Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]2[CH:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][CH:7]3[NH:8][C:9]=2[CH:10]=1.[H-].[Na+].[CH3:19][C:20]1([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:22][O:21]1>CN(C=O)C>[Cl:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[N:8]([CH2:19][C:20]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)([OH:21])[CH3:22])[C:9]=2[CH:10]=1
Reactant: CC1(c2ccncc2)CO1
Reactant: CN1CCC2Nc3cc(Cl)c(Cl)cc3C2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(Cl)c(Cl)cc3n2CC(C)(O)c2ccncc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A flask was charged with 7,8-dichloro-2-methyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (1 g, 3.9 mmol) in DMF (10 mL) and stirred for 5 min. To this was added NaH (60% in hexane) (470 mg, 11.7 mmol) and the mixture stirred at RT for 10 min. 4-(2-Methyloxiran-2-yl)pyridine (795 mg, 5.8 mmol) was added and the mixture stirred at RT for 16 h. The progress of reaction was monitored by TLC. The reaction mixture was poured into ice water and filtered. The filtrate was washed with water and concentrated. The residue was recrystallized from ether to get pure product. 1H NMR (CD3OD, formate salt) δ (ppm): 8.38 (d, 2H), 7.56 (s, 1H), 7.48 (d, 2H), 7.30 (s, 1H), 4.60 (m, 2H), 4.30 (m, 2H), 3.58 (m, 1H), 3.50 (m, 1H), 3.35 (m, 1H), 3.10 (m, 1H), 3.0 (s, 3H), 1.70 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([OH:29])[C:19]=2[C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])[N:6]=1.[Cl:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[N:34]=[C:33](S(C)(=O)=O)[N:32]=1.O>C1COCC1>[Cl:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[N:34]=[C:33]([O:29][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([O:13][C:7]3[N:6]=[C:5]([O:4][CH3:3])[CH:10]=[C:9]([O:11][CH3:12])[N:8]=3)[C:19]=2[C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])=[O:21])[N:32]=1
Reactant: COc1cc(Cl)nc(S(C)(=O)=O)n1
Reactant: COc1cc(OC)nc(Oc2cccc(O)c2C(=O)OCC[Si](C)(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)nc(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)OCC[Si](C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (0.4 g, purity: 60%) was suspended in 50 ml of THF. To this suspension, trimethylsilylethyl 6-(4,6-dimethoxypyrimidin-2-yl)oxysalicylate (3.0 g) was added, and the mixture was stirred at room temperature for 30 minutes. To this mixture, 4-chloro-6-methoxy-2-methylsulfonylpyrimidine (1.8 g) was added, and the mixture was stirred at room temperature for further 12 hours. After completion of the reaction, water was added thereto, and the mixture was extracted with ethyl ether. The ethyl ether layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The crude extract thus obtained was purified by silica gel column chromatography to obtain the above identified compound as a slightly yellow liquid (4.0 g).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([C:17]([O:19][CH3:20])=[O:18])=[N:12][CH:11]=[C:10]([OH:21])[C:9]=3[C:8]2=[O:22])=[CH:4][CH:3]=1.[OH:25]O>C(O)(=O)C>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([OH:21])[CH:11]=[N+:12]([O-:25])[C:13]=3[C:17]([O:19][CH3:20])=[O:18])[C:8]2=[O:22])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)cc1)C2=O
Reactant: OO
Solvent: CC(=O)O
Product: COC(=O)c1c2c(c(O)c[n+]1[O-])C(=O)N(Cc1ccc(F)cc1)CC2
Temperature: 100 °C

Procedure:
To a solution of methyl 6-(4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (0.509 g, 1.541 mmol) in acetic acid (2 mL) was added hydrogen peroxide (35% wt % in H2O, 0.262 g, 7.705 mmol). The reaction mixture was heated to 100° C. for 1 hour. The product mixture was concentrated under vacuum and purified by reverse phase HPLC eluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to afford the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]2[CH:19]=[O:20])=[CH:5][CH:4]=1.[BH4-].[Na+]>C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]2[CH2:19][OH:20])=[CH:21][CH:22]=1
Reactant: COc1ccc(Cn2cc(-c3ccccc3)nc2C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(Cn2cc(-c3ccccc3)nc2CO)cc1
Yield: 96 %

