Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([N:23]4[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]4)=[O:22])=[CH:17][CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH:30]([NH2:33])([CH3:32])[CH3:31].C([BH3-])#N.[Na+].Cl>CCO.CCOCC>[ClH:1].[CH3:31][CH:30]([NH:33][CH:26]1[CH2:27][CH2:28][N:23]([C:21]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:13]=[CH:12][N:11]=3)=[CH:20][CH:19]=2)=[O:22])[CH2:24][CH2:25]1)[CH3:32]
Reactant: O=C1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Reactant: CC(C)N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)NC1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.9 %

Procedure:
1-[(4-{[4-(4-chlorophenyl)pyrimidin-2yl]amino}phenyl)carbonyl]piperidin-4-one (400 mg, 0.980 mmol) was dissolved in 10 mL EtOH along with isopropylamine (58 mg, 0.980 mmol). Sodium cyanoborohydride (62 mg, 0.986 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction was quenched with water, extracted with ethyl acetate followed by flash chromatography (EtOAc/MeOH; 90:10) to give a residue. This was taken up in ETOH saturated with HCl(g), diluted with ether, filtered to give 4-{[4-(4-chlorophenyl)pyrimidin-2-yl]amino}phenyl 4-[(methylethyl)amino]piperidyl ketone hydrochloride (0.150 g, 30% yield): HPLC Retention time; 6.02 min. (Method B) M+1; 450.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[N:9]=[CH:8][N:7]=[C:6]2[O:21]C1C=CC=CC=1.Cl.C(=O)([O-])O.[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[N:9]=[CH:8][NH:7][C:6]2=[O:21]
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCN1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2c(=O)[nH]cnc2cc1OCCN1CCCC1
Temperature: 90 °C
Yield: 107 %

Procedure:
A mixture of 6-methoxy-4-phenoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline (565 mg, 1.55 mmol) and 2M hydrochloric acid (5 ml) was heated at 90° C. for 90 minutes and allowed to cool. The solution was neutralised with aqueous sodium hydrogen carbonate, and the water removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol/ammonia (100/8/1) to give 6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (480 mg). This material was used without further characterisation.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O.[CH2:22]([O:24][C:25](=[O:32])[C@H:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH2:27])[CH3:23].Cl.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([NH:27][C@@H:26]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:25]([O:24][CH2:22][CH3:23])=[O:32])=[O:12]
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: COc1ccc(CC(Sc2ccccc2Br)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)C(Cc1ccc(OC)cc1)Sc1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-bromophenyl)thio-3-(4-methoxyphenyl)propanoic acid (1.102 g) and L-leucine ethyl ester.HCl (704 mg) in DMF (10 mL), HOBt (551 mg) and EDC.HCl (690 mg) were added. The reaction mixture was stirred at r.t. overnight. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with 1N HCl, 5% Na2CO3 aq. and brine. The organic layer was dried over Na2SO4 and concentrated to give the pure product as a pale yellow oil (1.561 g, quant.).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[C:11]([CH2:17][O:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:27][C:28]1[C:29]([CH3:34])=[CH:30][CH:31]=[CH:32][CH:33]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])=[CH:13][CH:12]=[C:11]([CH2:17][O:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2cc(COC(=O)c3ccccc3)ccc2c1Cl
Reactant: Cc1ccccc1N
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2cc(COC(=O)c3ccccc3)ccc2c1Nc1ccccc1C
Reaction time: 16 h
Yield: 41 %

