Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[CH3:8][O:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:30][C:31]1[CH:32]=[C:33]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=2)[CH:34]=[CH:35][C:36]=1[CH:37]=O.CCOC(C)=O.CCCCCC>C1COCC1>[F:30][C:31]1[CH:32]=[C:33]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=2)[CH:34]=[CH:35][C:36]=1[CH:37]=[CH:8][O:9][CH3:10]
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1F
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To a an ambient temperature suspension of potassium tert-butoxide (419 mg, 3.73 mmol) in THF (20 mL) is added (methoxymethyl)triphenylphosphonium chloride (1.28 g, 3.73 mmol) and is stirred at room temperature for 30 min. 3-Fluoro-4′-trifluoromethyl-biphenyl-4-carbaldehyde (500 mg, 1.87 mmol) is added and the reaction mixture continues to stir at room temperature. After 2 h TLC (30% EtOAc/hexane) indicates complete consumption of starting material. The reaction is quenched with saturated aqueous NH4Cl and concentrated. The residue is partitioned between EtOAc (50 mL) and water (20 mL). The aqueous layer is extracted with EtOAc (50 mL) and the combined organic layers are washed with brine, dried (MgSO4), filtered, concentrated and chromatographed (120 g SiO2, 5% EtOAc/Hexanes) to yield the title compound (474 mg, 85%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Cl)=[N:6][OH:7])[CH3:2].[F:10][C:11]([F:21])([F:20])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH2:17])=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1>[F:10][C:11]([F:20])([F:21])[C:12]1[CH:13]=[CH:14][C:15]([CH:16]2[O:7][N:6]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:9])[CH2:17]2)=[CH:18][CH:19]=1
Reactant: C=Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(Cl)=NO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=NOC(c2ccc(C(F)(F)F)cc2)C1
Reaction time: 16 h
Yield: 88.3 %

Procedure:
To a stirred mixture of 2-chloro-2-hydroxyiminoacetic acid ethyl ester (2.11 g, 13.52 mmol) and 4-trifluoromethystyrene (2.0 g, 11.27 mmol) in anhydrous tetrahydrofuran (15 ml) was added dropwise a solution of triethylamine (3.0 ml, 21.52 mmol) in tetrahydrofuran (5 ml) at room temperature. The resulting reaction mixture was stirred at an atmosphere of nitrogen for 16 hours, filtered, partitioned between water and ethyl acetate (2×50 ml), washed with saturated aqueous sodium bicarbonate, 30% aqueous ammonium chloride, brine, dried over sodium sulfate, and concentrated to afford a pale yellow solid, which was purified by chromatography (2:8 EtOAc:Hexane) to afford ethyl 5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-carboxylate (2.86 g, M+1=288.2)
Reaction SMILES: C[O-].[Na+].[C:4](#[N:8])[CH2:5][C:6]#[N:7].Cl([O-])(=O)(=O)=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[CH:26]N(C)C)[CH:22]=[N+:23](C)C)=[CH:17][CH:16]=1.[OH-].[NH4+]>CO.N1C=CC=CC=1>[NH2:7][C:6]1[C:5]([C:4]#[N:8])=[CH:26][C:21]([C:18]2[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=2)=[CH:22][N:23]=1
Reactant: CN(C)C=C(C=[N+](C)C)c1ccc(Cl)cc1
Reactant: N#CCC#N
Agent: C[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: N#Cc1cc(-c2ccc(Cl)cc2)cnc1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Sodium methoxide (16.2 grams) in 300 ml methanol and malononitrile (19.8 grams) in 50-100 ml methanol were added to N-[2-(4-chlorophenyl)-3-(dimethylamino)-2-propenylidene]-N-methylmethanaminium perchlorate (101.1 grams) in 300 ml pyridine at 0° C. in an ice-alcohol bath. The reaction mixture was stirred at room temperature for about 20 hours and then recooled to 0° C. Ammonium hydroxide (120 ml) was added and after three hours, a copious precipitate formed. The solid was filtered, washed with water, and shown by NMR to be the desired product, yield 44 grams, m.p. 202°-204° C. Addition of 600-800 ml of water to the filtrate gave additional product although impurities were present.
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:13]2[C:12]3=[CH:14][C:15]4[CH:16]=[CH:17][C:18]([C:21]([O:23]C)=[O:22])=[CH:19][C:20]=4[N:11]3[CH2:10][CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl>C1COCC1.CO>[CH:3]1[C:13]2[C:12]3=[CH:14][C:15]4[CH:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][C:20]=4[N:11]3[CH2:10][CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Reaction time: 0.17 h

