Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:17]3[CH:25]=[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38].C1(C(N2CCC(OC3C=CC(NC4C5C=C(F)N=CC=5N=CN=4)=CC=3C)CC2)=O)CCCC1>>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([C:37]([N:12]2[CH2:13][CH2:14][CH:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:15][C:16]4[C:17]5[CH:25]=[C:24]([N:26]6[CH2:31][CH2:30][O:29][CH2:28][CH2:27]6)[N:23]=[CH:22][C:18]=5[N:19]=[CH:20][N:21]=4)=[CH:3][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[O:38])[CH:40]=[CH:41][CH:42]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Cc1cc(Nc2ncnc3cnc(N4CCOCC4)cc23)ccc1OC1CCNCC1
Agent: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCN(C(=O)C2CCCC2)CC1
Product: COc1cccc(C(=O)N2CCC(Oc3ccc(Nc4ncnc5cnc(N6CCOCC6)cc45)cc3C)CC2)c1

Procedure:
The title compound was prepared from [3-Methyl-4-(piperidin-4-yloxy)-phenyl]-(6-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-amine and 3-methoxy benzoylchloride by a procedure analogous to the synthesis of Cyclopentyl-{4-[4-(6-fluoro-pyrido[3,4-d]pyrimidin-4-ylamino)-2-methyl-phenoxy]-piperidin-1-yl}-methanone. LRMS: 555.2 (MH+). 1H NMR (DMSO-d6, 400 MHz): δ 9.57 (s, 1H), δ 8.79 (s, 1H), δ 8.32 (s, 1H), δ 7.47-7.53 (m, 3H), δ 7.32 (t, J=7.68, 1H), δ 7.31 (d, J=8.72, 1H), δ 6.93-6.99 (m, 3H), δ 4.62 (br. s, 1H), δ 3.76 (br. s, 1H), δ 3.52-3.54 (m, 6H), δ 3.75 (m, 6H), 3.302 (s, 3H), δ 2.18 (s, 3H), δ 1.97 (br. s, 1H), δ 1.90 (br. s, 1H), δ 1.66 (br. s, 1H).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:12])[CH3:11].[OH-].[K+].O>CS(C)=O>[C:10]([N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:12])[CH3:11]
Reactant: CCCCCCCCBr
Reactant: CC(=O)Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCN(C(C)=O)c1ccccc1
Temperature: 52.5 °C
Reaction time: 0.75 h
Yield: 98 %

Procedure:
1-Octylbromide (39 mL, 224 mmol, 1.12 eq) was added dropwise to a mixture of acetanilide (27 g, 200 mmol, 1 eq) in dimethylsulfoxide (130 mL), containing potassium hydroxide pellets (18.87 g, 300 mmol, 1.5 eq), at room temperature. After all the octyl bromide was added the reaction mixture was heated to 50-55° C. for 1.5 hours. The reaction mixture was cooled and poured into water (1 L), stirred for 45 minutes and extracted with hexanes (3×400 mL). The hexane extracts were combined, dried over sodium sulfate and evaporated to give 48.4 g (196 mmol, 98%) of colorless oil. The product was identified by NMR spectroscopy and mass spectrometry and was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12](C3C=CC(O)=CC=3)[S:13][C:6]=12.[OH:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:33]3[CH:34]=[C:29]([OH:28])[CH:30]=[CH:31][CH:32]=3)[S:13][C:6]=12
Reactant: OB(O)c1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(O)cc4)sc23)c(F)c1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4cccc(O)c4)sc23)c(F)c1
Yield: 66 %

Procedure:
Starting from the nitrobromo compound 42, following the procedure described above for the synthesis of compound 153 (scheme 28, example 109) but substituting 4-hydroxyphenylboronic acid for 3-hydroxyphenylboronic acid, title compound 160 was obtained in 66% yield as a gray solid. LRMS (M+1) 383.1 (100%).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:13]([Cl:23])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([I:24])[CH:11]=2)[N:6]=1.ClCCl>C1(C)C=CC=CC=1>[Cl:23][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([I:24])[CH:11]=2)[N:6]=[C:5]([O:2][CH3:1])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1
Reactant: Cc1ccc(Cc2c(Cl)nc3ccc(I)cc3c2Cl)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(C)cc1
Temperature: 105 °C
Reaction time: 18 h

