Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(C2[O:9]C(C(NC(=O)CC3C4C(=CC=C(F)C=4)NC=3)CC3C=C(F)C=C(F)C=3)=CN=2)=CC=1.FC(F)(F)[C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][CH:43]=[C:42]2[CH2:48][C:49]([OH:51])=O.[Cl:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[C:62]([C@@H:66]([NH2:76])[CH2:67][C:68]3[CH:73]=[C:72]([F:74])[CH:71]=[C:70]([F:75])[CH:69]=3)=[N:63][O:64][CH:65]=2)=[CH:57][CH:56]=1.Cl.ClC1C=CC(C2OC(C(N)CC3C=C(F)C=C(F)C=3)=CN=2)=CC=1>>[Cl:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[C:62]([C@@H:66]([NH:76][C:49](=[O:51])[CH2:48][C:42]3[C:41]4[C:45](=[CH:46][CH:47]=[C:39]([OH:9])[CH:40]=4)[NH:44][CH:43]=3)[CH2:67][C:68]3[CH:73]=[C:72]([F:74])[CH:71]=[C:70]([F:75])[CH:69]=3)=[N:63][O:64][CH:65]=2)=[CH:57][CH:56]=1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)c1nocc1-c1ccc(Cl)cc1
Reactant: O=C(O)Cc1c[nH]c2ccc(C(F)(F)F)cc12
Reactant: O=C(Cc1c[nH]c2ccc(F)cc12)NC(Cc1cc(F)cc(F)c1)c1cnc(-c2ccc(Cl)cc2)o1
Agent: Cl
Agent: NC(Cc1cc(F)cc(F)c1)c1cnc(-c2ccc(Cl)cc2)o1
Product: O=C(Cc1c[nH]c2ccc(O)cc12)N[C@@H](Cc1cc(F)cc(F)c1)c1nocc1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared according to the method presented in the synthesis of 19F substituting 2-(5-hydroxy-1H-indol-3-yl)acetic acid for 2-(5-(trifluoromethyl)-1H-indol-3-yl)acetic acid and (S)-1-(4-(4-chlorophenyl)isoxazol-3-yl)-2-(3,5-difluorophenyl)ethanamine for 19E to provide the desired compound (26): 1H NMR (400 MHz, DMSO) δ 10.46 (s, 1H), 9.04 (s, 1H), 8.65 (d, 1H), 7.35-7.20 (m, 3H), 7.06 (d, 1H), 6.92 (t, 1H), 6.87 (d, 1H), 6.77 (d, 1H), 6.71 (d, 2H), 6.54 (dd, 1H), 5.25 (q, 1H), 3.39-3.25 (m, 2H), 3.08 (d, 2H); MS (m/z) 508.8 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=O)=[CH:5][C:4]=1[CH3:25].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].C1(C)C(C)=CC=CC=1>C1CCCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[S:27])=[CH:5][C:4]=1[CH3:25]
Reactant: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccccc2)cc1C
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCCCC1
Solvent: Cc1ccccc1C
Product: COc1ccc(C(=CC(=S)N2CCOCC2)c2ccccc2)cc1C

Procedure:
6.75 g (20 mmols) of 3-(4-methoxy-3-methylphenyl)-3-phenylacrylic acid morpholide and 2.22 g (10 mmols) of finely ground phosphorus pentasulfide were refluxed unit 50 ml of absolute xylene for 3 horus. After cooling, the insoluble matter was filtered off, and the filtrate was washed with water, dried and concentrated by evaporation in vacuo. This concentrate was purified on a silica gel column. Elution was carried out first with toluene and then with a toluene/diisopropylether mixture in the proportions 90:10, then in the proportions 80:20. The fractions containing the substance with Rf 0.59 (toluene/diisopropylether 1:1) were concentrated by evaporation in vacuo, and the yellow oil obtained thereby was dissolved in cyclohexane, while heating. Upon cooling, the desired substance crystallized out.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[N:18]=3)[CH2:9]2)[N:5]=[C:4]([NH2:26])[N:3]=1.[F:27][C:28]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:29]=1[C:30]#[N:31].C([O-])([O-])=O.[Na+].[Na+].CC#N>O1CCOCC1.O.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>[NH2:26][C:4]1[N:3]=[C:2]([C:34]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([F:27])[CH:35]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[N:18]=3)[CH2:9]2)[N:5]=1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Reactant: Nc1nc(Cl)cc(N2CCOC(c3nc(-c4ccccc4Cl)c[nH]3)C2)n1
