Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][NH2+:8]1)=[O:6])[CH3:3].Cl[C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:17]=2[N:18]=1>>[F:23][C:20]1[CH:21]=[CH:22][C:16]2[O:15][C:14]([N:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]3[C:5]([O:4][CH2:2][CH3:3])=[O:6])=[N:18][C:17]=2[CH:19]=1
Reactant: Fc1ccc2oc(Cl)nc2c1
Reactant: CCOC(=O)[C@@H]1CCCC[NH2+]1
Agent: [Cl-]
Product: CCOC(=O)[C@@H]1CCCCN1c1nc2cc(F)ccc2o1

Procedure:
The title compound was prepared by a similar method to Preparation 2 from (2S)-2-(ethoxycarbonyl)piperidinium chloride [see J. Am. Chem. Soc. (1993), 115, 9925-9938] and 2-chloro-5-fluoro-1,3-benzoxazole [see J. Med. Chem. (1988), 31, 1719-1728]. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 3:1, by volume, hexane:ethyl acetate, to afford ethyl(2S)-1-(5-fluoro-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate as an oil.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][NH2:14]>>[CH3:13][NH:14][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CN
Product: CCCCCCC/C=C/C(=O)NC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and methylamine as starting materials to give the aimed compound.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH:13][CH:14]=[O:15])=[C:11]([C:16](=[O:18])[NH2:17])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>[OH-].[Na+]>[C:14]([NH:13][C:12]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=[N:10][C:11]=1[C:16](=[O:18])[NH2:17])(=[O:15])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(=O)c1nnn(Cc2ccccc2)c1NC=O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1nnn(Cc2ccccc2)c1NC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
1-Benzyl-4-carbamoyl-5-formamido-1,2,3-triazole (40 g.; prepared as described by A. Albert, J.Chem.Soc., 1969 (C), 152) was dissolved in 2N sodium hydroxide solution (156 ml.), and treated with alternate successive portions of benzoyl chloride (total 24 ml.) and 2N aqueous sodium hydroxide solution (total 140 ml.) with vigorous agitation, and cooling with ice, over a period of 2 hours. The solution was then acidified to pH 4 with concentrated hydrochloric acid, again cooling with ice, and the precipitated solid was filtered off, dissolved in 2N sodium hydroxide solution (208 ml.) and the solution stirred at 0° C. while portions of benzoyl chloride (total 57 ml.) and 2N sodium hydroxide solution (total 331 ml.) were added alternately over 45 minutes. The resultant mixture was stirred for a further 60 minutes at 0° C. before being acidified to pH 4 with concentrated hydrochloric acid, the temperature being maintained at 0° C. The solid was filtered off and washed successively with water, diethyl ether and water. The solid product was dried, and recrystallised from ethanol to give 5-benzamido-1-benzyl-4-carbamoyl-1,2,3-triazole (23.1 g.), m.p. 191°-192° C.
Reaction SMILES: [NH2:1][CH:2]([C:6]([NH2:8])=[O:7])[C:3]([NH2:5])=[O:4]>CO>[C:3]([C:2]1[N:1]=[C:6]([CH2:2][C:3]([NH2:5])=[O:4])[NH:8][C:6]=1[OH:7])(=[O:4])[NH2:5]
Reactant: NC(=O)C(N)C(N)=O
Solvent: CO
Product: NC(=O)Cc1nc(C(N)=O)c(O)[nH]1
Yield: 140.6 %

Procedure:
Ethyl imino α-carbamoylacetate hydrochloride (5.98 g) and aminomalonamide (3.51 g) were added to anhydrous methanol (80 ml) under ice-cooling while stirring. After stirring for 1/2 hour, the mixture was refluxed for 2 hours and then cooled with ice. The precipitated crystals were collected, washed with ethanol and diisopropyl ether and dried under vacuum to give 4-carbamoyl-5-hydroxy-1H-imidazole-2-acetamide (3.88 g, 70.3%), m.p. 270° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.ClC1C=C(C(=[N:35][OH:36])C(C2C=CC(F)=CC=2)=O)C=CN=1>>[Br:1][C:2]1[CH:7]=[C:6]([C:8](=[N:35][OH:36])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(C(=NO)c1ccnc(Cl)c1)c1ccc(F)cc1
Reactant: O=C(Cc1ccnc(Br)c1)c1ccc(F)cc1
Product: O=C(C(=NO)c1ccnc(Br)c1)c1ccc(F)cc1