Procedure:
Sodium methoxide (3.2 g, 60 mmol) was added to a solution of 2,4-dichloro-6-iodo-3-(4-methylbenzyl)quinoline (4.3 g, 10 mmol, Intermediate 22: step b) in toluene (50 mL) with stirring. The mixture was heated to 105° C. After 18 hours, the flask was allowed to cool to 23° C. Dichloromethane (100 mL) was added and then the mixture was filtered through Celite®. The filter cake was washed with dichloromethane. The filtrate was concentrated and the residue was purified by flash column chromatography on silica gel eluting with hexanes initially, grading to 20% ethyl acetate-hexanes to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([O:16][C@H:17]3[CH2:21][CH2:20][O:19][CH2:18]3)[CH:13]=[C:12]([O:22]CC3C=CC=CC=3)[CH:11]=2)=[N:6][CH:7]=1>[Pd].C(O)C.C1COCC1>[OH:22][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([O:16][C@H:17]2[CH2:21][CH2:20][O:19][CH2:18]2)[CH:13]=1)[C:9]([NH:8][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:30]
Reactant: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@H]3CCOC3)c2)cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cnc(NC(=O)c2cc(O)cc(O[C@H]3CCOC3)c2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
10% Palladium on charcoal (500 mg) was added to a solution of N-(5-methylpyrazin-2-yl)-3-[(phenylmethyl)oxy]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide (5.0 g, 12.34 mmol) in ethanol (50 mL) and THF (100 mL) and the mixture stirred under an atmosphere of hydrogen at RT for 16 hours. The mixture was filtered through Celite®, the solvents evaporated in vacuo to a residue which was crystallised from ethyl acetate to give the desired material (3.6 g). 1H NMR δ (d6-DMSO): 2.0 (m, 1H), 2.25 (m, 1H), 2.5 (s, 3H), 3.75-3.95 (m, 4H), 5.1 (m, 1H), 6.5 (d, 1H), 7.0 (d, 1H), 7.05 (d, 1H), 8.35 (s, 1H), 9.25 (s, 1H), 9.75 (s, 1H), 10.8 (s, 1H); m/z 316 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C@H:3]1[N:8]([C:9]2[C:10]3[CH:17]=[CH:16][S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[C@@H:7]([CH3:18])[CH2:6][N:5]([CH2:19][C:20](O)=[O:21])[CH2:4]1.[NH2:23][C:24]1[N:28]([CH3:29])[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N:25]=1>>[CH3:2][C@H:3]1[N:8]([C:9]2[C:10]3[CH:17]=[CH:16][S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[C@@H:7]([CH3:18])[CH2:6][N:5]([CH2:19][C:20]([NH:23][C:24]2[N:28]([CH3:29])[C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[N:25]=2)=[O:21])[CH2:4]1
Reactant: C[C@@H]1CN(CC(=O)O)C[C@H](C)N1c1ncnc2sccc12
Reactant: Cn1c(N)nc2ccccc21
Agent: Cl
Product: C[C@@H]1CN(CC(=O)Nc2nc3ccccc3n2C)C[C@H](C)N1c1ncnc2sccc12

Procedure:
The title compound was prepared from the product of Example 9 step (ii) (0.2 g) and 2-amino-1-methyl-benzimidazole (0.14 g) by the method of Example 38 step (iv). Purification was by silica gel chromatography followed by recrystallisation from methanol. Yield 45 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([S:17][C:18]4[CH:19]=[C:20]([NH2:25])[C:21]([NH2:24])=[CH:22][CH:23]=4)=[N:15][N:16]=3)[N:13]=2)=[CH:4][CH:3]=1.[N:26]#[C:27]Br.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([S:17][C:18]4[CH:23]=[CH:22][C:21]5[N:24]=[C:27]([NH2:26])[NH:25][C:20]=5[CH:19]=4)=[N:15][N:16]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: N#CBr
Reactant: Nc1ccc(Sc2nnc3ccc(-c4ccc(F)cc4)nn23)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2[nH]1

