Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)[CH:5]=O.ClC1C=CC(OC(F)F)=C(C=1)C=O.[C:28]([OH:34])([C:30](F)(F)F)=[O:29]>>[Cl:1][C:2]1[C:3]([F:14])=[C:4](/[CH:5]=[CH:30]/[C:28]([OH:34])=[O:29])[C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1
Reactant: O=C(O)C(F)(F)F
Reactant: O=Cc1c(C(F)(F)F)ccc(Cl)c1F
Agent: O=Cc1cc(Cl)ccc1OC(F)F
Product: O=C(O)/C=C/c1c(C(F)(F)F)ccc(Cl)c1F

Procedure:
Intermediate 16 was made in a similar manner as Intermediate 15 substituting 3-chloro-2-fluoro-6-(trifluoromethyl)benzaldehyde for 5-chloro-2-(difluoromethoxy)benzaldehyde followed by TFA deprotection. MS (ESI) m/z: 292 (M+Na)+. 1H NMR (400 MHz, CDCl3) δ 7.87 (1H, dd, J=16.17, 2.02 Hz), 7.49-7.62 (2H, m), 6.67 (1H, dd, J=16.30, 1.39 Hz) ppm.
Reaction SMILES: COC(=O)CC1C=CC([C:11]([F:14])([F:13])[F:12])=CC=1Cl.C1(COC2C=C(C(O)=O)C=CN=2)C=CC=CC=1.[CH2:34]([O:41][C:42]1[CH:47]=[C:46]([C:48](=[O:59])[CH:49]([C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][C:52]=2[Cl:58])[CH3:50])[CH:45]=[CH:44][N:43]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>N1C=CC=CC=1>[CH2:34]([O:41][C:42]1[CH:47]=[C:46]([C:48]([OH:59])([CH:49]([C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][C:52]=2[Cl:58])[CH3:50])[C:11]([F:14])([F:13])[F:12])[CH:45]=[CH:44][N:43]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C(=O)c1ccnc(OCc2ccccc2)c1)c1ccc(Cl)cc1Cl
Reactant: COC(=O)Cc1ccc(C(F)(F)F)cc1Cl
Agent: O=C(O)c1ccnc(OCc2ccccc2)c1
Solvent: c1ccncc1
Product: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccnc(OCc2ccccc2)c1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to the reaction sequence outlined in Example 1, steps 2 to 5, from 2-chloro-4-(trifluoromethyl)-benzeneacetic acid methyl ester and 2-(phenylmethoxy)-4-pyridinecarboxylic acid with the following modification: In the methylation step (Example 1, step 4), an inseparable mixture of the desired intermediate 1-(2-benzyloxy-pyridin-4-yl)-2-(2,4-dichloro-phenyl)-propan-1-one with the dimethylated compound 2-benzyloxy-4-[(E or Z)-2-(2,4-dichloro-phenyl)-1-methoxy-propenyl]-pyridine was obtained. This mixture was treated as follows:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)(=[O:37])=[O:36])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cncnc3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cncnc3)cc2)S(=O)(=O)c2ccccn2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-pyrimidin-5-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A of Example 11t, and pyridine-2-sulfonyl chloride hydrochloride, of Preparation 47, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 9.20 (s, 1H), 8.90 (s, 2H), 8.70 (d, 1H), 7.99 (m, 1H), 7.89 (m, 1H), 7.49 (m, 1H), 7.42 (d, 2H), 7.29 (d, 2H), 7.10 (m, 1H), 7.01 (d, 1H), 6.93 (d, 1H), 6.89 (s, 1H), 4.56 (s, 2H), 4.48 (s, 2H), 3.66 (s, 3H), 2.79 (t, 2H), 2.48 (t, 2H); MS 503 (M+1).
