Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=[N+:2]=[N-:3].[CH3:16][C@H:17]1[C:25]2[C:24]([C:26]3[S:30][C:29]([C:31](O)=[O:32])=[CH:28][CH:27]=3)=[N:23][CH:22]=[N:21][C:20]=2[CH2:19][CH2:18]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:1]([CH2:4][C@@H:5]([NH:15][C:31]([C:29]1[S:30][C:26]([C:24]2[C:25]3[C@H:17]([CH3:16])[CH2:18][CH2:19][C:20]=3[N:21]=[CH:22][N:23]=2)=[CH:27][CH:28]=1)=[O:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC[C@@H](N)Cc1ccc(Cl)cc1Cl
Reactant: C[C@@H]1CCc2ncnc(-c3ccc(C(=O)O)s3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(-c3ccc(C(=O)N[C@H](CN=[N+]=[N-])Cc4ccc(Cl)cc4Cl)s3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
(S)-1-Azido-3-(2,4-dichlorophenyl)propan-2-amine (33 mg, 0.134 mmol) was added to a solution of (R)-5-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylic acid (35 mg, 0.134 mmol) in DCM (0.7 mL). HBTU (56 mg, 0.148 mmol) was added, followed by DIPEA (0.23 mL, 1.34 mmol). The reaction mixture was stirred at room temperature for 1 hour. LC-MS of the reaction mixture showed no more starting material. The solvent was removed, and the resulting residue was purified on silica gel (0%-50% EtOAc/hexanes) gradient elution to yield N-((S)-1-azido-3-(2,4-dichlorophenyl)propan-2-yl)-5-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide as an oil (59 mg, 90%). m/z 486 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]2[C:17](=O)NC(=O)NC2=O)=[CH:6][CH:5]=1)[CH3:2].Cl.ClC1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.[OH-].[Na+].Cl>O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:17]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: Clc1ccncc1
Reactant: CCOc1ccc(CCC2C(=O)NC(=O)NC2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1ccc(CCCc2ccncc2)cc1
Reaction time: 0.29 h

Procedure:
A mixture of 6.5 g (0.0235 m) of 5-[2-(4-ethoxyphenyl)ethyl]barbituric acid and 7 g (0.047 m) of 4-chloropyridine hydrochloride was mixed with a mortar and pestle and heated in an oil bath until the reagents formed a melt (185° C.). The mixture was kept at 180°-185° for 15-20 minutes, when the mixture began to noticeably darken. When heat was removed, the mixture quickly formed a hard glass. To this product, 6.5 g of NaOH pellets and 40 mL of water was added, and the mixture was refluxed for 5-6 hours. After cooling, the mixture was acidified with concentrated HCl and refluxed for 11/2 hours. The mixture was then diluted over ice, and the pH was adjusted to neutral using dilute NaOH. The product was then extracted into CH2Cl2. The CH2Cl2 layer was separated, dried, adsorbed onto silica gel, and chromatographed using CH2Cl2 >50% EtOAc/CH2Cl2. The product was an oil which crystallized. Yield 0.5 g. MP 79°-81° C.
Reaction SMILES: C([N:8]1[CH2:39][CH2:38][C:11]2[N:12]=[C:13]([C:18]3[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][N:22]4[S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[N:14]=[C:15]([O:16][CH3:17])[C:10]=2[CH2:9]1)C1C=CC=CC=1.[H][H]>O.C(O)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:17][O:16][C:15]1[C:10]2[CH2:9][NH:8][CH2:39][CH2:38][C:11]=2[N:12]=[C:13]([C:18]2[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]3[C:19]=2[CH:20]=[N:21][N:22]3[S:28]([C:31]2[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[N:14]=1
Reactant: [H][H]
Reactant: COc1nc(-c2c(C)ccc3c2cnn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1nc(-c2c(C)ccc3c2cnn3S(=O)(=O)c2ccc(C)cc2)nc2c1CNCC2

