Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:25]=[C:24]2[O:26][CH2:27][O:28][C:23]2=[CH:22][C:5]=1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1>CN(C=O)C>[Cl:3][C:4]1[CH:25]=[C:24]2[O:26][CH2:27][O:28][C:23]2=[CH:22][C:5]=1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:35][C:34]3[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:39])[F:40])=[CH:38][CH:37]=3)=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1cc2cc(O)ccc2n1Cc1cc2c(cc1Cl)OCO2
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCc3ccc(C(F)(F)F)cc3)ccc2n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a stirring suspension of sodium hydride (0.016 g, (60% in mineral oil), 0.402 mmol) in DMF (2 mL) was added ethyl 1-(2-chloro-4,5-methylenedioxybenzyl)-5-hydroxyindole-2-carboxylate (0.100 g, 0.268 mmol). After 15 minutes, 4-trifluoromethylbenzyl bromide (0.096 g, 0.402 mmol) was added. After 1.5 hours, the mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and saturated brine, dried (MgSO4), filtered and concentrated to a residue that was purified by column chromatography (ethyl acetate/hexane) to give the title compound as a white solid (0.124 g, 87%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][CH:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[N:21]=2)[CH2:14][CH2:13]1)[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30]>ClCCCl>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][CH:10]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[N:21]=2)[C:32]([NH:31][CH2:29][CH3:30])=[O:33])[CH2:16][CH2:17]1)[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN=C=O
Reactant: CC(CCNC(=O)OC(C)(C)C)N1CCC(NCc2cccc(C#N)n2)CC1
Solvent: ClCCCl
Product: CCNC(=O)N(Cc1cccc(C#N)n1)C1CCN(C(C)CCNC(=O)OC(C)(C)C)CC1
Temperature: 55 °C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
(3-{4-[(6-Cyano-pyridin-2-ylmethyl)-amino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (0.067 g, 0.17 mmol) and ethyl isocyanate (20 μL, 0.25 mmol) were combined in 1,2-dichloroethane (5 ml) and the resulting mixture was stirred at 55° C. for 16 h. The solvent was removed in vacuo and the crude residue was purified by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 93:6:1, v/v/v) to give (3-{4-[1-(6-cyano-pyridin-2-ylmethyl)-3-ethyl-ureido]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (0.075 g, 95%) as a white foam. 1H NMR (CDCl3) δ 0.93 (d, 3H, J=6.0 Hz), 1.12 (t, 3H, J=7.5 Hz), 1.40 (s+m, 13H), 1.65 (m, 1H), 1.92 (m, 2H), 2.18 (br t, 1H, J=9.0 Hz), 2.52 (m, 2H), 2.69-2.85 (m, 3H), 3.09 (m, 1H), 3.21-3.33 (m, 3H), 4.12 (m, 1H), 4.44 (s, 2H), 5.33 (br s, 1H), 5.95 (br s, 1H), 7.57 (d, 1H, J=9.0 Hz), 7.61 (d, 1H, J=9.0 Hz), 7.83 (t, 1H, J=7.5 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][C:15]#[N:16])[C:8](=[O:17])[C:7]12[O:22][CH2:21][CH2:20][CH2:19][O:18]1)([O-])=O.N.C1COCC1>[Ni].CCO>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][NH2:16])[C:8](=[O:17])[C:7]12[O:22][CH2:21][CH2:20][CH2:19][O:18]1
Reactant: N#CCCN1C(=O)C2(OCCCO2)c2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CCO
Product: NCCCN1C(=O)C2(OCCCO2)c2cc(N)ccc21
Yield: 73 %

