Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:13]\[C:14]3[CH:19]=[CH:18][C:17]([S:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:25]1[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]1>CO.[Ni]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([S:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=3)[C:9]2=[O:12])=[CH:5][C:4]=1[N:25]1[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]1
Reactant: COc1cc2c(cc1N1CCC(C)CC1)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Agent: [Ni]
Solvent: CO
Product: COc1cc2c(cc1N1CCC(C)CC1)CC(Cc1ccc(SC(F)(F)F)cc1)C2=O
Reaction time: 2 h

Procedure:
The 139 (80 mg, 0.178 mmol) was dissolved in methanol 50 mL and Raney-Nickel (8 mg) added and the reaction stirred under hydrogen balloon for 2 h. The reaction was filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude compound 140 and purified by flash chromatography using 100-200 mesh silica gel. The compound 140 was eluted at 8% ethyl acetate in hexane as half white coloured solid compound 6-methoxy-5-(4-methylpiperidin-1-yl)-2-(4-((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one 140. 1HNMR (400 MHz, CDCl3) δ ppm 7.27 (m, 3H), 7.11 (m, 4H), 6.81 (s, 1H), 3.89 (s, 3H), 3.60 (bs, 2H), 3.37 (dd, 1H), 2.94 (m, 2H), 2.59 (m, 4H), 0.94 (m, 3H), 0.86 (m, 4H); MS (ESI) m/z 450.1 (M+H).
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2.[OH-].[Na+].C(OCC)(=O)C>FC(F)(F)C(O)=O>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH2:15][CH2:16][NH:17]2
Reactant: COc1ccccc1-c1cccc2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1cccc2c1CCN2
Temperature: -5 °C
Reaction time: 2 h
Yield: 31.5 %

Procedure:
0.26 g of sodium cyanoborohydride is gradually added to a solution of 0.44 g of 4-(2-methoxyphenyl)indole in 5 ml of trifluoroacetic acid under argon, cooled to a temperature of about −5° C. The reaction mixture is stirred at a temperature of about −5° C. for 2 hours, and is then poured into 15 g of ice and alkalinized with 8 ml of a concentrated sodium hydroxide solution. After the addition of 30 ml of ethyl acetate, the mixture is stirred at ambient temperature for 1 hour, and then separated by settling out. The organic phase is separated and the aqueous phase is extracted with 15 ml of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is treated again with a mixture of 15 ml of water, 15 ml of ethyl acetate and 3 ml of a concentrated sodium hydroxide solution and stirred at ambient temperature for 15 minutes, and then separated by settling out. The organic phase is separated and the aqueous phase is extracted with 2×15 ml of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 25 g cartridge of 15-40 μm silica, elution being carried out with pure dichloromethane, at a flow rate of 30 ml/min. 0.14 g of 4-(2-methoxyphenyl)-2,3-dihydro-1H-indole is thus obtained in the form of an off-white solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([N:4]([C@H:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[O:24][CH3:25])[CH2:15]1)[C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:2][CH3:3].C(N[C@H]1CCC2C(=CC=C[C:36]=2[O:40]C)C1)CC>>[CH2:1]([N:4]([C@H:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:40][CH3:36])[C:20]=2[O:24][CH3:25])[CH2:15]1)[C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:2][CH3:3]
Reactant: CCCN[C@H]1CCc2c(cccc2OC)C1
Reactant: CCCN(C(=O)CCCCC(=O)O)[C@H]1CCc2c(cccc2OC)C1
Product: CCCN(C(=O)CCCCC(=O)O)[C@H]1CCc2c(ccc(OC)c2OC)C1

Procedure:
(S)-N-propyl-N-[5-methoxy-1,2,3,4-tetrahydro-2-naphthyl]-5-carboxypentanamide (Intermediate 31) starting from (S)-N-propyl-5-methoxy-1,2,3,4-tetrahydro-2-naphthylamine, prepared as described in J. Med. Chem., 29, 912 (1986).
Reaction SMILES: [NH2:1][NH2:2].[F:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]([C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13](O)=[O:14])=O)=[CH:6][CH:5]=1>>[F:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]2[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]([OH:14])=[N:2][N:1]=2)=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccccc1C(=O)Cc1ccc(F)cc1
Reactant: NN
Product: Oc1nnc(Cc2ccc(F)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 3 M ethanolic solution of hydrazine (20 ml, 60 mmol) is added to 2-(4-fluorobenzyl carbonyl)benzoic acid (5.5 g, 20 mmol), and the mixture is stirred at room temperature for 5 hours. Precipitation gives 4-(4-fluorobenzyl)-1-hydroxy-phthalazine.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[C:14](=[O:17])[O:15][CH2:16][CH:10]2[CH2:9]1)C1C=CC=CC=1>[Pd].CCO>[CH2:16]1[CH:10]2[CH2:9][NH:8][CH2:13][CH2:12][N:11]2[C:14](=[O:17])[O:15]1
Reactant: O=C1OCC2CN(Cc3ccccc3)CCN12
Agent: [Pd]
Solvent: CCO
Product: O=C1OCC2CNCCN12
Reaction time: 8 h
Yield: 96.7 %