Procedure:
3-Butyryl-4-chloro-7-benzoyloxymethylquinoline (3.68 g, 10 mmol) and o-toluidine (1.61 g, 15 mmol) in dioxan (100 ml) were refluxed for 2.5 hours, then allowed to cool and stand for 16 hours. The solvent was evaporated and the product converted to the free base and recrystallised from ethanol to give the title compound (1.8 g), m.p. 110°-12°.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([C:12]1[N:29]([CH2:30][C@H:31]2[CH2:36][CH2:35][C@H:34]([CH3:37])[CH2:33][CH2:32]2)[C:15]2[C:16]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([Cl:28])[CH:27]=3)=[N:17][C:18]([C:20]#[N:21])=[CH:19][C:14]=2[N:13]=1)=[CH2:11])(C(C)(C)C)(C)C.[F-].[CH2:39]([N+](CCCC)(CCCC)CCCC)CCC.[H-].[Na+].CI>C1COCC1>[Cl:28][C:26]1[CH:27]=[C:22]([C:16]2[C:15]3[N:29]([CH2:30][C@H:31]4[CH2:36][CH2:35][C@H:34]([CH3:37])[CH2:33][CH2:32]4)[C:12]([C:10]([CH2:9][O:8][CH3:39])=[CH2:11])=[N:13][C:14]=3[CH:19]=[C:18]([C:20]#[N:21])[N:17]=2)[CH:23]=[N:24][CH:25]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C=C(CO[Si](C)(C)C(C)(C)C)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Agent: [F-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: C=C(COC)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Steps 5 & 6: A stirred solution of 2-(3-{[tert-butyl(dimethyl)silyl]oxy}prop-1-en-2-yl)-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (1.2 g, 2.24 mmol) in THF (20 mL) was cooled to 0° C. Tetrabutylammonium fluoride (3.36 mL, 3.36 mmol, 1M solution in THF) was added dropwise over a period of 5 minutes, and the reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (15 mL). The organic phase was separated, washed with brine solution (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude 4-(5-chloropyridin-3-yl)-2-(3-hydroxyprop-1-en-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (0.9 g, 2.14 mmol) was dissolved in dry THF (10 mL) and cooled to 0° C. NaH (0.123 g, 3.12 mmol, 60% in mineral oil) was added in several portions and stirred for 15 minutes. Methyl iodide (0.16 mL, 2.57 mmol) was added dropwise over a period of 5 minutes, and the reaction mixture was slowly warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with ice and extracted with ethyl acetate (100 mL). The organic layer was separated, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 15% ethyl acetate/petroleum ether as eluent to yield 4-(5-chloropyridin-3-yl)-2-(3-methoxyprop-1-en-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ES/APCI calcd. for C24H26ClN5O [M+H]+ 436. found 436
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:14]([CH:15]2[CH2:17][CH2:16]2)=[CH:13][C:9]([C:10]([OH:12])=O)=[C:8]([F:18])[CH:7]=1)[CH2:2][CH2:3][CH3:4].C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2.[CH:42]1([S:45]([NH2:48])(=[O:47])=[O:46])[CH2:44][CH2:43]1.Cl>O1CCCC1>[CH2:1]([O:5][C:6]1[C:14]([CH:15]2[CH2:17][CH2:16]2)=[CH:13][C:9]([C:10]([NH:48][S:45]([CH:42]2[CH2:44][CH2:43]2)(=[O:47])=[O:46])=[O:12])=[C:8]([F:18])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(F)c(C(=O)O)cc1C1CC1
Reactant: NS(=O)(=O)C1CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCOc1cc(F)c(C(=O)NS(=O)(=O)C2CC2)cc1C1CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 20.6 %

Procedure:
To a stirred solution of 4-butoxy-5-cyclopropyl-2-fluorobenzoic acid (0.039 g, 0.15 mmol) in tetrahydrofuran (1 mL) and under an atmosphere of nitrogen was added carbonyldiimidazole (0.030 g, 0.18 mmol) and the reaction mixture was stirred at 70° C. for 1 hour. The mixture was cooled down to room temperature and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.02 mL, 0.02 mmol) was added followed by cyclopropanesulfonamide (0.024 g, 0.20 mmol) and the stirring continued at ambient temperature for 18 hours. 5% aqueous hydrochloric acid solution (0.15 mL) was added and the mixture was concentrated and directly purified by column chromatography (0 to 30% gradient ethyl acetate in hexanes) to afford the title compound (0.011 g, 20%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.82-8.57 (m, 1H), 7.57 (d, J=9.24 Hz, 1H), 6.58 (d, J=14.42 Hz, 1H), 4.04 (t, J=6.30, 6.30 Hz, 2H), 3.16-3.05 (m, 1H), 2.18-1.74 (m, 3H), 0.72-0.61 (m, 2H), 1.71-0.84 (m, 13H), 0.74-0.60 (m, 2H); MS (ES+) m/z 356.1 (M+1); MS (ES−) m/z 354.2 (M−1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH2:14]([O:16][CH2:17]Cl)[CH3:15]>CN(C=O)C>[CH2:14]([O:16][CH2:17][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH3:15]
Reactant: CCOCCl
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCOc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
A mixture of 10 g of 3-(trifluoromethyl)phenol and 15 ml of DMF was added dropwise to a mixture of 2.71 g of sodium hydride (60%, oil-based) and 45 ml of DMF under ice-cooling, and the mixture was stirred for 30 minutes. Subsequently, a mixture of 7.0 g of chloromethyl ethyl ether and 5 ml of DMF was added dropwise thereto, and the mixture was stirred for 1 hour. The reaction mixture was added to ice water. This mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure, to obtain 13 g of 1-ethoxymethoxy-3-(trifluoromethyl)benzene.
Reaction SMILES: Cl.C([O:4][CH:5](OCC)[CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1)C>O1CCCC1>[O:4]=[CH:5][CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1
Reactant: CCOC(COc1ccc(CC2SC(=O)NC2=O)cc1)OCC
Agent: Cl
Solvent: C1CCOC1
Product: O=CCOc1ccc(CC2SC(=O)NC2=O)cc1
Reaction time: 8 h
Yield: 75.2 %

