Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][CH:6]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[N:22]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[C:14]([C:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]=2)[CH:13]=1)[CH2:7][O:8]C(=O)C)(=O)C.[OH-].[Na+].C(Cl)Cl.O>CC(O)C>[C:36]1([C:14]2[CH:13]=[C:12]([CH:6]([CH2:5][OH:4])[CH2:7][OH:8])[CH:17]=[CH:16][C:15]=2[NH:18][C:19]([C:21]2[N:22]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]=1
Reactant: CC(=O)OCC(COC(C)=O)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(CO)CO)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of acetic acid 3-acetoxy-2-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-propyl ester (as prepared in the previous step, 580 mg, 1.00 mmol) in i-PrOH (15 mL), 2N NaOH (1 mL, 2 mmol) was added. The reaction mixture was stirred at RT for 1 h, and DCM (200 mL) and water (200 mL) were added. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified on silica (40% EtOAc-hexane) to obtain the title compound (312 mg, 63%): Mass spectrum (ESI, m/z): Calcd. for C26H36N4O4Si, 497.2 (M+H). found 497.0.
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][NH:9][CH2:10][C@@H:11]([CH3:24])[CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:31][C:32]1[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O.COC(=O)C.[Cl:49]C1C(C(F)(F)F)=CC=CC=1C=O.Cl.CCOCC>CCOCC>[ClH:49].[F:31][C:32]1[C:39]([C:40]([F:41])([F:42])[F:43])=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][N:9]([CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:10][C@@H:11]([CH3:24])[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Reactant: O=Cc1cccc(C(F)(F)F)c1F
Reactant: C[C@H](CNCC(c1ccccc1)c1ccccc1)COc1cccc(CC(=O)O)c1
Agent: Cl
Solvent: COC(C)=O
Solvent: CCOCC
Product: C[C@@H](COc1cccc(CC(=O)O)c1)CN(Cc1cccc(C(F)(F)F)c1F)CC(c1ccccc1)c1ccccc1

Procedure:
Following the procedure of Example 7(d) except (R)-2-(3-{3-[(2,2-diphenylethyl)amino]2-methyl-propoxy}phenyl)acetic acid and 2-fluoro-3-trifluoromethylbenzaldehyde were used instead of (R)-2-(3-{3-(2,2-diphenylethyl)amino]-3-methyl-propoxy}-phenyl)acetic acid methyl ester and 2-chloro-3-trifluoromethylbenzaldehyde in step (d) the corresponding carboxylic acid was obtained. The resulting amine/carboxylic acid was dissolved in Et2O (diethylether) and acidified with 1.0 M HCl/Et2O. The reaction mixture was concentrated in vacuo and dried under reduced pressure to give the title compound as a white solid, 73 mg (68%). MS (ESI) 580.4 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23](C(NC3C=CC=CC=3)=O)[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.BrC1C(N2CCN([S:52]([CH3:55])(=[O:54])=[O:53])CC2)=C([N+]([O-])=O)C(N)=NC=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].CN(C1C=CC(C=O)=CC=1)C>C(O)C.CN(C=O)C>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Reactant: CS(=O)(=O)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2nc3c(N4CCN(S(C)(=O)=O)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 6 h
Yield: 39 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-4-(4-(methylsulfonyl)piperazin-1-yl)-3-nitropyridin-2-amine (100 mg, 0.26 mmol), DMF (1.6 mL), ethanol (0.2 mL), 1M Na2S2O4 (4 eq, 1.05 mmol, 1.05 mL) and 4-(N,N-dimethylamino)benzaldehyde (1.1 eq, 0.29 mmol, 43 mg). After 6 h, filtration of the precipitate and washing with cold ethanol (1 mL) and cold water (1 mL) gave the product (49 mg, 39%) as a pale yellow solid; 1H-NMR (500 MHz, DMSO-d6) 2.97 (s, 3H, SO2CH3), 3.01 (s, 6H, N(CH3)2), 3.34-3.38 (m, 4H, piperazine N(CH2)2), 3.70-3.73 (m, 4H, piperazine N(CH2)2), 6.83 (d, J=9.0 Hz, 2H, N,N-dimethylaminophenyl) 8.05 (d, J=8.9 Hz, 2H, N,N-dimethylaminophenyl), 8.21 (s, 1H, imidazo[4,5-b]pyridine H-5), 13.21 (br s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C@@H:14]1[CH2:16][C@@H:15]1[F:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].[CH:22]1([NH:25][CH2:26][C@@H:27]2[C@H:31]([F:32])[CH2:30][NH:29][CH2:28]2)[CH2:24][CH2:23]1>>[CH:22]1([NH:25][CH2:26][C@@H:27]2[C@H:31]([F:32])[CH2:30][N:29]([C:11]3[C:10]([F:13])=[C:9]4[C:4]([C:5](=[O:21])[C:6]([C:18]([OH:20])=[O:19])=[CH:7][N:8]4[C@@H:14]4[CH2:16][C@@H:15]4[F:17])=[CH:3][C:2]=3[F:1])[CH2:28]2)[CH2:24][CH2:23]1
Reactant: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Product: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(F)c(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)cc2c1=O
Yield: 52.6 %

