Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].C1(S([N:23]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[C:25]([C:32]3[CH:37]=[CH:36][N:35]=[C:34](Cl)[N:33]=3)=[CH:24]2)(=O)=O)C=CC=CC=1>>[NH:23]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[C:25]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([NH:6][C:5]3[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:33]=2)=[CH:24]1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: COc1cc(Nc2nccc(-c3c[nH]c4ncccc34)n2)cc(OC)c1OC
Yield: 34.4 %

Procedure:
Using the procedure of example 1, 3,4,5-trimethoxyaniline (158 mg) was reacted with compound 1f (100 mg) to provide compound 2 (35 mg, 34%). 1H NMR (400 MHz, CD3OD) δ 8.82 (d, J=8.0 Hz, 1H), 8.33 (d, J=5.2 Hz, 1H), 8.31 (d, J=4.8 Hz, 1H), 8.11 (s, 1H), 7.48 (s, 2H), 7.22 (dd, J=8.0 Hz, 4.8 Hz, 1H), 7.12 (d, J=4.8 Hz, 1H), 3.86 (s, 9H). MS (ESI) m/z: 378 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].[CH2:17](OC(OCC)OCC)C>>[CH3:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:2]2[C:3]=1[C:4](=[O:5])[N:6]([C:7]1[NH:11][N:10]=[N:9][N:8]=1)[CH:17]=[N:1]2
Reactant: Cc1cccc(N)c1C(=O)Nc1nnn[nH]1
Reactant: CCOC(OCC)OCC
Product: Cc1cccc2ncn(-c3nnn[nH]3)c(=O)c12

Procedure:
A mixture of 1.3 g of 2-amino-6-methyl-N-(1H-tetrazol-5-yl)benzamide and 10 ml of triethoxymethane was heated at reflux for 1 hour. The mixture was then cooled and the solid which formed was separated by filtration, washed with ethanol and air dried to give 5-methyl-3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone melting at about 280°-281° C. with decomposition. This compound has the following structural formula: ##STR3##
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([N+:13]([O-:15])=[O:14])[C:6]=1[O:16][CH3:17])(=O)C.[OH-].[Na+].Cl>O>[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([N+:13]([O-:15])=[O:14])[C:6]=1[O:16][CH3:17]
Reactant: COc1c(OC(C)=O)ccc(C=O)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(O)ccc(C=O)c1[N+](=O)[O-]
Temperature: 75 °C
Yield: 85 %