Procedure:
20 ml of 6 N aqueous hydrochloric acid were added to a solution of 10.07 g of 5-[4-(2,2-diethoxyethoxy)-benzyl]thiazolidine-2,4-dione (prepared as described in Preparation 46) in 80 ml of tetrahydrofuran, and the resulting mixture was allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure. The residue was diluted with water, after which it was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 2:3 by volume mixture of hexane and ethyl acetate as the eluent, to give 5.92 g of the title compound having Rf=0.37 (on silica gel thin layer chromatography using a 1:2 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][OH:8])=[C:5]([CH3:9])[O:4][N:3]=1.O[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]([NH:23][C:24]2[S:25][CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:28]=2)[C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C@H:18]([NH:23][C:24]3[S:25][CH:26]=[C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:28]=3)[C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=2)=[C:5]([CH3:9])[O:4][N:3]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)Nc1nc(-c2ccccc2)cs1
Reactant: Cc1noc(C)c1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(OCc2c(C)noc2C)cc1)Nc1nc(-c2ccccc2)cs1
Temperature: 5 °C
Reaction time: 21 h

Procedure:
(3,5-Dimethylisoxazol-4-yl)methanol (0.28 g, 1.5 mmol), methyl (2S)-3-(4-hydroxyphenyl)-2-[(4-phenyl-1,3-thiazol-2-yl)amino]propionate from Step A (0.35 g, 1 mmol) and triphenylphosphine (0.79 g, 3 mmol) were dissolved in tetrahydrofuran (THF). After cooling the reaction mixture to 5° C., DEAD (0.52 g, 3 mmol) was added. The reaction was then stirred at room temperature for 18-24 h. THF was evaporated to obtain crude methyl (2S)-3-{4-[(3,5-dimethylisoxazol-4-yl)methoxy]phenyl}-2-[(4-phenyl-1,3-thiazol-2-yl)amino]propionate.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:19][CH2:20][CH2:21]Br>C(O)(C)C>[C:12]1([C:10]2([OH:11])[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]3[CH2:19][CH2:20][CH2:21][N:1]=[C:2]23)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCCCBr
Reactant: NC1=Nc2ccccc2C1(O)c1ccccc1
Solvent: CC(C)O
Product: OC1(c2ccccc2)C2=NCCCN2c2ccccc21

