Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.[CH3:11][Mg]Br.CO.[BH4-].[Na+]>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([NH2:7])[CH3:11])=[C:4]([F:10])[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: C[Mg]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 6 h
Yield: 44 %

Procedure:
To a solution of 12 g of 4-bromo-2-fluorobenzonitrile (60 mM) in THF (120 ml) were added 75 ml (150 mM) of a 2 M solution of methylmagnesium bromide in diethyl ether at 0° C. The reaction mixture was stirred at 0° C., for 6 h. Then 200 min of methanol were added gradually to the reaction mixture. Subsequently, 5.7 g (150 mM) of sodium borohydride were added in portions, and the mixture was stirred at room temperature for 16 h. Thereafter, the reaction mixture was concentrated under reduced pressure, and 200 ml of water were added. The pH was adjusted to pH=˜1 with 2 M HCl, and the aqueous solution was extracted with chloroform. Subsequently, the pH was adjusted to pH=˜9 with 2M NaOH, and extraction was effected with chloroform (2×100 ml). The combined chloroform extracts were dried, and the solvent was removed under reduced pressure. 73 g (44%) of 1-(4-bromo-2-fluorophenyl)ethanamine were obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:35])([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=1)[CH:3]([F:25])[O:4][C:5]([F:24])([F:23])[C:6]([F:22])([O:11][C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[C:7]([F:10])([F:9])[F:8].[C:36](OC)(=[O:40])[C:37]([CH3:39])=[CH2:38]>CCCCO.CCCCO.CCCCO.CCCCO.[Ti]>[C:36]([O:34][CH2:33][C:30]1[CH:29]=[CH:28][C:27]([O:26][C:2]([F:35])([F:1])[CH:3]([F:25])[O:4][C:5]([F:23])([F:24])[C:6]([F:22])([O:11][C:12]([F:20])([F:21])[C:13]([F:18])([F:19])[C:14]([F:15])([F:17])[F:16])[C:7]([F:10])([F:9])[F:8])=[CH:32][CH:31]=1)(=[O:40])[C:37]([CH3:39])=[CH2:38]
Reactant: C=C(C)C(=O)OC
Reactant: OCc1ccc(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)cc1
Agent: [Ti]
Solvent: CCCCO
Product: C=C(C)C(=O)OCc1ccc(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)cc1

Procedure:
In the dry box, the (4-(1,1,2-trifluoro-2-(1,1,2,3,3,3-hexafluoro-2-(perfluoropropoxy)propoxy)ethoxy)phenyl)methanol (36.5 g, 0.656 mol) and methyl methacrylate (40.0 g, 0.40 mol) were added to a round bottom flask equipped with a stirrer. Titanium(iv) n-butoxide (0.50 mL) was then added to the round bottom flask. The reaction was placed in an oil bath and heated to reflux over about 3 hours. Then the reaction product was distilled to remove excess methyl methacrylate. The content was analyzed by proton NMR and shown to be 4-(1,1,2-trifluoro-2-(1,1,2,3,3,3-hexafluoro-2-(perfluoropropoxy)propoxy)ethoxy)benzyl methacrylate.
Reaction SMILES: [Cl:1][CH:2]([CH3:27])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][C:21]([F:26])([CH2:23][CH2:24][CH3:25])[CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.[CH2:28]1[O:30][CH2:29]1>CO>[Cl:1][CH:2]([CH3:27])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][C:21]([F:26])([CH2:23][CH2:24][CH3:25])[CH2:20][N:19]1[CH2:28][CH2:29][OH:30])=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: C1CO1
Reactant: CCCC1(F)CNC(C(=O)NC(C(C)Cl)C2OC(SC)C(O)C(O)C2O)C1
Solvent: CO
Product: CCCC1(F)CC(C(=O)NC(C(C)Cl)C2OC(SC)C(O)C(O)C2O)N(CCO)C1

