Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](OCC)=O)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[ClH:28]>O1CCCC1>[Cl:28][CH2:13][C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cl
Reactant: CCOC(=O)c1cnoc1-c1ccc(C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2oncc2CCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of ethyl 5-(4-methylphenyl)isoxazole-4-carboxylate (7.70 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride (1.0 M toluene solution, 83 ml) at 0° C. and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in toluene (100 ml) and thionyl chloride (5.94 g) was added dropwise at 0° C., after which the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 4-chloromethyl-5-(4-methylphenyl)isoxazole (6.49 g, yield 94%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:9, volume ratio). NMR (CDCl3) δ: 2.44 (3H, s), 4.62 (2H, s), 7.34 (2H, d, J=8 Hz), 7.67 (2H, d, J=8 Hz), 8.35 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[C:9]([C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O)#[N:10]>C(OC(=O)C)(=O)C>[CH3:8][C:4]1[N:3]=[C:2]([CH:1]=[CH:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[C:9]#[N:10])[CH:7]=[CH:6][CH:5]=1
Reactant: N#Cc1ccccc1C=O
Reactant: Cc1cccc(C)n1
Solvent: CC(=O)OC(C)=O
Product: Cc1cccc(C=Cc2ccccc2C#N)n1

Procedure:
A solution of 2,6-dimethyl pyridine (5.8 ml, and 50 mMol), and 2-cyanobenzaldehyde (6.81 g, and 52 mMol) in acetic anhydride (9.5 ml) is heated under reflux for 16 hours. The acetic anhydride is then evaporated in vacuo and the residue purified on column chromatography (silica gel 400 g). The column is first eluted with toluene (400 ml) and then with toluene/ethyl acetate 95:5. The fractions containing the desired compound are combined, evaporated in vacuo. The solid residue is recrystallized from methylene chloride/diisopropyl ether and white crystals are isolated. (melting point: 113-114°).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:22]([C:27]1[N:8]([CH2:9][CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[C:7]2[CH:6]=[CH:5][C:4]([NH:16][C:17](=[O:20])[O:18][CH3:19])=[CH:3][C:2]=2[N:1]=1)([CH3:26])([CH3:23])[CH3:21]
Reactant: COC(=O)Nc1ccc(NCC2CCOCC2)c(N)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl {3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}carbamate (2.29 g, 8.20 mmol) and DMAP (0.20 g, 1.64 mmol) were dissolved in 75 mL of DCM. Trimethylacetyl chloride (1.10 mL, 9.02 mmol) was added dropwise and the solution was stirred at rt for 2 h. The solution was washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The residue was dissolved in 25 mL of AcOH and was heated at 125° C. for 1 h using a Personal Chemistry microwave apparatus. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using 4:3/hexanes: acetone as eluent. Yield: 1.81 g (64%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.48-1.54 (m, 4 H), 1.56 (s, 9 H), 2.23-2.35 (m, 1 H), 3.27-3.35 (m, 2 H), 3.78 (s, 3 H), 3.96 (t, J=2.93 Hz, 1 H), 3.99 (t, J=3.03 Hz, 1 H), 4.18 (d, J=7.42 Hz, 2 H), 6.63 (br.s, 1 H), 7.24-7.28 (m, 1 H), 7.41 (br.s, 1 H), 7.61 (d, J=1.95 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccc(F)cc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2ccc(Br)cc2)c2ccc(F)cc2C)=N/O)ccn1

Procedure:
In analogy to example 74, step 7, from 3-(4-bromophenyl)-3-(4-fluoro-2-methylphenyl)-1-(2-methylpyridin-4-yl)propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound which contains less than 10% of the Z isomer as a white foam, MS (ESI+): m/z=427.08 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl-].[C:12]([C:16]1[CH:25]=[CH:24][C:19]([CH:20]=[N+:21]([CH3:23])[CH3:22])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].C(C1C=CC(C=O)=CC=1)(C)(C)C.CNC>>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([CH:20]([N:21]([CH3:23])[CH3:22])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[CH3:1])=[CH:24][CH:25]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1cc2ccccc2[nH]1
Reactant: C[N+](C)=Cc1ccc(C(C)(C)C)cc1
Agent: CC(C)(C)c1ccc(C=O)cc1
Agent: CNC
Agent: [Cl-]
Product: Cc1[nH]c2ccccc2c1C(c1ccc(C(C)(C)C)cc1)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-methylindole and (4-tert-butyl-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 4-tert-butyl-benzaldehyde and dimethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH2:15])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1.I[CH2:17][CH2:18][CH2:19][CH3:20]>>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([N:15]([CH2:14][CH2:2][CH2:3][CH3:4])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: CCCCI
Product: CCCCN(CCCC)c1ccc2c(c1)Cc1cc(Br)ccc1-2

