Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]3[C:15]4[C:20]([CH2:21][CH2:22][C:11]=23)=[CH:19][C:18]([OH:23])=[CH:17][CH:16]=4)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S([O:40][CH2:41][C@H:42]2[CH2:46]OC(C)(C)[O:43]2)(=O)=O)=CC=1.Cl>C(#N)C.C(O)C.CO>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]3[C:15]4[C:20]([CH2:21][CH2:22][C:11]=23)=[CH:19][C:18]([O:23][CH2:46][C@H:42]([OH:43])[CH2:41][OH:40])=[CH:17][CH:16]=4)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Reactant: CCCc1ccc(-c2onc3c2CCc2cc(O)ccc2-3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Solvent: CCO
Product: CCCc1ccc(-c2onc3c2CCc2cc(OC[C@H](O)CO)ccc2-3)cc1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-ol (Example 9, 0.1 g, 0.327 mmol) in acetonitrile (2 mL) was added potassium carbonate (0.100 g, 0.720 mmol) and (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (0.094 g, 0.327 mmol) at room temperature. The heterogeneous reaction mixture was heated at 120° C. in a microwave reactor for 1 h. Next, 2 mL of methanol was added followed by additional (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (100 mg). The contents were heated in the microwave reactor at 120° C. for 1 h. To the reaction mixture was added 1.0 mL of 2.5 M hydrochloric acid in ethanol at room temperature. The heterogeneous reaction mixture was stirred at room temperature for 1.5 h and concentrated under reduced pressure. Methanol (3 mL) was added followed by 3 drops of water and the contents were filtered. The pale yellow filtrate was subjected to Prep. HPLC (PHENOMENEX® Luna Axia 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA). Fractions corresponding to the desired product were isolated and concentrated to yield (R)-3-(3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yloxy)propane-1,2-diol (0.016 g, 0.042 mmol, 13% yield) as a white solid. The compound had an HPLC retention time=3.73 min (condition C); LC/MS M+1=380.1; 1H NMR (400 MHz, CDCl3) δ ppm 7.93 (d, J=8.53 Hz, 1H) 7.69 (d, J=8.28 Hz, 2H) 7.31 (d, J=8.28 Hz, 2H) 6.85-6.92 (m, 2H) 4.08-4.15 (m, 3H) 3.74-3.91 (m, 2H) 2.96-3.05 (m, 4H) 2.55-2.68 (m, 3H) 1.97 (t, J=5.90 Hz, 1H) 1.68 (sxt, J=7.43 Hz, 2H) 0.97 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:25][C:26]1([CH3:35])[CH2:31][CH:30]([C:32](O)=[O:33])[CH2:29][CH2:28][O:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:32]([CH:30]3[CH2:29][CH2:28][O:27][C:26]([CH3:35])([CH3:25])[CH2:31]3)=[O:33])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CC1(C)CC(C(=O)O)CCO1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCOC(C)(C)C2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(2,2-dimethyl-tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 2,2-dimethyl-tetrahydro-2H-pyrane-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 489.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:31]Br.O>C(O)(=O)C>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([Br:31])[C:21]([N:23]([CH3:24])[CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)Cc1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN(C)C(=O)C(Br)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture 2-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethylacetamide (1.1 g, 1 eq.) and sodium acetate (761 mg, 3 eq.) in acetic acid (15 ml), was added bromine (158 ul, 1 eq.) and the reaction was stirred at room temperature for 4 h. Water was added and the product extracted into ethyl acetate. The ethyl acetate layer was washed several times with water, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated to give 2-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-bromo-N,N-dimethylacetamide (1.44 g) as a yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:30])[C:13]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[CH:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[O:14])=[CH:8][CH:7]=1.N1C=CC=CC=1>ClCCl>[C:1]([O:30][CH:12]([C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][CH:10]=1)[C:13]([NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[CH:27])=[C:20]([O:28][CH3:29])[CH:19]=1)=[O:14])(=[O:3])[CH3:2]
Reactant: C#CCOc1ccc(CCNC(=O)C(O)c2ccc(Cl)cc2)cc1OC
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#CCOc1ccc(CCNC(=O)C(OC(C)=O)c2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetylchloride (0.7 g, 8.9 mmol) is slowly added to a cooled (0° C.) mixture of 2-(4-chloro-phenyl)-2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide (3.0 g, 8.0 mmol) and pyridine (0.7 g, 8.9 mmol) in 30 ml of dichloromethane. The reaction mixture is stirred for 2 hours at room temperature and subsequently poured on ice and extracted with ethyl acetate. The combined organic extracts are washed with brine, dried over sodium sulfate and the solvent is evaporated, the residue is purified by chromatography on silica gel to give 2-acetoxy-2-(4-chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide. 1H-NMR (300 MHz, CDCl3): 2.13 (s, 3H, CH3CO2), 2.52 (t, 1H, C≡CH), 2.80 (t, 2H, CH2CH2), 3.57 (t, 2H, CH2CH2), 3.87 (s, 3H, OCH3), 4.79 (d, 2H, OCH2C≡C), 6.03 (s, 1H, CHOH), 6.65–7.34 (m, 8H, CH arom., NH).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][OH:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[CH2:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>N1CCCC1>[CH2:15]([NH:19][C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:19]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:3][C:4]([CH3:14])=[N:5]2)=[CH:10][CH:9]=1)=[O:13])[CH2:16][CH2:17][CH3:18]
Reactant: Cc1cc(Cl)c2ccc(CO)cc2n1
Reactant: CCCCN
Solvent: C1CCNC1
Product: CCCCNC(=O)c1ccc2c(N3CCCC3)cc(C)nc2c1
Yield: 43 %

