Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:7][CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[Li+].[OH-].Cl>C1COCC1.O>[N:1]1([CH:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:25]=[CH:24][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:7][CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)c1ccc(-c2ccc(C(CC)n3ccnc3)nc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(c1ccc(-c2ccc(C(=O)O)cc2)cn1)n1ccnc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of ethyl 4-(6-(1-(1H-imidazol-1-yl)propyl)pyridin-3-yl)benzoate (25 mg, 0.07 mmol; prepared as described in Example 5) in THF (2 mL) and water (1 mL) was added LiOH (6 mg, 0.14 mmol) at rt and the reaction was stirred at rt for about 4 h. The reaction mixture was neutralized with 1N HCl (pH=6) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), the organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by prep TLC using 5% methanol in DCM to provide 4-(6-(1-(1H-imidazol-1-yl)propyl)pyridin-3-yl)benzoic acid as an off white solid (12 mg, 54.5% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.92 (s, 1H), 8.14 (dd, 1H), 8.01 (d, 2H), 7.83 (d, 3H), 7.40 (d, 1H), 7.31 (s, 1H), 6.90 (s, 1H), 5.39 (s, 1H), 2.34-2.19 (m, 2H), 0.81 (t, 3H), LC-MS m/z calcd for [M+H]+ 308.13. found 308.1.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[CH2:6]([NH:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[C:26]([Cl:38])[CH:25]=1)=[N:16][CH:17]=[N:18]2)[CH:7]=[CH2:8]>>[CH2:6]([N:9]([CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[C:26]([Cl:38])[CH:25]=1)=[N:16][CH:17]=[N:18]2)[C:1](=[O:5])[CH2:2][OH:3])[CH:7]=[CH2:8]
Reactant: C=CCNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C(O)CO
Product: C=CCN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)CO
Yield: 24 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and 5-[2-(allylamino)ethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 11, preparation of starting materials) to give the title compound in 24% yield; NMR spectrum (DMSO-d6) 3.79-4.19 (m, 6H), 4.38-4.63 (m, 3H), 5.06-5.19 (m, 2H), 5.31 (s, 2H), 5.69-5.90 (m, 1H), 7.16 (d, 1H), 7.25 (d, 1H), 7.33-7.39 (m, 2H), 7.56-7.63 (m, 2H), 7.70-7.76 (m, 1H), 7.86-7.91 (m, 1H), 7.98 (s, 1H), 8.45 (s, 1H), 8.61 (d, 1H), 9.80 (s, 1H); Mass spectrum MH+ 520.
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1>>[F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Reactant: O=C=Nc1cccc(F)c1
Product: COc1ccc(NC(=O)Nc2cccc(F)c2)cc1-c1c(F)cnn1C
Yield: 55 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3-fluorophenylisocyanate, in a similar manner as described in Example 1.68, providing 15 mg (55% yield) of Compound 33: LCMS m/z (%)=359 (M+H, 100). 1H NMR (400 MHz, J acetone-d6) δ: 8.38 (s, 1H), 8.21 (s, 1H), 7.64 (dd, J1=9.0 Hz, J2=2.6 Hz, 1H), 7.59 (d, J=12.0 Hz, 1H), 7.48 (d, J=2.8 Hz, 1H), 7.39 (d, JH,F=4.8 Hz, 1H), 7.27 (dd, J1=14.8 Hz, J2=8.0 Hz, 1H), 7.15 (d, J=9.6 Hz, 1H), 7.12 (s, 1H), 6.72 (dd, J1=9.6 Hz, J2=7.2 Hz, 1H), 3.83 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −114.00 (m, 1F), −177.35 (d, JH,F=3.8 Hz, 1F).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:13][C@H:14]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[F:1][C:2]1[CH:3]=[C:4]([S:9]([NH:13][C@H:14]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NS(=O)(=O)c3ccc(F)c(F)c3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using 3,4-difluorobenzenesulfonyl chloride and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 556.2 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH:13][C:14](=[O:37])[CH2:15][CH:16]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)(=[O:20])=[O:19])[CH2:8][CH2:7][CH2:6]2)=[O:2].[C:38](=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH:13][C:14](=[O:37])[CH2:15][CH:16]([N:17]([CH3:38])[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=1)(=[O:20])=[O:19])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:8][CH2:7][CH2:6]2)=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(CC(=O)NC1CCCc2cc(C=O)ccc21)c1ccccc1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Yield: 106.3 %

