Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:12]([C:13]2[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:20]3[C:15](=[CH:16][N:17]=[C:18]4[NH:28][CH:27]=[CH:26][C:19]4=3)[CH:14]=2)=[CH:11][C:10]([O:29][CH3:30])=[CH:9][C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[CH2:31]([O:33][C:34](=[O:37])[CH2:35]Cl)[CH3:32].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:31]([O:33][C:34](=[O:37])[CH2:35][N:28]1[C:18]2=[N:17][CH:16]=[C:15]3[C:20]([N:21]([CH2:24][CH3:25])[C:22](=[O:23])[C:13]([C:12]4[CH:11]=[C:10]([O:29][CH3:30])[CH:9]=[C:3]([C:4](=[O:5])[NH:6][CH2:7][CH3:8])[C:2]=4[Cl:1])=[CH:14]3)=[C:19]2[CH:26]=[CH:27]1)[CH3:32]
Reactant: CCNC(=O)c1cc(OC)cc(-c2cc3cnc4[nH]ccc4c3n(CC)c2=O)c1Cl
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCNC(=O)c1cc(OC)cc(-c2cc3cnc4c(ccn4CC(=O)OCC)c3n(CC)c2=O)c1Cl
Temperature: 60 °C

Procedure:
A mixture of 2-chloro-N-ethyl-3-(9-ethyl-8-oxo-8,9-dihydro-3H-3,4,9-triaza-cyclopenta[a]naphthalen-7-yl)-5-methoxy-benzamide (7.6 mg, 0.018 mmol), chloro-acetic acid ethyl ester (2.2 mg, 0.018 mmol), potassium carbonate (0.89 mg, 0.0064 mmol) and acetone (0.5 mL) is heated up to 60° C. for 2 h. Solvent is removed and water is added. The mixture is extracted with chloroform and methanol (20:1) and the extracts is combined and dried with MgSO4. After removal of the solvent, the residue is purified on silica gel column (ethyl acetate:hexane=4:1) to give desired product. MS m/z 511.1 (M+1). 2.5 mg of the product is hydrolyzed with LiOH.H2O in THF, MeOH and H2O at rt for 1 h to give the desired acid product. MS m/z 483.1 (M+1).
Reaction SMILES: B(Br)(Br)Br.[CH3:5][O:6][C:7]1[CH:21]=[CH:20][C:10]2[N:11]3[CH2:19][CH2:18][CH2:17][C:12]3=[N:13][S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=1.[OH2:22]>C(Cl)Cl>[O:15]=[S:14]1(=[O:16])[C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:9]=[C:8]([OH:22])[CH:7]=[CH:21][CH:20]=3)[CH:21]=[CH:20][C:10]=2[N:11]2[CH2:19][CH2:18][CH2:17][C:12]2=[N:13]1
Reactant: O
Reactant: COc1ccc2c(c1)S(=O)(=O)N=C1CCCN12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S1(=O)N=C2CCCN2c2ccc(Oc3cccc(O)c3)cc21
Reaction time: 24 h

Procedure:
A solution of 68.75 mmol of BBr3 in 25 ml of methylene chloride is added dropwise to a solution, cooled to 0° C., of 27.50 mmol of 7-methoxy-2,3-dihydro-1H-pyrrolo-[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide in 350 ml of methylene chloride. Stirring is carried out at ambient temperature for 24 hours. The reaction mixture is poured into a mixture of ice and water, and the suspension is stirred for 30 minutes. The precipitate is filtered off, rinsed several times with water, filtered under suction and dried in vacuo to yield the expected product.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[C:5]2[C:19]([CH3:26])=[C:20]([OH:25])[C:21]([CH3:24])=[C:22]([CH3:23])[C:4]=2[O:3]1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1>>[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][O:25][C:20]2[C:21]([CH3:24])=[C:22]([CH3:23])[C:4]3[O:3][C:2]([CH3:27])([CH3:1])[CH:6]([C:7]4[CH:8]=[CH:9][C:10]([N:13]5[CH2:14][CH2:15][O:16][CH2:17][CH2:18]5)=[CH:11][CH:12]=4)[C:5]=3[C:19]=2[CH3:26])=[CH:32][CH:31]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(N3CCOCC3)cc1)C(C)(C)O2
Product: COc1ccc(COc2c(C)c(C)c3c(c2C)C(c2ccc(N4CCOCC4)cc2)C(C)(C)O3)cc1
Yield: 38 %