Procedure:
As shown in Scheme 1, 7-bromo-9H-fluoren-2-ylamine is reacted with 1-iodobutane to form (7-bromo-9H-fluoren-2-yl)-dibutyl amine (11). Then, (7-bromo-9H-fluoren-2-yl)-dibutyl amine (11) is reacted with 5-formyl-2-thiopheneboronic acid by Suzuki coupling reaction to obtain 5-(7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (12a). Finally, in acetonitrile, 5-(7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (12a) is reacted with cyanoacetic acid by using piperidine as a catalyst, to obtain 2-cyano-3-[5-(7-dibutylamino-9H-fluoren-2-yl)-thiophen-2-yl]-acrylic acid (13a).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:9]=[C:10]([CH2:16][CH:17]([O:21][CH:22]([CH3:24])[CH3:23])[C:18]([OH:20])=[O:19])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15])=[O:5].[OH-].[Na+:31]>C(O)C>[Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:9]=[C:10]([CH2:16][CH:17]([O:21][CH:22]([CH3:24])[CH3:23])[C:18]([O-:20])=[O:19])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15])=[O:5].[Na+:31]
Reactant: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNC(=O)c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CNC(=O)c1ccc(Cl)cc1Cl

Procedure:
1.0 g of 3-(3-{[(2,4-dichlorobenzoyl)amino]methyl}-4-methoxyphenyl)-2-isopropoxypropanoic acid was dissolved in 5 ml ethanol, and 2.3 ml of 1 N aqueous sodium hydroxide solution was added thereto, and the solvent was removed, to give sodium 3-(3-{[(2,4-dichlorobenzoyl)amino]methyl}-4-methoxyphenyl)-2-isopropoxypropanoate was obtained.
Reaction SMILES: [CH2:1]([C:3]1([C:13](=[O:17])[C:14](O)=[O:15])[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[CH2:4]1)[CH3:2].C1(C)C=CC=CC=1.S(Cl)([Cl:27])=O>CN(C)C=O>[CH2:1]([C:3]1([C:13](=[O:17])[C:14]([Cl:27])=[O:15])[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[CH2:4]1)[CH3:2]
Reactant: CCC1=CC(CC)(C(=O)C(=O)O)CC(CC)=C1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCC1=CC(CC)(C(=O)C(=O)Cl)CC(CC)=C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To a 3 L volume four-necked flask, 2-(1,3,5-triethylphenyl)-2-oxoacetic acid (8-b) (214.8 g), toluene (anhydrous) (740 ml), and dimethylformamide (anhydrous) (22.8 ml) were added under a nitrogen atmosphere. After the temperature was raised to about 50° C., thionyl chloride (131 g) was added. The resulting mixture was stirred at 50° C. for 2 hours, and concentrated under reduced pressure to give 204.5 g of 2-(1,3,5-triethylphenyl)-2-oxoacetyl chloride (6-b).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][C@H:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11][C@H:10]1[NH:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([Cl:32])=[CH:27][CH:26]=2)=[O:22])=O)(C)(C)C.Cl>C(O)C>[ClH:32].[Cl:32][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([C:21]([NH:20][C@@H:10]1[CH2:11][CH2:12][C@@H:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][C@@H:9]1[NH2:8])=[O:22])=[CH:31]2
Reactant: CCOC(=O)[C@@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@@H](N)C1
Reaction time: 12 h
Yield: 207 %

