Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:15](=[O:37])[C@@H:16]([NH:23][C:24](=[O:36])[C@@H:25]([N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH3:28])[CH3:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:5])C.[OH-].[Li+]>C1COCC1.O.CO>[C:32]([O:31][C:29]([N:27]([CH3:28])[C@@H:25]([CH3:26])[C:24]([NH:23][C@@H:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:15]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][C@H:6]1[C:4]([OH:5])=[O:3])=[O:37])=[O:36])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](C(=O)N[C@H](C(=O)N1c2ccccc2C[C@H]1C(=O)O)c1ccccc1)N(C)C(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 2.5 h
Yield: 94.8 %

Procedure:
To a solution of (S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-2-phenyl-acetyl}-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester (2.28 g, 4.47 mmol, Eq: 1) in 60 mL of THF/water/MeOH (3:1:1) was added 1 M aqueous lithium hydroxide (13.4 mL, 13.4 mmol, Eq: 3). The reaction mixture was stirred at 23° C. for 2.5 h. The reaction was concentrated in vacuo and the residue was taken up in water and acidified with 6 M and then 1 M aqueous HCl to pH˜2. The mixture was extracted with EtOAc (2×50 mL) and the organic layers were combined, dried over Na2SO4 and concentrated in vacuo to afford (S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-2-phenyl-acetyl}-2,3-dihydro-1H-indole-2-carboxylic acid as a white foam (2.04 g), m/z=482 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH2:16][OH:17])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:25])C(=O)C1>CC#N>[Br:25][C:13]1[N:9]2[N:10]=[CH:11][CH:12]=[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[C:8]2=[N:15][C:14]=1[CH2:16][OH:17]
Reactant: OCc1cn2nccc(N3CCOCC3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: OCc1nc2c(N3CCOCC3)ccnn2c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of compound 5d (40.0 g, 171 mmol) in CH3CN (400 mL) was treated dropwise with a solution of NBS (30.2 g, 170 mmol) in CH3CN (906 mL) at −20° C. After addition, the reaction mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of 50 mL of saturated Na2S2O3 solution. The solids formed were collected by filtration and washed with diethyl ether to afford compound 83a as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C11H13BrN4O2: 313.0 (M+H). found: 313.0.
Reaction SMILES: CC([N:5]([CH2:9][C@@H:10]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]2[N:30]([CH3:31])[N:29]=[N:28][CH:27]=2)[CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(=O)[O-])(C)C.C1C(=O)N([Cl:39])C(=O)C1>>[NH2:5][CH2:9][C@@H:10]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]2[N:30]([CH3:31])[N:29]=[N:28][C:27]=2[Cl:39])[CH:25]=1)=[O:20])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cn1nncc1-c1csc(C(=O)N[C@@H](Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Cl
Product: Cn1nnc(Cl)c1-c1csc(C(=O)N[C@H](CN)CC2CCCCC2)c1

Procedure:
The title compound was prepared as an off white solid according to the procedure of 261, except substituting 1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-cyclolhexylpropyl]carbamate (100 mg, 0.22 mmol) for 1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate, and the amount of NCS was reduced to 1 eq. LCMS (ES) m/z 382.2 (M+H)+, 1H NMR (400 MHz, METHANOL-d4) ppm 8.15 (d, J=1 Hz, 1H), 8.08 (d, J=1 Hz, 1H), 4.45 (m, 1H), 4.16 (s, 3H), 3.14 (m 1H), 3.05 (m, 1H), 2.00-0.90 (m, 13H).
Reaction SMILES: C(O)(C(F)(F)F)=O.CC([N:12]([CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26]2[C:27]3[C:47](=[O:48])[NH:46][CH:45]=[CH:44][C:28]=3[N:29]=[C:30]([NH:32][CH2:33][CH2:34][CH2:35][NH:36]C(OC(C)(C)C)=O)[N:31]=2)[CH:20]=1)C(=O)[O-])(C)C>ClCCl>[NH2:36][CH2:35][CH2:34][CH2:33][NH:32][C:30]1[N:31]=[C:26]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][CH2:17][CH2:16][NH2:12])[CH:20]=2)[C:27]2[C:47](=[O:48])[NH:46][CH:45]=[CH:44][C:28]=2[N:29]=1
Reactant: CC(C)(C)OC(=O)NCCCNc1nc(Nc2cccc(CCCN(C(=O)[O-])C(C)(C)C)c2)c2c(=O)[nH]ccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCNc1nc(Nc2cccc(CCCN)c2)c2c(=O)[nH]ccc2n1
Reaction time: 0.5 h

