Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:27][C:28]1[S:29][C:30]([CH2:33]Cl)=[CH:31][N:32]=1.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:33][C:30]3[S:29][C:28]([Cl:27])=[N:32][CH:31]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: ClCc1cnc(Cl)s1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=c1n(Cc2cnc(Cl)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
500 mg (1.63 mmol) of the compound from Example 5A and 449 mg (3.25 mmol) of potassium carbonate were dissolved in 4 ml of acetonitrile, and 287 mg (1.71 mmol) of 2-chloro-5-(chloromethyl)-1,3-thiazole were added. The mixture was stirred at 80° C. for 1.5 h. After cooling to RT, 10 ml of water were added and the mixture was extracted three times with in each case 10 ml of ethyl acetate. The combined organic phases were washed with 10 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 7:1, then 1:1). This gave 619 mg (87% of theory) of the target compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20](=[O:41])[C@H:21]([CH2:33][C:34]1[CH:39]=[CH:38][C:37](Br)=[CH:36][CH:35]=1)[NH:22][C:23](=[O:32])[C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31]>>[CH3:18][O:19][C:20](=[O:41])[C@H:21]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:38][CH:39]=1)[NH:22][C:23](=[O:32])[C:24]1[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1c(Cl)cccc1Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2NC(=O)OC(C)(C)C)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 73.5 %

Procedure:
2-(tert-Butoxycarbonylamino)benzeneboronic acid (0.3 g) was coupled with N-(2,6-dichlorobenzoyl)-4-bromo-L-phenylalanine methyl ester (270 mg) by a similar procedure as described in Examples 15 to give 250 mg of N-(2,6-dichlorobenzoyl)-4-[2-(tert-butoxycarbonylamino)phenyl]-L-phenylalanine methyl ester. ESMS: m/z 543 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[N:47]=[C:46]([CH3:48])[O:45][N:44]=2)=[CH:38][C:37]=1[CH3:49].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:49])=[CH:38][C:39]([C:43]6[N:47]=[C:46]([CH3:48])[O:45][N:44]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1nc(-c2cc(C)c(Br)c(C)c2)no1
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6noc(C)n6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-(4-bromo-3,5-dimethyl-phenyl)-5-methyl-[1,2,4]oxadiazole following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 11): tR=1.28 min; Mass spectrum (ESI+): m/z=551 [M+Na]+.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=1)[CH3:4].[N:15]#[C:16][NH2:17].[O-]Cl.[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C>C(#N)C>[F:12][C:11]([F:14])([F:13])[C:8]1[N:7]=[CH:6][C:5]([CH:3]([S:2]([CH3:1])=[N:17][C:16]#[N:15])[CH3:4])=[CH:10][CH:9]=1
Reactant: CSC(C)c1ccc(C(F)(F)F)nc1
Reactant: N#CN
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(c1ccc(C(F)(F)F)nc1)S(C)=NC#N
Temperature: -5 °C
Reaction time: 0.75 h

Procedure:
A solution of 22.1 g (0.1 mol) of 3-[1-(methylthio)ethyl]-6-(trifluoromethyl)pyridine and 5.04 g (0.12 mol) of cyanamide in 150 mL of acetonitrile was cooled to −5° C. To this solution was added 150 g (0.115 mol, Clorox™ 5.7% wt) of aqueous NaOCl dropwise over 15 min. The reaction mixture was allowed to stir at −5° C. for 45 min, and then allowed to warm to 5° C. To the mixture was added 5 mL of 25% aq sodium metabisulfite and the two phase mixture was allowed to settle. To the organic phase was added 5.7 mL (0.1 mol) of glacial acetic acid, and the solution concentrated in vacuo to an oil. This oil was dissolved in 70 mL of CH2Cl2 and washed with 50 mL of water. The aqueous layer was reextracted with 30 mL of CH2Cl2. The organics were combined and dried over MgSO4. After filtration, the dichloromethane solution was analyzed by LC and contained 42:52 (area) ratio of isomers A and B above.
Reaction SMILES: [C:1]([O:7][CH2:8]C)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[C:10](OC)(=O)[CH2:11][SH:12].[Na]>ClCCl>[OH:4][C:3]1[CH:5]=[C:11]([CH3:10])[S:12][C:2]=1[C:1]([O:7][CH3:8])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: COC(=O)CS
Agent: [Na]
Solvent: ClCCl
Product: COC(=O)c1sc(C)cc1O
Yield: 52.3 %

