Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:30])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[CH:25]1([S:22]([N:19]2[CH2:20][CH2:21][CH:16]([C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([F:30])[CH:11]=4)[CH:6]=[C:5]([CH2:4][C:3]([OH:31])=[O:2])[C:14]=3[CH3:15])[CH2:17][CH2:18]2)(=[O:23])=[O:24])[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)C3CCCC3)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(S(=O)(=O)C2CCCC2)CC1
Reaction time: 3 h
Yield: 30.2 %

Procedure:
To a solution of [4-(1-cyclopentanesulfonyl-piperidin-4-yl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (64.8 mg, 0.145 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (69.5 mg, 1.7 mmol) in water (2.0 mL) at room temperature. The resulting solution was stirred for three hours under a nitrogen atmosphere. The solvent was evaporated. Water (20 mL) was added and the mixture was acidified with 1.0 N aqueous HCl (3 mL). The resulting white precipitate was collected by filtration, washed with water and hexanes, and dried under high vacuum. This crude product was further purified using preparative reverse-phase HPLC to give [4-(1-cyclopentane-sulfonyl-piperidin-4-yl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid (19 mg, 30%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.43 (br. s., 1H), 7.97-8.17 (m, 1H), 7.90 (dd, J=9.03, 6.53 Hz, 1H), 7.69 (s, 1H), 7.35 (t, J=7.53 Hz, 1H), 3.78 (br. s., 6H), 3.11 (br. s., 2H), 2.42 (br. s., 4H), 1.96-2.08 (m, 2H), 1.80-1.93 (m, 2H), 1.53-1.78 (m, 6H). MS cald. for C23H29FNO4S [(M+H)+]: 434, obsd. 434.2.
Reaction SMILES: C([O:3][P:4]([C:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)[C:20]2[S:21][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)=[CH:14][C:13]=1[Br:39])([F:11])[F:10])(=[O:8])[O:5]CC)C.C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.I[Si](C)(C)C>C(Cl)Cl>[Br:39][C:13]1[CH:14]=[C:15]([CH2:18][N:19]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)[C:20]2[S:21][CH:22]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:24]=2)[CH:16]=[CH:17][C:12]=1[C:9]([P:4](=[O:3])([OH:5])[OH:8])([F:10])[F:11]
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(CN(c2ccc(Cl)c(Cl)c2)c2nc(-c3ccccc3)cs2)cc1Br
Agent: C[Si](C)(C)I
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: ClCCl
Product: O=P(O)(O)C(F)(F)c1ccc(CN(c2ccc(Cl)c(Cl)c2)c2nc(-c3ccccc3)cs2)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 199.9 %

Procedure:
To [(2-bromo-4-{[(3,4-dichloro-phenyl)-(4-phenyl-thiazol-2-yl)-amino]-methyl}-phenyl)-difluoro-methyl]-phosphonic acid diethyl ester (0.176 g, 0.25 mmol) in CH2Cl2 (3 mL) was added bistrimethylsilyltrifluoroacetamide (0.66 g, 2.59 mmol) and reaction mixture was stirred at room temperature for 1 h after which the reaction mixture is cooled to 20° C. and iodotrimethylsilane (0.51 g, 2.59 mmol) is added drop wise. The resulting mixture was stirred at room temperature for 1.5 hours, after which it was concentrated in vacuo. The resulting material was stirred in CH3CN (4 mL), H2O (0.5 mL), and TFA (0.5 mL) for 0.5 hours, after which it was concentrated in vacuo and partitioned between ethyl acetate and acidic Na2S2O4. The organic layer was dried over MgSO4 and concentrated in vacuo to yield 0.31 g (99%) of a white foam; 1H NMR (300 MHz, DMSO-d6) δ 7.99-7.28 (m, 12 H), 5.33 (s, 2 H); LCMS m/z 619 [M−]
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].C(=O)([O-])[O-].[Na+].[Na+].N([O-])=O.[Na+].[C:24](Cl)(=[O:28])[C:25]([CH3:27])=[CH2:26]>O>[C:24]([NH:5][C@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[CH:3]=[O:2])(=[O:28])[C:25]([CH3:27])=[CH2:26]
Reactant: C=C(C)C(=O)Cl
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: C=C(C)C(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Glucosamine hydrochloride ( 0.06 mol; 13.25 g), sodium carbonate (0.2 mol; 21.2 g) and sodium nitrite (0.2 g) were dissolved under nitrogen atmosphere at 0° C. in 100 ml of H2O. Methacryloyl chloride (0.12 mol; 13.0 g) was added under vigorous stirring. The reaction was carried out similar to the synthesis of 1 and gave the product as a white powder after two recrystallizations from water/ethanol/ether. Yield: 8.3-8.9 g (56-60%), p.m. (decomp.): 198°-199° C.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[F:34][C:35]1[CH:36]=[C:37]([CH2:41]O)[CH:38]=[CH:39][CH:40]=1>C1COCC1>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([O:12][CH2:41][C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([F:34])[CH:36]=1)=[O:11])[CH2:3]2
