Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O-])(=O)(=O)C.[N:6]1[C:15]2[CH:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH3:32][C:33]#[N:34]>CCN(C(C)C)C(C)C>[N:34]1[C:13]([CH2:14][N:16]([CH:14]2[C:15]3[N:6]=[CH:7][CH:8]=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]2)[CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])=[CH:12][CH:11]=[CH:32][C:33]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:15][N:6]=1
Reactant: CC#N
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Agent: CS(=O)(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Product: NCCCCN(Cc1cccc(-c2ccccn2)n1)C1CCCc2cccnc21

Procedure:
Using the general alkylation procedure A: Reaction of the mesylate from above and 2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione in dry CH3CN and DIPEA gave the desired amine as a yellow oil. Deprotection with hydrazine following General Procedure E gave compound 361 as a colorless oil. 1H NMR (CDCl3) δ 1.42-1.58 (m, 4H), 1.63-1.72 (m, 1H), 1.86-2.04 (m, 2H), 2.14-2.19 (m, 1H), 2.08-2.19 (m, 2H), 2.60 (t, 2H, J=6.9 Hz), 2.65-2.90 (m, 4H), 3.83 (d, 1H, J=15.6 Hz), 3.99 (d, 1H, J=13.2 Hz), 4.18 (dd, 1H, J=9, 6 Hz), 7.03 (dd, 1H, J=7.8, 4.8 Hz), 7.25-7.33 (m, 2H), 7.74-7.82 (m, 3H), 8.15 (d, 1H, J=8.1 Hz), 8.34 (d, 1H, J=8.1 Hz), 8.51 (d, 1H, J=3.6 Hz), 8.66 (d, 1H, J=3.6 Hz); 13C NMR (CDCl3) δ 21.83, 26.64, 26.79, 29.72, 31.82, 42.40, 53.27, 58.48, 61.50, 119.30, 121.54, 121.86, 123.30, 123.82, 134.59, 136.81, 137.24, 137.52, 147.58, 149.56, 155.27, 156.91, 158.64, 162.20. ES-MS m/z 388 (M+H). Anal. Calcd. for C24H29N5.1.3CH2Cl2: C, 61.03; H, 6.40; N, 14.06. Found: C, 61.25; H, 6.36; N, 13.98.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][CH2:12][CH2:13][NH2:14]>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:10][O:11][CH2:12][CH2:13][NH:14][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCCN
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COCCNc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 17.2 %

Procedure:
To phenylboronic acid (5 g, 41.0 mmol) in DCM (50 mL) was added copper (II) acetate (0.78 g, 4.1 mmol) and the mixture was stirred for 5 min at room temperature. 2-Methoxyethanamine (3.08 g, 41.0 mmol) was added and the mixture was stirred at 40 C for 19 h. The mixture was then passed through a silica plug and then purified by FCC, eluting with 10% EtOAc in heptane to afford the title compound (1.065 g, 17% yield). Method B HPLC-MS: MH+ requires m/z=152 Found: m/z=152, Rt=1.08 min (87%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12]O)=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)([O-:3])=[O:2].CCN(S(F)(F)[F:24])CC>C(Cl)Cl>[F:24][CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:14]([F:17])([F:16])[F:15]
Reactant: O=[N+]([O-])c1ccc(CCCO)c(C(F)(F)F)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCCF)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
3-(4-Nitro-2-(trifluoromethyl)phenyl)propan-1-ol (450 mg, 1.8 mmol) was dissolved in DCM (10 mL), and DAST (0.4 mL, 3.03 mmol) was added thereto under ice-cooling. The mixture was stirred at 0° C. for 1 hour. The reaction solution was quenched with a saturated sodium bicarbonate solution. The organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (n-hexane:ethyl acetate=9:1) to give 1-(3-fluoropropyl)-4-nitro-2-(trifluoromethyl)benzene (300 mg, 66%) as a light-yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][C:5]=2[CH:4]=[C:3]1[C:18]([O:20]CC)=[O:19].[OH-].[Na+]>CCO>[C:14]([O:13][C:11]([N:7]1[CH2:8][CH2:9][C:10]2[N:2]([CH3:1])[C:3]([C:18]([OH:20])=[O:19])=[CH:4][C:5]=2[CH2:6]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOC(=O)c1cc2c(n1C)CCN(C(=O)OC(C)(C)C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(C(=O)O)cc2c1CCN(C(=O)OC(C)(C)C)C2