Procedure:
A mixture of 3-(5′-nitro-2′-oxospiro[1,3-dioxane-2,3′-indol]-1′(2′H) -yl)propanenitrile (2.12 g, 7.76 mmol) and wet Raney Nickel (2.29 g) in 2M EtOH.NH3 (95 mL) and THF (35 mL) was hydrogenated in a Parr Hydrogenation Bottle at 50 lb/in2 H2 for 17 hr. The Raney Nickel was removed by filtration through Celite and the filtrate was concentrated. The crude product was purified on Biotage KP silica gel eluting with a step gradient of CH2Cl2/CH3OH/NH4OH (95/3/2) to (85/10/5) to give the title compound as a yellow foam (1.57 g, 73% yield). NMR (300 Mz, DMSO-d6): consistent
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].Br[CH2:14][CH2:15][CH2:16][CH3:17].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:14]([O:12][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCBr
Reactant: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1cc(C)c([N+](=O)[O-])c(C)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
Formation of compound (c): A mixture of 3,5-dimethyl-4-nitrophenol (b) (2 g, 12 mmol), bromobutane (1.6 mL, 15 mmol), K2CO3 (2.1 g, 15 mmol) in DMF (6 mL) was stirred at 60° C. for 6 hours. The reaction mixture was poured into 50 mL of H2O and extracted with ether (3×50 mL). The combined ether layer was washed with H2O and subsequently with brine, dried over Na2SO4, filtered and concentrated to give compound (c), 4-butoxy-2,6-dimethyl-nitrobenzene (2.6 g, 97% yield) as a dark brown oil. 1H-NMR in CDCl3.
Reaction SMILES: [OH-:1].[Na+].[C:3]([CH2:6][CH2:7][S:8][CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20]#[N:21])[C:14]=2[CH2:13][O:12][C:11]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][C:32]([Cl:38])=[CH:33][CH:34]=4)[N:29]=3)=[CH:25][C:10]1=2)([OH:5])=[O:4].O>C(O)C>[C:20]([C:19]1[C:14]2[CH2:13][O:12][C:11]3[CH:22]=[CH:23][C:24]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][C:32]([Cl:38])=[CH:33][CH:34]=5)[N:29]=4)=[CH:25][C:10]=3[CH:9]([S:8][CH2:7][CH2:6][C:3]([OH:5])=[O:4])[C:15]=2[CH:16]=[CH:17][CH:18]=1)(=[O:1])[NH2:21]
Reactant: [OH-]
Reactant: N#Cc1cccc2c1COc1ccc(OCc3ccc4ccc(Cl)cc4n3)cc1C2SCCC(=O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1cccc2c1COc1ccc(OCc3ccc4ccc(Cl)cc4n3)cc1C2SCCC(=O)O

Procedure:
40 ml of a 1N-sodium hydroxide aqueous solution was added to 0.85 g of the compound 11-(2-carboxyethylthio)-2-(7-chloroquinolin-2-yl)methoxy-7-cyano-6,11-dihydrodibenz[b,e]oxepine obtained in Example 15 dissolved in 10 ml of ethanol and the mixture was refluxed under heating for 2 hours. After completion of the reaction, water was added to the residue obtained by removing the solvent, the mixture was adjusted to about pH 3 with 1N-hydrochloric acid and crystals precipitated were dissolved in ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and condensed. The resulting residue was applied to silica gel column chromatography to obtain 0.25 g of the title compound as slightly yellow powder.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:8]=1.Br[C:24]1[N:29]=[C:28]([NH2:30])[CH:27]=[CH:26][CH:25]=1>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.CN(C)C=O>[NH2:30][C:28]1[N:29]=[C:24]([C:3]2[CH:4]=[CH:5][C:6]3[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[O:13])[N:11]=3)[CH:8]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: C[Sn](C)(C)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Reactant: Nc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1cccc(-c2ccc3nc(C(=O)Nc4ccccc4)cn3c2)n1
Yield: 75.7 %