Procedure:
The aldehyde, N-(6-formyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3-phenyl-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide (0.11 g), was stirred in dry DMF (5 mL) with sodium carbonate (0.2 g) and methyl iodide (0.2 mL) at RT for 3 days. Aqueous workup gave the crude product, N-(6-formyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3-[methyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-3-phenyl-propionamide (0.12 g). MS: 545.1 (M+1). This aldehyde (0.12 g) was converted to 3-[methyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-3-phenyl-N-(6-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propionamide using the general reductive amination conditions (amine, NaBH(OAc)3, RT, DCE) described earlier in this application. MS: 614.1 (M+1).
Reaction SMILES: C(N([P:8]([N:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])[Cl:9])C(C)C)(C)C.P(Cl)(Cl)[Cl:18]>C(#N)C>[CH:11]([N:10]([P:8]([Cl:18])[Cl:9])[CH:14]([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: ClP(Cl)Cl
Reactant: CC(C)N(C(C)C)P(Cl)N(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)N(C(C)C)P(Cl)Cl
Temperature: 25 °C
Yield: 81 %

Procedure:
Bis-(N,N-Diisopropylamino)chlorophosphine, 10 grams (37 mmols), was dissolved in 500 ml of anhydrous acetonitrile. Phosphorus trichloride, 5.16 grams (37 mmols), was added to the solution and the reaction was allowed to stir over-night at room temperature. The reaction was assayed for completion by 31P NMR of an aliquot of the reaction using an external lock. Complete conversion of the starting material at δ 134 ppm to the product at δ 165 ppm was observed. The solvent was evaporated from the reaction mixture on a rotary evaporator and the resulting oil distilled under vacuum yielding 5.7 grams of product (81% yield).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=O)[CH2:8]2.Cl.[NH2:13][OH:14].O.O.O.C([O-])(=O)C.[Na+]>CO>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[N:13][OH:14])[CH2:8]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=C1C2CC3CC(C2)CC1C3
Yield: 90.9 %

Procedure:
To 30 g of 2-adamantanone (Aldrich Chem. Co.) in 100 mL of methanol was added 50 g of hydroxylamine hydrochloride and 92 g of sodium acetate trihydrate and the mixture was refluxed for 2 hours. The mixture was concentrated in vacuo, the residue was distributed between 250 mL of dichloromethane and 50 mL of water. The organic layer was separated, dried with magnesium sulfate and concentrated in vacuo to give 30 g of crude 2-adamantanone oxime. This was dissolved in 100 mL of chloroform and 135 g of PPE (polyphosphate ester, prepared by refluxing phosphorus pentoxide with diethyl ether in chloroform, as described by G. Schramm, H. Groetsch, and W. Pollmann, Angew. Chem., Internat. Ed., 1,1 (1962)) was added carefully. When the exothermic reaction ceased, the mixture was refluxed for 5 minute. Then it was cooled in ice, diluted with 500 mL of water and stirred overnight. The organic layer was separated, dried with magnesium sulfate and concentrated in vacuo to give 16.6 g of the crude lactam product. This was dissolved in 250 mL of chloroform and 11 mL of phosphorus oxychloride was added dropwise in 30 minutes. After stirring for additional 1 hour at room temperature, to this stirred mixture was added 25 mL of triethylamine and a solution of 16 g of 4,6-dichloro-2-aminobenzonitrile (4,6-dichloroanthranilonitrile) which was prepared by the methodology shown in Example 11.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:16])[CH2:12][C:13]([OH:15])=O)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([NH2:33])[CH3:32])=[CH:27][C:26]=2[C:34]([F:37])([F:36])[F:35])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:16])[CH2:12][C:13]([NH:33][CH:31]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH2:23][C:20]3[CH:19]=[CH:18][N:17]=[CH:22][CH:21]=3)=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:27]=2)[CH3:32])=[O:15])=[CH:8][CH:9]=1)(=[NH:3])[NH2:2]
Reactant: N=C(N)c1ccc(NC(=O)CC(=O)O)cc1
Reactant: CC(N)c1ccc(OCc2ccncc2)c(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(NC(=O)CC(=O)Nc1ccc(C(=N)N)cc1)c1ccc(OCc2ccncc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
134.1 mg (0.4 mmol) of N-(4-carbamimidoyl-phenyl)-malonamic acid*trifluoro-acetic acid salt (intermediate 4) was dissolved in absolute DMF and to this solution 118.5 mg (0.4 mmol) of the amine from step 2, 509 mg (0.8 mmol) 1-propane-phoshonic-acid-anhydride and 51.7 mg (0.4 mmol) N,N-diisopropy-ethyl-amine were added. After stirring for 24 h at ambient temperature the reaction mixture was filtered, evaporated to dryness and purified by preparative HPLC. Yield 45 mg (18%), colourless crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[CH:11]=[C:12]([NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:2]([N:19]1[CH2:20][CH2:21][N:16]([C:15]2[CH:14]=[CH:13][C:12]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:11][C:10]=2[Cl:9])[CH2:17][CH2:18]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCc1ccccc1
Reactant: O=C(Nc1ccc(N2CCNCC2)c(Cl)c1)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(Nc1ccc(N2CCN(Cc3ccccc3)CC2)c(Cl)c1)c1ccccn1
Yield: 192.2 %

