Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([O:11][C:12](=[O:27])[NH:13][C:14]1[C:15]([CH3:26])=[N:16][O:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[CH3:10].[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:22]2[CH:23]=[CH:24][C:19]([C:18]3[O:17][N:16]=[C:15]([CH3:26])[C:14]=3[NH:13][C:12]([O:11][CH:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[CH3:10])=[O:27])=[CH:20][CH:21]=2)=[CH:35][CH:34]=1)[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1cccc(F)c1F
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3cccc(F)c3F)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(2,3-difluoro-phenyl)-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide (4′-{4-[1-(2,3-difluoro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 34, Step 2.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][CH3:8])=[C:4]([CH:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[OH:10])[CH:3]=1.O[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>O1CCCC1>[Br:1][C:2]1[S:6][C:5]([CH2:7][CH3:8])=[C:4]([CH:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[O:10][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)[CH:3]=1
Reactant: CCc1sc(Br)cc1C(O)C1CCCCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCc1sc(Br)cc1C(Oc1ccc(C(=O)OC)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.5 %

Procedure:
To a mixture of (5-bromo-2-ethylthiophen-3-yl)(cyclohexyl)methanol (1.50 g) synthesized above, methyl 4-hydroxybenzoate (904 mg), 1,1′-(azodicarbonyl)dipiperidine (2.50 g) and tetrahydrofuran (30 mL) was added tributylphosphine (2.47 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the precipitate was removed by filtration and washed with diisopropyl ether. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9, volume ratio) to give the title compound (1.20 g, 55%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:29]=[CH:30][N:31]=2)[C:15]([NH:17][NH:18]C(OCC2C=CC=CC=2)=O)=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>[Pd].O1CCCC1>[NH:17]([C:15]([C:14]1[CH:29]=[CH:30][N:31]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=1)=[O:16])[NH2:18]
Reactant: O=C(CCc1ccccc1)Nc1cc(C(=O)NNC(=O)OCc2ccccc2)ccn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: NNC(=O)c1ccnc(NC(=O)CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of benzyl 2-[2-[(3-phenylpropanoyl)amino]isonicotinoyl]hydrazinecarboxylate (1.10 g, 2.63 mmol), 10% palladium on carbon (50 mg), methanol (20 mL) and tetrahydrofuran (20 mL) was stirred under a hydrogen atmosphere at room temperature 18 hr. The reaction mixture was filtered, and the filtrate was concentrated to give the title compound (748 mg, yield 100%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:9][CH:10]=2)[NH:5][C:4](=[O:17])[CH:3]=1.[I-].[Na+].C(=O)([O-])O.[Na+].[ClH:25].[CH3:26][N:27]([CH3:30])[CH:28]=O>CO.CC(C)=O>[ClH:16].[ClH:25].[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][N:5]3[CH2:6][CH2:28][N:27]([C:30]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH2:26][CH2:4]3)=[CH:9][CH:10]=2)[NH:5][C:4](=[O:17])[CH:3]=1
Reactant: Cc1cc(=O)[nH]c2cc(OCCCCl)ccc12
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CO
Solvent: CC(C)=O
Product: Cc1cc(=O)[nH]c2cc(OCCCN3CCN(c4ccccc4)CC3)ccc12
Reaction time: 3 h
Yield: 80 %