Procedure:
236 mg of 6-trimethylstannyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 4), 413 mg of 6-bromopyrid-2-ylamine, 95 mg of tetrakis(triphenylphosphine)palladium and 4 mL of N,N-dimethylformamide are placed in a microwave tube. The reaction mixture is heated for 45 minutes in a microwave machine set at 150° C. and concentrated to dryness. The residue is chromatographed on a silica cartridge, eluting with a mixture of dichloromethane and ethyl acetate. The fractions containing the expected product are combined and evaporated to dryness under reduced pressure to give 147 mg of 6-(6-aminopyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a yellow solid, which product is taken up in a mixture of dioxane and methanol and treated with 112 μL of a 4 M solution of hydrogen chloride in dioxane. After stirring for 1 hour at room temperature, the precipitate is filtered off by suction, washed with dioxane and dried to give 156 mg of 6-(6-aminopyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide hydrochloride (1:1) in the form of a pale yellow solid.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[N:4]/[C:5](/[C:10]#[N:11])=[C:6](/[NH2:9])\[C:7]#[N:8].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C=CC=N/C(/C#N)=C(/N)\C#N.C(#N)C>C(#N)C>[CH:2]([C:3]1[NH:4][C:5]([C:10]#[N:11])=[C:6]([C:7]#[N:8])[N:9]=1)=[CH2:1]
Reactant: C=CC=N/C(C#N)=C(/N)C#N
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC#N
Product: C=Cc1nc(C#N)c(C#N)[nH]1
Reaction time: 0.17 h
Yield: 82 %

Procedure:
The acrodamn, prepared as per the earlier described method, was used in this present synthesis. The acrodamn (7.00 g) was dissolved in 150 ml of distilled acetonitrile, yielding an orange solution. A solution of 22.5 g of lead (IV) tetraacetate and 300 ml of distilled acetonitrile was placed in a room temperature water bath. The acrodamn/acetonitrile solution was poured, in one portion, into the lead (IV) tetraacetate solution. The colorless lead solution immediately darkened to an orange-red solution and a white, voluminous precipitate with a metallic sheen appeared. The solution was allowed to stir for 10 minutes, and then filtered. The resulting precipitate was washed via filtration until no more color was liberated in the filtrate. The filtrate was then rotovapped and stripped with a vacuum pump. To the resulting residue, 400 ml of ether was added and allowed to stir overnight. The ether solution was filtered and rotovapped to yield 5.63 g of 2-vinyl-4,5-dicyanoimidazole (82%) as a reddish solid. This crude product shows very small traces of unidentified impurity and may be purified by dissolving in a minimum of ethyl acetate, pouring the ethyl acetate into ether, filtering the precipitate, and evaporating the filtrate to recover the product for essentially quantitative recovery.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].[Cl:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[Cl:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[CH:7]=[C:6]([S:8][C:9]([F:12])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[OH:13])=[O:18]
Reactant: Nc1cc(SC(F)(F)F)ccc1O
Reactant: O=C(O)c1ccncc1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc(SC(F)(F)F)ccc1O)c1ccncc1Cl
Temperature: 80 °C
Yield: 63.3 %

Procedure:
A mixture of 0.60 g of 2-amino-4-(trifluoromethylthio)phenol, 0.45 g of 3-chloroisonicotinic acid, 0.71 g of WSC and 6 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.63 g of 3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[N:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=3[CH3:29])[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1>>[CH3:29][C:23]1[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=1[N:19]1[CH2:18][CH2:17][N:16]([C:14]([C:11]2[CH:10]=[CH:9][C:8]([N:1]3[CH2:5][CH2:4][CH2:3][C:2]3=[O:6])=[N:13][CH:12]=2)=[O:15])[CH2:21][CH2:20]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCC4=O)nc3)CC2)c(C)c1
Yield: 56.6 %