Procedure:
To the solution 5-tert-butyl 2-ethyl 1-methyl-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-2,5-dicarboxylate (1.0 eq) in EtOH was added NaOH (1.05 eq.) and refluxed for 6 hrs. Reaction mixture was concentrated under reduced pressure and neutralized to get desired compound 5-(tert-butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[O-]CC.[Na+].[Na].[CH3:22][C@@H:23]1[O:25][C@H:24]1[CH3:26]>C(O)C>[CH3:13][C:12]([C:7]1[CH:8]=[C:9]([S:11][CH:23]([CH3:22])[CH:24]([OH:25])[CH3:26])[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[OH:16])([CH3:15])[CH3:14]
Reactant: C[C@@H]1O[C@H]1C
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CC(O)C(C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
2,6-bis(1,1-Dimethylethyl)-4-mercaptophenol (18.2 g, 0.076 mole) was added to a solution of sodium ethoxide freshly prepared from sodium (3.5 g, 0.15 mole) in ethyl alcohol (100 ml) and stirred for 1 hour. After cooling to 5° C. with an ice bath, trans-2,3-epoxybutane (5.0 g, 0.069 mole) was added and the ice bath removed. After stirring for 5.5 hours the reaction mixture was poured into ten percent hydrochloric acid (50 ml). The ethyl alcohol was removed using a rotary evaporator and the aqueous residue extracted with ethyl acetate (2X75 ml). The extracts were combined, dried over sodium sulfate, filtered, and concentrated to an orange oil. The product was purified by chromatography on silica to give a yellow solid which was recrystallized from hexane to give a white solid, m.p. ca. 73° C.
Reaction SMILES: [Br:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:7][N:6]1[CH3:26].[Cl:27]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.N.ClCCl>FC(F)(F)C(O)=O>[Br:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[C:13]([Cl:27])[CH:14]=2)[CH2:9][C@H:8]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:7][N:6]1[CH3:26]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(Br)c(c34)C[C@H]2N(C)C1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Cl)cc4[nH]c(Br)c(c34)C[C@H]2N(C)C1
Reaction time: 0.25 h

Procedure:
2.1 g of 3-(2-bromo-6-methyl-8alpha-ergolinyl)-1,1-diethylurea (5 mmol) and 388 mg of trichloroisocyanuric acid (1.67 mmol) are dissolved in 100 ml of trifluoroacetic acid at room temperature. After 15 minutes, ice is added, it is made alkaline with conc. ammonia and shaken out with dichloromethane. The organic phases are dried and concentrated by evaporation, the residue is chromatographed and the product crystallizes from ethyl acetate/ether, yield 480 mg (21% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>>[CH2:16]([N:18]([CH2:19][CH3:20])[C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:15])[CH3:17]
Reactant: CCNCC
Reactant: O=C(O)c1cnoc1-c1ccc(F)cc1
Product: CCN(CC)C(=O)c1cnoc1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 5-(4-fluorophenyl)isoxazole-4-carboxylic acid (10.4 mg, 0.050 mmol) and diethylamine (4.4 mg, 0.060 mmol) as described in synthetic method A and thereafter purified by preparative HPLC method A to give a solid (11.4 mg). MS (pos) m/z 263.1 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[S:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.FC(F)(F)C(O)=O>[N+](C)([O-])=O>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: c1ccsc1
Reactant: O=C(O)c1cccs1
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Product: O=C(c1cccs1)c1cccs1
Reaction time: 14 h
Yield: 41.6 %

Procedure:
To a mixture of 12.7 g (0.099 mol) of 2-thienylcarboxylic acid, 8.33 g (0.099 mol) of thiophene, and 34.9 ml of Amberlyst-15 in 250 ml of nitromethane was added 34.9 ml (0.247 mol) of trifluoroacetic acid at room temperature and stirred for 14 h. The reaction mixture was filtered, the filtrate was concentrated in vacuo, and a green oil residue was chromatographed on silica (hexane/methylene chloride 1:1) to afford 8 g (41.6%) of di-(2-thienyl)ketone, as white needles.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:27]1([NH:30][C:31]([CH:33]2[O:38][CH2:37][CH2:36][NH:35][CH2:34]2)=[O:32])[CH2:29][CH2:28]1.CCN(C(C)C)C(C)C>ClCCCl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:35]3[CH2:36][CH2:37][O:38][CH:33]([C:31]([NH:30][CH:27]4[CH2:28][CH2:29]4)=[O:32])[CH2:34]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(NC1CC1)C1CNCCO1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCOC(C(=O)NC4CC4)C3)ccc2n1CC1CCC(F)(F)CC1
Reaction time: 1 h