Reaction SMILES: C(=O)=O.C([O:6][C:7]([C:9]1[C:10]([CH3:25])=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)=O)C.CC(C[AlH]CC(C)C)C.Cl>C1COCC1.C1(C)C=CC=CC=1>[CH3:25][C:10]1[C:9]([CH2:7][OH:6])=[CH:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)[N:11]=1
Reactant: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CO
Temperature: -70 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a dry ice chilled solution of 1.66 g (5.35 mmol) 4-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester in 20 ml THF was dropped at −70° C. 12.35 ml (16.05 mmol) 1.2M DIBALH solution in toluene. The reaction mixture was stirred 1 h at −70° C. and after attaining RT the reaction was stirred for another 2 h at this temperature. A solution of 50 ml of 1N HCl was added dropwise, then the reaction mixture partitioned between ether and water. The ether solution was concentrated under reduced pressure to provide 1.42 g of pure [4-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[CH:10][C:11](C(O)=O)=[C:4]2[N:3]=1>C(=O)([O-])O.[K+]>[CH3:8][C:6]1[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=[C:2]([SH:1])[CH:7]=1
Reactant: Cc1cc(S)nc2c(C(=O)O)cnn12
Agent: O=C([O-])O
Agent: [K+]
Product: Cc1cc(S)nc2ccnn12

Procedure:
2.00 g of 5-mercapto-7-methylpyrazolo[1.5-a]pyrimidine-3-carboxylic acid were heated to 220° under argon for 1 hour. After cooling, the reaction mixture was taken up in 10 percent potassium hydrogen carbonate solution. The insoluble portion was filtered off under suction and taken up in water. The solution was acidified to pH 2 and the precipitate was filtered off under suction. After drying, there was obtained 7-methylpyrazolo[1,5-a]pyrimidine-5-thiol.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)=O.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1>O1CCCC1.C(OCC)(=O)C.[Na].[Ti]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[N:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)[C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1
Reactant: CN1CCC(N)CC1
Reactant: Cc1cccc(C(=O)c2nc3ccccc3s2)c1
Agent: [Ti]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc(C(=NC2CCN(C)CC2)c2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (benzothiazol-2-yl)(m-tolyl)methanone (1.06 g) and 4-amino-1-methylpiperidine (0.456 g) in tetrahydrofurane (4 mL) is added titanium tetraisopropoxyde (1.42 g). The mixture is stirred at room temperature for 1 h, then polymethyl hydrosiloxane (1.2 mL) is added. The mixture is stirred for one day at room temperature, diluted with ethyl acetate (50 mL), hydrolysed with 3N sodium hydroxyde (30 mL). The organic phase is separated by decantation, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue is cristallised by trituration in diisopropyl oxyde. A second crop can be obtained form the mother liquor by chromatography over silica gel (gradiant dichloromethane/methanol from 98/2 to 95/5) to give [(benzothiazol-2-yl)(m-tolyl)methylene](1-methylpiperidin-4-yl)amine meting at 125° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:10]#[N:11].[K+].[Cl:13][C:14]1[C:23]([Cl:24])=[C:22]2[C:17]([CH:18]=[CH:19][N:20]=[CH:21]2)=[CH:16][CH:15]=1>O>[C:1]([N:20]1[CH:19]=[CH:18][C:17]2[C:22](=[C:23]([Cl:24])[C:14]([Cl:13])=[CH:15][CH:16]=2)[CH:21]1[C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2ccncc2c1Cl
Reactant: O=C(Cl)c1ccccc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Product: N#CC1c2c(ccc(Cl)c2Cl)C=CN1C(=O)c1ccccc1

Procedure:
Benzoyl chloride (0.4 mole) is added over 3 hours to a stirred mixture of potassium cyanide (0.6 mole) in 250 ml. of water and 7,8-dichloroisoquinoline (0.2 mole) maintained at 25° C. The mixture is stirred for one more hour, cooled and filtered. The product is recrystallized from ethanol and dried to yield 2-benzoyl-7,8-dichloro-1-cyano-1,2,dihydroisoquinoline.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[C:16]([Cl:18])[N:15]=[N:14][C:13]=2[C:19]([O:21]C)=O)[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[NH3:25]>>[C:1]([C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[C:16]([Cl:18])[N:15]=[N:14][C:13]=2[C:19]([NH2:25])=[O:21])[CH:8]=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1nnc(Cl)cc1Nc1cccc(C(C)(C)C)n1
Reactant: N
Solvent: CO
Product: CC(C)(C)c1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
Methyl 4-(6-tert-butylpyridin-2-ylamino)-6-chloropyridazine-3-carboxylate (360 mg, 1.12 mmol) was suspended in 7N ammonia in methanol (12 mL, 84.0 mmol) and stirred at room temperature for 16 h. The mixture was concentrated in vacuo to give 4-(6-tert-butylpyridin-2-ylamino)-6-chloropyridazine-3-carboxamide (317 mg, 1.03 mmol, 92%) as a yellow powder. MS (EI/CI) m/z: 306.0 [M+H]. This material was used directly in the next step without further purification.