Procedure:
A mixture of 4-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}benzene-1,2-diamine and of 42 mg of cyanogen bromide in 10 cm3 of ethanol is brought to reflux for 3 hours. The resulting reaction mixture is then run into a 2.5N aqueous solution of sodium hydroxide and the mixture obtained is subsequently extracted with a 90/10 mixture of ethyl acetate and methanol. The organic phases are combined then dried over magnesium sulphate and then evaporated. A yellow powder is recovered, and is chromatographed on Biotage Quad 12/25 (KP-SIL, 60 A; 32-63 μM), elution being carried out with a gradient of dichloromethane and then dichloromethane/eluent B: 95/5, 92.5/7.5, 90/10, 87.5/12.5, 85/15 (eluent B=dichloromethane/methanol/aqueous ammonia 38/17/2). 43.2 mg of 6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1H-benzimidazol-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]1[CH:3]=[C:4]([NH:18][C:19](=[O:30])[CH2:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12.FC1C=C(N)C=CC=1OC1C=CN=C2C=C(C3N(C)C=CN=3)SC=12.NC1C=CC(OC2C=CN=C3C=C([C:70]([N:72]4[CH2:76][CH2:75][C@@H:74]([N:77]([CH3:79])[CH3:78])[CH2:73]4)=[O:71])SC=23)=C(F)C=1>>[CH3:78][N:77]([CH3:79])[C@@H:74]1[CH2:75][CH2:76][N:72]([C:70]([C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:18][C:19](=[O:30])[CH2:20][C:21]([NH:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[O:22])=[CH:3][C:2]=3[F:1])[CH:15]=2)=[O:71])[CH2:73]1
Reactant: CN(C)[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc(N)cc4F)c3s2)C1
Reactant: O=C(CC(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1)Nc1ccccc1
Agent: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Product: CN(C)[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5)cc4F)c3s2)C1
Yield: 38 %

Procedure:
Following the procedure described above for the compound 5a (step 5, example 1) but replacing the amine 9 with the compound 26, title compound 5g was obtained in 38% yield. MS (m/z): 562.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([N:11]1[C:16](=[O:17])[C:15]([Cl:18])=[C:14](Cl)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30]>>[CH3:1][O:2][C:3](=[O:20])[CH:4]([N:11]1[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][CH2:22][OH:21])[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)n1ncc(Cl)c(Cl)c1=O
Reactant: OCCc1ccccc1O
Product: COC(=O)C(CC1CCCC1)n1ncc(Oc2ccccc2CCO)c(Cl)c1=O
Yield: 48 %

Procedure:
In an analogous manner to the reaction outlined in Intermediate 19 step 1, starting from 3-cyclopentyl-2-(4,5-dichloro-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester and 2-(2-hydroxy-ethyl)-phenol afforded 2-{5-chloro-4-[2-(2-hydroxy-ethyl)-phenoxy]-6-oxo-6H-pyridazin-1-yl}-3-cyclopentyl-propionic acid methyl ester (10.1 g, 48%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:13][CH:14]=2)[C:9]1=[O:31].[F:32][C:33]([F:56])([F:55])[CH2:34][NH:35][C:36]([C:38]1([CH2:51][CH2:52][CH2:53]Br)[C:50]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:37]>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][N:21]([CH2:53][CH2:52][CH2:51][C:38]4([C:36](=[O:37])[NH:35][CH2:34][C:33]([F:32])([F:55])[F:56])[C:50]5[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=5[C:44]5[C:39]4=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH2:20][CH2:19]3)=[CH:13][CH:14]=2)[C:9]1=[O:31]
Reactant: O=C(NCC(F)(F)F)C1(CCCBr)c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)C(=O)N(CC2CCCCO2)CC3)CC1
Product: O=C1c2cc(N3CCN(CCCC4(C(=O)NCC(F)(F)F)c5ccccc5-c5ccccc54)CC3)ccc2CCN1CC1CCCCO1

