Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:21]1[CH2:25][CH:24]([CH2:26][CH3:27])[CH:23]=[N:22]1)=[N:5][S:6]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](C(=O)C)[CH2:13][CH2:12]2)(=[O:8])=[O:7])[CH3:2].Cl.C([O-])(O)=O.[Na+]>CCO>[CH2:1]([NH:3][C:4]([N:21]1[CH2:25][CH:24]([CH2:26][CH3:27])[CH:23]=[N:22]1)=[N:5][S:6]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH2:13][CH2:12]2)(=[O:7])=[O:8])[CH3:2]
Reactant: CCNC(=NS(=O)(=O)c1ccc2c(c1)CCN2C(C)=O)N1CC(CC)C=N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCNC(=NS(=O)(=O)c1ccc2c(c1)CCN2)N1CC(CC)C=N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 42.5 %

Procedure:
1.74 g 1-acetyl-2,3-dihydro-1H-indole-5-sulfonic acid ethylamino-(4-ethyl-4,5-dihydro-pyrazol-1-yl)-methyleneamide was dissolved in 100 mL EtOH, and 22.2 mL of 1M HCl was added. The mixture was stirred for 5 h. under reflux. After cooling to room temperature, the mixture was basified with a 5% NaHCO3 solution and extracted twice with DCM. The combined organic layers were dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (DCM→DCM/EA 4:1) to give 0.66 g (43%) of 2,3-Dihydro-1H-indole-5-sulfonic acid ethylamino-(4-ethyl-4,5-dihydro-pyrazol-1-yl)-methyleneamide as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 0.97 (t, J=7.52 Hz, 3H), 1.15 (t, J=7.22 Hz, 3H), 1.44-1.68 (m, 2H), 2.97-3.13 (m, 3H), 3.42-3.54 (m, 2H), 3.58-3.72 (m, 3H), 3.99-4.09 (m, 1H), 6.55 (d, J=8.13 Hz, 1H), 6.88 (d, J=1.50 Hz, 1H), 7.00 (br.s., 1H), 7.55-7.65 (m, 2H) [NH invisible].
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([NH:9][C:10]([C:12]2[CH:36]=[CH:35][N:15]3[C:16](=[O:34])[C:17]([C:20]4[N:21]=[N:22][N:23](CC5C=CC(OC)=CC=5)[N:24]=4)=[CH:18][N:19]=[C:14]3[CH:13]=2)=[O:11])[S:7][CH:8]=1)([CH3:3])[CH3:2]>FC(F)(F)C(O)=O>[CH:1]([C:4]1[N:5]=[C:6]([NH:9][C:10]([C:12]2[CH:36]=[CH:35][N:15]3[C:16](=[O:34])[C:17]([C:20]4[N:21]=[N:22][NH:23][N:24]=4)=[CH:18][N:19]=[C:14]3[CH:13]=2)=[O:11])[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(Cn2nnc(-c3cnc4cc(C(=O)Nc5nc(C(C)C)cs5)ccn4c3=O)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1csc(NC(=O)c2ccn3c(=O)c(-c4nn[nH]n4)cnc3c2)n1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
N8-(4-Isopropyl-1,3-thiazol-2-yl)-3-[2-(4-methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-8-carboxamide (330 mg, 0.66 mmol) was added with trifluoroacetic acid (10 ml) at room temperature and stirred for 3 days. The reaction solution was poured into ice water, and the deposited yellow crystals were collected by filtration, washed with water, then dissolved in chloroform and ethanol, and concentrated under reduced pressure. The resulting yellow crystals were suspended in a small amount of ethanol, and the crystals were taken by filtration and washed with diethyl ether to obtain 54 mg (21% for the two steps) of the title compound as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:26])[CH:3]=1.[CH3:27][C@@H:28]1[CH2:32][O:31][C:30](=[O:33])[NH:29]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:29]5[C@H:28]([CH3:27])[CH2:32][O:31][C:30]5=[O:33])=[CH:3][C:4]=4[CH3:26])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cc(N2C(=O)OC[C@H]2C)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Yield: 41.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methylphenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (347 mg) described in Preparation Example 130 and (R)-4-methyloxazolidin-2-one (127 mg) described in Preparation Example 25, the title compound (152 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:44])=[N:14][C:15]([CH3:43])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:44])=[N:14][C:15]([CH3:43])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCCCc3ccc(F)cc3)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCCCc2ccc(F)cc2)cc1
Yield: 86.3 %

Procedure:
A mixture of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(3-(4-fluorophenyl)propoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.031 g, 0.051 mmol) and LiOH (0.012 g, 0.513 mmol) in 9:1 EtOH/H2O (2 mL) was refluxed for 4 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(3-(4-fluorophenyl)propoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid (0.0254 g, 0.044 mmol, 86% yield) as solid. 1H NMR (500 MHz, CDCl3) δ 7.18-7.22 (m, 2H), 7.13-7.17 (m, 1H), 7.04-7.08 (m, 1H), 6.95-7.03 (m, 4H), 5.95 (br. s., 1H), 3.98-4.07 (m, 2H), 3.43-3.78 (m, 1H), 2.87-3.06 (m, 1H), 2.84 (t, J=7.7 Hz, 2H), 2.67 (s, 3H), 2.36 (br. s., 1H), 2.24 (s, 3H), 2.10-2.18 (m, 2H), 1.93-2.09 (m, 1H), 1.48-1.68 (m, 1H), 1.28-1.40 (m, 2H), 1.25 (s, 9H), 1.10-1.22 (m, 1H), 0.88 (br.s., 3H), 0.69 (br.s., 3H). LCMS (M+H)=577.3.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(OC1C=NC(C2C=CC([O:42][CH2:43][CH2:44][CH2:45][O:46][CH2:47][C:48]([O:51][C:52]([F:62])([F:61])[C:53]([F:60])([F:59])[O:54][C:55]([F:58])([F:57])[F:56])([F:50])[F:49])=CC=2)=NC=1)CCCCC>>[CH2:1]([O:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:42][CH2:43][CH2:44][CH2:45][O:46][CH2:47][C:48]([O:51][C:52]([F:61])([F:62])[C:53]([F:59])([F:60])[O:54][C:55]([F:57])([F:58])[F:56])([F:50])[F:49])=[C:18]([F:22])[CH:17]=2)=[N:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Reactant: CCCCCCCCOc1cnc(-c2cccc(F)c2)nc1
Product: CCCCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)c(F)c2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyloxy-2-(3-fluorophenyl)pyrimidine (2.0 g, 6.3 mmol) with 3-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)propoxy chloride (2.5 g, 7.0 mmol, Example 17). The reaction mixture was quenched with water, and the resulting crude product was further purified by recrystallization from ethanol, followed by Kugelrohr distillation (210-18° C. at 0.15 torr), to provide a yield of 3.2 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH:15]=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CC(=CC)C.O.P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].[Si](C=[N+]=[N-])(C)(C)C.[O:40]1CCC[CH2:41]1>O.CCOC(C)=O.CC(O)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:40][CH3:41])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Reactant: C1CCOC1
Agent: CC=C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: O=P([O-])(O)O
Solvent: O
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: COc1ccc([C@H]2CC[C@H](C(=O)OC)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trans-4-(4-methoxyphenyl)cyclohexanecarbaldehyde (774 mg, 3.55 mmol) was dissolved in tetrahydrofuran (7.2 ml) and t-BuOH (18 ml) was added followed by 2-methyl-2-butene (7.2 ml, 68.0 mmol). To this solution was added sodium dihydrogen phosphate, hydrate (1072 mg, 7.80 mmol) as a solution in water (4.1 mL). Finally, sodium chlorite (882 mg, 7.80 mmol) was added as a solution in water (4.1 mL). The reaction was stirred at room temperature for 2 hours and then diluted with EtOAc (100 mL) and washed with water (25 mL) and brine (25 mL). The aqueous washes were combined, acidified with 1N HCl and extracted with EtOAc (50 mL). The two EtOAc extracts (before and after acidification) were combined, dried over Na2SO4, filtered, and concentrated. The residue was taken up in toluene (20 ml) and MeOH (3 ml). TMS-diazomethane (2.82 ml, 5.64 mmol) was added dropwise. Evolution of gas was observed, and a yellow color persisted. After 45 minutes, the reaction was quenched with HOAc, diluted with EtOAc (75 mL), and washed with saturated NaHCO3 and brine (20 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 0 to 40% EtOAc/hexanes afforded methyl trans-4-(4-methoxyphenyl)cyclohexanecarboxylate. 