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: C1COCCO1
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(-c2cc(N3CCOC(c4nc(-c5ccccc5Cl)c[nH]4)C3)nc(N)n2)cc1F
Temperature: 140 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A mixture of 4-chloro-6-{2-[4-(2-chlorophenyl)-1H-imidazol-2-yl]-4-morpholinyl}-2-pyrimidinamine (100 mg, 0.256 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (82 mg, 0.332 mmol), Na2CO3 (67.7 mg, 0.639 mmol) and Pd(PPh3)4 (29.5 mg, 0.026 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated at 140° C. under microwave conditions with stirring for 1 hour. The reaction mixture was filtered, washed by EtOAc (100 mL), and concentrated. The resulting residue was purified by prep-HPLC using CH3CN in water (10 mmol NH4HCO3 in water) from 60% to 70% in 7 minutes to afford the title compound (50 mg) as a yellow solid. LC-MS (ES) m/z=476 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.Cl.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=O.Cl.[C:20]1([C:26]2([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:34]3[CH:30]([CH2:31][NH:32][CH2:33]3)[C:29](=[O:35])[CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:36]1([C:26]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:34]3[CH:30]([CH2:31][N:32]([C:16](=[O:18])[CH2:15][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=4)[CH2:33]3)[C:29](=[O:35])[CH2:28][CH2:27]2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccn3)CC12
Reaction time: 0.25 h
Yield: 39.1 %

Procedure:
Triethylamine (1.4 cc) is added to a suspension of 2-(2-pyridyl)acetic acid hydrochloride (1.73 g) in dry dichloromethane (30 cc). The solution is cooled to +5° C. and then treated with N,N'-carbonyldiimidazole (1.62 g). The mixture is stirred for 15 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (3.27 g) and triethylamine (2.8 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 2 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in a mixture of ethyl acetate (100 cc) and water (75 cc). The organic phase is washed with water (50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from a mixture of acetonitrile (30 cc) and isopropyl ether (30 cc). (3aRS,7aRS)-7,7-diphenyl-2-[2-(2-pyridyl)acetyl]-4-perhydroisoindolone (1.6 g) is obtained in the form of white crystals melting at 195° C.
Reaction SMILES: CC(C)=O.[CH3:5][O:6][C:7](=[O:18])[C@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[I-:19].CS[C:22]1[S:26][CH:25]=[CH:24][S+:23]=1>O>[I-:19].[S:23]1[CH:24]=[CH:25][S:26][C:22]1=[N+:9]([CH3:10])[CH:8]([C:7]([O:6][CH3:5])=[O:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CSc1scc[s+]1
Reactant: CN[C@@H](Cc1ccccc1)C(=O)OC
Agent: [I-]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C(Cc1ccccc1)[N+](C)=c1sccs1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
To 100 ml of acetone, 2.2 g of N-methylphenylalanine methyl ester was dissolved, and 2.0 g of 2-methylthio-1,3-dithiolium iodide was gradually added thereto under stirring at room temperature. The mixture was stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The residue was dissolved in water. The aqueous layer was washed with ethyl acetate, and then water was distilled off under reduced pressure, whereby 1.7 g (yield: 52%) of N-(1,3-dithiol-2-ylidene)-N-methyl-N-(2-phenyl-1-methoxycarbonylethyl)ammonium iodide (Compound No. 5) was obtained as oily substance.
