Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14]CC)=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:3]=1.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([OH:14])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(Cl)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1OB(O)c2cc(Oc3cnccn3)cc(Cl)c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
To the solution of ethyl 2-(4-chloro-1-hydroxy-6-(pyrazin-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (110 mg, 0.316 mmol) in THF (2 mL) was added an aqueous solution of lithium hydroxide (66 mg, 1.58 mmol) in water (1 mL) at 0° C. The resulting mixture was stirred at 0° C. for 2 h, acidified with diluted hydrochloric acid at 0° C. to pH=1˜2 and extracted with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound as a white powder (66.9 mg, Yield: 83.5%). 1H NMR (400 MHz, DMSO-d6)δ 9.51 (s, 1H), 8.61 (s, 1H), 8.43 (s, 1H), 8.24 (s, 1H), 7.53 (s, 1H), 7.47 (s, 1H), 5.53-5.55 (d, J=8.4 Hz, 1H), 3.23-3.36 (d, J=15.6 Hz, 1H), 2.33-2.40 (m, 1H); MS (ESI) m/z=321 [M+H]+.
Reaction SMILES: [CH3:1]N.[NH4+].[C:4]([CH:6]([CH2:11][CH3:12])[CH2:7][C:8]([O-])=[O:9])#[N:5]>[Pd].O>[CH2:11]([CH:6]1[CH2:4][N:5]([CH3:1])[C:8](=[O:9])[CH2:7]1)[CH3:12]
Reactant: CN
Reactant: CCC(C#N)CC(=O)[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: O
Product: CCC1CC(=O)N(C)C1
Temperature: 140 °C
Yield: 69.8 %

Procedure:
Into a 100 mL graduated cylinder was placed 79.4 mL of an aqueous reaction mixture containing 1.26 M 3-cyanopentanoic acid ammonium salt (0.1 mole 3-cyanopentanoic acid ammonium salt, produced by the enzymatic hydrolysis of 2-ethylsuccinonitrile; Example 13 filtered product mixture), then 17.2 mL of 40 wt. % methylamine (6.21 g methylamine, 0.2 mole) was added and the final volume adjusted to 100 mL with distilled water. The final concentrations of 3-cyanopentanoic acid ammonium salt and methylamine were 1.0 M and 2.0 M, respectively. To the resulting solution was added 0.636 g (5 wt. %/wt. of 3-cyanopentanoic acid) of 5% Pd on carbon powder, and the resulting mixture charged to a 300-mL 314 SS Autoclave Engineers EZE-Seal stirred autoclave equipped with a Dispersimax® turbine-type impeller. After flushing the reactor with nitrogen, the contents of the reactor were stirred at 1000 rpm and heated at 140° C. under 500 psig of hydrogen gas for 4 h. Samples (ca. 1.5 mL) were removed via a sampling tube over the course of the reaction for analysis. After cooling to room temperature, analysis of the final reaction mixture by gas chromatography indicated a 69.8% yield of 4-ethyl-1-methylpyrrolidin-2-one and a 20.4% yield of 4-ethylpyrrolidin-2-one, with no 3-cyanopentanoic acid ammonium salt remaining.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[OH:27])[C:6](=[O:23])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:18]([NH2:22])=[N:19][O:20][N:21]=1.CCN(C(C)C)C(C)C.[CH3:37][O:38][CH2:39]Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH2:37][O:38][CH3:39])[C:6](=[O:23])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:18]([NH2:22])=[N:19][O:20][N:21]=1
Reactant: COCCl
Reactant: COc1cc(C(=O)Cn2c(-c3nonc3N)nc3ccccc32)ccc1O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCOc1ccc(C(=O)Cn2c(-c3nonc3N)nc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 4-[1-(3-methoxy-4-hydroxyphenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine (0.10 g, 0.27 mmol), DIPEA and methoxymethyl chloride in dry DMF is stirred at room temperature for 14 hours. The reaction mixture is diluted with ethyl acetate, washed with water and dried over sodium sulphate. Filtration of the sodium sulphate and concentration of the filtrate under reduced pressure gives the title compound as colorless, pure solid, m.p. 190° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:20]1[O:22][C@H:21]1[CH2:23]Cl.[OH2:25]>C1COCC1>[C:1]1([C@:7]23[CH2:8][C@H:23]2[CH2:21][O:22][C:20]3=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccccc1
Reactant: O
Reactant: ClC[C@H]1CO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OC[C@@H]2C[C@]12c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Phenylacetonitrile (20 g) was dissolved in THF (500 ml), and NaHMDS (323 ml, 1.06 M) was then added dropwise to the solution under cooling in an ice-salt bath. The obtained mixture was stirred for 2 hours, and R-(−)-epichlorohydrin (15.8 g) was then added dropwise to the reaction solution (3 hours, 0° C.). The obtained mixture was stirred for 2 hours (wherein the internal temperature was maintained around 0° C.), and it was then stirred at room temperature overnight. Thereafter, the reaction solution was cooled on ice, and a small amount of water was added dropwise thereto. The reaction solution was concentrated under reduced pressure, and thereafter, ethanol (200 ml) and a 1 N potassium hydroxide aqueous solution (200 ml) were added to the residue. The obtained mixture was heated to reflux for 8 hours. Thereafter, the temperature of the reaction solution was returned to room temperature, and concentrated hydrochloric acid was then added to the solution, so that the pH value was adjusted to pH<2. Thereafter, the mixture was stirred at 0° C. for 2 hours. Thereafter, the reaction solution was stirred at room temperature for 1 hour. Subsequently, the reaction solution was concentrated under reduced pressure, and ethyl acetate and water were added to the concentrate to carry out liquid separation. The organic layer was successively washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution. The resultant organic layer was dried over magnesium sulfate, and the solvent was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate), so as to obtain the title compound (24.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][NH2:19])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH2:20][CH2:21][O:22][CH2:23][CH3:24])=[CH:4][CH:3]=1.[CH3:25][C:26](=O)[CH2:27][C:28](=O)[CH3:29]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([N:18]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:25])=[N:19]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH2:20][CH2:21][O:22][CH2:23][CH3:24])=[CH:4][CH:3]=1
Reactant: CC(=O)CC(C)=O
Reactant: CCOCCn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21
Product: CCOCCn1cnc2c(Nc3ccc(Cl)cc3)nc(-n3nc(C)cc3C)nc21