Procedure:
(4-Chloro-2-methyl-quinolin-7-yl)-methanol (example 2, 200 mg, 0.80 mmol) was refluxed in butylamine (2 mL) for 6 h. After cooling the reaction mixture was partitioned between sat. aq. ammonium chloride solution and dichloromethane. The organic layer was separated, dried (MgSO4), and evaporated. The residue was chromatographed (SiO2, CH2Cl2MeOH 19:1) to produce a yellow oil, which was heated in pyrrolidine (2 mL) at 70° C. for 16 h. After cooling the reaction mixture was partitioned between sat. aq. ammonium chloride solution and dichloromethane. The organic layer was separated, dried (MgSO4), and evaporated. Chromatography (SiO2, dichloromethane/methanol 19:1) afforded the title compound (108 mg, 43%). White solid, ISP-MS: m/e=312.3 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]1=[O:19].Cl>[Fe].[OH-].[Na+]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]2[O:9][CH2:8][C:7](=[O:19])[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]=2[CH:12]=1
Reactant: COCCCN1C(=O)COc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Product: COCCCN1C(=O)COc2ccc(N)cc21
Temperature: 70 °C
Reaction time: 15 h

Procedure:
At room temperature, an ethanolic solution (1100 mL) of 4-(3-methoxypropyl)-6-nitro-4H-benzo[1,4]oxazin-3-one (91.0 g, 0.34 mol) is treated with 6N HCl (170 mL, 1.02 mol of HCl) and powdered Fe (57.0 g, 1.02 mol), heated to 70° C., stirred for 15 h, cooled to 0° C., treated with 6N NaOH (250 mL), and filtered on a celite pad. The filtrate is diluted with CH2Cl2 (1000 mL), and the aq. layer is separated. The org. layer is washed with brine (2×300 mL), dried (Na2SO4), and evaporated to give 6-amino-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one as light brown solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:8]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=2[CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.S(=O)(=O)(O)O>CCOCC>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]2[CH:6]=[C:5]([CH2:3][OH:2])[C:8]=2[CH:9]=1
Reactant: COC(=O)C1=Cc2ccc(OC)cc21
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: COc1ccc2c(c1)C(CO)=C2
Reaction time: 0.5 h

Procedure:
Over a period of 30 minutes, while stirring, a solution of 1.92 g of 5-methoxybenzocyclobutene-1-carboxylic acid methyl ester in 30 ml of ether is added dropwise to a suspension of 0.21 g of lithium aluminium hydride in 30 ml of ether. The whole is stirred for 1 hour, a further 1.0 g of lithium aluminium hydride is added and stirring is carried out for a further 2 hours. 5 ml of water and, after a short time, 12.5 ml of 2N sulphuric acid are added dropwise thereto, stirring is carried out for 30 minutes and the ether phase is separated off, shaken twice with ether, dried over magnesium sulphate and concentrated to dryness by evaporation. 5-methoxybenzocyclobutene-1-methanol is obtained in the form of a colourless oil.
Reaction SMILES: CC(C1C(O)=CC=CC=1O)=O.[C:12]1([O:18][CH2:19][CH:20]2[O:22][CH2:21]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C(OCCO)C>[OH:22][CH:20]([CH2:19][O:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:21]
Reactant: c1ccc(OCC2CO2)cc1
Agent: CC(=O)c1c(O)cccc1O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCOCCO
Product: CC(O)COc1ccccc1