Reaction SMILES: [C:1]([CH:4]([CH2:32][CH2:33][C:34]([F:37])([CH3:36])[CH3:35])[CH2:5][CH:6]([O:28][C:29](=[O:31])[CH3:30])[CH:7]([NH:15][C:16]([C:18]1[CH:27]=[N:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1)=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[NH2:2].CO[CH:40](OC)[N:41]([CH3:43])[CH3:42]>C(Cl)Cl.O>[CH3:40][N:41]([CH:43]=[N:2][C:1]([CH:4]([CH2:32][CH2:33][C:34]([F:37])([CH3:36])[CH3:35])[CH2:5][CH:6]([O:28][C:29](=[O:31])[CH3:30])[CH:7]([NH:15][C:16]([C:18]1[CH:27]=[N:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1)=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:3])[CH3:42]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)OC(CC(CCC(C)(C)F)C(N)=O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC(CC(CCC(C)(C)F)C(=O)N=CN(C)C)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of acetic acid 3-carbamoyl-6-fluoro-6-methyl-1-{2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-heptyl ester (522 mg, 1.03 mmol) in N,N-dimethylformamide dimethyl acetal (2 mL) was heated to 50° C. for two hours, cooled to ambient temperature and diluted with methylene chloride and water. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated to give the title compound as a white foam (580 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.[F:15][C:16]1[C:17]([C:28]#N)=[N:18][CH:19]=[CH:20][C:21]=1[C:22]1[CH:23]=[N:24][CH:25]=[N:26][CH:27]=1.Cl.[OH-:31].[Na+]>C1COCC1.C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:28]([C:17]1[C:16]([F:15])=[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)[CH:20]=[CH:19][N:18]=1)=[O:31]
Reactant: N#Cc1nccc(-c2cncnc2)c1F
Reactant: Fc1ccc(I)c(Cl)c1
Reactant: [OH-]
Agent: CC(C)[Mg]Cl
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1Cl)c1nccc(-c2cncnc2)c1F
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 7.44 %

Procedure:
To a solution of 2-chloro-4-fluoro-1-iodobenzene (0.307 g, 1.199 mmol) in THF (Volume: 1.622 ml) cooled to −10° C. was added isopropylmagnesium chloride, 2M in THF (0.699 ml, 1.399 mmol) in one portion. After 30 min, 3-fluoro-4-(pyrimidin-5-yl)picolinonitrile (0.200 g, 0.999 mmol) was added. The reaction mixture was stirred at −10° C. for 30 min, then allowed to warm to room temperature and stirred overnight. Water and ice were carefully added, followed by acidification with 6 M HCl. After stirring for 1 hr, CH2Cl2 was added and the pH was adjusted to 8.5 with aqueous 4 M NaOH. The layers were separated. The aqueous phase was extracted with CH2Cl2 (5×). Organics combined, dried over Na2SO4, filtered, and concentrated to afford an orange residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (24 g column, 35 mL/min, 60-100% EtOAc in hexanes over 23 min, tr=9 min) gave the title compound (0.029 g, 0.074 mmol, 7.44% yield) as an orange solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[Cl:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([OH:46])[C:41]=1B(O)O>>[CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:41]5[C:42]([OH:46])=[CH:43][CH:44]=[CH:45][C:40]=5[Cl:39])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Reactant: OB(O)c1c(O)cccc1Cl
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5c(O)cccc5Cl)c4)nn23)CC1
Yield: 81 %

Procedure:
Prepared from (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate and (2-chloro-6-hydroxyphenyl)boronic acid using the same procedure as intermediate 168 in 81% yield. 1H NMR (400 MHz, CDCl3) [note: 4H of piperidine and phenolic —OH not observed] δ 8.13-8.06 (m, 1H), 7.97 (s, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.38 (d, J=7.5 Hz, 1H), 7.26-7.20 (m, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.97 (d, J=8.3 Hz, 1H), 6.89-6.77 (m, 1H), 6.06-5.90 (m, 1H), 5.39 (dd, J=17.1, 1.5 Hz, 1H), 5.29-5.20 (m, 1H), 5.15-5.04 (m, 1H), 3.99 (d, J=4.8 Hz, 2H), 3.76 (s, 3H), 2.63 (br. s., 3H), 2.07-1.91 (m, 3H), 1.79-1.65 (m, 1H), 1.35 (s, 3H), 1.25 (s, 9H). LCMS (M+1)=633.3.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH:21]=[O:22])[C@H:12]([CH3:23])[N:11]1[C:24](=[O:34])[CH2:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:35][Mg]Cl>C1COCC1>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH:21]([OH:22])[CH3:35])[C@H:12]([CH3:23])[N:11]1[C:24](=[O:34])[CH2:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@H]1c2cccc(CC=O)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(Cl)cccc1Cl
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(O)Cc1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)Cc1c(Cl)cccc1Cl)[C@H]2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
Dissolve 2-((1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-(2-(2,6-dichlorophenyl)acetyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)acetaldehyde (138 mg, 0.27 mmol) in THF (2.7 mL). Cool to 0° C., add MeMgCl (0.097 mL, 0.29 mmol, 3M in Et2O). Stir 30 min at 0° C. Add water and extract with ethyl acetate three times. Combine the ethyl acetate extracts, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by silica gel chromatography, eluting with ethyl acetate: hexanes (gradient, 2-60%) to give the title compound as a white foam (122 mg, 0.23 mmol). MS (m/z): 536.2 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16]([CH3:17])[C:11]3=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[N:28]([CH3:38])[C:29]5[C:34]([CH:35]=4)=[C:33]([O:36][CH3:37])[CH:32]=[CH:31][CH:30]=5)=[O:26])=[C:20]([O:39][CH3:40])[CH:19]=3)[N:9]=2)[CH2:4][CH2:3]1.[CH:41]1([N:46]=[C:47]=[O:48])[CH2:45][CH2:44][CH2:43][CH2:42]1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[CH:41]1([NH:46][C:47](=[O:48])[O:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]3[N:12]4[CH:13]=[CH:14][N:15]=[C:16]([CH3:17])[C:11]4=[C:10]([C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[N:28]([CH3:38])[C:29]6[C:34]([CH:35]=5)=[C:33]([O:36][CH3:37])[CH:32]=[CH:31][CH:30]=6)=[O:26])=[C:20]([O:39][CH3:40])[CH:19]=4)[N:9]=3)[CH2:4][CH2:3]2)[CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: COc1cc(-c2nc([C@H]3CC[C@H](O)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Reactant: O=C=NC1CCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc(-c2nc([C@H]3CC[C@H](OC(=O)NC4CCCC4)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-(4-(3-((trans)-4-hydroxycyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide (0.037 mmol, 20 mg) and N,N-dimethylpyridin-4-amine (7.41 μmol, 0.906 mg) in dichloromethane (2 ml) was added cyclopentyl isocyanate (0.185 mmol, 20.60 mg) and the mixture was stirred at room temperature overnight. Then pyridine (2 ml) was added and the mixture was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate and the obtained suspension was filtered. The filtrate was purified by column chromatography (silica gel; dichloromethane with gradient 0 to 5% methanol) to give (trans)-4-(1-(3-methoxy-4-(4-methoxy-1-methyl-1H-indole-2-carboxamido)phenyl)-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl cyclopentylcarbamate (6 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11][C:12]#[N:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(O)C.SCC(C(CS)O)O.ClC1N2[N:31]=[C:32]([O:35][CH2:36][CH3:37])[CH:33]=[CH:34][C:29]2=[N:28][N:27]=1>O.P([O-])(O)(O)=O.[K+]>[CH2:36]([O:35][C:32]1[CH:33]=[CH:34][C:29]2[N:13]([C:12]([S:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH2:1])[S:3][C:4]=4[CH:10]=3)=[N:27][N:28]=2)[N:31]=1)[CH3:37]