Procedure:
Was prepared according to Example 9 from (4-chloro-phenyl)-[9-(2-ethoxy-ethyl)-2-hydrazino-9H-purin-6-yl]-amine and 2,4-pentanedione.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:55]=[CH:56][CH:57]=1)[O:5][C:6]1[CH:32]=[C:31]([N:33]2[CH2:38][CH2:37][N:36]([CH2:39][C:40]3[CH2:45][CH2:44][C:43]([CH3:47])([CH3:46])[CH2:42][C:41]=3[C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=3)[CH2:35][CH2:34]2)[CH:30]=[CH:29][C:7]=1[C:8]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C@H:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)=[C:16]([N+:26]([O-:28])=[O:27])[CH:15]=1)(=[O:13])=[O:12])=[O:9].[CH2:58]=O>O1CCCC1.C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:55]=[CH:56][CH:57]=1)[O:5][C:6]1[CH:32]=[C:31]([N:33]2[CH2:34][CH2:35][N:36]([CH2:39][C:40]3[CH2:45][CH2:44][C:43]([CH3:47])([CH3:46])[CH2:42][C:41]=3[C:48]3[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=3)[CH2:37][CH2:38]2)[CH:30]=[CH:29][C:7]=1[C:8]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C@H:21]2[CH2:25][CH2:24][N:23]([CH3:58])[CH2:22]2)=[C:16]([N+:26]([O-:28])=[O:27])[CH:15]=1)(=[O:12])=[O:13])=[O:9]
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(N[C@H]5CCNC5)c([N+](=O)[O-])c4)c(Oc4cccc(Cl)c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reactant: C=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CN1CC[C@H](Nc2ccc(S(=O)(=O)NC(=O)c3ccc(N4CCN(CC5=C(c6ccc(Cl)cc6)CC(C)(C)CC5)CC4)cc3Oc3cccc(Cl)c3)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 194C (470 mg) in tetrahydrofuran (3 mL) and acetic acid (1 mL) was added 37% formaldehyde solution in water (0.42 mL) and MP-CNBH3 resin (947 mg, 2.38 mmol/g)). The reaction mixture was stirred overnight at room temperature. The resin was filtered off and reaction mixture was then concentrated. The residue was purified by flash chromatography, eluting with ethyl acetate, followed by a gradient of 3-10% methanol/dichloromethane. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ 8.42 (d, 1H), 8.34 (m, 1H), 7.78 (dd, 1H), 7.53 (d, 1H), 7.36 (d, 2H), 7.19 (t, 1H), 7.08 (m, 3H), 6.95 (m, 1H), 6.76 (dd, 1H), 6.67 (m, 2H), 6.45 (d, 1H), 3.53 (m, 2H), 3.16 (m, 7H), 2.83 (m, 4H), 2.61 (br m, 1H), 2.27 (m, 4H), 2.18 (m, 3H), 1.98 (m, 3H), 1.41 (m, 2H), 0.94 (s, 6H).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][NH:17][C:16](=O)[C:15]=1[N+:21]([O-:23])=[O:22]>CN(C=O)C>[Cl:3][C:16]1[C:15]([N+:21]([O-:23])=[O:22])=[C:14]([C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[Cl:6])[CH:19]=[CH:18][N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1Cl
Temperature: 25 °C
Yield: 19 %

