Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH2:21]([O:23][C:24](=[O:35])[CH2:25][CH2:26][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:22].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:28]([N:27]([CH2:26][CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:35])[C:15]([CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)=[O:17])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)CCNCc1ccccc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCOC(=O)CCN(Cc1ccccc1)C(=O)COc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 3-benzylamino-propionic acid ethyl ester via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H29NO7 [M+H]+: 444.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])[CH:5]=[C:4]([Cl:14])[N:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:11][CH2:10][C:9]([NH:8][C:6]1[CH:5]=[C:4]([Cl:14])[N:3]=[C:2]([Cl:1])[N:7]=1)([CH3:12])[CH3:13])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CO)Nc1cc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(COS(C)(=O)=O)Nc1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-((2,6-dichloropyrimidin-4-yl)amino)-2-methylpropan-1-ol (6.67 g, 28.3 mmol) and triethylamine (11.59 mL, 85 mmol) in dichloromethane (DCM) (100 mL) was added dropwise MsCl (4.40 mL, 56.5 mmol) at 0° C. The reaction mixture was stirred at rt for 2 h, diluted with DCM (100 mL), washed with water (50 mL×3) then brine (50 mL×2), dried over Na2SO4, filtered and concentrated to give the residue as a yellow solid, which was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[N+:15]([O-])([O-:17])=[O:16].[K+]>S(=O)(=O)(O)O>[N+:15]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[CH:12][C:3]([C:2]([F:1])([F:13])[F:14])=[N:4]2)([O-:17])=[O:16]
Reactant: O=[N+]([O-])[O-]
Reactant: FC(F)(F)c1ccc2ccccc2n1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cccc2nc(C(F)(F)F)ccc12
Reaction time: 20 h

Procedure:
1.52 g (7.7 mmol) of 2-(trifluoromethyl)quinoline is dissolved in 7.90 ml of concentrated sulfuric acid, and 1.47 g of potassium nitrate is added in portions at 0° C. After 20 hours at room temperature, the reaction solution is poured onto ice/water. It is extracted with ethyl acetate, the combined organic phases are washed with saturated sodium bicarbonate solution and dried on sodium sulfate. After removal of the solvent and chromatography on silica gel with hexane-ethyl acetate (10-100%), 390 mg (21% of theory) of the product is obtained.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Br[C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1>>[CH3:20][S:19][C:16]1[CH:17]=[CH:18][C:13]([C:7]2[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)=[CH:14][CH:15]=1
Reactant: CSc1ccc(Br)cc1
Reactant: CC(=O)c1ccc(B(O)O)s1
Product: CSc1ccc(-c2ccc(C(C)=O)s2)cc1

Procedure:
1-(5-(4-(Methylthio)phenyl)thien-2-yl)ethanone is prepared from 5-acetyl-2-thiopheneboronic acid and 1-bromo-4-(methylthio)benzene according to general procedure A.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1.[I:18]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.S(=O)(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[C:14]([I:18])=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)Cc1cc(O)c2cc(F)ccc2c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)Cc1cc2ccc(F)cc2c(O)c1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of (6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (600 mg, 2.56 mmol, the product of 8th step for example 1-1) in chloroform (260 mL) was added N-iodosuccinimide (577 mg, 2.56 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours. The resulting mixture was diluted with 10% aqueous solution of sodium bisulfate (100 mL). The organic layer was separated, washed with brine (100 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column (elution with 15% ethyl acetate in petroleum ether) to afford (6-fluoro-4-hydroxy-3-iodo-naphthalen-2-yl)-acetic acid methyl ester (500 mg, 54%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15](=[O:17])[CH3:16])=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(-c2ccccc2O)cc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccccc1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
A solution of 1.0 g (5.4 mmol) of 4-methyl-2'-hydroxy-1,1'-biphenyl in 2.0 mL of pyridine was treated with 2 mL of acetic anhydride. The reaction mixture was stirred at room temperature for 5 hours. The solvent was removed under vacuum to yield 1.11 g (4.9 mmol, 90%) of the product as an oil. 1H NMR (200 MHz, CDCl3): δ 2.07 (s, 3H), 2.36 (s, 3H), 7.07 (dd; 3, 8 Hz; 1H), 7.15 (d, 8 Hz, 2H), 7.2-7.4 (m, 5H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([F:22])[CH:14]=1.BrC1C=CC(C(NC2C=CC=C(C(C)(C)C)C=2)=O)=CC=1F>>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=2)=[O:18])=[C:15]([F:22])[CH:14]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CC(C)(C)c1cccc(N)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(Br)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(Br)cc2F)c1

