Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH:9]3[CH2:12][CH:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10]3)[N:7]=[N:6][C:5]=2[CH:17]([CH2:26][CH2:27][OH:28])[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:3][CH2:2]1.C(Cl)(Cl)Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH:1]1([C:4]2[N:8]([CH:9]3[CH2:10][CH:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:12]3)[N:7]=[N:6][C:5]=2[CH:17]([CH2:26][CH:27]=[O:28])[CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:2][CH2:3]1
Reactant: CC(C)CC1CC(n2nnc(C(CCO)CC(=O)OC(C)(C)C)c2C2CC2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)CC1CC(n2nnc(C(CC=O)CC(=O)OC(C)(C)C)c2C2CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
tert-Butyl 3-[5-cyclopropyl-1-(3-isobutylcyclobutyl)-1H-[1,2,3]triazol-4-yl]-5-hydroxyvalerate (106 mg) and chloroform (1 mL) were mixed. To the mixture was added Dess-Martin reagent (130 mg) at ice temperature. After stirring at RT for 1 hr, saturated aqueous sodium bicarbonate and ethyl acetate were added to the mixture at ice temperature. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (106 mg) as a crude product.
Reaction SMILES: [CH:1]12[CH2:9][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.[C:17]([C:19]1[CH:30]=[CH:29][C:22]([O:23][CH2:24][CH:25]=[CH:26][CH2:27]Cl)=[CH:21][CH:20]=1)#[N:18]>CC#N>[C:17]([C:19]1[CH:30]=[CH:29][C:22]([O:23][CH2:24][CH:25]=[CH:26][CH2:27][N:7]2[CH2:8][CH:1]3[CH2:9][CH:5]([CH2:4][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2]3)[CH2:6]2)=[CH:21][CH:20]=1)#[N:18]
Reactant: N#Cc1ccc(OCC=CCCl)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C2)C1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CC=CCOc3ccc(C#N)cc3)C2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.13 g; 5 mmol; see Example F above) was added to a stirred solution of 4-(4-cyanophenoxy)-1-chloro-2-butene (1.04 g; 5 mmol; from step (a) above) in MeCN (25 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and partitioned between diethyl ether and KHS04 (0.3 M). The aqueous layer was treated with NaOH (2M) and subsequently extracted with CH2Cl2. The organic layer was washed with water, dried, concentrated and purified using column chromatography (CH2Cl2:MeOH; 95:5) to give the title compound (0.84 g; 2.1 mmol).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6](O)[N:5]2[N:10]=[CH:11][CH:12]=[C:4]2[C:3]=1[C:13]#[N:14].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:6]1[N:5]2[N:10]=[CH:11][CH:12]=[C:4]2[C:3]([C:13]#[N:14])=[C:2]([OH:1])[C:7]=1[CH3:8]
Reactant: Cc1c(O)c(C#N)c2ccnn2c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1c(O)c(C#N)c2ccnn2c1Cl
Temperature: 25 °C

Procedure:
To the crude product (378 mg) of 5,7-dihydroxy-6-methylpyrazolo[1,5-a]pyridine-4-carbonitrile (5), N,N-dimethylaniline (380 μL) was added and this mixture was suspended in phosphoryl chloride (20 mL). This suspension was stirred under reflux with heating for 3 h. After the reaction solution was cooled to room temperature, excessive phosphoryl chloride was removed under reduced pressure. The residue was diluted with ethyl acetate and water, and two layers were separated. The organic layer was reversely extracted with saturated aqueous sodium hydrogen carbonate solution, and the aqueous extract was combined with the aqueous layer. The pH of combined aqueous layers were adjusted to 10 with 2 mol/L aqueous sodium hydroxide solution, and the solution was stirred for 4 days. This mixture was acidified to pH 2 with 1 mol/L hydrochloric acid and extracted with ethyl acetate three times. The combined organic layers were washed with a mixture of brine and 1 mol/L hydrochloric acid (5:1) and dried over sodium sulfate. The solvent was removed under reduced pressure to obtain the title compound (13) (211 mg), a part of which was purified with preparative HPLC and the NMR spectrum was recorded.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([NH2:19])[N:18]=3)[N:15]=2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33].[N-]=C=O>>[NH2:19][C:17]1[N:18]=[C:13]2[CH:12]=[CH:11][C:10]([C:9]#[C:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:32]([NH:31][C:22]4[CH:23]=[C:24]([C:27]([F:28])([F:30])[F:29])[CH:25]=[CH:26][C:21]=4[F:20])=[O:33])=[CH:3][CH:4]=3)=[N:15][N:14]2[CH:16]=1
Reactant: Nc1ccc(C#Cc2ccc3nc(N)cn3n2)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Agent: [N-]=C=O
Product: Nc1cn2nc(C#Cc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)ccc2n1