Procedure:
A mixture of 6-benzyl-4-methoxy-2-(5-methyl-1-tosyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (1.85 g, 3.43 mmol) and Pd(OH)2 on carbon (wet) (10%, 0.722 g, 1.03 mmol) in water (7.5 mL) and acetic acid (0.59 mL) was stirred under 1 atm of hydrogen at room temperature for 2.5 h. The reaction mixture was filtered through Celite® and the solids were washed with EtOAc. The combined filtrates were washed with saturated NaHCO3 solution. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (0-10% MeOH (10% NH4OH)/DCM) to provide 4-methoxy-2-(5-methyl-1-tosyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 450.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([CH2:21][CH3:22])[C:11](=O)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([CH2:30][NH:31][NH2:32])=[CH:28][CH:27]=1.C([O-])(=O)C.[Na+].C(O)(=O)C>CC(O)C>[CH2:1]([O:8][N:9]=[C:10]([CH2:21][CH3:22])[C:11](=[N:32][NH:31][CH2:30][C:29]1[CH:33]=[CH:34][C:26]([O:25][CH3:24])=[CH:27][CH:28]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CNN)cc1
Reactant: CCC(=NOCc1ccccc1)C(=O)C(=O)N1CCOCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CCC(=NOCc1ccccc1)C(=NNCc1ccc(OC)cc1)C(=O)N1CCOCC1
Yield: 82.2 %

Procedure:
1.0 g (3.3 mmol) of 4-(3-benzyloxyimino-2-oxovaleryl)morpholine was dissolved in 20 ml of 2-propanol and 1.24 g (6.6 mmol) of 4-methoxybenzylhydrazine hydrochloride, 1.08 g (13.2 mmol) of sodium acetate and 1 ml of acetic acid were added and the mixture was refluxed for 15 hours. After distilling the solvent off under reduced pressure, 20 ml of water was added and the mixture was extracted three times with 30 ml of diethylether. After washing with 1N aqueous hydrochloric acid, water, a saturated aqueous sodium bicarbonate, water and then a saturated aqueous sodium chloride followed by drying over with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a residue, which was purified by a column chromatography on a silica gel (n-hexane/ethyl acetate) to obtain 1.19 g (yield: 83%) of 4-(3-benzyloxyimino-2-(4-methoxybenzylhydrazono)valeryl)morpholine as a yellow oil.
Reaction SMILES: C(C1C=C(S[C:12]([S:15][C:16]2[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([O:26][CH2:27][C@H:28]3[C@H:32]([CH2:33][O:34][CH3:35])[O:31]C(OCC)[O:29]3)=[C:18]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:17]=2)([CH3:14])[CH3:13])C=C(C(C)(C)C)C=1O)(C)(C)C.[C:48]([OH:51])(=O)[CH3:49]>CO.O>[C:39]([C:18]1[CH:17]=[C:16]([SH:15]([CH:12]([CH3:13])[CH3:14])[S:15][C:16]2[CH:21]=[C:49]([C:22]([CH3:20])([CH3:23])[CH3:24])[C:48]([OH:51])=[C:18]([C:39]([CH3:42])([CH3:40])[CH3:41])[CH:17]=2)[CH:21]=[C:20]([C:22]([CH3:24])([CH3:25])[CH3:23])[C:19]=1[O:26][CH2:27][C@H:28]([OH:29])[C@@H:32]([OH:31])[CH2:33][O:34][CH3:35])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(=O)O
Reactant: CCOC1O[C@@H](COC)[C@H](COc2c(C(C)(C)C)cc(SC(C)(C)Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cc2C(C)(C)C)O1
Solvent: CO
Solvent: O
Product: COC[C@H](O)[C@@H](O)COc1c(C(C)(C)C)cc([SH](Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(C)C)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