Procedure:
Added 1M NaOH (aq.) (0.5 mL, 0.5 mmol) to a solution of methyl 7H-indolo[2,1-a][2]benzazepine-10-carboxylate, 13-cyclohexyl-3-methoxy-6-[[[2-(methylamino)-2-oxoethyl]amino]carbonyl]- (140 mg, 0.27 mmol) in THF/MeOH (1:1, 3 mL) and heated the reaction mixture in a sealed tube with microwave irradiation at 80° C. for 20 min., then at 85° C. for 10 min. The reaction was cooled, neutralized with 1M HCl (aq.) (0.5 mL, 0.5 mmol) and concentrated to remove organic solvents. The residue was slurried with H2O and the solids were collected by filtration, flushed with H2O and dried to yield 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-[[[2-(methylamino)-2-oxoethyl]amino]carbonyl]- (123 mg, 0.25 mmol, 90%) as a yellow solid. 1HNMR (500 MHz, CD3OD) δ 8.30 (s. 1H), 7.87 (d, J=8.5 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.62 (s, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 7.15 (s, 1H), 5.74-5.60 (m, 1H), 4.24-4.11 (m, 1H), 4.02-3.88 (m, 2H), 3.95 (s, 3H), 2.95-2.84 (m, 1H), 2.75 (s, 3H), 2.22-1.17 (m, 10H). LCMS: m/e 500 (M−H)−, ret time 1.38 min, column A, 3 minute gradient.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17]I.O>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:14][CH3:17])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(I)cc2)CCOCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1(c2ccc(I)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Under an argon atmosphere, a solution of tetrahydro-4-(4-iodophenyl)-2H-pyran-4-ol (2.99 g) in anhydrous DMF (10 ml) was added dropwise to a suspension of sodium hydride (60 wt %) (432 mg) in anhydrous DMF (20 ml) at room temperature, and the resulting mixture was stirred at room temperature for 75 minutes. Methyl iodide (0.92 ml) was added dropwise to the reaction solution and the resulting mixture was stirred at room temperature for 8.5 hours. Water was added thereto and the resulting mixture was extracted twice with ethyl acetate. Organic layers were washed with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:cyclohexane/ethyl acetate=10/1) to obtain tetrahydro-4-(4-iodophenyl)-4-methoxy-2H-pyran (2.87 g). NMR (H1, CDCl3): δ 1.90-2.02 (4H, m), 2.97 (3H, s), 3.80-3.88 (4H, m), 7.14 (1H, d, J=8.5 Hz), 7.70 (1H, d, J=8.5 Hz)
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH3:12][O:13][C:14](=[O:20])[CH2:15][C:16](=[O:19])[CH2:17][CH3:18].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]>O1CCCC1.O>[CH3:12][O:13][C:14](=[O:20])[CH:15]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30])[C:16](=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)CC(=O)OC
Reactant: Fc1ccc(CBr)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CCC(=O)C(Cc1ccc(F)cc1F)C(=O)OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of potassium tert-butoxide (3.2 g) in anhydrous tetrahydrofuran (40 mL) at 0° C. was treated with a mixture of tert-butanol (0.15 mL) and 3-oxopentanoic acid methyl ester (3.8 g). The mixture was warmed to room temperature over 30 minutes and then a solution of 1-bromomethyl-2,4-difluorobenzene (6.0 g) in tetrahydrofuran (10 mL) was added and the resulting mixture stirred at room temperature for 72 hours. The mixture was diluted with water (10 mL) and the tetrahydrofuran removed under reduced pressure. The residue was partitioned between ethyl acetate and dilute aqueous ammonium chloride solution and the aqueous phase extracted with diethyl ether. The combined organic phases were dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of toluene, dichloromethane and ethyl acetate (4:1:0 to 0:1:0 to 0:25:1 by volume) to afford title compound as colourless oil, 4.5 g.
Reaction SMILES: [C:1]1([Si:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(Cl)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[C:22]([Cl:28])[N:21]=1)OC>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]1([Si:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([O:19][C:20]2[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[C:22]([Cl:28])[N:21]=2)[O:19][C:20]2[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[C:22]([Cl:28])[N:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)Oc1nc(Cl)c(Cl)cc1Cl
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: Clc1cc(Cl)c(O[Si](Oc2nc(Cl)c(Cl)cc2Cl)(c2ccccc2)c2ccccc2)nc1Cl

