Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:12]=[CH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([N:21]1[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]1)[CH:15]=2)=[O:10].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:12]=[CH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([N:21]1[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]1)[CH:15]=2)=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(C(=O)Nc4ccccc4N)ncc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccccc1NC(=O)c1cc2ccc(N3CCNCC3)cc2cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a solution of tert-butyl 4-(3-(2-aminophenylcarbamoyl)isoquinolin-7-yl)piperazine-1-carboxylate (100 mg, 0.22 mmol) in DCM (3 mL) was added TFA (1.5 mL). The resulting mixture was stirred at r.t. for 1 h. The mixture was concentrated to a residue, which was purified by Pre-HPLC to afford the desired compound, N-(2-aminophenyl)-7-(piperazin-1-yl)isoquinoline-3-carboxamide (75 mg, 70%) as a light yellow solid. 1H NMR (500 MHz, DMSO) δ 10.12 (s, 1H), 9.18 (s, 1H), 8.48 (s, 1H), 8.03 (d, J=9.1 Hz, 1H), 7.73 (d, J=7.0 Hz, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.45 (s, 1H), 6.95 (t, J=7.6 Hz, 1H), 6.85 (d, J=7.8 Hz, 1H), 6.68 (t, J=7.5 Hz, 1H), 4.89 (s, 2H), 3.33-3.12 (m, 4H), 2.93-2.84 (m, 4H). LCMS: 1.69 min, m/z=348 (M+H)+
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([C:42]([OH:45])([CH3:44])[CH3:43])[C:38]2=[N:46][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:51][CH2:50][C:16]([CH3:52])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:49])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:48])=[CH:28][C:29]=2[C:30]2[CH:47]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([C:42]([OH:45])([CH3:44])[CH3:43])[C:38]2=[N:46][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:52])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:49])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:48])=[CH:28][C:29]=2[C:30]2[CH:47]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:50][CH2:51]1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C(C)(C)O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc3c1C(C)(C)O)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 11.7 %

Procedure:
Prepared in 11.7% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-5-(2-hydroxypropan-2-yl)-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.00 (d, J=7.3 Hz, 1H), 7.92 (s, 1H), 7.56 (t, J=7.7 Hz, 1H), 7.38 (d, J=7.3 Hz, 1H), 7.24-7.13 (m, 3H), 5.98 (br. s., 1H), 4.61 (br. s., 1H), 3.80 (t, J=11.6 Hz, 1H), 3.60 (t, J=12.1 Hz, 1H), 3.44 (d, J=14.7 Hz, 4H), 3.25 (br. s., 1H), 2.64 (d, J=9.5 Hz, 1H), 2.42 (s, 3H), 1.91-1.75 (m, 5H), 1.71 (s, 10H), 1.52 (br. s., 1H), 1.19 (s, 3H), 1.15 (s, 9H), 1.07 (d, J=5.9 Hz, 3H); LCMS (ESI, M+1): 686.4.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[C:24]=1[NH:32][C:33](=[O:36])[CH2:34]Br)([CH3:22])[CH3:21]>>[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:30])[CH3:31])[C:24]=1[NH:32][C:33](=[O:36])[CH2:34][N:17]1[CH2:18][CH2:19][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)[CH2:15][CH2:16]1)([CH3:21])[CH3:22]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CBr
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1CCC(c2ccc(Oc3ccccc3)cc2)CC1

Procedure:
The compound (4) synthesized in Reference Example 4 and the compound (24) synthesized in Reference Example 24 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[N:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:26]([C:30]1[CH:54]=[CH:53][C:33]([C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[C:38]=2[CH3:52])=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+].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.O.C(O)C>[C:26]([C:30]1[CH:54]=[CH:53][C:33]([C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:2]3[CH:3]=[C:4]([NH:11][C:12]4[CH:13]=[CH:14][C:15]([C:18]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)=[O:19])=[CH:16][N:17]=4)[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[N:7]=3)[C:38]=2[CH3:52])=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(c1ccc(Nc2cc(Cl)nn3ccnc23)nc1)N1CCOCC1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c2nccn2n1
Temperature: 170 °C
Reaction time: 3 h
Yield: 10.2 %