Procedure:
2.7 Grams of 4-methyl-7-(3-chloropropoxy)carbostyril and 1.8 g of sodium iodide are mixed with 50 ml of acetone and heated for 3 hours under refluxing conditions. Then 50 ml of dimethylformamide is added thereto and acetone is removed by distillation under reduced pressure. Next, 1.5 g of triethylamine and 1.8 g of 4-phenylpiperazine are added thereto and stirred for 3 hours at 80°-90° C. and dimethylformamide is removed by distillation under reduced pressure. To the residue thus obtained is added 5% sodium hydrogencarbonate aqueous solution to effect crystallization of the product and the precipitates formed are collected by filtration, washed with water, washed with isopropanol, further washed with ether and dried. The crude crystals thus obtained are dispersed in 80 ml of methanol, and dissolved by adding 5 ml of concentrated hydrochloric acid, then concentrated under a reduced pressure to dryness. The thus obtained residue is recrystallized from methanol-ether to obtain 3.6 g (yield: 80%) of 4-methyl-7-[3-(4-phenylpiperazinyl)propoxy]carbostyril dihydrochloride in the form of colorless crystals with a melting point of 253°-254° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=O)[C:8](=[O:21])[N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][C:3]=1[C:23]([O:25][CH3:26])=[O:24].O=P(Cl)(Cl)[Cl:29]>>[Cl:29][C:7]1[C:8](=[O:21])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:10]2[C:5]([N:6]=1)=[CH:4][C:3]([C:23]([O:25][CH3:26])=[O:24])=[C:2]([F:1])[CH:11]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cc2[nH]c(=O)c(=O)n(Cc3ccc(OC)cc3)c2cc1F
Product: COC(=O)c1cc2nc(Cl)c(=O)n(Cc3ccc(OC)cc3)c2cc1F
Temperature: 130 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Methyl 7-fluoro-1-(4-methoxybenzyl)-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (35.0 g, 98 mmol) was added to POCl3 with stirring overnight at 130° C. and concentrated in vacuo. The product was precipitated via the addition of methanol (150 ml) and collected by filtration to afford methyl 3-chloro-7-fluoro-1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (25.0 g, 68%).
Reaction SMILES: C[O:2][C:3](=[O:46])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:40])[CH:23]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:18]([CH2:41][CH:42]2[CH2:44][CH2:43]2)[C:17]1=[O:45])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.CO.[Li+].[OH-].Cl>C1COCC1.O>[C:36]([O:35][C:33]([NH:32][CH:23]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:22]([N:19]1[CH2:20][CH2:21][N:16]([CH:4]([CH2:5][C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=2)[C:3]([OH:46])=[O:2])[C:17](=[O:45])[CH:18]1[CH2:41][CH:42]1[CH2:44][CH2:43]1)=[O:40])=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: COC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)OC(C)(C)C)C(CC2CC2)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(F)cc1)C(=O)N1CCN(C(Cc2ccc3ccccc3c2)C(=O)O)C(=O)C1CC1CC1
Reaction time: 4 h

Procedure:
To a solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester, 15, (531 mg, 0.842 mmol) in a mixture of THF (5 mL)/CH3OH (1 mL)/H2O (2 mL) is added LiOH (100 mg, 4.17 mmol). The reaction mixture is stirred for 4 hours, acidified with 1N HCl to pH 3 and extracted several times with EtOAc. The combined extracts are dried over Na2SO4, filtered, concentrated in vacuo and dried under high vacuum to give the free acid in quantitative yield, which is used directly without further purification. 1H NMR (300 MHz, CD3OD, Rotamers) δ 7.72–7.87 (m, 3H), 7.68 (s, 1H), 7.37–7.53 (m, 3H), 7.12–7.28 (m, 2H), 6.99–7.06 (m, 2H), 5.54–5.66 (m, 1H), 4.52–4.80 (m, 1.5H), 3.82–4.38 (m, 1.5H), 3.18–3.64 (m, 4H), 2.70–3.02 (m, 3H), 0.80–1.43 (m, 11H), −0.78–0.10 (m, 5H); 13C NMR (75 MHz, CD3OD, Rotamers) δ 171.68, 171.58, 170.23, 169.29, 167.86, 163.70, 156.08, 134.69, 134.57, 133.71, 133.14, 132.70, 131.26, 131.15, 130.73, 130.64, 128.19, 128.12, 127.55, 127.38, 127.29, 127.07, 126.12, 125.64, 79.61, 79.34, 58.68, 57.04, 56.18, 52.13, 51.65, 43.21, 42.29, 41.29, 38.61, 37.32, 37.21, 36.27, 34.23, 33.93, 27.50, 27.41, 6.45, 3.92, 3.66, 3.33; MS (ESMS) m/z 618.2 (M+H)+.
Reaction SMILES: [C:1](=[N:34]O)([C:8]1[CH:33]=[CH:32][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[N:30]O)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.N.[Ni]>[NH2:30][CH:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:8]([CH:1]([NH2:34])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:33][CH:32]=2)=[CH:18][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: [H][H]
Reactant: ON=C(c1ccccc1)c1ccc(OCCCOc2ccc(C(=NO)c3ccccc3)cc2)cc1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NC(c1ccccc1)c1ccc(OCCCOc2ccc(C(N)c3ccccc3)cc2)cc1

