Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[N:4]([NH2:19])[CH:3]=1.Cl.Cl[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:9]=2)[N:4]([NH:19][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:3]=1
Reactant: Clc1ccncc1
Reactant: Cc1cn(N)c2ccc(OCc3ccccc3)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cn(Nc2ccncc2)c2ccc(OCc3ccccc3)cc12
Temperature: 80 °C
Yield: 91.7 %

Procedure:
To a solution consisting of 3-methyl-5-(phenylmethoxy)-1H-indol-1-amine (6.31 g) and 1-methyl-2-pyrrolidinone (109 ml) was added 4-chloropyridine hydrochloride (3.94 g). The resulting mixture was heated at 80° C. for 4-5 hours. Another batch of reaction was also carried out with the amine (2.94 g) and 4-chloropyridine hydrochloride (1.84 g) in nmp (50 ml) at 80° C. for 4 hours. The above reaction mixtures were poured together into dilute aqueous sodium bicarbonate and extracted with EtOAc (4×) and ether (1×). The combined organic layers were washed with water and brine followed by drying (K2CO3). Filtration, concentration and purification via flash column chromatography (silica gel, 2% Et3N/ether/0-5% MeOH) afforded 7.55 g of the desired product. Recrystallization from EtOAc gave a solid, m.p. 167.5°-169.5° C.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:7][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[CH2:5]1>CO>[OH:3][CH:4]1[CH2:5][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(=O)C2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC(O)C2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.89 g (23.57 mmoles) of sodium borohydride is added in portions at 0° C. to a solution of 3.54 g (15.71 mmoles) of tert-butyl 2-oxo-6-aza-spiro[3.4]octane-6-carboxylate (WO 9806720) diluted in 40 ml of methanol. The reaction mixture is stirred for 1 hr and 30 mins at ambient temperature. After evaporation of the solvent, water is added to the reaction mixture, the aqueous phase is separated, it is extracted several times with diethyl ether, and the combined organic phases are washed with a saturated aqueous solution of sodium chloride, they are dried over sodium sulphate and the filtrate is concentrated under reduced pressure. After evaporation of the solvent, 3.10 g of product are obtained in the form of a brown oil used as such in the following stage.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH2:6][N:7]=[C:8]=[S:9].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][NH2:19].COC1C=C(C=CC=1)CNC(N)=S>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH2:6][NH:7][C:8]([NH:19][CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([O:14][CH3:13])[CH:16]=1)=[S:9]
Reactant: COc1cccc(CN)c1
Reactant: COc1cccc(CN=C=S)c1
Agent: COc1cccc(CNC(N)=S)c1
Solvent: CCO
Product: COc1cccc(CNC(=S)NCc2cccc(OC)c2)c1
Temperature: 40 °C

Procedure:
The reaction of 3-methoxybenzyl isothiocyanate with 3-methoxybenzyl amine in ethanol was repeated doubling the reaction volume and reactants and heating for 2 h at 40° C. Crystallization at −10° C., followed by evaporation of the supernatant to 20 ml and a second crystallization gave 98.4% of the theoretical yield for the two crystallizations combined. Calculated elemental analysis of 3-methoxybenzyl thiourea: C, 64.53; H, 6.37; N, 8.85; S, 10.13. Found: C, 64.30; H, 6.46; N, 8.85; S, 10.09.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:11][C@H:10]([N:12]3[CH2:16][CH2:15][CH2:14][C@H:13]3[CH3:17])[CH2:9]2)=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.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>[CH3:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[C@@H:10]1[CH2:11][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:23]3[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=3)=[CH:3][CH:4]=2)[CH2:9]1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@@H](c2ccc(Br)cc2)C1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: C[C@@H]1CCCN1[C@H]1C[C@@H](c2ccc(-c3ccc(C#N)cc3)cc2)C1
Temperature: 25 °C
Yield: 33.5 %