Procedure:
4-Bromo-N-(3-tert-butyl-phenyl)-2-fluoro-benzamide was synthesized from 3-tert-butyl-phenylamine and 4-bromo-2-fluoro-benzoic acid in a manner similar to the one described in the synthesis of 4-bromo-N-(3-tert-butyl-phenyl)-3-fluoro-benzamide above. LCMS calcd for C17H17FNO (m/e) 349, obsd 350 (M+H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1.[CH2:34]([NH2:36])[CH3:35]>C(O)CCC>[CH2:34]([NH:36][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1)[CH3:35]
Reactant: CCN
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc2cnc(Cl)cc2n(C)c1=O
Solvent: CCCCO
Product: CCNc1cc2c(cn1)cc(-c1cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc1C)c(=O)n2C
Temperature: 100 °C
Reaction time: 16 h

Procedure:
N-[3-(7-Chloro-1-methyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-3-yl)-4-methyl-phenyl]-3-trifluoromethyl-benzamide (50 mg, 0.106 mmol) is mixed with ethylamine (0.14 mL 70% in water, 2.2 mmol) in a sealed tube. 1 mL of n-butanol is added and the reaction is stirred at 100° C. for 16 hours. After cooling and removal of solvent under vacuum, the crude product is dissolved in DMSO and purified by reverse phase preparative HPLC to give the final product as white solid: 1H NMR 400 MHz (DMSO-d6) δ 10.47 (s, 1H), 8.48 (s, 1H), 8.29 (s, 1H), 8.25 (d, 1H, J=8.0 Hz), 7.96 (d, 1H, J=7.8 Hz), 7.78 (m, 2H), 7.66 (m, 2H), 7.26 (d, 1H, J=9.0 Hz), 6.46 (s, 1H), 3.57 (s, 3H), 3.39 (q, 2H, J=7.1 Hz), 2.13 (s, 3H), 1.22 (t, 3H, J=7.1 Hz); MS m/z 481.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[N:27]1([C:33]([C:35]2[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:40][CH2:39][C:38]1[CH:37]=[CH:36][C:35]([C:33]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:34])=[CH:42][CH:41]=1
Reactant: NCc1ccc(C(=O)N2CCCCC2)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: O=C(c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)N1CCCCC1

Procedure:
Using a method similar to the General Procedure 5-2, react 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (500 mg, 1.17 mmol) with 4-(piperidin-1-ylcarbonyl)-benzylamine (308 mg, 1.41 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (20:1, 10:1, 7:1 and 5:1) to give 7-chloro-6-[4-(piperidine-1-carbonyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:14])=[C:3]([CH:12]=[O:13])[CH2:4][C:5]([O:7]C(C)(C)C)=[O:6].FC(F)(F)C(O)=O.C1CCCCC1>C(Cl)Cl>[CH3:1][C:2]([CH3:14])=[C:3]([CH:12]=[O:13])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: CC(C)=C(C=O)CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(C)=C(C=O)CC(=O)O
Temperature: 5 °C
Reaction time: 3 h
Yield: 64.8 %