Procedure:
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (0.95 g, 2.35 mmol) was added to a solution of N-cyclopropylmorpholine-2-carboxamide (0.8 g, 2.6 mmol) (see following steps B and C for preparation) and DIPEA (0.82 mL, 4.7 mmol) in DCE (80 mL) at 80° C. The reaction mixture was stirred for 1 h and the solvent was concentrated. The product was purified by MPLC on silica gel using 60-90% EtOAc/Heptane to provide the title compound as white solid. Yield: 1.1 g (71%); 1H NMR (400 MHz, CDCl3) δ 0.39-0.54 (m, 2 H), 0.69-0.80 (m, 2 H), 1.49-1.69 (m, 3 H), 1.72 (s, 9 H), 1.75-1.86 (m, 3 H), 2.09 (t, J=10.84 Hz, 1 H), 2.2 (m, 3 H), 2.38-2.50 (m, 1 H), 2.61-2.71 (m, 1 H), 3.56 (d, J=11.91 Hz, 1 H), 3.67 (td, J=11.52, 1.95 Hz, 1 H), 3.91-4.06 (m, 3 H), 4.44 (d, J=7.03 Hz, 2 H), 6.58 (d, J=3.12 Hz, 1 H), 7.63-7.73 (m, 2 H), 8.04 (s, 1 H); MS (ESI) (M+H)+=538.8; Anal. Calcd for C26H36F2N4O4S+2.2 TFA: C, 46.25; H, 4.88; N, 7.10. Found: C, 46.26; H, 5.00; N, 6.95.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C([N-]C(C)C)(C)C.[Li+]>C1COCC1.C(O)(=O)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][N:3]=[C:2]([NH:26][C:25]3[CH:24]=[CH:23][C:22]([N:19]4[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]4)=[CH:28][CH:27]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14])[CH3:13]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCn1c(=O)ccc2cnc(F)cc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCn1c(=O)ccc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)cc21
Reaction time: 8 h
Yield: 44 %

Procedure:
A stirred solution of (XV, where R2 is ethyl) (100 mg, 0.52 mmol), 4-(4-methyl-1-piperazinyl)aniline (0.26 g, 1.12 mmol) in THF (5.0 mL) under nitrogen at -78° C. was treated was treated with a solution (0.8 mL, 1.2 mmol) of lithium diisopropylamide (1.5 M in cyclohexane), then the temperature was allowed to rise slowly to 20° C. overnight. The resulting solution was treated with 3 drops of glacial acetic acid and concentrated to a dark residue that was purified by silica gel chromatography eluting with 90:9:1 EtOAc:MeOH:NH4OH. The product fractions were pooled and concentrated to a solid that was triturated in boiling hexanes. The solid was collected and crystallized to give 1-ethyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one (84 mg, 44%): mp (CH2Cl2 /hexanes) 188-189° C.
Reaction SMILES: O=[C:2]([CH3:13])[CH2:3][C:4]([O:6][CH:7]([CH3:12])[C:8]([F:11])([F:10])[F:9])=[O:5].C([O-])(=O)C.[NH4+:18].C(O)(=O)C>O>[NH2:18][C:2]([CH3:13])=[CH:3][C:4]([O:6][CH:7]([CH3:12])[C:8]([F:11])([F:10])[F:9])=[O:5]
Reactant: [NH4+]
Reactant: CC(=O)CC(=O)OC(C)C(F)(F)F
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: CC(N)=CC(=O)OC(C)C(F)(F)F
Temperature: 25 °C

Procedure:
2.4 g (12 mmol) of 2,2,2-trifluoro-1-methylethyl 3-oxobutanoate are heated with 1.8 g (24.6 mmol) of ammonium acetate and 0.6 g (11 mmol) of acetic acid with the addition of molecular sieves at 110° C. for 5 h. After cooling to room temperature, the reaction mixture is mixed with water and extracted with ethyl acetate. Washing of the organic phase with water and saturated sodium chloride solution is followed by drying over magnesium sulfate. After filtration, the solvent is removed in vacuo. The resulting crude product (1.5 g, 77% purity, 77% of theory) is employed without further purification in the next stage.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]1.Br[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1>>[CH3:17][O:16][C:14]([C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3][CH:2]2[O:1][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:13][CH:12]=1)=[O:15]
Reactant: BrCc1ccc2ccccc2c1
Reactant: COC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1

