Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[N:9][N:10]2[CH2:15][CH2:14][CH2:13][NH:12][C:11]=12.C(N(C(C)C)C(C)C)C.[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34][C:35](ON1C(=O)CCC1=O)=[O:36])=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34][C:35]([NH:6][C:7]1[CH:8]=[N:9][N:10]2[CH2:15][CH2:14][CH2:13][NH:12][C:11]=12)=[O:36])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCC(=O)ON1C(=O)CCC1=O
Reactant: Nc1cnn2c1NCCC2
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1cnn2c1NCCC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.2 %

Procedure:
To a solution of 3-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine sulfuric acid salt (4.44 g) and N-ethyldiisopropylamine (3.88 g) in methylene chloride (100 ml) was added N-[3-(tert-butoxycarbonylamino)propionyloxy]succinimide (4.29 g). The mixture was stirred at room temperature for 6 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 5% methanol/chloroform to give 3-[3-(tert-butoxycarbonylamino)propionyl]amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (3.67 g) as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[Br:18][C:19]([F:27])([F:26])[C:20]([F:25])([F:24])[C:21]([NH2:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[Br:18][C:19]([F:27])([F:26])[C:20]([F:25])([F:24])[C:21]([NH:23][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])=[O:22]
Reactant: NC(=O)C(F)(F)C(F)(F)Br
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-])C(F)(F)C(F)(F)Br

Procedure:
First, 4.6 g (17 mmol) of 2-chloro-1,3-dinitro-5-trifluoromethylbenzene and 4.0 g (18 mmol) of 3-bromo-2,2,3,3-tetrafluoropropionamide were dissolved in 40 ml of acetone, to which 5.0 g (36 mmol) of potassium carbonate was added, and the mixture was heated under reflux for 4 hours. Water was poured into the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 3-bromo-N-(2,6-dinitro-4-trifluoromethylphenyl)-2,2,3,3-tetrafluoropropionamide.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:23][C:24]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:25]=1[CH2:26][NH:27][NH2:28]>C(O)C>[NH2:10][C:6]1[NH:28][N:27]([CH2:26][C:25]2[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:24]=2[Cl:23])[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1cccc(Cl)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2cccc(Cl)c2Cl)[nH]1
Reaction time: 8 h