Procedure:
A solution of the product from Example 2A (100 mg, 0.34 mmol), 4-cyanophenyl boronic acid (65 mg, 0.44 mmol), dichlorobis(triphenylphosphine)palladium(II) (12 mg, 17 μmol) and potassium carbonate (120 mg, 0.85 mmol) under an atmosphere of nitrogen in isopropyl alcohol (8 mL) was heated at reflux for 5 hrs. Then, the reaction mixture was cooled to ambient temperature. The mixture was partitioned between ethyl acetate (25 mL) and H2O (10 mL). The organic layer was washed with brine, dried with magnesium sulfate, filtered, concentrated, and chromatographed on silica gel, eluting with 3% (9:1 MeOH:conc NH4OH) in dichloromethane to provide 36 mg of the title compound. 1H NMR (300 MHz, CD3OD) δ 1.21 (d, J=6 Hz, 3 H), 1.54 (m, 1 H), 1.84 (m, 2 H), 2.07 (m, 1 H), 2.18 (m, 2 H), 2.57 (m, 2 H), 2.71 (m, 2 H), 3.11 (m, 1 H), 3.27 (m, 2 H), 7.39 (d, J=9 Hz, 2 H), 7.64 (d, J=9 Hz, 2 H), 7.79 (s, 4 H); (DCl/NH3) m/z 317 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16]CC2C=CC=CC=2)[C:10]=1[C:24](=[O:26])[CH3:25])C1C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[C:34]([CH:39]=O)[CH:33]=[CH:32]2>>[OH:16][C:11]1[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([OH:8])[C:10]=1[C:24](=[O:26])[CH2:25][CH2:39][C:34]1[CH:33]=[CH:32][C:31]2[CH2:30][CH:29]([O:28][CH3:27])[CH2:38][CH2:37][C:36]=2[CH:35]=1
Reactant: COc1ccc2cc(C=O)ccc2c1
Reactant: CC(=O)c1c(OCc2ccccc2)cc(C)cc1OCc1ccccc1
Product: COC1CCc2cc(CCC(=O)c3c(O)cc(C)cc3O)ccc2C1

Procedure:
Intermediate 1-(2,6-bis-benzyloxy-4-methyl-phenyl)-ethanone, was treated with 6-methoxynaphthalene-2-carbaldehyde as described in Example 1, Part B. Subsequent catalytic hydrogenation as described in Example 1, Part C, provided 1-(2,6-dihydroxy-4-methyl-phenyl)-3-(6-methoxy-5,6, 7,8-tetrahydro-naphthalen-2-yl)-propan-1-one as a by-product. Further treatment of this by-product as described in Example 1, Part D and E, afforded the title compound. 1HNMR (300 MHz, CD3COCD3) δ 7.2–7.0(m, 2H), 6.95–6.85(m 3H), 6.6(s, 1H), 5.6(s, 1H), 5.27(d, J=7 Hz, 1H), 3.95–3.85(m, 1H), 3.75–3.55(m, 6H), 3.37(s, 3H), 3.3–3.2(m, 1H), 3.1–2.6(m, 8H), 2.05(s, 3H). MS: m/z (MH+) 499.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Br:9]Br.[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([Br:9])=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ncc(Cl)cc1Br
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-5-chloropyridine (10 g) in acetic acid (75 mL) at r.t. was added bromine (2.6 mL) slowly. After 30 min, the acid was neutralized by the careful addition of sodium hydroxide (10 N) at 0° C. The resulting orange precipitate was dissolved in ethyl acetate and washed successively with saturated potassium carbonate, saturated Na2S2O3 and brine, dried and concentrated. Flash chromatography (eluting with hexane/ethyl acetate, 3:1 v/v) of the residual solid provided the title compound as a pale yellow solid (14.8 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([F:21])[CH:15]=1)[OH:13])[CH2:8][CH2:9]O)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:7]1[CH2:8][CH2:9][O:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([F:21])[CH:15]=2)[CH2:11]1)=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCO)CC(O)c1ccc(Br)c(F)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)c(F)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
To a stirred solution of (RS)-[2-(4-bromo-3-fluoro-phenyl)-2-hydroxy-ethyl]-(2-hydroxy-ethyl)-carbamic acid tert-butyl ester (3.88 g) and triethylamine (1.71 ml) in THF (40 ml) at 0-5° C. was added dropwise methanesulfonyl chloride (873 μl). The reaction mixture was then stirred at room temperature for 30 min to afford a white suspension. The reaction mixture was then filtered to remove triethylamine hydrochloride, washing the filter with THF (6 ml). The filtrate was cooled to 0-5° C. and potassium 2-methyl-2-butoxide (9.05 ml, 1.7 M solution in toluene) was added. The reaction mixture was stirred at room temperature for 1 hour and then poured into water and extracted twice with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% EtOAc in hexanes) to afford (RS)-2-(4-bromo-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (1.73 g, 47%) as an orange viscous oil. MS (ISP): 306.1 ([{81Br}M+H—C4H8]+), 304.1 ([{79Br}M+H—C4H8]+), 262.0 ([{81Br}M+H—C4H8—CO2]+), 260.1 ([{79Br}M+H—C4H8—CO2]+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[CH3:25][CH:26]1[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[NH:27]1>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:2]([N:27]2[C@H:26]([CH3:25])[CH2:30][CH2:29][S:28]2(=[O:32])=[O:31])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)c(C)c1
Reactant: CC1CCS(=O)(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3[C@H](C)CCS3(=O)=O)CC2)c(C)c1
Yield: 20.6 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 12 and using (2-bromo-4-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (408.7 mg) described in Preparation Example 119 and 3-methylisothiazolidine-1,1-dioxide (135 mg), the title compound (95.1 mg) was obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:31]2[S:35][C:34]([CH3:36])=[N:33][C:32]=2[C:37](O)=[O:38])[CH:28]=[CH:29][CH:30]=1>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:31]2[S:35][C:34]([CH3:36])=[N:33][C:32]=2[C:37]([N:6]2[CH2:5][C@H:4]3[C@H:8]([CH2:9][CH:2]([CH3:1])[CH2:3]3)[C@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])=[O:38])[CH:28]=[CH:29][CH:30]=1
Reactant: COc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Product: COc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(3-methoxy-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [C:1]([N:5]1[CH2:26][CH2:25][CH2:24][C:8]2[C:9]([Br:23])=[C:10]3[C:19]4[CH:18]=[C:17](Br)[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C([O-])([O-])=O.[K+].[K+]>C(COC)OC.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>[C:1]([N:5]1[CH2:26][CH2:25][CH2:24][C:8]2[C:9]([Br:23])=[C:10]3[C:19]4[CH:18]=[C:17]([C:30]5[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=5)[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: COc1cc2c(cc1Br)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
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: O
Solvent: COCCOC
Product: COc1cc2c(cc1-c1cccnc1)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
Temperature: 90 °C
Yield: 63.6 %