Procedure:
The compound of Example 4 was made by preparing 6-[(4-aminophenyl)ethynyl]imidazo[1,2-b]pyridazin-2-amine as in Example 20, followed by a procedure similar to Example 3 using 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene as the isocyanate (see also Schemes 1, 2, and 9).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][N:23]2[C:31](=[O:32])C3C(=CC=CC=3)C2=O)[C:19](C(OCC)=O)=[C:18]([NH:39][C:40]2[CH:41]=[C:42]([CH3:46])[CH:43]=[CH:44][CH:45]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>CCO>[O:32]=[C:31]1[C:19]2[C:18]([NH:39][C:40]3[CH:41]=[C:42]([CH3:46])[CH:43]=[CH:44][CH:45]=3)=[N:17][C:16]([NH:15][C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[N:21][C:20]=2[CH2:22][NH:23]1
Reactant: CCOC(=O)c1c(CN2C(=O)c3ccccc3C2=O)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nc3c2C(=O)NC3)c1
Temperature: 65 °C
Reaction time: 12 h
Yield: 44.2 %

Procedure:
A mixture of ethyl 2-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-((1,3-dioxoisoindolin-2-yl)methyl)-6-(m-tolylamino)pyrimidine-5-carboxylate (109 mg, 0.174 mmol) and hydrazine hydrate (36.5 mg, 0.729 mmol) in EtOH (2 mL) was stirred at 65° C. for 12 h. After cooling, the mixture was concentrated under reduced pressure and the residue was treated with water and extracted with EtOAc. The combined organic layers were washed with aqueous NaHCO3, water, and brine, were filtered through SiO2, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from EtOAc/hexanes and filtered to give the title compound (34.8 mg). The filtrate was concentrated and triturated with IPE to give a second batch (20.3 mg) of the title compound (total 65.1 mg, 83%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24-1.79 (m, 17H), 2.32 (s, 3H), 3.84 (br s, 1H), 4.06 (br s, 1H), 4.14 (s, 2H), 6.55-6.70 (m, 1H), 6.87-7.04 (m, 2H), 7.20-7.24 (m, 1H), 7.40-7.48 (m, 1H), 7.68-7.80 (m, 1H), 8.01-8.06 (m, 1H), 8.56-8.59 (m, 1H). [M+H] calc'd for C24H33N6O3, 453. found, 453.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:17])[N:3]=1)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=3.[CH3:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>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>[F:16][C:9]1[CH:8]=[C:7]2[C:12]([N:13]=[C:14]([CH3:15])[C:5]3[N:6]2[C:2]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:18])[CH:24]=2)=[N:3][C:4]=3[CH3:17])=[CH:11][CH:10]=1
Reactant: Cc1nc(Br)n2c1c(C)nc1ccc(F)cc12
Reactant: Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cccc(-c2nc(C)c3c(C)nc4ccc(F)cc4n23)c1
Yield: 91.7 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 5A (75 mg, 0.25 mmol), 3-methylphenylboronic acid (42 mg, 0.30 mmol), K2CO3 (105 mg, 0.75 mmol) and Pd(PPh3)4 (5.8 mg, 0.005 mmol) provided the coupling product as a white powder (70 mg, 92% yield). EIMS 306.1 [M+H]+.
Reaction SMILES: [C:1]([O:11]CC)(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:14]1([NH:20][NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C[O-].[Na+].Cl>O.C(#N)C.CO>[C:14]1([N:20]2[CH:3]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:2][C:1](=[O:11])[NH:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C=Cc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: O=C1CC(c2ccccc2)N(c2ccccc2)N1
Yield: 75.6 %

Procedure:
176 g of ethyl cinnamate, 108 g of phenylhydrazine, 200 ml of a 28% methanol solution of sodium methoxide and 400 ml of acetonitrile were mixed and heated under reflux for 1 hour in a nitrogen stream. The reaction solution was poured into 2 l of water and 100 ml of hydrochloric acid was added thereto to produce precipitate. The precipitate was collected by filtration and recrystallized from acetonitrile to obtain 180 g of 1-phenyl-5-phenylpyrazolidin-3-one (A) as white crystals. ##STR14## Synthesis of Compound (B):
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([N:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)[CH3:13])[N:3]=1.[OH-].[K+]>C(O)C.[Pd]>[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([N:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)[CH3:13])[N:3]=1
Reactant: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccccc3c(Cl)n2)cc1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccccc3cn2)cc1
Yield: 14.5 %