Procedure:
A solution of 2,6-dihydroxyacetophenone (15.2g.), phenylglycidyl ether (15.0 g) and benzyltrimethylammonium hydroxide (5 drops of a 40% solution) in 2-ethoxyethanol (75 ml) was heated under reflux for 48 hours. The solvent was removed under reduced pressure and the resulting solid was washed with ether. Recrystallization from aqueous ethanol gave 1-(2-acetyl-3-hydroxyphenoxy(-2-hydroxy-3-phenoxypropane, 19.0 g, as pale lemon needles, m.p. 100.5°-101.5° C.
Reaction SMILES: [CH:1]1([N:4](CC2C=CC(OC)=CC=2)[C:5]2[C:10]3=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.[NH2:29][C:30]1[N:35]=[C:34]([C:36]#[N:37])[CH:33]=[CH:32][CH:31]=1>>[C:36]([C:34]1[N:35]=[C:30]([NH:29][C:7]2[N:6]=[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)[C:10]3=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]3[N:8]=2)[CH:31]=[CH:32][CH:33]=1)#[N:37]
Reactant: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: N#Cc1cccc(N)n1
Product: N#Cc1cccc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)n1

Procedure:
The compound was prepared starting from 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (50 mg, 0.125 mmol) and 6-aminopicolinonitrile (17.94 mg, 0.151 mmol) using the procedure for Example 1E. Material was carried forward into the next step as is.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:36]Br>C(Br)CBr>[Br:36][CH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6]
Reactant: COc1ccc(C(=O)c2cccc(C)c2)cc1
Reactant: BrBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: BrCCBr
Product: COc1ccc(C(=O)c2cccc(CBr)c2)cc1
Reaction time: 17 h
Yield: 60.8 %

Procedure:
A solution of the benzophenone (17.5 g, 77.4 mmole) of Step A in ethylene bromide (26.5 mL) (containing a small amount of benzoyl peroxide) is heated at reflux. A solution of bromine (12.7 g, 79.6 mmole) in ethylene bromide (15 mL) is added dropwise over 30 minutes while the mixture is irradiated with a Photolamp (300 W). Reflux is continued for 17 hours (TLC, 9:1 petrolether-ethylacetate, traces of starting material still present). The solvent is removed in vacuo and the residue (brown oil, 39.22 g) is purified by flask chromatography (on silica Merck-60, preabsorbed in dichloromethane, eluted with 9:1 petrolether-ethyl acetate) to give unreacted starting material (2.59 g, ca.. 15%) along with the desired product (14.36 g, 61% or 71.5% based on recovered unreacted starting material) and some mixed fractions (ca. 5.20 g). The light yellow solid melts at 58°-61 ° C. and it is used as such in the next step.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([Cl:21])[CH:14]=1)[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH4-].[Na+]>CCO>[Cl:21][C:15]1[CH:14]=[C:13]([NH:12][C@H:3]([CH2:2][NH:1][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:4][C:5]([O:7][C:8]([CH3:10])([CH3:9])[CH3:11])=[O:6])[CH:18]=[CH:17][C:16]=1[C:19]#[N:20]
Reactant: CC(C)(C)OC(=O)C[C@@H](CN)Nc1ccc(C#N)c(Cl)c1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CNCc1ccccc1)Nc1ccc(C#N)c(Cl)c1
Reaction time: 1 h
Yield: 58.7 %

