Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=2)=[CH:6][C:5]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:38][N:39]([CH3:46])[C@H:40]1[CH2:44][NH:43][CH2:42][C@@H:41]1[OH:45]>CC(O)C>[CH3:38][N:39]([CH3:46])[C@@H:40]1[C@@H:41]([OH:45])[CH2:42][N:43]([C:2]2[C:7]([C:8]3[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=3)=[CH:6][C:5]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:28])[F:26])=[CH:20][CH:19]=3)=[O:16])=[CH:4][N:3]=2)[CH2:44]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncc(F)c2)c1
Reactant: CN(C)[C@H]1CNC[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN(C)[C@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncc(F)c2)C[C@@H]1O
Temperature: 110 °C
Reaction time: 16 h

Procedure:
2-Chloro-5′-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide (Stage 236.1, 60 mg, 0.137 mmol) and DIPEA (0.167 mL, 0.959 mmol) were added to a vial containing iPrOH (1 mL). (3S,4S)-4-(dimethylamino)pyrrolidin-3-ol (50 mg, 0.246 mmol) was added. The mixture was stirred at 110° C. for 16 h. The solvent was evaporated off under reduced pressure and the residue was purified by preparative SFC (Column DEAP, from 15% to 20% in 6 min) to afford the title product as a beige foam. HPLC (Condition 10) tR=5.93 min, UPLC-MS (Condition 3) tR=0.81 min, m/z=506.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.14 (s, 6H) 2.52-2.58 (m, 1H) 2.88 (dd, J=11.14, 5.28 Hz, 1H) 3.21 (dd, J=11.34, 5.86 Hz, 1H) 3.28 (dd, J=10.56, 5.86 Hz, 1H) 3.44 (dd, J=11.34, 7.00 Hz, 1H) 4.07 (quin, J=5.28 Hz, 1H) 5.07 (d, J=5.08 Hz, 1H) 7.35 (d, J=9.38 Hz, 2H) 7.85 (d, J=9.38 Hz, 3H) 8.09 (d, J=2.35 Hz, 1H) 8.52 (s, 1H) 8.61 (d, J=2.35 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 10.19 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=CC(O)=[CH:8][C:9]=1O)=O.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[CH2:22][C:23]([OH:25])=[O:24].[C:26]([O:29][C:30](=[O:32])[CH3:31])(=[O:28])[CH3:27].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[CH:22]1[C:9]([CH3:8])=[C:4]2[C:5](=[CH:27][C:26]([O:29][C:30](=[O:32])[CH3:31])([OH:28])[CH:1]=[CH:2]2)[O:24][C:23]1=[O:25]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CC(=O)O)c(OC)c1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: COc1ccc(C2C(=O)OC3=CC(O)(OC(C)=O)C=CC3=C2C)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,4-dihydroxyacetophenone (2.233 g, 14.67 mmol, 1 eq), 2, 4-dimethoxyphenylacetic acid (2.88 g, 14.67 mmol, 1 eq), acetic anhydride (7.5 mL, 78 mmol, 5 eq) and triethylamine (1.49 mL, 2.05 mmol, 1 eq) was stirred and heated to reflux under nitrogen for 48 hours. After cooling to room temperature the dark syrupy reaction mixture was poured into ice water (˜450 mL). The suspension of sticky, semisolid product was neutralized by slowly adding solid NaHCO3 to the mixture. The mixture was then allowed to solidify overnight. The dark solid was isolated by filtration, washed with water, sucked dry, and recrystallized from acetic acid to yield the title compound as an ivory crystalline solid. A second crop (0.95g, 18.3%) was isolated from the mother liquor.
Reaction SMILES: FC1C=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:9]#[N:10])=CC=1.[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH2-:24].[Na+].CCCCCCCC>O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:8]([CH2:5][CH2:6][N:24]1[CH2:23][CH:17]2[CH2:22][CH2:21][CH:20]1[CH2:19][CH2:18]2)[C:9]#[N:10]
Reactant: N#CC(c1ccc(F)cc1)c1ccccn1
Reactant: [NH2-]
Reactant: Cc1ccccc1
Agent: [Na+]
Solvent: CCCCCCCC
Solvent: O
Product: N#CC(CCN1CC2CCC1CC2)c1ccccn1
Temperature: 90 °C