Procedure:
Using 2,2,4,6,7-pentamethyl-3-[4-(4-morpholinyl)phenyl]-2,3-dihydrobenzofuran-5-ol and 4-methoxybenzyl chloride, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.[C:17]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)(=O)[CH3:18].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH3:18])=[CH:9][CH:10]=1
Reactant: CC(=O)c1cccnc1
Reactant: Nc1ccc(Oc2ccc(F)cc2F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(Nc1ccc(Oc2ccc(F)cc2F)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of N-(4-(2,4-difluorophenoxy)phenyl)amine (1.0 equiv.) in dichloromethane (0.2 M) was cooled to 0° C. and treated with 3-acetylpyridine (Aldrich; 1.4 equiv.), acetic acid (5.0 equiv.), and sodium triacetoxyborohydride (2.5 equiv.). The reaction was allowed to warm to ambient temperature and stirred an additional 22 hours. The reaction was cautiously quenched with saturated aqueous NaHCO3 then adjusted to pH=10 with 1 N NaOH. The mixture was stirred for 4 hours then the layers were separated. The aqueous layer was extracted twice with DCM. The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified via radial chromatography eluting with 50:50 to 60:40 ethyl acetate/hexanes to give N-(4-(2,4-difluorophenoxy)phenyl)-1-pyrid-3-ylethylamine. 1H NMR (400 MHz) 1.54 (3H, d, J=6.7 Hz), 3.96 (1H, bs), 4.48 (1H, q, J=6.7 Hz), 6.44 (2H, m), 6.76 (2H, m), 6.83-6.93 (2H, m), 7.24 (1H, m), 7.44 (1H, m), 7.68 (1H, td, J=1.8, 7.9 Hz), 8.50 (1H, d, J=3.8 Hz), 8.64 (1H, bs). HRMS calcd 327.1309. Found 327.1308.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]1[C:14]2[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:35])C(=O)C1>CC#N>[C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]1[C:14]2[CH:15]=[C:16]([Br:35])[C:17]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCCCc2cc(OCC3CCCCC3)ccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCCCc2cc(OCC3CCCCC3)c(Br)cc21
Reaction time: 1.5 h
Yield: 88.6 %

Procedure:
To (2-cyclohexylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-carbamic acid tert-butyl ester (7.93 g, 21.2 mmol) in CH3CN (300 mL) was added NBS (3.96 g, 22.3 mmol). The mixture was stirred for 1.5 h, then blown dry under a stream of N2. The residue was resuspended in CCl4, filtered, and concentrated to a solid. The solid was recrystallized from CH3CN to yield a white solid (8.5 g, 88%). MS [M−H]− 452, m.p. 142-144° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[C-]#N.[Na+].[C:12](O)(=[O:14])[CH3:13]>[O-2].[O-2].[Mn+4].C(O)C>[Br:1][C:2]1[S:6][C:5]([C:7]([O:14][CH2:12][CH3:13])=[O:8])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: CC(=O)O
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 1.092 g (5.7157 mmol) of 5-bromothiophene-2-carboxaldehyde was added sequentially, 1.507 g (30.75 mmol) sodium cyanide, 60 ml ethanol, 602.5 mg (10.04 mmol) of acetic acid and 10.62 g (122.16 mmol) of manganese dioxide. This mixture was stirred at room temperature for 24 hours, then filtered through celite and the residue washed several times with ether. The combined filtrates were concentrated, then the residue taken up in water and extracted with 3×75 ml ether. Combined ether extracts were washed with saturated NaHCO3, saturated NaCl, dried (MgSO4), concentrated in vacuo and kugelrohr distilled (70° C.; 0.1 mm) to give the captioned compound as a pale yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]=1[CH2:34][C:35]#[N:36].CN(C)C=O.[H-].[Na+]>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH2:34][C:35]#[N:36])=[CH:4][CH:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: N#CCc1c(O)ccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc3ccccc3c2CC#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (4.52 g), 2-(2-hydroxy-1-naphthyl)acetonitrile (0.58 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60%, oil, 0.14 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (1.11 g, 76%) of 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 178-179° C.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([N:39]1[CH2:38][CH2:37][N:36]([C:33]2[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=2)[CH2:41][CH2:40]1)=[O:16]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Nc1onc(-c2ccccc2Cl)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2ccccc2Cl)c1C(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 76.1 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-chlorophenyl)isoxazol-4-carboxylic acid (440 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(4-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (561 mg, 1.40 mmol, 76%) was obtained.
Reaction SMILES: F[C:2]1[C:3]([C:10]#[N:11])=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[I:8].O.[NH2:13][NH2:14]>C(O)CCC>[F:9][C:6]1[C:7]([I:8])=[C:2]2[NH:14][N:13]=[C:10]([NH2:11])[C:3]2=[N:4][CH:5]=1
Reactant: N#Cc1ncc(F)c(I)c1F
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: Nc1n[nH]c2c(I)c(F)cnc12
Temperature: 105 °C
Yield: 28 %