Procedure:
A mixture of 150 mg of 13c, 44 mg of pyridine-3-boronic acid, 80 mg of K2CO3 and 22 mg of Pd(PPh3)4 in 3 ml of degassed dimethoxyethane was heated at 90° C., for 16 hr. The reaction mixture was cooled and diluted with 20 ml of water and the product was extracted with ethyl acetate. The extract was washed once with 2N KOH and once with water, dried and concentrated. The crude material was chromatographed over silica gel, using a gradient of heptane/ethyl acetate as eluent. The product isolated was triturated with pentane, to provide 95 mg of 13d as white, crystalline material. Mp 184-186° C. Rf 0.25 (heptane/ethyl acetate 1/1). MS-ESI: [M+1] 494.11 and 496.11.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([OH:19])[CH:5]=2.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][CH2:43]O>>[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][CH2:43][O:19][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([C:11]3[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=3)=[C:2]([Br:1])[C:3]2=[O:20])=[CH:8][CH:7]=1
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Reactant: CN(C)CCCO
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: CN(C)CCCOc1ccc2c(c1)C(=O)C(Br)=C2c1cc(F)cc(F)c1
Reaction time: 96 h
Yield: 86 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-hydroxy-1H-inden-1-one obtained in Step 5 of Example 36 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 3-(dimethylamino)propanol instead of 4-(2-hydroxyethyl)morpholine, being stirred for 4 d, and being purified by silica gel column chromatography (CH2Cl2/EtOAc=1:1) to obtain the title compound (86%).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[C:12]3[O:13][C:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C:15]=4[C:11]=3[CH:10]=[C:9](Br)[CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[C:28]1([S:34]([O-:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Na+]>>[N:1]1([CH2:6][C:7]2[C:12]3[O:13][C:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C:15]=4[C:11]=3[CH:10]=[C:9]([S:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:36])=[O:35])[CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=S([O-])c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cn4cccn4)cc(Br)cc3c2C1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cn4cccn4)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Yield: 39 %