Procedure:
To solution of 41 parts of α-(4-fluorophenyl)-2-pyridinylacetonitrile (U.S. Pat. No. 3,225,054) in 350 parts of dry toluene is added 9 parts of sodamide and the mixture is stirred and heated at 90° C for 30 minutes. Heating is stopped and a solution of 40 parts of 2-(2-chloroethyl)-2-azabicyclo[2.2.2.]octane in 110 parts of dry toluene is added slowly over a period of 30 minutes. The mixture is stirred and refluxed for 6 hours before it is cooled and decomposed by the addition of water. The toluene layer is separated and washed with water and extracted with 6N hydrochloric acid. The extract is made alkaline and extracted with toluene. The toluene solution is washed with water and dried and the solvent is evaporated. Distillation provides 2-(4-fluorophenyl)-2-(2-pyridyl-4-(2-azabicyclo[2.2.2]oct-2-yl)butyronitrile. According to the procedure of Example 1 this nitrile is converted to 5-[1-(4-fluorophenyl)-1-(2-pyridyl)-3-(2-azabicyclo[2.2.2]-oct-2-yl)propyl]-1H-tetrazole and in turn to 5-[1-(4-fluorophenyl)-1-(2-pyridyl)-3-(2-azabicyclo[2.2.2.] oct-2-yl)propyl]-1,3,4-oxadiazole having the following structural formula. ##STR34##
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[N:16]=[C:15]([C:17]([N:19]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:28]3[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=3[CH2:36][OH:37])[CH:13]=2)[N:8]=1.C(OCC)(=O)C.O>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([O:37][CH2:36][C:29]1[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:28]=1[C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:6])[N:16]=[C:15]2[C:17]([N:19]1[CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27]1)=[O:18])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CO)ccc2n1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
33 μl of propionyl chloride are added to a solution of 150 mg of [2-amino-6-(4,5-difluoro-2-hydroxymethylphenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone and 2 mg of 4-(dimethylamino)pyridine (DMAP) in 5 ml of dimethylformamide, and the mixture is stirred at 80° C. for 16 h. 8 ml of ethyl acetate and 8 ml of water are added, the organic phase is separated off and evaporated to dryness in vacuo. The residue is dissolved in 1 ml of dimethyl sulfoxide and purified by chromatography (reversed phase HPLC).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CCOC(C)=O.O>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=2[NH2:8])[CH2:15][CH2:14]1
Reactant: Nc1c(Br)cncc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCN(c2cncc([N+](=O)[O-])c2N)CC1
Yield: 56.9 %

Procedure:
A solution of 3-bromo-5-nitropyridin-4-amine (LXIX) (618 mg, 2.83 mmol) in 1-methylpiperazine (1 mL, 8.51 mmol) was heated at 140° C. overnight. The reaction was poured into an EtOAc/H2O mixture; the organic layer was separated, dried over MgSO4 and concentrated under vacuum. The crude product was purified on a silica gel column (100% CHCl3→3:97 MeOH(7N NH3):CHCl3) to give 3-(4-methylpiperazin-1-yl)-5-nitropyridin-4-amine (CXVII) as a yellow solid (382 mg, 1.61 mmol, 56.7% yield). 1H NMR (CDCl3, 500 MHz) δ ppm 2.20 (s, 3H), 2.35-2.37 (m, 4H), 4.52-3.54 (m, 4H), 5.96 (s, 1H), 7.42 (s, 2H), 8.78 (s, 1H); ESIMS found C10H15N5O2 m/z 238 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH2:24])=[C:14]([O:16]CC3C=CC=CC=3)[CH:15]=2)=[CH:6][CH:5]=1>CCO.O.[Pd]>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH2:24])=[C:14]([OH:16])[CH:15]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-c2cnc(N)c(OCc3ccccc3)c2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(-c2cnc(N)c(O)c2)cc1
Reaction time: 22 h
Yield: 31 %