Procedure:
4-Acetoxy-3-methoxy-2-nitrobenzaldehyde (1120 g., 4.72 moles) was added portionwise to a freshly prepared 33% (w/w) NaOH solution (4.5 liters). The resulting slurry was heated on steam bath at 75° C. for 10 minutes after which it was diluted with 5 liters of water. The reaction mixture was acidified with 6.4 liters of 6 N hydrochloric acid while cooling, and the resulting product (794 g., 85% yield) was filtered and washed with water. Recrystallization from ether/cyclohexane gave the desired product as light yellow solid, M.P. 136°-137° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[C:14]([NH2:15])=[CH:13][CH:12]=[N:11]1.[Na+].[I-].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][C:14]2[NH:10][N:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Nc1ccn[nH]1
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2ccn[nH]2)nc(Cl)n1
Temperature: 80 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
To the solution of 2,4-dichloro-6-methylpyrimidine (3.00 g) and 1H-pyrazol-5-amine (1.31 g) in NMP (30 ml) was added NaI (2.36 g) and DIEA (6.33 ml). And the mixture was heated to 80° C. under stirring. After 1 day, the mixture was cooled to room temperature. The mixture was diluted with EtOAc. The precipitate was collected by filtration, washed with the mixed solvent of hexane and EtOAc and dried in vacuo to give 2-chloro-6-methyl-N-(1H-pyrazol-5-yl)pyrimidin-4-amine (2.60 g) as a pale pink solid.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O1CCCCC1[O:27][C:28]([C:30]12[CH2:37][CH2:36][C:33]([NH:38][CH2:39][C:40]([N:42]3[CH2:46][C@@H:45]([F:47])[CH2:44][C@H:43]3[C:48]#[N:49])=[O:41])([CH2:34][CH2:35]1)[CH2:32][CH2:31]2)=[O:29].Cl>O1CCOCC1.O>[CH2:10]([O:17][C:18]([N:38]([CH2:39][C:40]([N:42]1[CH2:46][C@@H:45]([F:47])[CH2:44][C@H:43]1[C:48]#[N:49])=[O:41])[C:33]12[CH2:36][CH2:37][C:30]([C:28]([OH:29])=[O:27])([CH2:35][CH2:34]1)[CH2:31][CH2:32]2)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OC3CCCCO3)(CC1)CC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)O)(CC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyldiisopropylamine (194 μL) and benzylchloroformate (137 μL) were added dropwise to (2S,4S)-1-[[N-[4-(2-tetrahydropyranyl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (379 mg) in dioxane (5 mL) while the solution was cooled in water. The mixture was stirred at room temperature for 1 hour, followed by addition of 1N hydrochloric acid (0.1 mL) and stirring at room temperature for additional 1 hour. The solvent was evaporated under reduced pressure. The resulting crystal was then washed with diisopropylether and water and was dried under reduced pressure. The dried crystal was purified by silica gel chromatography (eluant:dichloromethane:methanol=10:1) to give (2S,4S)-1-[[N-benzyloxycarbonyl-N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (335 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=12.[CH3:11][C:12]1([CH3:28])[C:16]([CH3:18])([CH3:17])[O:15][B:14](C2C=NN3C=CC=CC=23)[O:13]1>>[CH3:11][C:12]1([CH3:28])[C:16]([CH3:18])([CH3:17])[O:15][B:14]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[CH:9][N:8]=[CH:7][C:6]=23)[O:13]1
Reactant: CC1(C)OB(c2cnn3ccccc23)OC1(C)C
Reactant: Brc1cnn2ccncc12
Product: CC1(C)OB(c2cnn3ccncc23)OC1(C)C

Procedure:
Obtained from 3-bromopyrazolo[1,5-a]pyrazine (Preparation 23c) following the experimental procedure as described in Preparation 27a, irradiating the reaction mixture at 100° C. for 1 h. The crude product was used without further purification in the next synthetic step.
Reaction SMILES: [K].[CH3:2][C:3]([CH3:11])([CH3:10])[CH2:4][CH2:5][S:6]([NH2:9])(=[O:8])=[O:7].[Cl:12][C:13]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])=[C:17](Cl)[N:16]=[C:15]([C:29]2[N:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[N:14]=1>CS(C)=O>[Cl:12][C:13]1[N:14]=[C:15]([C:29]2[N:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[N:16]=[C:17]([NH:9][S:6]([CH2:5][CH2:4][C:3]([CH3:11])([CH3:10])[CH3:2])(=[O:8])=[O:7])[C:18]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1Cl
Reactant: CC(C)(C)CCS(N)(=O)=O
Agent: [K]
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)CCC(C)(C)C
Temperature: 120 °C
Reaction time: 6 h
Yield: 91.1 %