Procedure:
16.7 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulphonic acid were dissolved in 100 ml of ethanol and 20.2 g of 2,3-dichlorobenzylhydrazine were added. After standing overnight at room temperature, the precipitate which had formed was filtered off and dissolved in 2 N sodium hydroxide solution. The alkaline solution was again extracted with ether and subsequently slightly acidified with dilute acetic acid. Hereupon the compound identified above precipitated and after recrystallisation from ethanol the melting point was 161°-162° C. Yield: 11 g (40%).
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][C:21]=1[O:30][CH3:31].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:31][O:30][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:20]=1[NH:19][CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5])[C:24]([OH:26])=[O:25]
Reactant: Cc1oc(-c2ccccc2)cc1C(Cl)CC(C)C
Reactant: COC(=O)c1ccc(N)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(C(=O)O)ccc1NC(CC(C)C)c1cc(-c2ccccc2)oc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-2-methyl-5-phenylfuran (1.3 g), methyl 4-amino-3-methoxybenzoate (1.1 g), sodium carbonate (1.1 g) and sodium iodide (3.0 g) in N,N-dimethylacetamide (20 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). 2N Lithium hydroxide (6 mL) was added, and the mixture was stirred at 70° C. for 6 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (1.0 g, 50%) as an amorphous compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C:35]1([CH2:40][OH:41])[CH2:39][CH2:38][CH2:37][CH2:36]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C:35]4([CH2:40][OH:41])[CH2:39][CH2:38][CH2:37][CH2:36]4)(=[O:32])=[O:33])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(NC1(CO)CCCC1)c1ccccc1Br
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)NC3(CO)CCCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 584 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-bromo-N-(1-(hydroxymethyl)-cyclopentyl)benzene-sulfonamide in Step B. MS (ESI): mass calcd. for C22H23FN4O3S, 442.15; m/z found, 443.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.42 (s, 1H), 8.39 (s, 1H), 8.18 (d, J=7.3, 1H), 8.08 (m, 1H), 7.66-7.60 (m, 1H), 7.58-7.52 (m, 1H), 7.43 (dd, J=8.1, 1.8, 1H), 7.38-7.32 (m, 2H), 4.12 (s, 1H), 3.49 (s, 2H), 1.64-1.39 (m, 8H).
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]=[C:21]1[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][CH2:23][N:22]1[CH2:38][C:39](O)=[O:40].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:39](=[O:40])[CH2:38][N:22]2[CH2:23][CH2:24][C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:21]2=[O:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzhydrylpiperazine (0.58 g, 2.30 mmol) in dichloromethane (20 mL) under nitrogen was added the product from Example 1C (0.68 g, 2.30 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.88 g, 4.60 mmol) and N,N-dimethylpyridin-4-amine (0.014 g, 0.12 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:3) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.42-7.46 (m, 4H), 7.19-7.33 (m, 16H), 4.31 (s, 1H), 4.15-4.16 (br s, 2H), 3.38-3.47 (m, 4H), 3.35 (t, J=6.3 Hz, 2H), 2.71 (t, J=6.5 Hz, 2H), 2.23-2.29 (m, 4H); MS (DCI+) m/z 530 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:14])[O:8][C@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[CH2:2]1.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=2)[N:19]=[C:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])[N:17]=1.C(N(CC)CC)C>C(Cl)Cl>[F:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33])[N:17]=[C:16]2[N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:14])[O:8][C@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[CH2:2]1
Reactant: O=C(N[C@@H]1CCNC1)O[C@H]1CCOC1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1)O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
A mixture of (S)-tetrahydrofuran-3-yl(R)-pyrrolidin-3-ylcarbamate (225 mg, 1.12 mmol), 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (250 mg, 0.86 mmol), and triethylamine (0.240 mL, 1.72 mmol) in CH2Cl2 (10 mL) was stirred at room temperature. The reaction was complete in one hour. The reaction was quenched with water, the aqueous layer was extracted twice with CH2Cl2, and the combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc/CH2Cl2 gave (S)-tetrahydrofuran-3-yl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate (250 mg, 66%). LC/MS: m/z 439.5 (M+H)+ at 2.40 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.43 (dd, J=7.8, 1.5 Hz, 1H), 7.99 (d, J=2.6 Hz, 1H), 7.87-7.91 (m, 1H), 7.74-7.79 (m, 1H), 7.70 (d, J=6.2 Hz, 1H), 7.35-7.39 (m, 1H), 6.91-6.96 (m, 2H), 5.15 (s, 1H), 4.21-4.25 (m, 2H), 4.12-4.14 (m, 1H), 4.01-4.06 (m, 1H), 3.87-3.89 (m, 1H), 3.65-3.78 (m, 4H), 2.02-2.26 (m, 3H), 1.82-1.89 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].O1CCOCC1.[CH:30]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH2:31].C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:19][CH2:20][N:21]([CH2:31][CH2:30][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:22][CH2:23]3)[CH2:16][CH2:17]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: C=CS(C)(=O)=O
Reactant: COc1cc(N2CCC(N3CCNCC3)CC2)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(N2CCC(N3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Yield: 99.7 %

Procedure:
To a suspension of 1-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (Intermediate B120, 10.0 g, 23.27 mmol) and 1,4-dioxane (400 mL) was added MeOH (˜100 mL) to enhance solubility. Methyl vinyl sulfone (6.1 mL, 69.8 mmol) and Na2CO3 (7.4 g, 69.8 mmol) were added and the resultant mixture was heated at 80° C. overnight. The solvent was evaporated and the residue was taken up in DCM (300 mL) and filtered to remove salts. The filtrate was concentrated in vacuo to afford 1-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-4-[2-(methylsulfonyl)ethyl]piperazine (9.9 g, >95%) which was carried forward with no further purification. MS (ES+, m/z) 427 (M+1).
Reaction SMILES: [C:1](#N)[C:2]([CH3:4])=[CH2:3].C1(CC(O)(C)C#N)[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.[OH-].[K+]>CO.O>[OH:21][C:11]1[CH:12]=[C:13]2[C:3]3[C:17](=[CH:16][CH:15]=[CH:14]2)[C:18](=[O:20])[C:19]2[C:4](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:2]=3[CH:1]=1
Reactant: CC(O)(C#N)Cc1cccc2c1C(=O)c1ccccc1C2=O
Reactant: C=C(C)C#N
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1c2ccccc2-c2cc(O)cc3cccc1c23

