Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[CH:14]([C:20]1[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=1)[C:13]2=[O:28]>O>[OH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[CH:14]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:13]2=[O:28]
Reactant: COc1ccc(C2C(=O)c3ccc(OC)cc3C2=O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C1c2ccc(O)cc2C(=O)C1c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
Pyridine hydrochloride (400 mg) was heated to 190° C. To the melt was added 5-methoxy-2-(4-methoxyphenyl)-1H-inden-1,3(2H)-dione (150 mg, 0.53 mmol) and the reaction was stirred for 3 h. The mixture was cooled to room temperature and dissolved in water and extracted with ethyl acetate. The organic layers were combined and washed with 1 N HCl, water then brine and dried over MgSO4. Evaporation and flash chromatography (50%-60% EtOAc/petroleum ether) gave the product as a light brown solid, (81 mg, 60% yield, m.p. 227-228° C.); MS m/e 255 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:23][C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=3)=[C:20]([OH:22])[CH:21]=1)=[N:5][CH:6]=[N:7]2.I[CH2:35][CH2:36][CH3:37].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:23][C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=[CH:26][N:25]=3)=[C:20]([O:22][CH2:35][CH2:36][CH3:37])[CH:21]=1)=[N:5][CH:6]=[N:7]2
Reactant: Oc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1Oc1cc(C(F)(F)F)ccn1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCOc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1Oc1cc(C(F)(F)F)ccn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
To a solution of 5-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-2-(4-trifluoromethylpyridin-2-yloxy)-phenol (0.462 g, 0.5 mmol) in DMSO (5 mL) was added 1-iodopropane (0.204 g, 1.2 mmol) and K2CO3 (0.207 g, 1.5 mmol). The reaction mixture was stirred at 50° C. overnight and then at 70° C. for another 24 h. After cooling to room temperature, the mixture was poured into water and the gum-like material was separated via suction filtration and washed with water. The gum-like product then was partitioned between CH2Cl2 and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo, and the product was purified by preparative reverse phase HPLC to give 0.161 g (32%) of (5,8-difluoroquinazolin-4-yl)-{2-[3-propoxy-4-(4-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-amine as a brown gum; MS m/z 504. 1H NMR (CDCl3): δ 8.68 (s, 1H), 8.26 (d, J=4.8 Hz, 1H), 7.33 (m, 1H), 7.08-7.15 (m, 3H), 6.87-7.03 (m, 3H), 6.70-6.83 (br, 1H), 3.89-3.97 (m, 2H), 3.80-3.86 (m, 2H), 3.02 (t, J=6.9 Hz, 2H), 1.51 (m, 2H), 0.66 (t, J=7.2 Hz, 3H). LC/MS: 506.10 (M++1).
Reaction SMILES: C([C:5]1([OH:21])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1)(C)(C)C>C(O)=O.Cl>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[NH:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[OH:21])[C:19]=12
Reactant: CC(C)(C)C1(O)C=CC=CC1c1n[nH]c2ncnc(N)c12
Agent: Cl
Solvent: O=CO
Product: Nc1ncnc2[nH]nc(-c3ccccc3O)c12

Procedure:
1-tert-butyl-2-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol (5 mg, 0.014 mmol) was dissolved in a solution of formic acid (2 mL) and conc. HCl (0.2 mL) and heated to reflux for 30 min. Reaction was concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA). ESI-MS (M+H)+ m/z calcd 228.1, found 228.3.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:31]([C@@H:33]([O:35]C(=O)C)[CH3:34])=[O:32]>>[OH:35][C@@H:33]([CH3:34])[C:31]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH:27]4[CH2:28][CH2:29]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:32]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3ccccc3OCC3CC3)ncnc12
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: C[C@H](O)C(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A162) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[C:6]([NH:16][CH:17]([CH3:19])[CH3:18])[N:5]2[N:20]=[CH:21][C:22]([C:23]([O:25]C)=[O:24])=[C:4]2[N:3]=1.[OH-].[K+].Cl>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[C:6]([NH:16][CH:17]([CH3:19])[CH3:18])[N:5]2[N:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[C:4]2[N:3]=1
Reactant: COC(=O)c1cnn2c(NC(C)C)c(-c3ccc(Cl)cc3Cl)c(Cl)nc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Nc1c(-c2ccc(Cl)cc2Cl)c(Cl)nc2c(C(=O)O)cnn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
5 g of methyl 5-chloro-6-(2,4-dichlorophenyl)-7-isopropylaminopyrazolo[1,5-a]pyrimidine-3-carboxylate were dissolved in 75 ml of 1,4-dioxane, and 75 ml of 2 N aqueous potassium hydroxide solution were added. The mixture was stirred at room temperature for 15 h (monitored by TLC) and then introduced into 1 N hydrochloric acid. The precipitated solid was filtered off with suction.
Reaction SMILES: [Br:1]Br.[N+]([C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1)([O-])=O.[N+](C1C=CC=CC=1)([O-])=O>O>[Br:1][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: BrBr
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)c2c(Br)cccc21
Temperature: 200 °C

