Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[CH:30]=[C:29]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH:28]=[CH:27][C:26]=1[NH:39][CH2:40][C:41]1[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[C:43]([O:51][CH3:52])[CH:42]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[Si:32]([O:31][C:29]1[CH:28]=[CH:27][C:26]([NH:39][CH2:40][C:41]2[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[C:43]([O:51][CH3:52])[CH:42]=2)=[C:25]([NH:24][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:17][CH:16]=2)[CH:30]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: O=C(O)c1ccc(OCCN2CCCC2)cc1
Reactant: COC(=O)c1ccc(CNc2ccc(O[Si](C)(C)C(C)(C)C)cc2N)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNc2ccc(O[Si](C)(C)C(C)(C)C)cc2NC(=O)c2ccc(OCCN3CCCC3)cc2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
To 4-[2-(1-pyrrolidinyl)ethoxy]benzoic acid (350 mg, 1.29 mmol) in CH2Cl2 (2 ml) was added oxalyl chloride (327 mg, 2.58 mmol) and a catalytic amount of DMF. The mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The acid chloride was dried, under vacuum, overnight. To the aniline (Example 1, Part D; 0.49 g, 1.17 mmol), in pyridine (0.158 g, 2.34 mmol) and CH2Cl2 (3 mL) at 0° C. and under N2, was added the previously formed acid chloride (see Example 5, Part D) in 4 mL CH2Cl2 dropwise. Upon completion of addition, the mixture was stirred for 15 minutes at room temperature and then the reaction quenched by the addition saturated NaHCO3. Product was extracted with EtOAc, the organics washed with H2O, and concentrated under reduced pressure; yielding 583 mg of desired product after flash chromatography (SiO2, 10% MeOH in CHCl3).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][CH2:7]2)[N:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:4][N:3]1[C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32]([O:34]C)=[O:33].O.[OH-].[Li+].Cl.O1CCOCC1>CO.O>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][C:15](=[O:22])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11]2)[N:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:4][N:3]1[C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32]([OH:34])=[O:33]
Reactant: COC(=O)c1cccc(N2CN(c3ccccc3)C3(CCN(CCCC(=O)c4ccccc4)CC3)C2=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(N2CN(c3ccccc3)C3(CCN(CCCC(=O)c4ccccc4)CC3)C2=O)c1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 3-(4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate (0.08 g, 0.16 mmol) in methanol (3 mL) was added lithium hydroxide monohydrate (0.013 g, 0.32 mmol) in water (1 mL). After stirring at 55° C. for 18 h, the reaction mixture was concentrated in vacuo, isolated by preparatory TLC (10% methanol/dichloromethane/0.1% acetic acid) and lyophilized with 4M HCl/dioxane (0.5 mL) to obtain the title compound as a hydrochloride salt (0.011 g, 13%); 1H NMR (DMSO-d6): δ 2.07-2.16 (m, 4H), 2.91 (br, 2H), 3.21-3.24 (m, 4H), 3.56-3.62 (m, 4H), 5.25 (s, 2H), 6.90 (t, 1H, J=7.2 Hz), 7.24-7.34 (m, 4H), 7.53-7.68 (m, 4H), 7.81 (d, 1H, J=7.6 Hz), 7.92 (dd, 1H, J=8 and 1.6 Hz), 8.00 (d, 2H, J=8 Hz), 8.69 (s, 1H), 10.29 (br, 1H), 13.18 (br, 1H); MS for C30H31N3O4 m/z 498 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C:9]3[CH2:10][CH2:11][C:12]4[CH:13]=[C:14]([O:21]C5CCCCO5)[CH:15]=[CH:16][C:17]=4[C:18]=3[CH2:19][CH2:20][C@:4]12[CH3:5].C(O)(=O)C(O)=O>CO.O>[F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C:9]3[CH2:10][CH2:11][C:12]4[CH:13]=[C:14]([OH:21])[CH:15]=[CH:16][C:17]=4[C:18]=3[CH2:19][CH2:20][C@:4]12[CH3:5]
Reactant: C[C@]12CCC3=C(CCc4cc(OC5CCCCO5)ccc43)[C@@H]1CCC2=C(F)F
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Product: C[C@]12CCC3=C(CCc4cc(O)ccc43)[C@@H]1CCC2=C(F)F
Yield: 68.9 %