Reactant: O=C(O)C1CN2CCC1CC2
Reactant: OCc1cccc(F)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(OCc1cccc(F)c1)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Quinuclidine-3-carboxylic acid hydrochloride (95 mg, 0.50 mmol), EDC (143 mg, 0.74 mmol), HOBT (114 mg, 0.74 mmol), and triethylamine (242 μl, 1.73 mmol) were dissolved in dry THF (5 ml). (3-Fluorophenyl)methanol (68.8 mg, 0.54 mmol) was dissolved in dry THF (2 ml) and added to the reaction mixture. The resulting reaction was stirred at room temperature overnight. The volatiles were evaporated, and the crude was taken up with EtOAc and washed with water and then with sat. NaHCO3. The organic phase was separated, dried over sodium sulfate, filtered, and evaporated under vacuum to obtain 3-fluorobenzyl quinuclidine-3-carboxylate (120 mg, racemic mixture). The compound was used in the next step without any further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:19].O>C(OCC)C>[Br:19][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCCCCCCc1ccccc1
Reactant: BrP(Br)Br
Solvent: O
Solvent: CCOCC
Product: BrCCCCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In diethylether (200 mL), 10-phenyl-1-decanol (10 g) was dissolved, phosphorus tribromide (4.0 mL) was carefully added thereto, at 0° C., followed by stirring at room temperature for 6 hours. Water was added carefully to the reaction solution, followed by extraction with tert-buthylmethylether. The organic layer was washed with water, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the title compound (7.0 g) having the following physical property values.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14].O>O1CCOCC1>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:16]([NH:15][CH2:13][CH3:14])=[O:17])=[N:7][C:6]=2[CH:11]=1
Reactant: Nc1nc2cc(Br)c(F)cc2s1
Reactant: CCN=C=O
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(Br)c(F)cc2s1
Temperature: 80 °C
Yield: 65 %

Procedure:
To a solution of 5-bromo-6-fluoro-benzothiazol-2-ylamine IV (0.36 g, 1.45 mmol) in 1,4-dioxane (25.0 mL) was added ethyl isocyanate (0.69 mL, 8.74 mmol) and the resulting reaction mixture was heated at 80° C. for 15 h. After the completion of the reaction (TLC monitoring) the solvent was evaporated. The residue thus obtained was stirred with water at 60° C. for 5 h. The solution was then filtered and washed with ether to get the title compound (0.30 g, 69%). 1H-NMR (400 MHz, DMSO-d6): δ 1.08 (t, J=6.80 Hz, 3H), 3.17 (m, 2H), 6.69 (br s, 1H), 7.92 (d, J=6.40 Hz, 1H), 8.0 (d, J=8.40 Hz, 1H) and 10.86 (br s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Br:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27](O)=[O:28].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[Br:19][C:17]1[CH:18]=[C:11]([O:10][C:5]2[C:4]([F:20])=[C:3]([CH2:2][NH:1][C:27]([C:26]3[NH:25][C:24]([CH3:30])=[N:23][C:22]=3[Cl:21])=[O:28])[CH:8]=[CH:7][C:6]=2[Cl:9])[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=1
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Br)cc(C#N)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 44.4 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (900 mg, 2.53 mmol) and 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (813 mg, 2.53 mmol) in DMF (10 ml) was added HOBT (388 mg, 2.53 mmol) and EDC (485 mg, 2.53 mmol) and the reaction mixture was stirred for 6 hours at rt. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give N-({3-[(3-bromo-5-cyanophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-2-methyl-1H-imidazole-5-carboxamide (0.560 g, 1.124 mmol, 44% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.68 (s, 1H), 7.29-7.45 (m, 3H), 7.25 (s, 1H), 4.63 (s, 2H), 2.34 (s, 3H). LC-MS (ES+) m/z 496.87, [M+H].