Procedure:
(1R*,2S*,4R*)-N2-tert-Butoxycarbonyl-N1-[(5-chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-1,2-cyclohexanediamine (1.40 g) was suspended in ethanol (8 ml), and a saturated ethanol solution (10 ml) of hydrochloric acid was added at room temperature to stir the mixture for 12 hours. The solvent was distilled off under reduced pressure to obtain (1R*,2S*,4R*)-N1-[(5-chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-1,2-cyclohexanediamine hydrochloride (1.25 g) as a colorless solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]([C:15]2[N:19]3[CH:20]=[C:21]([N:24]4[CH2:28][CH2:27][CH2:26][C@H:25]4[C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=4[F:36])[CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[CH2:9]1)(C)(C)C.Cl.O1CCOCC1>O1CCOCC1>[NH2:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]([C:15]2[N:19]3[CH:20]=[C:21]([N:24]4[CH2:28][CH2:27][CH2:26][C@H:25]4[C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=4[F:36])[CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)c2cnc3ccc(N4CCC[C@H]4c4cc(F)ccc4F)cn23)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CCN(C(=O)c2cnc3ccc(N4CCC[C@H]4c4cc(F)ccc4F)cn23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
To a stirred solution of tert-butyl((S)-1-(6-((S)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)pyrrolidin-3-yl)carbamate (Isomer-II) (prepared by method similar to Example-1, employing (S)-tert-butyl pyrrolidin-3-ylcarbamate as amine followed by chiral separation in LUXAMYLOSE-2 column with eluent 1:1 Hexane:Ethanol isocratic solution) (0.16 g, 0.31 mmol), in Dioxane (2 mL), cooled to 5-10° C. was added Dioxane HCl (4 Molar) (2 mL) and stirred for 2 h at room temperature, after completion of reaction solvent was remove under vacuum and residue was dissolved in water and washed with diethylether and water was basified with sat.NaHCO3 (pH˜9) and solid was filter and dried to afford ((S)-3-aminopyrrolidin-1-yl)(6-((S)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridin-3-yl)methanone (0.07 g, 54.68% yield). MS (ESI): m/z 412.2 (M+H); 1H NMR (300 MHz, CDCl3) δ 8.66 (1H, bs), 7.98 (1H, bs), 7.54-7.51 (1H, d J=9 Hz), 7.31-7.29 (1H, m), 7.20-7.09 (1H, m), 6.94-6.91 (2H, m), 4.99-4.96 (1H, d J=9 Hz), 3.95-3.50 (4H, m), 2.19-1.80 (5H, m), 1.99 (1H, bs) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:22][CH:23]([F:33])[O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:29][C:28]2[CH:27]=[CH:26][C:25]([O:24][CH:23]([F:22])[F:33])=[CH:32][CH:31]=2)[C@@H:12]2[CH2:18][C:17]([F:19])([F:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C1NCCC(F)(F)C[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: FC(F)Oc1ccc(CBr)cc1
Product: O=C1NCCC(F)(F)C[C@H]1N(Cc1ccc(OC(F)F)cc1)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
4-Chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide was alkylated using 4-(difluoromethoxy)benzyl bromide analogous to Example 1 to afford 4-chloro-N-(4-difluoromethoxy-benzyl)-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][CH3:39]>CC(N(C)C)=O>[CH2:36]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12])[CH2:37][CH2:38][CH3:39]
Reactant: CCCCBr
Reactant: O=C(c1cc([N+](=O)[O-])ccc1O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCOc1ccc([N+](=O)[O-])cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1

Procedure:
A solution of (2-Hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (50 mg), potassium carbonate (87 mg) and 1-bromobutane (0.15 mL) in dimethylacetamide (0.3 mL) was heated at 150° C. for 15 minutes in a microwave oven. The reaction mixture was then concentrated and purified by column chromatography (SiO2) to give the title compound (55 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[NH:13][N:12]=[C:11]([CH3:14])[N:10]=1.[Cu][C:16]#[N:17]>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]#[N:17])=[C:3]([C:9]2[NH:13][N:12]=[C:11]([CH3:14])[N:10]=2)[CH:4]=1
Reactant: Cc1n[nH]c(-c2cc(F)ccc2Br)n1
Reactant: N#C[Cu]
Product: Cc1n[nH]c(-c2cc(F)ccc2C#N)n1
Yield: 26 %

Procedure:
5-(2-Bromo-5-fluorophenyl)-3-methyl-1H-1,2,4-triazole (4.00 g, 15.6 mmol) was treated with copper (I) cyanide as described in the procedure for intermediate 150 to give 0.83 g (26% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.66 (3H, s, CH3), 7.21-7.25 (1H, m, aromatic), 7.84 (1H, dd, J=5.6 Hz and J=8.6 Hz, aromatic), 8.10 (1H, dd, J=2.8 Hz and J=9.3 Hz, aromatic). HRMS (ESI+) calculated for C10H8FN4 [M+H+]: 203.0733; found: 203.0743.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:38])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]3[CH3:37])[C:15]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[C:18]([CH3:30])([CH3:29])[C:16]=3[N:17]=2)=[CH:8][CH:7]=1)[CH3:2].C(Cl)Cl.FC(F)(F)C(O)=O>>[CH3:30][C:18]1([CH3:29])[C:16]2[N:17]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:38])=[CH:7][CH:8]=3)[N:13]=[C:14]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]3[CH3:37])[C:15]=2[CH2:21][CH2:20][NH:19]1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CCOC[C@@H]3C)c3c(n2)C(C)(C)N(C(=O)OC(C)(C)C)CC3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc(-c2nc(N3CCOC[C@@H]3C)c3c(n2)C(C)(C)NCC3)cc1
Reaction time: 1 h