Procedure:
Ethyl 2-{4-[N-(1-chloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (2.87 g), in a solution of potassium hydroxide (0.42 g) in ethanol, was hydrogenated at atmospheric pressure over a palladium on carbon catalyst. After uptake of the theoretical amount of hydrogen the solution was filtered to remove the catalyst and the solvent was removed by distillation under reduced pressure. The product was purified by column chromatography over silical gel (eluant dichloromethane/ethylacetate; 99:1) to give ethyl 2-{4-[N-(isoquinolin-3-yl)-N-methylamino]phenoxy}propionate (0.38 g) as a green oil. The assigned structure was confirmed by proton magnetic resonance spectroscopy and mass spectrometry. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.20 (3H, t); 1.60 (3H, d); 3.45 (3H, s); 4.20 (2H, q); 4.70 (1H, q); 6.60 (1H, s); 6.8-7.4 (7H, m); 7.65 (1H, d); 8.90 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:11]2[CH2:13][CH2:12]2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH:14](=O)/[CH:15]=[CH:16]/[CH3:17].[OH-].[Na+].C(Cl)Cl>Cl>[CH:11]1([C:3]2[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=[C:10]3[C:2]=2[N:1]=[C:16]([CH3:17])[CH:15]=[CH:14]3)[CH2:12][CH2:13]1
Reactant: C/C=C/C=O
Reactant: Nc1cccc(C(=O)O)c1C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc2ccc(C(=O)O)c(C3CC3)c2n1
Temperature: 25 °C
Yield: 27.7 %

Procedure:
A solution of 3-amino-2-cyclopropylbenzoic acid (0.507 g, 2.86 mmol) in 6 N HCl (8 mL) was added (E)-but-2-enal (0.47 mL, 5.72 mmol) dropwise at reflux. The reaction mixture was stirred at reflux for 2 hours. After cooling to ambient temperature, the reaction mixture was basified with sodium hydroxide to about pH 12 and DCM (20 mL) was added. The aqueous layer was separated and acidified with saturated potassium hydrogen sulfate to about pH 3-4. The aqueous layer was then extracted with 3:1 CHCl3/IPA (2×30 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure to give 8-cyclopropyl-2-methylquinoline-7-carboxylic acid (0.18 g, 27.7%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([C:25](=[O:27])[CH3:26])[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[C:25](=[O:27])[CH3:26])[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC(=O)c1cccc2c1CCNC2C
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC(=O)c1cccc2c1CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-(1-Methyl-1,2,3,4-tetrahydro-isoquinolin-5-yl)-ethanone to provide the title compound in moderate yield.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:14]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[NH:15][C:16](=[O:24])[NH:17][C:18]=2[CH2:19][O:20][CH2:21][CH2:22]Cl)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:32]=[N+:33]=[N-:34].[Na+].[I-].[Na+]>CN(C=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:14]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[NH:15][C:16](=[O:24])[NH:17][C:18]=2[CH2:19][O:20][CH2:21][CH2:22][N:32]=[N+:33]=[N-:34])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NC(COCCCl)=C(C(=O)NCCCc2ccccc2)C(c2cccc(Cl)c2)N1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOCC1=C(C(=O)NCCCc2ccccc2)C(c2cccc(Cl)c2)NC(=O)N1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
180 mg (0.389 mmol) of 6-(2-chloroethoxymethyl)-4-(3-chlorophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (3-phenylpropyl)amide was dissolved in 10 ml of DMF. 38.0 mg (0.584 mmol) of sodium azide and 58.3 mg (0.389 mmol) of sodium iodide were added to the obtained solution, and they were stirred at 60° C. for 2 days. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=100/1) to obtain the title compound.
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[C:12]([C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:24](=O)[C:25]([O:27]C)=O)=[CH:19][N:20]2[CH3:23])=[CH:16][CH:15]=1)#[N:13].[CH3:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH:38]=2)[C:33]([CH2:46][C:47]([NH2:49])=[O:48])=[CH:32]1>>[CH3:23][N:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]([C:12]#[N:13])[CH:22]=2)[C:18]([C:24]2[C:25](=[O:27])[NH:49][C:47](=[O:48])[C:46]=2[C:33]2[C:34]3[C:39](=[CH:38][C:37]([N:40]4[CH2:41][CH2:42][O:43][CH2:44][CH2:45]4)=[CH:36][CH:35]=3)[N:31]([CH3:30])[CH:32]=2)=[CH:19]1
Reactant: COC(=O)C(=O)c1cn(C)c2cc(C#N)ccc12
Reactant: Cn1cc(CC(N)=O)c2ccc(N3CCOCC3)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1cc(C2=C(c3cn(C)c4cc(N5CCOCC5)ccc34)C(=O)NC2=O)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
A solution of t-BuOK in THF (1 M, 18.9 mL, 18.9 mmol) was added dropwise to a mixture of methyl (6-cyano-1-methyl-1H-indol-3-yl)glyoxylate (1.85 g, 7.64 mmol) and (1-methyl-6-morpholin-4-yl-1H-indol-3-yl)-acetamide (1.74 g, 6.36 mmol) at 0° C. The cooling bath was removed after 15 min and the mixture was stirred at room temperature for 3 h. Concentrated hydrochloric acid (37%, 10 mL) was added and the reaction mixture was stirred for a further 30 min. The mixture was made basic with aqueous NaHCO3 and extracted with CHCl3 (3×500 mL). The combined organic extracts were washed with aqueous Na2CO3 and dried (K2CO3). The extracts were filtered through a pad of silica gel, then evaporation of the solvents and crystallization of the crude product from acetone/EtOAc gave 1-methyl-3-[4-(1-methyl-6-morpholin-4-yl-1H-indol-3-yl)-2,5 -dioxo-2,5-dihydro-1H-pyrrole-3-yl-]-1H-indole-6-carbonitrile (2.05 g, 69%). Ref: Faul, M. M.; Winneroski, L. L.; Krumrich, C. A. J. Org. (Chem. 1998, 63, 6053.
Reaction SMILES: CN(/[CH:4]=[CH:5]/[C:6]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)=O)C.[N+]([O-])(O)=O.[CH2:18]([O:20][C:21](=[O:33])[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([NH:29][C:30]([NH2:32])=[NH:31])[CH:23]=1)[CH3:19].[N+]([O-])(O)=O.C(OC(=O)C1C=CC(NC(N)=N)=CC=1)C>>[CH2:18]([O:20][C:21](=[O:33])[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([NH:29][C:30]2[N:32]=[C:6]([C:8]3[CH:13]=[N:12][CH:11]=[CH:10][N:9]=3)[CH:5]=[CH:4][N:31]=2)[CH:23]=1)[CH3:19]
Reactant: CN(C)/C=C/C(=O)c1cnccn1
Reactant: CCOC(=O)c1ccc(C)c(NC(=N)N)c1
Agent: CCOC(=O)c1ccc(NC(=N)N)cc1
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1ccc(C)c(Nc2nccc(-c3cnccn3)n2)c1