Procedure:
2-Amino-3-phenyl-3H-indol-3-ol (2.24 g) was heated under reflux with isopropanol (20 ml) and 1,3-dibromopropane (2.0 g) for 20 hours. The reaction mixture was evaporated to 10 ml and diluted with a little ether. The title compound was obtained as its hydrobromide salt 0.73 g., m.p. 260°-262°C (decomp.) and could be recrystallized from methanol, ethanol or isopropanol with or without the addition of ethyl acetate or ether.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:18][CH2:19][CH2:20][CH2:21]I.[Na+].[Cl-]>CN(C)C=O.O>[Cl:18][CH2:19][CH2:20][CH2:21][O:15][C:11]1[CH:10]=[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:14]=[N:13][CH:12]=1
Reactant: ClCCCI
Reactant: Oc1cncc(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCOc1cncc(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a solution of 5-(phenylmethoxy)pyridine-3-ol (1.52 g, 7.56 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added drop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.238 g of an 80% dispersion in mineral oil, 7.94 mmol) in DMF (15 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. Next, 1-chloro-3-iodopropane (1.85 g, 9.07 mmol) was added drop-wise over 5 min. The resulting dark-brown mixture was stirred at ambient temperature for 4 h. Water (25 mL) was added, followed by saturated NaCl solution (25 mL), and the mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[CH:19]=[CH:20][N:21]=[CH:22][C:14]2=3)=O)[CH:5]=[C:6]([Br:10])[C:7]=1[O:8][CH3:9].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[CH:19]=[CH:20][N:21]=[CH:22][C:14]2=3)=[S:32])[CH:5]=[C:6]([Br:10])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(Br)cc(C(=O)N2CCOc3ccncc32)cc1Br
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1c(Br)cc(C(=S)N2CCOc3ccncc32)cc1Br
Reaction time: 2 h
Yield: 97.9 %

Procedure:
In a 25 ml flask, (3,5-dibromo-4-methoxy-phenyl)-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone (100 mg, 0.23 mmol) was suspended in toluene, and Lawesson's reagent (113 mg, 1.2 equivalents) was added thereto and then stirred at 120□ for 2 hours. Toluene was evaporated under reduced pressure and the residue was purified on amine silica by using a solvent of dichloromethane:methanol=50:1 to obtain (3,5-dibromo-4-methoxy-phenyl)-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanethione (100 mg, 98%).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:13])[NH:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[N:4][C:3]=1[O:14][CH:15]([CH3:17])[CH3:16].[H-].[Na+].[CH2:20]([O:27][C:28]1[C:33]([CH2:34]Cl)=[C:32]([CH3:36])[CH:31]=[C:30]([CH3:37])[N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O>CN(C=O)C>[CH2:20]([O:27][C:28]1[C:33]([CH2:34][N:9]2[C:8](=[O:13])[C:7]3[C:2]([CH3:1])=[C:3]([O:14][CH:15]([CH3:17])[CH3:16])[N:4]=[CH:5][C:6]=3[O:12][CH2:11][CH2:10]2)=[C:32]([CH3:36])[CH:31]=[C:30]([CH3:37])[N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1c(OC(C)C)ncc2c1C(=O)NCCO2
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CN2CCOc3cnc(OC(C)C)c(C)c3C2=O)c(OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94608.2 %

Procedure:
To a solution of 6-methyl-7-(propan-2-yloxy)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one (131f, 70 mg, 0.30 mmol) in dry DMF (6 mL) was added NaH (36 mg, 0.90 mmol, 60% in oil) at 0° C. The mixture was stirred at 0° C. for 10 minutes. To the mixture was added 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 155 mg, 0.6 mmol). The reaction mixture was stirred at room temperature for 14 hours. To the reaction mixture was added EtOAc (20 mL). The solution was washed with brine (5×15 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 10/1) to give 4-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-6-methyl-7-(propan-2-yloxy)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one (131 g, 0.14 g, 100%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13])=[O:8])=[CH:5][CH:4]=1)#[N:2].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:60][O:61][C:62](=[O:70])[CH2:63][CH:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>C(Cl)Cl>[CH3:60][O:61][C:62](=[O:70])[CH2:63][CH:64]1[CH2:65][CH2:66][N:67]([C:12](=[O:13])[C:11]([CH3:15])([CH3:16])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[NH:9][C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:25][CH:24]=2)[CH2:68][CH2:69]1
Reactant: CC(C)(C(=O)O)C(NC(=O)c1ccc(C#N)cc1)c1cccc(Cl)c1
Reactant: COC(=O)CC1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC1CCN(C(=O)C(C)(C)C(NC(=O)c2ccc(C#N)cc2)c2cccc(Cl)c2)CC1
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
N-4-Cyanobenzoyl-β-m-chlorophenyl-α,α-dimethyl-β-alanine (300 mg, 0.84 mmol) was dissolved in methylene chloride (30 ml). To the resulting solution, BOP reagent (409 mg, 0.92 mmol) and triethylamine (1 ml) were added under cooling with ice and the mixture was stirred for 30 minutes. To the reaction mixture was added 4-piperidineacetic acid methyl ester (572 mg, 3.36 mmol) and the resulting mixture was stirred overnight. After the solvent was distilled off, the residue was applied to a silica gel column (2.2×20 cm) and eluted with a mixed solution (hexane:ethyl acetate=3:1). The desired fractions were collected and the solvents were distilled off to yield an oil of N-4-cyanobenzoyl-β-m-chlorophenyl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid methyl ester (270 mg, 65.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][OH:17])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27])[CH2:20][CH2:19]1.O>ClCCl>[O:18]1[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][S:26]([O:17][CH2:16][CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[N:10]=2)(=[O:27])=[O:28])[CH2:22][CH2:23]1
Reactant: OCCOc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Reactant: O=S(=O)(Cl)CCN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(CCN1CCOCC1)OCCOc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Yield: 39.4 %