Procedure:
To a premixed solution of TFA (0.5 mL, 6.49 mmol) and dichloromethane (0.5 mL) was added to 1,1-dimethylethyl(3-{3-[(2-{[3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl]amino}-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-4-yl)amino]phenyl}propyl)carbamate (39 mg, 0.069 mmol) and the mixture was stirred for 30 min. It was then concentrated and the product was lyophilized (30 mg, white solid).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]([OH:31])=O)[CH:22]=2)=[N:8][CH:7]=1)=[O:5])C.[CH2:33]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[CH2:33]([N:40]1[CH2:45][CH2:44][N:43]([C:29](=[O:31])[CH2:28][O:27][C:23]2[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=2)[C:20]([C:9]2[C:10]3[C:15](=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=3)[C:6]([C:4]([OH:3])=[O:5])=[CH:7][N:8]=2)=[O:32])[CH2:42][CH2:41]1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCOC(=O)c1cnc(C(=O)c2cccc(OCC(=O)O)c2)c2cc(OC)c(OC)cc12
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)N4CCN(Cc5ccccc5)CC4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of 1-(3-carboxymethoxybenzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester (103.5 mg, 0.22 mmol) in 8 ml of methylene chloride was added 1.0 equivalent of N-benzylpiperazine, 1.05 equivalent of HBTU and 4 equivalent of triethylamine. The mixture was stirred at room temperature overnight. The solvents were evaporated and the residue was extracted with ethyl acetate and water. The organic phase was dried and solvents were evaporated. The residue was dissolved in 4 ml of methanol and aqueous lithium hydroxide was added (0.5N, 1 ml). The mixture was stirred overnight until all starting material disappeared. The reaction was loaded on a preparative HPLC for purification to give 1-{3-[2-(4-Benzyl-piperazin-1-yl)-2-oxo-ethoxy]-benzoyl}-6,7-dimethoxy-isoquinoline-4-carboxylic acid as a fluffy solid (43 mg, 35%). ES-MS calcd for C32H31N3O7 (m/e) 569.6, obsd 570.3 (M+H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)O1.Br[C:24]1[CH:25]=[C:26]([NH:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[C:27]([Cl:30])=[N:28][CH:29]=1.O1CCOCC1>C([O-])([O-])=O.[Na+].[Na+].[Pd]>[Cl:30][C:27]1[N:28]=[CH:29][C:24]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)=[CH:25][C:26]=1[NH:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)(=[O:33])=[O:34]
Reactant: COc1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3ccc4nc(NC(C)=O)sc4c3)cnc2Cl)cc1
Yield: 40.9 %

Procedure:
A mixture of N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.18 g, 0.6 mmol), N-(5-bromo-2-chloropyridin-3-yl)-4-methoxybenzenesulfonamide (0.15 g, 0.4 mmol) and Pd FibreCat® in 1 mL of 10% Na2CO3 and 3 mL of dioxane was heated at 100° C. for 12 minutes. The mixture was then filtered and the filtrate was concentrated in vacuo, washed with small amount of EtOAc, and recrystallized in MeOH to give white solid N-(6-(6-chloro-5-(4-methoxyphenylsulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.08 g, 41% yield). MS (ESI pos. ion) m/z: calc'd for C21H17ClN4O4S2: 488.0. found: 489.0 (MH+). 1H NMR (300 MHz, MeOH) δ ppm 2.29 (s, 3H) 3.85 (s, 3H) 6.97-7.07 (m, 2H) 7.66 (dd, J=8.48, 1.90 Hz, 1H) 7.70-7.78 (m, 2H) 7.81-7.90 (m, 2H) 8.11 (d, J=1.61 Hz, 1H) 8.17 (d, J=2.34 Hz, 1H) 8.44 (d, J=2.34 Hz, 1H).
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](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]2[C:16]3[C:11](=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:19]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccccc1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccccc4)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 469.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:38](=[O:39])[C:37]4[CH:41]=[CH:42][C:34]([F:33])=[CH:35][CH:36]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cncc2c(COc3cccc(N)c3)csc12
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccc(F)cc4)c3)csc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(3-amino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (25.6 mg, 0.078 mmol) (from Example 3 supra) in THF (2 mL) were added diisopropylethyl-amine (22 mg, 0.170 mmol) (Aldrich) and then 4-fluorobenzoyl chloride (13.4 mg, 0.085 mmol) (Aldrich). The reaction was stirred at room temperature for 30 minutes before it was concentrated to remove the solvent. The residue was diluted with EtOAc (40 mL), washed with aqueous 1N NaOH (10 mL), brine (2×10 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (hexanes/EtOAc, 70/30) to give 3-[3-(4-fluoro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 29 mg, 82.5%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:6]([F:22])=[C:7]2[C:12](=[CH:13][C:14]=1[F:15])[N:11]=[CH:10][C:9]([C:16]1[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=1)=[CH:8]2.[NH2:24][NH2:25]>CO>[F:22][C:6]1[C:5]([CH2:4][C:3]([NH:24][NH2:25])=[O:2])=[C:14]([F:15])[CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:16]1[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=1)[CH:10]=[N:11]2
Reactant: NN
Reactant: COC(=O)Cc1c(F)cc2ncc(-c3cnn(C)c3)cc2c1F
Solvent: CO
Product: Cn1cc(-c2cnc3cc(F)c(CC(=O)NN)c(F)c3c2)cn1
Temperature: 55 °C
Yield: 83.7 %