Procedure:
A suspension of 927 mg of 17-difluoromethylene-3-tetrahydropyranyloxy-estra-1,3,5(10),8-tetraene in 20 ml of methanol and 2.0 ml of water is refluxed with 950 mg of oxalic acid for 0.5 hour at a bath temperature of 100° C. Then, it is concentrated by evaporation in a vacuum diluted with ethyl acetate, washed three times with water, once with sodium bicarbonate solution as well as with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. After crystallization from hexane, 0.5 g of 17-difluoromethylene-estra-1,3,5(10),8-tetraen-3-ol is obtained as colorless crystals with a melting point of 127-128° C., [α]D22 =-1.5° (c-0.515% in pyridine).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]#[N:17])[C:13]3[N:18]=[CH:19][NH:20][C:12]=3[CH:11]=2)=[CH:6][C:5]=1[C:21]([F:24])([F:23])[F:22])[CH3:2].Br[CH2:26][CH2:27][CH2:28][C:29]([O:31]C)=[O:30]>>[C:16]([C:14]1[C:13]2[N:18]=[CH:19][N:20]([CH:28]([CH2:27][CH3:26])[C:29]([OH:31])=[O:30])[C:12]=2[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:21]([F:23])([F:24])[F:22])[CH:6]=2)[N:15]=1)#[N:17]
Reactant: CCOc1ccc(-c2cc3[nH]cnc3c(C#N)n2)cc1C(F)(F)F
Reactant: COC(=O)CCCBr
Product: CCOc1ccc(-c2cc3c(ncn3C(CC)C(=O)O)c(C#N)n2)cc1C(F)(F)F

Procedure:
This compound was from 6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo-[4,5-c]pyridine-4-carbonitrile (Example 1) with the use of methyl 4-bromobutyrate instead of methyl bromoacetate and using the methods described in examples 2 and 3. 1H NMR (DMSO): δ 8.69 (m, 2H) 8.43-8.38 (m, 2H) 7.42 (d, 1H) 4.44 (t, 2H) 4.27 (q, 2H) 2.29 (t, 2H) 2.11 (m, 2H) 1.38 (t, 3H). MS m/z 419.5 (M+1).
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([CH:31]2[CH2:33][O:32]2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>>[OH:32][CH:31]([C:29]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([O:22][CH3:21])[CH:30]=1)[CH2:33][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[C:10]2[CH:19]=[CH:18][C:13]3[C:14](=[O:17])[O:15][CH2:16][C:12]=3[C:11]=2[CH3:20])[CH2:5][CH2:6]1
Reactant: COc1cc(C2CO2)ccc1C#N
Reactant: Cc1c(C(O)CN2CCNCC2)ccc2c1COC2=O
Product: COc1cc(C(O)CN2CCN(CC(O)c3ccc4c(c3C)COC4=O)CC2)ccc1C#N

Procedure:
4-(1-hydroxy-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-(methyloxy)benzonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLES 2C and 28-29 starting from 5-(1-hydroxy-2-piperazin-1-ylethyl)-4-methyl-2-benzofuran-1(3H)-one and 2-(methyloxy)-4-oxiran-2-ylbenzonitrile.
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1.C1(S([S:24][CH2:25][CH:26]([N:38]([CH3:40])[CH3:39])[CH2:27][S:28]S(C2C=CC=CC=2)(=O)=O)(=O)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C:13]([C:12]1([C:9]2[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=2)[S:28][CH2:27][CH:26]([N:38]([CH3:40])[CH3:39])[CH2:25][S:24]1)#[N:14]
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CN(C)C(CSS(=O)(=O)c1ccccc1)CSS(=O)(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CN(C)C1CSC(C#N)(c2ccc(Cl)cc2)SC1
Reaction time: 4 h
Yield: 87 %