Reaction SMILES: FC1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C@@H:11](C)[CH2:10][N:9]([C:13]3[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=3)[C:8]2=[O:22])=CC=1.C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)CC=C.[N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][NH2:51])[CH:45]=1>>[CH2:6]([N:7]1[CH2:11][CH2:10][N:9]([C:13]2[S:14][C:15]([C:19]([NH:51][CH2:50][C:46]3[CH:45]=[N:44][CH:49]=[CH:48][CH:47]=3)=[O:21])=[C:16]([CH3:18])[N:17]=2)[C:8]1=[O:22])[CH2:5][CH:23]=[CH2:24]
Reactant: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: C=CCCN1CCN(c2nc(C)c(C(=O)O)s2)C1=O
Product: C=CCCN1CCN(c2nc(C)c(C(=O)NCc3cccnc3)s2)C1=O
Yield: 62 %

Procedure:
Following the procedure as described in Example 2, making variations as required to replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(but-3-enyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as an off-white solid in 62% yield: mp 144-145° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 8.57-8.52 (m, 2H), 8.45 (d, J=3.8 Hz, 1H), 7.70 (ddd, J=7.8, 7.8, 1.8 Hz, 1H), 7.35 (dd, J=7.8, 4.8 Hz, 1H), 5.85-5.72 (m, 1H), 5.15-5.01 (m, 2H), 4.39 (d, J=5.8 Hz, 2H), 3.98 (d, J=9.0, 7.1 Hz, 2H), 3.59-3.54 (m, 2H), 3.31 (t, J=7.0 Hz, 2H), 2.47 (s, 3H), 2.32-2.25 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ161.9, 157.4, 154.9, 151.2, 148.8, 148.0, 135.5, 135.1, 135.1, 123.4, 117.3, 116.8, 42.4, 41.9, 41.6, 40.4, 31.1, 17.1; MS (ES+) m/z 372.1 (M+1).