Procedure:
Step 2—Synthesis of compound wa: (S)-tert-butyl 2-(4-(3-ethylureido)phenyl)-8,8-dimethyl-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (0.0861 g, 0.000164 mol) in Methylene chloride (2.00 mL, 0.0312 mol) was added Trifluoroacetic Acid (0.38 mL, 0.0049 mol). The reaction mixture was stirred for 1 hour. The reaction mixture was concentrated, diluted with sat NaHCO3, extracted three times with 10% MeOH in dichloromethane, dried over Magnesium sulfate, filtered, concentrated, and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 8.19 (d, J=8.8, 2H), 7.48 (d, J=8.8, 2H), 6.17 (t, J=5.5, 1H), 4.02 (d, J=6.9, 1H), 3.86 (d, J=11.1, 1H), 3.70 (dd, J=11.2, 2.5, 1H), 3.61 (t, J=11.0, 2H), 3.44 (dd, J=22.6, 9.4, 2H), 3.18-3.04 (m, 2H), 2.90-2.77 (m, 2H), 2.55 (t, J=5.1, 2H), 1.40 (d, J=6.9, 6H), 1.22 (d, J=6.6, 3H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+425.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:3]=1.[N+:12]([O-])([OH:14])=[O:13]>>[OH:8][C:6]1[C:7]([N+:12]([O-:14])=[O:13])=[C:2]([OH:1])[N:3]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:5]=1
Reactant: O=[N+]([O-])O
Reactant: CC(C)c1nc(O)cc(O)n1
Product: CC(C)c1nc(O)c([N+](=O)[O-])c(O)n1
Reaction time: 1 h

Procedure:
220 g of 4,6-dihydroxy-2-isopropyl-pyrimidine are added at 0° C to 500 ml of 100% nitric acid and the mixture is stirred for 1 hour. Subsequently the nitration mixture is poured on ice water, filtered, washed with water, and dried in vacuo over P2O5, to yield 110 g of 4,6-dihydroxy-2-isopropyl-5-nitro-pyrimidine; m.p. 300° C.
Reaction SMILES: [N:1]1([C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)[CH:15]=[C:11]3[N:10]=[C:9]([NH:22][NH2:23])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C.[C:28]1([CH3:36])[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]=O)[CH:29]=1>C(O)C>[CH3:36][C:28]1[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=1)[CH:34]=[N:23][NH:22][C:9]1[CH:8]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:12]2[N:13]=[C:14]([C:16]3[CH:17]=[N:18][CH:19]=[N:20][CH:21]=3)[CH:15]=[C:11]2[N:10]=1
Reactant: Cc1cccc(C=O)c1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3cncnc3)cc2n1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4cncnc4)cc3n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.7 %

Procedure:
There was suspended, in ethanol (1.0 mL), (7-morpholin-4-yl-2-pyrimidin-5-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (18 mg, 0.1 mM) prepared in the preceding step 2, then acetic acid (3.0 μL, 0.05 mM) and metatolualdehyde (14 μL, 0.12 mM) were added to the suspension and the mixture was stirred at room temperature for 16 hours. The precipitated solid was recovered through filtration and then washed with diethyl ether to thus give the title compound (4.0 mg, yield: 16.7%).
Reaction SMILES: Cl.Cl.[N:3]1([NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[O:11])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:24](Cl)(=[O:26])[CH3:25].CCN(CC)CC>CN(C=O)C>[C:24]([N:6]1[CH2:5][CH2:4][N:3]([NH:9][C:10]([C:12]2[CH:17]=[N:16][C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][CH:13]=2)=[O:11])[CH2:8][CH2:7]1)(=[O:26])[CH3:25]
Reactant: O=C(NN1CCNCC1)c1cnc(-c2ccccc2)nc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(NC(=O)c2cnc(-c3ccccc3)nc2)CC1
Yield: 70 %