Procedure:
Treat a solution of 1-(4-methoxybenzyl)-2-formyl-4-phenylimidazole (1.75 g, 5.99 mmol) in CH2Cl2/MeOH (1:1, 60 mL) with NaBH4 (480 mg, 12.7 mmol) at room temperature for 15 minutes. Quench with H2O (50 mL), extract with CH2Cl2 (2×100 mL), dry (Na2SO4), and concentrate in vacuo. Purify the residue by flash chromatography (SiO2, CH2Cl2/MeOH 20:1→7:1) to provide 1.69 g (96% yield). MS(ES+): m/z=295 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Br:10][CH2:11][C:12](Br)=[O:13].C(N(CC)CC)C>C(OCC)(=O)C>[Br:10][CH2:11][C:12]([NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: NCc1ccc(F)cc1
Reactant: O=C(Br)CBr
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CBr)NCc1ccc(F)cc1

Procedure:
Commercially available 4-fluorobenzylamine (500 mg, 3.99 mmol) was reacted with bromoacetyl bromide (380 μl, 4.39 mmol) in presence of triethylamine (600 μl, 4.39 mmol) at room temperature for 20 min. The progress of the reaction was monitored by a faster moving spot in silica TLC (60% ethyl acetate in hexanes). At the end of the reaction, the mixture was filtered, and the solvent was dried to obtain 2-bromo-N-[4-fluorobenzyl]acetamide. Potassium iodide (166 mg, 1 mmol) and Cs2CO3 (325 mg, 1 mmol) and 2-bromo-N-(4-fluorobenzyl)acetamide (270 mg, 1.20 mmol) were added to the compound 1 (311 mg, 1 mmol) in DMF (2 ml). The reaction mixture was heated at 95° C. for 60 min. The solvent was evaporated to dryness, and the residue was dissolved in chloroform. After brine and water wash, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain a crude yellow solid. The crude compound was recrystallized from chloroform and hexanes to get the title compound 23 as a yellow crystalline solid (252 mg, 53% yield). 1H NMR (300 MHz, CDCl3): 7.93 (s, 1H), 7.83 (s, 2H, C═CH), 7.75-7.02 (m, 8H, Ar—H), 6.97 (dd, 2H, Ar—H, J=7.2, 2.1), 6.68 (t, 2H, Ar—H, J=7.2), 4.19 (s, 2H, benzylic), 4.17 (s, 2H, benzylic), 3.76 (s, 4H). ESI Mass calculated for C28H23F3N2NaO2(M+Na)+499.16. found 499.91.
Reaction SMILES: [CH3:1][N:2]([C@@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4].C(N(CC)CC)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[CH2:40][C:41](O)=[O:42].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[CH2:40][C:41]([N:13]1[CH2:14][CH2:15][CH:10]([C:7]2[S:8][CH:9]=[C:5]([C:3]([N:2]([CH3:1])[C@@H:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:17][CH3:18])=[O:4])[N:6]=2)[CH2:11][CH2:12]1)=[O:42]
Reactant: O=C(O)Cc1cc(Cl)ccc1Cl
Reactant: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCNCC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCN(C(=O)Cc3cc(Cl)ccc3Cl)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Methyl-N-[(1R)-1-phenylpropyl]-2-(4-piperidinyl)-4-thiazolecarboxamide (i.e. the product of Example 1, Step E) (171 mg, 0.5 mmol) was dissolved in 3 mL of dry dichloromethane. To this was added triethylamine (35 μL, 0.25 mmol), 2,5-dichlorobenzeneacetic acid (102 mg, 0.5 mmol) (i.e. the product of Example 3, Step A), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg, 0.56 mmol) and a catalytic amount of 4-(dimethylamino)pyridine (˜1 mg). The mixture was shaken overnight at ambient temperature, diluted with dichloromethane, washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate to give 170 mg of the title product, a compound of the present invention as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:6][N:7]([CH3:29])[C:8](=[O:28])[C@@H:9]([N:17]([CH2:25][CH:26]=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.[NH:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]([CH2:47][C@H:48]([NH2:53])[CH2:49][C:50]([OH:52])=[O:51])=[CH:39]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:6][N:7]([CH3:29])[C:8](=[O:28])[C@@H:9]([N:17]([CH2:25][CH2:26][NH:53][C@H:48]([CH2:49][C:50]([OH:52])=[O:51])[CH2:47][C:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[NH:38][CH:39]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1cc(CN(C)C(=O)[C@H](Cc2ccccc2)N(CC=O)C(=O)OC(C)(C)C)cc(OC)c1OC
Reactant: N[C@H](CC(=O)O)Cc1c[nH]c2ccccc12
Agent: Cl
Product: COc1cc(CN(C)C(=O)[C@H](Cc2ccccc2)N(CCN[C@H](CC(=O)O)Cc2c[nH]c3ccccc23)C(=O)OC(C)(C)C)cc(OC)c1OC