Procedure:
The dioxime from Step 2 (20 g) is dissolved in ethyl alcohol saturated with ammonia gas (220 ml) and Raney nickel W-6 (2 g) added. The mixture is subjected to 500 psi hydrogen pressure and heated at 90° for four hours. The catalyst is removed by filtration and the solvent is removed by distillation to yield 15.5 g (83% of theory) of pale yellow crystals mp 118°-9°.
Reaction SMILES: [CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C@H:32]12[C@H:38]([OH:39])[C@H:35]([CH2:36][CH2:37]1)[CH2:34][NH:33]2>>[CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([N:33]5[CH2:34][C@@H:35]6[C@@H:38]([OH:39])[C@H:32]5[CH2:37][CH2:36]6)=[O:24])=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27]([N:28]([CH3:30])[CH3:29])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O[C@@H]1[C@@H]2CC[C@H]1NC2
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4C[C@H]5CC[C@@H]4[C@@H]5O)cn3)nc2n1C1CCCCCC1
Yield: 77 %

Procedure:
Following general amide formation method 3, 6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid was combined with (1R,4R,7R)-2-azabicyclo[2.2.1]heptan-7-ol which gave 7-cycloheptyl-2-(5-((1R,4R,7R)-7-hydroxy-2-azabicyclo[2.2.1]heptane-2-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (50 mg) in 77% yield.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([OH:10])=[O:9].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:42]12[CH2:49][CH2:48][CH:45]([CH2:46][CH2:47]1)[C@@H:44](O)[CH2:43]2.C(Cl)Cl.CO.[NH4+].[OH-]>C1COCC1>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([O:10][C@@H:44]1[CH:45]2[CH2:48][CH2:49][N:42]([CH2:47][CH2:46]2)[CH2:43]1)=[O:9]
Reactant: C[C@@H]1CCCN1[C@@H](C(=O)O)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: C[C@@H]1CCCN1C(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.5 %

Procedure:
To a suspension of (R)-2-((R)-2-methylpyrrolidin-1-yl)-2-phenylacetic acid 22c (150 mg, 0.68 mmol) in dry THF (6.8 ml), were added DCC (282 mg, 1.37 mmol), HOBT (185 mg, 1.37 mmol) and (R)-quinuclidin-3-ol (174 mg, 1.37 mmol). The mixture was stirred at room temperature under nitrogen for 24 hours. The pale yellow suspension was filtered washing with THF (5 ml) and the yellow solution was evaporated. The crude was purified by flash chromatography (DCM/MeOH=95/5 to 9/1 and then with DCM/MeOH/NH4OH=95/5/0.2) to collect the title compound (48 mg, 21.4% yield) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[N+:12]([C:15]1C=CC=CC=1)([O-:14])=[O:13].CN>CO>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:15][N+:12]([O-:14])=[O:13])=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: CN
Solvent: CO
Product: CN(C)c1ccc(C=C[N+](=O)[O-])cc1
Reaction time: 72 h
Yield: 41.1 %