Procedure:
4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide 18a (Example 32) was treated with ethylene oxide in methanol as detailed in scheme 19 to furnish the title compound. MS (ESPOS): 473.3 [M+H]+.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:18]C(C)(C)C)=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])=O)(C)(C)C.OC1C2N=NNC=2C=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.O[C:49]1[CH:57]=[CH:56][C:52]([C:53]([NH2:55])=[S:54])=[CH:51][CH:50]=1>CN(C)C=O.C(OCC)(=O)C>[C:53]([C:52]1[CH:56]=[CH:57][C:49]([O:16][C:14](=[O:15])[C:13]2[CH:17]=[C:9]([NH2:8])[CH:10]=[CH:11][C:12]=2[OH:18])=[CH:50][CH:51]=1)(=[S:54])[NH2:55]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(C)(C)C)c(C(=O)O)c1
Reactant: NC(=S)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=S)c1ccc(OC(=O)c2cc(N)ccc2O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To the solution of 4- or 5-tert-butoxycarbonylamino-2-hydroxy-benzoic acid (2) (3.0 mmol) in 50 mL of dimethylformamide, hydroxybenzotriazole (3.3 mmol) and DCC (3.3 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture, 4-hydroxy-thiobenzamide (3.0 mmol) was added and stirred mechanically for 3 h at 0°C. and 72 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer washed with brine, dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude intermediate (7) was treated with a solution of 40% TFA in CH2Cl2. After 2 h the solvent was removed to obtain compound (8) as a crude residue. The residue was loaded on a silica gel open column and eluted with CH2Cl21MeOH (8/2), from which 4- or 5-Amino-2-hydroxy-benzoic acid 4-thiocarbamoyl-phenyl ester (8), compound of Formula XXVII, was obtained (48% yield).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[C:23]([C:24]5[CH:29]=[CH:28][N:27]=[C:26](S(C)(=O)=O)[N:25]=5)=[CH:22][N:21]([CH2:34][C:35]#[N:36])[N:20]=4)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:37][CH2:38][C@@H:39]([OH:41])[CH3:40]>C1COCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[C:23]([C:24]5[CH:29]=[CH:28][N:27]=[C:26]([NH:37][CH2:38][C@@H:39]([OH:41])[CH3:40])[N:25]=5)=[CH:22][N:21]([CH2:34][C:35]#[N:36])[N:20]=4)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)c1nccc(-c2cn(CC#N)nc2-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)n1
Reactant: C[C@H](O)CN
Solvent: C1CCOC1
Product: C[C@H](O)CNc1nccc(-c2cn(CC#N)nc2-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)n1
Temperature: 80 °C
Yield: 71.3 %

Procedure:
A Mixture of the [3-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(2-methanesulfonyl-pyrimidin-4-yl)-pyrazol-1-yl]-acetonitrile (C-1-5) (310 mg, 0.6 mmol) and (S)-(+)-1-amino-2-propanol (134 mg, 1.8 mmol) in THF (5 mL) was heated at 80° C. for 18 hr. The mixture was concentrated onto silica gel then purified on silica gel using a gradient of 0-6% methanol in a mixture of dichloromethane and ethyl acetate (1:1) as eluent to yield 220 mg (72%) of {3-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-[2-((S)-2-hydroxy-propylamino)-pyrimidin-4-yl]-pyrazol-1-yl}-acetonitrile (C-1-6) as a foam from methyl tert-butyl ether. 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.52 (d, J=2.02 Hz, 1H), 8.20 (s, 1H), 8.07-8.17 (m, 4H), 7.81 (d, J=4.04 Hz, 1H), 7.63-7.73 (m, 1H), 7.52-7.60 (m, 2H), 6.75 (d, J=4.04 Hz, 1H), 6.53 (br. s., 1H), 5.67 (br. t, J=4.93 Hz, 1H), 5.24 (s, 2H), 3.56 (br. s., 1H), 2.64-3.28 (br. m, 3H), 0.74 (br. s., 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][NH:15][CH3:16]>CN1CCCC1=O>[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][N:15]([CH3:16])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNCCN(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CN1CCCC1=O
Product: CN(C)CCN(C)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C

Procedure:
A mixture of 4-fluoronitrobenzene (0.35 g, 2.5 mmol) and N,N,N′-trimethylethylenediamine (1.5 g, 1.9 mmol) in N-methylpyrrolidinone (10 mL) is heated for 19 hours in a 100° C. shaking block. After cooling to room temperature, the reaction mixture is partitioned between ethyl acetate and water. The organic phase is washed four times with water and with saturated aqueous sodium chloride solution and then concentrated under reduced pressure to give N,N,N′-trimethyl-N′-(4-nitrophenyl)ethane-1,2-diamine as a brown semisolid.
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]([CH2:15][CH2:16][OH:17])[C:8]([CH3:14])([CH3:13])[C:9](=[O:12])[CH2:10][CH3:11])(C)(C)C.C(OCC)C.[CH3:25][C:26]([CH3:28])=O.C(O)(C(F)(F)F)=O>>[CH3:25][C:26]1([CH3:28])[O:6][C@H:7]([C:8]([CH3:13])([C:9](=[O:12])[CH2:10][CH3:11])[CH3:14])[CH2:15][CH2:16][O:17]1.[CH2:8]([C:7]([CH2:15][CH3:16])=[O:6])[CH3:9]
Reactant: CCC(=O)C(C)(C)[C@H](CCO)O[Si](C)(C)C(C)(C)C
Reactant: CC(C)=O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)C(C)(C)[C@@H]1CCOC(C)(C)O1
Product: CCC(=O)CC