Procedure:
Using 6,7,8-trifluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (301 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (190 mg), the same procedure was followed as in Example 23 to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6,8-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as pale yellow crystals (231 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:16]=1[O:17][C:18]1[CH:19]=[C:20]([CH2:24]O)[CH:21]=[CH:22][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:14][C:15]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:16]=1[O:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: Cc1cccc(C)c1Oc1cccc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCc2cccc(Oc3c(C)cccc3C)c2)cc1
Temperature: 0 °C
Yield: 49.7 %

Procedure:
To a solution of methyl 3-(4-hydroxyphenyl)propanoate (0.25 g, 1.39 mmol), [3-(2,6-dimethylphenoxy)phenyl]methanol (0.41 g, 1.81 mmol) and triphenylphosphine (0.47 g, 1.81 mmol) in tetrahydrofuran (5 mL) was added dropwise diethyl azodicarboxylate toluene solution (40%, 0.82 mL) with stirring at 0° C., and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane/ethyl acetate=4/1) to give the title compound (0.27 g, yield 50%) as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[N:8]([CH2:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:18])[C:6]2[C:19]([OH:27])=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[S:21][C:5]=2[CH:4]=1)[CH3:2].[C:28](OCC)(=O)[CH2:29]S.C(N(CC)CC)C>>[CH2:28]([O:27][C:19]1[C:6]2[C:7](=[O:18])[N:8]([CH2:9][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[S:21][C:20]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:29]
Reactant: CCOC(=O)c1sc2cc(CC)n(CC(=O)c3ccccc3)c(=O)c2c1O
Reactant: CCOC(=O)CS
Solvent: CCN(CC)CC
Product: CCOC(=O)c1sc2cc(CC)n(CC(=O)c3ccccc3)c(=O)c2c1OCC

Procedure:
In the same manner as in Reference Example 5, ethyl 6-ethyl-3-hydroxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylate was obtained from the compound of Reference Example 39 (3.6 g, 10.3 mmol), ethyl thioglycolate (14.4 mL, 103 mmol) and triethylamine (2.3 mL, 20.6 mmol). The title compound (900 mg, 47%) was obtained as a white solid from the thus-obtained ethyl 6-ethyl-3-hydroxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylate (1.8 g, 4.7 mmol) by a method similar to that in Reference Example 43.
Reaction SMILES: [C:1]([O:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH3:18])(=[O:17])=[O:16])(=[O:8])=[O:7])(=[O:3])[CH3:2].C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>ClCCl>[C:1]([O:4][N:5]([S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH3:18])(=[O:16])=[O:17])(=[O:8])=[O:7])[C:27](=[O:28])[O:29][CH2:30][CH3:31])(=[O:3])[CH3:2].[C:1]([O:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH3:18])(=[O:16])=[O:17])(=[O:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cl
Agent: CC(=O)ONS(=O)(=O)c1ccccc1S(C)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N(OC(C)=O)S(=O)(=O)c1ccccc1S(C)(=O)=O
Reaction time: 3 h

