Cl2). The sample was further purified using MDPS to yield 1-{4-[8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]piperidin-1-yl}ethanone as a pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 1.95 (ddd, 1H, J=22.4, 11.2, 4.0 Hz), 2.03-2.23 (m, 6H), 2.90 (ddd, 1H, J=13.6, 13.6, 2.8 Hz), 3.19-3.32 (m, 2H), 4.01 (bd, 1H, J=13.6 Hz), 4.64 (bd, 1H, J=13.2 Hz), 5.44 (bs, 2H), 7.11 (d, 1H, J=4.8 Hz), 7.24 (d, 1H, J=5.6 Hz), 7.46 (ddd, 1H, J=6.0, 2.4, 0.8 Hz), 7.50-7.54 (m, 2H), 7.86-7.94 (m, 3H), 8.16 (ddd, 2H, J=7.2, 3.6, 1.6 Hz), 8.24 (d, 1H, J=8.4 Hz), 8.38 (s, 1H); MS (ES+): m/z 463 (10) [MH+]; HPLC: tR=2.1 min (OpenLynx, polar—5 min).
Reaction SMILES: [Si:1]([N:8]1[CH:11]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][C:9]1=[O:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:33][C:34]1[O:35][C:36]([CH:40]=[O:41])=[C:37]([CH3:39])[N:38]=1.N1CCC1=O>C(Cl)Cl>[Si:1]([N:8]1[CH:11]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:10]([CH:40]([C:36]2[O:35][C:34]([CH3:33])=[N:38][C:37]=2[CH3:39])[OH:41])[C:9]1=[O:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1nc(C)c(C=O)o1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C1CCN1
Solvent: ClCCl
Product: Cc1nc(C)c(C(O)C2C(=O)N([Si](C)(C)C(C)(C)C)C2SC(c2ccccc2)(c2ccccc2)c2ccccc2)o1

Procedure:
1-t-Butyldimethylsilyl-4-tritylthioazetidin-2-one (1) (1.99 g, 4.34 mmol) was reacted with 2,4-dimethyloxazole-5-carboxaldehyde (45) (520 mg, 4.16 mmol) using the method described in preparation 1(a) to give after work-up two fractions which were partially separable by chromatography. The less polar fraction (290 mg) contained a 4:1 mixture of a trans (isomer A) and a cis isomer (isomer B) of the title azetidinone (46); νmax (CH2Cl2) 3600-3300, 1745 cm-1 ; δ(CDCl3) 0.13 (4.8H, s), 0.35 (0.6H, s), 0.38 (0.6H, s), 0.89 (7.2H, s), 0.98 (1.8H, s) 1.59 (0.8H, d, J5.6 Hz), 1.95 (0.6H, s), 1.99 (2.4H, s), 2.35 (2.4H, s), 2.36 (0.6H, s), 2.90 (0.2H, d, J5.3 Hz), 3.53 ( 0.2H, dd, J1.5, 4.6 Hz), 3.67 (0.8H, dd, J1.7, 3.2 Hz), 3.76 (0.2H, bd, J 4.7 Hz), 4.13 (0.8H, dd, J3.2, 5.6 Hz), 4.43 (0.8H d, J1.7 Hz), 4.79 (0.2H, d, J4.7 Hz), 7.15-7.56 (15H m). (Found [MH]+ 585). The more polar fraction (610 mg) contained a trans isomer (isomer C) of the title azetidinone (46); νmax (CH2Cl2) 3600-3300, 1740 cm-1 ; δ(CDCl3), -0.02 (3H, s). 0.09 (3H, s), 0.87 (9H, s), 1.81 (3H, s), 2.31 (3H, s), 2.56 (1H, d, J9.8 Hz), 3.79 (1H, dd, J1.9, 7.2 Hz), 4.04 (1H, d, J1.9 Hz), 4.09 (1H, dd, J7.3, 6 Hz), 7.12-7.53 (15H, m). (Found [MH]+ 585).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:19][C:20]1[CH:21]=[C:22]([C@H:27]([NH2:29])[CH3:28])[CH:23]=[CH:24][C:25]=1[F:26].C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[F:19][C:20]1[CH:21]=[C:22]([C@H:27]([NH:29][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:28])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: O=C(c1ccccc1)c1cccc([N+](=O)[O-])c1
Reactant: C[C@@H](N)c1ccc(F)c(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: C[C@@H](NC(c1ccccc1)c1cccc([N+](=O)[O-])c1)c1ccc(F)c(F)c1
Yield: 87 %

Procedure:
Following a procedure similar to that described in Example (1a), 1.0 g of 3-nitrophenyl phenyl ketone, 1.24 g of (R)-1-(3,4-difluorophenyl)ethylamine hydrochloride, 3.27 ml of triethylamine, 0.56 ml of titanium tetrachloride, 1.13 g of sodium cyanoborohydride and 0.37 ml of acetic acid were reacted, to obtain 1.41 g of the title compound as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[N:8][C:7]2[N:10]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[C:5]=1[NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][O:25][CH2:24]1)([O-])=O>C(OCC)(=O)C.[Pd]>[C:16]1([S:13]([N:10]2[C:7]3=[N:8][CH:9]=[C:4]([NH2:1])[C:5]([NH:22][CH:23]4[CH2:28][CH2:27][CH2:26][O:25][CH2:24]4)=[C:6]3[CH:12]=[CH:11]2)(=[O:14])=[O:15])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCOC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCOC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.1 %

Procedure:
To a solution of 5-nitro-1-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine (11.7 g, 29.1 mmol) in ethyl acetate (400 mL) was added 10% palladium on carbon (3.0 g, 3.0 mmol). The mixture was stirred at ambient temperature under an atmosphere of hydrogen for 16 h. Filtration and concentration afforded 10.2 g (94.2%) of 1-(phenylsulfonyl)-N4-(tetrahydro-2H-pyran-3-yl)-1H-pyrrolo[2,3-b]pyridine-4,5-diamine. LCMS (Method E, ESI): RT=1.16 min, m+H=373.3; 1H NMR (400 MHz, CDCl3) δ 8.25-7.99 (m, 2H), 7.84 (s, 1H), 7.61-7.35 (m, 4H), 6.58 (d, J=4.2 Hz, 1H), 5.04 (t, J=12.8 Hz, 1H), 4.02-3.82 (m, 2H), 3.80-3.55 (m, 2H), 3.47 (dd, J=11.1, 6.1 Hz, 1H), 2.86 (s, 2H), 2.11-1.93 (m, 1H), 1.80 (dtd, J=14.6, 7.2, 3.7 Hz, 1H), 1.74-1.51 (m, 3H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[CH2:30][CH2:29]1.[OH-].[Na+]>CN(C=O)C.CO>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH:40]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:38][CH:37]=2)[CH2:30][CH2:29]1
Reactant: CN1CCN(CCc2ccc(N)cc2)CC1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN1CCN(CCc2ccc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)cc2)CC1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-[2-(N-methylpiperazino)-ethyl]-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH2:17]([O:19][C:20]([C:22]1[NH:23][N:24]=[C:25]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=1)=[O:21])[CH3:18].[Br:35][CH2:36][CH2:37]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:17]([O:19][C:20]([C:22]1[N:23]([CH2:37][CH2:36][Br:35])[N:24]=[C:25]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Reactant: OCCBr
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(COc2ccccc2)nn1CCBr
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
Di-tert-butyl azodicarboxylate (1.68 g, 7.30 mmol) was added portionwise to a stirred solution of 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (1.0 g, 4.06 mmol), 2-bromoethanol (0.58 mL, 8.12 mmol) and triphenylphosphine (1.92 g, 7.30 mmol) in THF (24.5 mL) at 0° C. The mixture was stirred at 120° C. for 30 minutes under microwave irradiation and then the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; DCM). The desired fractions were collected and concentrated in vacuo to yield 2-(2-bromoethyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (1.08 g, 71% yield) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7](C(OC(C)(C)C)=O)[NH:8]C(OC(C)(C)C)=O)[CH:4]=[N:3]1.[CH:23]1([C:26](=O)[CH2:27][C:28]#[N:29])[CH2:25][CH2:24]1>>[CH:23]1([C:26]2[CH:27]=[C:28]([NH2:29])[N:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[N:8]=2)[CH2:25][CH2:24]1
Reactant: Cn1cc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cn1
Reactant: N#CCC(=O)C1CC1
Product: Cn1cc(-n2nc(C3CC3)cc2N)cn1

Procedure:
The title compound was prepared according to the method described for Preparation 296: using di-tert-butyl 1-(1-methyl-1H-pyrazol-4-yl)hydrazine-1,2-dicarboxylate (Preparation 295) and 3-cyclopropyl-3-oxopropanenitrile to afford the title compound in 48% yield, 1.7 g.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=1.CN1CCCC1=O>O>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[C:20]([C:25]([F:26])([F:27])[F:28])[CH:19]=1
