Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:11])[CH:9]=2)[N:4]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[C:3]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].[Cl:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]/B1OC(C)(C)C(C)(C)O1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O[Pd]OC(=O)C)(=O)C>[Cl:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]/[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:11])[CH:9]=2)[N:4]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[C:3]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1c(Br)c2cc(F)ccc2n1CCCOc1cccc2ccccc12
Reactant: CC1(C)OB(/C=C/CCCCl)OC1(C)C
Agent: CC(=O)O[Pd]OC(C)=O
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Product: CCOC(=O)c1c(/C=C/CCCCl)c2cc(F)ccc2n1CCCOc1cccc2ccccc12
Temperature: 100 °C

Procedure:
A mixture of ethyl 3-bromo-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate (The synthesis of this compound was described in EXAMPLE 134B as an intermediate) (404 mg), (E)-2-(5-chloropent-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.394 ml), diacetoxypalladium (19.28 mg), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (70.5 mg) and K3PO4 (547 mg) was heated in a microwave reactor (CEM Discover) at 100° C. for 1 hour. The insoluble material was removed by filtration and the filtrate was concentrated. The residue was purified by flash chromatography, eluting with dichloromethane to provide the title compound.
Reaction SMILES: CO[N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH:6]=1.C(=O)=O.C(O)(=O)C.[H][H]>C(O)C.O1CCCC1.[Pd]>[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([O:14][Si:15]([CH:19]([CH3:21])[CH3:20])([CH:22]([CH3:24])[CH3:23])[CH:16]([CH3:17])[CH3:18])[CH:6]=1
Reactant: CON=Cc1ccc([N+](=O)[O-])c(O[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C=O
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1cc(CN)ccc1N)(C(C)C)C(C)C

Procedure:
A solution of 4-nitro-3-[(triisopropylsilyl)oxy]benzaldehyde O-methyloxime (3.1 g, 9.8 mmol) in ethanol (100 mL) and tetrahydrofuran (80 mL) is degassed with solid carbon dioxide, then charged with 10% palladium on carbon (200 mg) and glacial acetic acid (1.3 mL). The mixture is shaked under 45 psi hydrogen gas for 36 hours. The mixture is then filtered through a pad of diatomaceous earth, and the filtrate is concentrated under reduced pressure to give {4-(aminomethyl)-2-[(triisopropylsilyl)oxy]phenyl}amine, a golden semi-solid, as its diacetic acid salt. This material is used in the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([F:14])=[CH:4][C:5]2[S:9][C:8](S(C)=O)=[N:7][C:6]=2[CH:13]=1.[NH2:15][C@@H:16]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=2[C:30]([F:33])([F:32])[F:31])=[O:22])[CH2:17]1.C([O-])(O)=O.[Na+]>CS(C)=O.O>[F:1][C:2]1[C:3]([F:14])=[CH:4][C:5]2[S:9][C:8]([NH:15][C@@H:16]3[CH2:20][CH2:19][N:18]([C:21]([C:23]4[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=4[C:30]([F:33])([F:31])[F:32])=[O:22])[CH2:17]3)=[N:7][C:6]=2[CH:13]=1
Reactant: CS(=O)c1nc2cc(F)c(F)cc2s1
Reactant: Cc1ccc(C(F)(F)F)c(C(=O)N2CC[C@@H](N)C2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(C(F)(F)F)c(C(=O)N2CC[C@@H](Nc3nc4cc(F)c(F)cc4s3)C2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