Procedure:
Using pyrrolidin-2-one (89 mg) and (6-bromopyridin-3-yl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (374 mg) described in Preparation Example 115 and by the reaction and treatment in the same manner as in Example 1, the title compound (214 mg) was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C@@H:14]2[CH2:19][CH2:18][NH:17][CH2:16][C@@H:15]2[CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:22]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:42](Cl)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]>ClCCl>[C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C@@H:14]2[CH2:19][CH2:18][N:17]([C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:16][C@H:15]2[CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:22]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(NC(=O)N[C@@H]2CCNC[C@@H]2CN2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cccc(NC(=O)N[C@@H]2CCN(C(=O)C(C)(C)C)C[C@H]2CN2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reaction time: 17 h
Yield: 46.7 %

Procedure:
In a dry flask 1-(3-acetyl-phenyl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea (43 mg, 0.07 mmol) was dissolved in dichloromethane (2 mL), and then triethylamine (65 μL, 0.47 mmol) and pivaloyl chloride (12 μL, 0.10 mmol) were added. The reaction mixture was stirred for 17 hours. The reaction mixture was concentrated in vacuo then was purified by preparative reverse-phase HPLC (10-80% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (18 mg, 38%). 1H NMR (300 MHz, CD3OD), δ: 8.04 (s, 1H), 7.64 (d, 1H, J=7), 7.58 (dd, 1H, J=7, J′=1), 7.40 (t, 1H, J=8), 7.19 (m, 2H), 6.99 (t, 2H, J=9), 4.27 (d, 1H, J=14), 4.14 (d, 1H, J=15), 3.71 (m, 1H), 3.48 (bm, 3H), 3.25 (m, 2H), 3.07 (m, 1H), 2.95 (m, 2H), 2.66 (m, 2H), 2.57 (s, 3H), 1.98 (m, 4H), 1.76 (m, 2H), 1.62 (m, 1H), 1.28 (s, 9H), 1.20 (m, 1H). HRMS (ESI), C32H44FN4O3 m+/z: calc. 551.3397, found=551.3402.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]([C:9](=O)[CH2:10]Br)=[C:6]([CH3:8])[N:7]=1.[NH2:13][C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(N(CC)CC)C>C(O)C>[NH2:2][C:3]1[S:4][C:5]([C:9]2[N:13]=[C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]3[CH:10]=2)=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1nc(N)sc1C(=O)CBr
Reactant: Nc1ncccn1
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(N)sc1-c1cn2cccnc2n1
Yield: 15.2 %

Procedure:
A solution of 2-amino-4-methyl-5-(2-bromoacetyl)thiazole hydrobromide (7.2 g), 2-aminopyrimidine (3.8 g) and triethylamine (11 ml) in ethanol (200 ml) was refluxed for 8 hours and the reaction mixture was evaporated in vacuo. To the residue was added water and the resulting mixture was acidified to pH 1.0 with 10% hydrochloric acid. The acidified solution was treated with charcoal and filtered. The filtrate was adjusted to pH 7.0 with 20% aqueous potassium carbonate. The resulting precipitate was collected by filtration, washed successively with water and ethyl acetate, and recrystallized from aqueous ethanol to give 2-(2-amino-4-methyl-5-thiazolyl)imidazo[1,2-a]pyrimidine (0.8 g). mp 285°-286° C. (dec.)
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[C:14]([NH:18][NH2:19])(=O)[CH2:15][CH3:16]>C(O)CCC>[CH2:15]([C:14]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:19][N:18]=1)[CH3:16]
Reactant: Clc1ccc(-c2ccccc2)nn1
Reactant: CCC(=O)NN
Solvent: CCCCO
Product: CCc1nnc2ccc(-c3ccccc3)nn12