2,6-Di-tert-butyl-4-{1-[3,5-di-tert-butyl-4-(2-ethoxy-5(s)-methoxymethyl-[1,3]dioxolan-4(S)-ylmethoxy)-phenylsulfanyl]-1-methyl-ethylsulfanyl}-phenol (Ex-15A, 0.72 g, 1.1 mmol) was dissolved in methanol (3 mL). Acetic acid (0.14 mL) and water (0.14 mL) were added and the resultant mixture was stirred at reflux for 3 h. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over sodium sulfate and concentrated to an off-white foam. The residue was dissolved in methanol (3 mL) and potassium carbonate (0.085 g) was added. The mixture was stirred at room temperature for 30 min and diluted with water (10 mL). The solution was extracted with dichloromethane (3×10 mL), dried over sodium sulfate, and concentrated to a white foam. Silica gel chromatography (3:1 ethyl acetate: hexanes) gave 0.18 g (99%) of 1-{2,6-di-tert-butyl-4-[1-(3,5-di-tert-butyl-4-hydroxyphenylsulfanyl)-1-methylethylsulfanyl]phenoxy}-4-methoxybutane-2(S),3(S)-diol as a white solid, mp 62–64° C. 1H-NMR (CDCl3) δ 7.55 (s, 2H), 7.45 (s, 2H), 5.36 (s, 1H), 4.25–4.26 (m, 1H), 3.86–3.90 (m, 3H), 3.59–3.61 (m, 2H), 3.41 (s, 3H), 2.79 (d, 1H, J=4.8 Hz), 2.63 (d, 1H, J=4.8 Hz), 1.42–1.45 (m, 42H). HRMS (ESI) calcd for C36H58O5S2 (M+Na), 657.3624; Found, 657.3630. Anal. calcd. for C36H58O5S2: C, 68.10, H, 9.21, S, 10.10; Found: C, 68.47, H, 9.38, S, 9.85.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[NH:4][CH:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:10][CH:9]=1)[C:6]#N.O=[CH:24][C:25](=C)[CH3:26]>>[F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[N:4]1[CH:24]=[C:25]([CH3:26])[CH:6]=[C:5]1[C:8]1[CH:13]=[CH:12][C:11]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:10][CH:9]=1
Reactant: C=C(C)C=O
Reactant: N#CC(Nc1ccc(F)cc1F)c1ccc(S(N)(=O)=O)cc1
Product: Cc1cc(-c2ccc(S(N)(=O)=O)cc2)n(-c2ccc(F)cc2F)c1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(2,4-difluoroanilino)-α-(4-sulfamoylphenyl)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a white powder (yield 63%), melting at 140-141° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:13][NH2:14])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[Br:22][CH:23]([CH3:27])[C:24](O)=[O:25].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[Cl:2][C:3]1[C:4]([CH2:13][NH:14][C:24](=[O:25])[CH:23]([Br:22])[CH3:27])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Reactant: CC(Br)C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)NCc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (3-chloro-5-trifluoromethyl-2-pyridyl)methylamine hydrochloride (1.0 g) in tetrahydrofuran (5 ml) and triethylamine (0.41 g) which had been stirred at room temperature for 30 minutes, was added a mixture of 2-bromopropionic acid (0.62 g) and carbonyldiimidazole (0.65 g) in tetrahydrofuran (5 ml) which had also been stirred at room temperature for 30 minutes. The combined mixture was stirred at room temperature for 12 hours and then the solvent was removed. The residue was partitioned between diethyl ether and water and the layers separated. The organic phase was dried (MgSO4) and the solvent removed to give the title product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.Cl.[CH:16]1([C:19]2[CH:20]=[C:21]([CH3:31])[C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:23][CH:24]=2)[CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:29][CH2:30][N:25]([C:22]3[C:21]([CH3:31])=[CH:20][C:19]([CH:16]4[CH2:17][CH2:18]4)=[CH:24][N:23]=3)[CH2:26][CH2:27]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2S(C)(=O)=O)CC1
Yield: 94.1 %