Procedure:
In the manner described in Examples 1-7, diphenyldichlorosilane was reacted with about two moles of methyl 3,5,6-trichloro-2-pyridyl carbonate in the presence of tetrabutylammonium chloride to produce a good yield of diphenyl bis(3,5,6-trichloro-2-pyridyloxy)silane, a crystalline solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-:25])=[O:24])[CH2:13][CH2:12]1)(C)(C)C.Cl>C(OCC)(=O)C>[N+:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:14]1[CH2:13][CH2:12][CH:11]([NH:10][CH2:9][CH2:8][NH2:7])[CH2:16][CH2:15]1)([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)NCCNC1CCN(c2ccccc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCNC1CCN(c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 9 (576 mg, 1.66 mmol) in ethyl acetate (50 mL) was cooled to 0° C. and treated with anhydrous HCl (5 min). The mixture was. stirred at room temperature (2 h). The solvent was removed in vacuo and the residue disolved in dichloromethane and sodium carbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound (10). The crude product was used directly.
Reaction SMILES: ClC1C=CC2SC=C([CH2:9][N:10]3CCN(C4SC(C(O)=O)=C(C)N=4)[C:11]3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44](O)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.Cl.CNC>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([N:10]([CH3:11])[CH3:9])=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Agent: CNC
Agent: Cl
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)N(C)C
Yield: 34 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with dimethylamine hydrochloride, the title compound was obtained as a colorless solid in 34% yield: mp 162-164° C.; 1H NMR (300 MHz, CDCl3) δ 7.29-7.25 (m, 2H), 7.06-7.01 (m, 2H), 4.45 (s, 2H), 4.06 (t, J=9.0 Hz, 2H), 3.45 (t, J=9.0 Hz, 2H), 3.07 (s, 6H), 2.34 (s, 3H); MS (ES+) m/z 363.3 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][O:22][CH3:23])=[CH:16][CH:15]=2)=[CH:6]1.C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C.O>C1(C)C=CC=CC=1>[CH3:23][O:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[C:8]3[N:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:5]3[C:6]=2[CH2:2][CH2:3][CH2:4]3)=[CH:15][CH:16]=1
Reactant: COCOc1ccc(-c2cn(CCCBr)c3cccnc23)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: COCOc1ccc(-c2c3n(c4cccnc24)CCC3)cc1
Temperature: 110 °C
Yield: 23.1 %