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[C:66]([O:70][C:71]([N:73]1[CH2:78][CH2:77][N:76]([CH2:79][CH:80]([OH:83])[CH2:81][NH2:82])[CH2:75][CH2:74]1)=[O:72])([CH3:69])([CH3:68])[CH3:67]>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[C:66]([O:70][C:71]([N:73]1[CH2:74][CH2:75][N:76]([CH2:79][CH:80]([OH:83])[CH2:81][NH:82][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH2:77][CH2:78]1)=[O:72])([CH3:69])([CH3:67])[CH3:68]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(O)CN)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)NCC(O)CN2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 75.5 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.031 g (0.12 mmole) 4-(3-amino-2-hydroxy-propyl)-piperazine-1-carboxylic acid tert-butyl ester was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.052 g of 4-{3-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-2-hydroxy-propyl}-piperazine-1-carboxylic acid tert-butyl ester (I-120) as a white solid.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:30]([OH:33])[CH2:31][OH:32])[CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][N:10]=[C:9]2[NH:14][CH2:15][C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:29])OC(C)(C)C)[CH:19]=[CH:20][CH:21]=1)=[O:3].Cl.O1[CH2:40][CH2:39][O:38][CH2:37]C1>CO>[OH:33][CH:30]([C:6]1[CH:7]=[C:8]2[C:13](=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23](=[O:29])[C:4]2[CH:2]=[CH:40][C:39]([O:38][CH3:37])=[CH:8][CH:13]=2)[CH:17]=1)[CH2:31][OH:32]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CNc2ncnc3c(C(N)=O)cc(C(O)CO)cc23)c1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COc1ccc(C(=O)Nc2cccc(CNc3ncnc4c(C(N)=O)cc(C(O)CO)cc34)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl [3-({[8-(aminocarbonyl)-6-(1,2-dihydroxyethyl)quinazolin-4-yl]amino}methyl)phenyl]carbamate (25.00 mg; 0.06 mmol; 1.00 eq.) in methanol was added 4.0M hydrogen chloride in dioxane (0.14 ml; 4.00 M; 0.55 mmol; 10.00 eq.). The reaction mixture was stirred at RT for 1 h and evaporated off the solvent to obtain the title compound MS (M+1) 354.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[NH:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21](OCC)=[O:22])[CH:14]=2)[CH:7]=1.[NH3:29]>>[C:21]([CH2:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[NH:12][C:8]1[CH:7]=[C:6]([NH:5][C:4]2[CH:26]=[CH:27][CH:28]=[C:2]([CH3:1])[CH:3]=2)[N:11]=[CH:10][N:9]=1)(=[O:22])[NH2:29]
Reactant: N
Reactant: CCOC(=O)COc1cccc(Nc2cc(Nc3cccc(C)c3)ncn2)c1
Product: Cc1cccc(Nc2cc(Nc3cccc(OCC(N)=O)c3)ncn2)c1
Yield: 81 %

Procedure:
Using an analogous procedure to that described in Example 25, 6-(3'-methylanilino)-4-[3'-(ethoxycarbonylmethoxy)anilino]pyrimidine was reacted with saturated methanolic ammonia to give 4-[3'-(carbamoylmethoxy)anilino]6-(3'-methylanilino)pyrimidine in 81% yield, m.p. 192°-194° C.;
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13](=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC(S(OC)(=O)=O)=CC=1>CN(C=O)C.O>[CH2:8]([O:7][C:5](=[O:6])[CH:4]=[C:3]([O:10][CH3:13])[C:2]([F:11])([F:12])[F:1])[CH3:9]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=C(OC)C(F)(F)F
Temperature: 70 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
To a solution of ethyl 4,4,4-trifluoroacetoacetate (12 mL, 82 mmol) in DMF (80 mL) is added cesium carbonate (26.4 g, 82 mmol). The reaction mixture is heated to 70° C. A solution of methyl p-toluenesulfonate (13.5 mL, 90 mmol) in DMF (30 mL) is then added dropwise during 30 min and the reaction mixture is stirred for an additional 1 hr. After cooling to room temperature, the reaction mixture is diluted with H2O (150 mL) and extracted with Et2O (2×150 mL). The organic extracts are combined and washed with H2O and brine, then dried (Na2SO4), filtered and concentrated to afford the title compound (9.0 g, 56%) as an oil which is used without further purification.