Procedure:
3,5-Difluoro-4-iodopicolinonitrile (1.0 g) was combined with butan-1-ol (10 mL) and hydrazine hydrate (100%, 0.82 mL) was added. The reaction was heated at 105° C. and after 2 hours cooled to room temperature, filtered, the filter rinsed with water, and the filtrate was concentrated to give a residue. The residue was washed with water and filtered to give 6-fluoro-7-iodo-1H-pyrazolo[4,3-b]pyridin-3-amine (27) as a solid (290 mg, 28% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (s, 1H) 5.59 (s, 2H). MS [M+H] found 279.0
Reaction SMILES: O[C@H:2]1[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.OC[C@@H]1CCCN1C(OC(C)(C)C)=O.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][N:40]([C:43]3[CH:48]=[CH:47][C:46]([O:49][C@@H:50]4CCN(C(OC(C)(C)C)=O)C4)=[CH:45][CH:44]=3)[C:39](=[O:62])[CH:38]=2)=[N:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][N:40]([C:43]3[CH:44]=[CH:45][C:46]([O:49][CH2:50][C@@H:3]4[CH2:2][CH2:6][CH2:5][NH:4]4)=[CH:47][CH:48]=3)[C:39](=[O:62])[CH:38]=2)=[N:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(-n3ccc(OCc4ccc(Cl)cn4)cc3=O)cc2)C1
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Product: O=c1cc(OCc2ccc(Cl)cn2)ccn1-c1ccc(OC[C@@H]2CCCN2)cc1

Procedure:
Example 120 was repeated except that tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate was replaced with tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate. The resulting compound was used in placed of 4-[(5-chloro-2-pyridinyl)methoxy]-1-(4-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy}phenyl)-1H-pyridin-2-one which was used in Example 121. Otherwise repeating Example 121, the title compound was obtained.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:13]=[C:12]([CH2:14][N:15]3[N:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[N:16]3)[O:11][N:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[CH:13]=[C:12]([CH2:14][N:15]3[N:19]=[C:18]([NH2:20])[CH:17]=[N:16]3)[O:11][N:10]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2cc(Cn3ncc([N+](=O)[O-])n3)on2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC1(c2cc(Cn3ncc(N)n3)on2)OCCO1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-[3-(2-methyl-[1,3]dioxolan-2-yl)-isoxazol-5-ylmethyl]-4-nitro-2H-[1,2,3]triazole (95 mg, 0.34 mmol), iron powder (57 mg, 1.01 mmol) and NH4Cl (91 mg, 1.69 mmol) in a mixture of EtOH (2.0 mL) and water (1.0 mL) was stirred at 85° C. for 15 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (10 mL) was added followed by 1N NaOH (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a light yellow oil. LC-MS-conditions 02: tR=0.66 min; [M+H]+=252.34.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH3:13][C:14]([O-])(C)C.[K+].C(Br)C>CN(C=O)C.Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:13][CH3:14])[C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCc2cc(Br)ccc2N1
Agent: Cl
Agent: [K+]
Solvent: CCBr
Solvent: CN(C)C=O
Product: CCN1C(=O)CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of 6-bromo-3,4-dihydro-1H-quinolin-2-one (750 mg, 3.32 mmol) in 20 ml dry DMF was added potassium tert-butylate (804 mg, 6.64 mmol). After the mixture was stirred for 30 min at room temperature, a solution of ethyl bromide (724 mg, 6.64 mmol) in 10 ml dry DMF was added. Following overnight stirring, the mixture was diluted with 150 ml 1 N HCl. Extraction with ethyl acetate (2×100 mL) followed by washing of the organic extracts with water and brine, drying over MgSO4 and removal of the solvent in vacuo gave a light yellow solid. Purification by flash chromatography (hexanes/ethyl acetate, 1/1, Rf=0.52) gave 6-bromo-1-ethyl-3,4-dihydro-1H-quinolin-2-one (583 mg, 2.29 mmol, 59%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[O:8][CH:7]([CH2:9][OH:10])[C@H:6]([OH:11])[C@@H:5]([OH:12])[C@@H:4]1[OH:13].[C:14](O)(=[O:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[C:14]([O:10][CH2:9][C@H:7]1[O:8][CH:3]([O:2][CH3:1])[C@H:4]([OH:13])[C@@H:5]([OH:12])[C@@H:6]1[OH:11])(=[O:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCC(=O)O
Reactant: CO[C@H]1OC(CO)[C@H](O)[C@@H](O)[C@@H]1O
Product: CCCCCCCCCC(=O)OC[C@H]1OC(OC)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 59 %