Procedure:
A solution of 0.956 g of tert.-butyl 4-methyl-3-formyl-pent-3-enoate in 8.7 ml of methylene chloride was added at 0° to 5° C. to a mixture of 15.5 ml of trifluoroacetic acid and 20 ml of methylene chloride and the mixture was stirred at 5° C. for 3 hours. Cyclohexane was added to the mixture which was then evaporated to dryness under reduced pressure. The residue was empasted with isopropyl ether to obtain 0.444 g of 4-methyl-3-formyl-pent-3-en-1-oic acid melting at 102° C. The mother liquors were chromatographed over silica gel and elution with a 1-1-1 benzene-acetone-chloroform mixture yielded 40 mg of 4-methyl-3-formyl-pent-3-en-1-oic acid melting at 102° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:7][C:6]([CH3:13])=[CH:5][C:4]=1Br.CCCCCC.C([Li])CCC.[CH2:26]([Si:28]([CH2:31]C)(Cl)[Cl:29])C>C(OCC)C>[CH3:1][O:2][C:3]1[C:8]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:7][C:6]([CH3:13])=[CH:5][C:4]=1[Si:28]([Cl:29])([CH3:31])[CH3:26]
Reactant: CC[Si](Cl)(Cl)CC
Reactant: COc1c(Br)cc(C)cc1C(C)(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, 2-methoxy-1-bromo-3-tert-butyl-5-methylbenzene (20.00 g, 77.77 mmol) was dissolved in 200 mL of diethyl ether. A 1.57 M hexane solution of n-butyllithium (59.44 mL, 93.32 mmol) was dropwise added at −50° C. or lower, and a temperature was raised to room temperature, followed by stirring for 1 hour. All the amount of diethyldichlorosilane (24.44 g, 155.54 mmol) was added to the mixture at once at −50° C. or lower, and a temperature was gradually raised to room temperature. After being refluxed for 1 hour, the solution was concentrated under reduced pressure. Hexane was added, the insolubles were filtered off with a Celite filter, and the filtrate was concentrated under reduced pressure. Concentration was further continued at 70° C. under reduced pressure for 3 hours to obtain (2-methoxy-3-tert-butyl-5-methylphenyl)chlorodimethylsilane. Resultant (2-methoxy-3-tert-butyl-5-methylphenyl)chlorodimethylsilane was used in a subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[S:43](=[O:45])(=[O:44])[NH:42][C:41](=[O:46])[CH2:40]2)=[C:35](Br)[CH:34]=1)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:22]=1[C:23]([O:25]C)=[O:24])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:48]1(B(O)O)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1.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>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:32][C:33]1[CH:34]=[C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:36]([CH:39]2[S:43](=[O:45])(=[O:44])[NH:42][C:41](=[O:46])[CH2:40]2)=[CH:37][CH:38]=1)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:22]=1[C:23]([OH:25])=[O:24])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1)NC(=O)OCc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CC(c2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)NCCCCOc3cccc(O)c3C(=O)O)cc2-c2ccccc2)S(=O)(=O)N1
Temperature: 100 °C
Yield: 33.2 %

Procedure:
To a solution of methyl 2-[4-((2S)-2-[(benzyloxy)carbonyl]amino-3-[3-bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoylamino)butoxy]-6-hydroxybenzoate (12.0 mg, 0.0164 mmol) in toluene (0.4 mL) and 1,4-dioxane (0.4 mL) was added phenylboronic acid (2.40 mg, 0.0196 mmol) and 2 M sodium carbonate in water (0.049 mL). The resulting mixture was degassed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.95 mg, 0.82 μmol) was then added to reaction mixture and heated at 100° C. overnight. The reaction mixture was filtered and purified by preparative LCMS to afford a white solid (3.9 mg, 33%). 1H NMR (400 MHz, CD3OD): δ 7.59 (m, 1H), 7.36 (m, 13H), 6.57 (m, 2H), 5.04 (m, 3H), 4.36 (m, 1H), 4.11 (m, 2H), 3.22 (m, 5H), 2.96 (m, 1H),1.78 (m, 2H), 1.59 (m, 2H). LCMS found for C37H378N3O10S (M+H)+: m/z=716.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][OH:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][OH:28])[N:8]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccccn1
Reactant: CCCCc1nc(CO)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(CO)n(Cc2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 49.8 %