A mixture of 30 mg (0.129 mmol) rac-5,6-difluoro-2-methanesulfinyl-benzothiazole and 70.3 mg (0.258 mmol) ((R)-3-Amino-pyrrolidin-1-yl)-(5-methyl-2-trifluoromethyl-phenyl)-methanone (intermediate 13) in 540 μL dimethyl sulfoxide was heated in a 100° C. oil-bath for 4 h. The solution was cooled to room temperature, diluted with water and basified with a saturated NaHCO3 solution. The mixture was stirred for 1 h. The solid was filtered, washed with water and dissolved in dichloromethane. The solution was dried over Na2SO4, filtered and concentrated in vacuo. The crude compound was purified with flash column chromatography on silica eluting with a gradient formed from n-heptane and ethyl acetate to provide 27 mg (47.6%) of the title compound as a white solid. MS(m/e): 442.2 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.O[C@H]1CCNC1.Cl[C:15]1[CH:24]=[CH:23][C:22]2[C:21]([C:25]([NH:27][CH2:28][C@:29]3([OH:36])[CH2:34][CH2:33][CH2:32][C@H:31]([CH3:35])[CH2:30]3)=[O:26])=[C:20]([Cl:37])[CH:19]=[CH:18][C:17]=2[N:16]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:37][C:20]1[CH:19]=[CH:18][C:17]2[N:16]=[C:15]([N:1]3[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]3)[CH:24]=[CH:23][C:22]=2[C:21]=1[C:25]([NH:27][CH2:28][C@:29]1([OH:36])[CH2:34][CH2:33][CH2:32][C@H:31]([CH3:35])[CH2:30]1)=[O:26]
Reactant: OC1CCNCC1
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Agent: O[C@H]1CCNC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(O)CC4)ccc23)C1

Procedure:
The title compound was prepared by the method of Example 1, step e) by reacting piperidin-4-ol (28 mg) (instead of (S)-3-hydroxypyrrolidine) with the product of Example 1, step d) (0.10 g) and diisopropylethylamine (0.11 g) in acetonitrile (2 ml) to afford the title compound as a white solid (99 mg). m.p. 120° C. dec.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Mg].[C:12](=O)([O:16]CC)[O:13][CH2:14][CH3:15].[Cl-].[NH4+]>C1COCC1>[CH2:14]([O:13][C:12]([C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:16])[CH3:15]
Reactant: CCOC(=O)OCC
Reactant: Brc1cccc2ccsc12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc2ccsc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
7-bromobenzo[b]thiophene (500 mg, 2.36 mmol) is dissolved in dry THF (5.0 mL) under nitrogen. Magnesium turnings (530 mg, 2.83 mmol, 1.20 equiv.) are added and the resulting mixture is heated at reflux until dissolution of the magnesium has occurred. The resulting cloudy yellow solution is allowed to cool to rt and diethyl carbonate (2 mL, excess) is added and stirring continued for one hour, when ammonium chloride (10% aq) is added. The resulting mixture is partitioned between DCM and water and the aqueous layer is extracted with DCM. The organic fractions are combined, washed with brine, dried over Na2SO4 and adsorbed onto silica. Purification by LC using 8/2 cyclohexane/dichloromethane as the eluent afforded the title compound as a pale orange oil (346.2 mg, 71%).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:30]=[CH:29][C:13]2[NH:14][C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1.CO.[OH-].[Li+].Cl>CCOC(C)=O.O>[F:28][C:25]([F:26])([F:27])[C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:15]2[NH:14][C:13]3[CH:29]=[CH:30][C:10]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]([OH:31])=[O:2])=[CH:11][C:12]=3[N:16]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reaction time: 12 h
Yield: 90.9 %

Procedure:
To a solution of 2-[2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazol-5-yl]-benzoic acid methyl ester (0.494 g, 1.16 mmol) in mixed solvent (30 mL, MeOH: H2O=3:1) was added lithium hydroxide (0.166 g, 6.95 mmol). After stirring for 12 hours, the reaction mixture was diluted with EtOAc and acidified by aqueous 3N HCl. The organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a white solid (0.435 g, 91%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>C(OCCO)C>[N:14]1([C:2]2[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[N:7]3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: N#Cc1ccc(Cl)c2cccnc12
Reactant: C1CCNC1
Solvent: CCOCCO
Product: N#Cc1ccc(N2CCCC2)c2cccnc12