Procedure:
To 10 mL of POCl3 was added 4-(2,4-dichloro-phenyl)-3-nitro-1H-pyridin-2-one (1.0 g, 3.51 mmol), followed by the addition of DMF (1-2 mL) and the reaction refluxed for 5 h. The reaction mixture was cooled to room temperature and poured over ice-H2O (200 mL). The solution was extracted with EtOAc, washed with H2O, brine, dried (MgSO4), filtered, and concentrated in vacuo to give 0.20 g (19%) of 2-chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine as a brown viscous oil: crude 1H NMR (300 MHz, CDCl3): δ 8.6 (d, 1H), 7.5 (s, 1H), 7.38 (s, 1H), 7.34 (d, 1H), 7.20 (d, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH3:8].[Br:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[O:27][CH3:28].[Cl-].[Al+3].[Cl-].[Cl-]>CN(C)C=O.C(Cl)(Cl)Cl.O>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:14]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:7][CH3:8])=[CH:18][CH:17]=2)=[O:16])[C:21]=1[O:27][CH3:28]
Reactant: COc1cc(Cl)ccc1Br
Reactant: CCOc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)c2c(Cl)ccc(Br)c2OC)cc1
Reaction time: 5 h
Yield: 31.1 %

Procedure:
A suspension of 2-bromo-5-chlorophenol (2.85 g, 13.7 mmol; synthesized in reference to International Patent Publication WO0109122), potassium carbonate (1.89 g, 13.7 mmol), n-Bu4NI (50 mg, 0.137 mmol), methyl iodide (1.28 mL, 20.6 mmol) and N,N-dimethylformamide (8.0 mL) was stirred for two hours. An iced water was added and the obtained mixture was extracted with ethyl acetate twice. The combined organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to obtain colorless oily 2-bromo-5-chloroanisole (2.94 g, 97%). Then, oxalyl chloride (1.23 mL, 15.1 mmol) and N,N-dimethylformamide (2 drops) were added to 4-ethoxybenzoic acid (2.28 g, 13.7 mmol) in chloroform (8 mL) and stirred for five hours. The yellow oil obtained by evaporating the solvent under reduced pressure was dissolved in chloroform (5 mL). To this solution, a chloroform solution (10 mL) of 2-bromo-5-chloroanisole (2.94 g, 13.3 mmol) was added and then aluminum chloride (2.07 g, 15.5 mmol) was added portion wise at −10° C. over five minutes. After stirred at 5° C. for one hour, the reaction mixture was to room temperature and stirred for 13 hours. The reaction mixture was poured into an iced water and extracted with chloroform three times. After washed with 1 M hydrochloric acid, water, brine, the combined organic layer was dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by NH type silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain (5-bromo-2-chloro-6-methoxyphenyl)(4-ethoxyphenyl)methanone (1.53 g, 31%) as a colorless crystal.
Reaction SMILES: [Si]([O:8][C@H:9]([C:46]1[CH:47]=[CH:48][C:49]([OH:57])=[C:50]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH:51]=1)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C@@H:30]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:31][CH2:32][N:33]([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[CH:24]=1)(C(C)(C)C)(C)C.CCN(CC)CC.F.F.F>O1CCCC1>[NH3:11].[CH:37]([N:33]([CH:34]([CH3:36])[CH3:35])[CH2:32][CH2:31][C@@H:30]([C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]([C:46]2[CH:47]=[CH:48][C:49]([OH:57])=[C:50]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH:51]=2)[OH:8])[CH:28]=[CH:27][C:26]=1[OH:29])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([CH3:39])[CH3:38]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c(NS(C)(=O)=O)c2)ccc1O)C(C)C
Agent: F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOCCCCCCNC[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)ccc1O)C(C)C
Product: N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-{5-[(1R)-1-{[tert-Butyl(dimethyl)silyl]oxy}-2-{[6-(4-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}butoxy)hexyl]amino}ethyl]-2-hydroxyphenyl}methanesulfonamide (Preparation 28, 420 mg, 0.51 mmol) was dissolved in tetrahydrofuran (6 ml) and triethylaminetrihydrofluoride (415 ul, 2.55 mmol) was added. The reaction was stirred at room temperature for 4 hours and the solvent removed in vacuo, the residue was dissolved in methanol (1 ml) and 880 ammonia (1 ml) and the solvent removed in vacuo, the residue was dissolved in methanol (1 ml) and 880 ammonia (1 ml) and the solvent removed in vacuo. The resulting oil was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (89/11/1.1 by volume) to furnish the title compound as a yellow solid, 26 mg.