Procedure:
Methyl-D-glucopyranoside (a 2:3 mixture of the α- and β-anomers) (24 g, 0.12 mol, prepared according to Example 6) was esterified with decanoic acid (43 g, 0.25 mol) by the procedure described in Example 1 using 2.4 g of an immobilized lipase (derived from Candida antarctica). After 17 hours the enzyme was removed by filtration (at 80° C.) HPLC analysis of the crude product showed 77% of the title compound, 15% diesters and 8% methyl-D-glucopyranoside. Part of the crude product was purified by chromatography, yielding 39.4 g (59%) of the title compound which was identified by NMR spectroscopy.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1.[I-].[K+].[CH3:26][CH:27]=[CH:28][CH2:29][NH2:30]>O1CCCC1>[CH2:28]([CH2:29][NH:30][CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1)[CH:27]=[CH2:26]
Reactant: ClCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2
Reactant: CC=CCN
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCNCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 32, 1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide, and methylallylamine in tetrahydrofuran are reacted to give 1-[(allylmethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].CS[C:17]1[NH:22][C:21](=[O:23])[C:20]([O:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:19][N:18]=1>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]2[NH:22][C:21](=[O:23])[C:20]([O:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:19][N:18]=2)[N:9]=1)[CH3:1]
Reactant: CSc1ncc(OCc2cccnc2)c(=O)[nH]1
Reactant: CN(C)Cc1nc(CSCCN)cs1
Solvent: c1ccncc1
Product: CN(C)Cc1nc(CSCCNc2ncc(OCc3cccnc3)c(=O)[nH]2)cs1

Procedure:
A reaction mixture was prepared from 1.26 g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine and 1.36 g. of 2-methylthio-5-(3-pyridyl)methoxy-4-pyrimidone in 20 ml. of pyridine. The reaction mixture was heated to reflux temperature for about 2 days. The pyridine was then removed by evaporation in vacuo and the resulting residue subjected to high pressure liquid chromatography over silica. Fractions shown by tlc to contain the desired compound were combined and the combined fractions rechromatographed on a silica preparative plate using 3% ammoniated ethanol as the solvent. 2-[2-(2-Dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(3-pyridyl)methoxy-4-pyrimidone free base thus obtained was converted to the trihydrochloride salt by standard procedures. Recrystallization of the crude trihydrochloride salt from ethanol yielded 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(3-pyridyl)methoxy-4-pyrimidone trihydrochloride melting at 183°-185° C.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][O:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.N1CCCC1>C(O)C>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[C:18]2[O:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]3[N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=3)[C:19]2=[O:20])=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C1COC(=O)N1CCCCSc1cccc2nccn12
Solvent: CCO
Solvent: C1CCNC1
Product: O=C1OC(=Cc2ccc(Cl)cc2)C(=O)N1CCCCSc1cccc2nccn12