Procedure:
Prepared by the method described in Example 1 from ethyl acetoacetate (130 g, 1.0 mole), methyl thioglycolate (212 g, 2.0 moles) and sodium (53 g, 2.3 moles). The crude product is shaken with two portions of dichloromethane, filtered, and the filtrate stripped of solvent under reduced pressure to afford the product (90.1 g); mp 50°-53° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[N+:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([O-:34])=[O:33].O>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:43][CH:42]=3)[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 59.3 %

Procedure:
11.2 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are dissolved in 120 ml of acetone, and 7.56 g of sodium bicarbonate are added thereto. 6.4 g of 4-nitrobenzoyl chloride are added to the mixture under ice-cooling and under stirring, and said mixture is stirred at room temperature for 2 hours. After the reaction, 10 ml of water are added to the mixture to dissolve inorganic materials, and said mixture is evaporated under reduced pressure to remove acetone. The oil thus obtained is extracted with ethyl acetate, and the extract is washed with water, dried and then eveporated to remove solvent. 9.3 g of (+)-cis-2-(4-methoxyphenyl)-3-(4-nitrobenzoyloxy)-5-[2-(dimethylamino)-ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].Cl.[C:7]([O:11][C:12](=[O:15])[CH2:13][NH2:14])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:7]([O:11][C:12](=[O:15])[CH2:13][NH:14][C:3](=[O:4])[CH2:2][Br:1])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(Br)CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CNC(=O)CBr

Procedure:
77.8 g (385.5 mmol) of bromoacetic acid bromide is added in drops at 0° C. to 50 g (296.5 mmol) of glycine-tert-butyl ester hydrochloride salt and 90 g (889.5 mmol) of triethylamine in 500 ml of methylene chloride. In this case, the temperature remains between 0° C.-5° C. 1000 ml of 5% aqueous hydrochloric acid is added, and the organic phase is separated. The organic phase is extracted once more with 500 ml of 5% aqueous hydrochloric acid, dried on magnesium sulfate and evaporated to dryness in a vacuum. The residue is recrystallized from diisopropyl ether/n-hexane.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[O:20]=[C:21]1[NH:25][C:24]2[CH:26]=[CH:27][C:28]([C:30]#[N:31])=[CH:29][C:23]=2[O:22]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:25]3[C:24]4[CH:26]=[CH:27][C:28]([C:30]#[N:31])=[CH:29][C:23]=4[O:22][C:21]3=[O:20])[CH2:6][CH2:7]2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: N#Cc1ccc2[nH]c(=O)oc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(C#N)ccc43)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (190 mg, 0.625 mmol, 1 eq), 2-oxo-2,3-dihydro-benzooxazole-6-carbonitrile (48) (100 mg, 0.625 mmol, 1 eq), cesium carbonate (400 mg, 1.23 mmol, 2 eq) in DMF (2 ml) was stirred at rt overnight. The reaction mixture was diluted with ethyl acetate, washed with water and purified with flash chromatography to give 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazole-6-carbonitrile (49).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:32][CH3:33])=[CH:4][C:5]([C:10]2[CH:27]=[CH:26][C:13]([O:14][CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:12]([C:28]([F:31])([F:30])[F:29])[CH:11]=2)=[N:6][C:7]=1[C:8]#[N:9].Cl.[N:35]([O-])=O.[Na+]>O1CCOCC1.O>[C:8]([C:7]1[C:2]2[N:1]=[N:35][N:32]([CH3:33])[C:3]=2[CH:4]=[C:5]([C:10]2[CH:27]=[CH:26][C:13]([O:14][CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[C:12]([C:28]([F:29])([F:30])[F:31])[CH:11]=2)[N:6]=1)#[N:9]
Reactant: O=N[O-]
Reactant: CNc1cc(-c2ccc(OCCN(C)C(=O)OC(C)(C)C)c(C(F)(F)F)c2)nc(C#N)c1N
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN(CCOc1ccc(-c2cc3c(nnn3C)c(C#N)n2)cc1C(F)(F)F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(4-(5-amino-6-cyano-4-(methylamino)pyridin-2-yl)-2-(trifluoro-methyl)phenoxy)ethyl(methyl)carbamate (7.43 mmol, 3.46 g) was dissolved in 1M Hydrochloric Acid (14.87 mmol, 14.87 ml) and Dioxane (5 ml). Sodium nitrite (10.41 mmol, 0.718 g) in Water (5.00 ml) was added to the reaction mixture and it was stirred at room temperature for 1 hr. The acetonitrile was removed and the reaction taken up in dioxane/water. The reaction mixture was filtered and the solid washed with water to afford tert-butyl 2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl(methyl)carbamate. (2.82 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([CH3:27])=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH2:26])[CH:20]=[CH:19]2.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([CH3:27])=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH:26][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:20]=[CH:19]2
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc4cc(N)ccc4c3C)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc4cc(NC(=O)c5ccccc5)ccc4c3C)c2cc1OC