Procedure:
1,1-Dimethylethyl (3S)-4-amino-3-[(3-chloro-4-cyanophenyl)amino]butanoate (0.355 g, 1.15 mmol), benzaldehyde (0.12 g, 1.15 mmol), and 4 Å molecular sieves in EtOH (4 mL) were stirred at room temperature for 3 h. To this mixture, NaBH4 (excess amount) was added and the reaction was stirred for additional 1 h. The reaction was filtered. The filtrate was diluted with H2O and extracted with Et2O (2×). The organic extracts were washed with H2O, dried over Na2SO4, filtered, concentrated, and purified via silica gel chromatography with 0% MeOH in CH2Cl2 grading to 5% MeOH in CH2Cl2 to yield the titled product (0.27 g, 59%) as a white solid. LC-MS (ES) m/e 400.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[C:12]([O:14][CH3:15])=[O:13].CC1(C)COB([C:23]2[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29][OH:30])=[CH:25][CH:24]=2)OC1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:6][NH:7]2)=[CH:3][C:2]=1[C:23]1[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29][OH:30])=[CH:25][CH:24]=1
Reactant: CC1(C)COB(c2ccc(OCCO)cc2)OC1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCO)cc3)cc12
Temperature: 90 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
A mixture of methyl 5-bromo-6-chloro-1H-indole-3-carboxylate (5.2 g, 18.0 mmol), 2-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy)ethanol (5.7 g, 22.8 mmol), PdCl2(dppf) (0.54 g, 0.72 mmol), 2 M aqueous solution of potassium carbonate (27 ml, 54.0 mmol), ethanol (30 ml), and toluene (90 ml) was stirred in a closed bottle at 80° C. for 2 hours and at 90° C. for 2 more hours. The reaction mixture was cooled to room temperature, ethyl acetate (50 ml) was added, and the mixture was filtered through a pad of Celite. The organic phase of the mother liquor was separated. Filter cake was washed with 10% of methanol in THF and this wash was combined with the first organic extract. The combined organic solution was dried over anhydrous magnesium sulfate and loaded on silica gel. Chromatography on a silica gel column, eluting with a gradient from 40% to 90% of ethyl acetate in heptanes to give the title compound (6.15 g, 98%). MS (ES+) 346.0 (M+1)+. 1H NMR (CDCl3): δ 8.74 (br. s, 1H), 8.13 (s, 1H), 7.95 (d, J=2.4 Hz, 1H), 7.56 (s, 1H), 7.44 (d, J=8.5 Hz, 2H), 7.02 (d, J=8.5 Hz, 2H), 4.18 (t, 2H), 4.02 (t, 2H), 3.92 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)CCO.C(O)(=O)C.[CH:21](N)=[NH:22]>>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:22][CH:21]=[N:1]2)=[CH:7][CH:8]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: N=CN
Solvent: CC(=O)O
Solvent: OCCCO
Product: O=c1[nH]cnc2cc(F)ccc12
Temperature: 120 °C
Reaction time: 3.5 h