Procedure:
A mixture of 4-dimethylaminobenzaldehyde (1.5 g, 10 mmol) in 3 mL methanol, 0.61 g (10 mmol) nitrobenzene and 0.15 mL of 22% methylamine aqueous solution was stirred for 3 days. The dark red solid obtained after filtration was recrystallized from nitromethane and rinsed with cold methanol to yield 0.79 g (41.1%) of red crystals, mp 180.6-180.9° C. (ref mp 181° C. (see Richter-Egger, D. L. et al. J. Chem. Educ. 2001, 78, 1375-1378)). 1H NMR 3.08 (s, 6H, Ar—N(CH3)2); 6.68 (2H, d, JHH 8.7 Hz, Ar—H); 7.43 (2H, d, JHH 9.0 Hz, Ar—H); 7.50 (1H, d, JHH 13.2 Hz, Ar—CH); 7.97 (1H, d, JHH 13.5 Hz, CH—NO2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:21])[CH3:20])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]1.[CH3:22][C:23]([CH3:28])([CH3:27])[C:24](Cl)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:23]([C:28]1[N:8]([CH2:9][CH:10]2[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]2)[C:7]2[CH:6]=[CH:5][C:4]([NH:18][C:19](=[O:21])[CH3:20])=[CH:3][C:2]=2[N:1]=1)([CH3:27])([CH3:24])[CH3:22]
Reactant: CC(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c(N)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(3-Amino-4-{[(4,4-difluorocyclohexyl)methyl]amino}phenyl) acetamide (1.32 g, 4.44 mmol) was dissolved in 100 mL of DCM containing DMAP (108 mg, 0.89 mmol). Trimethylacetyl chloride (0.60 mL, 4.88 mmol) was added dropwise and the solution was stirred at rt for 2 h. The solution was washed with saturated aqueous NaHCO3 solution, saturated aqueous NaCl solution and dried over anhydrous Na2SO4. Part of the product precipitated during the washings and was filtered. The organic phase was evaporated and combined with the precipitate. The product was dissolved in 30 mL of AcOH and placed in 6 sealed tubes (5 mL/tube). Each tube was heated at 150° C. in a Personal Chemistry microwaves instrument for 2.5 h. The fractions were pooled and the solvent was evaporated. The product was dissolved in EtOAc and washed with aqueous NaHCO3 solution, saturated aqueous NaCl solution and dried over anhydrous Na2SO4. The product was purified by silica gel flash chromatography using 2:1/acetone:hexanes as eluent. Yield: 1.11 g (68%). 1H NMR (400 MHz, METHANOL-D4) δ 1.40-1.49 (m, 2 H), 1.52 (s, 9 H), 1.60-1.65 (m, 2 H), 1.67-1.77 (m, 1 H), 1.96-2.06 (m, 3 H), 2.11 (s, 3 H), 2.15-2.23 (m, 1 H), 4.28 (d, J=7.62 Hz, 2 H), 7.35-7.39 (m, 1 H), 7.40-7.44 (m, 1 H), 7.85 (d, J=1.76 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:13][CH:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccccc2)C1
Reaction time: 1 h
Yield: 110.5 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)-3-hydroxy-pyrrolidine (430 mg, 2.30 mmol) in N,N-dimethylformamide (3 ml) was added to a solution of sodium hydride (60% dispersion in mineral oil, 137 mg, 3.43 mmol) and the mixture was stirred for one hour. A solution of benzyl bromide (562 mg, 3.29 mmol) in N,N-dimethylformamide (1 ml) was added to the solution and the mixture was stirred overnight. Reaction was quenched with water and the reaction mixture was extracted with diethyl ether. The organic layer was washed with water and dried over sodium sulfate. Removal of solvent afforded crude 3-benzyloxy-1-(tert-butoxycarbonyl)-pyrrolidine (705 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[ClH:32]>O1CCOCC1.CCOCC>[ClH:32].[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
1,1-Dimethylethyl 4-({[4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)-1-piperidinecarboxylate (Example 1, 87 mg, 0.20 mmol) was dissolved in 1,4-dioxane (4 mL). Ether (3 mL) was added followed by addition of 4M HCl in 1,4-dioxane (3 mL) and 2M HCl in ether (3 mL). The reaction mixture was stirred at ambient temperature overnight. Ether (15 mL) was added, and the white solid was collected via filtration and washed with ether to yield 71 mg (95%) of 4-({[4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)piperidine hydrochloride as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.98 (d, 2H, J=8.5 Hz), 7.83 (d, 2H, J=8.3 Hz), 7.66 (d, 2H, J=8.8 Hz), 7.05 (d, 2H, J=8.8 Hz), 3.97 (d, 2H, J=5.8 Hz), 3.50-3.40 (m, 2H), 3.13 (s, 3H), 3.10-3.00 (m, 2H), 2.25-2.05 (m, 3H), 1.70-1.55 (m, 2H); LRMS (ESI), m/z 346 (M+H).
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][N:16]2[C:20]3[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[O:30][CH2:31][CH2:32][CH3:33])=[CH:11][CH:10]=1)#[N:2].C[Sn]([N:38]=[N+:39]=[N-:40])(C)C>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:17]1[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:40][N:39]=[N:38][N:2]=3)=[CH:14][CH:13]=2)[C:20]2[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1)[CH2:32][CH3:33]
Reactant: CCCOc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCCOc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-propoxybenzimidazole-7-carboxylate (0.69 g) and trimethyltin azide (0.7 g) in toluene (15 ml) was heated for 4 days under reflux. The reaction mixture was concentrated to dryness and to the mixture was added methanol (20 ml) and 1N-HCl (10 ml). After stirring at room temperature for 30 minutes, the mixture was adjusted to pH 3-4 with 1N NaOH. After removal of the solvent, the residue was extracted with chloroform-water. The organic layer was washed with water and dried, and the solvent was evaporated to dryness to give a syrup. The syrup was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals (0.31 g, 43%), m.p. 157°-159° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:23]=[CH:22][C:21]2[C:17](=[CH:18][N:19]([CH3:24])[N:20]=2)[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:24][N:19]1[CH:18]=[C:17]2[C:21]([CH:22]=[CH:23][C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])=[CH:16]2)=[N:20]1
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Cn1cc2cc(Br)ccc2n1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3nn(C)cc3c2)C1=O
Yield: 2.1 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 100 mg, 0.564 mmol) was reacted with 5-bromo-2-methyl-2H-indazole (120 mg, 0.5741 mmol), 1,4-dioxane (15 mL), copper iodide (10 mg, 0.056 mmol), trans-1,2-diamino cyclohexane (19 mg, 0.166 mmol) and potassium phosphate (360 mg, 1.698 mmol) to afford the crude product. Purification by preparative HPLC afforded 3.6 mg of the product (6.228% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[O:7].[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1C=CC=CC=1>[C:14]1([NH:20][C:21](=[O:22])[NH:1][C:2]2[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[O:7])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C=Cc1ccccc1N
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Product: COC(=O)C=Cc1ccccc1NC(=O)Nc1ccccc1
Reaction time: 12 h