Procedure:
22d was prepared from 21c (5.0 g; 17 mmol) using the method described in the synthesis of 22a.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:54]([CH2:56][CH2:57][NH:58][CH2:59][CH2:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)#[N:55]>O1CCCC1>[C:54]([CH2:56][CH2:57][N:58]([CH2:59][CH2:60][CH2:61][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)[C:18](=[O:20])[C@H:9]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])#[N:55]
Reactant: N#CCCNCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)N(CCC#N)CCCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of Boc-homophenylalanine (136 mg, 0.49 mmol), diisopropylethylamine (169 μl mg, 0.97 mmol), and tetrahydrofuran (3 ml) was treated with PyBrop (248 mg, 0.63 mmol) at 0° C. (2-cyanoethyl)-3-phenylpropylamine (109 mg, 0.58 mmol) in tetrahydrofuran (2 ml) was added dropwise and the reaction mixture was stirred overnight. The solid was filtered and rinsed with ethyl acetate, and the filtrate was concentrated and purified by chromatography to give Boc-homophenylalanine (2-cyanoethyl)-3-phenylpropylamide. A mixture of above product (200 mg), 10% palladium-on-carbon (20 mg), and methanol (40 ml) was hydrogenated on a Parr hydrogenator (40 psi) overnight. The catalyst was removed by filtration through Celite and the filtrate was concentrated in vacuo. The residue was then treated with trifluoroacetic acid for 30 min. The solvent was removed in vacuo and the product was purified by reverse phase HPLC to give white solid: 1H NMR (400 MHz, D2O) δ1.8-2.1 (m, 6H), 2.5-2.8 (m, 4H), 3.0-3.3 (m, 4H), 3.3-3.7 (m, 2H), 4.0-4.1 (m, 1H), and 7.3-7.5 (m, 10H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].C(N(CCCC)CCCC)CCC.C(C(C)=[O:25])C>>[O:25]1[CH:2]([C:1]([OH:8])=[O:7])[CH:3]1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)CCC(=O)O
Reactant: CCC(C)=O
Solvent: CCCCN(CCCC)CCCC
Product: O=C(O)C1OC1C(=O)O
Temperature: 150 °C

Procedure:
A reaction vessel was charged with 442 parts Epoxy B, 442 parts Epoxy E, 116.0 parts succinic acid, 110 parts methyl ethyl ketone, and 3 parts tri-n-butylamine (catalyst). The temperature was raised to 150° C., while removing sufficient MEK (100 parts) to maintain controlled reflux at this temperature. The reaction maintained at 150° C., for 1.5 l hours and then poured into a poly(tetrafluoroethylene) lined tray and allowed to cool to ambient temperature. The resulting solid resin had an acid number of 32.0 and an epoxy content of 0.03 meq./g.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[CH3:16][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: CI
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1ccn2C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl indole-4-carboxylate (402 mg, 2.30 mmol) in DMF (5 mL) was cooled with an ice/water bath and treated with NaH (100 mg, 2.5 mmol, 60% in mineral oil). The resulting yellow solution was allowed to stir at 0° C. for 30 min., then a solution of MeI (482 mg, 212 μL, 3.4 mmol) in DMF (3.5 mL) was added dropwise. The solution was allowed to warm to ambient temperature. The reaction was quenched at 0° C. with saturated aqueous NH4Cl and extracted with EtOAc (10 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated to give methyl (N-methyl)-indole-4-carboxylate as a yellow oil, 430 mg (99%). The N-methyl carboxy indole was converted into the N-methyl-[5,6,7]-tricyclic indole in a manner similar to that described for Compound (10) to give 1-N-methyl-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one as a shiny white solid, 256 mg (54%, after recrystallization (CH2Cl2/MeOH/hexanes)). mp 194-195° C.; 1H NMR (300 MHz, d6-DMSO) δ 2.96 (m, 2H), 3.43 (m, 2H), 3.82 (s, 3H), 7.29 (m, 2H), 7.64 (d, 1H, J=7.7 Hz), 7.72 (d, 1H, J=7.7 Hz), 8.09 (br t, 1H); HRMS (FAB, MH+) Calcd for C12H13N2O: 201.1028, Found: 201.1020; Anal. (C12H12N2O.0.2H2O) C, H, N.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[C:8](#N)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(O)C>[C:9]1([C:8]2[S:4][CH2:3][CH:2]([C:5]([OH:7])=[O:6])[N:1]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#Cc1ccccc1
Reactant: N[C@@H](CS)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)C1CSC(c2ccccc2)=N1
Yield: 66 %