Procedure:
A mixture of crude [6-(6-chloro-imidazo[1,2-b]pyridazin-8-ylamino)-pyridin-3-yl]-morpholin-4-yl-methanone (0.048 g, “0.133 mmol”), 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (0.087 g, 0.23 mmol), potassium carbonate (0.056 g, 0.41 mmol), Pd(PPh3)4 (0.016 g, 0.014 mmol), 1 mL of toluene, 0.25 mL of ethanol and 0.25 mL of water under N2 was stirred at 170° C. in a microwave for 3 h. More Pd(PPh3)4 was added (0.025 g, 0.021 mmol) and the mixture was stirred for an additional 1 h at 170° C. in a microwave. The mixture was partitioned between 5 mL of water and 5 mL of ethyl acetate, and the aqueous layer was extracted with 5 mL of ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated to 0.126 g of a yellow oil. Column chromatography (1st column: 0->10% MeOH/CH2Cl2; 2nd column: 0->5% MeOH/EtOAc) afforded 0.008 g (10%) of 4-tert-butyl-N-(2-methyl-3-{8-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-imidazo[1,2-b]pyridazin-6-yl}-phenyl)-benzamide as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]#[CH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1>CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]#[C:15][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(C#Cc2ccc(F)cc2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a suspension of CuI (4 mg, 0.02 mmol) in Et3N (1 ml) was added 3-Ethynyl-piperidine-1-carboxylic acid tert-butyl ester (80 mg, 0.38 mmol) followed by PdCl2(PPh3)2 (13 mg, 0.02 mmol) and 1-Iodo-4-fluoro-benzene (85 mg, 0.38 mmol). The mixture was stirred 1 h at R.T then heated to 60° C. for 12 h. Et3N was removed by evaporation. The product was purified by flash chromatography (DCM 100%) to give 0.1 g (89%) of 3-(4-Fluoro-phenylethynyl)-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil.
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[C:17]1[N:18]=[C:19]([C:30](OCC)=[O:31])[N:20]([CH3:29])[C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1>>[CH:1]1([NH:8][C:30]([C:19]2[N:20]([CH3:29])[C:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[C:17]([C:11]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=3[Cl:9])[N:18]=2)=[O:31])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCCC1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1C
Product: Cn1c(C(=O)NC2CCCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Using essentially the same procedure as Example 36, Step B (Method B), but using neat cycloheptylamine (1.5 mL), ethyl 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-methylimidazole-2-carboxylate (30 mg, 0.073 mmol) was converted to the title compound after purification by Prep TLC (25% ethyl acetate in hexanes).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[F:16][C:17]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20].[I:26]I>C1COCC1>[F:16][C:17]1[C:24]([I:26])=[C:23]([CH3:25])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: Cc1ccc(C#N)c(F)c1
Reactant: II
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C#N)c(F)c1I
Temperature: -78 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
An oven-dried, 3-necked 500 ml round bottom flask with magnetic stirrer, thermometer, addition funnel, and nitrogen inlet was purged with N2 for 20 min. 2,2,6,6-tetramethylpiperidine (41.84 ml, 241 mmol) was introduced into flask via syringe, followed by 100 ml of anhydrous THF. The reaction mixture was cooled to −78° C., and n-BuLi (2.5M solution in hexane, 102 ml, 254 mmol) was introduced via cannula. The addition was done slowly, drop-wise, making sure that temperature stayed in the −70° C. to −80° C. range. (˜40 min). The addition flask was washed with 100 ml of anhydrous THF and the reaction mixture warmed to −50° C. for 30 min. during which time the clear solution became turbid. The reaction mixture was cooled to −78° C. again and 2-fluoro-4-methylbenzonitrile (30 g, 222 mmol) dissolved in 80 ml of anhydrous THF was added drop wise to the stirred solution while the internal temperature was maintained below −70° C. (approx 20 min). The addition funnel was washed once with 100 ml portion of THF and the reaction mixture was warmed up to −50° C. for 60 min. The reaction mixture was cooled again to −78° C. and a saturated solution of iodine (62 g, 244 mmol) in 100 ml of THF was introduced into the addition funnel. The quench was done stepwise, and the resulting yellow mixture was kept at an internal temperature below −60° C. (approx 20 min). The addition funnel was washed twice with 50 ml of THF and then the mixture was allowed to warm-up to room temperature. After stirring overnight, the entire mixture was added to a solution of 20 g thiosulfite in 1000 ml of water, stirred for 1 hour, and washed with ethyl acetate 3×250 ml. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified using an ISCO system. The product fractions were combined and concentrated. The product was re-crystallized from ether/hexane to give 33 g (57%) of the product. 1H NMR (CDCl3, 400 MHz) δ 7.50 (dd, 1H), 7.16 (d, 1H), 2.50 (s, 3H). LC-MS (M+1)=262 M/Z.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[O:13][C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[O:24]CC3C=CC=CC=3)=[N:11][C:10]=12)=[O:4]>[Pd].CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[O:13][C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[OH:24])=[N:11][C:10]=12)=[O:4]
Reactant: COC(=O)c1cccc2oc(-c3ccc4ccccc4c3OCc3ccccc3)nc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2oc(-c3ccc4ccccc4c3O)nc12