Yield: 69.2 %

Procedure:
5-Chloro-8-nitroquinoline, 5 g, was reduced, diazonized, and cyanized in the same manner as in Example 1 to produce 2.62 g (yield: 58%) of 5-chloro-8-quinolinecarbonitrile. A mixture of 1.88 g of 5-chloro-8-quinolinecarbonitrile thus prepared and 7.10 g of pyrrolidine was dissolved into 30 ml of 2-ethoxyethanol and the solution was heated under reflux for 3 hours. The solvent was evaporated, and the residue, after addition of water, was extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. Chloroform was evaporated, and the residue was refined by column chromatography on silica gel using a chloroform-methanol (95:5) mixed solvent as an eluent. The crystals thus obtained were recrystallized from ethanol to yield 1.54 g (yield: 69%) of 5-pyrrolidino-8-quinolinecarbonitrile (Compound No. 7).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.BrCC.[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>O1CCCC1>[CH2:18]([O:17][C:15](=[O:16])[C:14]([C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1)=[O:20])[CH3:19]
Reactant: Brc1cccc2nccn12
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCBr
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cccc2nccn12
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
Add Mg turnings (0.25 g, 9.95 mmol) to a solution of 5-Bromoimidazo[1,2-a]pyridine (1.5 g, 7.65 mmol) in tetrahydrofuran (20 ml). Heat the reaction to 60° C. and add bromoethane (1.2 ml, 11.1 mmol). Reflux for another 0.5 hours, cool and cannula dropwise into a solution of diethyl oxalate (5 ml) in tetrahydrofuran (5 ml) at −15° C. Stir at −15° C. for 0.5 hours and at room temperature for 0.5 hours. Quench the reaction by adding pH 7 buffer, extract into ethyl acetate, wash with saturated sodium chloride, dry over magnesium sulfate, and concentrate under reduced pressure. Purification by flash chromatography, eluting with ethyl acetate:hexane:methanol gradient gives the title compound as a light brown oil.
Reaction SMILES: [CH2:1](N)[CH2:2][CH3:3].[Cl:5][C:6]1[CH:7]=[C:8]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:20]([CH3:27])[CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:15]1[CH:14]=[C:13]([C:28](=[S:30])[NH2:29])[CH:12]=[CH:11][C:10]=1[S:9]2.Cl>C(O)C.C(OCC)(=O)C.C(OCC)C>[Cl:5][C:6]1[CH:7]=[C:8]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:20]([CH3:27])[CH2:21][N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])[C:15]1[CH:14]=[C:13]([C:28](=[S:30])[NH:29][CH2:1][CH2:2][CH3:3])[CH:12]=[CH:11][C:10]=1[S:9]2
Reactant: CCCN
Reactant: CCN(CC)CC(C)N1c2ccc(Cl)cc2Sc2ccc(C(N)=S)cc21
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCNC(=S)c1ccc2c(c1)N(C(C)CN(CC)CC)c1ccc(Cl)cc1S2
Reaction time: 4 h

Procedure:
Propylamine (0.75 cc) is added to a solution of 7-chloro-10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbothioamide (0.6 g) in absolute ethanol (5 cc). The mixture is brought to 200° C. for 4 hours and then diluted with ethyl acetate (50 cc), washed with distilled water (2×100 cc), dried over magnesium sulphate and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual solid is purified by chromatography on a column (height: 8.5 cm; diameter: 2 cm) of silica gel (0.6-0.02 mm), eluting with a 20:80 (by volume) mixture (1.5 liters) of ethyl acetate and cyclohexane, collecting 30-cc fractions. Fractions 25 to 36 are combined and concentrated under reduced pressure (30 mm Hg; 4 kPa) to give a brown oil, which is dissolved in ethyl ether (10 cc). 2.2N ethereal hydrochloric acid (2 cc) is added to this solution. The suspension obtained is filtered to give 7-chloro-10-[(2RS)-1-diethylamino-2-propyl]-N-propyl-2-phenothiazinecarbothioamide (0.06 g), m.p. 130° C.