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(COc2ccc(Br)cc2C(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (25.8 g) and 1-(chloromethyl)-4-methoxybenzene (14.4 mL) were added to a mixture of 4-bromo-2-(trifluoromethyl)phenol (15 g) and N-methyl pyrrolidone (100 mL) at room temperature, and the mixture was stirred at 90° C. for 3 hours. After the reaction mixture was cooled to room temperature, water was added thereto, then extraction thereof was performed using EtOAc, and the extract was washed with water. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=9:1 to 6:1), whereby 4-bromo-1-[(4-methoxybenzyl)oxy]-2-(trifluoromethyl)benzene (22 g) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]1[S:6][CH:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:4][C:3]1=[O:13].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[H-].[Na+]>>[C:19]([O:18][C:16]([CH2:15][N:4]1[C:3](=[O:13])[CH:2]([CH3:1])[S:6][CH:5]1[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1SC(c2cccnc2)NC1=O
Agent: [H-]
Agent: [Na+]
Product: CC1SC(c2cccnc2)N(CC(=O)OC(C)(C)C)C1=O

Procedure:
According to the procedure of Example 24 the trans-isomer and the cis-isomer of the title compound were prepared by using 5-methyl-2-(3-pyridyl)thiazolidin-4-one, t-butyl bromoacetate, and sodium hydride.
Reaction SMILES: [ClH:1].Cl.Cl.[Cl:4][C:5]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:6]=1[CH:7]=[C:8]([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:21]=1)[N:9]=[CH:10]2.[Cl:34]C1C=C2C(=C(Cl)C=1)C=NC(OS(C(F)(F)F)(=O)=O)=C2>>[ClH:4].[ClH:34].[ClH:1].[Cl:34][C:14]1[CH:5]=[C:6]2[C:11](=[C:12]([Cl:15])[CH:13]=1)[CH:10]=[N:9][C:8]([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:21]=1)=[CH:7]2
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Cl)ccc(Cl)c2cn1
Reactant: O=S(=O)(Oc1cc2cc(Cl)cc(Cl)c2cn1)C(F)(F)F
Agent: Cl
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2cc(Cl)cc(Cl)c2cn1

Procedure:
The procedure for the preparation of 3-(5,8-dichloroisoquinolin-3-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine trihydrochloride was followed, except using trifluoromethanesulfonic acid 6,8-dichloroisoquinolin-3-yl ester in place of trifluoromethanesulfonic acid 5,8-dichloroisoquinolin-3-yl ester. This afforded the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.10-2.31 (m, 4H), 3.04-3.18 (m, 2H), 3.33-3.46 (m, 2H), 4.45-4.59 (m, 1H). 8.11 (d, J=1.8 Hz, 1H), 8.14 (s, 1H), 8.22 (d, J=1.3 Hz, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.50 (s, 1H), 8.63 (br. s., 1H), 8.75 (s, 1H), 8.83 (d, J=2.0 Hz, 1H), 8.95 (br. s., 1H), 9.07 (br. s., 1H), 9.65 (s, 1H). MS (ES+): m/z=439.07/441.07/443.06 [MH+]. HPLC: tR=2.00 min (ZQ2, polar—5 min).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:13]=[N:14][C:15]([CH:18]3[CH2:20][CH2:19]3)=[CH:16][CH:17]=2)[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].O>CO.O1CCCC1>[CH:18]1([C:15]2[N:14]=[CH:13][C:12]([N:9]3[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)=[CH:17][CH:16]=2)[CH2:19][CH2:20]1
Reactant: CCOC(=O)c1cnn(-c2ccc(C3CC3)nc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)cnn1-c1ccc(C2CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