Procedure:
Using 4-bromo-2-methanesulfonylbenzoic acid (558 mg) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (508 mg) described in Preparation Example 82 and by the reaction and treatment in the same manner as in Preparation Example 119, the title compound (0.9 g) was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11])=[O:2].[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:2]
Reactant: O=Cc1ccccc1CC(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)Cc1ccccc1C=O
Yield: 18652 %

Procedure:
24.0 g (0.15 mole) of 2-formylphenylacetic acid and 0.1 g of p-toluenesulfonic acid in 250 ml of methanol are refluxed for 2 hours. Thereafter, the solution is evaporated down, the residue is taken up in diethyl ether and the solution is washed with dilute HCl. The organic phase is separated off, dried over MgSO4 and evaporated down. The residue is purified by distillation (90° C., 0.4 mbar). 19.3 g (74%) of methyl 2-formylphenylacetate are obtained as a colorless liquid in this manner.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:9][CH:10]=[CH:11][CH2:12]Cl.[C:14]1([C@H:24]([NH2:26])[CH3:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>C(O)(C)C>[Cl:9][CH:10]=[CH:11][CH2:12][NH:26][C@@H:24]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:25]
Reactant: ClC=CCCl
Reactant: C[C@@H](N)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: C[C@@H](NCC=CCl)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
Potassium carbonate (161.2 g) and potassium iodide (5 g) were added to the mixture of 1,3-dichloropropene (97.3 g) and (R)-1-(1-naphthyl)ethylamine (100 g) in isopropyl alcohol (500 mL) at room temperature. The reaction mixture was refluxed at 80° C. to 85° C. for about 4 hours. After the completion of the reaction, mixture was cooled to room temperature and filtered through hyflo bed. Hyflo bed was washed with isopropyl alcohol (500 mL). The filtrate was combined and treated with hydrochloric acid (6 Normal; 100 mL) at room temperature. The solution was allowed to stir for about one hour at room temperature to give solid. The solid was filtered and was washed twice with isopropyl alcohol (2×100 mL). Methanol (750 mL) was added to the wet solid and stirred for 10-15 minutes at room temperature. The pH of solution was adjusted to 11 to 12 using a solution of sodium hydroxide in water (20%). The solution was diluted with de-ionized water (750 mL) and extracted with dichloromethane (500 mL). Layers were separated and the organic layer was washed twice with de-ionized water (2×500 mL). The organic layer was completely concentrated under vacuum at 40° C. to 45° C. to give 3-chloro-N-[(1R)-1-(naphthalen-1-yl)ethyl]prop-2-en-1-amine as oil.
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])=[C:16]([CH:19]=1)[C:17]#[N:18].N1C=CC=CC=1>C(Cl)Cl>[C:17]([C:16]1[CH:19]=[C:12]([NH:11][C:8](=[O:9])[O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:14][C:15]=1[S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])#[N:18]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCS(=O)(=O)c1ccc(N)cc1C#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1C#N
Reaction time: 1 h
Yield: 85 %

Procedure:
Phenylchloroformate (0.63 mL, 5 mmol) was added dropwise to a solution of 6B in methylene chloride (10 mL) and pyridine (0.60 mL, 7.1 mmol) at 0° C. After stirring for 1 h, the reaction mixture was partitioned between 1.0 M HCl (150 mL) and EtOAc (150 mL). The layers were separated and the organic phase was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (0% to 100% EtOAc in hexanes) to yield 25A (1.34 g, 85%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.32 (t, J=7.45 Hz, 3 H) 3.36 (q, J=7.33 Hz, 2 H) 7.14-7.21 (m, J=7.58 Hz, 2 H) 7.26-7.31 (m, J=7.45, 7.45 Hz, 1 H) 7.37-7.45 (m, J=7.83, 7.83 Hz, 2 H) 7.66 (bs, 1 H) 7.83 (dd, J=8.72, 2.15 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.ClC1C=CC=CC=1Cl.Cl>[N+](C)([O-])=O>[CH3:13][O:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([S:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)(=[O:11])=[O:10])=[CH:17][CH:16]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cccc2ccccc12
Agent: Cl
Solvent: Clc1ccccc1Cl
Solvent: C[N+](=O)[O-]
Product: COc1ccc(S(=O)(=O)c2ccc(OC)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
p-Methoxybenzenesulfonyl chloride, 2.0 mol, anhydrous stannic chloride, 2.25 mol, 1-methoxynaphthalene, 2.25 mol, and 3 l of o-dichlorobenzene were mixed at room temperature under nitrogen. The mixture was stirred at room temperature overnight (ca 7 hours needed) and decomposed with 3N hydrochloric acid. The organic layer was diluted with 1250 ml of nitromethane and washed with 2 portions of 1N hydrochloric acid followed by pure water. The organic layer was treated with magnesium sulfate, filtered, evaporated, extracted with hot toluene and dried at 120° c. for two hours to give 577 g, 88% yield, m.p. 160°-162° C.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:5]([C:20]([O:22]C)=[O:21])=[N:6][C:7]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2.Cl>C1COCC1.CO>[OH:3][C:4]1[C:5]([C:20]([OH:22])=[O:21])=[N:6][C:7]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: COC(=O)c1nc(N(C)S(C)(=O)=O)c2cccnc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1nc(C(=O)O)c(O)c2ncccc12)S(C)(=O)=O
Temperature: 50 °C