Procedure:
3,3-dimethylbutane-1-sulphonic acid amide potassium salt (616 mg) was added to a solution of 4,6-dichloro-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)-pyrimidine (Can. Pat. Appl. 2071193) (353 mg) in dry dimethyl sulphoxide (10 ml) and the resulting mixture stirred at 120° C. for 6 hours under nitrogen. The reaction mixture was allowed to cool and then partitioned between ethyl acetate (30 ml ) and 2N aqueous hydrochloric acid (30 ml ) and the organic phase separated. The aqueous was extracted with ethyl acetate (30 ml) and the organic phases combined, washed (water 2×20 ml), dried (Na2SO4) and evaporated under reduced pressure. Column chromatography on silica eluting with a solvent gradient of pentane:ethyl acetate 50:50 changing to 0:100 and finally ethyl acetate:methanol 98:2 gave N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-3,3-dimethyl-1-butanesulfonamide as an off-white solid (440 mg).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18]>CO.C1COCC1.[Zn].[Cu]>[Cl:11][C:4]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[CH:2][N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=1
Reactant: Fc1ccccc1-c1c(Cl)nc2nccn2c1Cl
Agent: [Cu]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Fc1ccccc1-c1cn2ccnc2nc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.86 g (3.05 mmol) 5,7-Dichloro-6-(2-fluorophenyl)-imidazo[1,2-a]pyrimidine are given in 1.5 mL methanol and 8.6 mL THF. After addition of 0.589 g (4.6 mmol) zinc/copper pair the mixture is stirred at rt for 18 hours. The reaction mixture is filtered via a glass microfibre filter and washed with plenty of methanol. The solvent is evaporated and the residue is treated and evaporated three times with toluene. After chromatography on silicagel (eluents dichloromethane/methanol) 672.4 mg (89%) of the desired product containing bisdeschloro compound are obtained which is used without further purification.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)(C)(C)C.Br[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][N:33]=1)=[O:30]>>[F:38][C:35]1[CH:36]=[CH:37][C:32]([NH:31][C:29](=[O:30])[CH2:28][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]4[CH:24]=[CH:25][CH:26]=[C:20]4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])=[N:33][CH:34]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Reactant: O=C(CBr)Nc1ccc(F)cn1
Product: O=C(COc1ccc2oc(-c3cc4cccn4cn3)cc(=NO)c2c1)Nc1ccc(F)cn1

Procedure:
N-(5-Fluoro-pyridin-2-yl)-2-{4-hydroxyimino-2-pyrrolo[1,2-c]pyrimidin-3-yl-4H-chromen-6-yloxy}-acetamide was prepared in 2% overall yield using the method described in example 147, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 81A) and 2-Bromo-N-(5-fluoro-pyridin-2-yl)-acetamide (Bioorg. Med. Chem. 11 (2003) 2769-2782).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13]([OH:15])=O.C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13]([Cl:19])=[O:15]
Reactant: O=C(O)/C=C1\CCc2c(F)cc(F)cc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)/C=C1\CCc2c(F)cc(F)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of (E)-2-(4,6-difluoro-1-indanylidene)acetic Acid (5.49 g, 0.026 mol) in a mixture of dichloromethane: dimethylformamide (50 mL: 5 drops) was treated with oxalyl chloride (6.6 g 0.052 mol, Aldrich) and allowed to stir at ambient temperature for 18 h. The resulting solution was concentrated in vacuo and the residue used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[N:14]([CH3:16])[C:13]3[C:12](=[O:17])[N:11]([CH3:18])[CH2:10][CH2:9][C:8]=3[C:7]=2[C:6]([C:19]([OH:21])=[O:20])=[CH:5][CH:4]=1.[CH:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24](O)[CH:23]=1.CCN=C=NCCCN(C)C.Cl.O>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:1][O:2][C:3]1[C:15]2[N:14]([CH3:16])[C:13]3[C:12](=[O:17])[N:11]([CH3:18])[CH2:10][CH2:9][C:8]=3[C:7]=2[C:6]([C:19]([O:21][C:24]2[CH:23]=[CH:22][C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=2)=[O:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)c2c3c(n(C)c12)C(=O)N(C)CC3
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2c3c(n(C)c12)C(=O)N(C)CC3