Procedure:
To 20 ml of chloroform were added 1.52 g (0.01 mole) of p-chlorophenylacetonitrile and 4.3 g (0.01 mole) of 1,3-bis(benzenesulfonylthio)-2-(N,N-dimethylamino)propane, and then 3.1 g (0.02 mole) of 1,8-diazabicyclo[5,4,0]undeca-7-ene was added thereto at room temperature. After completion of addition, the reaction was allowed to proceed at 40° C. for 4 hours. The reaction mixture was washed with two 20-ml portions of water, dried over anhydrous magnesium sulfate and concentrated to dryness. The crystals thus obtained were heated in 10 ml of toluene for dissolution and the solution was allowed to stand in the cold overnight. The resulting crystalline precipitate was collected by filtration to give 2.6 g (87%) of 2-cyano-2-(p-chlorophenyl)-5-(N,N-dimethylamino)-1,3-dithiane as light-yellow crystals melting at 110°-111° C.
Reaction SMILES: C(OC(=O)[N:7]([S:11]([C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1[OH:21])(=[O:13])=[O:12])[CH2:8][CH2:9]Cl)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C(O)C.CCCCCCC>[Br:20][C:18]1[CH:17]=[CH:16][C:15]2[O:21][CH2:9][CH2:8][NH:7][S:11](=[O:13])(=[O:12])[C:14]=2[CH:19]=1
Reactant: CC(C)(C)OC(=O)N(CCCl)S(=O)(=O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCO
Product: O=S1(=O)NCCOc2ccc(Br)cc21
Reaction time: 1 h

Procedure:
37 g (81 mmol) of the product obtained in Step D above are heated at reflux in the presence of 2.69 g (16 mmol) of KI and 33.6 g (240 mmol) of K2CO3 in 1.2 L of ethanol for about 18 hours. After cooling, the salts are filtered off and rinsed with acetone. After evaporation, the filtrate is taken up in water. The mixture is acidified with 1N HCl solution and then extracted 3 times with CH2Cl2. The organic phase is washed twice with brine, dried over MgSO4 and evaporated. The residue obtained (˜22 g) is then triturated in heptane, and then the mixture is allowed to separate in order to remove the heptane supernatant. The residue is again triturated in a heptane/isopropyl ether mixture to obtain a solid. After filtration, the product is rapidly dried and then ground in a mortar. The solid obtained is dissolved in heptane, stirred for about 1 hour and filtered to yield the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[N:23]([CH2:24][C:25]([OH:27])=O)[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[NH:30]1[CH2:35][CH2:34][CH:33]([CH2:36][OH:37])[CH2:32][CH2:31]1.C(Cl)CCl.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:19][O:20][C:21]([CH3:28])([CH3:29])[CH2:22][N:23]3[CH2:24][C:25]([N:30]3[CH2:35][CH2:34][CH:33]([CH2:36][OH:37])[CH2:32][CH2:31]3)=[O:27])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC1(C)CN(CC(=O)O)C(C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Reactant: OCC1CCNCC1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC1(C)CN(CC(=O)N2CCC(CO)CC2)C(C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
[5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid (200 mg, 0.48 mmol) and piperidin-4-yl-methanol (111 mg, 0.96 mmol) were dissolved in pyridine (4 mL). The resulting yellow solution was stirred at room temperature for 10 min and then EDC (184 mg, 0.96 mmol) was added in a single portion. The reaction mixture was allowed to stir over night (16 h). Water (4 mL) was added and the mixture was concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate (50 mL) and 1 M aqueous potassium carbonate. The aqueous layer was back-extracted with ethyl acetate (3×50 mL) and the combined extracts were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel chromatography (methylene chloride and methanol gradient) to afford pure 4-[2-(4-hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-beta-carbolin-8-yl)-amide as a yellow foam (152 mg, 62%). The bis-HCl salt was prepared by adding 2 equivalents of conc. HCl to an ethanolic solution of the freebase. Concentration, followed by ether trituration afforded the salt as a free-flowing, yellow powder. 1H-NMR (freebase, 300 MHz, CDCl3) δ: 11.03 (d, 1H), 10.51 (d, 1H), 8.97-8.80 (m, 1H), 8.47-8.27 (m, 2H), 7.94-7.76 (m, 2H), 4.84 (d, 1H), 4.16-3.77 (m, 3H), 3.68-3.26 (m, 5H), 3.08 (ddd, 1H), 2.89-2.64 (m, 2H), 2.50-2.37(m, 2H), 1.98-1.70 (m, 3H), 1.38 (s, 3H), 1.25 (s, 3H), 1.19-0.97 (m, 1). MS (NH4OAc standard conditions, ES+) e/z=514 (M+H)+DAD Rf=1.51 min
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([OH:17])[CH:9]=2.[H-].[Na+].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>CN(C)C=O>[CH3:22][O:21][C:19]1[CH:18]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:20]=1)[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:25][CH:27]1[O:29][CH2:28]1)[CH:9]=2
Reactant: ClCC1CO1
Reactant: COc1cc(OC)cc(-c2cc(=O)c3ccc(O)cc3o2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(-c2cc(=O)c3ccc(OCC4CO4)cc3o2)c1