Procedure:
A solution of 1-(3-bromopropyl)-3-[4-(methoxymethoxy)phenyl]-1H-pyrrolo[3,2-b]pyridine (486 mg), tri-n-butyltin hydride (0.697 mL), and AIBN (21.27 mg) in toluene (25 mL) was heated at 110° C. overnight. To the mixture was added AIBN (21.27 mg), and the mixture was heated at 110° C. for 2 h. The mixture was added to water and extracted with AcOEt. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (88 mg).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([S@@:12]([NH2:14])=[O:13])([CH3:11])([CH3:10])[CH3:9].C(=O)(O)[O-].[Na+]>C1COCC1.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[C:1]1(=[N:14][S:12]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C1CCCCC1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 76.1 %

Procedure:
Titanium tetraethoxide (2 eq, 3.56 mL, d 1.088) was added to a solution of cyclohexanone (1.2 eq, 1.0 g, 1.05 mL, d 0.947) in 20 mL of dry THF under nitrogen atmosphere. After 5 min, (S)-t-butanesulfinamide (1200-A, 1.028 g) in 10 mL of THF was added dropwise. The mixture was heated to 60° C. overnight. The reaction mixture was poured into an equal volume of aqueous saturated sodium bicarbonate solution with rapid stirring and immediately filtered through celite. The filter cake was washed with ethyl acetate (50 mL). The layers in the filtrate were separated and the aqueous layer was extracted with ethyl acetate (30 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (gradient:ether/hexanes; 1:9 to 1.1) to afford the product 1200-B (1.3 g; 76%) as a colorless oil. The product was kept under inert atmosphere at −20° C.
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15](Br)[CH:16]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].[Cu]I.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:1]([C:15]1[CH:14]=[N:13][CH:12]=[C:11]([Br:10])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: Brc1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: C1CCOC1
Product: Brc1cncc(Cc2ccccc2)c1
Temperature: 50 °C

Procedure:
Benzylmagnesium bromide (1.0 M in THF, 20 mL, 20 mmol) was added to a solution of zinc chloride (2.73 g, 20 mmol) in THF (20 mL) and the reaction was heated to 50° C. for 2.5 hours. The solution was then added by cannula to a solution of 3,5-dibromo-pyridine (3.07 g, 13 mmol), copper(I) iodide (0.0148 g, 0.78 mmol), and (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.048 g, 0.65 mmol) in THF (20 mL). The reaction was heated to 50° C. for 48 hours then quenched with H2O, submitted to standard aqueous workup, and purified via silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [C:1]([NH2:6])([CH2:4][CH3:5])([CH3:3])[CH3:2].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12](Cl)=[O:13].S(Cl)(Cl)=O.Cl>ClCCl>[C:1]([NH:6][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:9]([O:8][CH3:7])[CH:10]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: CCC(C)(C)N
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCC(C)(C)NC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
30 ml of tert-amylamine are added at 10° C. to a solution of 27 g of 3-methoxy-4-nitrobenzoyl chloride (obtained from 25 g of the corresponding acid and thionyl chloride at reflux for 4 hours, followed by evaporation under vacuum) in 250 ml of dichloromethane. The reaction mixture is stirred for 30 minutes at 20° C., 100 ml of a 1N hydrochloric acid solution are then added, the organic phase is separated by settling, washed and dried over MgSO4, the solvent is then evaporated and the residue is chromatographed on silica gel, elution being carried out with dichloromethane, to obtain 31 g of the expected product; M.p.=65° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:21])([F:20])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[N:8]=[C:7]2[S:22][CH3:23].[CH:24]1(B(O)O)[CH2:26][CH2:25]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl.O>[CH:24]1([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([C:12]([F:20])([F:21])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)[N:8]=[C:7]3[S:22][CH3:23])[CH2:26][CH2:25]1
Reactant: OB(O)C1CC1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(Br)cccc12
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(C3CC3)cccc12
Temperature: 100 °C
Yield: 83 %