Procedure:
A mixture of 4′-{[4-butyl-2-(hydroxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1 g), cesium carbonate (2.1 g), 2-(bromomethyl)pyridine hydrobromide (0.81 g) and N,N-dimethylformamide (10 mL) was stirred at 50° C. for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.62 g, 50%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[CH:16](O)=O>>[CH3:10][O:9][C:6]1[C:7]2[N:8]=[CH:16][NH:1][C:2]=2[C:3]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:4][CH:5]=1
Reactant: COc1ccc(CCN(C)C)c(N)c1N
Reactant: O=CO
Product: COc1ccc(CCN(C)C)c2[nH]cnc12

Procedure:
0.30 g of N-[2-(2,3-diamino-4-methoxyphenyl)ethyl]-N,N-dimethylamine is heated under reflux for 3 hours with 10 ml of formic acid. The solution is filtered and concentrated, thus obtaining 0.23 g of 7-methoxy-4-[2-(N,N-dimethylamino)ethyl]benzimidazole, formate, as a vitreous mass.
Reaction SMILES: [NH2:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[C:21](OC)(OC)(OC)[CH3:22].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C>[CH3:21][C:22]1[O:20][C:19]2[C:2]([N:1]=1)=[CH:3][C:4]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:7][CH2:6][C:5]=1[CH:18]=2
Reactant: COC(C)(OC)OC
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)c(O)cc2CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: Cc1nc2cc3c(cc2o1)CCN(C(=O)OC(C)(C)C)CC3
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl 7-amino-8-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (1.7 g) and trimethyl orthoacetate (1.2 ml) in the presence of pyridinium para-toluenesulfonate (0.16 g) were heated in dry DMF (20 ml) for 90 min at 70° C. followed by 2 h at 105° C. Volatiles were evaporated under reduced pressure to give the title compound which was used without further purification.
Reaction SMILES: OO.[C:3]([O:8][CH2:9][CH3:10])(=[O:7])[C:4]([CH3:6])=O.[C:11]([C:14]1C=C[N:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12].S(=O)(=O)(O)O>O.ClCCl>[C:11]([C:14]1[CH:15]=[CH:16][N:17]=[C:4]([C:3]([O:8][CH2:9][CH3:10])=[O:7])[CH:6]=1)(=[O:13])[CH3:12]
Reactant: CCOC(=O)C(C)=O
Reactant: CC(=O)c1ccncc1
Agent: O=S(=O)(O)O
Agent: OO
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc(C(C)=O)ccn1
Yield: 24.2 %