Reaction SMILES: Cl.[C:2]1([CH:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:9][NH:10][C:11]2[N:19]=[C:18]([CH2:20][NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:23])[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C@@H:39]1[O:51][C@H:50]([CH2:52][O:53][C:54](=[O:56])[CH3:55])[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:40]1[O:41][C:42](=[O:44])[CH3:43])(=O)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>ClC(Cl)(Cl)C.C(OCC)(=O)C>[C:47]([O:46][C@H:45]1[C@@H:40]([O:41][C:42](=[O:44])[CH3:43])[C@H:39]([N:15]2[CH:14]=[N:13][C:12]3[C:16]2=[N:17][C:18]([CH2:20][NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])=[O:24])=[N:19][C:11]=3[NH:10][CH2:9][CH:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:51][C@@H:50]1[CH2:52][O:53][C:54](=[O:56])[CH3:55])(=[O:49])[CH3:48]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)CS(=O)(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(Cl)(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)CC(C)C)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
A suspension of N-({6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-2-methyl-1-propanesulfonamide hydrochloride (Preparation 8) (0.21 g, 0.42 mmol) in 1,1,1-trichloroethane (10 ml) was treated with N,O-bis(trimethylacetamide) (0.6 ml, 2.45 mmol) and the mixture was heated under reflux for 2 hours. The solvent was removed under reduced pressure and the residue was azeotroped with toluene (×2). The residue was dissolved in toluene (10 ml) and treated with the β-D-ribofuranose-1,2,3,5-tetraacetate (0.16 g, 0.50 mmol) and trimethylsilyltriflate (0.1 ml, 0.5 mmol). The mixture was then heated at reflux for 4 hours. The mixture was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate solution and brine and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (98:2 by volume) gradually changing to dichloromethane:methanol (95:5 by volume) to afford the title compound as a 1:3 mixture of α-and β-anomers (188 mg).
Reaction SMILES: P([NH:5][C:6]([O:8][CH2:9][C:10]1[CH2:11][S:12][C@@H:13]2[C@H:20]([NH:21][C:22](=[O:32])/[C:23](/[C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)=[N:24]\[O:25][CH3:26])[C:19](=[O:33])[N:14]2[C:15]=1[C:16]([OH:18])=[O:17])=[O:7])(O)(O)=O>O.O1CCOCC1>[C:6]([O:8][CH2:9][C:10]1[CH2:11][S:12][C@@H:13]2[C@H:20]([NH:21][C:22](=[O:32])/[C:23](/[C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)=[N:24]\[O:25][CH3:26])[C:19](=[O:33])[N:14]2[C:15]=1[C:16]([OH:18])=[O:17])(=[O:7])[NH2:5]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)NP(=O)(O)O)CS[C@H]12)c1ccco1
Solvent: C1COCCO1
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1

Procedure:
A solution of (6R,7R)-3-phosphonocarbamoyloxymethyl-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid (0.35 g) in water (4 ml) and dioxan (1 ml) was kept successively at 40° for 5 hours, room temperature for 16 hours, 40° for 6 hours and 20° for 16 hours. The conversion to the title compound was monitored by t.l.c. A precipitate was formed and this was filtered off. The pH was altered from 4 to 7 by addition of saturated aqueous sodium bicarbonate solution.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[O:12]([CH2:19][CH:20]1[O:25][CH2:24][CH2:23][NH:22][CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[O:12]([CH2:19][CH:20]1[O:25][CH2:24][CH2:23][N:22]([CH2:2][C:3]2[NH:4][C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=3[N:7]=2)[CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: c1ccc(OCC2CNCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: c1ccc(OCC2CN(Cc3nc4ccccc4[nH]3)CCO2)cc1