Procedure:
Cysteine, benzonitrile, and 5 equivalents of triethylamine were refluxed in ethanol for 6-8 hours to obtain a 66-70% yield of 2-phenylthiazoline-4-carboxylic acid. The 2-phenylthiazoline-4 carboxylic acid was reacted with 2.05 equivalents of base and 1 equivalent of methyl iodide in tetrahydrofuran at 0° C. to form 2-phenyl-4-methylthiazoline-4 carboxylic acid. The 2-phenyl-4-methylthiazoline-4 carboxylic acid can be resolved and isolated as the (S)-enantiomer using emulsion crystallization, and subsequently hydrolyzed with hydrochloric acid, thereby obtaining (S)-2-methylcysteine hydrochloride.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][C:13]([O:15]CC)=O)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([N:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][NH2:24])[CH3:19].O>CN(C=O)C>[CH2:18]([N:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][NH:24][C:13](=[O:15])[CH2:12][N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[N:9]1)[CH3:19]
Reactant: CCOC(=O)Cn1cc(-c2ccccc2)cn1
Reactant: CCN(CC)CCCN
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCCNC(=O)Cn1cc(-c2ccccc2)cn1
Yield: 19.9 %

Procedure:
A solution of 13.5g (0.059 mol) of ethyl 4-phenyl-1H-pyrazole-1-acetate of example 3 and 12.6 mL (0.08 mol) of 3-(diethylamino)propanamine in 130 mL of DMF was stirred at 100° C. for 4hr. The reaction was poured into water, extracted into methlene chloride, and stripped. The residue was triturated in ether and the resulting solid was recrystallized from ether-hexane to yield 3.70g of product, mp 55°-57° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[C:8]([CH3:14])[NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].Cl>[OH-].[Na+]>[CH3:14][C:8]1[NH:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]=2[CH:7]=1
Reactant: COC(=O)c1cccc2[nH]c(C)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc2c(C(=O)O)cccc2[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
To a solution of 2-methylindole-4-carboxylic acid methyl ester (4.3 g; prepared in Reference Example 9) in methanol—dioxane (10 ml+10 ml) was added 5N aqueous solution of sodium hydroxide (10 ml), and the mixture was stirred at 60° C. overnight. To the reaction solution was added 2N hydrochloric acid, and then extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, successively, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform-methanol) to give the title compound (1.6 g) having the following physical data.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12].C(N(C(C)C)CC)(C)C>CN(C=O)C.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.[Cu]I>[CH3:14][Si:13]([C:11]#[C:12][C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)([CH3:16])[CH3:15]
Reactant: Brc1cnc2cccnn12
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)C#Cc1cnc2cccnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A mixture of 3-bromoimidazo[1,2-b]pyridazine (36.78 g, 0.186 mol; prepared according to Stanovnik, B. et al. Synthesis (1981), 12, 987-989), ethynyltrimethylsilane (21.89 g, 0.223 mol), Pd(PPh3)4 (10.73 g, 9.29 mmol), CuI (5.30 g, 0.028 mol), and diisopropylethylamine (32.4 mL, 0.279 mol) in 150 mL of DMF was stirred at ambient temperature, under an atmosphere of N2, for 1 h. The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 0-5% MeOH/DCM) to provide 28.46 g of product.
Reaction SMILES: [C-:1]#[N:2].[K+].C1OCCOCCOCCOCCOCCOC1.Cl[C:23]1[N:32]2[CH:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:35]=[C:31]2[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[N:24]=1.O>C(#N)C>[C:1]([C:23]1[N:32]2[CH:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:35]=[C:31]2[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[N:24]=1)#[N:2]
Reactant: [C-]#N
Reactant: Clc1nc2c(c3nc(-c4ccccc4)cn13)CCCC2
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1nc2c(c3nc(-c4ccccc4)cn13)CCCC2