Procedure:
3-dimethylamino-1-pyrazin-2-yl-propenone prepared in Preparation 2 and 3-guanidino-4-methylbenzoic acid ethyl ester nitrate were used instead 3-dimethylamino-1-pyridin-3-yl-propenone and 4-guanidino-benzoic acid ethyl ester nitrate according to the similar procedure to Preparation 8 to give the titled compound as yellow solid.
Reaction SMILES: [C:1]1([C:7]2[NH:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19]C1C=CC=CC=1C=O>>[CH3:18][O:19][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: O=c1[nH]c(-c2ccccc2)nc2ccccc12
Reactant: COc1ccccc1C=O
Product: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Yield: 89.1 %

Procedure:
According to the preparation of 41, 2-methoxybenzaldehyde (33) (1.0 g, 7.3 mmol) was used to afford 42 (1.6 g, 89.1%) as pale yellow needles.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:21][C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=2.Cl.[CH2:32]([O:34][C:35](=[O:39])[CH2:36][NH:37][CH3:38])[CH3:33]>>[CH2:32]([O:34][C:35](=[O:39])[CH2:36][N:37]([CH3:38])[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([CH2:21][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:11]([OH:20])([C:12]([F:14])([F:13])[F:15])[C:16]([F:19])([F:18])[F:17])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[CH:23]=1)[CH3:33]
Reactant: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1cccc(C(=O)O)c1
Reactant: CCOC(=O)CNC
Agent: Cl
Product: CCOC(=O)CN(C)C(=O)c1cccc(Cn2c(C)cc3cc(C(O)(C(F)(F)F)C(F)(F)F)ccc32)c1