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.[C:29]([C:31]1[CH:32]=[C:33]([NH:42][C:43](=[O:55])[O:44][CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50](Br)=[CH:49][C:48]=2[CH3:54])[CH:34]=[CH:35][C:36]=1[S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])#[N:30]>>[C:29]([C:31]1[CH:32]=[C:33]([NH:42][C:43]([O:44][CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([B:25]([OH:27])[OH:26])=[CH:49][C:48]=2[CH3:54])=[O:55])[CH:34]=[CH:35][C:36]=1[S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])#[N:30]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Reactant: CCS(=O)(=O)c1ccc(NC(=O)OCCc2ccc(Br)cc2C)cc1C#N
Product: CCS(=O)(=O)c1ccc(NC(=O)OCCc2ccc(B(O)O)cc2C)cc1C#N
Yield: 68 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 31A (745 mg, 1.66 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 31B (468 mg, 68%) as a tan foam. 1H NMR (400 MHz, MeOD) δ ppm 1.25 (t, J=7.33 Hz, 3 H) 2.34-2.40 (m, 3 H) 3.03 (t, J=6.95 Hz, 2 H) 3.35 (q, J=7.33 Hz, 2 H) 4.39 (t, J=7.07 Hz, 2 H) 7.20 (d, J=7.33 Hz, 1 H) 7.30-7.43 (m, 2 H) 7.86 (dd, J=8.84, 1.77 Hz, 1 H) 7.99 (d, J=8.84 Hz, 1 H) 8.11 (d, J=2.02 Hz, 1 H) 10.05 (s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[NH:5][CH:6]([CH3:31])[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([C:18]#[N:19])[CH:17]=1)[N:14]([CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:13][CH2:12]2)=O)[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:32])[NH:5][CH:6]([CH3:31])[CH2:7][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([C:18]#[N:19])[CH:17]=1)[N:14]([CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH2:13][CH2:12]2)[CH3:2]
Reactant: CCOC(=O)NC(C)C(=O)c1cc(C#N)c2c(c1)CCN2CCCO[Si](C)(C)C(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)NC(C)Cc1cc(C#N)c2c(c1)CCN2CCCO[Si](C)(C)C(C)(C)C
Temperature: 27.5 °C
Reaction time: 6 h
Yield: 75.2 %

Procedure:
A mixture of (2-{1-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-7-cyano-2,3-dihydro-1H-indol-5-yl}-1-methyl-2-oxo-ethyl)-carbamic acid ethyl ester (IV) (10 g, 0.02 mole), toluene (80 ml), triethyl silyl hydride (5.57 g, 0.04 mol) and trifluoroacetic acid (1.36 g, 0.01 mole), was stirred at 25-30° C. for a period of 6 hours. The reaction mass was quenched with water (50 ml) and toluene layer was dried over sodium sulphate. The solvent was evaporated under reduced to give 6.7 g of (V) as oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:15])=[CH:4][C:5]([CH2:10][CH2:11][CH2:12][CH:13]=[O:14])=[C:6]([CH:9]=1)[C:7]#[N:8].C1COCC1.[BH4-].[Na+]>CO>[NH2:1][C:2]1[C:3]([Cl:15])=[CH:4][C:5]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(N)c(Cl)cc1CCCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(N)c(Cl)cc1CCCCO
Temperature: 0 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
5-amino-4-chloro-2-(4-oxobutyl)benzonitrile (544 mg, 2.443 mmol) was taken up in MeOH (6 mL) and THF (2.000 mL) and cooled to 0° C. NaBH4 (277 mg, 7.33 mmol) was added, and the reaction was stirred at 0° C. for 2 h (reaction followed by TLC until no SM detected). The reaction was quenched with water and extracted 2× with DCM. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-50% EtOAc/DCM; 40 g column). 5-amino-4-chloro-2-(4-hydroxybutyl)benzonitrile (260 mg) was obtained as a yellow glass.