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH2:5].C(N(CC)CC)C.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24](Cl)=[O:25])[CH:20]=[CH:21][CH:22]=1.O>C(Cl)(Cl)Cl>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]2[CH2:3][CH2:4][NH:5][C:24](=[O:25])[CH2:23][C:19]=2[CH:18]=1
Reactant: COC(CN)OC
Reactant: COc1cccc(CC(=O)Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc2c(c1)CC(=O)NCC2
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 28.8 %

Procedure:
The title compound was synthesized by referring to the synthetic method of EP285287. To a solution of(3-methoxyphenyl)acetic acid (16 g) in tetrahydrofuran (150 ml) were sequentially added N,N-dimethylformamide (0.1 ml) and oxalyl chloride (10 ml) under a nitrogen atmosphere, the solution was stirred for 5 hours at room temperature, and then the reaction mixture was concentrated in vacuo to provide (3-methoxyphenyl)acetyl chloride (18.8 g). To a solution of aminoacetaldehyde dimethylacetal (11 g) and triethylamine (11 g) in chloroform (150 ml) was added (3-methoxyphenyl)acetyl chloride (18.8 g) on an ice bath, and the solution was stirred for 9.5 hours at room temperature. Water was added thereto, the solution was stirred, extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. Obtained by purifying the residue by NH silica gel column chromatography (hexane-ethyl acetate system), a solution of N-(2,2-dimethoxyethyl)-2-(3-methoxyphenyl)acetamide (24.9 g) in acetic acid (75 ml) was added dropwise to concentrated hydrochloric acid (50 ml), and the solution was stirred overnight at room temperature. The reaction mixture was poured into an ice water, ethyl acetate and tetrahydrofuran were sequentially added thereto, insoluble material was removed by filtration, then the filtrate was concentrated in vacuo. To the residue was added water, the resulting solid was filtered and collected. To a solution of the resulting 8-methoxy-1,3-dihydrobenz[d]azepin-2-one (6.3 g) in acetic acid (100 ml) was added 10% palladium-activated charcoal (1.5 g), and the solution was stirred for 23 hours at room temperature under a hydrogen atmosphere at 4 atmospheric pressures. After filtration through celite pad, the solvent was evaporated in vacuo, was neutralized by sequentially adding water and aqueous ammonia. The resulting solid was filtered to provide 8-methoxy-1,3,4,5-tetrahydrobenz[d]azepin-2-one (5.6 g). To a suspension of this compound (1.5 g) in tetrahydrofuran (15 ml) was added dropwise borane-tetrahydrofuran complex (1.0 M solution in tetrahydrofuran) (15 ml), and the solution was refluxed for 2 hours. 5N hydrochloric acid (5 ml) was added thereto on an ice bath, the solution was refluxed for 45 minutes, and then neutralized with aqueous ammonia. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (752 mg).
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:11]=1[O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].ClC1C=CC=C(C)C=1O.C([SiH](C)C)(C)(C)C.BrN1C(=O)CCC1=O.[CH3:49][O:50][C:51](=[O:61])[C:52]1[CH:57]=[C:56]([CH3:58])[C:55]([Br:59])=[C:54]([SH:60])[CH:53]=1>C(Cl)(Cl)Cl.CO>[CH3:49][O:50][C:51](=[O:61])[C:52]1[CH:57]=[C:56]([CH3:58])[C:55]([Br:59])=[C:54]([S:60][CH2:9][C:10]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:11]=2[O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:53]=1
Reactant: COC(=O)c1cc(C)c(Br)c(S)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1c(Cl)cccc1CBr
Agent: C[SiH](C)C(C)(C)C
Agent: Cc1cccc(Cl)c1O