Procedure:
To a stirring solution of 4-(6-amino-5-benzyloxy-pyridin-3-yl)-benzoic acid methyl ester (10.0 g, 0.03 mol) in EtOH:H2O (95:5, 600 mL) was added Pd/C (15.9 g, 0.015 mol) (the reaction was de-gassed under vacuum). The solution was allowed to stir under an H2 atmosphere for 22 hr. The solution was filtered through wet celite and the celite washed with EtOH. The filtrate was concentrated under vacuum to yield 4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoic acid methyl ester (2.3 g, 9.3 mmol, 31%). 1H NMR (MeOD, 300 MHz) δ 3.90 (s, 3H), 7.21 (d, 1H, J, 1.9 Hz), 7.62 (d, 2H, J, 8.5 Hz), 7.76 (d, 1H, J, 1.9 Hz), 8.04 (d, 2H, J, 8.5 Hz).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:12][CH3:13])[N:5](COC)[C:6]=1[CH:7]=[O:8].[ClH:14]>>[Cl:14][C:2]1[N:3]=[C:4]([CH2:12][CH3:13])[NH:5][C:6]=1[CH:7]=[O:8]
Reactant: Cl
Reactant: CCc1nc(Br)c(C=O)n1COC
Product: CCc1nc(Cl)c(C=O)[nH]1
Temperature: 90 °C

Procedure:
4-Bromo-2-ethyl-1-(methoxymethyl)imidazole-5-carbaldehyde (365 g) was dissolved in 35% conc. hydrochloric acid (1.8 L), and the mixture was heated at 90° C. for 20 hr. The solvent was evaporated under reduced pressure, and sodium hydrogencarbonate was added to the residue under ice-cooling until the mixture assumed weak alkalinity. The mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the residue. The mixture was heated and allowed to cool. The precipitated crystals were collected by filtration and dried by heating under reduced pressure to give 4-chloro-2-ethylimidazole-5-carbaldehyde (211.5 g) as brown crystals.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C(O)C.O.[Pd]>[N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccc(NCCCN2CCOCC2)c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Nc1cccc(NCCCN2CCOCC2)c1
Reaction time: 12 h
Yield: 90.8 %

Procedure:
40 g N-3-(morpholin4-yl)propyl-3-nitroaniline was dissolved in 450 ml ethanol and 50 ml water, and 0.5 Pd/C (5%) was added. After purging with nitrogen, hydrogenation was performed for 12 h at 50° C. under 50 bar of hydrogen pressure. After cooling, nitrogen purging was repeated, the catalyst was filtered off, and the filtrate was reduced in a rotary evaporator. 32.2 g of pasty black oil was obtained; this was distilled in a ball tube (220–232° C., 0.06–0.08 mbar). The product obtained was a crystalline orange material.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[C:3]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]([O:20]C)=[O:19])[N:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)=[CH:24][CH:23]=2)[C:7](=[O:33])[C:6]=1[OH:34])=[O:4].C1COCC1.[OH-].[Li+].Cl>O.CO>[OH:20][C:18]([CH2:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH:9]1[N:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)=[CH:24][CH:23]=2)[C:7](=[O:33])[C:6]([OH:34])=[C:5]1[C:3](=[O:4])[C:2]([CH3:35])([CH3:1])[CH3:36])=[O:19]
Reactant: COC(=O)COc1ccccc1C1C(C(=O)C(C)(C)C)=C(O)C(=O)N1c1ccc(-c2ccsc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)C1=C(O)C(=O)N(c2ccc(-c3ccsc3)cc2)C1c1ccccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a mixture of 4-(2,2-dimethylpropionyl)-3-hydroxy-5-(2-methoxycarbonylmethyloxyphenyl)-1-(4-thiophene-3-ylphenyl)-1,5-dihydropyrrole-2-one (0.172 g, 0.34 mmol), THF (1.72 mL), and methanol (1.72 mL) was added 1 mol/L aqueous lithium hydroxide solution (1.02 mL), and the resulting mixture was stirred at room temperature for 1 hour. After the reaction was completed, 2 mol/L hydrochloric acid (0.52 mL) and water (14 mL) were added to the reaction mixture, and the precipitated aimed compound was collected by filtration. The resulting aimed compound was dissolved in ethyl acetate, and the mixture was dried over anhydrous sodium sulphate and then concentrated in vacuo. The resulting residue was triturated with ethyl ether and diisopropyl ether to give 5-(2-hydroxycarbonylmethyloxyphenyl)-4-(2,2-dimethylpropionyl)-3-hydroxy-1-(4-thiophene-3-ylphenyl)-1,5-dihydropyrrole-2-one (0.137 g, yield: 82%) as pale yellow solid.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[S:11][C:12]2[C:17]([NH:18][C@H:19]([CH3:22])[CH2:20][OH:21])=[N:16][C:15]([S:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])=[N:14][C:13]=2[N:32]=1.C(#N)C.C(Br)(Br)[Br:37]>>[Br:37][C:10]1[S:11][C:12]2[C:17]([NH:18][C@H:19]([CH3:22])[CH2:20][OH:21])=[N:16][C:15]([S:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])=[N:14][C:13]=2[N:32]=1
Reactant: C[C@H](CO)Nc1nc(SCc2ccccc2F)nc2nc(N)sc12
Reactant: BrC(Br)Br
Agent: CC(C)CCON=O
Solvent: CC#N
Product: C[C@H](CO)Nc1nc(SCc2ccccc2F)nc2nc(Br)sc12
Yield: 38 %