To a solution of 1-(6-cyclopropylpyridin-3-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (910 mg) in methanol (3 ml) and tetrahydrofuran (5 ml) were added 4 N aqueous solution of sodium hydroxide (7 ml) and water (3 ml), and stirred at room temperature overnight. After completion of the reaction, the organic solvent was evaporated in vacuo, then water and diethyl ether were added thereto, and the aqueous layer was separated. To the aqueous layer was added concentrated hydrochloric acid under ice-cooling to adjust the layer to pH 5, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. To the obtained residue were added ethyl acetate and n-hexane, the precipitated solid was collected by filtration, washed with ethyl acetate/n-hexane solution, and heat-dried in vacuo at 60° C. to give the titled compound (321 mg) as a pale yellow solid. MS (ESI) m/z: 244 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]([C:17]([OH:19])=O)[CH2:14][CH2:13][N:12]2[C:20]([O:22][CH3:23])=[O:21])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:36]([O:38][C:39](=[O:44])[CH2:40]C([O-])=O)[CH3:37].[K+].[Cl-].[Mg+2].[Cl-].Cl>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O.CC(OC)(C)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]([C:17](=[O:19])[CH2:40][C:39]([O:38][CH2:36][CH3:37])=[O:44])[CH2:14][CH2:13][N:12]2[C:20]([O:22][CH3:23])=[O:21])[CH:8]=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)N1CCC(C(=O)O)CC1c1cccc(C(C)(C)C)c1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: COC(C)(C)C
Product: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(c2cccc(C(C)(C)C)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
2-(3-tert-Butylphenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (2.73 g, 8.55 mmol) (reference compound 14) was dissolved in methyl THF (40 mL) and di(1H-imidazol-1-yl)methanone (2.079 g, 12.82 mmol) added. The suspension was stirred at room temperature under nitrogen for 2 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (2.62 g, 15.39 mmol) was suspended in methyl THF (60 mL) and magnesium chloride (1.465 g, 15.39 mmol) added. The suspension was stirred at 50° C. under nitrogen for 3 h using an oversized stirring bar (flask 2). The beige suspension in flask 1 was now added to the white suspension in flask 2. The resulting beige suspension was stirred under nitrogen at room temperature for 23 h. The mixture was acidified to pH 1 with 0.5 M HCl (100 mL) and MTBE (200 mL) was added. The phases were separated and the organic phase extracted with water (30 mL), satd NaHCO3 (30 mL) and water (30 mL), dried over anhydrous Na2SO4, and evaporated to yield crude methyl 2-(3-tert-butylphenyl)-4-(3-ethoxy-3-oxopropanoyl)-piperidine-1-carboxylate (3.14 g, 95%) as a brown oil.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:15])[CH2:9][C:8](=[O:10])[CH2:7][CH2:6][CH:5]1[C:11]([O:13][CH3:14])=[O:12].Cl>C(O)C>[OH:10][CH:8]1[CH2:7][CH2:6][CH:5]([C:11]([O:13][CH3:14])=[O:12])[C:4]([CH3:15])([CH3:3])[CH2:9]1
Reactant: COC(=O)C1CCC(=O)CC1(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C1CCC(O)CC1(C)C
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (1.85 g, 48.9 mmol) was added to a solution of methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (3.0 g, 16.3 mmol) in ethanol (65 mL) at −20° C. The solution was stirred at −20° C. for 2 hours. Aqueous hydrochloric acid (1M) was added drop wise and the mixture was extracted with dichloromethane (3×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford methyl 4-hydroxy-2,2-dimethylcyclohexanecarboxylate. 1H NMR (500 MHz, DMSO-d6) δ 3.70-3.58 (m, 1H), 3.54 (s, 3H), 2.16-2.11 (m, 1H), 1.73-1.68 (m, 1H), 1.65-1.48 (m, 4H), 1.07-0.99 (m, 1H), 0.91 (s, 6H).