Procedure:
A mixture of 7.6 g. of 3-chloro-6-phenylpyridazine, 7.4 g. of propionic acid hydrazide and 60 ml of n-butanol is stirred at reflux temperature for 48 hours. The solution is cooled in a chilled room, concentrated to remove the solvent and triturated with water giving crystals. The mixture is filtered, washed with petroleum ether and water and dried. The product is recrystallized from 20 ml. of ethanol giving 3-ethyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine, m.p. 133°-135° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].Br[CH:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13].CCN(C(C)C)C(C)C>C(#N)C>[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][CH:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: Nc1cc(F)ccc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(Nc1cc(F)ccc1F)c1ccccc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
2,5-Difluoroaniline (0.19 ml, 1.85 mmol), ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol), and DIPEA (0.32 ml, 1.85 mmol) were dissolved in acetonitrile (3 ml) and heated under MW irradiation at 100° C. for 6 hours and then at 110° C. for 4 hours. Acetonitrile was evaporated, and the crude product was purified by flash chromatography (Petroleum ether/EtOAc=97/3) to obtain intermediate I19 (240 mg, 67% yield).
Reaction SMILES: C[Al](C)C.[N:5]([Si](C)(C)C)=[N+:6]=[N-:7].[I:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)[N:21]=2)[CH:18]=1.Cl>C1(C)C=CC=CC=1>[I:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]3[CH:29]=[CH:28][C:25]([C:26]4[NH:27][N:7]=[N:6][N:5]=4)=[CH:24][CH:23]=3)[N:21]=2)[CH:18]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccc(-c2cn3cc(I)ccc3n2)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Ic1ccc2nc(-c3ccc(-c4nnn[nH]4)cc3)cn2c1
Temperature: 80 °C

Procedure:
Trimethylaluminum (150 μL) and azidotrimethylsilane (42 μL) were added to a solution (1 mL) of 4-(6-iodoimidazo[1,2-a]pyridin-2-yl)benzonitrile (104 mg) in toluene, followed by heating at 80° C. for 2 hours. The mixture was left to cool to room temperature, and 6N hydrochloric acid solution was added thereto. The precipitated matter was recovered through filtration and dried, to thereby yield the title compound (17 mg).
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O)(=[NH:4])[NH2:3].[NH2:13][N:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]=[C:15]1[NH2:25]>>[ClH:1].[ClH:1].[C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[N:13][N:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]=[C:15]1[NH2:25])(=[NH:4])[NH2:3]
Reactant: Nc1nc(-c2ccccc2)cn1N
Reactant: N=C(N)c1cccc(C=O)c1
Agent: Cl
Product: N=C(N)c1cccc(C=Nn2cc(-c3ccccc3)nc2N)c1

Procedure:
Analogously to Example 31, 3-amidinobenzaldehyde hydrochloride is reacted with 1,2-di-amino-4-phenyl-imidazole, yielding the title compound.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH:24]=[O:25])=[CH:18][CH:17]=1.CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[N:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH2:24][OH:25])=[CH:18][CH:17]=1
Reactant: O=C/C=C/c1ccc(-c2ncccn2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CO
Product: OC/C=C/c1ccc(-c2ncccn2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
DIBAL (1.0 M in THF, 18.0 mL) was added over 10 min to a −78° C. suspension of (2E)-3-[4-(2-pyrimidinyl)phenyl]-2-propenal (2.50 g, 11.89 mmol, prepared as described in Reference Example 29) in dichloromethane (100 mL). The resulting suspension was stirred for 30 min at −78° C., methanol (2 mL) was added cautiously, and stirring was continued for 5 min at −78° C. The mixture was poured into a mixture of 10% aq. citric acid (300 mL) and dichloromethane (200 mL) and allowed to stir for 1 h. The organic layer was separated, washed with sat. aq. NaHCO3 (200 mL) and brine (200 mL), dried (MgSO4), filtered through Celite, and concentrated. The resulting material was triturated with ether and dried in vacuo to provide 2.08 g (82%) of the title compound. MS 213 (M+H)+.
Reaction SMILES: C([S:8]([C:11]1[N:16]=[C:15]([N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[C:13]([NH:30][C@H:31]([CH3:34])[CH2:32][OH:33])[N:12]=1)(=O)=O)C1C=CC=CC=1.O.[SH-].[Na+:37].[SH-].[Na+]>CS(C)=O>[OH:33][CH2:32][C@H:31]([NH:30][C:13]1[CH:14]=[C:15]([N:17]([S:18]([CH3:21])(=[O:19])=[O:20])[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[N:16]=[C:11]([S-:8])[N:12]=1)[CH3:34].[Na+:37]
Reactant: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(C)(=O)=O)nc(S(=O)(=O)Cc2ccccc2)n1
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(C)(=O)=O)nc([S-])n1
Reaction time: 2 h