Procedure:
Isoamyl nitrite (0.3 ml) was added to a suspension of the product of example 32 step c) (0.23 g) in bromoform (15 ml) and acetonitrile (15 ml) at 50° C. Stirring was maintained for 10 min before concentrating to approximately, 3 ml. The residue was purified by column chromatography using 20% EtOAc/DCM as eluent to yield the subtitle compound as a yellow solid (102 mg, 38%).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCC(C(O)=O)CC=1.[N+:28]([O-:33])([N+]([O-])=O)=[O:29].O>C(O)(=O)C.C(OCC)C>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:5]2[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:2]([N+:28]([O-:33])=[O:29])[O:3][C:4]=2[CH:16]=1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: COc1ccc2c(-c3ccccc3)c(Br)oc2c1
Agent: O=C(O)C1CC=CCC1
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1ccc2c(-c3ccccc3)c([N+](=O)[O-])oc2c1

Procedure:
To a solution of 33.9 g (0.112 mole) of 2-bromo-6 -methoxy-3-phenylbenzofuran in 1 l. of acetic acid is added 21.2 g (0.168 mole) of cyclohexene-4-carboxylic acid, then 15.5 g (0.168 mole) of dinitrogen tetraoxide in 20 ml of acetic acid is added dropwise over 1.5 hours. After 3 additional hours the mixture is poured into cold water to give a yellow gum. The mixture is treated with diethyl ether and the solid residue is collected by filtration. This residue is recrystallized from aqueous ethanol, cyclohexane and ethanol to provide yellow solid 6-methoxy-2-nitro-3-phenylbenzofuran, m.p. 100°-106° C., containing 20 % 7-bromo-6-methoxy-2-nitro-3-phenylbenzofuran.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=O)[CH2:5]Cl.[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>CO>[ClH:1].[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]1[CH2:5][S:16][C:15]([NH2:17])=[N:14][N:13]=1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: NNC(N)=S
Solvent: CO
Product: Cl
Product: NC1=NN=C(c2ccc(Cl)cc2Cl)CS1
Temperature: 65 °C
Yield: 61.5 %

Procedure:
11.17 g (0.05 mole) of 2,4-dichlorophenacyl chloride and 4.36 g (0.05 mole) of thiosemicarbazide are stirred and heated in 250 ml of methanol at reflux (65° C.) for 30 minutes. The resultant suspension is allowed to cool and is filtered to yield a first crop of 4.56 g of 5-(2,4-dichlorophenyl)-6H-1,3,4-thiadiazin-2-amine hydrochloride. The reaction mixture is then diluted with ethyl acetate and concentrated on a steam bath further yielding 6.2 g of the same compound. The two products are added together and recrystallized from methanol/ethyl acetate. m.p. 170°-172° C.
Reaction SMILES: [C:1]([OH:5])(=O)[C:2]#[CH:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>ClCCl.C(O)C>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:1](=[O:5])[C:2]#[CH:3])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2ccc(N)cc2)cc1
Reactant: C#CC(=O)O
Solvent: ClCCl
Solvent: CCO
Product: C#CC(=O)Nc1ccc(-c2ccc(OC)cc2)cc1