Agent: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C)c(Br)c(SCc2cccc(Cl)c2O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethyl amine (36 mL, 0.263 mol) was added to a solution of (2-bromomethyl-6-chloro-phenoxy)-tert-butyl-dimethyl-silane (72 g, 0.214 mol) [prepared from 6-chloro cresol by protecting the hydroxy group with t-butyldimethylsilane followed by bromination using N-bromosuccinimide] and compound of Example 1f (43 g, 0.164 mol) in chloroform (600 mL) at 5° C. over a period of 20 min. The reaction mixture was stirred at 25° C. for 30 min. The reaction mixture was washed with water (2×200 mL) and brine (100 mL). The solvent was removed under reduced pressure and to the oily mass obtained, methanol (300 mL) was added with stirring. The crystalline solid obtained was filtered, washed with methanol and dried to obtain the title compound. Yield: 70 g, (83%); 1H NMR (CDCl3, 300 MHz): δ 0.28 (s, 6H, 2CH3), 1.03 (s, 9H, 3CH3), 2.45 (s, 3H, CH3), 3.89 (s, 3H, OCH3), 4.19 (s, 2H, CH2), 6.89 (t, 1H, Ar), 7.24 (t, 1H, Ar), 7.32 (d, 1H, Ar), 7.61 (s, 1H, Ar), 7.69 (s, 1H, Ar); MS: m/e (ES−) 515 (M−1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)#[CH:2].I[C:10]1[CH:11]=[C:12]([CH:40]=[CH:41][C:42]=1[CH3:43])[C:13]([NH:15][C:16]1[CH:35]=[CH:34][C:19]([CH2:20][N:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)=[C:18]([C:36]([F:39])([F:38])[F:37])[CH:17]=1)=[O:14]>>[CH3:43][C:42]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]2[CH:35]=[CH:34][C:19]([CH2:20][N:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]3)=[C:18]([C:36]([F:39])([F:37])[F:38])[CH:17]=2)=[O:14])=[CH:40][C:41]=1[C:2]#[C:1][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cnccn1
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCNCC3)c(C(F)(F)F)c2)cc1C#Cc1cnccn1

Procedure:
The title compound can be synthesized from 2-ethynylpyrazine and tert-butyl 4-(4-(3-iodo-4-methylbenzamido)-2-(trifluoromethyl)benzyl)piperazine-1-carboxylate in a manner similar to that described for Example 1. Following deprotection using saturated MeOH/HCl (g), the product can be obtained as an HCl salt. 2-ethynylpyrazine is prepared from 2-bromopyrazine and ethynyltrimethylsilane according to the 2 steps procedure described in Example 1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:36])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:33]=[CH:32][C:18]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)=[O:20])=[C:17]([O:34][CH3:35])[CH:16]=3)[N:10]=2)[CH:8]=1.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:36][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:40]([CH:37]2[CH2:39][CH2:38]2)=[O:41])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:33]=[CH:32][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[O:20])=[C:17]([O:34][CH3:35])[CH:16]=2)[N:10]=1
Reactant: COc1cc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)(F)F)c1
Yield: 31 %

Procedure:
The title compound was prepared by following the procedure as described for step-2 of Intermediate-30 by using 4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide (Intermediate-26, 0.060 g, 0.11 mmol), cyclopropylcarbonyl chloride (0.019 g, 0.17 mmol), DIPEA (1 mL) and THF (5 mL) to afford 0.020 g of desired product. 1H NMR (300 MHz, DMSO d6): 1.06 (m, 2H), 1.22 (m, 2H), 3.17 (m, 1H), 3.95 (s, 3H), 4.34 (d, J=6.0 Hz, 2H), 7.44-7.84 (m, 8H), 7.95 (d, J=9.0 Hz, 1H), 8.25 (s, 1H), 8.70 (m, 1H), 10.43 (m, 1H), 12.05 (m, 1H); MS (m/z): 584.35 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][F:17].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23](Cl)=[O:24]>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][CH2:16][F:17])[C:23](=[O:24])[C:22]1[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=[C:20]([C:19]([F:18])([F:33])[F:34])[CH:21]=1
Reactant: FCCNc1cnccc1-c1ccccc1Cl
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(CCF)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-chloro-phenyl)-pyridin-3-yl]-(2-fluoro-ethyl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification to give a first batch of compound (light yellow solid). A second chromatographic purification of the remaining impure fractions and mother liquor gave a second batch of compound. Yellow solid (25% overall). MS (ESI): m/z=491.08 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][N:20]1[CH:24]=[C:23]([C:25](O)=[O:26])[N:22]=[CH:21]1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:25]([C:23]3[N:22]=[CH:21][N:20]([CH3:19])[CH:24]=3)=[O:26])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cn1cnc(C(=O)O)c1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn(C)cn1
