Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([NH:10][C:11]([C:13]2([NH:19][C:20]([C:22]3[N:26]4[C@@:27]([CH2:40][C:41]5[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][CH:42]=5)([CH3:39])[C:28](=[O:38])[N:29]([C:30]5[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=5)[C:25]4=[N:24][CH:23]=3)=[O:21])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])[CH2:9][CH2:8]1.[C:49](OC(=O)C)(=[O:51])[CH3:50]>N1C=CC=CC=1>[C:49]([N:16]1[CH2:17][CH2:18][C:13]([NH:19][C:20]([C:22]2[N:26]3[C@@:27]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][CH:42]=4)([CH3:39])[C:28](=[O:38])[N:29]([C:30]4[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=4)[C:25]3=[N:24][CH:23]=2)=[O:21])([C:11](=[O:12])[NH:10][C:7]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:9][CH2:8]2)[CH2:14][CH2:15]1)(=[O:51])[CH3:50]
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5ccccn5)CC4)CCNCC3)n21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCC(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)(C(=O)NC2(c3ccccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-5-(4-cyanobenzyl)-7-(3,5-dichlorophenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid [4-(1-pyridin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-amide (20 mg, 0.03 mmol) in pyridine (0.5 mL) was added acetic anhydride (0.5 mL). The reaction mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the remaining residue was dissolved in water and extracted with CH2Cl2 (3×10 mL). The organic layer was washed with brine and dried over Na2SO4. After removal of the solvent in vacuo, the title compound was obtained as a white solid (21 mg), m/z 725.5 [M+1]+.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:6]=[N:7][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][C:10]=1[C:11]#[N:12]>N1C=CC=CC=1>[C:13]1([C:8]2[CH:9]=[C:10]3[C:11]([NH2:12])=[N:7][NH:6][C:5]3=[N:2][N:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NN
Reactant: N#Cc1cc(-c2ccccc2)nnc1Cl
Solvent: c1ccncc1
Solvent: O
Product: Nc1n[nH]c2nnc(-c3ccccc3)cc12

Procedure:
Hydrazine hydrate (0.7 ml, 14.3 mmol) was added to a stirred solution of 3-chloro-6-phenyl-pyridazine-4-carbonitrile (cf J. Med. Chem., 1999, 42, 730; 1.024 g, 4.7 mmol) in pyridine (10 ml). The reaction mixture was stirred at reflux for 6 hours, cooled and the resulting solid was filtered and dried in vacuo, affording the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[CH:4][CH:3]=1.C[O-].[Na+].Cl.Cl.[NH2:17][C:18]1[C:23](N)=[CH:22][CH:21]=[CH:20][C:19]=1[OH:25]>CO>[OH:25][C:19]1[C:18]2[NH:17][C:8]([CH2:7][O:6][C:5]3[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)=[N:9][C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(OCC#N)cc1
Reactant: Nc1cccc(O)c1N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(OCc2nc3cccc(O)c3[nH]2)cc1

Procedure:
In a 50 ml single neck round bottom flask, under a nitrogen atmosphere, 4-methylphenoxyacetonitrile (2.79 mmol) was admixed in methanol (11 ml). The contents were stirred to achieve dissolution. To this solution were added sodium methoxide (0.164 g, 3.0 mmol). The resulting mixture was stirred for about 40 minutes. To this mixture was added 2,3-diaminophenol dihydrochloride salt (0.5 g, 2.5 mmol) and the resulting mixture was stirred for two hours at room temperature. The reaction mixture was filtered and the filtrate was added to 60 ml of water. A light brown precipitate formed and this precipitate is removed by filtration, and washed with 20 ml of water. The solid was dried in a vacuum oven overnight.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[O:8])=[CH:5][CH:4]=1.B.[Na].O.Cl.[CH2:24](O)[CH3:25]>>[CH2:24]([O:8][CH:7]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=1)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH3:25]
Reactant: CCO
Reactant: CCOC(=O)CCCCC(=O)c1ccc(OC)cc1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: O
Product: CCOC(CCCCC(=O)O)c1ccc(OC)cc1
Reaction time: 1 h

Procedure:
A solution of ethyl 5-(4-methoxybenzoyl)pentanoate (50 g, 0.19 mole) in ethanol (500 ml) was cooled with ice, and sodium boron hydride (10 g) was added gradually to the solution. After the reaction was allowed to proceed for 1 hour, water (200 ml) and 2N hydrochloric acid (50 ml) were added to the reaction solution, followed by concentration under reduced pressure. The resulting residue was dissolved in ethyl acetate, and the organic layer was washed with water, dried and concentrated under reduced pressure. Methanol (300 ml), water (100 ml) and sodium hydroxide (40 g) were added to the resulting residue, followed by stirring for 2 hours, and the methanol was removed under reduced pressure. The water layer was washed with isopropyl ether and then adjusted to pH 4.0 with hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure, and the residue was chromatographed on a silica gel column, followed by elution with isopropyl ether-ethyl acetate (1:1) to give firstly 6-ethoxy-6-(4-methoxyphenyl)hexanoic acid (21 g) and then 6-hydroxy-6-(4-methoxyphenyl)hexanoic acid (20 g).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[O:24][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:31][OH:32])([C:14]([CH3:17])([CH3:16])[CH3:15])([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.C(P(CCCC)CCCC)CCC.[CH3:46][C:47]1[O:51][C:50]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[N:49][C:48]=1[CH2:58][O:59][C:60]1[CH:65]=[CH:64][C:63](O)=[CH:62][CH:61]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Si:1]([O:18][CH2:19][C:20]1[O:24][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:22][C:21]=1[CH2:31][O:32][C:63]1[CH:62]=[CH:61][C:60]([O:59][CH2:58][C:48]2[N:49]=[C:50]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:51][C:47]=2[CH3:46])=[CH:65][CH:64]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCc1oc(-c2ccccc2)nc1CO)(c1ccccc1)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2nc(-c3ccccc3)oc2CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Reaction time: 15 h
Yield: 81.9 %

Procedure:
To a mixture of [5-(tert-butyldiphenylsilyloxymethyl)-2-phenyl-1,3-oxazol-4-yl]methanol (1.11 g), tributylphosphine (1.01 g), 4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenol (0.70 g) and tetrahydrofuran (80 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.26 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 5-(tert-butyldiphenylsilyloxymethyl)-4-[[4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy]methyl]-2-phenyl-1,3-oxazole as an oil (1.44 g, yield 81%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([N:12]=[CH:13][N:14]=2)[N:11]=1)=[O:4].[C:15]1([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[C:28]1([CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:22]2[CH2:23][CH2:24][N:25]([CH2:2][C:3]([NH:5][C:6]3[CH:7]=[CH:8][C:9]4[N:10]([N:12]=[CH:13][N:14]=4)[N:11]=3)=[O:4])[CH2:26][CH2:27]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(CBr)Nc1ccc2ncnn2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)Nc1ccc2ncnn2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
6-(2-Bromoacetamido)[1,2,4]triazolo[1,5-b]pyridazine (636 mg) and 1-(diphenylmethyl)piperazine (627 mg) were dissolved in acetonitrile (20 ml), followed by addition of potassium carbonate (411 mg). The mixture was stirred at room temperature for 2 hours, followed by addition of ice-water and extraction with ethyl acetate. The extract was washed with aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. The resulting crystals were collected by filtration and recrystalized from methanol to yield the captioned compound (525 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH2:10]([NH:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13]>C(#N)C.O>[CH2:10]([NH:14][CH2:15][CH2:16][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([CH3:1])[N:7]=1)[CH2:11][CH2:12][CH3:13]
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: CCCCNCC
Solvent: CC#N
Solvent: O
Product: CCCCNCCc1cc(Cl)nc(C)n1
Yield: 99.7 %

Procedure:
A mixture of 2-methyl-4,6-dichloro-pyrimidine (1.63 g, 10 mmol) in 5 ml of acetonitrile was treated with N-butyl-ethyl-amine (2.000 g, 20 mmol) and heated at reflux for 0.5 hours. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give 2.271 g (100%) of title compound as a light-brown oil. 1H NMR (CDCl3) δ 0.93 (t, 3H), 1.13 (t, 3H), 1.22-1.36 (m, 2H), 1.45-1.6 (m, 2H), 2.43 (s, 3H), 3.25-3.60 (m, 4H), 6.15 (s, 1H) ppm.