Procedure:
2-Amino-4-fluorobenzoic acid and 1,3-propanediol were stirred together and heated to 120° C. Formamidine acetate was added and the mixture stirred for 3.5 hour to yield 7-fluoroquinazoline-4-one. A solution of potassium hydroxide in 1,3-propanediol was then added to the mixture over a period of 2 hours and 50 minutes, which was then cooled 15° C. Following this, the mixture was heated to 125° C. for 5 hour before cooling to 75° C. Dilute hydrochloric acid (about 6% w/w) was gradually added to the reaction mixture until pH 4.5 was achieved. The mixture was cooled to 0° C. over 6 hour and maintained at that temperature for a further hour prior to isolation of the crude product by centrifugation. The crude material washed with water and dried in vacuo before dissolving in methanol at gentle reflux and partially concentrating under reduced pressure at a temperature of 42° C. This solution was then cooled to 0° C. over a period of 3 hour and the resultant product was isolated by filtration, prior to drying in vacuo. 7-(3-Hydroxypropoxy)quinazolin-4(3H)-one was recovered in a 73% yield.
Reaction SMILES: [CH2:1]([OH:10])[C@H:2](O)[CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH3:8].[H-].[Na+].C(C1C=CC(S(Cl)(=O)=O)=C(C(C)C)C=1C(C)C)(C)C>C1COCC1>[CH2:3]([C@@H:2]1[CH2:1][O:10]1)[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH3:8]
Reactant: CC/C=C\CC[C@@H](O)CO
Agent: CC(C)c1ccc(S(=O)(=O)Cl)c(C(C)C)c1C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC/C=C\CC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (R,Z)-oct-5-ene-1,2-diol (8.50 g, 58.9 mmol) in THF (230 mL) at 0° C. was added NaH (60% dispersion in mineral oil, 7.06 g, 177 mmol) (7.06 g as dispersion). The mixture was warmed to ambient temperature and stirred for 40 min. The reaction was cooled to 0° C. and triisopropylbenzenesulfonyl chloride (20.7 g, 61.8 mmol) was added. The reaction was warmed to room temp, stirred for 1 h, quenched with H2O and extracted with Et2O. The organics were washed with brine, dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (2% Et2O in pentane gradient to 8% Et2O in pentane) gave (R,Z)-2-(hex-3-enyl)oxirane. It was determined that slight racemization occurred at this step (98% ee to 84% ee). In order to ensure optical purity the enantioenriched product was further resolved using Jacobsen's hydrolytic kinetic resolution (HKR, Step E). 1H NMR (400 MHz, CDCl3): δ 5.41 (1H, m), 5.35 (1H, m), 2.93 (1H, m), 2.75 (1H, dd, J=5.2, 4.4 Hz), 2.49 (1H, dd, J=5,2, 2.8 Hz), 2.20 (2H, q, J=6.8 Hz), 2.06 (2H, quin, 7.6 Hz), 1.59 (2H, m), 0.97 (3H, t, J=7.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH2:23]([N:26]1[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[N:27]1)[CH2:24][CH3:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:20])([F:21])[F:22])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:32][CH2:31][C:28]2[CH:29]=[CH:30][N:26]([CH2:23][CH2:24][CH3:25])[N:27]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: CCCn1ccc(CN)n1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: CCCn1ccc(CNC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CAS Registry No. 1018782-82-5) and 1-propyl-1H-pyrazole-3-methanamine (CAS Registry No. 1006333-47-6) as starting materials, LC-MS (UV peak area/ESI) 96%, 453.29 (M+H)+.
Reaction SMILES: C[Mg+].[Br-].[Cl:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH:11]=[O:12])[C:6]=1[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1.[C:21]([O-])(O)=O.[Na+]>C1COCC1>[Cl:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH:11]([OH:12])[CH3:21])[C:6]=1[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1
Reactant: O=C([O-])O
Reactant: O=Cc1nccc(Cl)c1COC1CCCCO1
Agent: C[Mg+]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)c1nccc(Cl)c1COC1CCCCO1

Procedure:
MeMgBr (3.0 M in Diethylether. 582 μL. 1.75 mmol) was added to a stirred solution of 4-Chloro-3-(tetrahydro-pyran-2-yloxymethyl)-pyridine-2-carbaldehyde (149 mg. 0.58 mmol) in THF (6 mL). After stirring for 10 min at room temperature sat. NaHCO3 solution (30 mL) was added and extracted three times with DCM (50 mL). The combined organic layers were dried over Na2SO4 filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with a gradient of ethyl acetate and MeOH) to give the title compound. MS (m/z): 271.8 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: OB(O)c1cccnc1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3cccnc3)cc1OCC2)c1ccccc1Cl

Procedure:
Following Examples 44 and 60 and General Procedure C, 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 and 3-pyridylboronic acid were reacted to give 122. MS: (ESI+) 447.1
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.[Mg].II.[CH2:13]([N:20]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:13]([N:20]1[CH2:24][CH2:23][C:22]([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[CH:3]=2)([OH:25])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Fc1cc(Cl)cc(Br)c1
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2cc(F)cc(Cl)c2)CCN(Cc2ccccc2)C1
Yield: 12.6 %

Procedure:
To a solution of 1-bromo-3-chloro-5-fluorobenzene (5 g, 23.9 mmol) in dry tetrahydrofuran (50 mL), under nitrogen, was added magnesium turnings (0.58 g, 26.2 mmol) and one crystal of iodine. The mixture was heated until self sustained reflux started. When the reflux ceased a solution of 1-N-benzyl-3-pyrrolidone (4.17 g, 23.9 mmol) in dry tetrahydrofuran (50 mL) was added drop wise. The resulting mixture was stirred at ambient temperature for 15 min after which aqueous saturated ammonium chloride solution (40 mL) was added. The aqueous phase was extracted with tert-butyl methyl ether the combined organic phases were extracted with aqueous HCl (10%, 200 mL), the aqueous phase was basified with aqueous NaOH (5 M) and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic phase was dried (MgSO4), filtered and evaporated. Purification on silica gel (isooctane/ethyl acetate, 1:1 to 0:1) gave the title compound (0.92 g).