Procedure:
There was obtained a distillate containing 35.7 g of methacrylonitrile, besides methanol and water. The distillation residue was then mushed or slurried with water, filtered, washed with water to neutrality, and finally well squeezed. The solid product thus obtained, consisting of 3-(1-anthraquinonyl)-2-hydroxy-2-methylpropionitrile: ##STR9## is suspended, still humid, in a solution of 500 cc of methanol containing 25 g of potassium hydroxide. This suspension was then reflux-heated for 1.5 hours and the red tinged solution thus obtained was freed of the insoluble impurities by filtering. It was then diluted with water up to 1.5 liters and then acidified with concentrated hydrochloric acid. Thereby was formed a yellow tinged precipitate which was filtered, washed with water to neutrality, and finally dried at 100° C. under vacuum until attaining a constant weight. In this way there were obtained 44.8 g of 2-hydroxybenzanthrone in the form of a yellow powder.
Reaction SMILES: CO.[OH-].[K+].Cl[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][N:17]3[C:21]4=[N:22][C:23]([CH3:27])=[CH:24][C:25]([CH3:26])=[C:20]4[N:19]=[C:18]3[CH2:28][CH3:29])[CH:14]=2)[N:9]=[C:8]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[N+:36]([O-])=O)[CH:7]=1>[C].[Pd].C(Cl)(Cl)Cl>[CH2:28]([C:18]1[N:17]([CH2:16][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH2:36])[CH:7]=[CH:6]3)[C:21]2=[N:22][C:23]([CH3:27])=[CH:24][C:25]([CH3:26])=[C:20]2[N:19]=1)[CH3:29]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2nc(-c3ccccc3[N+](=O)[O-])cc(Cl)c2c1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2nc(-c3ccccc3N)ccc2c1
Reaction time: 17 h
Yield: 47.1 %

Procedure:
To 240 ml of methanol containing 8.0 g of potassium hydroxide, 8.12 g (17.2 mmol) of 4-chloro-6-[(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-2-(nitrophenyl)quinoline obtained in Example 4 and 0.80 g of a 5% palladium-carbon catalyst were added and the thus-prepared mixture was stirred under a hydrogen atmosphere for 17 hours. After adding 120 ml of chloroform thereto, the thus-prepared mixture was filtered through celite. To the resulting filtrate, 120 ml of water was added, and the thus-prepared mixture was then separated out. The resulting organic layer was washed with 120 ml of water. Then, 60 ml of water was added to the organic layer, and a 130 ml portion thereof was distilled off by heating under atmospheric pressure. After allowing to stand at 0° C., the crystals precipitated were collected by filtration, and the resulting filtration residue was further recrystallized from a mixture of chloroform with methanol to obtain 3.30 g of 2-{6-[(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]quinolin-2-yl}aniline.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][C@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:40])([F:39])[F:38])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:41]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:41])=[O:26])=[C:21]([O:28][C@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:39])([F:38])[F:40])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O[C@@H](C)c1ccccc1C(F)(F)F
Solvent: CO
Product: C[C@H](Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example A5, 368 mg of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{(1S)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxylate and 41 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11](O)=[O:12])=[CH:8][CH:9]=2)[C:4]([C:14]2[NH:22][C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)=[CH:3]1.[NH2:23][C:24]([CH3:29])([CH2:27][OH:28])[CH2:25][OH:26]>>[OH:26][CH2:25][C:24]([NH:23][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[CH:3]=[C:4]2[C:14]1[NH:22][C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[CH:15]=1)=[O:12])([CH2:27][OH:28])[CH3:29]
Reactant: Cn1cc(-c2cc3cccnc3[nH]2)c2cc(C(=O)O)ccc21
Reactant: CC(N)(CO)CO
Product: Cn1cc(-c2cc3cccnc3[nH]2)c2cc(C(=O)NC(C)(CO)CO)ccc21

Procedure:
By proceeding in a manner similar to Example 14(a) above but using 1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indole-5-carboxylic acid [Example 15(d)] and 2-amino-2-methyl-1,3-propanediol, there was prepared 1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indole-5-arboxylic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide as a yellow solid, m.p. 180-182° C. MS: 379 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:19][C:20]4[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=4)=[C:13]([C:15]([O:17]C)=O)[N:14]=[C:7]3[C:6]=2[CH:26]=1.C[O-].[Na+].C([NH2:33])=O>>[Br:1][C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:19][C:20]4[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=4)=[C:13]([C:15]([NH2:33])=[O:17])[N:14]=[C:7]3[C:6]=2[CH:26]=1
Reactant: NC=O
Reactant: COC(=O)c1nc2n(c1Cc1ccnn1C)CCOc1cc(F)c(Br)cc1-2
Agent: C[O-]
Agent: [Na+]
Product: Cn1nccc1Cc1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2