Procedure:
Step (b) of Example 97 was repeated, except that the compound prepared in step (a) of Example 99 and the compound prepared in step (a) of Example 93 were used as the starting compounds. Thus, the title compound was prepared.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([OH:10])=O)[C:4](=[O:11])[CH2:3]1.[CH3:12][C:13]1([CH3:19])[NH:17][C:16](=[O:18])[CH2:15][NH:14]1>>[CH3:12][C:13]1([CH3:19])[NH:17][C:16](=[O:18])[CH2:15][N:14]1[C:8](=[O:10])[CH2:7][N:5]1[CH2:6][CH:2]([OH:1])[CH2:3][C:4]1=[O:11]
Reactant: CC1(C)NCC(=O)N1
Reactant: O=C(O)CN1CC(O)CC1=O
Product: CC1(C)NC(=O)CN1C(=O)CN1CC(O)CC1=O

Procedure:
The same procedure of Example 10, starting from 4-hydroxy-2-oxo-1-pyrrolidineacetic acid and 2,2-dimethyl-4-imidazolidinone, afforded the title compound, m.p. 250° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([NH:35]O)=[NH:34])=[CH:31][N:30]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]4[O:26][N:35]=[C:33]([C:32]5[CH:37]=[CH:38][C:29]([NH2:28])=[N:30][CH:31]=5)[N:34]=4)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:11])[F:10]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(F)c3)nc12
Reactant: N=C(NO)c1ccc(N)nc1
Product: Nc1ccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)c(F)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 5-(3-fluoro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.18) (197 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (95 mg, 37%). MS (ISP) 510.3 [(M+H)+]; mp 233° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:10]=1[O:11][CH2:12][C@H:13]([OH:42])[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[C:17]=1[C:23]1[NH:34][C:33]2[C:25](=[CH:26][C:27]3[CH2:28][N:29]([CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[C:30](=[O:35])[C:31]=3[CH:32]=2)[N:24]=1.[CH:48]1([CH:51]=O)[CH2:50][CH2:49]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.O.CC#N>[CH:48]1([CH2:51][N:39]2[CH2:38][CH2:37][CH:36]([N:29]3[CH2:28][C:27]4[CH:26]=[C:25]5[C:33]([NH:34][C:23]([C:17]6[C:18](=[O:22])[NH:19][CH:20]=[CH:21][C:16]=6[NH:15][CH2:14][C@@H:13]([OH:42])[CH2:12][O:11][C:10]6[CH:43]=[CH:44][C:45]([CH3:47])=[CH:46][C:9]=6[CH3:8])=[N:24]5)=[CH:32][C:31]=4[C:30]3=[O:35])[CH2:41][CH2:40]2)[CH2:50][CH2:49]1
Reactant: O=CC1CC1
Reactant: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCNCC2)C4)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(CC3CC3)CC2)C4)c(C)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of the TFA salt of 2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (40 mg, 0.061 mmol) and cyclopropanecarbaldehyde (150 μL, 2.0 mmol) in a mixed solvent of CH3CN (6 mL) and H2O (2 mL) was added AcOH (500 μL) at 0° C. and the resulting reaction mixture was stirred at 0° C. for 20 min and followed by addition of Na(OAc)3BH (254 mg, 1.2 mmol). The reaction mixture was stirred at 0° C. for 1 h and at the room temperature for 1 h and then evaporated. The residue was subjected to HPLC purification to afford the title compound in TFA salt form. 1H NMR (DMSO-d6) δ 0.39 (m, 2H), 0.67 (m, 2H), 1.10 (m, 1H), 2.03 (m, 2H), 2.12 (m, 2H), 2.19 (s, 3H, CH3), 2.21 (s, 3H, CH3), 3.01 (m, 2H), 3.18 (m, 2H), 3.50-4.15 (7H), 4.32 (m, 1H), 4.47 (s, 2H), 6.22 (d, J=7 Hz, 1H), 6.80 (d, J=7 Hz, 1H), 6.91 (d, J=7 Hz, 1H), 6.97 (s, 1H), 7.38 (d, J=7 Hz, 1H), 7.57 (br s, 1H), 7.82 (br s, 1H), 11.13 (br s, 1H, NH), 11.22 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 597.3 (MH+).
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][N:10]2[CH2:15][C:14]3[CH:16]=[C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)[CH:18]=[N:19][C:13]=3[NH:12][C:11]2=[O:25])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl.[CH3:27][N:28]1[CH2:34][C:33]2[CH:35]=[C:36](/[CH:39]=[CH:40]/[C:41](O)=O)C=N[C:32]=2[NH:31][C:30](=O)[CH2:29]1.CNCC1N(C)C2C(C=1)=CC=CC=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[CH3:32][N:31]([CH2:30][C:29]1[N:28]([CH3:27])[C:34]2[C:40]([CH:41]=1)=[CH:39][CH:36]=[CH:35][CH:33]=2)[C:22](=[O:24])/[CH:21]=[CH:20]/[C:17]1[CH:18]=[N:19][C:13]2[NH:12][C:11](=[O:25])[N:10]([CH2:9][CH2:8][N:2]3[CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)[CH2:15][C:14]=2[CH:16]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CNCc1cc2ccccc2n1C
Agent: Cl
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Yield: 61 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-[3-(2-morpholin-4-yl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the tide compound (355 mg, 61%) was prepared as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 10.16-9.98 (m, 2H), 8.42-8.37 (m, 1H), 8.00-7.92 (m, 1H), 7.58-7.39 (m, 3H), 7.24-6.99 (m, 3H), 6.42-6.15 (m, 1H), 5.06-4.85 (m, 2H), 4.57-4.51 (m, 2H), 4.00-3.97 (m, 2H), 3.73-3.37 (m, 11H), 3.15-2.98 (m, 5H); MS (ESI) m/e 489 (M+H)+.
Reaction SMILES: Br[CH:2]([C:7]1[CH:8]=[C:9]([Cl:15])[C:10]([Cl:14])=[C:11]([Cl:13])[CH:12]=1)[C:3]([F:6])([F:5])[F:4].[CH:16]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[CH2:22][CH2:21]2)=[CH2:17].N1C=CC=CC=1C1C=CC=CN=1>ClC1C=CC=CC=1Cl.Cl[Cu]>[F:4][C:3]([F:6])([F:5])[CH:2]([C:7]1[CH:8]=[C:9]([Cl:15])[C:10]([Cl:14])=[C:11]([Cl:13])[CH:12]=1)/[CH:17]=[CH:16]/[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[CH2:22][CH2:21]2
Reactant: C=Cc1ccc2c(c1)CCC2=O
Reactant: FC(F)(F)C(Br)c1cc(Cl)c(Cl)c(Cl)c1
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: O=C1CCc2cc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Yield: 52.6 %