Procedure:
6-(6,7-Dimethoxy-quinolin-4-yloxy)-5-methyl-naphthalen-2-ylamine (Step b, 0.100 g, 0.2 mmol), benzoyl chloride (0.04 mL, 0.3 mmol) and K2CO3 (0.116 g, 0.6 mmol) in CH2Cl2 were stirred overnight under inert atmosphere. The reaction was quenched with water and diluted with CH2Cl2. The aqueous layer was extracted 3 times with CH2Cl2. The organics were collected, dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by silica-gel column chromatography in EtOAc/Hexanes to give the titled compound as a rust colored film. MS (ESI, pos. ion) m/z: 465 (M+1). Mass Calc'd for C29H24N2O4: 464.17.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:20]C([N-]C(C)C)C.IC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH:10]([CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2ccccc21
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1CN(C(=O)OC(C)(C)C)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-quinolinone (structure 68A of Scheme LI, where R1-2 =H) (EXAMPLE 325) (500 mg, 0.002 mol) in THF (5 mL) at -78° C. was added 2.0M LDA in THF (1.01 mL, 0.002 mol). The reaction mixture was stirred at -78° C. for 15 min and iodomethane (126 mL, 0.002 mol) was added all at once. The temperature was raised to 0° C. and the resulting mixture stirred for 4 h. The reaction was then quenched with sat'd NH4Cl (5 mL), extracted with ethyl acetate (2×10 mL), dried (Na2SO4) and concentrated in vacuo to a solid residue that was subjected to flash column chromatography (silica gel, hexanes/ethyl acetate, 95:5) to give 117 mg (23%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3-methyl-4-quinolinone (structure 69A of Scheme LI, where R1-2 =H, R3 =methyl), 128 mg (23%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3,3-dimethyl-4-quinolinone (structure 70A of Scheme LII, where R1-2 =H, R3-4 =methyl) and 200 mg (40%) of recovered starting material. Data for 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3-methyl-4-quinolino 1H NMR (400 MHz, CDCl3) 7.99 (dd, J=7.9, 1.7, 1H), 7.77 (d, J=8.4, 1H), 7.48 (ddd, J=7.3, 7.3, 1.7, 1H), 7.13 (dd, J=7.4, 1.0, 1H), 4.32 (dd, J=13.4, 4.4, 1H), 3.69 (dd, J=13.3, 9.8, 1H), 2.76 (ddq, J=9.8, 7.0, 4.4, 1H), 1.56 (s, 9H), 1.24 (d, J=7.0, 3H).
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[NH:17]1[C:21]2[CH:22]=[C:23]([N:26]3[CH:30]([C:31]4[CH:32]=[N:33][C:34]5[C:39]([CH:40]=4)=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:29]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[C:28]([OH:47])[C:27]3=[O:48])[CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1>CO.O>[NH:19]1[C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]([C:31]4[CH:32]=[N:33][C:34]5[C:39]([CH:40]=4)=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:29]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[C:28]([O:47][CH3:3])[C:27]3=[O:48])=[CH:22][C:21]=2[N:17]=[CH:18]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: O=C1C(O)=C(c2ccccc2)C(c2cnc3ccccc3c2)N1c1ccc2nc[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC1=C(c2ccccc2)C(c2cnc3ccccc3c2)N(c2ccc3[nH]cnc3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (10 eq in water), diazald (5 eq) ethylene glycol/Et2O (3/1 v/v), 1-(1H-benzo[d]imidazol-6-yl)-5-(quinolin-3-yl)-3-hydroxy-4-phenyl-1H-pyrrol-2(5H)-one (0.230 g, 0.5 mmol, 1 eq) and MeOH/H2O (90/10 v/v); yield: 0.003 g (1.4%); MS m/z: 433.4 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 4.17 (s, 3H), 6.85, 6.87 (2s, 1H), 7.19-7.22 (m, 1H), 7.30-7.34 (m, 2H), 7.37-7.41 (m, 1H), 7.45-7.53 (m, 2H), 7.60-7.63 (m, 1H), 7.69-7.71 (m, 2H), 7.78-7.80 (m, 1H), 7.84-7.86 (m, 2H), 8.11 (s, 1H), 8.35 (s, 1H), 8.84 (s, 1H); HPLC (METHOD [A]): rt 12.26 min (100%)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[F:18].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cnc2cc(Cl)c(F)cc2c1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(F)c(Cl)cc2N(Cc2ccccc2)C1
Yield: 81 %