Procedure:
According to Scheme 5 Step 5 Method B: A suspension of (bromomethyl)benzene (0.61 mmol, 74 μL), N-(3-chloro-4-(piperazin-1-yl)phenyl)picolinamide (0.51 mmol, 161 mg) and of K2CO3 (0.51 mmol, 70 mg) in ACN (3 mL) was stirred at 80° C. for 30 minutes. After evaporation of the solvent, water and AcOEt were added. The aqueous phase was extracted with AcOEt. The organic phase was washed with brine, was dried over Na2SO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel using DCM/AcOEt (80:20) as eluent and finally crystallized in pentane to obtain N-(4-(4-benzylpiperazin-1-yl)-3-chlorophenyl)picolinamide (0.98 mmol, 40 mg, 20%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([C:18]4(C(O)=O)[CH2:20][CH2:19]4)[CH:15]=[N:16][CH:17]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:24].C1(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C1COCC1>C1(C)C=CC=CC=1>[NH2:39][C:18]1([C:14]2[CH:13]=[C:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[N:2]([CH3:1])[C:3](=[O:24])[CH2:4][CH2:5]4)[CH:17]=[N:16][CH:15]=2)[CH2:20][CH2:19]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CN1C(=O)CCc2cc(-c3cncc(C4(C(=O)O)CC4)c3)ccc21
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN1C(=O)CCc2cc(-c3cncc(C4(N)CC4)c3)ccc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 74.7 %

Procedure:
To solution of 1-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)cyclopropanecarboxylic acid (0.551 g, 1.52 mmol) in toluene (20 mL) were added TEA (0.185 g, 1.83 mmol) and diphenylphosphoryl azide (0.419 g, 1.52 mmol) and then the reaction mixture was heated to reflux for 4 h. After cooling to 0° C., a 1 M solution of sodium trimethylsilanoate in THF (3.04 mL, 3.04 mmol) was added and the mixture was stirred for 45 min at room temperature. After quenching with 0.1 M aq. HCl (40 mL), the aqueous solution was washed with ether (2 times), then basified with 1 M aq. NaOH and then extracted with DCM (2×100 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give the title compound (0.333 g, 71%) as a yellow foam. MS: 294.4 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Br:21]Br.OS([O-])=O.[Na+]>C(O)(=O)C>[Br:21][C:20]1[CH:19]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])=[CH:10][CH:9]=1
Reactant: BrBr
Reactant: COc1ccc(Cc2ccc(NS(C)(=O)=O)cc2)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Cc2ccc(NS(C)(=O)=O)cc2)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
A round bottom was charged with N-[4-(4-Methoxy-benzyl)-phenyl]-methane sulfonamide (8) (1.4 g, 4.8 mmol), acetic acid (15 mL) and slow addition of bromine (5 minute period, 0.23 mL, 5.2 mmol). The reaction mixture was stirred at room temperature overnight. To the yellow homogeneous reaction mixture 15% w/v of aq. NaHSO3 (50 mL) was added. The reaction mixture formed a white precipitate. The reaction mixture was stirred for 30 minutes. Then the solid was collected, rinsed several times with water and dried in vacuo to provide 961.9 mg (56% yield) of product (9).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][NH:9][C:8]2=[O:17])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:27][O:28][C:29]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:27][O:28][C:29]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:30]=1[C:31]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][NH:9][C:8]2=[O:17])[CH2:5][CH2:6]1)=[O:32]
Reactant: O=C1NCc2ccccc2N1C1CCNCC1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCC(N3C(=O)NCc4ccccc43)CC2)c(OC)c1
Reaction time: 2 h