Yield: 42.6 %

Procedure:
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.77 mmol) was coupled with 1-methyl-1H-imidazole-4-carboxylic acid (145 mg, 1.15 mmol) using the method of Example 34(d). Crude product was purified twice by CombiFlash (1st column: C-18, eluent: 0-100% MeCN in water; 2nd column: silica, eluent 100% DCM) to yield a total of 121 mg (43%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.22 (d, 3H), 3.74 (s, 3H), 4.27 (dd, 1H), 4.41 (dd, 1H), 4.50-4.62 (m, 1H), 6.61 (d, 1H), 7.43 (d, 1H), 7.48 (d, 1H), 7.50 (d, 1H), 7.66 (d, 1H), 7.78 (dd, 1H), 7.86 (d, 1H), 8.17 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[F:9].[CH:10]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[C:14]=2[CH:13]=[CH:12][N:11]=1.CCO.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[F:9][C:3]1[CH:4]=[C:5]([NH2:8])[CH:6]=[CH:7][C:2]=1[C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][N:11]=[CH:10]2
Reactant: OB(O)c1cccc2cnccc12
Reactant: Nc1ccc(Br)c(F)c1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2cccc3cnccc23)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.9 %

Procedure:
4-Bromo-3-fluorobenzenamine (2.51 g, 13 mmol) and 5-isoquinolineboronic acid (4.23 g, 24 mmol) were suspended in toluene (35 ml) and EtOH (35 ml) and tetrakis(triphenylphosphine)palladium (812 mg, 0.70 mmol) was added, followed by 10% aqueous sodium carbonate (40 ml). The flask was fitted with a reflux condenser and placed in a preheated oil bath (110 C) and stirred under nitrogen for 4 hours. The reaction was then cooled to room temperature, partially concentrated, and diluted with water. The aqueous phase was extracted with DCM, and the organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on silica gel (50:1->30:1->20:1 DCM/MeOH). The fractions with product were collected, concentrated, and washed with DCM and hexanes. The remaining solid was dried under high vacuum to afford the desired 3-fluoro-4-(isoquinolin-5-yl)benzenamine (2.568 g, 10.78 mmol, 94% purity, 82% yield). MS (ESI pos. ion) m/z: 497 (MH+). Calc'd exact mass for C15H11FN2: 239. 1H NMR (400 MHz, CDCl3): 9.30 (s, 1H), 8.50 (dd, J=6.0 Hz, 2.0 Hz, 1H), 8.02-7.96 (m, 1H), 7.68-7.63 (m, 2H), 7.58-7.54 (m, 1H), 7.16 (dt, J=8.0 Hz, 2.0 Hz, 1H), 6.61 (dt, J=8.0 Hz, 2.0 Hz, 1H), 6.56 (dt, J=11.5 Hz, 2.0 Hz, 1H), 3.93 (br s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:7]([Cl:14])=[N:8][C:9]([Cl:13])=[N:10][C:11]=1Cl)[CH3:2].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C(#N)C.CC(N(C)C)=O>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:11]2[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])=[C:7]([Cl:14])[N:8]=[C:9]([Cl:13])[N:10]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCOC(=O)Cc1c(Cl)nc(Cl)nc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCOC(=O)Cc1c(Cl)nc(Cl)nc1NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A solution of (2,4,6-trichloro-pyrimidin-5-yl)-acetic acid ethyl ester (1.00 g, 3.71 mmol, 1.0 equiv; commercially available from Tyger Scientific Inc, USA), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.26 g, 6.31 mmol, 1.7 equiv) and triethylamine (0.77 mL, 0.56 g, 5.57 mmol, 1.5 equiv) in acetonitrile (9 mL) and DMAc (2 mL) was heated by microwave irradiation to 120° C. for 30 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 0.87 g (54%) of the title compound. 1H NMR (400 MHz, DMSO): δ1.19 (t, J=8.0 Hz, 3H), 1.35-1.44 (m, 2H), 1.40 (s, 9H), 1.76-1.79 (m, 2H), 2.84 (br s, 2H), 3.73 (s, 2H), 3.93-3.96 (m, 2H), 4.11 (q, J=8.0 Hz, 2H), 4.08-4.13 (m, 1H), 7.52 (d, J=8.0 Hz, 1H). MS (ISP): 433.3 [M+H]+.