Procedure:
2-(1-benzyloxy-naphthalen-2-yl)benzoxazole-4-carboxylic acid methyl ester, EtOAc (15.4 mL). 10% Pd/C (0.041 g, 0.376 mmol), 0.5 psi of H2(g) was consumed. Yield: 0.059 g of orange-yellow solid (75%). m.p. −185-186.5° C.; 1H NMR (400 MHz, CDCl3) δ 4.10 (s, 3H), δ 7.42-7.46 (m, 2H), δ 7.57-7.62 (m, 2H), δ 7.82 (d, J=8.3 Hz, 2H), δ 8.00 (d, J=8.7 Hz, 1H), δ 8.08 (dd, J=7.8 Hz, 1 Hz, 1H), δ 8.52 (d, J=8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 52.45, 103.11, 114.83, 119.42, 120.95, 122.10, 123.93, 124.38, 126.05, 127.40, 127.68, 129.06; Anal. calcd for C19H13NO3 C, 71.47; H, 4.10; N, 4.39. Found C, 71.40; H, 4.12; N, 4.29.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH2:22](Br)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccccc2)C1

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.6 g--see Preparation 8), phenethyl bromide (0.4 g), anhydrous potassium carbonate (0.6 g) and acetonitrile (20 ml) was heated under reflux for 1.25 hours. The mixture was partitioned between 10% aqueous potassium carbonate (20 ml) and dichloromethane (50 ml), the layers were separated, and the aqueous layer extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 4%). The product-containing fractions were combined and concentrated in vacuo to give a foam which was crystallised from diisopropyl ether to give the title compound, yield, 0.21 g, m.p. 124°-129° C.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[BH4-].[Li+]>C(O)C>[CH3:29][CH:10]1[CH:11]=[C:12]2[CH:13]([CH:14]([CH2:19][CH2:20][CH:21]([OH:27])[CH2:22][CH:23]([OH:28])[CH2:24][CH2:25][OH:26])[CH:15]([CH3:18])[CH:16]=[CH:17]2)[CH:8]([O:7][C:5](=[O:6])[CH:3]([CH3:4])[CH2:2][CH3:1])[CH2:9]1
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Product: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC(O)CC(O)CCO)C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 65 mg (0.15 mmol) of mevinolin in 5 ml of ethanol are added 22 mg (1.0 mmol) lithium borohydride and the resulting mixture is stirred overnight at room temperature. The reaction is quenched with 0.1 N aqueous HCl. The phases are separated and the aqueous phase is extracted twice with ethyl acetate. The organic phases are combined, washed with brine and dried over sodium sulfate. The solvent is evaporated and the crude product purified by silica gel chromatography (ethyl acetate) to afford 2-methyl-butyric acid 3,7-dimethyl-8-(3,5,7-trihydroxy-heptyl)-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester as an oil.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21](O)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[O:7])[CH2:3][CH2:2]1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:21]([C:16]2[CH:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:6]([NH:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)=[O:7])=[CH:13][CH:12]=3)[C:19]([CH3:20])=[CH:18][CH:17]=2)=[O:22])[CH2:26][CH2:25]1
Reactant: NC1CC1
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N3-Cyclopropyl-N4′-cyclopropylmethyl-6-methyl-1,1′-biphenyl-3,4′-dicarboxamide was synthesised from {4′-[(cyclopropylmethylamino)carbonyl]-6-methyl-1,1′-biphenyl-3-yl}carboxylic acid and cyclopropylamine using method A. NMR: δH [2H6]-DMSO 8.62, (1H, t), 8.43, (1H, d), 7.93, (2H, d), 7.74, (1H, dd), 7.68, (1H, d), 7.46, (2H, d), 7.38, (1H, d), 3.16, (2H, t), 2.83, (1H, m), 2.26, (3H, s), 1.04, (1H, m), 0.67, (2H, m), 0.54, (2H, m), 0.43, (2H, m), 0.24, (2H, m). LCMS: retention time 2.89 min, MH+349.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH3:17].[H-].[Na+].[CH2:20]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[CH2:20])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1cc(Oc2ccc(C=O)cc2)ccc1Cl
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=Cc1ccc(Oc2ccc(Cl)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
To a stirred suspension of 4-[(4-chloro-3-methylphenyl)oxy]benzaldehyde (4.2 g, 17.03 mmol) and methyl(triphenyl)phosphonium bromide (6 g, 16.80 mmol) in dry THF (50 mL) was added NaH (3.4 g, 85 mmol) under nitrogen at 0° C. The mixture was stirred at room temperature for 3 h. The organic layer was washed three times with brine, dried over Na2SO4, filtered, and concentrated. Purification via flash chromatography afforded the title compound (2.46 g, 59% yield) as a light green oil. LCMS: rt=4.34 min, [M+H+]=280
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:32]=[CH:31][C:25]([O:26][CH2:27][CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:59](OC(=O)C)(=[O:61])[CH3:60].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:32]=[CH:31][C:25]([O:26][CH2:27][CH2:28][CH2:29][NH:30][C:59](=[O:61])[CH3:60])=[CH:24][CH:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:33]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: NCCCOc1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCOc1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Reaction time: 1 h