Procedure:
A solution of 8-methoxy-2,9-dimethyl-1-oxo-1,2,3,4-tetrahydro-β-carboline-5-carboxylic acid (from step 5) (1 mmol), p-nitrophenol (1.5 mmol), EDCl (1.5 mmol) and DMAP (0.1 mmol) in dry THF was stirred at r.t. for 18 h. Minimum water was then added and the precipitated p-nitrophenylester was filtered and washed with water and dried (50-60%).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[N:5][C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1.P(Br)(Br)[Br:25].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C1C=CC=CC=1>[Br:25][CH2:2][C:3]1[N:4]=[N:5][C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: O=[N+]([O-])c1cccc(-c2cc(-c3ccccc3)nnc2CO)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1cccc(-c2cc(-c3ccccc3)nnc2CBr)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 3-hydroxymethyl-4-(3-nitrophenyl)-6-phenylpyridazine (0.86 g) in tetrahydrofuran (5 ml) was dropwise added to a solution of phosphorus tribromide (0.18 ml) in a mixture of tetrahydrofuran (10 ml) and benzene (5 ml) under ice cooling. After stirring for 4 hours at the same temperature, the reaction mixture was poured into ice-water (50 ml) adjusted to pH 9 with saturated aqueous potassium carbonate and extracted with ethyl acetate (50 ml). The separated organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a column chromatography on silica gel (50 g) and eluted with a mixture of chloroform and acetone (5:1 V/V). The fractions containing the desired compound were combined and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give 3-bromomethyl-4-(3-nitrophenyl)-6-phenylpyridazine (0.73 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[C:4]([O:6]C)=O.[C:14]([C:20]([O:22][CH3:23])=[O:21])#[C:15][C:16]([O:18][CH3:19])=[O:17].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Cl:13][C:8]1[CH:9]=[C:10]([Cl:12])[CH:11]=[C:2]2[C:3]=1[C:4]([OH:6])=[C:14]([C:20]([O:22][CH3:23])=[O:21])[C:15]([C:16]([O:18][CH3:19])=[O:17])=[N:1]2
Reactant: COC(=O)C#CC(=O)OC
Reactant: COC(=O)c1c(N)cc(Cl)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)c1nc2cc(Cl)cc(Cl)c2c(O)c1C(=O)OC
Temperature: 25 °C
Yield: 59 %

Procedure:
A solution of methyl 2-amino-4,6-dichlorobenzoate (1.30 g, 5.91 mM) and dimethyl acetylenedicarboxylate (0.96 g, 6.78 mM) in t-butanol (14 mL) was refluxed for 18 hr under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and potassium t-butoxide (0.76 g, 6.8 mM) was added to the stirred mixture whereupon a precipitate formed. After refluxing for 1.5 hr, the reaction mixture was cooled to room temperature and filtered to separate the precipitated solids. The solids were washed with t-butanol and then dissolved in water. The resulting solution was acidified with IN H2SO4 and the resulting precipitate was collected, washed thoroughly with water and dried to give the title compound as a light green solid (1.15 g, 59%). An analytical sample was obtained by recrystallization of a portion from toluene to provide the title compound as a light tan solid, mp 109.5°-111° C. (d); MS(CI): 330 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([NH:25]CC4C=CC=CC=4)=O)=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.FC1N=CC(C2C=CC(OCCN3CCOCC3)=CC=2)=CC=1>C(#N)C>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]#[N:25])=[N:20][CH:21]=3)=[CH:14][CH:15]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Agent: Fc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Solvent: CC#N
Product: N#CCc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1

Procedure:
In another aspect, the invention relates to a process for preparing 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide comprising the step of reacting 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine with acetonitrile to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](F)[C:5]([O:9][CH3:10])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]1.CN1CCOCC1.O>CN1CCCC1=O>[Br:1][C:2]1[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:12]2)[C:5]([O:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: COc1ccc(Br)nc1F
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CN1CCOCC1
Product: COc1ccc(Br)nc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 120 °C
Yield: 94.8 %