Procedure:
30% Hydrogen peroxide (130 ml) was added to ethyl pyruvate (216 g) at -5° to 5° C. with stirring. This solution was then added to a mixture of 4-acetylpyridine (15.0 g), concentrated sulfuric acid (12.4 g), ferrous sulfate heptahydrate (345 g), dichloromethane (1.5 l) and water (100 ml) at the same temperature with stirring. After further stirring for 30 minutes, the resulting organic layer was separated. The solution was washed with aqueous sodium sulfite and then water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography by eluting with a mixture of ethyl acetate and toluene (1:20) to give ethyl 4-acetyl-2-pyridinecarboxylate (5.79 g).
Reaction SMILES: [N:1]1[S:2](=[O:15])(=[O:14])[CH2:3][CH2:4][N:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([OH:13])=O)[C:6]=12.[CH:16]1([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)[CH2:18][CH2:17]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:16]1([C:19]2[CH:25]=[CH:24][C:22]([NH:23][C:11]([C:7]3[C:6]4=[N:1][S:2](=[O:15])(=[O:14])[CH2:3][CH2:4][N:5]4[CH:10]=[CH:9][CH:8]=3)=[O:13])=[CH:21][CH:20]=2)[CH2:18][CH2:17]1
Reactant: Nc1ccc(C2CC2)cc1
Reactant: O=C(O)C1=CC=CN2CCS(=O)(=O)N=C12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C2CC2)cc1)C1=CC=CN2CCS(=O)(=O)N=C12
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
3,4-Dihydropyrido[2,1-c][1,2,4]thiadiazine-9-carboxylic acid 2,2-dioxide (150 mg) was dissolved in DMF (5 ml), 4-cyclopropylaniline (131 mg), HOBt (151 mg), EDCI HCl (189 mg) and DIEA (0.23 mL) were added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was suspended in ethyl acetate, and insoluble crystals were collected by filtration to give the title compound (168 mg) as pale-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([NH:21][CH2:22][C@H:23]([NH:28][S:29]([C:32]4[C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH:35]=[CH:34][CH:33]=4)(=[O:31])=[O:30])[C:24]([O:26]C)=[O:25])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[N:11]2)[N:3]=1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([NH:21][CH2:22][C@H:23]([NH:28][S:29]([C:32]4[C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH:35]=[CH:34][CH:33]=4)(=[O:30])=[O:31])[C:24]([OH:26])=[O:25])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[N:11]2)[N:3]=1
Reactant: COC(=O)[C@H](CNC(=O)c1ccc2c(cnn2Cc2cc(=O)[nH]c(N)n2)c1)NS(=O)(=O)c1cccc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc(Cn2ncc3cc(C(=O)NC[C@H](NS(=O)(=O)c4cccc5ccccc45)C(=O)O)ccc32)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
Methyl 3-[1-[2-amino-4-oxopyrimidin-6-ylmethyl]-indazol-5-yl-carbonylamino]-2(S) -(1-naphthalenesulfonylamino)propionate. A mixture of the product prepared according to Example E-24 Part F (85 mg, 298 μmol) and the product prepared according to Example E-24 Part H (113 mg, 328 μmol) in N,N-dimethylformamide (3 mL) was treated sequentially with triethylamine (52 μL, 373 μmol), 1-hydroxybenzotriazole hydrate (40 mg, 298 μmol) and dicyclohexylcarbodiimide (68 mg, 328 μmol). The mixture was stirred at room temperature for 24 h and concentrated. The residue was purified by flash chromatography (dichloromethane-methanol, 97:3 then 9:1) to provide the title product (154 mg, 89%) as a gum: 1H NMR (MeOH-d4) d 8.64 (d, 1H), 8.15 (s, 2H), 7.92 (d, 1H), 7.89 (s, 1H), 7.71 (d, 1H), 7.6-7.3 (4H), 5.35 (s, 2H), 5.03 (s, 1H), 4.20 (dd, 1H), 3.64 (dd, 1H), 3.46 (dd, 1H); ester methyl signal obscured by residual MeOH signal.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:18]1([CH2:24][CH2:25][CH:26]=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[C:18]1([CH2:24][CH2:25][CH2:26][N:2]2[CH2:3][CH2:4][CH:5]([O:8][C:9]3[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=3)[CH2:6][CH2:7]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=CCCc1ccccc1
Reactant: NC(=O)c1ccc(OC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Product: NC(=O)c1ccc(OC2CCN(CCCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
Combine 4-(piperidin-4-yloxy)-benzamide hydrochloride (102 mg, 0.397 mmol), 3-phenyl-propionaldehyde (106 μL, 0.796 mmol) and triacetoxy-borohydride (127 mg, 0.597 mmol) in CH2Cl2 (3 mL). Stir the reaction mixture at room temperature overnight. Dilute the reaction mixture with CH2Cl2 (3 mL) and wash with sodium hydroxide (1N, aq. 5 mL). Separate the organic layer and placed onto an SCX column directly eluting with ammonia (2.0 in methanol). The resulting residue was triturated with CH2Cl2 and diethyl ether to provide the title compound (63 mg, 47%) as a white solid. mass spectrum (ion spray): m/z=339.1 (M+1); 1H NMR (CDCl3): 7.79 (ad, J=9.0 Hz, 3H), 7.28–7.12 (m, 6H), 6.95 (d, J=9.0 Hz, 2H), 4.74–4.40 (m, 1H), 2.70–2.63 (bm, 2H), 2.56 (t, J=7.6 Hz, 2H), 2.31–2.25 (bm, 2H), 2.22–2.15 (bm, 2H), 1.96–1.89 (bm, 2H), 1.71 (pentet, J=7.3 Hz, 2H), 1.63–1.56 (m, 2H).