Procedure:
Methyl 2-aminocinnamate (2) (6.35 g, 35.8 mmol) was dissolved in 150 ml of benzene and phenylisocyanate (5.12 g, 43.0 mmol) was slowly dropped thereto at a room temperature. The reaction mixture was stirred for 12 hours to obtain a solid precipitate. Then, the precipitate was washed with ether in order to obtain the title compound (3) in the form of a white crystal (10.2 g, 96%) (mp 184° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[C:14]([CH3:18])[CH:13]=[C:12]([CH3:19])[C:11]=2[C:10](=O)[CH2:9]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[C:14]([CH3:18])[CH:13]=[C:12]([CH3:19])[C:11]=2[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]1
Reactant: Cc1cc(C)c2c(n1)CC(c1ccccc1F)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2c(n1)CC(c1ccccc1F)CC2=NNC(=N)N
Yield: 74.4 %

Procedure:
A mixture of 7-(2-fluorophenyl)-2,4-dimethyl-5,6,7,8-tetrahydroquinolin-5-one (0.12 g), aminoguanidine hydrochloride (0.052 g), concentrated hydrochloric acid (0.067 ml), water (0.067 ml) and ethanol (10 ml) was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 7-(2-fluorophenyl)-5-guanidinoimino-2,4-dimethyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 85) (0.12 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[F:75][CH2:76][CH2:77][NH2:78]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:78][CH2:77][CH2:76][F:75])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: NCCF
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NCCF)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 2-fluoroethylamine hydrochloride (8.09 mg, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (11.1 mg, 33%). LC-MS m/z 619 (M+H)+.