Procedure:
Ethyl (acetyloxy){[2-(methylsulfonyl)phenyl]sulfonyl}-carbamate (48) is prepared according to Scheme 3. To a stirred solution of N-(acetyloxy)-2-(methylsulfonyl)benzene-sulfonamide (0.085 g, 0.29 mmol) in dichloromethane (5 ml) is added triethylamine (50 μl, 0.35 mmol) and ethyl chloroformate (30 μl, 0.32 mmol). The reaction mixture is stirred for 3 hours before quenching with water (1 ml). The organics are separated and dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound which is purified by silica column chromatography, eluting with 40% ethyl acetate: heptane. (60 mg, 57%), 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 8.47-8.58 (1H, m), 8.34-8.45 (1H, m), 7.82-7.94 (2H, m), 4.25 (2H, q, 7.2 Hz), 3.42 (3H, s), 2.31 (3H, s), 1.25 (3H, t, 7.2 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:11]2[N:12]=[C:13]([NH2:15])[S:14][C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[S:25]([N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38](O)=[O:39])[CH:36]=2)[CH2:31][CH2:30][CH2:29]1)(=[O:27])=[O:26]>>[CH2:1]([O:3][C:4]([CH:6]1[C:11]2[N:12]=[C:13]([NH:15][C:38]([C:35]3[CH:36]=[C:37]4[C:32]([CH2:31][CH2:30][CH2:29][N:28]4[S:25]([C:19]4[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=4[O:17][CH3:16])(=[O:27])=[O:26])=[CH:33][CH:34]=3)=[O:39])[S:14][C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1ccc(C)cc1S(=O)(=O)N1CCCc2ccc(C(=O)O)cc21
Reactant: CCOC(=O)C1CCCc2sc(N)nc21
Product: CCOC(=O)C1CCCc2sc(NC(=O)c3ccc4c(c3)N(S(=O)(=O)c3cc(C)ccc3OC)CCC4)nc21

Procedure:
1-(2-Methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid was converted to the title compound in analogy to example 8, steps 3 and 4. Step 3 was performed using 2-amino-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acid ethyl ester and 1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid and yielded 2-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acid ethyl ester, which was hydrolyzed to 2-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acid in step 4, MS (ISP): m/e=540.3 (M−H).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:30])=[N:27][CH:28]=1)=O.[C:39]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1.CC(O)=O>CCOC(C)=O.C1COCC1>[C:39]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:40]=[CH:41][C:42]([NH:45][CH2:15][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:30])=[N:27][CH:28]=2)=[CH:43][CH:44]=1
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2ccccc2C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2ccccc2CNc2ccc(-c3ccccc3)cc2)cn1
Temperature: 40 °C

Procedure:
Solid NaBH(OAc)3 (214 mg, 1.0 mmol) was added to a THF solution of ethyl 3-(5-(2-formylphenyl)picolinamido)propanoate (220 mg, 0.7 mmol), [1,1′-biphenyl]-4-amine (171 mg, 1.0 mmol), and AcOH (0.04 mL, 0.7 mmol) and the resulting mixture was warmed to 40° C. After 18 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[C:26](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH3:26])[C:16]2([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)OC)CCCCC2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C2(C(=O)OC)CCCCC2)cc1
Temperature: 25 °C

Procedure:
A mixture of methyl 1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)cyclohexanecarboxylate (4.5 g., 12.3 mmol), anhydrous potassium carbonate (20.0 g, excess) and methyl iodide (2 g, 14.08 mmol) was refluxed in acetone for sixteen hours. The reaction mixture was then cooled to room temperature and filtered. The acetone layer was concentrated and extracted with chloroform. The chloroform layer was washed well with water, dried over anhydrous MgSO4, filtered and concentrated to provide methyl 1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]cyclohexanecarboxylate as a yellow oil. Yield: 4.6 g. (quantitative) Electrospray Mass Spec 380 (M+H)+.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH:5]1([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>CCO>[CH:5]1([CH:11]2[CH2:12][CH2:13][N:14]([CH2:3][CH2:2][C:1]#[N:4])[CH2:15][CH2:16]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: C=CC#N
Reactant: C1CCC(C2CCNCC2)CC1
Solvent: CCO
Product: N#CCCN1CCC(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.7 %