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:19][CH3:20])=[CH:7][C:6]=1[C:21](=[O:23])[CH3:22].[CH:24](OCC)=O.Cl>O.COCCOC>[CH2:12]([O:11][C:9]1[CH:10]=[C:5]2[C:6]([C:21](=[O:23])[CH:22]=[CH:24][NH:4]2)=[CH:7][C:8]=1[O:19][CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1
Reactant: CCOC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
A mixture of sodium methylate (270 mmol, 14.75 g, favorable prepared from sodium metal and methanol before use), 1,2-dimethoxyethane (122 ml) and 1-(2-amino-4-benzyloxy-5-methoxy-phenyl)-ethanone (6.68 g 24 mmol) was stirred at 0° C. for 1 hour. Ethyl formate (10.7 ml, 9.81 g, 132 mmol) was added to the reaction mixture, that was allowed to come to room temperature and stirred for further 4 hours. The mixture was diluted with water (50 ml) and acidified to pH 1 by adding hydrochloric acid (1N, 185 ml). The precipitate was filtered, washed with water and dried to give 6.51 g of product [D]. Yield: 94%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[NH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.CN(C=O)C.C1(C)C=CC=CC=1.S(Cl)([Cl:38])=O>>[Cl:38][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2nc[nH]c(=O)c2cc1OCCCN1CCOCC1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1
Temperature: 80 °C
Yield: 58 %

Procedure:
A solution of 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (990 mg, 3.1 mmol) in thionyl chloride (10 ml) containing DMF (0.1 ml) was heated at 80° C. for 1.5 hours. After cooling, toluene was added and the solvent was removed by evaporation. The residue was triturated with ether, and the volatiles were removed by evaporation. The residue was partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH7.5 with 2M sodium hydroxide. The organic layer was washed with brine, dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by flash chromatography eluting with methylene chloride/methanol (1/9 followed by 95/5). The solid was triturated with hexane, collected by filtration and washed with ether to give 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline (614 mg, 58%).
Reaction SMILES: C([O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[N:8][NH:9][N:10]=1)C.[C:12](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.[OH-].[K+]>C1COCC1.C(O)C>[C:12]([N:8]1[N:9]=[N:10][C:6]([CH2:5][C:4]([OH:3])=[O:11])=[N:7]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)Cc1nn[nH]n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 18 h
Yield: 14.8 %

Procedure:
To a mixture of (2H-tetrazol-5-yl)-acetic acid ethyl ester (2.0 g, 12.81 mmol), trityl chloride (3.7 g, 13.45 mmol) in dry THF (75 ml) was added TEA (3.7 ml). The resulting mixture was stirred for 18 hrs. at room temperature. Water (10 ml) was added and the precipitate filtered off, redissolved in EtOAc (25 ml) and washed with saturated aqueous ammonium chloride (2×15 ml). The organic phase was dried (Na2SO4), filtered and evaporated in vacuo. The residue was suspended in ethanol (150 ml) and potassium hydroxide (0.8 g, 13.45 mmol) dissolved in ethanol (100 ml) was added. The resulting mixture was stirred for 18 hrs. at room temperature. The precipitate was filtered off and dissolved in water (150 ml) and acidified with conc. HCl (use diluted HCl). The precipitate was filtered off and washed with diethyl ether and dried in vacuo at 50° C. affording 0.7 g (15%) of (2-trityl-2H-tetrazol-5-yl)-acetic acid as a solid.
Reaction SMILES: C1(N2CC[O:10]CC2)CCCCC=1.C(N(CC)CC)C.[C:20](Cl)(=[O:25])[CH2:21][CH:22]([CH3:24])[CH3:23].Cl.[C:28]1(C)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:23][CH:22]([CH3:24])[CH2:21][C:20]([CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][C:28]1=[O:10])=[O:25]
Reactant: C1=C(N2CCOCC2)CCCC1
Reactant: CC(C)CC(=O)Cl
Reactant: Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)C1CCCCC1=O
Yield: 90 %