Procedure:
Prepare by the method of Example 1 using (S)-N-(3,4,5-trimethoxybenzyl)-N-methyl-2-[N'-(t-butoxycarbonyl)-2-oxo-ethylamino]-3-phenyl-propionamide (0.25 g, 1.0 mmol) and (S)-2-(1H-indol-3-yl)-1-carboxymethyl-ethylamine hydrochloride salt ((S)-tryptophan methyl ester hydrochloride salt) (0.41 g, 1.0 mmol). Purify by chromatography eluting sequentially with 1% methanol/dichloromethane and 5% methanol/dichloromethane to give the title compound: TLC Rf =0.83 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[NH2:29][C@H:30]([CH:33]([CH3:35])[CH3:34])[CH2:31][OH:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:32][CH2:31][C@H:30]([NH:29][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:20][CH:21]=1)[CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)[C@@H](N)CO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N[C@@H](CO)C(C)C)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with (R)-2-amino-3-methylbutan-1-ol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=461.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:25])[C:9]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])([OH:16])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:4][CH:3]=1.[C:26](Cl)(=O)[O:27]C1C=CC=CC=1.C(=O)([O-])O.[Na+].C(Cl)Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:25][C:26](=[O:27])[O:16][C:9]2([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1OC(c2ccc(Cl)cc2)C(Cn2cncn2)(c2ccc(Cl)cc2Cl)O1
Yield: 87.5 %

Procedure:
To a solution of 500 mg of 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol in 1 ml of dry pyridine is added 300 mg of phenyl chlorocarbonate, and the resultant mixture is allowed to react at room temperature for 18 hours. The reaction mixture is mixed with aqueous sodium hydrogencarbonate solution and shaken with methylene chloride. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica-gel, which is eluted with 2% methanolmethylene chloride. The eluate is concentrated and the residue is crystallized from ethyl acetate-isopropyl ether to give 466 mg of 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-2-oxo-4-(1H-1,2,4-triazol-1-yl)methyl-1,3-dioxolane as crystals melting at 178° to 179° C. The yield is 87%.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22](Br)=[C:21]([CH2:24][CH2:25][O:26][C:27]([F:30])([F:29])[F:28])[N:20]=[C:19]([C:31]([CH3:34])([CH3:33])[CH3:32])[N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CC(=O)OCC.[Pd]>[C:31]([C:19]1[N:18]=[C:17]([N:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[CH:22]=[C:21]([CH2:24][CH2:25][O:26][C:27]([F:29])([F:30])[F:28])[N:20]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)c1nc(CCOC(F)(F)F)c(Br)c(N2CCN(C(=O)OCc3ccccc3)CC2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nc(CCOC(F)(F)F)cc(N2CCNCC2)n1
Reaction time: 0.67 h