Procedure:
In analogy to example 34, from 3-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-benzoic acid (example 31) and sarcosine ethylester hydrochloride was prepared (methyl-{3-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-benzolyl}-amino)-acetic acid ethyl ester, colorless solid, MS: 531 (MH+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[C:24]([F:27])([F:26])[F:25])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:28]([OH:31])[CH2:29][CH3:30])=[CH:6][CH:5]=1.[CH3:32]I>CN(C)C=O.O>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[C:24]([F:25])([F:27])[F:26])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:28]([O:31][CH3:32])[CH2:29][CH3:30])=[CH:6][CH:5]=1
Reactant: CI
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Reaction time: 0.08 h
Yield: 78.3 %

Procedure:
Sodium hydride (60% in oil, 40.0 mg, 1.00 mmol) was added to a stirred solution of 1-{9-chloro-1-[4-chloro-2-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}propan-1-ol (370 mg, 0.833 mmol) in N,N-dimethylformamide (3.0 mL) at room temperature. After stirring 5 min, methyl iodide (177 mg, 1.25 mmol) was added to the mixture, and the mixture was stirred at room temperature for 4 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (299 mg, 0.652 mmol, 78%).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:9]1)=O)(C)(C)C.[ClH:24].CO>>[ClH:24].[NH:8]1[CH2:9][CH:10]([C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(c2ncccc2-c2ccccc2)C1
Agent: Cl
Solvent: CO
Product: c1ccc(-c2cccnc2C2CNC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of 3-(3-phenyl-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (79) (130 mg, 0.60 mmol) in HCl/MeOH solution (5 mL) was stirred at RT for 30 min. Then the solvent was evaporated at 40° C. to give 2-Azetidin-3-yl-3-phenyl-pyridine hydrochloride (80) (100 mg, 100% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11](N)=[CH:10][CH:9]=2)[CH2:6][N:5]=[C:4]2[O:15][CH:16]=[CH:17][C:3]=12.CC(C1C=CC=C([NH2:27])C=1)=O>>[NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:27])[CH:9]=2)[CH2:6][N:5]=[C:4]2[O:15][CH:16]=[CH:17][C:3]=12
Reactant: CC(=O)c1cccc(N)c1
Reactant: NC1=c2ccoc2=NCN1c1ccc(N)cc1
Product: NC1=c2ccoc2=NCN1c1cccc(N)c1

Procedure:
The compound was prepared following the procedures described in making 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9), using 3-aminoacetophenone instead of 4-aminoacetophenone as starting material. MS(ES) m/e 227 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][C:4]2[NH:8][C:9]([O:11][C:3]=2[CH:2]=1)=[O:10].C(O)(=O)C.[N+:16]([O-])([OH:18])=[O:17]>N([O-])=O.[Na+].O>[Cl:7][C:6]1[C:1]([N+:16]([O-:18])=[O:17])=[CH:2][C:3]2[O:11][C:9](=[O:10])[NH:8][C:4]=2[CH:5]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]c2cc(Cl)ccc2o1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2o1
Temperature: 50 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
In a 250-ml flask, place 17.0 g (0.1 m) of chlorzoxazone (1b; X=Cl), 50 ml of acetic acid, and 0.14 g of sodium nitrite. Warm and stir the slurry to 50° C. Add 11.3 g (0.125 m) of concentrated nitric acid (70%) and stir the mixture at 55°-63° C. for 5 hrs. Add 100 ml of hot water, cool to room temperature and let it stand overnight. Collect solid, wash with water, and dry in air to give 18.7 g (87%) of 5-chloro-6-nitro-benzoxazol-2-one (2b; X=Cl) as pale yellow solids.
Reaction SMILES: [N:1]1([CH:6]=[CH:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH:5]=[CH:4][N:3]=[CH:2]1>CN(C)C=O.[O-2].[O-2].[O-2].[Ni+3].[Ni+3]>[N:1]1([CH:6]=[CH:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCc2cc(C=Cn3ccnc3)ccc2N1
Agent: [Ni+3]
Agent: [O-2]
Solvent: CN(C)C=O
Product: O=c1ccc2cc(C=Cn3ccnc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1.5 g of 6-[2-(imidazol-1-yl)ethenyl]-3,4-dihydrocarbostyril in 15 ml of N,N-dimethylformamide was added 7.0 g of freshly prepared nickel peroxide. The suspension was stirred under nitrogen for 72 hours at room temperature, then filtered and solvent removed from the filtrate under reduced pressure. The residue was chromatographed on silica gel, eluting with 5% methanol in methylene chloride, to give 6-[2-(imidazol-1-yl)ethenyl]carbostyril, m.p. 211°-213° C.