Procedure:
16.2 g of 7-chloro-3-ethoxycarbonyl-6-fluoro-4-hydroxyquinoline, 16.8 g of potassium carbonate and 150 cm3 of DMF were heated for one hour, whilst stirring, in a round-bottomed flask equipped with a reflux condenser. 27.5 cm3 of benzyl chloride were added and the heating and stirring were maintained until the pH of the medium was neutral, which required about 2 hours. The major part of the solvent was removed by distillation in vacuo (15 mm Hg) at 100° C. The residue was taken up in 300 cm3 of water. The mixture was extracted with 3×100 cm3 of chloroform. The combined organic extracts were washed with water, dried (MgSO4) and evaporated to dryness. The residue was recrystallised from methylcellosolve. 17.5 g (81%) of 1-benzyl-7-chloro-3-ethoxycarbonyl-6-fluoroquinoline, m.p. 211°-212° C., were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6](=[S:13])[NH:5][C:4](=[O:14])[C:3]=1[N:15]=O.N.O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(=O)C>[NH2:15][C:3]1[C:4](=[O:14])[NH:5][C:6](=[S:13])[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:2]=1[NH2:1]
Reactant: CCCCCn1c(N)c(N=O)c(=O)[nH]c1=S
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCn1c(N)c(N)c(=O)[nH]c1=S
Temperature: 75 °C
Reaction time: 0.08 h
Yield: 74.7 %