Procedure:
To the solution of 4-[5-bromo-2-tert-butyl-6-(2-trifluoromethoxy-ethyl)-pyrimidin-4-yl]-piperazine-1-carboxylic acid benzyl ester (26 mg, 0.048 mmol) in EA (3 mL) was added Pd/C (10.15 mg). Then the mixture was stirred for 40 min under H2 (15 psi) atmosphere. Then the mixture was concentrated and the residue was used in the next step directly.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](I)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[N:6]2[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].CN(C)C=O.[CH2:31]([C:33]1([OH:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[CH3:32]>[Cu]I.C(N(CC)CC)C>[NH2:1][C:2]1[N:10]=[C:9]([C:32]#[C:31][C:33]2([OH:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[N:6]2[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: CCC1(O)CCCCC1
Reactant: COC(=O)CCCn1c(-c2cccc(F)c2)nc2c(N)nc(I)nc21
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCCn1c(-c2cccc(F)c2)nc2c(N)nc(C#CC3(O)CCCCC3)nc21
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 89.6 %

Procedure:
To 162 mg of methyl 4-[6-amino-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl]butanoate were added 8 ml of N,N-dimethylformamide, 30 mg of copper(I) iodide, 30 mg of dichlorobis(triphenylphosphine)palladium(II)l, 80 mg of 1-ethylcyclohexanol and 74 μl of triethylamine and the mixutre was stirred in a nitrogen stream at 70° C. for 2.5 hours. After it was allowed to cool, the solvent was evaporated and the resulting reside was subjected to a silica gel column chromatography (25 g of silica gel; chloroform-methanol (100:0-100:1-50:1) to give 144 mg of the title compound. The yield was 90%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].F[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[S:19]([OH:21])=[O:20].[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[S:19]([OH:21])=[O:20]
Reactant: Sc1ccccc1Br
Reactant: O=C(O)c1ccc(F)c(S(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(Sc2ccccc2Br)c(S(=O)O)c1
Temperature: 140 °C

Procedure:
2-Bromobenzenethiol (25 g, 132 mmol) was added to a solution of 4-fluoro-3-sulfino-benzoic acid (13.5 g, 66 mmol) and NaOH pellets (11 g, 264 mmol) in water (30 ml). The yellow mixture was then degassed for 10 minutes and then heated to 140° C. for 48 hours. The reaction was then cooled to 0° C. and acidified to pH 4-5 (pH paper) with concentrated HCl. The precipitate formed was filtered, washed with hexane and was dried in a vacuum dessicator over activated silica overnight (20.69 g, 84%). m/z (LC-MS, ESP), RT=3.67 min, M−−1)=373.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:13](=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=2)[CH3:10])[C:5]([C:36]#[N:37])=[CH:4][N:3]=1.C(=N[OH:41])C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:13](=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:26]=[N:25][C:24]([O:27][CH3:28])=[N:23][CH:22]=2)[CH3:10])[C:5]([C:36]([NH2:37])=[O:41])=[CH:4][N:3]=1
Reactant: CC=NO
Reactant: COc1ncc(-c2cccc3cc([C@H](C)Nc4nc(N)ncc4C#N)n(-c4ccccc4)c(=O)c23)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ncc(-c2cccc3cc([C@H](C)Nc4nc(N)ncc4C(N)=O)n(-c4ccccc4)c(=O)c23)cn1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-2-amino-4-((1-(8-(2-methoxypyrimidin-5-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carbonitrile 5 (34 mg, 0.070 mmol) in anhydrous toluene (4 mL) under argon, acetaldoxime (13 μL, 0.21 mmol), palladium(II) acetate (5 mg, 0.01 mmol) and triphenyl phosphine (5 mg, 0.017 mmol) were added and the resulting mixture was stirred at 80° C. for 3 h. The mixture was allowed to cool to RT and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried with Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO column chromatography (silica gel cartridge, 0-10% MeOH/DCM) to afford the product, (S)-2-amino-4-((1-(8-(2-methoxypyrimidin-5-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carboxamide 11. ESI-MS m/z: 509.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1[CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH3:18][N:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=[N:20]1>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:7][C:6]1[S:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[C:23]1[N:19]([CH3:18])[N:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1cc(Br)c(C)s1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccnn2C)c(C)s1