Procedure:
Prepared analogously to Example 1.1.b. from propynoic acid and 4′-methoxybiphenyl-4-ylamine. Yield: 1.3 g (17.2% of theory); C16H13NO2 (M=251.28); calc.: molecular ion peak (M+H)+: 252; found: molecular ion peak (M+H)+: 252; Rf value: 0.6 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)=O.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[C:21]([C:28](O)=O)=[C:22]2[CH2:27][CH2:26][CH2:25][N:23]2[N:24]=1>Cl>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[C:21]([C:28]2[NH:8][C:7]3[C:2]([N:1]=2)=[N:3][CH:4]=[CH:5][CH:6]=3)=[C:22]2[CH2:27][CH2:26][CH2:25][N:23]2[N:24]=1
Reactant: O=C(O)c1c(-c2ccccn2)nn2c1CCC2
Reactant: Nc1cccnc1N
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(-c2nn3c(c2-c2nc4ncccc4[nH]2)CCC3)nc1
Reaction time: 0.17 h
Yield: 48.2 %

Procedure:
Add 2,3-diaminopyridine (Fluka; 120 mg, 1.09 mmol) and phosphorous oxychloride (4.4 mL) to 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid (Preparation 3; 251 mg, 1.09 mmol) and heat the reaction at 106° C. for 3 h. Cool the reaction to 0° C. and add 1N aqueous hydrochloric acid (10 mL) slowly and stir for 10 min. Neutralize the mixture with saturated aqueous sodium bicarbonate and extract with chloroform. Wash the combined organic layers with brine, dry with sodium sulfate, concentrate in vacuo, purify by flash column chromatography, and triturate with hexanes to provide the title compound (159 mg, 48%) as a tan solid. Mp 170-172° C. MS ESI+ m/e 303 (M+1). 1H NMR (CDCl3) δ 8.80 (br, 1H), 8.34 (m, 2H), 7.88 (m, 2H), 7.36 (m, 1H), 7.11 (m, 1H), 4.29 (m, 2H), 3.54 (m, 2H), 2.71 (m, 2H). HPLC: 96.3%, Rt=13.59 min. TLC (SiO2): Rf0.3 (1:3 [80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][N:20]=2)[N:15]=[CH:14][CH:13]=1>CCCCO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][N:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: Clc1ccnc2cccnc12
Reactant: COc1ccc(CN)cc1
Solvent: CCCCO
Product: COc1ccc(CNc2ccnc3cccnc23)cc1
Temperature: 150 °C
Yield: 88.5 %