Procedure:
Reaction of 3′,5′-dimethoxy-7-hydroxy-flavone, 26 (2 g, 6.7 mol), 50% sodium hydride (0.96 g, 40 mmol) and epichlorohydrin (1.6 mL, 20 mmol) in dry dimethyl formamide (90 mL) using identical procedure as described for 28 furnished 32. Yield 1.7 g (72%); mp 181-182° C.; MS (FAB) 355 (M++1); IR (KBr) 1630; 1H NMR (200 MHz, CDCl3) δ 8.14 (dd, J=8.3 Hz, 0.77 Hz, 1H), 7.04-6.99 (m, 4H), 6.73 (s, 1H), 6.61 (t of dd, J=2.2 Hz, 2.2 Hz, 2.2 Hz, 1H), 4.39 (dd, J=11.1 Hz, 2.9 Hz, 1H), 4.06 (dd, J=11.1 Hz, 5.8 Hz, 1H), 3.87 (s, 6H), 3.44-3.39 (m, 1H), 2.96 (t, J=4.5 Hz, 4.5 Hz, 1H), 2.80 (dd, J=4.8 Hz, 2.6 Hz, 1H).
Reaction SMILES: [C:1]([CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:13][CH3:14])[C:4]1=[O:15])#[N:2].[BH4-].[Na+]>CO>[C:1]([CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:13][CH3:14])[CH:4]1[OH:15])#[N:2]
Reactant: COc1cccc2c1CCC(C#N)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc2c1CCC(C#N)C2O

Procedure:
The compound obtained in step (iii) above (16.2 g, 0.080 mol) is reduced with sodium borohydride (3.1 g, 0.082 mol) in absolute methanol (500 ml). The reaction mixture is concentrated under vacuum, ice-water is added thereto, the mixture is made acidic by the addition of concentrated hydrochloric acid and extracted with ethyl acetate. Upon evaporation of the solvent 2-cyano-5-methoxy-1,2,3,4-tetrahydro-1-naphthol (16.2 g) is obtained; m.p. 96°-98° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl-].C([Al+]CC)C.[CH3:17][C:18]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>ClCCl>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:24]([C:18]3([CH3:17])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:25])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: CC1(C(=O)Cl)CCCCC1
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
A suspension of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (104 mg, 0.53 mmol) in anhydrous dichloromethane (3 ml) was cooled to 0° C. under N2. Diethyl aluminum chloride (1M in hexanes, 1.57 ml, 1.57 mmol) was added quickly, and the reaction mixture was stirred for 30 minutes. 1-Methyl-cyclohexanecarbonyl chloride (844 mg, 5.3 mmol) was added dropwise, and the reaction mixture was refluxed overnight. The reaction mixture was cooled to 0° C. and quenched with saturated aqueous NaHCO3. The biphasic solution was concentrated, and the remaining aqueous solution was extracted with ethyl acetate (3×). The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a greenish oil. The residue was purified by silica gel chromatography using 20-50% EtOAc in hexanes as eluant to provide 144 mg (85%) of (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone as a light yellow solid. MP 198-199° C., M+H=322.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH:13]3[CH2:14][CH2:15][N:10]([C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)[CH2:11][CH2:12]3)[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCN(c4ccc(F)cc4)CC3)CC2)cc1