Procedure:
To a mixture of 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline from Example 35 step B (200 mg, 0.5 mmol), dichlorobis(tricyclohexylphosphine)palladium(II) (37 mg, 0.05 mmol), cyclopropylboronic acid (65 mg, 0.75 mmol) and K3PO4 (371 mg, 1.75 mmol) were added toluene (6 mL) and water (0.5 mL). The reaction vessel was evacuated and flushed with argon (3×), and then the mixture was heated at 100° C. for 4 h. The mixture was concentrated under reduced pressure onto Celite and the residue was purified by silica gel chromatography eluting with 10-50% EtOAc/hexanes to afford impure 8-cyclopropyl-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline (150 mg, 84%) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[CH:12]([Mg]Br)=[CH2:13].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]2[C:3]=1[CH:12]=[CH:13][NH:9]2
Reactant: O=[N+]([O-])c1cc(Br)ccc1Cl
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1ccc(Br)c2cc[nH]c12
Temperature: 40 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
To a solution of 4-bromo-1-chloro-2-nitro-benzene (14 g, 0.059 mol) in 400 mL THF at −40° C. was added dropwise vinylmagnesium bromide (177 mL of 1.0M solution in THF, 0.177 mol). The reaction mixture was stirred for 2 hrs at 40° C. Aqueous NH4Cl was added and the mixture extracted with ether. The organic phase was dried over Na2SO4, concentrated and the residue purified by silica gel column chromatography to give the title compound (6 g, 44%).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][CH:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]([OH:25])[CH2:23][N:24]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11]>ClCCCl>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[O:20][CH:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]([O:25][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:23][N:24]=2)=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: O=C=Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(C2=NCC(O)C(c3ccccc3)O2)cc1
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)OC1CN=C(c2ccc([N+](=O)[O-])cc2)OC1c1ccccc1
Yield: 24.1 %

Procedure:
Phenyl isocyanate (1.6 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, o[(5RS, 6SR)-2-(4-nitrophenyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (4.1 g) in 1,2-dichloroethane (45 cc). The solution obtained is heated to reflux for 4 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica (0.063-0.2 mm; 100 g) contained in a column 2.5 cm in diameter [eluent: dichloromethane/methanol (97:3 by volume)], collecting 20-cc fractions. Fractions 10 to 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in acetonitrile, (5RS, 6SR)-2-(4-nitrophenyl)-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (1.35 g), m.p. 170° C., is obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Br[CH2:31][CH3:32].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([CH2:31][CH3:32])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCBr
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(CC)C3)cc1
Temperature: 100 °C
Yield: 56.4 %

Procedure:
To a solution of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (130 mg, 0.33 mmol) in DMF (2.5 mL) was added bromoethane (29 μL, 0.39 mmol) and DIPEA (69 μL, 0.39 mmol). The reaction mixture was then heated by microwave at 100° C. for 1 h. The crude reaction mixture was then partitioned between water and EtOAc, the phases separated and the organic layer washed with NaHCO3 and brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (2-10% MeOH/DCM) to give a light brown solid (79 mg, 57%).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([CH2:17][C:18](O)=[O:19])=[CH:10][C:11]2[O:15][CH2:14][O:13][C:12]=2[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([C:8]1[C:9]([CH2:17][CH2:18][OH:19])=[CH:10][C:11]2[O:15][CH2:14][O:13][C:12]=2[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cc2c(cc1Cc1ccccc1)OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1cc2c(cc1Cc1ccccc1)OCO2
Temperature: 25 °C
Yield: 82.3 %

Procedure:
A solution of 1.82 g of (6-benzyl-1,3-benzodioxol-5-yl) acetic acid in 22 ml of anhydrous tetrahydrofuran was dropwise added at 0° C. to a suspension of 0.38 g of lithium aluminum hydride in anhydrous tetrahydrofuran. The obtained mixture was warmed to a room temperature to carry out the reaction for 4 hours, followed by the addition of water. The mixture was filtered to remove the precipitate. The filtrate was concentrated in a vacuum to obtain a yellow oil residue. This residue was purified by silica gel column chromatography (ethyl acetate/hexane=2:8) to obtain 1.42 g of the title compound as a colorless crystal.