Procedure:
10-bromo-9-fluoro-3-((1-methyl-1H-pyrazol-5-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was prepared similarly to as described in General Procedure L. Methyl 10-bromo-9-fluoro-3-((1-methyl-1H-pyrazol-5-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate was reacted with sodium methoxide and formamide to afford 11 mg (11% crude yield) of the crude title compound which was carried forward without further purification.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][NH:27]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][NH:27]2)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Nc1cccc2[nH]ccc12
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cccc3[nH]ccc23)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 55 mg (0.417 mmol) of 4-aminoindole was added. The resulting mixture was stirred at room temperature for one hour and the final product was collected by filtration and washed with diethylether to yield the title compound (83 mg, 79.8% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C(=O)(O)[O-].[Na+]>C(O)C>[N+:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:15]#[N:16])=[C:2]2[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([C:18]([F:17])([F:26])[F:27])[CH:20]=1)([O-:14])=[O:13]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1cccc(C(F)(F)F)c1
Yield: 66.6 %

Procedure:
A mixture of 10.6 g (45.7 mmol) of 4-chloro-6-nitro-quinoline-3-carbonitrile and 8.82 g (54.8 mmol) of 3-(trifluoromethyl)aniline in 270 mL of ethanol was refluxed under N2 for 5 h. The reaction was diluted with ethanol, neutralized with satd sodium bicarbonate and evaporated. The residue was slurried with hexane, collected, washed with hexane and water and dried in vacuo (60° C.) to give 10.9 g of yellow solid. A 2.00 g sample was recrystallized from ethanol to give 1.20 g of bright yellow solid; mp 260-261° C.
Reaction SMILES: [OH:1][C:2]([OH:23])([OH:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].Cl.[CH2:25](O)[CH3:26]>>[CH2:25]([O:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([OH:1])([OH:22])[OH:23])[CH3:26]
Reactant: O=C(O)CCCCCCCCCCCCCCCCC(O)(O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CCCCCCCCCCCCCCCCC(O)(O)O

Procedure:
3 kg of trihydroxystearic acid are suspended in 10 l of absolute ethanol. Hydrogen chloride gas is slowly introduced at room temperature whilst stirring, until the acid has almost completely dissolved. The alcoholic ester solutionh is freed of a slight residue by filtration; thereafter the ester is precipitated by pouring the alcoholic solution into a 10-fold volume of water. The ester is filtered off and dried. The excess ethanol is recovered from the filtrate by distillation.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:5][CH2:4][O:3]1.[NH3:13]>CO>[OH:3][CH2:4][CH2:5][CH:6]([N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[C:2]([NH2:13])=[O:1]
Reactant: N
Reactant: O=C1OCCC1N1CCCC1=O
Solvent: CO
Product: NC(=O)C(CCO)N1CCCC1=O
Reaction time: 0.5 h
Yield: 90 %

Procedure:
10.15 g (0.06 mol) of 1-(tetrahydro-2-oxo-3-furyl)-2-pyrrolidinone are dissolved in 100 ml of methanol and the solution is saturated with ammonia, the temperature rising spontaneously to 40° C. The mixture is kept at that temperature for 30 minutes, whereupon it is allowed to return to ambient temperature. The reaction mixture is then evaporated under reduced pressure and the resulting powder is recrystallized from absolute ethanol. 10 g of alpha-(2-hydroxyethyl)-2-oxo-1-pyrrolidineacetamide are obtained. M.P.: 164°-165° C.; yield: 90% of theory.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].N1C=CC=CC=1>ClCCl>[C:12]([O:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cn2cccc(O)c2n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1cccn2cc(C)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
A mixture of 8-hydroxy-2-methylimidazo[1,2-a]pyridine (10 g), acetic anhydride (10.3 g) and pyridine (10.7 g) in anhydrous dichloromethane (100 ml) was stirred for 1 hour at ambient temperature and allowed to stand overnight. The mixture was washed with water, and the organic layer was separated. The aqueous layer was neutralized with sodium bicarbonate and extracted with chloroform. The combined organic layers were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo to give 8-acetoxy-2-methylimidazo[1,2-a]pyridine (13.1 g) as oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.CCOC(C)=O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCC2)nc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirring mixture of 2-chloro-5-nitropyridine (5.0 g, 31.5 mmol), potassium carbonate (7.0 g, 50.4 mmol), in 65 ml of DMF add pyrrolidine (6.7 g, 95 mmol) and stir at room temperature for 72 h. Dilute reaction mixture with 100 ml EtOAc and wash 2 times with 100 ml saturated NaHCO3, and 2 times with 100 ml of brine. Dry organics over Na2SO4, and evaporate in vacuo to obtain 5-nitro-2-pyrrolidin-1-yl-pyridine. Mass spec.: m+1=194 (AP+). B. 6-Pyrrolidin-1-yl-pyridin-3-ylamine