Procedure:
A 1 liter double mantle flask equipped with propeller or anchor stirrer, bromine inlet with metering pump, and reflux condenser attached to a waste gas adsorption unit, is charged with 1265 parts by weight of 1-nitroanthraquinone and 60 parts by weight of nitrobenzene. The mixture is heated to 240° C. and, at this temperature and with efficient stirring, elementary bromine is pumped in by means of the metering pump. The rate of addition is so chosen that gentle bromine reflux is always maintained in the reflux condenser. After about 200 to 220 ml of bromine have been added over 10 hours, no more bromine is taken up by the reaction mixture and the presence of 1-nitroanthraquinone can no longer be detected in a thin-layer chromatogram. The mixture is then cooled to 200° C. and the melt is discharged through the bottom outlet into 2 liters of vigorously stirred water. The resultant suspension is then refluxed and nitrobenzene is separated in a water separator. After about 1 hour the suspension is cooled to about 80° C., filtered, and the filter cake is washed with hot water and dried in vacuo at 120° C., affording 1400 parts by weight of 1-bromoanthraquinone in 96-97% purity. The yield, based on 1-nitroanthraquinone, is 97.5 %.
Reaction SMILES: [CH:1]12[O:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2]2.Cl[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.BrBr.C([O-])([O-])=O.[K+].[K+]>>[N:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][CH2:19][CH2:18][N:7]2[CH2:6][CH:5]3[O:9][CH:1]([CH2:2][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]3)[CH2:8]2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: ClCCCCc1ccncc1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CC2CN(CCCCc3ccncc3)CC(C1)O2
Yield: 45.5 %

Procedure:
tert-Butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.35 g, 5.9 mmol, see Preparation A and Preparation C(iii) above) was mixed with 4-(4-chlorobutyl)pyridine (1.35 g, 7.37 mmol, see Example 10(i) above), Br2 (0.094 g, 0.59 mmol ) and K2CO3 (3.26 g, 23.6 mmol). The mixture was refluxed under argon for 3 days. The reaction mixture was filtered, evaporated and purified by chromatography (DCM, 2-5% MeOH) giving 0.97 g (44%) of the sub-title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([O:13][CH3:14])[S:6][C:7]=1[CH:8]1OCC[O:9]1.[OH-].[Na+]>O1CCCC1>[Cl:2][C:3]1[N:4]=[C:5]([O:13][CH3:14])[S:6][C:7]=1[CH:8]=[O:9]
Reactant: COc1nc(Cl)c(C2OCCO2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1nc(Cl)c(C=O)s1
Reaction time: 1 h
Yield: 90 %

Procedure:
5N HCl (10 ml) is added to a solution of 4-chloro-5-([1,3]dioxolan-2-yl)-2-methoxy-thiazole (1.80 g, 8.13 mmol) in tetrahydrofuran (50 ml). After 1 h, the reaction is poured into 2N NaOH (100 ml) and extracted with ethyl acetate (3×100 ml). The ethyl acetate is washed with aqueous saturated brine solution, dried with anhydrous Na2SO4, filtered, and concentrated. The crude product is purified by flash chromatography on silica gel eluting with 20% ethyl acetate/hexanes to yield (1.30 g, 90%) of 4-chloro-2-methoxy-thiazole-5-carboxaldehyde: mass spectrum (ion spray): m/z=178.0 (M+1); 1H NMR (CDCl3): δ=9.95 (1H, s), 4.22 (3H, s).
Reaction SMILES: O[CH2:2][C:3]1[N:4]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:5]2[C:10]([C:11]=1[C:12](=[O:16])[C:13]([OH:15])=[O:14])=[CH:9][C:8]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)=[CH:7][CH:6]=2.[K].Cl>>[CH2:28]([N:4]1[C:5]2[C:10](=[CH:9][C:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)=[CH:7][CH:6]=2)[C:11]2[C:12](=[O:16])[C:13](=[O:14])[O:15][CH2:2][C:3]1=2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)C(=O)c1c(CO)n(Cc2ccccc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Agent: Cl
Agent: [K]
Product: O=C1OCc2c(c3cc(-c4ccc(OC(F)(F)F)cc4)ccc3n2Cc2ccccc2)C1=O