Procedure:
To a mixture of 6-amino-1-pentyl-5-nitroso-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (6.4 g, 0.0264 mol), aqueous ammonia (60 mL, 0.60 mol) and water (60 mL) at 75° C. was added sodium dithionite (9.0 g, 0.050 mol) in small portions. After the addition was complete, the color of the solution changed from red to pale yellow. After stirring at 75° C. for another 5 mins, a precipitate was formed. Stirring was continued at room temperature for 1.5 h. The solution was then neutralized with 10% acetic acid (150 mL). The solid was filtered and washed with water to yield the product (4.5 g, 86.1%). LCMS calculated for C9H17N4OS: (M+H) 229.1. found 229.1.
Reaction SMILES: [NH3:1].[N+:2]([C:5]1[C:6]2[C:7]3[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10](C(=O)C(F)(F)F)[CH2:9][C:8]=3[CH:21]=[CH:22][C:23]=2[S:24](Cl)(=[O:26])=[O:25])([O-:4])=[O:3]>CO>[N+:2]([C:5]1[C:6]2[C:7]3[C:12](=[CH:13][CH:14]=1)[CH2:11][NH:10][CH2:9][C:8]=3[CH:21]=[CH:22][C:23]=2[S:24]([NH2:1])(=[O:26])=[O:25])([O-:4])=[O:3]
Reactant: O=C(N1Cc2ccc([N+](=O)[O-])c3c(S(=O)(=O)Cl)ccc(c23)C1)C(F)(F)F
Reactant: N
Solvent: CO
Product: NS(=O)(=O)c1ccc2c3c(ccc([N+](=O)[O-])c13)CNC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 2M solution of ammonia in methanol (10 mL) is added to a solution of 7-nitro-2,3-dihydro-2-trifluoroacetyl-1H-Benz[de]isoquinoline-6-sulfonyl chloride (4 mmol) in 40 mL of methanol and the resulting mixture is stirred at room temperature for 24 hours. The mixture is then concentrated under vacuum and the residue is partitioned between ethyl acetate and water. The organic layer is dried over magnesium sulfate and concentrated to afford the title compound. The crude product can be purified by recrystallization or chromatography.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[NH2:16][C@@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]1.[OH-].[Na+]>CC#N.O>[N:9]1([C:4]2[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:16][C@@H:17]3[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]3)[N:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Clc1nc(Cl)nc(N2CCCCCC2)n1
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C(O)[C@H]1CC[C@@H](Nc2nc(Cl)nc(N3CCCCCC3)n2)CC1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To the solution of crude 1-(4,6-dichloro-1,3,5-triazin-2-yl)azepane (0.77 mmol) in CH3CN/H2O (1/1, 20 ml) was added cis-4-amino-cyclohexanecarboxylic acid (110 mg, 0.77 mmol, 1 equivalent), followed by 1N NaOH (1.54 ml, 1.54 mmol, 2 equivalents). The reaction mixture was stirred at room temperature 5-6 hrs. The crude product was used in the next step.
Reaction SMILES: N1(O[C:11](=[O:24])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][CH:13]=2)C2C=CC=CC=2N=N1.[NH2:25][NH:26][C:27]([NH2:29])=[S:28].C(OC(C)C)(C)C>CN(C)C=O>[CH2:19]([O:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([NH:25][NH:26][C:27]([NH2:29])=[S:28])=[O:24])=[CH:17][CH:16]=1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: NNC(N)=S
Reactant: CCCCCOc1ccc(C(=O)On2nnc3ccccc32)cc1
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: CCCCCOc1ccc(C(=O)NNC(N)=S)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 115.6 %

Procedure:
To a solution of 4-n-pentyloxybenzoic acid benzotriazole-1-yl ester (20 g) in N,N-dimethylformamide (100 ml) was added thiosemicarbazide (6.73 g) and stirred for 7 hours at ambient temperature. The reaction mixture was pulverized with diisopropyl ether. The precipitate was collected by filtration to give 1-(4-n-pentyloxybenzoyl)-3-thiosemicarbazide (20 g).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH:10]2[CH2:17][CH2:16][C:13]3([CH2:15][CH2:14]3)[CH2:12][CH2:11]2)[C:6]([C:18]([OH:20])=O)=[CH:5][N:4]=1)#[N:2].[C:21]1([CH2:27][C@@H:28]([NH2:35])[CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.O.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[C:21]1([CH2:27][C@@H:28]([NH:35][C:18]([C:6]2[C:7]([CH2:9][CH:10]3[CH2:11][CH2:12][C:13]4([CH2:14][CH2:15]4)[CH2:16][CH2:17]3)=[N:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=2)=[O:20])[CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: N[C@H](Cc1ccccc1)CN1CCCC1
Reactant: N#Cc1ncc(C(=O)O)c(CC2CCC3(CC2)CC3)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ncc(C(=O)N[C@H](Cc2ccccc2)CN2CCCC2)c(CC2CCC3(CC2)CC3)n1
Reaction time: 24 h

Procedure:
To a solution of the crude 2-cyano-4-(spiro[2.5]oct-6-ylmethyl)pyrimidine-5-carboxylic acid (22 mg, step 74.5) in DMF (1.5 mL) are added (R)-2-phenyl-1-pyrrolidin-1-ylmethylethylamine (0.083 mmol), EDCl—H2O (0.11 mmol), and HOAt (0.11 mmol) at room temperature. The reaction mixture is stirred for 24 h and the reaction is quenched by the addition of H2O. The mixture is extracted with AcOEt, and the organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by RP-HPLC to give the title compound; MS (M+1)+: 474, Rf (solvent): 0.63 (CH2Cl2:MeOH=10:1).