Procedure:
A solution of 2-phenyl-pyrimidine-5-carboxylic acid piperazin-1-ylamide dihydrochloride (0.43 mmol), acetyl chloride (1.28 mmol) and Et3N (1.72 mmol) in DMF (8 mL) is stirred at rt overnight. mixture is concentrated in vacuo. The residue is dissolved in EtOAc (15 mL), washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is triturated with ether to afford 2-phenyl-pyrimidine-5-carboxylic acid (4-acetyl-piperazin-1-yl)-amide (98 mg, 71%) as a solid. MS: 326 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.12 (s, 3H), 2.92-3.10 (m, 4H), 3.40-4.10 (m, 4H), 7.43-7.60 (m, 3H), 7.75 (br, N—H), 8.52 (m, 2H), 9.11-9.38 (br, 2H).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10](=[O:14])[CH2:11][CH2:12]Cl)[CH3:8].C([O-])([O-])=O.[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:7]([O:9][C:10](=[O:14])[CH2:11][CH2:12][NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:8]
Reactant: CCOC(=O)CCCl
Reactant: NC1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Product: CCOC(=O)CCNC1CCCC1
Temperature: 80 °C
Yield: 82.7 %

Procedure:
Cyclopentylamine (1.72 g, 17.5 mmol) and 3-chloro-propionic acid ethyl ester (2.4 g, 18 mmol) were combined neat and K2CO3 (2.4 g, 18 mmol) and a catalytic amount of tetrabutylammonium iodide (ca. 5 mg) was added. The mixture was heated at 80° C. overnight. The resulting mixture was then partitioned between water and DCM. The organic layer was dried (MgSO4) and concentrated to provide 2.68 g (83%) of the title compound. 1H-NMR (400 MHz, CDCl3:) δ ppm 4.13 (p, 2H, J=7.0 Hz), 3.07 (p, 1H, J=6.7 Hz), 2.81-2.94 (m, 4H), 2.51 (t, 1H, J=6.5 Hz), 2.44 (t, 1H, J=7.4 Hz), 1.29-1.88 (m, 6H), 1.25 (t, 3H, J=7.1 Hz)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:14]([CH2:22][CH2:23][N:24]=3)[C:15]([NH2:21])=[N:16][C:17]=2[C:18]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:14]([CH2:22][CH2:23][N:24]=3)[C:15]([NH:21][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=3)=[N:16][C:17]=2[C:18]=1[O:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccnc1
Reactant: COc1c(OCc2ccccc2)ccc2c1N=C(N)N1CCN=C21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(OCc2ccccc2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21

Procedure:
8-(Benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (21 g, 65 mmol) and nicotinic acid (12 g, 97.7 mmol) were suspended in DMF (240 mL). Diisopropylethylamine (33.7 g, 260.4 mmol) and then PYBOP (51 g, 97.7 mmol) were added and the resulting mixture stirred with overhead stirring for 3 days at ambient temperature. At this time, the resultant precipitate was isolated by vacuum filtration. After repeated washing with EtOAc, the material was dried under vacuum with slight heating to yield the title compound (27.3 g, 98%): HPLC MS RT=1.09 min, MH+=481.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 9.32 (1H, s), 8.89 (1H, br m), 8.84 (1H, d), 7.89 (1H, br m), 7.82 (1H, d), 7.37 (1H, d), 7.27 (1H, d), 7.16 (6H, m), 5.18 (2H, s), 4.36 (2H, t), 4.04 (2H, t), 3.78 (3H, s).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:12]1[CH:24]=[CH:23][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH:13]=1)(=[O:11])[CH3:10]>>[CH:13]1[C:14]2[NH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]=2[CH:23]=[CH:24][C:12]=1[C:9](=[O:11])[CH:10]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccc2c(c1)[nH]c1ccccc12
Product: O=C(C=Cc1ccccc1)c1ccc2c(c1)[nH]c1ccccc12

Procedure:
By a procedure similar to that of example 1.59.1, starting from benzaldehyde and 2-acetylcarbazole, 1-(9H-carbazol-2-yl)-3-phenylprop-2-en-1-one was obtained as yellow solid.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]1([CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:17][NH:16][C:15](=[O:18])[CH2:14]1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:16]1[CH2:17][C:13]([C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:3]=2)([CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:14][C:15]1=[O:18])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CC(CCOC2CCCCO2)(c2ccc3ccccc3c2)CN1
Agent: [H-]
Agent: [Na+]
Product: O=C1CC(CCOC2CCCCO2)(c2ccc3ccccc3c2)CN1Cc1ccccc1
Yield: 113.2 %

Procedure:
Sodium hydride (0.07 g, 2.94 mmol, 1.25 eq.) was added slowly to a solution of 4-naphthalen-2-yl-4-[2(tetrahydropyran-2-yloxy)-ethyl]-pyrrolidin-2-one (003F144) (0.81 g, 2.39 mmol). The solution was treated with benzyl bromide (0.6 mL, 4.9 mmol, 2 eq.) at 20° C. for 7 hours. The solution was partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel with 50% ethyl acetate in hexane to give 1.1620 g (92%) of the title compound.