Procedure:
The product of step B and sodium benzenesulfinate were coupled using the procedure of Example 29, step C. Purification by flash chromatography (SiO2, 80:20 hexanes/ethyl acetate) provided tert-butyl 6-((1H-pyrazol-1-yl)methyl)-8-(phenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (18 mg, 39%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.05-7.96 (m, 1H), 7.95-7.85 (m, 2H), 7.62-7.40 (m, 6H), 6.32-6.25 (m, 1H), 5.60 (s, 2H), 4.56 (s, 2H), 3.83 (t, J=5.1 Hz, 2H), 2.95-2.80 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [F:1][CH:2]([C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(=O)C.[NH4+:20].C(O)C.[Na]>C(O)(=O)C>[F:1][C:2](=[C:8]([NH2:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [NH4+]
Reactant: CCOC(=O)C(F)C(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(F)=C(N)c1ccccc1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
6.0 g of ethyl a-fluorobenzoylacetate and 7.0 g of ammonium acetate were added to 50 ml of ethanol, followed by dropwise addition of 6.0 g of acetic acid to this solution with stirring at room temperature. The mixed solution was further stirred under reflux for 4 hours and added to a cooled aqueous solution of sodium hydrogencarbonte. This aqueous mixture was extracted with 200 ml of diethyl ether, and the organic layer was washed with a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then the solvent was distilled away under reduced pressure to obtain 5.5 g of ethyl 2-fluoro-3-amino-3-phenyl-2-propenoate.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:46]([O:53][C:54]1[CH:61]=[CH:60][C:57]([CH2:58][NH2:59])=[CH:56][CH:55]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.N1C2C(=NC=CC=2)C=C1>CN(C)C=O.[Cl-].[Na+].O>[NH2:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:59][CH2:58][C:57]1[CH:60]=[CH:61][C:54]([O:53][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:55][CH:56]=1)=[O:6]
Reactant: Nc1nc(Cl)ccc1C(=O)O
Reactant: NCc1ccc(OCc2ccccc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)ccc1C(=O)NCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
2-Amino-6chloro-nicotinic acid described in Preparation Example A-1 (220 mg, 1.4 mmol), triethylamine (0.47 mL, 3.37 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (764 mg, 1.73 mmol) were dissolved in N,N-dimethylformamide (3 mL), 4-benzyloxy-benzylamine described in Preparation Example 1 (399 mg, 1.87 mmol) was added thereto, followed by stirring at room temperature for 17 hours 30 minutes. After the reaction was completed, the reaction solution was poured into brine, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then concentrated, the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1), and the title compound (115 mg, 0.31 mmol, 22%) was obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][C:6]=1[O:15][CH3:16].[OH-].[Na+].Cl>CO>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[O:15][CH3:16]
Reactant: COC(=O)c1ccc(OCCCl)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)ccc1OCCCl
Temperature: 40 °C
Yield: 96.4 %

Procedure:
In a 300 mL volume glass flask equipped with a stirrer, a thermometer and a dropping funnel were placed 17.40 g (69.7 mmol) of methyl 4-(2-chloroethoxy)-3-methoxybenzoate, 69.7 mL of aqueous sodium hydroxide solution (2 mol/L), and 69.7 mL of methanol. The resulting mixture was heated to 40° C. for 4 hours in an argon gas atmosphere. After the reaction was complete, the reaction mixture was cooled to 10° C., and neutralized by 69.7 mL of hydrochloric acid (2 mol/L). The reaction mixture was then placed to distill methanol off, and cooled to 10° C., to precipitate a crystalline product. The crystalline product was collected and dried under reduced pressure, to give 15.5 g (isolated yield: 95.2%, purity: 99% in terms of area percentage by high performance liquid chromatography) of 4-(2-chloroethoxy)-3-methoxybenzoic acid as a white crystalline product.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:4]=[C:5]([CH:16]=[C:17](Cl)[CH:18]=1)[CH2:6][N+:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12.[Br-].[Cl:21]C1C=C(C=CC=1Cl)C[N+]1C=CN2C=CC=CC=12.[Br-].COC1C=CC=CC=1C[N+]1C=CN2C=CC=CC=12.[Cl-].COC1C=C(C=CC=1)C[N+]1C=CN2C=CC=CC=12.[I-].C(C1C=C(C=CC=1)C[N+]1C=CN2C=CC=CC=12)#N.[Br-].BrC1C=C(C=CC=1)C[N+]1C=CN2C=CC=CC=12.[Br-].FC1C=C(C=CC=1)C[N+]1C=CN2C=CC=CC=12.[Cl-].C1(C2C=C(C=CC=2)C[N+]2C=CN3C=CC=CC=23)C=CC=CC=1.[Cl-].S(C1C=C(C=CC=1)C[N+]1C=CN2C=CC=CC=12)(=O)(=O)N.[Cl-].CS(C1C=CC=CC=1C[N+]1C=CN2C=CC=CC=12)(=O)=O.[Br-].FC(F)(F)C1C=CC(C[N+]2C=CN3C=CC=CC=23)=CC=1>>[Cl-:2].[Cl:21][C:4]1[C:3]([Cl:2])=[CH:18][CH:17]=[CH:16][C:5]=1[CH2:6][N+:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12
Reactant: Clc1ccc(C[n+]2ccn3ccccc32)cc1Cl
Reactant: Clc1cc(Cl)cc(C[n+]2ccn3ccccc32)c1
Agent: Brc1cccc(C[n+]2ccn3ccccc32)c1
Agent: COc1cccc(C[n+]2ccn3ccccc32)c1
Agent: COc1ccccc1C[n+]1ccn2ccccc21
Product: Clc1cccc(C[n+]2ccn3ccccc32)c1Cl