Procedure:
To a 40 ml vial was added methanol (12 mL), [5,7-difluoro-3-(1-methyl-1H-pyrazol-4-yl)-quinolin-6-yl]-acetic acid methyl ester (508 mg, 1.6 mmol) and hydrazine anhydrous (4 eq., 6.4 mmols). After 1 hour at 55° C. a second portion of hydrazine (4 eq., 6.4 mmol) was added and the reaction heated at 55° C. for a further 1 hour. The reaction mixture was cool down to room temperature, filtered and washed with cold methanol. The product was dried to return the title compound as a white solid (425 mg, 83% yield). MS: m/z 318.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:16].[Cl:17][C:18]1[CH:19]=[C:20]([S:24]([NH2:27])(=[O:26])=[O:25])[S:21][C:22]=1[Cl:23].CCN=C=NCCCN(C)C>CN(C)C1C=CN=CC=1.ClCCl.Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9](/[CH:11]=[CH:12]/[C:13]([NH:27][S:24]([C:20]3[S:21][C:22]([Cl:23])=[C:18]([Cl:17])[CH:19]=3)(=[O:25])=[O:26])=[O:15])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:16]
Reactant: Cc1c[nH]c2c(/C=C/C(=O)O)cc(F)cc12
Reactant: NS(=O)(=O)c1cc(Cl)c(Cl)s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1c[nH]c2c(/C=C/C(=O)NS(=O)(=O)c3cc(Cl)c(Cl)s3)cc(F)cc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 68.3 %

Procedure:
A mixture of (E)-3-(5-fluoro-3-methyl-1H-indol-7-yl)-acrylic acid (772 g, 3.53 mole), 4,5-dichloro-2-thiophenesulfonamide (900 g, 3.88 mole), 4-(dimethylamino)pyridine (861 g, 7.06 mole) and EDCI (1.348 kg, 7.06 mole) in dichloromethane (25.5 L) was stirred at ambient temperature for 14 h. The solution was diluted with 2 M aqueous HCl (16 L), and stirred for 1.5 h, which induced precipitation of the product. The product was collected via vacuum filtration and washed sequentially with water (2×2 L), dichloromethane (2×2 L), and hexanes (2 L) to provide 1.044 kg (71% yield) of the desired title compound. 1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 6.71 (d, 1H, J=15.6 Hz), 7.22 (dd, 1H, J=10.0, 2.6 Hz), 7.27 (br s, 1H), 7.39 (dd, 1H, J=9.6, 2.6 Hz), 7.95 (s, 1H), 8.15 (dd, 1H, J=15.6, 1.2 Hz), 11.35 (s, 1H).
Reaction SMILES: C1COCC1.Cl.[F:7][C:8]1[CH:9]=[C:10]([CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][C:21](=[CH:24][O:25]C)[CH2:20][CH2:19]2)[CH:11]=[C:12]([F:15])[C:13]=1[F:14]>O>[F:7][C:8]1[CH:9]=[C:10]([CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH:21]([CH:24]=[O:25])[CH2:20][CH2:19]2)[CH:11]=[C:12]([F:15])[C:13]=1[F:14]
Reactant: COC=C1CCC(CCc2cc(F)c(F)c(F)c2)CC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=CC1CCC(CCc2cc(F)c(F)c(F)c2)CC1
Reaction time: 2 h
Yield: 89.4 %