Yield: 66 %

Procedure:
2-(Chloromethyl)benzimidazole (172 mg, 1.03 mmol) and 2(RS)-(phenoxymethyl)morpholine (200 mg) were heated in ethanol (8 ml) at 80° C. (oil bath temperature) in the presence of potassium carbonate (142 mg, 1.03 mmol) for 2 hours. The mixture was cooled then evaporated to dryness. The residue was partitioned between water (10 ml) and ethyl acetate (25 ml). The organic layer was separated and the aqueous re-extracted with ethyl acetate (25 ml). The combined organics were dried (sodium sulphate) then evaporated to give a beige gum which was purified by column chromatography on silica (150 g) using ethyl acetate to ethyl acetate/methanol (25:1) to afford the title compound as a pale yellow solid (220 mg, 66%). mp 171°-172° C. (ethyl acetate/n-hexane). MS, CI+, mz=324 for (M+H)+. 1H NMR (360 MHz, CDCl3) δ2.40 (1H, dd, J1 =J2 =10 Hz), 2.51 (1H, ddd, J1 =3, J2 =J3 =10 Hz), 2.79 (1H, d, J=10 Hz), 2.99 (1H, d, J=10 Hz), 3.82 (1H, ddd, J1 =3, J2 =J3 =10 Hz), 3.91-4.06 (6H, m), 6.88 (2H, dd, J1 =1, J2 =8 Hz), 6.95 (1H, ddd, J1 =1, J2 =J3 =8 Hz), 7.24-7.29 (4H, m), 7.57-7.61 (2H, m). Found: C, 70.55; H, 6.51; N, 12.96. C19H21N3O2 requires C, 70.57; H, 6.55; N, 12.99%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)/[S:6][C:5]1=[O:20].C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29]>ClCCl>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11](/[CH:10]=[C:7]2/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][C:28](=[O:30])[CH3:29])[C:5](=[O:20])[S:6]/2)=[CH:12][CH:13]=1)[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(/C=C2\SC(=O)N(CCNC(C)=O)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a solution of compound 76 (101 mg, 0.25 mmol) in 5 mL of dichloromethane was added triethylamine (105 μL, 0.75 mmol) and acetic anhydride (26.0 μL, 0.28 mmol). After being stirred at room temperature overnight, the reaction solution was diluted with 50 mL of dichloromethane, washed with water, collected the organic layer, dried over Na2SO4, filtered, concentrated and purified by silica column chromatography (33% dichloromethane in ethyl acetate) to afford 74 mg (88.6%) of the title compound 25a as a light-yellow solid.
Reaction SMILES: CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:45]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:46]=1[CH:47]=[C:48]1[CH2:67][C:59]3([CH2:64][O:63][C:62]([CH3:66])([CH3:65])[O:61][CH2:60]3)[CH2:58][C:49]1=[C:50]2[C:55](=[O:57])[CH3:56].[NH:68]1[CH2:72][CH2:71][CH2:70][CH2:69]1>C1COCC1.CCCCCC.CCOC(C)=O>[CH3:66][C:62]1([CH3:65])[O:63][CH2:64][C:59]2([CH2:58][C:49]3=[C:50]([C:55](=[O:57])[CH3:56])[C:51]4[C:46]([CH:47]=[C:48]3[CH2:67]2)=[C:45]([N:68]2[CH2:72][CH2:71][CH2:70][CH2:69]2)[CH:54]=[CH:53][CH:52]=4)[CH2:60][O:61]1
Reactant: CC(=O)c1c2c(cc3c(Cl)cccc13)CC1(COC(C)(C)OC1)C2
Reactant: C1CCNC1
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)c1c2c(cc3c(N4CCCC4)cccc13)CC1(COC(C)(C)OC1)C2
Yield: 35 %

Procedure:
Follows general procedure (pag. 13): [RuPhos Palladacyle] (0.0020 g, 0.0028 mmol), LHMDS (0.23 mL of a 1.0 M solution in THF, 0.23 mmol), 5a (0.040 g, 0.12 mmol) in THF (0.3 mL), pyrrolidine (0.014 mL, 0.17 mmol). The title compound was isolated (n-hexane/AcOEt 8:2, 0.016 g, 35% yield) as a yellow solid.