Procedure:
A solution of methyl 4-bromo-5-methyl-2-thiophenecarboxylate (2 g, 8.51 mmol)[prepared in Preparation 10], potassium carbonate (5.88 g, 42.5 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.12 g, 10.21 mmol)[prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (0.22 g, 0.43 mmol) in 1,4-Dioxane (35 ml) and H2O (7 ml) was stirred at 80° C. in a sealed tube for 1 h. The reaction mixture was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 25% EtOAc in hexanes) affording methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate. This reaction was run in several batches (1 g, 3×2 g) which were combined for workup and purification affording the title compound (5.5 g, 78% combined yield) as a viscous yellow oil: LC-MS (ES) m/e 236 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]=1[CH3:14].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[C:9]2[C:10](=[O:15])[CH2:11][CH2:12][C:13]=2[CH3:14])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1=C(c2cc(C)ccc2N)C(=O)CC1
Solvent: c1ccncc1
Product: CC1=C(c2cc(C)ccc2NS(=O)(=O)c2ccc(C)cc2)C(=O)CC1

Procedure:
0.600 g (2.79 mmol) of 2-(2-amino-5-methylphenyl)-3-methyl-2-cyclopenten-1-one, 0.243 g (3.07 mmol) f pyridine, 0.858 g (3.07 mmol) of p-toluenesulfonyl chloride, and 3 mL of M.C were loaded to a 20 mL vial, and then reacted for 12 hours. The work-up was the same as in Example 7 (0.800 g, 78%).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[C:16]([F:23])[CH:15]=1.O.Cl>O1CCOCC1>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:12][S:9]([CH:8]=[CH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:11])=[O:19])=[C:16]([F:23])[CH:15]=1
Reactant: NS(=O)(=O)C=Cc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(NS(=O)(=O)C=Cc1ccccc1)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a solution of 2-phenyl-ethenesulfonic acid amide (500 mg, 2.7 mmol) in dioxane (25 ml) sodium hydride (197 mg, 55% dispersion in mineral oil) were added and the mixture was stirred at room temperature for 30 minutes. 4-Chloro-2-fluoro-benzoyl chloride (527 mg, 2.7 mmol) were added and the mixture was stirred at room temperature overnight. After addition of water (50 ml) the pH was adjusted to 7 with 1 N HCl and the mixture was extracted with ethyl acetate (3 times 50 ml). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Preparative HPLC (RP18, methanol-water-gradient) returned the title compound (730 mg, 79% yield) as a white solid.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[F:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>O1CCCC1>[F:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][CH:1]=[O:3]
Reactant: O=CO
Reactant: Nc1ccccc1F
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=CNc1ccccc1F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Under argon gas, at 0° C., formic acid (6.1 ml) was dropped to acetic anhydride (15.5 ml), which was stirred at 50° C. for 2 hours. The reaction solution was left up to room temperature, and diluted with tetrahydrofuran (10 ml). At room temperature, tetrahydrofuran (20 ml) solution containing 2-fluoroaniline (5.56 g) added to the above solution, which was stirred at room temperature for 1 hour. The reaction solution was concentrated to give a title compound having the following physical properties. The obtained title compound was used for the following reaction without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[N+:9]([C:12]1[CH:13]=[C:14]([N:18]=[C:19]=[O:20])[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10]>CN(C=O)C>[CH3:1][N:2]1[CH2:3][C:4](=[O:5])[NH:6][C:7]1=[N:8][C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=1)=[O:20]
Reactant: CN1CC(=O)N=C1N
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1cccc([N+](=O)[O-])c1
Reaction time: 9 h

Procedure:
To a stirred slurry of 12.45 g (0.11mole) of creatinine in 100 ml of dry DMF is added 16.41 g (0.1 mole) of m-nitrophenyl isocyanate (previously recrystallized from benzene-pentane). After nine hours, ice water is gradually added until crystallization occurres. A large excess of ice water precipitates the product as gummy crystals which then crystallize. The crude product is allowed to air dry for several days. Recrystallization from THF-H2O followed by THF gives pure product, 1-(1-methyl-4-oxo-2-imidazolidinylidene)-3-m-nitrophenyl urea; m.p. 182°-188° C. sl. dec.