1H NMR (CDCl3, 500 MHz) δ 7.12 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.5 Hz, 2H), 3.79 (s, 3H), 3.69 (s, 3H), 2.47 (m 1H), 2.35 (m, 1H), 1.92-2.12 (m, 4H), 1.53-1.63 (m, 2H), 1.40-1.49 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:40]1[CH2:45][CH2:44][CH:43]([C:46]2[CH:53]=[CH:52][C:49]([C:50]#[N:51])=[CH:48][CH:47]=2)[CH2:42][CH2:41]1>CN(C)C=O.CCN(C(C)C)C(C)C>[CH2:1]([C:3]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=[O:14])=[CH:8][C:4]=1[C:5]([N:40]1[CH2:45][CH2:44][CH:43]([C:46]2[CH:53]=[CH:52][C:49]([C:50]#[N:51])=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)=[O:7])[CH3:2]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: CCc1cc(C)c(C=O)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C)c(C=O)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a round-bottom flask was added a solution of 2-ethyl-5-formyl-4-methylbenzoic acid (compound 211.4, 450 mg, 2.34 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL). DIEA (907 mg, 7.02 mmol, 3.00 equiv) and HBTU (1.30 g, 3.43 mmol, 1.50 equiv) were added to the reaction mixture. The resulting solution was stirred for 30 min at 25° C. A solution of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 624 mg, 2.80 mmol, 1.20 equiv) in DIEA (2 mL) was added dropwise. The resulting solution was stirred for 30 min at 25° C., then quenched with 20 mL of water. The aqueous phase was extracted with 3×30 mL of ethyl acetate. The combined organic layers were washed with 1×50 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (5:1) as eluent to furnish 720 mg (85%) of the title compound as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[CH2:39][C:40](O)=[O:41])=[CH:29][CH:28]=4)=[O:26])[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.CNC.[CH2:46]([NH:48][CH2:49][CH3:50])[CH3:47]>>[CH2:46]([N:48]([CH2:49][CH3:50])[C:40](=[O:41])[CH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:30]1[CH:31]=[CH:32][C:27]([C:25]([N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][N:20]3[C:11]([C:9]([NH:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:10])=[CH:12][CH:13]=[C:14]3[CH2:15]2)=[O:26])=[CH:28][CH:29]=1)[CH3:47]
Reactant: O=C(O)Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Reactant: CCNCC
Agent: CNC
Product: CCN(CC)C(=O)Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Yield: 60 %

Procedure:
The title compound was prepared in essentially the same manner as Example 68, replacing 4′-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1′-biphenyl-2-carboxylic acid with (4′-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1′-biphenyl-2-yl)acetic acid of Example 35, and dimethylamine with diethylamine. Purification by flash chromatography using a solvent gradient of 1 to 4% methanol in dichloromethane gave the title compound (0.158 g, 60%) as an off-white solid.
Reaction SMILES: C([N:8]1[C@@H:13]2[C:14](=[O:16])[CH2:15][C@@:9]1([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@H:10]([O:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1>[Pd]>[F:28][C:25]([F:26])([F:27])[C:23]1[CH:24]=[C:19]([CH2:18][O:17][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:15][C:14]3=[O:16])[CH:20]=[C:21]([C:29]([F:30])([F:31])[F:32])[CH:22]=1
Reactant: O=C1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Product: O=C1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of (1R*,2R*,5S*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6-one (Example 41; 53 mg 0.1 mmol), 5% palladium on charcoal (230 mg, 0.11 mmol) ethanol (10 ml) was stirred under hydrogen atmosphere (1 atm) at room temperature for 45 minutes. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound. The hydrochloride salt of the title compound was prepared by treatment with ethereal HCl and recrystallised from dichloromethane:diethyl ether.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])=[CH:20][C:21]([CH2:24][O:25][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:22][CH:23]=2)=[C:14]([C:53]([O:55][CH2:56][O:57][CH3:58])=[O:54])[CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(NC1C=C(C(O)=O)C(O)=CC=1)=O)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:43]([O:45][CH2:46][C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[O:44])=[CH:20][C:21]([CH2:24][OH:25])=[CH:22][CH:23]=2)=[C:14]([C:53]([O:55][CH2:56][O:57][CH3:58])=[O:54])[CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOC(=O)c1cc(NC(=O)OCc2ccccc2)ccc1-c1ccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(Nc1ccc(O)c(C(=O)O)c1)OCc1ccccc1