Procedure:
While 5 mL solution of 37 mg 3-(4-{6-[3-(4-Fluorophenyl)-1-trityl-1H-4-pyrazolyl]imidazo[1,2-a]pyridin-3-yl}phenoxy)-propylamine obtained in Example 16 and 20 mg triethylamine in dichloromethane was stirred under ice-coolingd water in a stream of nitrogen, 9 μL acetic anhydride was added thereto and stirred for 1 hour. An aqueous saturated sodium bicarbonate solution and ethyl acetate were added to the reaction solution, the organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, the filtrate was concentrated, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) to give 30 mg of the title compound as a colorless oil.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:12]3[N:16]4[CH:17]=[CH:18][C:19]([C:21]5[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=5)[CH:24]=O)=[CH:20][C:15]4=[N:14][CH:13]=3)[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl.CCOC(C)=O>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:24][C:23]2[CH:22]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]4[C:12]([C:8]5[CH:9]=[CH:10][CH:11]=[C:6]([N:1]6[CH:5]=[CH:4][CH:3]=[N:2]6)[CH:7]=5)=[CH:13][N:14]=[C:15]4[CH:20]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:32][CH2:31]1
Reactant: CN1CCNCC1
Reactant: O=Cc1cccc(-c2ccn3c(-c4cccc(-n5cccn5)c4)cnc3c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCN(Cc2cccc(-c3ccn4c(-c5cccc(-n6cccn6)c5)cnc4c3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[3-(3-pyrazol-1-yl-phenyl)-imidazo[1,2-a]pyridin-7-yl]-benzaldehyde (Ex. 1.9) (1 eq, 0.110 mmol, 40 mg) in DCM (2 ml) is added methyl piperazine (2 eq, 0.220, 0.24 ml) and the reaction mixture is stirred at room temperature for 2 h. After this time sodium triacetoxyborohydride (1.5 eq, 0.165 mmol, 36.7 mg) and acetic acid (0.1 ml) are added to the reaction mixture and this is stirred for a further one hour. The reaction is diluted with EtOAc and the organic phase is washed with NaHCO3. The aqueous layer is further extracted with EtOAc. The combined organic layers are washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo. The reaction mixture is purified by flash column chromatography eluting with 8:2 DCM/MeOH to yield 7-[3-(4-methyl-piperazine-1-ylmethyl)-phenyl]-3-(3-pyrazol-1-yl-phenyl)-imidazo-[1,2-a]pyridine as a yellow solid; [M+H]+=449
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:2]1(=[O:1])[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCC12CCNCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (I-11) (5.0 g, 19.7 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (15.2 mL, 197 mmol) and the resulting solution was stirred at rt for 1 h. After evaporating the volatiles the residue was basified on ion exchange column washed with methanol followed by 1 N ammonia in methanol to give 2,8-diazaspiro[4.5]decan-1-one. LC/MS: (M+1)+: 155.11
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]([F:19])([F:18])[F:17].CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[F:15][C:12]1[CH:13]=[CH:14][C:9]([N:6]2[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]2)=[C:10]([C:16]([F:17])([F:18])[F:19])[CH:11]=1
Reactant: Fc1ccc(Br)c(C(F)(F)F)c1
Reactant: C[C@@H]1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1
Temperature: 100 °C
Yield: 82.4 %

Procedure:
(R)-2-methyl-piperazine (3.5 g, 34.9 mmol), 2-bromo-5-fluoro benzotrifluoride (7.74 g, 31.7 mmol), BINAP (0.59 g, 0.95 mmol), tBuONa (4.58 g, 47.65 mmol) and Pd2(dba)3 (0.29 g, 0.32 mmol) were mixed in the flask and purged with N2. Anhydrous toluene (50 mL) was added and purged with N2 again. The resulting mixture was heated in an oil bath at 100° C. under N2 for 3 hours. The mixture was cooled to room temperature, diluted with dichloromethane (150 mL), washed with H2O (30 mL) first, then washed with saturated brine (30 mL). The combined organic layer was dried over Na2SO4, concentrated down under reduced pressure to give a brown color liquid as crude. The crude product was purified on silica gel column eluted with 5-10% MeOH in DCM to give (3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-3-methylpiperazine as a light yellow oil (6.85 g, 82%).