Procedure:
p-Methoxybenzylamine (1.45 g, 10.6 mmol) was added to a solution of 4-chloro-[1,5]naphthyridine 484 (0.35 g, 2.13 mmol) in n-BuOH (9 ml) and the mixture was heated at 150° C. for 18 h. The solvent was removed in vacuo. The crude residue was purified by column chromatography with n-hexane/EtOAc (80:20) as the eluent to give the title compound (0.5 g, 89%).
Reaction SMILES: CO[C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]([C:19]2[O:23][C:22]3[CH:24]=[CH:25][CH:26]=[C:27]([N:28]4[CH2:31][CH2:30][CH2:29]4)[C:21]=3[CH:20]=2)[C:14](=[O:18])[CH:15]=[CH:16][CH3:17])=[CH:6][CH:5]=1.[NH2:33][OH:34].CO.[ClH:37]>C1COCC1.O.[OH-].[Na+]>[ClH:37].[N:28]1([C:27]2[C:21]3[CH:20]=[C:19]([N:13]([C:14](=[O:18])[CH:15]=[CH:16][CH3:17])[CH2:12][CH2:11][O:10][C:7]4[CH:6]=[CH:5][C:4]([C:3]([NH:33][OH:34])=[O:32])=[CH:9][CH:8]=4)[O:23][C:22]=3[CH:24]=[CH:25][CH:26]=2)[CH2:29][CH2:30][CH2:31]1
Reactant: CC=CC(=O)N(CCOc1ccc(C(=O)OC)cc1)c1cc2c(N3CCC3)cccc2o1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC=CC(=O)N(CCOc1ccc(C(=O)NO)cc1)c1cc2c(N3CCC3)cccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[2-(4-azetidin-1-yl-3-benzofuran-2-yl-but-2-enoylamino)ethoxy]-benzoic acid methyl ester (158 mg, 0.362 mmol) in THF (4 ml), a solution of hydroxylamine in 50% water (2.78 ml) and 1N NaOH (0.1 ml) were added. Methanol was added dropwise until a homogeneous solution was obtained. The reaction mixture was stirred overnight at rt. After cooling the mixture at 0° C., 6 N HCl was added until pH 7 was reached. The solid was separated by filtration and the crude solid purified by HPLC to give the title compound (25 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[CH:3]=1.[SH-:18].[Na+]>O>[CH:15]([C:4]1[CH:3]=[C:2]([SH:18])[N:7]2[N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=[C:6]2[N:5]=1)([CH3:17])[CH3:16]
Reactant: [SH-]
Reactant: COC(=O)c1nc2nc(C(C)C)cc(Cl)n2n1
Agent: [Na+]
Solvent: O
Product: COC(=O)c1nc2nc(C(C)C)cc(S)n2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
The product obtained in Step 2 (40 g) was added at 0° C. to a solution of sodium hydrosulfide (40 g) in one liter of water with stiring under a nitrogen stream. The mixture was stirred at 0° C. for one hour, then at room temperature for three hours, and the resulting yellow solution was washed with 200 ml of ethyl acetate. The aqueous layer was acidified with concentrated hydrochloric acid to pH 2.0, and the formed crystals were collected by filtration and washed with 100 ml of ethanol, affording 36 g of the objective compound as faint yellow crystals.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4]1.[CH2:11]([NH:13][C:14]1[C:19]([CH:20]=O)=[CH:18][N:17]=[C:16]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:15]=1)[CH3:12].O>C(OCCO)C>[CH2:11]([N:13]1[C:14]2[N:15]=[C:16]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:17]=[CH:18][C:19]=2[CH:20]=[C:8]([C:5]2[CH:6]=[CH:7][S:3][CH:4]=2)[C:9]1=[NH:10])[CH3:12]
Reactant: CCNc1nc(Nc2ccccc2)ncc1C=O
Reactant: N#CCc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCCO
Product: CCn1c(=N)c(-c2ccsc2)cc2cnc(Nc3ccccc3)nc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.9 %

Procedure:
To a suspension of NaH (60% in mineral oil, 27 mg) in 5 mL of 2-ethoxyethanol was added 3-thiopheneacetonitrile (168 mg, 1.36 mmol). After stirring for 5 minutes at room temperature, 4-ethylamino-2-phenylamino-pyrimidine-5-carbaldehyde (300 mg, 1.24 mmol) was added, and the reaction heated at 120° C. for 2 hours, resulting in a dark brown solution. Upon cooling, the solution was poured into water which caused precipitation. The resulting precipitate was removed by filtration and washed with water. The crude product was purified by flash chromatography, eluting with 5% methanol/methylene chloride, followed by 10% methanol/methylene chloride. Concentration of product fractions yielded 340 mg (78%) of (8-ethyl-7-imino-6-thiophen-3-yl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-phenylamine; mp 220°-222° C.
Reaction SMILES: [CH2:1]([C:3]([CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O)([CH:6]=[CH:7][CH2:8][CH3:9])[CH:4]=O)[CH3:2].Cl.C(Cl)Cl>COCCOC.[Zn]>[CH2:6]([C:3]1([CH2:1][CH3:2])[CH:4]=[CH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][CH2:10]1)[CH2:7][CH2:8][CH3:9]
Reactant: CCC=CC(C=O)(CC)CSc1ccccc1C=O
Agent: Cl
Agent: [Zn]
Solvent: COCCOC
Solvent: ClCCl
Product: CCCCC1(CC)C=Cc2ccccc2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 141.6 %

Procedure:
A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiCl3, and 50 mL of DME was held at reflux for 2 h and cooled to room temperature. To this mixture was added 2.4 g (8.6 mmole) of 17 in 20 mL of DME in 10 min. The reaction mixture was stirred at room temperature for 2 h and held at reflux for 1 h then was let standing at room temperature over weekend. The reaction mixture was poured into dilute HCl and was stirred with methylene chloride. The methylene chloride-water mixture was filtered through Celite. The methylene chloride layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give 3.0 g of a residue. Purification by HPLC gave 0.41 g (20%) of 18 as an oil in the early fraction.