Procedure:
To a solution of 1-(4-piperidinyl)-3,4-dihydroquinazolin-2(1H)-one (680 mg, 1.40 mmol) from Step 5 in DCM (15 mL) was added DIEA (0.366 mL, 2.1 mmol) followed by 2,4-dimethoxybenzoyl chloride (309 mg, 1.54 mmol). The reaction was stirred for 2 h and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with 5% aqueous citric acid (50 mL) and saturated aqueous NaHCO3 (2×50 mL). The EtOAc layer was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography eluting first with 95:5 EtOAc:CHCl3 and then with 95:3:2 EtOAc:CHCl3 :MeOH. The title compound was obtained as a white solid (77% yield).
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C@H:8]([CH2:23][C:24]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=1[F:32])[CH2:9][C:10](=O)[NH:11][NH:12][C:13]1[N:18]2[N:19]=[CH:20][N:21]=[C:17]2[CH:16]=[CH:15][N:14]=1)(C)(C)C.[C:34](O)(=O)C>>[N:12]1[N:11]=[C:10]([CH2:9][C@H:8]([NH:7][C:6](=[O:5])[CH3:34])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=2[F:32])[N:14]2[CH:15]=[CH:16][C:17]3=[N:21][CH:20]=[N:19][N:18]3[C:13]=12
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NNc1nccc2ncnn12)Cc1cc(F)c(F)cc1F
Product: CC(=O)N[C@H](Cc1cc(F)c(F)cc1F)Cc1nnc2n1ccc1ncnn12

Procedure:
A solution of 93.1 mg (0.2 mmol) of tert-butyl[(1R)-3-oxo-3-(2-[1,2,4]triazolo[1,5-c]pyrimidin-5-ylhydrazino)-1-(2,4,5-trifluorobenzyl)propyl]carbamate in 10 mL of glacial acetic acid was stirred at reflux under nitrogen for 40 h. The cooled solution was concentrated, and the residue was partitioned between 5 mL of ethyl acetate and 3 mL of saturated sodium carbonate aqueous solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative thin-layer chromatography on silica gel (92.5:7.5 dichloromethane:methanol), giving the title compound as a white solid, mp 233-235° C. LC-MS 390 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:15])[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])=[N:5][O:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[C:28]([F:29])=[C:27](F)[N:26]=[CH:25][N:24]=1>C(#N)C>[CH3:1][NH:2][C:3](=[O:15])[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:27]1[C:28]([F:29])=[C:23]([F:22])[N:24]=[CH:25][N:26]=1)=[N:5][O:6][CH3:7]
Reactant: CNC(=O)C(=NOC)c1ccccc1O
Reactant: Fc1ncnc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)C(=NOC)c1ccccc1Oc1ncnc(F)c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6 g (0.0280 mol) of N-methyl-2-(2-hydroxyphenyl)-2-methoxyiminoacetamide (Example I-1g from process step 1; HPLC: 43.7% N-methyl-E-2-(2-hydroxyphenyl)-2-methoxyimino-acetamide of log p=0.98 and 53.5% N-methyl-Z-2-(2-hydroxyphenyl)-2-methoxyiminoacetamide of log p=1.29) are dissolved in 80 ml of acetonitrile. The solution is cooled to 0° C., 4.7 g (0.034 mol) of potassium carbonate are added and the mixture is stirred for another 30 minutes. 3.8 g (0.0283 mol) of 4,5,6-trifluoropyrimidine are then added dropwise and the mixture is stirred at 20° C. for two hours. The solvent is then distilled off under reduced pressure, the residue is mixed with water, the product is extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. This gives 5.7 g (61.4% of theory) of crude N-methyl-2-[2-(5,6-difluoropyrimidin-4-yloxy)phenyl]-2-methoxyiminoacetamide which, according to HPLC, contains 45.5% N-methyl-E-2-[2-(5,6-difluoropyrimidin-4-yloxy)-phenyl]-2-methoxyiminoacetamide of log p=1.95 and 46.6% N-methyl-Z-2-[2-(5,6-difluoro-pyrimidin-4-yloxy)phenyl]-2-methoxyiminoacetamide of log p=1.87.
Reaction SMILES: [P:1]([O:19][C:20]([C:23]1[N:28]=[CH:27][C:26]([C:29]2[C:43]([F:44])=[C:42]([C@H:45]3[CH2:49][CH2:48][CH2:47][O:46]3)[C:32]3[NH:33][C:34]([NH:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38])=[N:35][C:31]=3[CH:30]=2)=[CH:25][N:24]=1)([CH3:22])[CH3:21])([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2].CCO.[OH-].[Na+:54]>[Pd].O>[P:1]([O-:11])([O-:3])([O:19][C:20]([C:23]1[N:28]=[CH:27][C:26]([C:29]2[C:43]([F:44])=[C:42]([C@H:45]3[CH2:49][CH2:48][CH2:47][O:46]3)[C:32]3[NH:33][C:34]([NH:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38])=[N:35][C:31]=3[CH:30]=2)=[CH:25][N:24]=1)([CH3:21])[CH3:22])=[O:2].[Na+:54].[Na+:54]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)OP(=O)(OCc4ccccc4)OCc4ccccc4)nc3)c(F)c([C@H]3CCCO3)c2[nH]1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)OP(=O)([O-])[O-])nc3)c(F)c([C@H]3CCCO3)c2[nH]1
Temperature: 23 °C
Reaction time: 2.5 h
Yield: 94.1 %