Procedure:
Acrylonitrile (4.16 mL, 63.1 mmol, 2.50 equiv) was added at 0° C. to a solution of 4-cyclohexylpiperidine (4.20 g, 25.3 mmol, 1.00 equiv) in EtOH (50 mL) and the resulting solution was stirred for 1.5 hours at room temperature. The solvent was removed to give 5.11 g (92%) of white solid, which was characterized spectroscopically and used without purification for the next reaction.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][C:15]1([CH3:24])[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17](=O)[CH2:16]1>C1COCC1>[CH3:14][C:15]1([CH3:24])[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17](=[CH:5][C:3]#[N:4])[CH2:16]1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CC(=CC#N)CC(C)(C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
60% NaH dispersion in mineral oil (0.96 g, 24 mmol) was added to a solution of diethyl cyanomethylphosphonate (4.25 g, 24 mmol) in THF (30 ml) while cooling with ice water. The mixture was stirred for 30 min and a solution of 3,3,5,5-tetramethylcyclohexanone (3.08 g, 20 mmol) in THF (10 ml) was added dropwise. Cooling bath was removed and the mixture was stirred at room temperature for 72 h. It was poured into ice water (100 ml) and extracted with diethyl ether (350 ml). The combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (light petroleum ether-ethyl acetate, 10:1) to give 20 (2.38 g, 71%) as a colorless oil. 1H-NMR (CDCl3, TMS):0.97 and 1.01 (total 12H, both s, 3′,5′-CH3); 1.36 (2H, s, 4′-CH2); 2.01 (2H, s, 2′-CH2); 2.26 (2H, s, 6′-CH2) and 5.14 ppm (1H, s, ═CH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].Cl.[NH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36].C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>CCOC(C)=O.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: COC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: COC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1

Procedure:
The product of Example 48 (2.25 g mg, 5.0 mmol), methyl glycinate hydrochloride (3.13 g, 25.0 mmol), anhyd K2CO3 (3.45 g, 25.0 mmol) and NMP (25 mL) were stirred for 1 h at 60°. The reaction was diluted with EtOAc (200 mL), washed with 10% aq citric acid (2×25 mL), H2O (25 mL) and satd aq NaCl (40 mL) dried (Na2SO4) and concentrated. The resulting brown residue was filtered through a plug of silica (350 mL) (dichloromethane/methanol) to afford a brown foam. Trituration with Et2O afforded the title compound, methyl N-[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7,8-dihydro-7-oxopyrido[2,3-d]pyrimidin-2-yl]glycinate as a white solid. mp=212-213°.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](OC(Cl)(Cl)Cl)=[O:10].[NH2:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2.[NH2:27][CH2:28][C:29]([N:31]([CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>ClCCl.O>[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[C:17]([NH:16][C:9](=[O:10])[NH:27][CH2:28][C:29]([N:31]([CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:30])[CH:18]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cnc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)CN(C(=O)CNC(=O)Nc1cnc2ccccc2c1)c1ccccc1
Reaction time: 0.25 h
Yield: 74.3 %