Procedure:
To a solution of the product of step iii) (3.97 g) in DMSO (30 ml) was added sodium hydrosulphide hydrate (0.84 g). Stirring was continued for a further 2 h and additional aliquots of 0.42 g of sodium hydrosulphide were added until complete disappearance of starting material as assessed by reverse phase HPLC-MS. The subtitle compound was also kept as a stock solution for further reaction with alkyl halides described in examples 43-53 and 137.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][CH:6]=1.BrCC1CCCCO1.[O:17]=[C:18]1[C:26]2([C:30]3=[CH:31][C:32]4[O:36][CH2:35][O:34][C:33]=4[CH:37]=[C:29]3[O:28][CH2:27]2)[C:25]2[C:20](=[C:21]([C:38]#[N:39])[CH:22]=[CH:23][CH:24]=2)[NH:19]1.N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][C:21]=3[C:38]#[N:39])[C:26]3([C:30]4=[CH:31][C:32]5[O:36][CH2:35][O:34][C:33]=5[CH:37]=[C:29]4[O:28][CH2:27]3)[C:18]2=[O:17])=[CH:5][CH:6]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: N#Cc1cccc2c1NC(=O)C21COc2cc3c(cc21)OCO3
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: N#Cc1cccc2c1N(Cc1ccc(Cl)s1)C(=O)C21COc2cc3c(cc21)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-chloro-5-(chloromethyl)thiophene to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2′-oxo-1,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrile to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 1′-[(5-chloro-2-thienyl)methyl]-2′-oxo-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrile was obtained (78%) as a colorless solid: mp 192-193° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 7.72 (dd, J=8.0, 1.1 Hz, 1H), 7.54 (dd, J=7.4, 1.1 Hz, 1H), 7.21 (dd, J=7.7, 7.7 Hz, 1H), 7.03 (s, 2H), 6.73 (s, 1H), 6.35 (s, 1H), 5.95 (dd, J=4.0, 0.7 Hz, 2H), 5.29 (d, J=1.5 Hz, 2H), 4.78 (dd, J=20.4, 9.6 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 177.0, 155.5, 148.7, 143.2, 141.8, 137.6, 133.6, 133.2, 128.8, 127.9, 126.6, 126.5, 123.7, 118.5, 116.9, 103.0, 101.5, 93.4, 92.6, 79.5, 56.4, 40.0; MS (ES+) m/z 437.3 (M+1), 439.3 (M+1).
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[C:10]([CH:12]=1)[OH:11])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:14][CH:15]1[S:19][CH:18]([C:20](OC)=[O:21])[C:17](=O)[CH2:16]1>>[OH:13][C:8]1[C:9]2[C:17]3[CH2:16][CH:15]([CH3:14])[S:19][C:18]=3[C:20](=[O:21])[O:11][C:10]=2[CH:12]=[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:7]=1
Reactant: COC(=O)C1SC(C)CC1=O
Reactant: CCCCCc1cc(O)cc(O)c1
Product: CCCCCc1cc(O)c2c3c(c(=O)oc2c1)SC(C)C3
Yield: 62 %

Procedure:
5-n-Pentyl resorcinol is reacted with methyl 5-methyl-3-oxo-tetrahydrothiophene-2-carboxylate to produce 1,2-dihydro-9-hydroxy-2-methyl-7-n-pentyl-4-oxo-4H-thieno[2,3-c][1] benzopyran, m.p. 188°-190°C, in 62% yield.