Procedure:
5-(1-Bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (4 g, 11.7 mmol), 5-vinyl-2,3-dihydro-1H-inden-1-one (0.92 g, 5.8 mmol), CuCl (0.115 g, 1.171 mmol) and 2,2-bipyridyl (0.053 g, 0.34 mmol) in 1,2-dichlorobenzene (25 mL) were heated at 180° C. for 16 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 5% EtOAc in petroleum ether) to afford the title compound as a liquid (1.28 g, 25%): 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=7.4 Hz, 1H), 7.52 (m, 3H), 6.68 (d, J=7.4 Hz, 1H), 6.52 (m, 1H), 4.18 (m, 1H), 3.18 (m, 2H), 2.75 (m, 2H); ESIMS m/z 419.14 ([M+H]−); IR (thin film) 1708.94, 1113.60, 807.77 cm−1.
Reaction SMILES: [C:1]([S:4][CH2:5][C@@H:6]([CH3:10])[C:7]([OH:9])=[O:8])(=O)[CH3:2].[OH-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17]C=C.Cl>CO.CCOC(C)=O>[CH2:1]([S:4][CH2:5][C@@H:6]([CH3:10])[C:7]([OH:9])=[O:8])[CH2:2][CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: CC(=O)SC[C@@H](C)C(=O)O
Reactant: C=CCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C=CCCCCSC[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.62 g (10 mmol) (S)-3-acetylsulfanyl-2-methyl-propionic acid in 20 ml MeOH is treated with 7.5 ml 4N NaOH and 1.63 g (10 mmol) 6-bromo-hex-1-ene. After being stirred for 1 h at rt the mixture is diluted with 50 ml EtOAc and acidified with 25 ml 1N HCl. The organic phase is washed with brine, dried with sodium sulfate and concentrated in vacuo to yield (S)-3-hex-5-enylsulfanyl-2-methyl-propionic acid as an oil which is used without purification for the next step.
Reaction SMILES: C([Mg]Br)C.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=1.Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[C:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24][CH:23]=1>O1CCCC1>[CH2:33]([O:32][C:30]([C:29]([CH3:35])=[CH:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[C:7]2[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=2)=[CH:23][CH:24]=1)=[O:31])[CH3:34]
Reactant: c1cncc(-c2cc3ccccc3[nH]2)c1
Reactant: CCOC(=O)C(C)=Cc1ccc(CCl)cc1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=Cc1ccc(Cc2c(-c3cccnc3)[nH]c3ccccc23)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 6.0 ml of a 2M solution of ethylmagnesium bromide in tetrahydrofuran under nitrogen at 0° is added dropwise over 20 minutes a solution of 2-(3-pyridyl)indole (1.9 g) in 12 ml of tetrahydrofuran. After complete addition the mixture is stirred at 0° for 0.5 hour and is then treated dropwise with a solution of 2.39 g of ethyl 3-(p-chloromethylphenyl)-2-methylacrylate in 5 ml of tetrahydrofuran. The resulting mixture is stirred at 0° for 1 hour, then at room temperature for 1 hour, and poured in 100 ml of ice-water. The resulting mixture is extracted with ether (2×50 ml) and the organic layer is washed with 100 ml of brine, dried over magnesium sulfate and evaporated to yield 3-[p-(2-ethoxycarbonylpropen-1-yl)benzyl]-2-(3-pyridyl)indole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([Cl:28])=[C:23]([F:29])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:30]N1C(=O)CCC1=O>CC#N.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][C:16]([Cl:30])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([F:29])[C:24]([Cl:28])=[C:25]([F:27])[CH:26]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(Cl)c(F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(Cl)c(F)c1
Temperature: 70 °C