Procedure:
To a solution of 1.527 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]oxazolidine-2,4-dione and 0.703 g (5.0 mmol) of 4-chlorobenzaldehyde in 20 ml of ethanol, 0.04 ml (0.5 mmol) of pyrrolidine was added, followed by refluxing for 23 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=3/1) to yield 0.301 g (14.1%, white crystal) of the desired product.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][N:18]=1)[C:13]([OH:15])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:25]([NH:33][NH2:34])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:25]([NH:33][NH:34][C:13]([C:12]1[CH:16]=[CH:17][N:18]=[C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:11]=1)=[O:15])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NNC(=O)c1ccccc1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NNC(=O)c1ccnc(NC(=O)c2ccccc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a solution of 2-benzamidoisonicotinic acid (0.30 g, 1.23 mmol) and N,N-dimethylformamide (0.1 mL) in dichloromethane (5 mL) was added oxalyl chloride (0.13 mL, 1.48 mmol) at ambient temperature. The reaction mixture was stirred for 1 hour and concentrated in vacuo. The residue was dissolved in N,N-dimethylformamide (2 mL) and added to a solution of benzohydrazide (0.20 g, 1.48 mmol) and pyridine (0.3 mL, 3.70 mmol) in N,N-dimethylformamide (1 mL) at 0° C. The reaction mixture was warmed to ambient temperature, stirred for 3 hours, diluted with ethyl acetate (30 mL), and washed with water (25 mL) and brine (25 mL). The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from ethyl acetate to give N-(4-(2-benzoylhydrazinecarbonyl)pyridin-2-yl)benzamide (0.30 g, 67%): 1H NMR (300 MHz, DMSO-d6) δ 11.01 (s, 1H), 10.80 (s, 1H), 10.59 (s, 1H), 8.61 (s, 1H), 8.02-7.88 (m, 5H), 7.65-7.49 (m, 7H); MS (ES+) m/z 361.4 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][CH:7]1[CH2:12][NH:11][CH2:10][CH:9]([CH3:13])[NH:8]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:6][CH:7]1[NH:8][CH:9]([CH3:13])[CH2:10][N:11]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12]1
Reactant: CC1CNCC(C)N1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CN(S(C)(=O)=O)CC(C)N1
Reaction time: 0.5 h

Procedure:
A solution of methanesulfonyl chloride (1.42 mL, 18.4 mmol) in DCM (10 mL) was added dropwise to a solution of 2,6-dimethylpiperazine (2 g, 17.5 mmol) and triethylamine (2.56 mL, 18.4 mmol) in DCM (10 mL) under nitrogen. The mixture was stirred for 30 min. The solvent was removed and the residue was applied to a 5 g aminopropyl SPE cartridge to give the product as a yellow solid (2.3 g), ˜10:1 mixture of cis and trans isomers by NMR.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=2[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:4]=1)=O.[NH2:23][C:24]1([CH2:37][CH3:38])[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:33]([O:32][C:30]([N:27]1[CH2:26][CH2:25][C:24]([NH:23][CH2:1][C:3]2[C:11]3[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=3[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:4]=2)([CH2:37][CH3:38])[CH2:29][CH2:28]1)=[O:31])([CH3:34])([CH3:36])[CH3:35]
Reactant: CCC1(N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: COC(=O)c1ccnc2c1c(C=O)cn2C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCC1(NCc2cn(C(=O)OC(C)(C)C)c3nccc(C(=O)OC)c23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
1-tert-Butyl 4-methyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate (211 mg, 0.692 mmol) was dissolved in MeOH (10 mL) and tert-butyl 4-amino-4-ethylpiperidine-1-carboxylate (158 mg, 0.692 mmol) were added followed by 2 drops of acetic acid. The solution was allowed to stir at room temperature for 2 h. Then sodium cyanoborohydride (44 mg, 0.692 mmol) was added over the course of 6 h at room temperature. The solution was quenched with water and extracted with ethyl acetate. The organics were dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (70% EtOAc/Hexanes) gave 127 mg of 1-tert-butyl 4-methyl 3-((1-(tert-butoxycarbonyl)-4-ethylpiperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate. [M+H] found 417.