Reactant: N#CSc1ccc2nc(N)sc2c1
Reactant: CCOc1ccc2nnc(Cl)n2n1
Agent: O=P([O-])(O)O
Agent: OC(CS)C(O)CS
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOc1ccc2nnc(Sc3ccc4nc(N)sc4c3)n2n1
Yield: 80.3 %

Procedure:
The 6-[(6-ethoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulphanyl]-1,3-benzothiazol-2-amine was prepared according to the method described in Example 17a, but using 587 mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate (commercial), 20 cm3 of degassed ethanol, 13 mg of potassium dihydrogen phosphate in 0.2 cm3 of water, 1.31 g of DL-dithiothreitol and 562 mg of 3-chloro-6-ethoxy[1,2,4]triazolo[4,3-b]pyridazine. 783 mg of 6-[(6-ethoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulphanyl]-1,3-benzothiazol-2-amine are thus obtained in the form of a whitish powder, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][N:4]=1.Br[CH2:15][CH2:16][O:17][CH3:18].CC([O-])(C)C.[K+]>O1CCOCC1>[CH3:18][O:17][CH2:16][CH2:15][CH:9]([C:6]1[CH:7]=[N:8][C:3]([C:2]([F:1])([F:12])[F:13])=[N:4][CH:5]=1)[C:10]#[N:11]
Reactant: N#CCc1cnc(C(F)(F)F)nc1
Reactant: COCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COCCC(C#N)c1cnc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
A solution of 2-(2-(trifluoromethyl)pyrimidin-5-yl)acetonitrile (500 mg, 2.67 mmol) and 1-bromo-2-methoxyethane (419 mg, 2.81 mmol) in 1,4-dioxane (5 mL) was degassed and added t-BuOK (2.81 mL, 2.81 mmol, 1M in THF) at 0° C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched by sat.NH4Cl and extracted with EtOAc (3×10 mL). The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography (EtOAc: petroleum ether=1:10) to give 4-methoxy-2-(2-(trifluoromethyl)pyrimidin-5-yl)butanenitrile (100 mg, yield: 15%, 85% purity in LCMS, [M+H]=246).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[N:19][CH:20]=1>>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=3)[CH:7]=2)[CH:18]=[N:19][CH:20]=1
Reactant: OB(O)c1cncc(C(F)(F)F)c1
Reactant: O=Cc1cnc2ccc(Br)cn12
Product: O=Cc1cnc2ccc(-c3cncc(C(F)(F)F)c3)cn12
Yield: 48 %

Procedure:
The title compound was prepared by following the procedure as described for Intermediate 1 using 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde and 5-(trifluoromethyl)pyridin-3-ylboronic acid. Yield: 48%; 1H NMR (DMSO-d6; 300 MHz): δ 10.04 (s, 1H), 9.71 (s, 1H), 9.27 (s, 1H), 9.07 (s, 1H), 8.62 (s, 2H), 8.16-8.19 (dd, 1H, J=1.8&9.3 Hz), 8.03-8.04 (d, 1H, J=9.3 Hz); MS: m/z 292 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](OC(N1CCC(OS(C2C=CC(C)=CC=2)(=O)=O)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[CH3:18])[CH2:9][CH2:19]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1CCCN1[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: C[C@H]1CCCN1C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared in a manner substantially the same as intermediate (2R,3′S)-2-Methyl-[1,3′]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester by condensing 4-(Toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid tert-butyl ester with (S)-(−)-2-methylpiperindine to get 2.60 g (97% yield) of the product as a pale yellow oil.