Procedure:
A solution of 0.200 g of compound 34 in 5 ml of acetone/CF3COOH is heated to 35° for 18 h. Trethyl amine (1 ml) is then added to the mixture at 0° followed by 20 ml of diethyl ether. The solution is then three times extracted with 10 ml of water each, dred, and the solvent evaporated. FC of the residue in hexanelether 3/1 (+1% of triethyl amine) gives 0.118 g of 30. MS (C12H22O3; 214): 215 [M+H]. 1H-NMR (CDCl3): δ=4.05-3.80 m (3H); 2.5 q (2H); 1.40 s (3H); 1.30 m (includ. s) (4H); 1.10 s (3H); 1.00 s (3H); 0.95 t (3H).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:20].[Na+].O>CO.C(O)(=O)C>[C:1]1([N:7]2[CH2:12][CH2:11][CH:10]([NH2:20])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCN(c2ccccc2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: NC1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-Phenylpiperidin-4-one (3.0 g, 17.1 mmol) was dissolved in methanol (250 mL) and acetic acid (147 mL), and ammonium acetate (67 g, 870 mmol) was added portionwise. The mixture was stirred for 4 hrs at room temperature, then cooled to 0° C. (ice-water) and sodium cyanoborohydride (1.6 g, 25 mmol) was added, then the reaction mixture was stirred at room temperature for 18 hrs. Water (20 mL) was added, and the mixture was concentrated under reduced pressure. The residue was adjusted to pH 12 with 15% aqueous NaOH and the resulting mixture was extracted with dichloromethane (3×100 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with dichloromethane—3% methanol—0.3% NH4OH to give the product as a pale solid.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:5][N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O>[OH:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C@H:2]([NH:1][S:27]([C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:26][CH:25]=2)(=[O:28])=[O:29])[CH2:3][N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCCO)[C@H](N)C1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](CCCO)[C@H](NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (3S*,4R*)-tert-butyl 3-amino-4-(3-hydroxypropyl)pyrrolidine-1-carboxylate (0.55 g, 2.25 mmol) and p-nitrophenylsulfonyl chloride (0.50 g, 2.25 mmol) and Na2CO3 (0.29 g, 2.70 mmol) in 8 mL THF-water, 3:1, was stirred overnight at room temperature. THF was evaporated, the mixture was diluted with H2O, extracted with CH2Cl2, the combined organic extracts were dried with Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 1→5% MeOH in CH2Cl2 giving the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C[O-].[Na+].Cl[CH2:10][CH:11]([OH:22])[CH2:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21].O>CO.CN(C)C=O>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[NH:13][CH2:12][CH:11]([OH:22])[CH2:10][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OC(CCl)CNc1ccc(Cl)cc1Cl
Reactant: c1c[nH]cn1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: OC(CNc1ccc(Cl)cc1Cl)Cn1ccnc1
Yield: 90.5 %

Procedure:
108 Grams (1.586 mol) of imidazole and 283 g (1.574 mol) of sodiummethylate solution 30% in methanol are mixed and the solution is then concentrated to dryness under reduced pressure at 50° C. The crystalline residue is dissolved in 400 ml dimethylformamide at 110° C. A solution of 259 g (1.017 mol) of N-(3-chloro-2-hydroxypropyl)-2,4-dichloroaniline in 500 ml of dimethylformamide is added dropwise at 110° C. within 30 minutes. Upon completion the reaction mixture is refluxed for 2 hours and then cooled down. The solution is now added dropwise to 3400 ml of water at room temperature within 30 minutes and stirred for another hour. The precipitated granular substance is filtered off, washed with water and dried in vacuum at 50° C. to yield 263.5 g 1-[3-(2,4-dichloroanilino)-2-hydroxypropyl]-imidazole, M.P. 107°-109° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].C(N(CC)CC)C.[CH2:19]=[C:20]1[O:24][C:22](=[O:23])[CH2:21]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:22]([O:1][CH2:2][C:3](=[O:4])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:23])[CH2:21][C:20]([CH3:19])=[O:24]
Reactant: C=C1CC(=O)O1
Reactant: O=C(CO)Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCC(=O)Nc1ccccc1