Procedure:
To a solution of 2-(1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy)ethanol (154 mg, 0.53 mmol) and tryethylamine (0.22 ml, 1.58 mmol) in dichlorometane (9 ml) was added a solution of 2-morpholinoethanesulfonyl chloride (prepared from 0.69 mmol of 2-morpholinoethanesulfonic acid and 1.14 ml of oxalyl dichloride in dichlorometane at 0° C.) and the final mixture was stirred at room temperature overnight. Water was added, the organic phase separated and the aqueous phase extracted with more dichlorometane. The combined organic phases were washed with saturated aqueous solution of NaHCO3 and water, and after drying over sodium sulphate, filtered and evaporated to dryness yielding 222 mg of crude compound. After column chromatography purification (silica gel, eluent: petroleum ether/ethyl acetate 8:2), 94 mg of 2-(1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy)ethyl 2-morpholinoethanesulfonate as a solid was obtained, with a m.p.=120-122° C. after crystallization in acetone-petroleum ether.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:27]=[CH:26][C:13]([O:14][CH2:15][CH2:16][N:17]([CH3:25])C(=O)OC(C)(C)C)=[CH:12][CH:11]=2)=O)=[N:6][CH:7]=1.[C:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=O)[CH2:29][CH3:30]>>[CH3:25][NH:17][CH2:16][CH2:15][O:14][C:13]1[CH:12]=[CH:11][C:10]([C:8]([C:5]2[N:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH3:30])=[CH:27][CH:26]=1
Reactant: CN(CCOc1ccc(C(=O)c2ccc(O)cn2)cc1)C(=O)OC(C)(C)C
Reactant: CCC(=O)c1ccccc1
Product: CCC(=C(c1ccc(OCCNC)cc1)c1ccc(O)cn1)c1ccccc1

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, tert-butyl 2-(4-(5-hydroxypicolinoyl)phenoxy)ethyl(methyl)carbamate (1.0 eq) was reacted with propiophenone (3.0 eq) to give the desired product (Z/E=1/1). m/z=375[M+1]+.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[CH:19][C:20]3[CH:24]=[C:23]([C:25](O)=[O:26])[S:22][C:21]=3[CH:28]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C(Cl)CCl.Cl.[CH3:38][NH:39][CH3:40]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:38][N:39]([CH3:40])[C:25]([C:23]1[S:22][C:21]2[CH:28]=[C:17]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:30])[C:2]([CH3:32])([CH3:31])[CH3:1])=[C:7]([CH3:29])[CH:8]=3)([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:18]=[CH:19][C:20]=2[CH:24]=1)=[O:26]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)O)sc2c1
Reactant: CNC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)N(C)C)sc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.9 %

Procedure:
6-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-2-carboxylic acid (290 mg, 0.642 mmol) in CH2Cl2 (5.0 mL) is treated with DMAP (235 mg, 1.93 mmol) and EDC (184 mg, 0.962 mmol). The mixture is stirred for 15 min at RT, and dimethylamine hydrochloride (78 mg, 0.962 mmol) is added. The reaction is stirred for 18 h and quenched with aqueous NH4Cl (5.0 mL). The organic layer is loaded onto a silica gel column and purified with 50% EtOAc/Hex to afford the title compound (280 mg, 91%).