Procedure:
A mixture of 6-bromo-2-fluoro-3-methoxy-pyridine (2.030 mmol; 418.1 mg), tert-butyl N-[(3S)-3-piperidyl]carbamate (3.044 mmol; 609.7 mg), and N-Methylmorpholine (6.089 mmol; 622 mg; 0.676 mL) in 1-methyl-2-pyrrolidinone (5 mL) in a sealed pressure vial was heated at 120° C. overnight. The mixture was poured into water, and extracted with EtOAc. The organic layer was concentrated. The residue was purified on silica eluted with 0 to 40% EtOAc in Heptane to afford tert-butyl N-[(3S)-1-(6-bromo-3-methoxy-2-pyridyl)-3-piperidyl]carbamate (743.5 mg, 95%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH:17]3[CH2:19][CH2:18]3)=[CH:15][C:14]([CH:20]3[CH2:22][CH2:21]3)=[N:13]2)=[CH:8][CH:7]=1)=[O:4].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[H-].[Na+].O>CN(C=O)C.CCOC(C)=O>[CH:20]1([C:14]2[CH:15]=[C:16]([CH:17]3[CH2:19][CH2:18]3)[N:12]([C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:7][CH:8]=3)[N:13]=2)[CH2:22][CH2:21]1
Reactant: C1COCCN1
Reactant: O=C(CCl)Nc1ccc(-n2nc(C3CC3)cc2C2CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CN1CCOCC1)Nc1ccc(-n2nc(C3CC3)cc2C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Intermediate 41 (150 mg, 0.475 mmol) and morpholine (40 mg, 0.475 mmol) were dissolved in DMF (3 mL) at 0° C. and Sodium Hydride (30 mg, 1.25 mmol) was added to the reaction mixture. Reaction was allowed to stir at ambient temperature overnight. Work-up (H2O:AcOEt) followed by purification on column afforded the title compound as a white solid. M.P. 178-184° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.87 (s, 1H), 7.74 (d, J 8.7, 2H), 7.49 (d, J 8.7, 2H), 5.77 (s, 1H), 3.63 (t, J 4.2, 4H), 3.13 (s, 2H), 2.48-2.45 (m, 4H), 1.89-1.69 (m, 2H), 0.92-0.81 (m, 4H), 0.69-0.60 (m, 4H). MS (m/z): 367.32 [M+H]+.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([O:20]C(C)(C)C)=[O:19])=[C:10]1[CH3:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].O1CCCC1.CO>O>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([OH:20])=[O:19])=[C:10]1[CH3:25])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)OC(C)(C)C)c2ccccc2n1C(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)c2ccccc2n1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.6 %

Procedure:
A mixture of tert-butyl 1-benzoyl-2-methyl-1H-indole-3-carboxylate (440 mg, 1.3 mmol), lithium hydroxide monohydrate (276 mg, 6.6 mmol), tetrahydrofuran (12 mL), methanol (4 mL) and water (4 mL) was stirred at room temperature for 4 hours. The mixture was concentrated, acidified to pH=2 with concentrated hydrochloric acid and extracted with ethyl acetate (20 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 1-benzoyl-2-methyl-1H-indole-3-carboxylic acid (260 mg, 72%). LRMS (M+H+) m/z: calcd 279.13. found 279.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([N:9]([CH3:11])[CH3:10])=[O:8])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:21][OH:22]>CCO.CCOC(C)=O>[OH:22][NH:21][C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([N:9]([CH3:11])[CH3:10])=[O:8])=[CH:5][CH:4]=1)=[NH:2]
Reactant: NO
Reactant: CN(C)C(=O)c1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)C(=O)c1ccc(C(=N)NO)cc1
Temperature: 80 °C
Reaction time: 25 h
Yield: 79 %