Procedure:
To a solution of 200 mg of potassium cyanide and 300 mg of 18-crown-6 in 20 mL of acetonitrile was added 5-Chloro-2-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (220 mg). The mixture was refluxed for 2 hours, cooled and poured into water. The aqueous layer was extracted with dichloromethane, the organic layer separated and dried and the solvent removed in vacuum. The resultant crude reaction mixture was chromatographed using 15% ethyl acetate/hexane as eluent to yield 5-Cyano-2-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (Compound 44), m.p. 203°-205° C. "
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Clc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)sc2n1
Reactant: c1c[nH]cn1
Product: Clc1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2,6-dichloro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-chloro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CC([O-])(C)C.[K+].[CH2:7]1[O:15][C:14]2[CH:13]=[CH:12][C:11]([OH:16])=[CH:10][C:9]=2[O:8]1.[K].C(S([C:23]1[CH:28]=[CH:27][C:26](S(CC)(=O)=O)=[CH:25][N:24]=1)(=O)=O)C>CS(C)=O.C1COCC1>[CH2:7]1[O:15][C:14]2[CH:13]=[CH:12][C:11]([O:16][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:10][C:9]=2[O:8]1
Reactant: CCS(=O)(=O)c1ccc(S(=O)(=O)CC)nc1
Reactant: Oc1ccc2c(c1)OCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [K]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: c1ccc(Oc2ccc3c(c2)OCO3)nc1
Temperature: 0 °C

Procedure:
Into a reaction flask was weighed 5.6 g of t-BuOK and then 50 ml of THF was added. In 50 ml of DMSO was dissolved 6.2 g of 3,4-methylenedioxyphenol which was then slowly added to the t-BuOK solution with stirring. To the resulting potassium phenate solution was added 10.5 g of 2,5-bis(ethylsulfonyl)pyridine and this mixture heated at 50°-55° C. for 3 hrs. After cooling, the reaction mixture was poured into 400 g of ice, stirred and then filtered. The solid which was recovered was dissolved in CH2Cl2, treated with charcoal, dried over MgSO4 and then filtered. The CH2Cl2 solution was concentrated to 50 ml, diluted with an equal volume of hexane and then chilled and a crystalline material recovered, which provided 9.9 g, (80% yield), of 5-ethylsulfonyl)-2-(3,4-methylenedioxyphenoxy)pyridine, m.p. 97°-99° C.
Reaction SMILES: [Br-].[Li+].[CH3:3][Li].[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH3:32])[C:19]2[C:24]([NH:25][C:26]3(OCC)[CH2:28][CH2:27]3)=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH3:32])[C:19]2[C:24]([NH:25][C:26]3([CH3:3])[CH2:27][CH2:28]3)=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [Li]C
Reactant: CCOC1(Nc2cccnc2N(C)C2CCN(Cc3ccccc3)CC2)CC1
Agent: [Br-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CN(c1ncccc1NC1(C)CC1)C1CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a mixture of methyllithium-lithium bromide (1.5M in ether, 2.28 ml) in dry toluene (6.3 ml) at -78° under nitrogen in a flame-dried flask is added a mixture of 1-benzyl-4-[N-methyl-N-(3-(1-ethoxycyclopropylamino)-2-pyridinyl)amino]piperidine (EXAMPLE 123, 325 mg) in dry toluene (8.5 ml) at -78°. The mixture is stirred at -78° C. for 1 hr, quenched carefully with saturated aqueous ammonium chloride (10 ml) and water (10 ml) and warmed to 20°-25°. The mixture is extracted with ethyl acetate (25 ml) and the organic phase is washed with water (10 ml) and saline (10 ml), dried over magnesium sulfate and concentrated to give the crude product which is chromatographed (silica gel, 230-400 mesh, 35 g; eluting with a gradient of methanol/chloroform (1/99-4/96)) to give the title compound, NMR (CDCl3) 7.72, 7.31, 7.25, 7.17, 6.91, 5.02, 3.50, 3.02, 2.88, 2.59, 2.01, 1.71, 1.32, 0.75 and 0.65δ.
Reaction SMILES: [CH2:1]([N:4]([CH2:36][CH2:37][CH3:38])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:32][C:33]([OH:35])=[O:34])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:26][C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)[CH2:19][C:20]2[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=2)=[CH:13][CH:12]=1)[CH2:2][CH3:3].C(Cl)(Cl)Cl.[CH2:43]([OH:49])[CH2:44][O:45][CH2:46][CH2:47]O>>[OH:49][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:34][C:33](=[O:35])[CH2:32][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:36][CH2:37][CH3:38])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:26][C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)[CH2:19][C:20]2[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=2)=[CH:13][CH:12]=1
Reactant: OCCOCCO
Reactant: CCCN(CCC)CCCCN(CC(=O)O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)CCCCN(CC(=O)OCCOCCO)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
The compound (424.0 mg) obtained in Example 65-1 was dissolved in diethylene glycol (8.0 ml) and the whole was stirred at 80° C. for 3 days. After completion of the reaction, the resultant was added with chloroform and washed with water, followed by drying with magnesium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (280.2 mg) of the subject compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12]C)=[O:11])=[N:8][CH:9]=1.[OH-].[K+:17].CO>O>[F:15][C:2]([F:1])([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([O-:12])=[O:11])=[N:8][CH:9]=1.[K+:17]
Reactant: COC(=O)c1ccc(OC(F)(F)F)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C([O-])c1ccc(OC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 122 %