Procedure:
THF (100 ml) and 2N-hydrochloric acid (100 ml) were added to 4-(2'-(3",4",5"-trifluorophenyl)ethyl)methoxymethylenecyclohexane (20 g), followed by heating the mixture under reflux with stirring for 2 hours, adding to water (300 ml) after completion of the reaction, extracting with ethyl acetate (300 ml), drying the organic layer over anhydrous MgSO4 and concentrating under reduced pressure, to obtain 4-(2'-(3",4",5"-trifluorophenyl)ethyl)cyclohexane carbaldehyde (17 g).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:25][O:26][C:27](=[O:34])[C@H:28]([CH2:30][CH2:31][S:32][CH3:33])[NH2:29].C(N(C(C)C)CC)(C)C>ClCCl.CCOCC>[CH3:25][O:26][C:27](=[O:34])[C@H:28]([CH2:30][CH2:31][S:32][CH3:33])[NH:29][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][Br:1])=[CH:4][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=C(O)c1ccc(CBr)cc1-c1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CBr)cc1-c1ccccc1
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To a solution in dichloromethane (25 mL) of 4-bromomethyl-2-phenylbenzoic acid (2.16 g, 7.42 mmol), prepared as in Example 234B, was added oxalyl chloride (0.84 mL, 965 mmol) and 2 drops on DMF and the reaction mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo and azeotroped with toluene. The residue was dissolved in dichloromethane (15 mL) and then was added to a solution in dichloromethane (15 mL) of methionine methyl ester hydrochloride (1.78 g, 8.90 mmol) and diisopropylethylamine (3.10 g, 17.81 mmol) (prepared at −10° C.) dropwise. The reaction mixture was stirred for 30 minutes and then was poured into ether and extracted with water, aqueous 3N HCl (2×) and brine, dried, filtered and concentrated in vacuo. Chromatography on silica gel (5% ethyl acetate-chloroforn) to give (4-bromomethyl-2-phenylbenzoyl)methionine methyl ester (2.42 g, 75%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:9]=[CH:10][C:11]=1[S:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[CH:15](O)=[O:16]>C(OC(=O)C)(=O)C>[CH:15]([NH:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:9]=[CH:10][C:11]=1[S:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])=[O:16]
Reactant: O=CO
Reactant: COC(=O)c1ccc(SC)c(N)c1C
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(SC)c(NC=O)c1C
Temperature: 0 °C
Reaction time: 5 h

Procedure:
At 40° C., 4.75 g of methyl 3-amino-2-methyl-4-methylsulfanylbenzoate (0.05 mol) were added a little at a time to a mixture of 30 ml of acetic anhydride and 2.2 g of formic acid (0.05 mol). After 5 h, the solution was allowed to cool and poured into ice-water, and the mixture was extracted exhaustively with methylene chloride. The organic phases were washed and dried, and the solvent was subsequently removed. Yield: 4.7 g (0.044 mol).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>>[CH3:15][C:14]([CH3:17])([CH3:16])[C:13]([O:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([O:10][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C:3]1([CH3:12])[CH3:11])=[O:18]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Product: CC(C)(C)C(=O)OC1CC(C)(C)N(OC(=O)C(C)(C)C)C(C)(C)C1
Yield: 67 %

Procedure:
Using 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, prepared as described by: Paleos C. M. et al., loc. cit., and pivaloyl chloride in a procedure otherwise similar to the preparation of the compound 101 gives a 67% yield of the compound 108 which is obtained in the form of colourless crystal; melting point: 43-46° C. (pentane).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([CH2:31]Cl)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:33]([CH2:35][NH2:36])[OH:34]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([CH2:31][NH:36][CH2:35][CH2:33][OH:34])[N:18]=[CH:17][N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccc(Cl)c(Oc2c(CCl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: NCCO
Product: COc1ccc(Cl)c(Oc2c(CNCCO)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1

Procedure:
By reacting 4-tert-butyl-N-[6-chloromethyl-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide with ethanolamine there was obtained 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethylaminomethyl)-pyrimidin-4yl]-benzenesulphonamide.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]1[CH2:16][C:17]([OH:19])=O.[Cl:20][C:21]1[S:25][C:24]([NH2:26])=[C:23]([C:27]2[NH:31][CH:30]=[N:29][N:28]=2)[CH:22]=1>>[Cl:20][C:21]1[S:25][C:24]([NH:26][C:17](=[O:19])[CH2:16][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([F:15])([F:13])[F:14])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])=[C:23]([C:27]2[NH:28][N:29]=[CH:30][N:31]=2)[CH:22]=1
Reactant: Nc1sc(Cl)cc1-c1nnc[nH]1
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Product: O=C(Cn1c(=O)ccc2cc(C(F)(F)F)ccc21)Nc1sc(Cl)cc1-c1ncn[nH]1