Procedure:
A 1 L round bottom flask was charged with (R)-dibenzyl 2-(5-(2-(3-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl phosphate (24) (9.37 g, 13.61 mmol), EtOH (300 mL), water (150 mL), Pd/C (10 wt % dry basis, wet, Degussa type, 3 g) and 1 M aqueous NaOH (27.22 mL, 27.22 mmol). The suspension was evacuated for 3 min (needle to pump) then placed under an atmosphere of hydrogen gas (balloon). After stirring 2.5 h at 23° C., the reaction was filtered through a 0.22 μm PES membrane (disposable Corning filter system, 1 L, polystyrene, #431098) to remove catalyst and washed with EtOH (50 mL). The resulting solution was concentrated, the residue dissolved in water (80 mL), treated with MeCN (80 mL), then frozen and lyophilized to give disodium (R)-2-(5-(2-(3-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl phosphate (W) (7.10 g, 12.81 mmol, 94.12%) as a white solid. ESMS (M+1)=509.3; 1H NMR (300 MHz, D2O) δ 8.58 (s, 2H), 6.92 (d, J=6.3 Hz, 1H), 5.13 (t, J=7.5 Hz, 1H), 3.98-3.81 (m, 2H), 3.04 (q, J=7.2 Hz, 2H), 2.26 (t, J=5.7 Hz, 1H), 1.97-1.92 (m, 2H), 1.67 (s, 6H) and 1.01 (t, J7.2 Hz, 3H) ppm.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:4]=1.C(=O)([O-])[O-:19].[Ca+2]>C(O)C.O>[F:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH:2]=[O:19])=[CH:11][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(Oc2cccc(C(Br)Br)c2)cc1
Agent: [Ca+2]
Solvent: O
Solvent: CCO
Product: O=Cc1cccc(Oc2ccc(F)cc2)c1
Yield: 92.4 %

Procedure:
A solution of the product of step (b) (16.04 g) in a mixture of ethanol (100 ml) and water (25 ml) was treated with precipitated calcium carbonate (13.37 g) and the mixture refluxed for 20 hours. After cooling, the mixture was filtered, the filtrate stripped, and the residue taken up in 2 M aqu. HCl (100 ml) and extracted with ether (200 ml). The extract was washed with water (100 ml), dried over Na2SO4 and stripped to give a pale yellow oil which was distilled under reduced pressure to give the desired product (8.90 g), bp 100°-130° C./0.2 mm Hg.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[CH3:10].[CH3:11][Si:12](Cl)([CH3:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Cl-].[NH4+]>O1CCCC1>[CH3:11][Si:12]([CH3:21])([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[CH3:10]
Reactant: Cc1ccc(C)c(Br)c1
Reactant: CCCCCCCC[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCCCC[Si](C)(C)c1cc(C)ccc1C
Temperature: 70 °C
Yield: 42.7 %

Procedure:
1.95 g (80.2 mmol) of finely cut magnesium metal was placed in a 200 ml four-necked flask, and 50 ml of anhydrous tetrahydrofuran was further charged. The mixture was heated up to 70° C. while stirring, and 50 ml of a solution of 5 g (27.0 mmol) of 2-bromo p-xylene in anhydrous tetrahydrofuran was added dropwise while caring for steep reaction (reflux). After completion of the addition, it was refluxed for 30 minutes, then, cooled to 40° C., and to this was added 6.7 g (32.4 mmol) of dimethyloctylsilyl chloride while stirring. The solution was again heated and refluxed for 3 hours. The reaction mixture was charged in an aqueous saturated ammonium chloride solution, and extracted (toluene/water) and the organic phase was dried over sodium sulfate. After concentration, the product was purified and isolated by silica gel column chromatography (n-hexane) to obtain 3.19 g of 2-(dimethyloctylsilyl)-p-xylene.