Reaction SMILES: [C:1]1([C:7]2[N:12]3[N:13]=[C:14]([NH:16][C:17]4[CH:25]=[CH:24][C:20]5[CH:21]=N[O:23][C:19]=5[CH:18]=4)[N:15]=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2N3N=C(N)N=C3C=CC=2)C=CC=CC=1.BrC1C=CC(C=O)=C([F:51])C=1.C1(NC2N=C3C=CC=C(C4C=CC=CC=4)N3N=2)C=CC=CC=1>>[F:51][C:21]1[CH:18]=[C:17]([NH:16][C:14]2[N:15]=[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:12]3[N:13]=2)[CH:25]=[CH:24][C:20]=1[CH:19]=[O:23]
Reactant: c1ccc(-c2cccc3nc(Nc4ccc5cnoc5c4)nn23)cc1
Reactant: O=Cc1ccc(Br)cc1F
Agent: Nc1nc2cccc(-c3ccccc3)n2n1
Agent: c1ccc(Nc2nc3cccc(-c4ccccc4)n3n2)cc1
Product: O=Cc1ccc(Nc2nc3cccc(-c4ccccc4)n3n2)cc1F

Procedure:
N-(5-Phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzo[d]isoxazol-6-amine. 2-Fluoro-4-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzaldehyde was prepared from 5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine and 4-bromo-2-fluoro-benzaldehyde following the procedure described for the synthesis of N,5-diphenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine.
Reaction SMILES: NCC1C=NC=CC=1.[CH3:9][N:10]1[CH:14]=[C:13]([CH2:15][NH2:16])[CH:12]=[N:11]1.[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[C:27](=[O:28])[N:26]([C:29]3[S:33][C:32]([C:34](O)=[O:35])=[C:31]([CH3:37])[CH:30]=3)[CH:25]=[N:24]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[C:27](=[O:28])[N:26]([C:29]3[S:33][C:32]([C:34]([NH:16][CH2:15][C:13]4[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=4)=[O:35])=[C:31]([CH3:37])[CH:30]=3)[CH:25]=[N:24]2)=[CH:20][CH:19]=1
Reactant: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cn1cc(CN)cn1
Agent: NCc1cccnc1
Product: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cnn(C)c1
Yield: 80 %

Procedure:
Following the procedure as described in Example 31, making variations as required to replace 3-(aminomethyl)pyridine with (1-methyl-1H-pyrazol-4-yl)methylamine to react with 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylic acid, the title compound was obtained as a colorless solid in 80% yield: mp 168-170° C.; 1H NMR (300 MHz, CDCl3) δ 7.71 (s, 1H), 7.44 (s, 1H), 7.39 (s, 1H), 7.40-7.33 (m, 2H), 7.06-6.98 (m, 2H), 6.86 (s, 1H), 6.02 (t, J=5.0 Hz, 1H), 4.95 (s, 2H), 4.41 (d, J=5.0 Hz, 2H), 3.87 (s, 3H), 2.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.6 (d, JC-F=247.1 Hz), 162.2, 150.4, 140.0, 138.7, 134.3, 132.3, 131.2 (d, JC-F=3.3 Hz), 130.3 (d, JC-F=8.3 Hz), 129.5, 125.9, 120.2, 118.1, 115.7 (d, JC-F=21.7 Hz), 48.9, 38.9, 34.4, 15.9; MS (ES+) m/z 427.1 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[O:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:35]2[NH:39][CH:38]=[N:37][N:36]=2)[CH2:30][CH2:29]1>>[F:27][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:14]=[CH:13][C:12]=1[CH2:15][C:16]1[C:17](=[O:18])[N:34]([CH:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)[C:35]2[N:36]([N:37]=[CH:38][N:39]=2)[C:22]=1[CH2:23][CH2:24][CH3:25]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Reactant: c1nnc(NC2CCOCC2)[nH]1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCOCC2)c2ncnn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 81.3 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (1.1 g) and N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.25 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.57 g, 81%). 1H NMR (300 MHz, CHLOROFORM-d) δ1.07 (t, J=7.4 Hz, 3H), 1.62-1.79 (m, 4H), 2.90-3.10 (m, 4H), 3.55 (td, J=12.0, 1.8 Hz, 2H), 4.03 (s, 2H), 4.08-4.17 (m, 2H), 5.30 (tt, J=12.2, 4.1 Hz, 1H), 7.23-7.28 (m, 2H), 7.36-7.51 (m, 3H), 7.63 (dd, J=7.5, 1.1 Hz, 1H), 7.75 (d, J=0.9 Hz, 1H), 7.93 (s, 1H)