Procedure:
The title compound was prepared from {2-(Hydroxymethyl)-1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid, potassium salt and aqueous HCl in substantially the same manner, as described in step 7 of Example 1. The product was obtained as an off-white solid; mp: 239-240° C. Mass spectrum (ESI, [M+H]+) m/z 452. 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.81 (dd, 2H, J=8.86 and 2.14 Hz), 7.74 (d, 1H, J=8.56 Hz), 7.68 (dd, 1H, J=8.54 and 1.83 Hz), 7.46 (d, 2H, J=7.94 Hz), 7.37-7.26 (m, 5H,), 5.93 (s, 2H), and 5.56 ppm (s, 2H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[C:26]([CH3:46])=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH:31]([CH2:35][C:36]([OH:38])=[O:37])[N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[C:26]([CH3:46])=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH:31]([CH2:35][C:36]([OH:38])=[O:37])[NH:30][CH2:29][CH2:28]4)[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9]
Reactant: Cc1c(-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)ccc2c1CCN(C(=O)OC(C)(C)C)C2CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)ccc2c1CCNC2CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
Trifluoroacetic acid (1.0 ml, 13.0 mmol) was added dropwise at 25° C. under nitrogen to a solution of (6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2-{[(1,1-dimethylethyl)oxy]carbonyl}-5-methyl-1,2,3,4-tetrahydro-1-isoquinolinyl)acetic acid (Preparation 23; 42 mg, 0.079 mmol) in dichloromethane (3.0 ml) and the mixture was stirred at room temperature for ca. 2 h. The solvent was removed in vacuo and the residue co-evaporated with toluene, dried for 20 min under vacuum then triturated with diethyl ether to give the title compound (20 mg) as a white solid.
Reaction SMILES: N[C@@H]1CCN([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)C1.[CH3:25][C@@:26]1([OH:31])[CH2:30][CH2:29][NH:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[OH:31][C@:26]1([CH3:25])[CH2:30][CH2:29][N:28]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:27]1
Reactant: N#Cc1ccc(-c2ccc(OCCCN3CC[C@@H](N)C3)cc2)cc1
Reactant: C[C@@]1(O)CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@]1(O)CCN(CCCOc2ccc(-c3ccc(C#N)cc3)cc2)C1
Yield: 40 %

Procedure:
4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile (177 mg, 0.65 mmol), (3R)-3-methyl-3-pyrrolidinol (75 mg, 0.74 mmol), potassium carbonate (153 mg) and potassium iodide (184 mg) in 10 mL of DMF were heated at 110° C. for 10 hours. The mixture was evaporated under reduced pressure and the residue was purified by chromatography (CHCl3:MeOH:NH4OH, 9:1:0.1) to provide the title compound (40 % yield).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([N:13]([CH3:42])[C:14]([N:16]([CH3:41])[C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]([O:31]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:18]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1>>[F:44][C:2]([F:43])([F:1])[C:3]1[CH:4]=[C:5]([N:13]([CH3:42])[C:14]([N:16]([C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]([N:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)=[O:31])[CH2:18]2)[CH3:41])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: CN(C(=O)N(C)[C@@H]1CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C1CCNC1
Product: CN(C(=O)N(C)[C@@H]1CN(C(=O)N2CCCC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
By reaction and purification in the same manner as in the method described in Example 420 and using the compound obtained in Example 362 and pyrrolidine, the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10](C(OC(C)(C)C)=O)[CH:11]([CH3:13])[CH3:12].FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)N(CCCCOCc1ccccc1F)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NCCCCOCc1ccccc1F