Procedure:
4-cyano-N,N-dimethylbenzamide (200 mg, 1.148 mmol), potassium carbonate (952 mg, 6.89 mmol) and hydroxylamine hydrochloride (479 mg, 6.89 mmol) were dissolved in EtOH (11.4 mL). The reaction mixture was stirred at 80° C. for 25 h. The mixture was diluted with EtOAc (50 mL), washed with water (10 mL), water phase extracted with EtOAc (20 mL). Combined organic phases were washed with brine (10 mL) and dried over sodium sulfate. The solvent was removed to give 188 mg of white crystalline needles. The crude material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[CH:39][CH:40]=1)[C:6]([NH:8][C:9]1[C:18]([C:19]#[N:20])=[C:17]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:29]3[CH2:34][CH2:33][N:32]([C:35](=[O:37])[CH3:36])[CH2:31][CH2:30]3)[CH:15]=2)[N:10]=1)=[O:7].[S:41]([O:51][NH2:52])([C:44]1[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=1)(=[O:43])=[O:42]>CN(C)C=O.ClCCl>[S:41]([C:44]1[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=1)([O-:51])(=[O:43])=[O:42].[NH2:52][N+:10]1[C:11]2[C:16](=[CH:15][C:14]([N:29]3[CH2:30][CH2:31][N:32]([C:35](=[O:37])[CH3:36])[CH2:33][CH2:34]3)=[CH:13][CH:12]=2)[C:17]([NH:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:18]([C:19]#[N:20])[C:9]=1[NH:8][C:6](=[O:7])[C:5]1[CH:38]=[CH:39][CH:40]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(C(=O)Nc2nc3ccc(N4CCN(C(C)=O)CC4)cc3c(NCc3ccccc3)c2C#N)c1
Reactant: Cc1ccc(S(=O)(=O)ON)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)Nc2c(C#N)c(NCc3ccccc3)c3cc(N4CCN(C(C)=O)CC4)ccc3[n+]2N)c1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 5 h

Procedure:
To the solution of 0.72 g 3-methoxy-N-[6-(4-acetylpiperazin-1-yl)-4-benzylamino-3-cyanoquinolin-2-yl]benzamide in 20 ml dimethylformamide, 0.6 g of O-tosylhydroxylamine in 25 ml dichloromethane is added dropwise at 20° C. in 15 minutes. After 5 hours of stirring the precipitated crystalline material is filtered off. After drying 0.65 g of the title compound is obtained (MH+: 551).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])/[C:5](/O)=[CH:6]/[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=1)=O)[CH3:2].[CH3:22][NH:23][NH2:24]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[N:23]([CH3:22])[N:24]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=2)[CH:6]=1)=[O:21])[CH3:2].[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=2)[N:23]([CH3:22])[N:24]=1)=[O:21])[CH3:2]
Reactant: CCOC(=O)/C(O)=C/C(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CNN
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(F)c(C(F)(F)F)c2)n(C)n1
Product: CCOC(=O)c1cc(-c2ccc(F)c(C(F)(F)F)c2)nn1C

Procedure:
In analogy to the procedure described for example 4 b], (Z)-4-(4-fluoro-3-trifluoromethyl-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester was reacted with methylhydrazine in ethanol under reflux conditions to give 5-(4-fluoro-3-trifluoromethyl-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester as colorless crystals and 5-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2].[Cl:13][C:14]1[N:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[ClH:13].[CH2:29]([N:26]1[CH2:27][CH2:28][N:23]([S:20]([C:17]2[CH:16]=[CH:15][C:14]([C:6]3[C:5]4[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=4)[NH:8][C:7]=3[OH:12])=[N:19][CH:18]=2)(=[O:22])=[O:21])[CH2:24][CH2:25]1)[CH3:30]
Reactant: CCN1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Product: CCN1CCN(S(=O)(=O)c2ccc(-c3c(O)[nH]c4ccc(C#N)cc34)nc2)CC1
Product: Cl
Yield: 4 %

Procedure:
The title compound was prepared as described for Example 82 using 5-cyanooxindole and 1-[(6-chloropyridin-3-yl)sulfonyl]-4-ethylpiperazine. Yield: 4% of the title compound as a yellow solid: 1H NMR (DMSO-d6, 400 MHz) δ 11.15 (br s, 1 H), 10.75 (br s, 1 H), 8.56 (br s, 1 H), 8.04 (s, 1 H), 7.93-7.82 (m, 1 H), 7.73 (dd, J=9, 2 Hz, 1 H), 7.41 (dd, J=8, 1 Hz, 1 H), 7.05 (d, J=8 Hz, 1 H), 3.83-3.69 (m, 2 H), 3.69-3.42 (m, 2 H), 3.18-2.92 (m, 6 H), 1.20 (t, J=7.2 Hz, 3 H); MS (ES) m/z 412 (M++1).