Procedure:
Sodium hydroxide (2.31 mL, 2.31 mmol, 1N solution) was added to a suspension of methyl 8-hydroxy-5-[methyl(methylsulfonyl)amino]-1,6-naphthyridine-7-carboxylate (240 mg, 0.77 mmol) in a 1:1 solution of THF/methanol (5 mL) and the resulting mixture was heated overnight at 50° C. In the morning, the homogeneous solution was acidified to a pH=4 using 1N HCl solution. The reaction was cooled and the solids that had precipitated out of solution were collected by vacuum filtration to give the desired product as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1.[C:12]([C:16]1[CH:29]=[CH:28][C:19]([CH2:20][N:21]2[CH2:25][CH2:24]OS2(=O)=O)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][CH2:25][CH2:24][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=2)=[CH:28][CH:29]=1)([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(C)(C)c1ccc(CN2CCOS2(=O)=O)cc1
Reactant: CC(C)c1cc(Br)ccc1Cl
Product: CC(C)c1cc(CCNCc2ccc(C(C)(C)C)cc2)ccc1Cl
Yield: 42.2 %

Procedure:
The title compound was synthesized in analogy to example S6-C using 4-bromo-1-chloro-2-isopropylbenzene (120 mg, 0.51 mmol), and 3-(4-tert-butylbenzyl)-[1,2,3]oxathiazolidine 2,2-dioxide (138 mg, 0.51 mmol). The residue was purified by flash column chromatography to give the desired product (74 mg, 42%) as a light yellow oil. MS (ISP) 344.3 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.CCN(S(F)(F)[F:39])CC>C(Cl)Cl>[F:39][C:20](=[O:21])[C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[C@@H:23]([CH3:26])[CH2:24][CH3:25]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of (2S,3S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methylpentanoic acid (Fmoc-Isoleucine) (7 g, 19.81 mmol) and pyridine (1.602 mL, 19.81 mmol) in DCM (120 mL) was added via cannula a solution of DAST (3.11 mL, 23.77 mmol) in DCM (20 mL) over 10 min. The reaction mixture was stirred at room temperature for 1 hour, diluted with DCM (80 mL), washed with ice-cold water (2×200 mL), the organic layer was dried over MgSO4, filtered, and evaporated in vacuo to give (9H-fluoren-9-yl)methyl (2S,3S)-1-fluoro-3-methyl-1-oxopentan-2-ylcarbamate (6.65 g, 94%) as a white solid. An esterification test was performed to assure quantitative acid fluoride formation by dissolving Fmoc-Ile-F (5 mg) in anhydrous MeOH (0.3 mL) and DIEA (0.030 mL) and allowing to react at room temperature for 15 min. The mixture was then evaporated in vacuo and analyzed by LCMS, showed less than 1% of Fmoc-Ile-OH present.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:24])[N:15]([CH3:23])[CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH:8]=2)=[C:4]([F:27])[CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([C:38]2([C:41](O)=[O:42])[CH2:40][CH2:39]2)=[O:37])=[CH:31][CH:30]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[F:27][C:4]1[CH:3]=[C:2]([NH:1][C:41]([C:38]2([C:36]([NH:35][C:32]3[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=3)=[O:37])[CH2:40][CH2:39]2)=[O:42])[CH:26]=[CH:25][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:15]([CH3:23])[CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)=[O:24])[CH:8]=1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)CC1
Reaction time: 3.5 h
Yield: 41.6 %

Procedure:
3-[4-(4-Amino-2-fluorophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (40.8 mg) was dissolved in N,N-dimethylformamide (1.0 ml). 1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (73 mg), triethylamine (0.0456 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (145 mg) were added under a nitrogen atmosphere at room temperature and stirred for 3.5 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was removed and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=97:3) to provide the titled compound as white powder (26.3 mg, 42%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1[C:42]2[C:33](=[CH:34][C:35]3[C:40]([C:41]=2[CH:43]=O)=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:32]=[CH:31][CH:30]=1>>[CH:39]1[C:40]2[C:35](=[CH:34][C:33]3[C:42]([C:41]=2[CH2:43][NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:17]4[C:16]5[C:11](=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:13]=[CH:14][CH:15]=5)[N:10]=[CH:9][C:8]=4[CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:19]=2)=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:36]=[CH:37][CH:38]=1
Reactant: O=Cc1c2ccccc2cc2ccccc12
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4c5ccccc5cc5ccccc45)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and anthracene-9-carbaldehyde. MS (ESI) m/z 569.