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COCOC(=O)c1cc(NC(=O)OCc2ccccc2)ccc1-c1ccc(CO)cc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
To a solution of benzyl 4′-benzyloxycarbonylamino-2′-methoxymethyloxycarbonyl-4-t-butyidiphenylsilyloxymethyl-2-biphenyl carboxylate (777 mg) which was prepared by the same procedure as a series of reaction of Reference Example 6→Reference Example 1 (without an esterfication of benzyl)→Reference Example 4→Reference Example 5→Reference Example 7, using 5-benzyloxycarbonylaminosalicylic acid; in anhydrous tetrahydrofuran (10 ml), a solution of 1.0 M tetrabutylammonium fluoride in anhydrous tetrahydrofuran (1.0 ml) was added. The mixture was stirred for 2 hours at room temperature. Water (100 ml) was added to the reaction mixture, the solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:3) to give the title compound (370 mg) having the following physical data.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C:21](OC)=[O:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][OH:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
To a solution of (2S,4R)-4-(tert-butyldimethylsilyloxy)-1-(tert-butoxycarbonyl)-2-methoxycarbonylpyrrolidine (56 g) in tetrahydrofuran (400 ml) was added slowly lithium aluminum hydride (6 g) at 0° C. After stirring for 30 minutes, to the reaction mixture were added dropwise water (6 ml), 4N-aqueous sodium hydroxide (6 ml) and water (18 ml). The precipitate was filtered off, and the solvent was removed in vacuo to give (2S,4R)-4-(tert-butyldimethylsilyloxy)-1-(tert-butoxycarbonyl)-2-hydroxymethylpyrrolidine (44.15 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]C)[C:5]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:15]2)=[O:11])=[CH:4][C:3]=1I.CC1NC=CN=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:10]([NH:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CCCCN1CCC(CNC(=O)c2cc(I)c(N)nc2OC)CC1
Agent: [Cu]
Agent: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Product: CCCCN1CCC(CNC(=O)c2ccc(N)[nH]c2=O)CC1
Temperature: 160 °C
Yield: 45.7 %

Procedure:
A mixture of 6-amino-N-[(1-butyl-4-piperidinyl)methyl]-5-iodo-2-(methyloxy)-3-pyridinecarboxamide (step 3, 112 mg, 0.25 mmol), 2-methylimidazole (420 mg, 5 mmol), copper powder (32 mg, 0.5 mmol) and potassium carbonate (69 mg, 0.5 mmol) was heated at 140° C. for 25 min, 150° C. for 30 min and 160° C. for 45 min. After cooling, the mixture was chromatographed on a column of silica gel eluting with 25% ammonium hydroxide/methanol/dichloromethane (1:10:90) to give 35 mg (46%) of the title compound as a pale yellow solid.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)#[N:13].C([O-])([O-])=O.[K+].[K+]>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>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:18]3[CH:19]=[C:14]([CH:15]=[CH:16][CH:17]=3)[C:12]#[N:13])=[CH:3][N:4]=2)[N:7]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: N#Cc1cccc(B(O)O)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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cccc(-c2cnc3ccc(Cl)nn23)c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 54.8 %

Procedure:
To a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (2 g, 8.6 mmol) and 3-(cyano)phenylboronic acid (1.26 g, 8.6 mmol) in dioxane/H2O (100 mL, 4:1) was added K2CO3 (2.38 g, 17.2 mmol) and Pd(PPh3)4 (0.19 g, 0.172 mmol), the mixture was stirred at 110° C. for 3 h. The solution was concentrated and partitioned in EtOAc/H2O. The aqueous layer was washed with EtOAc (50 mL) 3 times. The collected organic layers were dried over Na2SO4, concentrated and purified by column chromatography to give compound 3-(6-chloroimidazo[1,2-b]pyridazin-3-yl)benzonitrile (1.2 g, 4.71 mmol, yield 55%) as a brown solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[C:10]([CH:35]=[C:36]([Br:39])[C:37]=1[OH:38])[CH2:11][C@H:12]([C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:25][CH2:24]1)=O)[NH:13][C:14](OC(C)(C)C)=O.[Cl-].[NH4+]>O1CCCC1>[Br:7][C:8]1[CH:9]=[C:10]([CH2:11][C@@H:12]([NH:13][CH3:14])[CH2:21][N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:25][CH2:24]2)[CH:35]=[C:36]([Br:39])[C:37]=1[OH:38]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cc(Br)c(O)c(Br)c1)C(=O)N1CCC(N2CCCCC2)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CN[C@H](Cc1cc(Br)c(O)c(Br)c1)CN1CCC(N2CCCCC2)CC1

Procedure:
To a suspension of 2.3 g (60 mmol) lithium aluminium hydride in 100 ml anhydrous tetrahydrofuran, a solution of 11.0 g (18.66 mmol) 1-[3,5-dibromo-N-(1,1-dimethylethoxycarbonyl)-D-tyrosyl]-4-(1-piperidinyl)piperidine in 100 ml anhydrous tetrahydrofuran was added dropwise at room temperature whilst being stirred. It was stirred for a further 15 minutes at room temperature and then refluxed for 3 hours. 3 ml 20% aqueous ammonium chloride solution was added to the cooled mixture, then it was dried with magnesium sulphate. The filter cake was filtered and washed with 300 ml of an ethyl ethanoate-methanol mixture (1/1 v/v), and the combined filtrates were evaporated in a vacuum. The residue was purified by column chromatography over silica gel using ethyl ethanoate/methanol (8/2 v/v) for elution.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[C:14]([O:16]C)=O)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:16])[C@@H:10]3[C@H:9]2[CH2:13][CH2:12][CH2:11]3)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1Nc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1[C@H]2CCC[C@H]2N1c1ccc(F)cc1
Reaction time: 1.5 h

Procedure:
A 500-mL, three-necked, round-bottomed flask was charged with cis-methyl 2-((4-fluorophenyl)amino)cyclopentanecarboxylate (racemic cis-17A′) (15.77 g, 66.5 mmol) and 75 mL of THF. The reaction mixture was cooled at 5° C. while a 1M solution of LiHMDS (73.1 mL, 73.1 mmol) was added dropwise via syringe over 10 min. The resulting reaction mixture was stirred at 5° C. to 15° C. for 1.5 h. The reaction mixture was then quenched into 200 mL of aqueous ammonium chloride and 250 mL of ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated to give 14 g of cis-6-(4-fluorophenyl)-6-azabicyclo[3.2.0]heptan-7-one (racemic 17DP) as an orange oil.
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].C(N(CC)C(C)C)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[C:2]1([CH:8]2[CH2:9][CH2:10][N:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[C:22](=[O:31])[C:23]4[C:24](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]3=[O:26])[CH2:12][CH2:13]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Reactant: c1ccc(C2CCNCC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1CCCCCCN1CCC(c2ccccc2)CC1
Temperature: 100 °C
Reaction time: 72 h
Yield: 78.6 %

Procedure:
To the 500 ml RB-flask was added 4-phenylpiperidine hydrochloride (5 g, 25 mmol), N-(6-bromohexyl)phthalimide (15.5 g, 50 mmol), N,N-diisopropylethylamine (21.8 ml, 125 mmol), tetrabutylammonium iodide (0.2 g), and dioxane (250 ml) at room temperature. The reaction mixture was stirred at 100° C. for 72 h. The solvent was removed in vacuo and the crude product was purified by flash chromatography (98:2=Chloroform:2N ammonia in methanol) to afford 7.67 g of the desired product (77% yield): 1H NMR (400 MHz, CDCl3) δ 7.78-7.79 (m, 2H), 7.74-7.65 (m, 2H), 7.32-7.14 (m, 5H), 3.69 (t, 2H, J=7.35 Hz), 3.06 (d, 2H, J=11.0 Hz), 2.49 (quintet, 1H, J=7.6 Hz), 2.36 (t, 2H, J=7.6 Hz), 2.02 (t, 2H, J=12.5 Hz), 1.82 (br s, 4H), 1.69 (t, 2H, J=6.3 Hz), 1.54 (br s, 2H), 1.37 (br s, 4H); ESMS m/e: 391.3 (M+H)+; Anal. Calc. for C25H30N2O2+0.2H2O: C, 76.19; H, 7.77; N, 7.11. Found: C, 76.14; H, 7.38; N, 7.13.