Procedure:
The desired intermediate was prepared from the deprotection of 4-(2-fluorobenzyloxy)-N-(t-butoxycarbonyl)-N-(isopropyl)butylamine using standard techniques. The 4-(2-fluorobenzyloxy)-N-(t-butoxycarbonyl)-N-(isopropyl)butylamine was admixed with a 4:1 mixture of methylene chloride and trifluoroacetic acid. The progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]([CH2:15][C:16](=O)[CH3:17])[C:12]([CH3:14])=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:17][C:16]1[N:1]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[C:12]([CH3:14])=[CH:11][CH:15]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(C)n1-c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 250 mL argon purged round bottom flask containing a magnetic stirbar and a solution of 5-aminoindole (91) (15.00 g, 113 mmol) in anhydrous toluene (50 mL) was added acetonylacetone (25.4 mL, 216 mmol, 1.9 eq). The flask was fitted with a Dean-Stark trap with a 10 mL reservoir filled with toluene. The uppermost portion of the flask and the condensing arm of the trap were wrapped with foil and the reaction vessel placed into an oil bath preheated to a temperature of 125° C. The dark brown solution was allowed to stir under a continuous flow of argon at this temperature for 45 minutes, followed by draining of the trap solvent reservoir. After a total of 4 hours, TLC (5% ethyl acetate, 95% hexanes) revealed the reaction was complete. The reaction was cooled gradually to room temperature overnight. The reaction was poured onto a plug of silica gel and the solvent pulled through by vacuum filtration. The silica was washed with hexanes (200 mL). A white precipitate started to form almost immediately in the filtrate. The silica was washed again with a solution of 6% diethyl ether, 94% hexanes (800 mL). Crystals were collected from both washes, and the filtrates combined. The plug was washed with ether (150 mL) and the filtrate combined with the washes. The combined filtrates were concentrate to afford a brown oil. The oil was purified on the Biotage SP-1 (0-8% ether in hexanes). TLC revealed that all products were identical (white solids) and all products were combined. (Yield: 17.10 g of white solid, compound 92 (72%). 1H NMR (CDCl3) δ: 8.26 (bs, NH), 7.48-7.48 (d, 1H, J=1.2 Hz), 7.46-7.43 (d, 1H, J=8.7 Hz), 7.31-7.29 (t, 1H, J=2.7), 7.04-7.00 (dd, 1H, J=2.1, 8.4), 6.61 (s, 1H), 5.92 (s, 2H), 2.05 (s, 6H). MS-ESI m/z (%): 211 (M+, 100).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][CH:3]=1.[C:9]1([CH2:15][CH2:16][CH:17]([C:23]([CH3:25])=O)[C:18](OCC)=[O:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH2:7]([N:6]1[C:2]2[N:1]=[C:23]([CH3:25])[C:17]([CH2:16][CH2:15][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[C:18]([OH:19])[C:3]=2[CH:4]=[N:5]1)[CH3:8]
Reactant: CCn1nccc1N
Reactant: CCOC(=O)C(CCc1ccccc1)C(C)=O
Solvent: O
Product: CCn1ncc2c(O)c(CCc3ccccc3)c(C)nc21
Temperature: 25 °C

Procedure:
33 g. of 5-amino-1-ethylpyrazole (0.3 mol.) in 310 g. of polyphosphoric acid are heated to 80° (bath temperature). While stirring, 70.5 g. of 2-(2-phenylethyl)acetoacetic acid, ethyl ester (0.3 mol.) are added to the mixture. The bath temperature is increased to 100°, the temperature of the solution rising to about 130°. As soon as the reaction temperature begins to drop the bath temperature is elevated to 140° and maintained for 45 minutes. After the mixture has cooled to room temperature, 650 ml. of water are added in portions and stirring is continued until the polyphosphoric acid is dissolved. Then the aqueous phosphoric acid solution is decanted and the undissolved residue is treated with 400 ml. of 5% aqueous ammonia to neutralize the mixture. The mixture is extracted with chloroform and the chloroform extract is washed with water and dried with Na2SO4. Addition of ether precipitates 37 g. (44%) of 1-ethyl-6-methyl- 5-(2-phenylethyl)-1H-pyrazolo[3,4-b]pyridin-4-ol; m.p. 251°-256°. Recrystallization from ethanol raises the m.p. to 258°-260°.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:14])=O)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[S:15][C:16]([CH2:18][CH2:19][CH3:20])=[CH:17][C:3]1=2.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]#[N:14])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[S:15][C:16]([CH2:18][CH2:19][CH3:20])=[CH:17][C:3]1=2
Reactant: CCCc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCc1cc2c(=O)n3cc(C#N)ccc3nc2s1
Yield: 95.5 %