Procedure:
4.36 g (28.8 mmol)) of 2-hydroxy-N-phenylacetamide, 0.8 ml (5.74 mmol) of triethylamine and 6.5 ml (84.3 mmol) of diketene were heated at 70° C. under stirring in 50 ml of toluene for 7.5 hours. After the addition of a saturated aqueous sodium hydrogencarbonate solution at room temperature followed by the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1C=CC(CC(=N)OCC)=CC=1.Cl.ClC1C=[CH:20][C:19]([CH2:22][C:23]([NH:25][C:26](=[O:32])[NH:27][CH2:28][C:29]([Cl:31])=[O:30])=[NH:24])=CC=1.[OH-].[Na+].Cl.[CH2:36]([CH2:39][O:40][CH3:41])OC>>[ClH:1].[CH3:41][O:40][C:39]1[CH:36]=[CH:2][C:22]([C:23]([NH:25][C:26](=[O:32])[NH:27][CH2:28][C:29]([Cl:31])=[O:30])=[NH:24])=[CH:19][CH:20]=1
Reactant: CCOC(=N)Cc1ccc(Cl)cc1
Reactant: COCCOC
Reactant: N=C(Cc1ccc(Cl)cc1)NC(=O)NCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(=N)NC(=O)NCC(=O)Cl)cc1

Procedure:
Ethyl 2-(p-chlorophenyl)acetimidate is converted into 2-(3-[2-(p-chlorophenyl)acetimidoyl]ureido)acetyl chloride hydrochloride using the above procedure, except that the hydrolysis step is carried out using 1N sodium hydroxide and dimethoxyethane (3:1), followed by acidification with 4N hydrochloric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].[Cl:16][C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][CH2:23][CH2:24]Br)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:24][CH2:23][CH2:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([Cl:16])=[CH:27][CH:26]=1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: Clc1ccc(OCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(Cl)cc2)c(Cl)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 55.9 %