Procedure:
1-(3,5-dichlorobenzyl)imidazo[1,2-a]pyridinium chloride; 1-(3,4-dichlorobenzyl)imidazo[1,2-a]pyridinium bromide; 1-(2-methoxybenzyl)imidazo[1,2-a]pyridinium bromide; 1-(3-methoxybenzyl)imidazo[1,2-a]pyridinium chloride; 1-(3-cyanobenzyl)imidazo[1,2-a]pyridinium iodide; 1-(3-bromobenzyl)imidazo[1,2-a]pyridinium bromide; 1-(3-fluorobenzyl)imidazo[1,2-a]pyridinium bromide; 1-(3-phenylbenzyl)imidazo[1,2-a]pyridinium chloride; 1-(3-sulfamoylbenzyl)imidazo[1,2-a]pyridinium chloride; 1-(2-methylsulfonylbenzyl)imidazo[1,2-a]pyridinium chloride; 1-(4-trifluoromethylbenzyl)imidazo[1,2-a]pyridinium bromide; and 1-(3-furfuryl)imidazo[1,2-a]pyridinium bromide.
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]([CH2:14]/[CH:15]=[CH:16]/[C:17]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21]C)=[O:20])=[C:12]([O:28][CH3:29])[C:11]([CH3:30])=[C:10]2[C:6]=1[C:7](=[O:31])[O:8][CH2:9]2)(=[O:3])[CH3:2].[OH-].[Li+].Cl>CO.O>[C:1]([O:4][C:5]1[C:13]([CH2:14]/[CH:15]=[CH:16]/[C:17]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([OH:21])=[O:20])=[C:12]([O:28][CH3:29])[C:11]([CH3:30])=[C:10]2[C:6]=1[C:7](=[O:31])[O:8][CH2:9]2)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cccc(C)c1/C=C/Cc1c(OC)c(C)c2c(c1OC(C)=O)C(=O)OC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1c(C)c2c(c(OC(C)=O)c1C/C=C/c1c(C)cccc1C(=O)O)C(=O)OC2

Procedure:
A solution of methyl (E)-2-[3-(4-acetoxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-prop-1-en-1-yl]-3-methylbenzoate (0.1 g) and lithium hydroxide (0.06 g) in methanol (1 ml) and water (1 ml) was heated at 70° C. for 48 hours. The solution was cooled and poured into water, then acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extract was dried and evaporated to give (E)-2-[3-(4-acetoxy-1,3-dihydro -6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-prop -1-en-1-yl ]-3-methylbenzoic acid, mp 180°-3° C. (ethyl acetate/cyclohexane).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12](C(=O)C1C=CC=CC=1)[CH:11]=[C:10]2[CH:24]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25]1.[OH-].[Na+]>CO>[O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:24]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25]1
Reactant: CN1CCC(c2cn(C(=O)c3ccccc3)c3ccc(C4CCC=CO4)cc23)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCC(c2c[nH]c3ccc(C4CCC=CO4)cc23)C1
Temperature: 25 °C
Yield: 30.3 %

Procedure:
To a solution of 5-(2,3-dihydropyran-2-yl)-3-(N-methylpyrrolidin-3-yl)-1-benzoylindole (Example 18a, 0.158 g, 0.409 mmol) in methanol (5 mL) was added 2N NaOH (6.8 mmol) and the mixture was heated at reflux for 2 hours. The solution was cooled to room temperature and the solvent was evaporated and the product was extracted with CH2Cl2 (3×). The organic layer was dried and concentrated by reduced pressure and purified by column chromatography [10% NH3 (2M in MeOH) in CH2Cl2 ] to yield the title compound (0.035 g, 30%) as a yellow foam; HRMS-FAB+ for C18H22N2O; calc. MH+ :283.1810; found MH+ :283.1839.