Procedure:
A mixture of methyl 5-(trifluoromethoxy)pyridine-2-carboxylate (0.313 g, 1.41 mmol), potassium hydroxide (0.076 g, 1.35 mmol) in a 5:1 MeOH:water mixture (3 mL) was stirred at room temperature for 1 h. Additional potassium hydroxide (0.015 g, 0.267 mmol) in water (0.2 mL) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated to dryness and azeotroped twice with toluene to give the potassium 5-(trifluoromethoxy)pyridine-2-carboxylate intermediate (404 mg 100%). A fraction of this intermediate (0.173 g, 0.706 mmol) was dissolved in oxalyl chloride (4 mL) and the mixture was stirred at room temperature for 2 h before being evaporated to dryness and used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH:8]([OH:12])[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8](=[O:12])[CH2:9][O:10][CH3:11])=[CH:13][CH:14]=1
Reactant: COCC(O)COc1ccc(F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCC(=O)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
Dissolve 1-(4-fluorophenoxy)-3-methoxy-propan-2-ol (2.6 g, 12.99 mmol) in DCM (26 mL) and add molecular sieves, pyridinium chlorochromate (7.14 g, 32.47 mmol), and pyridine (5.25 mL, 64.93 mmol). Stir the mixture at ambient temperature overnight. Filter the mixture through a Celite® plug and wash the plug with Et2O. Concentrate the filtrate; then purify via flash column chromatography using 25% EtOAc in hexanes to provide the product as a clear oil (872 mg, 33.9%). MS (m/z): 216 (M+NH4).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14](I)=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1.[CH2:19]([O:22][CH2:23]C#C)[C:20]#[CH:21]>C(NCC)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.[Cu]I>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:21]#[C:20][CH2:19][O:22][CH3:23])=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1
Reactant: CN1Cc2c(I)ncn2-c2ccc(F)cc2C1=O
Reactant: C#CCOCC#C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: COCC#Cc1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2

Procedure:
7 g (19.9 mmol) of 8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 3 hours with 2.5 ml (29 mmol) of propargyl ether, 100 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 30 mg of copper(I) iodide in 70 ml of diethylamine. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate there was obtained 8-fluoro-4,5-dihydro-3-(3-methoxy-1-propynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 146°-147°.
Reaction SMILES: I[C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1>C(#N)C>[C@@H:7]1([N:6]2[CH:15]=[CH:2][C:3]([NH2:17])=[N:4][C:5]2=[O:16])[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1
Reactant: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Solvent: CC#N
Product: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Temperature: 25 °C
Yield: 111.9 %

Procedure:
Into acetonitrile (30 mL), 1.0 g of 5-iodo-2′-deoxycytidine [the compound (57) in the above synthesis route], (manufactured by Wako Pure Chemical Industries, Ltd.), was suspended, and after the addition of o-bis(trimethylsilyl)acetamide (TMS-Acetamide) (3 mL) by purging with Ar, the solution was subjected to stirring under refluxing for 2 hours. After cooling the reaction solution to room temperature, bis(acetonitrile)dichloropalladium (II) [PdCl2(CH3CN)2] (40 mg) and 2 g of the partial linker A [the compound (53) in the above synthesis route] were added to further stirring at 50 to 60° C. for 20 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was subjected to purification by using silica gel column (elution liquid: trichloromethane/methanol=9/1) to give 720 mg of a 2′-deoxycytidine derivative [the compound (58) in the above synthesis route] by crystallization from diethyl ether (yield; 67.3%).