Procedure:
A mixture of 1.14 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 1.20 g of 3-(4-chlorophenoxy)propyl bromide, 0.83 g of potassium carbonate and 20 ml of N,N-dimethylformamide was stirred at 80° C. for 6 hours. The reaction mixture was poured into ice-water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 1.01 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(4-chlorophenoxy)propyloxy)benzene (55% yield), nD25.0 1.5822.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([O:12][CH3:13])[CH:3]=1.[H-].[Na+].CI.[C:18]([O-])(O)=O.[Na+]>CN(C=O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH:6][CH3:18])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(Cl)cc([N+](=O)[O-])c1N
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CNc1c(OC)cc(Cl)cc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
To the title compound of Example 21, Step B (19.9 mmol, 4.03 g) in DMF (50 mL) at 0° C. was added portionwise NaH (31.8 mmol, 1.27 g of 60% suspension in mineral oil) (exothermic, gas evolution). After 10 min MeI (23 mmol, 1.5 mL) was added and the reaction was allowed to stand at ambient temperature for 3 h. Saturated NaHCO3 and brine were added to the reaction resulting in formation of a precipitate, which was filtered, washed with water and dried in vacuo. Flash chromatography on silica eluting with 15% EtOAc in hexanes afforded the product as a bright red solid. LC-MS (ESI, Method B): 2.31 min, m/z 217.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([NH:15][C:16]2[NH:17][CH2:18][CH:19]([OH:22])[CH2:20][N:21]=2)[CH:14]=1)[C:5]([NH:7][CH2:8][C:9]([OH:11])=O)=[O:6].Cl.[NH2:24][C@H:25]([C:32]1[CH:37]=[C:36]([C:38]2([CH:41]([F:43])[F:42])[CH2:40][CH2:39]2)[CH:35]=[C:34]([Br:44])[CH:33]=1)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>CN(C=O)C.C(Cl)Cl>[Br:44][C:34]1[CH:33]=[C:32]([C@@H:25]([NH:24][C:9](=[O:11])[CH2:8][NH:7][C:5](=[O:6])[C:4]2[CH:12]=[C:13]([NH:15][C:16]3[NH:17][CH2:18][CH:19]([OH:22])[CH2:20][N:21]=3)[CH:14]=[C:2]([OH:1])[CH:3]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:37]=[C:36]([C:38]2([CH:41]([F:43])[F:42])[CH2:39][CH2:40]2)[CH:35]=1
Reactant: O=C(O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1
Reactant: CCOC(=O)C[C@H](N)c1cc(Br)cc(C2(C(F)F)CC2)c1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@H](NC(=O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1)c1cc(Br)cc(C2(C(F)F)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetic acid (Example B) (197.22 mg, 0.64 mmol), (S)-ethyl 3-amino-3-(3-bromo-5-(1-(difluoromethyl)cyclopropyl)phenyl)propanoate hydrochloride salt (from step 1 above) (253 mg, 0.635 mmol) and 1-hydroxybenzotriazole hydrate (19.44 mg, 0.127 mmol) was dissolved in a mixture of DMF/DCM (1:1) (8 mL) and stirred at room temperature under nitrogen atmosphere for 10 min to give a cream suspension. N,N′-diisopropylcarbodiimide (142 μL, 0.917 mmol) was added to the above suspension and the reaction mixture was stirred at room temperature overnight (16 h) under nitrogen atmosphere. The solvent was evaporated in vacuo to give a yellow gummy residue of the intermediate product. LC-MS analysis shows the desired product: (3S)-ethyl 3-(3-bromo-5-(1-(difluoromethyl)cyclopropyl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoate's mass: m/z 652 (79BrM+H), m/z 654 (81BrM+H). The crude residue will be used as such for the saponification with lithium hydroxide monohydrate (Step 3).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[NH:18][C:17](=[O:22])[N:16]3[CH2:23][CH2:24][N:25]=[C:15]3[C:14]=2[CH:13]=1>N1C=CC=CC=1>[C:1]1([S:7]([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[NH:18][C:17](=[O:22])[N:16]4[CH2:23][CH2:24][N:25]=[C:15]4[C:14]=3[CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc2c(c1)C1=NCCN1C(=O)N2
Solvent: c1ccncc1
Product: O=C1Nc2ccc(NS(=O)(=O)c3ccccc3)cc2C2=NCCN12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.1 g of benzenesulphonic acid chloride were added to 4.04 g of 9-amino-5-oxo-2,3,5,6-tetrahydroimidazo-[1,2-c]-quinazoline in 50 ml of absolute pyridine, whilst cooling with ice. The cooling was removed and the mixture was stirred for 2 hours at room temperature. A large quantity of H2O was then added to the reaction mixture, and the precipitated crystals were filtered off under suction. The crystals were dissolved in aqueous NH3 and the solution was clarified using active charcoal and neutralised using hydrochloric acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[C:13]([S:15](Cl)(=[O:17])=[O:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:28][NH:29][CH3:30].O1CCCC1.Cl>C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[C:13]([S:15]([N:29]([CH3:30])[CH3:28])(=[O:17])=[O:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2noc(C)n2)c(S(=O)(=O)Cl)cc1OCc1ccccc1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(-c2noc(C)n2)c(S(=O)(=O)N(C)C)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzenesulfonylchloride, dimethyl-amine hydrochloride (203 mg) and tetrahydrofuran (20 mL) was added triethylamine (0.693 mL) under ice-bath cooling. After stirring at room temperature overnight, 2 mol/L hydrochloric acid was added to the mixture. The separated organic layer was washed with 2 mol/L hydrochloric acid and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 5-benzyloxy-4-methoxy-N,N-dimethyl-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzenesulfonamide.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:23][CH3:24])=[C:19]([OH:22])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.O[CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[C:36]([O:35][C:33]([N:30]1[CH2:31][CH2:32][CH:27]([CH2:26][O:22][C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][C:18]=2[O:23][CH3:24])[N:15]=[CH:14][N:13]=[C:12]3[O:11][C:10]2[C:2]([F:1])=[C:3]3[C:7](=[CH:8][CH:9]=2)[NH:6][CH:5]=[CH:4]3)[CH2:28][CH2:29]1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 76 %

Procedure:
A mixture of 4-[(4-fluoro-1H-indol-5-yl)oxy]-6-hydroxy-7-methoxyquinazoline (250 mg, 0.77 mmol), (prepared as described for the starting material in Example 10), tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (199 mg, 0.92 mmol), (prepared as described for the starting material in Example 11), and triphenylphosphine (242 mg, 0.92 mmol) in dichloromethane (15 ml) was stirred and cooled to 0° C. Diisopropyl azodicarboxylate (182 μl, 0.92 mmol) in dichloromethane (2 ml) was added. The mixture was stirred for 3 hours and then a further 0.5 mole equivalent of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate, triphenylphosphine and diisopropyl azodicarboxylate added. The mixture was stirred for 1 hour and then concentrated under reduced pressure. The residue was purified by column chromatography eluting with ethyl acetate/bexane (1/1) followed by methylene chloride/methanol (99/1) to give 6-[1-(tert-butoxycarbonyl)piperidin-4-yl]methoxy-4-[(4-fluoro-1H-indol-5-yl)oxy]-7-methoxyquinazoline (306 mg containing 10% w/w triphenylphosphine oxide) which was used without further purification in the next step.