Reaction SMILES: [Cl-].C[SiH](C)C.[CH3:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]Br.[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[CH:18][N:17]=1.O>O1CCCC1.BrC(Br)C.[Zn]>[Cl:15][C:16]1[CH:21]=[C:20]([CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[CH3:6])[N:19]=[CH:18][N:17]=1
Reactant: Cc1ccccc1CBr
Reactant: Clc1cc(Cl)ncn1
Agent: CC(Br)Br
Agent: C[SiH](C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1Cc1cc(Cl)ncn1
Reaction time: 0.33 h
Yield: 25 %

Procedure:
In 10 ml of tetrahydrofuran was suspended 1.3 g of zinc (powder), to which dibromoethane (2 drops) was added. The mixture was heated under reflux for 5 minutes, to which trimethylsilane chloride was added. The mixture was further heated under reflux for 5 minutes, to which a solution of 1.9 g of 2-methylbenzyl bromide dissolved in 20 ml of tetrahydrofuran was slowly added with heating under reflux, followed by stirring for 20 minutes. (The solution thus obtained is referred to as solution D). In 10 ml of tetrahydrofuran were suspended 1.5 g of 4,6-dichloropyrimidine and 0.1 g of dichlorobistriphenylphosphine palladium, to which the above solution D was added, followed by heating under reflux for 3 hours and further stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.55 g of 4-chloro-6-(2-methylbenzyl)pyrimidine.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[CH2:11][NH:10][C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[CH:11]=[N:10][C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NCc2cc(Cl)ccc2N1Cc1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: O=c1ncc2cc(Cl)ccc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a stirring solution of 1-benzyl-6-chloro-3,4-dihydroquinazolin-2(1H)-one (0.15 g, 0.55 mmol) in DCM (5 mL) was added DDQ (0.13 g, 0.55 mmol) at 0° C. upon which the solution turned black. The mixture was stirred for 4 h at 0° C. and quenched with 1N NaOH(aq). The mixture was passed through a short path of Celite. The separated aqueous layer was extracted with DCM (2×15 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a crude residue, which was purified using flash column chromatography (100% DCM to 4% MeOH in DCM gradient). The product fractions were concentrated, and washed with ether-hexanes and iPrOH successively to obtain the title compound 1-Benzyl-6-chloroquinazolin-2(1H)-one as an off-white solid. MS m/e 271 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([CH3:19])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.[CH:21]([N-]C(C)C)(C)C.[Li+].CI.Cl>O1CCCC1>[CH3:1][O:2][C:3](=[O:20])[C:4]([CH3:21])([CH3:19])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:8][CH2:7]1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C(C)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2-methyl-3-(N-Boc-piperidine-4-yl)-propionic acid methyl ester (789 mg, 2.77 mmol) from above was dissolved in dry tetrahydrofuran (2 mL) and cooled to −78° C. To this solution was added lithium diisopropylamide (5.5 mmol, prepared from diisopropylamine and n-butyl lithium). The mixture was stirred at −78° C. for 1 hr and methyl iodide (0.7 mL, 11.24 mmol) was added. The mixture was stirred at −78° C. for 2 hrs until complete consumption of the starting material. The mixture was treated with hydrochloric acid (1N, 10 mL) and extracted with ether. The organic layer was washed with brine and dried over sodium sulfate. After evaporation of the solvents, the residue was purified using flash chromatography (eluting with hexanes and ethyl acetate) to give 2,2-dimethyl-3-(N-Boc-piperidine-4-yl)-propionic acid methyl ester as a colorless oil that slowly turned into a solid (598 mg).