Procedure:
3.0 g (13.6 mmol) of 1-(4-nitrophenyl)-4-piperidone [cf. Taylor et al., Synthesis (1981) 606], 2.5 g (13.6 mmol) of N-(4-fluorophenyl)piperazine, 0.8 g (13.6 mmol) of acetic acid and 0.9 g (13.6 mmol) of sodium cyanoborohydride were reacted as in Example 1.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[CH:6]=1)=[O:4].[BH4-].[Na+].O1CCCC1.Cl>CO>[CH3:1][NH:2][C:3]([CH:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[CH2:6]1)=[O:4]
Reactant: CNC(=O)C1=CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)C1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
A mixture of 0.53 g of N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide, 0.38 g of sodium borohydride, 5 ml of tetrahydrofuran, and 5 ml of methyl alcohol was stirred at room temperature for 20 minutes. 2N Hydrochloric acid was added thereto, followed by extracting with dichloromethane. The extract was dried over magnesium sulfate and recrystallized from ethyl acetate and n-hexane to obtain 0.42 g of N-methyl-3,4-dihydro-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide represented by formula shown below.
Reaction SMILES: [O:1]=[C:2]1[C:12]2=[C:13]3[C:8](=[CH:9][C:10]([CH2:14][C:15]([O:17]CC)=[O:16])=[CH:11]2)[CH2:7][CH2:6][CH2:5][N:4]3C1=O.[OH-:21].[Na+].OO.Cl>O>[C:2]([C:12]1[CH:11]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:9]=[C:8]2[C:13]=1[NH:4][CH2:5][CH2:6][CH2:7]2)([OH:1])=[O:21]
Reactant: CCOC(=O)Cc1cc2c3c(c1)C(=O)C(=O)N3CCC2
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1cc2c(c(C(=O)O)c1)NCCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
To a solution of ethyl 5,6-dihydro-1,2-dioxo-4H-pyrrolo[3,2,1-ij]quinolin-8-ylacetate (21.5 g) and sodium hydroxide (18.5 g) in water (1 litter) was added 35% hydrogen peroxide solution (10 ml) and stirred for 3 hours at room temperature. The mixture was acidified at pH 2 with concentrated hydrochloric acid, resulting precipitate was collected by filtration, washed with water and dried to yield 17.6 g (95.1%) of the title compound. The compound was recrystallized from ethanol to give pale yellow needles, mp 210°-211° C.
Reaction SMILES: [OH:1][C:2]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][O:3]1.[CH3:23]O>>[CH3:23][O:1][C:2]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:6](=[O:7])[C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][O:3]1
Reactant: CO
Reactant: O=C(O)c1ccc(C2=COC(O)(c3ccccc3)C2=O)cc1
Product: COC1(c2ccccc2)OC=C(c2ccc(C(=O)O)cc2)C1=O
Reaction time: 408 h
Yield: 91.6 %

Procedure:
A solution of 1.50 g of 2-hydroxy-2-phenyl-4-(4-carboxyphenyl)-3(2H)-furanone in 100 ml of methanol was heated under reflux with stirring for 17 days. The reaction mixture was concentrated to a volume of 20 ml, seeded with the product and the precipitate was collected after standing at 0° C. for 3 days. The precipitate was collected, washed with cold methanol and ether and dried at 0° C. for 4 hrs. to give 1.42 g (91.6%) of 2-methoxy-2-phenyl-4-(4-carboxyphenyl)-3(2H)-furanone as colorless crystals, m.p. 212°-214° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][NH2:12].[CH2:24](Br)[CH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[C:3]([CH2:13][S:14][C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:24][CH2:25][OH:26]
Reactant: OCCBr
Reactant: Cc1c(SCCCN)ccnc1CSc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(SCCCNCCO)ccnc1CSc1nc2ccccc2[nH]1
Reaction time: 2 h