Procedure:
To a yellow homogeneous solution of 8-[2-(4-chloro-3,5-difluoro-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.150 g; 2.700 mmol) in anhydrous MeCN (40 ml) was added dropwise, at rt, a solution of N-chlorosuccinimide (0.367 g; 2.700 mmol; 1 eq.) in anhydrous MeCN (10 ml). The resulting solution was then heated to 70° C., under nitrogen, for 3 h30. Concentration to dryness afforded a yellow oily residue which was dissolved in EA (80 ml), and this organic layer was washed with aq. sat. NaHCO3 (2×120 ml), was then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/EA=2/3) gave the expected 1-chloro-8-[2-(4-chloro-3,5-difluoro-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (0.724 g; 58%). LC-MS: tR=1.08 min.; [M+H]+=461.94 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11]Br)=[CH:6][CH:5]=1.[NH2:15][C:16]([NH2:18])=[S:17].C(O)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:16]([NH2:18])[S:17][CH:11]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)CBr)cc1
Reactant: NC(N)=S
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COC(=O)c1ccc(-c2csc(N)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
A mixture of 4-(2-bromo-acetyl)-benzoic acid methyl ester (1 g, 3.89 mmol) and thiourea (0.29 g, 3.89 mmol) were taken isopropyl alcohol (100 ml) and refluxed for 10 minutes followed by addition of sodium carbonate (0.206 g, 1.94 mmol) and stirred for 30 minutes. Reaction mixture was cooled to room temperature and poured in water. The precipitate obtained was filtered off, washed with water and diethyl ether and dried under vacuum to afford 4-(2-amino-thiazol-4-yl)-benzoic acid methyl ester (0.500 g, 55%).