Reaction SMILES: [C:1]1([C:7]2[CH:18]=[CH:17][C:10]([CH:11]=[N:12][O:13][CH2:14][CH2:15][OH:16])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:20]1[CH:52]=[CH:51][C:23]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]2=[O:50])=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:7]2[CH:18]=[CH:17][C:10]([CH:11]=[N:12][O:13][CH2:14][CH2:15][O:16][C:20]3[CH:52]=[CH:51][C:23]([CH2:24][CH:25]4[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:26]4=[O:50])=[CH:22][CH:21]=3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCON=Cc1ccc(-c2ccccc2)cc1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1SC(Cc2ccc(OCCON=Cc3ccc(-c4ccccc4)cc3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 86.3 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 483 mg of 2-(4-phenylbenzylideneaminooxy)ethanol (prepared as described in Preparation 9), 716 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 525 mg of triphenylphosphine and 348 mg of diethyl azodicarboxylate, 914 mg of the title compound were obtained as a crystalline powder, melting at 157-159° C.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:27])[NH:10][C@@H:11]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:12]([NH:14][C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[NH:14][C:12](=[O:13])[C@@H:11]([NH:10][C:9]([C@H:8]1[O:7][C@@H:6]1[C:4]([OH:5])=[O:3])=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)Nc1c(F)cccc1F
Agent: [Li+]
Agent: [OH-]
Product: CC(C)C[C@H](NC(=O)[C@H]1O[C@@H]1C(=O)O)C(=O)Nc1c(F)cccc1F
Yield: 7.8 %

Procedure:
Followed general procedure using: the corresponding peptidomimetic epoxide ethyl ester 17b (28 mg, 0.72 mmol); LiOH (1.7 mg, 0.072 mmol); after extraction afforded the desired product as a white solid (20 mg, 77.0%). 1H NMR (MeOD-d4, 400 MHz): δ 7.91 (s, 1H); 7.36-7.31 (m, 1H); 7.07-7.02 (t, 2H); 4.72 (m, 1H); 3.65 (s, 1H); 3.52 (s, 1H); 1.74-1.68 (m, 3H); 1.01-0.99 (d, 6H). 13C NMR (DMSO-d6, 100 MHz): 171.26, 169.20, 165.81, 159.49 (d, J=5.2 Hz), 157.00 (d, J=5.2 Hz), 128.98 (t, J=19.7 Hz); 115.34 (t, J=34.0 Hz); 113.10 (d, J=5.2 Hz), 107.43, 106.22, 52.96, 51.51, 51.32, 41.30, 24.71, 23.81. ESI-HRMS (m/z): [M−H]+ calcd, for C16H20N2O5: 355.3216, observed: 355.3101. HPLC Method 1: Rt=19.7 min, purity=95.0%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[O:18]1[C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:22]=2[O:21][CH2:20][CH2:19]1>>[O:18]1[C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([N:28]3[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]4([CH2:16][CH3:17])[C:14]5[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=5)[NH:8][C:7]4=[O:15])[CH2:30][CH2:29]3)[C:22]=2[O:21][CH2:20][CH2:19]1
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCO2
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Product: CCC1(CCCCN2CCN(c3cccc4c3OCCO4)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)-piperazine.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][O:8][C:9]2[CH:22]=[CH:21][C:20]3[C:19](=[O:23])[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:24][CH2:25][CH2:26][N:27]5C(=O)C6=CC=CC=C6C5=O)[CH:17]=4)[C:12](=[O:38])[C:11]=3[CH:10]=2)C(=O)C2=CC=CC=C12.O.NN.Cl>CO.O>[NH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:22]=[CH:21][C:20]2[C:19](=[O:23])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:24][CH2:25][CH2:26][NH2:27])[CH:17]=3)[C:12](=[O:38])[C:11]=2[CH:10]=1
Reactant: O=C1c2ccc(OCCN3C(=O)c4ccccc4C3=O)cc2C(=O)c2ccc(OCCN3C(=O)c4ccccc4C3=O)cc21
Agent: Cl
Agent: NN
Solvent: O
Solvent: CO
Product: NCCOc1ccc2c(c1)C(=O)c1ccc(OCCN)cc1C2=O
Temperature: 0 °C

Procedure:
A mixture of 17.4 g (0.03 mole) of the intermediate 2,6-bis-(2-phthalimidoethoxy)anthraquinone, prepared in (A) above, 200 ml. of methanol, and 3.6 g. (0.06 mole) of hydrazine hydrate (85%) is heated to reflux for four hours. Water (100 ml.) is added and the methanol boiled out of the mixture. Then, 75 ml. of 37% hydrochloric acid is added and the resulting mixture heated to reflux for another hour. The mixture is allowed to cool, then chilled at 0° C., and the precipitate of phthalhydrazide removed by filtration with suction. The filtrate is evaporated to dryness, made alkaline with 10% sodium hydroxide, and the base is extracted into chloroform. The chloroform layer is washed with water, dried with anhydrous magnesium sulfate, filtered, and the chloroform evaporated. The 2,6-bis-(2-aminoethoxy)anthraquinone base is converted to the dihydrochloride salt as described in Example 1, and recrystallized from a solvent or solvent mixture such as isopropanol, ethanol/ether, or butanone/methanol. In a similar manner, 2,7-bis(2-aminoethoxy)anthraquinone can be prepared from 2,7-bis(2-chloroethoxy)anthraquinone.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)=O)(C)(C)C.Cl.[OH-].[Na+]>C(OCC)C.O>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: CC(C)(C)OC(=O)NCCCCCCOc1ccc2ccccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: NCCCCCCOc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-[6-(N-tert-Butoxycarbonylamino)-1-hexyl-oxy]-quinoline (480 mg) was treated with a large excess of hydrogen chloride in dietyl ether with stirring for 1 hour at room temperature. The crystalline product was isolated by filtration and redissolved in water whereafter the solution was made strongly alkaline with sodium hydroxide and extracted twice with chloroform. The organic phase was dried over potassium carbonate, filtered and evaporated to yield the title compound as a colourless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH2:12][OH:13].Cl.C([O-])(O)=O.[Na+]>CO>[OH:13][NH:12][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2)=[NH:11]
Reactant: N#Cc1ccc2[nH]ncc2c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N=C(NO)c1ccc2[nH]ncc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
5-cyano indazole (D1) (500 mg), hydroxylamine.HCl (485 mg) and NaHCO3 (1.47 g) were dissolved/suspended in MeOH (18 ml), heated to 50° C. and stirred for 19 hours and overnight. The reaction mixture was then filtered, washed with MeOH and evaporated to give the title compound (584 mg) as a white solid. MS (ES): C8H8N4O requires 176; found 177 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:7].[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([C:22]3[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=3)[CH2:27][CH2:28]2)=[CH:9][CH:10]=1
Reactant: O=C(CCCCCl)c1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme E using 5-chloro-1-(4-fluorophenyl)-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:23])[CH:12]([CH3:22])[CH2:13][N:14]2[CH2:19][CH:18]([CH3:20])[O:17][CH:16]([CH3:21])[CH2:15]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24][Si:25]([CH3:28])([CH3:27])Cl>C(N(CC)CC)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([O:23][Si:25]([CH3:28])([CH3:27])[CH3:24])[CH:12]([CH3:22])[CH2:13][N:14]2[CH2:15][CH:16]([CH3:21])[O:17][CH:18]([CH3:20])[CH2:19]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CN(CC(C)C(O)c2ccc(C(C)(C)C)cc2)CC(C)O1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: CC1CN(CC(C)C(O[Si](C)(C)C)c2ccc(C(C)(C)C)cc2)CC(C)O1
Yield: 102.1 %

Procedure:
10 g (0.03 mole) of 1-(p-tert.-butyl-phenyl)-2-methyl-3-(2,6-dimethylmorpholin-4-yl)-1-propanol (obtanied according to Example 2) were dissolved in 160 ml of petroleum ether with 4.4 ml of triethylamine at room temperature and 3.4 g of trimethylchlorosilane in 40 ml of petroleum ether were added dropwise. The precipitate was filtered off and the filtrate was concentrated. 12 g (98% of theory) of 1-(p-tert.-butyl-phenyl)-1-trimethylsilyloxy-2-methyl-3-(2,6-dimethylmorpholin-4-yl)-propane were obtained as a viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)[O:5][CH:6]=1.S(Cl)([Cl:14])=O>ClC(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]([Cl:14])=[O:11])[O:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)/C=C/c1cc(Br)co1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)/C=C/c1cc(Br)co1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of (E)-3-(4-bromofuran-2-yl)acrylic acid (3.8 g, 17.51 mmol) in 35 mL of trichloromethane was added a solution of 2.6 mL of thionyl chloride in 200 μL of DMF. The reaction mixture was refluxed for 1 h and after cooling to room temperature concentrated to give 4 g (97% yield) of the title compound as light brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:3]=1.CCN(C(C)C)C(C)C.Cl[CH:43]([CH3:47])[C:44](Cl)=[O:45].C(=O)(O)[O-].[Na+]>C1COCC1>[C:22]([O:21][C:20](=[O:26])[NH:19][C:15]1([C:12]2[CH:11]=[CH:10][C:9]([C:5]3[C:4]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:3][C:2]4[NH:1][C:44](=[O:45])[CH:43]([CH3:47])[O:8][C:7]=4[N:6]=3)=[CH:14][CH:13]=2)[CH2:18][CH2:17][CH2:16]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3[nH]c(=O)c(N)cc3-c3ccccc3)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2NC1=O
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of tert-butyl 1-(4-(5-amino-6-oxo-3-phenyl-1,6-dihydropyridin-2-yl)phenyl)cyclobutylcarbamate (0.5 g, 1.159 mmol) in THF (Volume: 20 ml) was added DIPEA (1.01 ml) followed by the addition of 2-chloropropanoyl chloride (0.235 g, 1.854 mmol) in THF (5 ml) in dropwise at 0 degree over 1 h. The resulted mixture was stirred at r.t. over night. Sodium bicarbonate saturated solution (30 ml) was added. The resulted mixture was heated to reflux for 16 h. The reaction mixture was cooled down to room temperature. The organic phase was separated. The aqueous phase was extracted with ethyl acetate (40 ml). The organic phase was combined and washed with water (30 mlX2), brine (25 ml) then concentrated at reduced pressure. The residue was suspended in DCM (10 ml). The precipitate was collected by filtration and washed with DCM (5 ml) to afford product (439 mg). 1H NMR (500 MHz, CD3OD): 7.20-7.29 (m, 8H), 7.13-7.15 (m, 2H), 4.98 (q, 1H), 2.41-2.47 (m, 4H), 2.05 (m, 1H), 1.86 (m, 1H), 1.64 (d, 3H), 1.21-1.36 (br, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].Br[CH2:15][CH2:16][O:17][CH3:18]>CN(C=O)C>[CH3:18][O:17][CH2:16][CH2:15][O:10][C:9]1[C:8]([CH3:11])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[CH3:1]
Reactant: COCCBr
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1c(C)cc(C=O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a solution of 3,5-dimethyl-4-hydroxy benzaldehyde (2.0 g, 13.33 mmol) in DMF was added NaH (640 mg, 16.0 mmol, 60% in oil) and the mixture was stirred for 1 h at room temperature. A solution of 1-bromo-2-methoxy ethane (1.85 g, 13.33 mmol) was added and the mixture was stirred for 72 h at room temperature. The reaction mixture was quenched by addition of saturated NH4Cl solution and diluted with water. The product was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. Upon removal of solvent, it gave 2.1 g of 4-(2-methoxy ethoxy)-3,5-dimethyl benzaldehyde (76 yield). To a solution of 2-amino-4,6-dimethoxy-benzamide (200 mg, 1.02 mmol) and 4-(2-methoxy ethoxy)-3,5-dimethyl benzaldehyde (212 mg, 1.02 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (199 mg, 1.12 mmol) and p-TSA (22 mg, 0.102 mmol) were added and the reaction mixture was heated at 150° C. for 3 h. Cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was diluted with water and the solid was collected to give the crude product. The crude product was purified by chromatography using 2% MeOH in CH2Cl2 to give 5,7-dimethoxy-2-(4-(2-methoxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (170 mg, 43%). Selected data: MS (ES) m/z: 385.10; MP 201-202° C.