Procedure:
2-((3-Methyl-4-(3-aminopropylthio)-2-pyridyl)methylthio)-1H-benzimidazole (2.0 g) was dissolved in dimethylformamide (20 ml) and thereto were added ethylene bromohydrin (0.83 g) and potassium carbonate (1.25 g). The mixture was stirred at 60°-70° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled away under reduced pressure. The residue was subjected to column chromatography and extracted with chloroform-methanol to give 2-((3-methyl-4-(3-(2-hydroxyethylamino)propylthio)-2-pyridyl)methylthio)-1H-benzimidazole.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)=O.[Na].[CH2:13]([NH:19][OH:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:13]([N+:19]([O-:20])=[CH:1][C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=Cc1ccc(S(=O)(=O)O)o1
Reactant: CCCCCCNO
Agent: [Na]
Product: CCCCCC[N+]([O-])=Cc1ccc(S(=O)(=O)O)o1
Yield: 76 %

Procedure:
Following the procedure of Example 1 above and using 5-formylfuran-2-sulfonic acid, sodium salt hydrate and N-n-hexylhydroxylamine, the title compound was prepared in 76% yield as the sodium salt, m.p. 225.5° C. (dec.).
Reaction SMILES: C[OH:2].S(=O)(=O)(O)O.[F:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15](C(C)=C)=[CH:14][CH:13]=1.OO>O>[F:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:2])=[CH:14][CH:13]=1
Reactant: CO
Reactant: C=C(C)c1ccc(OCCF)cc1
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Product: Oc1ccc(OCCF)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Then, a mixture of 30 ml of methanol and 2 ml of concentrated sulfuric acid was warmed to 40° C., and 9.0 g of the resulting crude 4-(2-fluoroethoxy)-isopropenylbenzene prepared as above and a 30% aqueous solution of hydrogen peroxide were separately added dropwise to the warmed mixture over the course of 20 minutes. The reaction was continued for 1 hour. The reaction mixture was cooled, poured into water, and extracted with toluene. The toluene layer was washed with water, and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure to give 7.3 g of crude 4-(2-fluoroethoxy)phenol. The resulting crude phenol was recrystallized to give 6.8 g of pure 4-(2-fluoroethoxy)phenol as crystals.
Reaction SMILES: [CH3:1][CH:2]([NH2:6])[CH2:3][CH2:4][CH3:5].[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20])[C:11](Cl)=[O:12]>>[CH3:1][CH:2]([NH:6][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]#[CH:20])=[C:8]([F:7])[CH:9]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(C)N
Reactant: C#CCOc1ccc(C(=O)Cl)cc1F
Product: C#CCOc1ccc(C(=O)NC(C)CCC)cc1F

Procedure:
According to the same method as that of Production Example 1, 1-methylbutylamine was used in place of 2,2-dimethylpropylamine, 3-fluoro-4-(2-propynyloxy)benzoyl chloride was used in place of 4-(2-propynyloxy)-3-methoxybenzoyl chloride to obtain N-(1-methylbutyl)-3-fluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 57 of the present invention) represented by the formula:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=[O:18])[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=[O:18]
Reactant: C#CCCn1ccccc1=O
Reactant: Ic1ccccn1
Product: O=c1ccccn1CCC#Cc1ccccn1
Yield: 22.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 192(A), from 2-iodopyridine (50 mg, 0.2 mmol) and 1-(but-3-ynyl)pyridin-2(1H)-one (33 mg, 0.2 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 97/3 as eluent) to afford 10 mg of 1-(4-(pyridin-2-yl)but-3-ynyl)pyridin-2(1H)-one as a yellow oil (Yield: 20%).