Procedure:
From 2.0 g (0.007 mol) of 4-oxo-2-propyl-4H-pyrido[1,2-a]thieno[2,3d]pyrimidine-7-carboxamide (Example 23), 30 ml of phosphorus oxychloride and 30 ml of chloroform, following the procedure of Example 27, there is obtained 1.8 g of 4-oxo-2-propyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile; mp 217°-218° C. after recrystallization from glacial acetic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=4)[N:14]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:12]=3[CH3:28])[CH2:9][C:8]3([CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[N:44][NH:45][CH:46]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[F:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([N:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:42]5[CH:43]=[N:44][NH:45][CH:46]=5)[CH:3]=4)[C:8]4([CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH2:9]3)=[C:12]([CH3:28])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ncc(Br)cc21
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ncc(-c3cn[nH]c3)cc21
Temperature: 140 °C

Procedure:
A stirred solution of 6′-bromo-1′-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (25 mg, 0.049 mmol), 4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (9.60 mg, 0.049 mmol), PdCl2(PPh3)2 (3.5 mg, 4.95 μmol) and Na2CO3 (10.5 mg, 0.099 mmol) in toluene:water (2 mL:1 mL) was heated in the microwave for 2 h at 120° C. After this time PdCl2(PPh3)2 (5.0 mg) and 4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (9.60 mg, 0.049 mmol) was added and the reaction was heated in the microwave for 1 h at 140° C. After this time the reaction was partitioned between EtOAc (50 mL) and water (20 mL). The separated organic layer was dried with MgSO4, filtered and evaporated in vacuo. Reverse phase HPLC (10 to 60% acetonitrile:water) gave 1′-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6′-(1H-pyrazol-4-yl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]. Mass Spectrum (ESI) m/e=493.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([N+:14]([O-])=O)[CH:8]=2)[CH:6]=1>CO.[Ni]>[NH2:14][C:9]1[CH:8]=[C:7]([N:5]2[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]2)[CH:13]=[CH:12][C:10]=1[NH2:11]
Reactant: Cc1cn(-c2ccc(N)c([N+](=O)[O-])c2)cn1
Agent: [Ni]
Solvent: CO
Product: Cc1cn(-c2ccc(N)c(N)c2)cn1
Yield: 95.6 %

Procedure:
4-(4-Methyl-1H-imidazol-1-yl)-2-nitroaniline (0.22 g, 1 mmol) was suspended in 20 mL of anhydrous methanol. The mixture was reduced with 0.11 g of Raney Ni at 40 psi for 7 hrs. Then the Raney Ni was removed by filtration. The filtrate was evaporated to give the title compound 0.18 g as a yellow solid (95.7%).
Reaction SMILES: C([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[Cl:15])=[O:7])(=O)C>Cl>[ClH:14].[Cl:15][C:9]1[C:10]([Cl:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6](=[O:7])[CH2:5][NH2:4]
Reactant: CC(=O)NCC(=O)c1cccc(Cl)c1Cl
Agent: Cl
Product: NCC(=O)c1cccc(Cl)c1Cl

Procedure:
50.0 g of the N-acetyl-2,3-dichlorophenacylamine obtained in (a) are heated for 2 hours under reflux in 500 ml of hydrochloric acid. The slightly turbid reaction solution is concentrated by evaporation and the residue is digested with ethyl acetate. The crystalline 2,3-dichlorophenacylamine hydrochloride is isolated by filtration and dried. Melting point: 217°-218° C. IR (solid/KBr) in cm-1 : 1695 (CO). (Another crystal modification shows two carbonyl resonance bands at 1690 and 1705 cm-1). 1H-NMR (DMSO, d6) in ppm: 4.54 (s, 2H); 7.6 (t,1H); 7.9 (m, 2H); 8.6 (s, 3H, replaceable with D2O).