Procedure:
In an analogous manner to that described in Example 22(i), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(4-methoxycarbonyl-phenyl)-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-methoxycarbonyl-phenyl)-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate as a colourless oil; MS: 476 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[C:9]2[C:10](=[O:26])[NH:11][C:12]3([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH2:13][C:8]=2[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[ClH:27]>C(OCC)(=O)C.O1CCOCC1>[ClH:27].[C:1]([N:5]1[C:9]2[C:10](=[O:26])[NH:11][C:12]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:13][C:8]=2[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Cc1cnn(C(C)(C)C)c1C(=O)N2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)n1ncc2c1C(=O)NC1(CCNCC1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 1′-tert-butyl-7′-oxo-1′,4′,6′,7′-tetrahydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridine]-1-carboxylate (137 mg, 0.39 mmol) in ethyl acetate (4 mL) was added 4 N HCl in dioxane (2 mL). After stirring 1 hour at room temperature, the volatiles were removed under reduced pressure and the resultant colorless solid was triturated from heptane (10 mL) to yield 112 mg of the title compound as a colorless solid. +APCI (M+H) 263.3; 1H NMR (400 MHz, DMSO-d6, δ): 8.84 (m, 2H), 8.00 (s, 1H), 7.29 (s, 1H), 3.13 (d, J=6.1 Hz, 2H), 3.03 (br. s., 2H), 2.78 (s, 2H), 1.76 (m, 4H), 1.60 (s, 9H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:22])[NH:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C.C(O)C.[OH-].[K+].Cl>O>[C:16]1([C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7](=[O:22])[C:6]=2[C:4]([OH:5])=[O:3])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2ccccc2[nH]c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1c(-c2ccccc2)c2ccccc2[nH]c1=O
Yield: 93.1 %

Procedure:
A mixture of 1,2-dihydro-4-phenyl-2-oxo-3-quinoline carboxylic acid ethyl ester (5 g, 17 mmol), ethanol (20 ml), water (40 ml) and potassium hydroxide (5 g, 89 mmol) was refluxed with heat for 1.5 hours. To the reaction mixture was added 60 ml of 2N-HCl to acidify the mixture to obtain a precipitated crystal by filtration. The crystal obtained was recrystallized from ethanol to give 4.2 g (yield: 92.9%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:16][CH:15]=2)[N:10]=[CH:9][C:8]=1[CH2:28][C:29]([NH2:31])=[O:30].[N-:36]=[N+:37]=[N-:38].[Na+].CCCCCC>CN(C)C=O>[N:36]([CH2:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:11]2[N:10]=[CH:9][C:8]([CH2:28][C:29]([NH2:31])=[O:30])=[C:7]([NH:6][CH2:5][C:4]3[CH:32]=[C:33]([F:35])[CH:34]=[C:2]([F:1])[CH:3]=3)[CH:12]=2)=[CH:19][CH:18]=1)=[N+:37]=[N-:38]
Reactant: CS(=O)(=O)OCCCc1ccc(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCc1ccc(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
268 mg of 4-[(3,5-difluorobenzyl)amino]-6-{[4-(3-methanesulfonyloxypropyl)phenyl]amino}pyridine-3-carboxyamide (the compound of Example 199) was dissolved in 1.5 mL of N,N-dimethylformamide, to which 71 mg of sodium azide was added and stirred at 80° C. for 30 minutes. After cooling, hexane was added to the reaction mixture, and the deposit was filtered. The filtered product was dissolved in chloroform, washed with water and saturated saline, and dried on anhydrous sodium sulfate. By evaporating the solvent, 229 mg (94%) of the title compound was obtained as a slight yellow crystalline powder.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])C=C.[CH2:13]1[C@H:22]2[C@@H](CCCC2)CC[CH2:14]1>>[CH2:22]([C:6]1[C:5]([OH:4])=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])[CH:13]=[CH2:14]
Reactant: C=CCOc1cccc(C=O)c1
Reactant: C1CC[C@H]2CCCC[C@@H]2C1
Product: C=CCc1c(O)cccc1C=O
Temperature: 217 °C
Reaction time: 18 h