Procedure:
10% Palladium on carbon (18 mg, 20% by wt.) was placed under an inert atmosphere and suspended in EtOH (1 mL). A solution of 7-benzyl-hexahydro-oxazolo[3,4-a]pyrazin-3-one (90 mg, 0.39 mmol) dissolved in EtOH (3.8 mL) was added. The reaction mixture was placed under H2 atmosphere (1 atmosphere pressure) and stirred overnight. The resulting mixture was filtered through a pad of Celite® and the solvent was concentrated in vacuo to give 53.6 mg (97%) of the title compound as clear oil. 1H-NMR (300 MHz, CD3Cl) 4.36 (t, 1H), 3.89 to 3.81 (m, 1H), 3.79 to 3.69 (m, 2H), 3.10 to 2.88 (m, 3H), 2.67 to 2.50 (m, 2H), 2.00 to 1.90 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[C:17]([C:19]#[C:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:36].C=O.O.[C:41]([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[C:17]([C:19]#[C:20][CH:21]2[CH2:26][CH2:25][N:24]([CH3:41])[CH2:23][CH2:22]2)[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:36]
Reactant: [BH3-]C#N
Reactant: CCN(c1cc(C#CC2CCNCC2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN(c1cc(C#CC2CCN(C)CC2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.5 %

Procedure:
To a solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(piperidin-4-ylethynyl)benzamide (100 mg, 0.198 mmol) in methanol (5 mL) was added 35% formaldehyde in H2O (0.155 mL, 1.98 mmol) at 0° C. After stirring at 0° C. for 10 min, sodium cyanoborohydride (24.9 mg, 0.396 mmol) was added. The resulting mixture was stirred at 0° C. for 1 h. LCMS indicated that the reaction was completed. The reaction was quenched with sat. NaHCO3/brine and extracted with EtAOc/Heptane. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (10 g column, MeOH/DCM=1:9, and then MeOH/7 M NH3 in MeOH/DCM=1:1:8) to afford the titled compound (96.0 mg, 93%). 1H-NMR (500 MHz, CD3OD) δ ppm 7.22 (brs, 1H), 7.08 (brs, 1H), 6.10 (s, 1H), 4.46 (s, 2H), 3.94-3.87 (m, 2H), 3.35-3.30 (m, 2H), 3.07 (q, J=7.0 Hz, 2H), 3.04-2.97 (m, 1H), 2.79-2.71 (m, 2H), 2.67-2.58 (m, 1H), 2.38 (s, 3H), 2.28 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H), 2.28-2.21 (m, 2H), 1.97-1.91 (m, 2H), 1.78-1.67 (m, 4H), 1.64-1.54 (m, 2H), 0.85 (t, J=7.0 Hz, 3H); MS (ESI) [M+H]+519.4.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8]Cl)=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1>C(Cl)(Cl)Cl>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:8][CH:7]=[CH:6][C:5]3[CH:10]=[CH:11][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: Fc1ccc(C=CCCl)cc1
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(s1)CCN(CC=Cc1ccc(F)cc1)CC2
Yield: 13 %

Procedure:
Prepared from 4-fluoro-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 13% of theory, Melting point: 142°-146° C.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:11]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[CH:10][C:7]=2[CH:8]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>>[N:1]1([C:6]2[CH:13]=[CH:12][C:11]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[CH:10][C:7]=2/[CH:8]=[CH:20]/[C:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[O:21])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: O=Cc1cc(-c2cccs2)ccc1N1CCCC1
Product: O=C(O)c1ccc(C(=O)/C=C/c2cc(-c3cccs3)ccc2N2CCCC2)cc1