Reaction SMILES: [C:1]([C:4]1[C:13]([F:14])=[C:12]2[C:7]([C:8](=[O:20])[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][NH:11]2)=[CH:6][C:5]=1[F:21])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:28](I)[CH3:29]>CN(C)C=O>[C:1]([C:4]1[C:13]([F:14])=[C:12]2[C:7]([C:8](=[O:20])[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][N:11]2[CH2:28][CH3:29])=[CH:6][C:5]=1[F:21])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(F)c(C(C)=O)c(F)cc2c1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2c(F)c(C(C)=O)c(F)cc2c1=O
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To 22.3 g (76.6 mmol) of the ethyl 7-acetyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 900 ml of dimethylformamide was added 25.6 g (2.5 eq) of potassium carbonate and 22 ml (3.6 eq) of ethyl iodide. The mixture was stirred at 45° C. overnight. The mixture was concentrated. The residue was dissolved in water and extracted into dichloromethane. The dichloromethane was concentrated and the residual oil was purified by column chromatography on silica gel to give 10.5 g of ethyl 7-acetyl-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylate, mp 129°-130° C.
Reaction SMILES: [C:1](OC)(OC)(OC)[CH3:2].[CH3:9][S:10]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[CH:21][C:20]=1[NH2:29])(=[O:12])=[O:11].Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:18]([CH2:17][CH2:16][O:15][CH2:14][CH2:13][S:10]([CH3:9])(=[O:12])=[O:11])[C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:29]=1
Reactant: CS(=O)(=O)CCOCCNc1c(N)cnc2ccccc12
Reactant: COC(C)(OC)OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1nc2cnc3ccccc3c2n1CCOCCS(C)(=O)=O
Yield: 70.9 %

Procedure:
Trimethyl orthoacetate (1 g, 8.1 mmol) was added to a mixture of N4-{2-[2-(methylsulfonyl)ethoxy]ethyl}quinoline-3,4-diamine (˜2.3 g, ˜7.4 mmol) and toluene (45 mL). Pyridine hydrochloride (0.25 g) was added and the reaction mixture was heated to reflux with the volatiles being collected in a Dean Stark trap. Pyridine was added to help solubilize the starting material. After 2 hours the reaction mixture was concentrated under reduced pressure to provide a dark oil. This material was purified by column chromatography (silica gel eluting sequentially with 95/5 dichloromethane/methanol and 9/1 dichloromethane/methanol) to provide 1.75 g of 2-methyl-1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinoline as a white foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:18])[CH2:16]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[FH:42].[F-]>C1COCC1.CCOCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:18])[CH2:16][F:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccccc1OCc1ccccc1
Reactant: F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(CF)c1ccccc1OCc1ccccc1
Yield: 33.1 %

Procedure:
To a solution of 1-[2-(benzyloxy)phenyl]-2-bromoethanone (2.59 g, 8.5 mmol) and pyridine (1.37 mL, 17 mmol) in THF was added tetrabutylammonium hydrogen difluoride (4.78 g, 17 mmol). The reaction mixture was stirred under reflux for 22 hrs. The mixture was diluted with ether (250 mL), then washed with 1N aqueous hydrochloric acid (100 mL) and brine (100 mL), successively. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (hexane/ethyl acetate, 4:1) to give 1-[2-(benzyloxy)phenyl]-2-fluoroethanone (688 mg, yield; 33%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1.[OH:26][CH2:27][C:28]#[CH:29]>N1CCCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:29]#[C:28][CH2:27][OH:26])[CH:20]=2)[N:3]=1
Reactant: C#CCO
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(Br)c2)N=C1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Solvent: O
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C#CCO)c2)N=C1N
Temperature: 70 °C
Yield: 45 %

Procedure:
A mixture of 2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (2.4 g, 5.85 mmol), 3-hydroxy-1-propyne (3.27 g, 58.5 mmol) and Pd(PPh3)4 (670 mg, 0.585 mmol) in pyrrolidine is heated at 70° C. under a nitrogen atmosphere for 16 h, diluted with water and extracted with CH2Cl2. The extracts are combined, dried over MgSO4 and concentrated in vacuo to give a residue. The residue is purified by chromatography on a silica cartridge, to give 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxyprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one, 1 g (45% yield), identified by NMR and mass spectral analyses.