Procedure:
The title compound was synthesized from 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid and 5-chloro-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine according to protocol A. Retention time (min)=6.178, method [7], MS(ESI) 454.1 (M+H).); 1H NMR (300 MHz, CD3Cl) δ 11.93 (b s, 1H), 8.0 (s, 1H), 7.92-7.86 (m, 2H), 7.84-7.81 (m, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.17 (s, 1H), 6.97 (d, J=9.34 Hz, 1H), 5.30 (s, 2H).
Reaction SMILES: [CH:1]1([CH2:7][PH:8](=[O:10])[O-:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11](N(CC)CC)[CH3:12]>O1CCCC1>[CH:1]1([CH2:7][PH:8](=[O:9])[O:10][CH2:11][CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[PH]([O-])CC1CCCCC1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CCO[PH](=O)CC1CCCCC1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
19.3 g of cyclohexylmethylphosphinate are dissolved in 60 ml of absolute tetrahydrofuran under an inert atmosphere. The solution is cooled to 0° C. and a suspension forms which is treated with 12.14 g of triethylamine. An exothermic reaction occurs. The suspension is re-cooled to 0° C. before dropwise addition of 13.02 g of ethylcycloformate. A further exothermic reaction with gas-evolution is observed together with the formation of a white precipitate. The resulting suspension is warmed to 20° and stirred for 20 hours. The solid is removed by filtration and the filtrate is evaporated to dryness. The residue is dissolved in dichloromethane and washed with water. Drying and removal of the solvent affords a pale yellow oil. Distillation under high vacuum affords ethyl cyclohexylmethylphosphinate, b.p. 120°-130° C./2×10-1 mbar. 'H-NMR (CDCl3): δ (ppm)=7.17 (1 H, d, t, 5=527 MZ, P-H), 4.13 (2 H, m, CH2OP), 1.95-1.58 (7 H, m, 3×CH2 +CH), 1.38-0.95 (6 H, m, 3×CH2).
Reaction SMILES: Br[C:2]1[C:3]([NH2:13])=[C:4]([C:9]([NH2:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:14]([C:16]1[O:17][CH:18]=[CH:19][C:20]=1B1OC(C)(C)C(C)(C)O1)=O.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:12][C:9]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]2[C:2]([C:20]3[CH:19]=[CH:18][O:17][C:16]=3[CH:14]=[N:13]2)=[CH:11][CH:10]=1
Reactant: CC1(C)OB(c2ccoc2C=O)OC1(C)C
Reactant: COC(=O)c1c(N)ccc(Br)c1N
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1c(N)ccc2c1ncc1occc12
Temperature: 60 °C
Yield: 85.3 %

Procedure:
A mixture of methyl 3-bromo-2,6-diaminobenzoate (Intermediate 25, 1.34 g), 2-formylfuran-3-boronic acid pinacol ester (1.46 g), tri-tert-butylphosphonium tetrafluoroborate (0.305 g), cesium carbonate (5.15 g) and tris-(dibenzylideneacetone)dipalladium (0.49 g) in a mixture of dioxane (80 mL) and water (30 mL) was degassed and purged with argon then heated at 60° C. for 1 hour. After cooling, the mixture was filtered through Celite and the pad was washed thoroughly with ethyl acetate. The filtrate was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100% to give methyl 7-aminofuro[2,3-c]quinoline-6-carboxylate (1.13 g) as a brown gum.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH:8]=[CH:9][C:10]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1.O>CN(C)C=O>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:8]([C:7]3[CH:23]=[CH:24][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH:9]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[NH:35]2)=[CH:30][CH:29]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C(C=Cc1ccc([N+](=O)[O-])cc1)C=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2NC(C=Cc3ccc([N+](=O)[O-])cc3)=CC2c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A solution of bis (4-nitrobenzal)acetone (1.62 g; 0.005 m) and 4-methoxy-phenyl-hydrazine hydrochloride (0.87 g; 0.005 m) in dimethylformamide (25 ml.) was heated at 100° C. for 4 hours to give a dark red solution, which was drowned into water (100 ml.) The crude solid product was filtered, water washed and was recrystallised from butanol to give a dark red solid (1.0 g; 45% theory)