Procedure:
The title compound was prepared by condensing 2-pyrrolidin-1-yl-5-thiophen-2-yl-benzaldehyde (Ex-63A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Red solid, mp 208–209° C. 1H-NMR (DMSO-d6) δ 12.50 (bs, 1H), 8.22 (d, J=8.5 Hz, 2H), 8.09–7.99 (m, 4H), 7.73 (d, J=15.5 Hz, 1H), 7.52–7.41 (m, 3H), 7.10–7.07 (m, 1H), 6.93 (d, J=9.0 Hz, 1H), 3.28 (m, 4H), 1.87 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)#[CH:2].[F:11][C:12]1[CH:19]=[CH:18][C:17](I)=[CH:16][C:13]=1[C:14]#[N:15].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:11][C:12]1[CH:19]=[CH:18][C:17]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=2)=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: C#Cc1cncc(OC)c1
Reactant: N#Cc1cc(I)ccc1F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cncc(C#Cc2ccc(F)c(C#N)c2)c1
Temperature: 60 °C
Yield: 87.9 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (77 mg, 0.1 mmol), copper (I) iodide (44 mg, 0.23 mmol), and 3-ethynyl-5-methoxypyridine (300 mg, 2.3 mmol), (prepared as described in PREPARATION 10), to a solution of 2-fluoro-5-iodobenzonitrile (670 mg, 2.7 mmol) in triethylamine (3.4 mL, 34 mmol) and heat at 60° C. for 2.75 h. Cool to room temperature and concentrate. Purify the residue by silica gel chromatography, eluting with 100:0 to 80:20 dichloromethane/ethyl acetate followed by a second silica gel chromatography, eluting with 75:25 to 60:40 hexanes:ethyl acetate to give the title compound as a white solid (510 mg, 90%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][NH2:25]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH2:5][CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=2)[N:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[Cl:17])[N:25]=1)=[O:15]
Reactant: NNc1ccccc1Cl
Reactant: COC(=O)C(=O)C=Cc1cccc(Br)c1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)C1=NN(c2ccccc2Cl)C(c2cccc(Br)c2)C1
Temperature: 125 °C
Reaction time: 4 h
Yield: 75.1 %

Procedure:
4-(3-Bromo-phenyl)-2-oxo-3-butenoic acid methyl ester (10.0 g, 37.2 mmol) prepared in Step 2 and 2-chlorophenylhydrazine hydrochloride (7.3 g, 40.9 mmol) were added to acetic acid (150.0 mL). The reaction mixture was stirred at 125° C. for 4 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 11.0 g of the titled compound as a yellow liquid.
Reaction SMILES: NC1C(NC2C=CC=C(O)C=2)=NC(NC2C=CC=C(O)C=2)=NC=1C(OCC)=O.[CH2:29]([O:31][C:32]([C:34]1[N:39]=[C:38]([NH:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[N:37]=[C:36]([NH:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:35]=1[N+:54]([O-])=O)=[O:33])[CH3:30].[H][H]>[Pd]>[NH2:54][C:35]1[C:36]([NH:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[N:37][C:38]([NH:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[N:39][C:34]=1[C:32]([O:31][CH2:29][CH3:30])=[O:33]
Reactant: CCOC(=O)CNc1nc(NCC(=O)OCC)c([N+](=O)[O-])c(C(=O)OCC)n1
Reactant: [H][H]
Agent: [Pd]
Agent: CCOC(=O)c1nc(Nc2cccc(O)c2)nc(Nc2cccc(O)c2)c1N
Product: CCOC(=O)CNc1nc(NCC(=O)OCC)c(N)c(C(=O)OCC)n1