Procedure:
In a 500 ml three-necked Morton flask equipped with mechanical stirrer, thermometer and reflux condenser was added 100 g of 3-allyloxybenzaldehyde (0.62 moles, 1 eq.) and 150 g of cis/trans decalin (1.5 vol). The mixture was purged with nitrogen and then heated to a reflux temperature of 217° C. The reaction was maintained at this reflux temperature for seven hours then cooled and 231 mL of toluene was added. The reaction mixture was then allowed to cool to room temperature. After stirring for 18 hours and further cooling to 0-5° C., reaction mixture was filtered and the cake washed with 200 mL of heptane. The wet cake was stirred in 200 mL of heptane for 1-2 hours at room temperature. After filtration and drying of the cake at 40° C., 54.27 g of crude 2-allyl-3-hydroxybenzaldehyde were obtained. This represents a recovery of 82% of the available 2-allyl product produced by the Claisen rearrangement.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]([O:17]C)=[O:16])[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)Cc1ccnc(-c2ccnc(C)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2cc(CC(=O)O)ccn2)ccn1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 2-(2′-methyl-2,4′-bipyridin-4-yl)acetate 238-2 (621 mg, 2.56 mmol) and NaOH (409 mg, 10.24 mmol) in 1,4-dioxane (6 mL) and water (6 mL) was stirred at 80° C. for 3 hours. After cooled down to room temperature, the mixture was treated with 3N HCl aqueous solution to adjust the pH to around 4, and then stirred for 15 minutes. The resulting solution was evaporated to dryness and the remaining solid was extracted with 20% methanol in ethyl acetate. The organic extraction was concentrated to give 2-(2′-methyl-2,4′-bipyridin-4-yl)acetic acid 238-3 as pale white solid. MS m/z 229.1 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[C:8]2[CH2:9][C:10]3[S:14][C:13]([SH:15])=[N:12][C:11]=3[C:16]=2[CH:17]=[CH:18][CH:19]=1)C.[C:21]1([CH:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][CH2:29]I)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([CH:27]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:28][CH2:29][S:15][C:13]2[S:14][C:10]3[CH2:9][C:8]4[C:7]([O:6][CH2:5][C:4]([OH:3])=[O:20])=[CH:19][CH:18]=[CH:17][C:16]=4[C:11]=3[N:12]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)COc1cccc2c1Cc1sc(S)nc1-2
Reactant: ICCC(c1ccccc1)c1ccccc1
Product: O=C(O)COc1cccc2c1Cc1sc(SCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 34 %

Procedure:
Using ethyl[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and 3,3-diphenylpropyl iodide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 34%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][NH2:25].[OH:26][CH2:27][CH:28]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][N:25]=[CH:28][CH2:27][OH:26]
Reactant: O=CCO
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1
Product: CC1=C(CCON=CCO)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylsulfinylphenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with hydroxyacetaldehyde by the method of Example 1.
Reaction SMILES: N1C=CC=CC=1.[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:16][N:15]=2)=[CH:10][CH:9]=1.[C:31]([O:38][CH:39]([C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][CH:42]=1)[CH3:40])(=[O:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>O>[C:31]([O:38][CH:39]([C:41]1[CH:49]=[CH:48][C:44]([C:45]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:16][N:15]=3)=[CH:12][CH:13]=2)=[O:46])=[CH:43][CH:42]=1)[CH3:40])(=[O:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCC(=O)OC(C)c1ccc(C(=O)O)cc1
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCOc1cnc(-c2ccc(OC(=O)c3ccc(C(C)OC(=O)CCCCC)cc3)cc2)nc1
Yield: 96 %

Procedure:
Into 20 ml of pyridine were dissolved 1.97 g (6 millimoles) of 2-(4-hydroxyphenyl)-5-decyloxypyrimidine, and then 1.41 g (5 millimoles) of an acid chloride derived from (+)-4-(1-hexanoyloxyethyl)benzoic acid were added thereto, to subject to reaction at 30° to 40° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into 200 ml of water, adjusted to pH 3 to 4 with hydrochlolic acid, followed by extraction with 200 ml of toluene, and the organic phase was washed with water, 5% aqueous sodium hydrogen carbonate solution and water in this order and then the organic phase was dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent; toluene:ethyl acetate) to obtain 2.76 g (yield: 96%) of 4-(5-decyloxy-2-pyrimidyl)phenyl (+)-4-(1-hexanoyloxyethyl)benzoate.