Procedure:
Compound IVd is obtained in 90% yield as a pale yellow liquid, according to Example 4, from 4-cyclohex-1-enyl-morpholine (82.64 g, 0.5 mol, obtained in Example 1), triethylamine (71.34 g, 0.71 mol), isovaleryl chloride (85.01 g, 0.71 mol), toluene (760 mL) and 20% aqueous HCl (166 mL).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:10])=[C:4]([NH:8]N)[CH:5]=[CH:6][CH:7]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)C.C1(C)C=CC=CC=1>[CH2:17]([O:16][C:11]([C:12]1[NH:8][C:4]2[C:5]([CH:14]=1)=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[CH3:10])=[O:15])[CH3:18]
Reactant: Cc1c(F)cccc1NN
Reactant: CCOC(=O)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cc2ccc(F)c(C)c2[nH]1
Temperature: 0 °C
Reaction time: 15 h
Yield: 12.7 %

Procedure:
3-Fluoro-2-methyl-phenylhydrazine (8.4 g, 0.06 mol) was dissolved in ethanol and the solution cooled to 0° C. (ice-bath). ethyl pyruvate (6.9 ml, 0.062 mol) was added dropwise and the solution stirred 15 h at room temperature. The solvent was evaporated under reduced pressure, and the residue stirred with hexane. The mixture of hydrazones that formed upon cooling in an ice-bath was filtered and dried under vacuum. Yield: 9.1 g, 64%. The hydrazone mixture (7.6 g, 0.032 mol) was dissolved in toluene (45 ml), anhydrous p-toluenesulfonic acid (8.2 g, 0.048 mol) added and the mixture heated 1 h at reflux. The mixture was cooled to room temperature, poured into half-saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (8:1 to 6:1 hexane/ethyl acetate eluant) to afford the product as a light brown solid (1.68 g, 24%). EI MS: 221.1 (M+)
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CS(C)=O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2[nH]1
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: O=C(c1ccc(Oc2nccnc2N2CCOCC2)cc1)c1nc2ccccc2[nH]1

Procedure:
A solution of (1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)-methanone (23.00 g, 65.6 mmol) and morpholine (17.2 mL, 197 mmol) was heated to 90° C. in DMSO (165 mL). After complete consumption of the starting material, the hot solution was dripped into ice water which caused a yellow solid to precipitate. The solid was slurried in boiling EtOH (600 mL) and enough tetrahydrofuran was added to completely dissolve the solids. The solution was transferred to the freezer for crystallization. The solid was collected by filtration and air-dried to give (1H-benzo[d]imidazol-2-yl)(4-(3-morpholinopyrazin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 402.1 (M+1). IC50 (uM) ++++.
Reaction SMILES: [BH4-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:15]3[C:16](=[O:20])[CH2:17][CH2:18][CH2:19][C:14]=3[N:13]=[C:12]2[CH:21]([CH3:23])[CH3:22])[CH:7]=[CH:8][CH:9]=1>ClCCl.CO>[I:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:15]3[CH:16]([OH:20])[CH2:17][CH2:18][CH2:19][C:14]=3[N:13]=[C:12]2[CH:21]([CH3:23])[CH3:22])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)c1nc2c(n1Cc1cccc(I)c1)C(=O)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1nc2c(n1Cc1cccc(I)c1)C(O)CCC2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.8 %

Procedure:
NaBH4 (1.670 g) was added to a stirred solution of Intermediate 90 (5.8 g) in Dichloromethane (DCM) (30 mL) and Methanol (30 mL). The reaction mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated in vacuo before being partitioned between EtOAc (60 ml) and water (60 ml). The two phases were separated and the aqueous phase was extracted with further EtOAc (2×60 ml). The organic phases were combined, filtered through a hydrophobic frit and concentrated in vacuo to give the desired product (5.7 g) as an off white solid. LC/MS MH+ 397, Rt 2.54 min (5 min run).