Procedure:
In a manner similar to the preparation of 5-amino-6-ethoxycarbonyl-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine, 6-ethoxycarbonyl-N2,N4-bis(ethoxycarbonylmethyl)-5-nitro-2,4-pyrimidinediamine, hydrogen, and 10% Pd/C were reacted to yield 5-amino-N2,N4-bis(ethoxycarbonylmethyl)-6-ethoxycarbonyl-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 6.25 (bs, 2H), 4.38 (q, 2H, J=6.9 Hz), 4.23-4.14 (m, 6H), 4.05 (bs, 2H), 1.39 (t, 3H, J=6.9 Hz), 1.30-1.22 (m, 6H); LCMS: ret. time: 17.67 min.; purity: 95%; MS (m/e): 370 (MH+).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH2:16]([O:18][C:19]([C:21]1[C:22](O)=[N:23][C:24]2[C:29]([C:30]=1[CH3:31])=[CH:28][CH:27]=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=2)=[O:20])[CH3:17].CCN(CC)CC>C(Cl)Cl>[CH2:16]([O:18][C:19]([C:21]1[C:22]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[N:23][C:24]2[C:29]([C:30]=1[CH3:31])=[CH:28][CH:27]=[C:26]([C:32]([F:35])([F:33])[F:34])[CH:25]=2)=[O:20])[CH3:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1c(O)nc2cc(C(F)(F)F)ccc2c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2cc(C(F)(F)F)ccc2c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
840 μl (5.0 mmol) trifluoromethanesulphonic acid anhydride was added in drops at 0° C. to a solution of 1.0 g (3.3 mmol) 2-hydroxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester and 930 μl (6.7 mmol) NEt3 in DCM (30 ml). After 4 h of stirring at RT, the mixture was diluted with DCM (30 ml) and washed with water, a sat. aq. NaHCO3 sol. and brine. The organic phase was dried over Na2SO4 and concentrated in a vacuum. 1.32 g (3.1 mmol, 92%) 4-methyl-7-(trifluoromethyl)-2-(trifluoromethyl-sulfonyloxy)quinoline-3-carboxylic acid ethyl ester was obtained as a residue. The raw product was further converted without additional purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[S:18][C:19](N)=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(OC(C)(C)C)=O.[Cl-].[NH4+]>[Cu](Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[S:18][CH:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(C2CCN(C(=O)OCc3ccccc3)CC2)sc1N
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Agent: [Cl-]
Product: CCOC(=O)c1csc(C2CCN(C(=O)OCc3ccccc3)CC2)c1
Reaction time: 1.5 h
Yield: 83.3 %

Procedure:
4-(5-Amino-4-ethoxycarbonyl-thiophen-2-yl)-piperidine-1-carboxylic acid benzyl ester (1.46 g, 3.76 mmol) was added to t-butyl nitrite (5.64 mmol) and copper(II)chloride (3.76 mmol) in IMS (40 mL). The reaction was stirred for 1.5 hours then saturated aqueous ammonium chloride (7 mL) was added and the resulting mixture stirred for a further 15 minutes. The solvent was removed under vacuum and product partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulphate, filtered and the solvent removed to give the title compound (1.17 g). LCMS m/z 374 [M+H]+ RT=4.18 min (Analytical Method 4).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[S:5][C:6]=1[C:7](O)=[O:8].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:55][CH:56]([CH3:59])[CH2:57][OH:58]>CN(C=O)C>[OH:58][CH2:57][CH:56]([NH:55][C:7]([C:6]1[S:5][C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:3][C:2]=1[CH3:1])=[O:8])[CH3:59]
Reactant: CC(N)CO
Reactant: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)NC(C)CO
Reaction time: 2 h
Yield: 49.4 %

Procedure:
To a solution of 4-methyl-2-[2-(5-methyl-3-phenyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (100 mg, 0.31 mmol) in DMF (3 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (108 mg, 0.33 mmol), N,N-diisopropyl ethyl amine (197 μL, 1.67 mmol) and rac-2-amino-1-propanol (30 mg, 0.40 mmol). The resulting reaction mixture was stirred for 2 h. The reaction mixture was extracted with ethyl acetate. The combined organic layers were then dried over sodium sulfate, filtered and evaporated. Concentration and purification by chromatography (silica, 0 to 2.5% methanol in dichlormethane) afforded the title compound (59 mg, 50%) as a colourless oil. MS: m/e=386.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12])=[O:4].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[N:35]=[C:34]([C:40](O)=[O:41])[N:33]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[N:35]=[C:34]([C:40]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])(=[O:13])=[O:12])=[O:41])[N:33]=1
Reactant: COC(=O)c1ccccc1S(N)(=O)=O
Reactant: COc1cc(OC)nc(C(=O)O)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)c1nc(OC)cc(OC)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2.2 g of 2-methoxycarbonylbenzenesulfonamide are added in portions at 0° C. to 2° C. to a mixture of 2.3 g of dicyclohexylcarbodiimide, 120 mg of 4-dimethylaminopyridine and 2.2 g of 4,6-dimethoxypyrimidine-2-carboxylic acid in 80 ml of absolute dichloromethane. The mixture is stirred for 0.5 hour at 0° C. and 2 hours at room temperature, and allowed to stand overnight. The urea which has precipitated is filtered off, the filtrate is concentrated in vacuo, and the residue is stirred for 0.5 hour with 100 ml of 2 N sodium carbonate solution. The aqueous phase is extracted using ether, and a pH of 2-3 is established using concentrated hydrochloric acid. The product which has precipitated is filtered off with suction and dried in vacuo. This gives 1.3 g of N-(4,6-dimethoxypyrimidin-2-yl)carbonyl]-2-methoxycarbonylbenzenesulfonamide of melting point 163°-165° C. (from ethyl acetate).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[N:9]([CH3:12])=[C:10]=[S:11].O1CCCC1>C(#N)C>[NH2:8][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][C:4]=1[NH:7][C:10]([NH:9][CH3:12])=[S:11]
Reactant: CN=C=S
Reactant: Nc1ccncc1N
Solvent: C1CCOC1
Solvent: CC#N
Product: CNC(=S)Nc1ccncc1N