Procedure:
1 g of triethylamine and 0.49 g of trichloromethyl chloroformate are added, at a temperature close to 0° C., to a solution of 0.72 g of 3-aminoquinoline in 30 cm3 of dichloromethane. The suspension obtained is stirred for 15 minutes at a temperature close to 0° C. and a solution of 1.3 g of tert-butyl 2-(2-amino-N-phenylacetamido)acetate in 10 cm3 of dichloromethane is then added. The reaction mixture is stirred for 3 hours at a temperature close to 20° C. and 20 cm3 of water are then added. The aqueous phase is separated off by decantation and then reextracted with twice 15 cm3 of 1,2-dichloroethane. The organic phases are combined, washed with twice 10 cm3 of water, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The oil obtained is purified by chromatography on 50 g of silica (0.063-0.2 mm) contained in a column 1.5 cm in diameter [eluent: dichloromethane/methanol (98/2 by volume)], collecting 10-cm3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from ethyl acetate, 0.8 g of tert-butyl 2-{2-[3-(3-quinolyl)ureido]-N-phenylacetamido}acetate melting at 191° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[C:6]([C:8]2[C:9]([O:16][CH2:17][CH3:18])=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][C:63]=1[CH2:69][C:70](O)=[O:71]>CC(N(C)C)=O>[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][C:63]=1[CH2:69][C:70]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[C:6]([C:8]2[C:9]([O:16][CH2:17][CH3:18])=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1)=[O:71]
Reactant: O=C(O)Cc1cc(F)ccc1Cl
Reactant: CCOc1cc(=O)n(C)cc1-c1cc(N)ccc1Oc1ccc(F)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(=O)n(C)cc1-c1cc(NC(=O)Cc2cc(F)ccc2Cl)ccc1Oc1ccc(F)cc1F

Procedure:
A solution of Example 1G and DIPEA (0.182 M and 0.52 M in DMA, respectively, 221 μL, 0.40 mmol Example 1G (1.0 equivalent) and 1.21 mmol DIPEA (3.0 equivalents)), HATU (0.182 M in DMA, 221 μL, 0.40 mmol, 1 equivalent) and 2-(2-chloro-5-fluorophenyl)acetic acid (0.40 M in DMA, 151 μL, 0.60 mmol, 1.5 equivalents) were mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL min−1 (10 minute residence time). Upon exiting the reactor, the solution was loaded directly into an injection loop and purified by preparative HPLC on a Phenomenex Luna C8(2) 5 μm 100 Å AXIA column (50 mm×21.2 mm), eluting with a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) at a flow rate of 30 mL/min (0-0.5 min 5% A, 0.5-6 5 min linear gradient 5-100% A, 6.5-8.5 min 100% A, 8.5-9.0 min linear gradient 100-5% A, 9.0-10 min 5% A) to provide the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 10.37 (s, 1H), 7.59-7.46 (m, 4H), 7.37-7.27 (m, 2H), 7.18 (td, J=8.5, 3.1 Hz, 1H), 7.14-6.93 (m, 2H), 6.90 (d, J=8.7 Hz, 1H), 5.82 (s, 1H), 3.92 (q, J=7.0 Hz, 2H), 3.85 (s, 2H), 3.36 (s, 3H), 1.14 (t, J=7.0 Hz, 3H). MS (APCI+) m/z 543.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1)[OH:4].[CH3:11][O:12][CH2:13]Cl.Cl>C1COCC1>[CH3:11][O:12][CH2:13][O:4][C:3]1[CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1
Reactant: Oc1ccc(O)cc1
Reactant: COCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(O)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
A mixture of 60% sodium hydride (1.80 g, 45.0 mmol) and dry THF (20 mL) was cooled to −20° C. After addition of a solution of hydroquinone (2.00 g, 18.2 mmol) in THF (30 mL), the mixture was stirred at room temperature for one hour and then cooled again to −20° C. After dropwise addition of chloromethyl methyl ether (1.3 mL, 18.0 mmol), the cooled mixture was slowly warmed to 10° C., stirred at room temperature for one hour, and poured onto ice pieces (500 g). To the resulting mixture was added 3 mol/L aqueous hydrochloric acid until the mixture reached pH 4-5. Subsequently, the mixture was subjected to extraction with dichloromethane (100 mL×2). The extract was washed with water (100 mL×2) and saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, and placed under reduced pressure to distill the solvent off. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), to obtain 581 mg (yield 21%) of the titled compound as pale yellow oil.