Procedure:
A mixture of 4.4 parts of 3,4-pyridinediamine, 4.0 parts of isothiocyanatomethane, 90 parts of tetrahydrofuran and 40 parts of acetonitrile was stirred and refluxed overnight. The reaction mixture was evaporated, yielding 7.3 parts of N-(3-amino-4-pyridinyl)-N'-methylthiourea as a residue (intermediate 95).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:15]([OH:21])([CH3:20])[CH2:16][S:17][CH2:18][CH3:19])[N:8]2S(C)(=O)=O)=[CH:4][C:3]=1[F:22].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:15]([OH:21])([CH3:20])[CH2:16][S:17][CH2:18][CH3:19])[NH:8]2)=[CH:4][C:3]=1[F:22]
Reactant: CCSCC(C)(O)c1cc2cc(F)c(Cl)cc2n1S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCSCC(C)(O)c1cc2cc(F)c(Cl)cc2[nH]1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(6-chloro-5-fluoro-1-methanesulfonyl-1H-indol-2-yl)-1-ethylsulfanyl-propan-2-ol (0.30 g, 0.82 mmol) in methanol (10 mL) was added 4M sodium hydroxide solution (0.4 mL). The reaction was allowed to proceed overnight at room temperature. Complete reaction was not achieved, so additional 1M sodium hydroxide solution (1 mL) was added and the reaction mixture was heated to 50° C. The reaction mixture was kept at 50° C. for two hours then allowed to stir overnight at room temperature. The reaction mixture was concentrated and to the concentrate was added 1N hydrochloric acid solution and water. The mixture was extracted twice with ethyl ether. The extracts were dried over Mg2SO4, filtered, and evaporated to yield a residue. The residue was purified by column chromatography eluting with dichloromethane to yield the title compound as a yellow oil.
Reaction SMILES: Cl.[NH2:2][C@@H](CC1C=C(F)C=C(F)C=1)[C@H](O)CNC1(C2C=CC=C(C(F)(F)F)C=2)CC1.[CH3:30][S:31]([NH:34][C:35]1[CH:36]=[C:37]([C:53]([OH:55])=O)[C:38]2[CH2:39][CH2:40][N:41]([CH:46]([CH2:50][CH2:51][CH3:52])[CH2:47][CH2:48][CH3:49])[C:42](=[O:45])[C:43]=2[CH:44]=1)(=[O:33])=[O:32].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C.O.C(N(CC)CC)C>[CH3:30][S:31]([NH:34][C:35]1[CH:36]=[C:37]([C:53]([NH2:2])=[O:55])[C:38]2[CH2:39][CH2:40][N:41]([CH:46]([CH2:50][CH2:51][CH3:52])[CH2:47][CH2:48][CH3:49])[C:42](=[O:45])[C:43]=2[CH:44]=1)(=[O:32])=[O:33]
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Reactant: CCCC(CCC)N1CCc2c(C(=O)O)cc(NS(C)(=O)=O)cc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC(CCC)N1CCc2c(C(N)=O)cc(NS(C)(=O)=O)cc2C1=O
Reaction time: 24 h

Procedure:
Added to a solution of 185 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), 150 mg of 7-[(methylsulfonyl)amino]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid and 0.176 cm3 of triethylamine in 1.6 cm3 of anhydrous dimethylformamide are 64 mg of 1-hydroxy-7-azabenzotriazole then 90 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The solution is kept stirring for 24 h at a temperature close to 20° C. 20 cm3 of water and 50 cm3 of ethyl acetate are added to the reaction medium. After decantation, the organic phase is washed with 20 cm3 of a saturated aqueous solution of ammonium chloride, five lots of 20 cm3 of water, 20 cm3 of saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa). The residual solution (around 3 cm3) is filtered through a pellet of 15 g of 40-63 μm silica. The silica pellet is washed with 75 cm3 of ethyl acetate. The filtrate is concentrated to dryness under reduced pressure (5 kPa). 300 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-7-[(methylsulfonyl)amino]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained in the form of a directly salified white powder.