Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].C1(C)C=CC=CC=1.[OH-].[Na+].Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>O>[CH2:1]([NH:4][C:15](=[O:16])[O:17][CH2:18][CH3:19])[C:2]#[CH:3]
Reactant: C#CCN
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: C#CCNC(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
115 g (2. 1 mol) of propargylamine is introduced into 1 1 of toluene, 91 g of sodium hydroxide dissolved in 400 ml of water are added, and 239 g (2.2 mol) of ethyl chloroformate are added dropwise at 10° C. The mixture is stirred for three hours at room temperature, the organic phase is separated off, the aqueous phase is extracted using toluene, the organic solutions are dried over magnesium sulphate and concentrated, and the concentrate is distilled.
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]3[N:22]([CH2:23][C:24]4[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=4[F:31])[C:21]([CH3:32])=[C:20]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:19](=[O:40])[N:18]3[C:41]=2[CH2:42][N:43]([CH3:51])[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:11][CH:10]=1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[F:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([F:31])[C:24]=1[CH2:23][N:22]1[C:21]([CH3:32])=[C:20]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:19](=[O:40])[N:18]2[C:41]([CH2:42][N:43]([CH3:51])[CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([NH2:8])=[CH:10][CH:11]=3)[N:16]=[C:17]12
Reactant: Cc1c(Cc2ccccc2)c(=O)n2c(CN(C)Cc3ccccc3)c(-c3ccc(NC(=O)OC(C)(C)C)cc3)nc2n1Cc1c(F)cccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cc2ccccc2)c(=O)n2c(CN(C)Cc3ccccc3)c(-c3ccc(N)cc3)nc2n1Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of the compound obtained in Example 19 (0.53 g, 0.77 mol) in dichloromethane (20 ml) is added trifluoroacetic acid (0.24 ml, 3.07 mmol) with ice-cooling. An additional amount of trifluoroacetic acid (1.5 ml) is added at room temperature and is stirred for 5 hours at room temperature. The reaction mixture is partitioned between chloroform (100 ml) and aqueous saturated NaHCO3 solution (30 ml). The aqueous layer is extracted with chloroform (30 ml). The combined organic solution is washed with saturated saline (20 ml), dried over Na2SO4, successively evaporated under reduced pressure to give the residue, which is chromatographed on silica gel to afford a pale brown colorless amorphous (0.41 g, 90%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ccc(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)s1
Yield: 27.6 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, starting from 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.05 mmol) and 2-methoxyphenylboronic acid (9 mg, 0.06 mmol) giving 5.7 mg (28%) of the title compound. MS (ESI+) calcd for C18H15N5O3S2 413.061631, found 413.062971.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:43](=[O:45])[CH3:44])=[N:16][N:17]2[CH2:20][C:21]([N:23]2[CH2:27][C@H:26]([F:28])[C@@H:25]([O:29][CH3:30])[C@H:24]2[C:31](=[O:42])[NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[F:41])=[O:22])=[CH:13][CH:12]=1)=[O:10])C1C=CC=CC=1>CO.[Pd]>[C:43]([C:15]1[C:14]2[C:18](=[CH:19][C:11]([C:9]([OH:10])=[O:8])=[CH:12][CH:13]=2)[N:17]([CH2:20][C:21]([N:23]2[CH2:27][C@H:26]([F:28])[C@@H:25]([O:29][CH3:30])[C@H:24]2[C:31](=[O:42])[NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[F:41])=[O:22])[N:16]=1)(=[O:45])[CH3:44]
Reactant: CO[C@H]1[C@@H](C(=O)NCc2cccc(Cl)c2F)N(C(=O)Cn2nc(C(C)=O)c3ccc(C(=O)OCc4ccccc4)cc32)C[C@@H]1F
Agent: [Pd]
Solvent: CO
Product: CO[C@H]1[C@@H](C(=O)NCc2cccc(Cl)c2F)N(C(=O)Cn2nc(C(C)=O)c3ccc(C(=O)O)cc32)C[C@@H]1F
Reaction time: 1 h

Procedure:
3-Acetyl-1-{2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-3-methoxy-pyrrolidin-1-yl]-2-oxo-ethyl}-1H-indazole-6-carboxylic acid benzyl ester (47 mg, 0.063 mmol) was dissolved in MeOH (5 mL), Pd/C (10%, 5 mg) was added and the solution was degassed 3 times replacing air by nitrogen and finally nitrogen by hydrogen. The reaction mixture was further stirred under hydrogen atmosphere for 1 h. The catalyst was removed through a pad of Celite and washed with MeOH. The solvent was concentrated under reduced pressure and the crude residue was purified by preparative HPLC (Waters Sunfire C18-ODB, 5 μm, 30×100 mm, eluent: 5% to 100% CH3CN in H2O in 25 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min). MS (LC/MS): 549.5 [M+H]+; 547.5 [M−H]−; tR (HPLC conditions f): 1.93 min.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[F:19])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][N:32]=2)[CH:28]=O)[CH:24]=[CH:23][CH:22]=[N:21]1>>[N:20]1([C:25]2[CH:26]=[C:27]([CH2:28][N:1]3[CH:2]([C:11]4[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=4[F:19])[CH2:3][CH:4]([CH3:10])[C:5]3=[O:7])[CH:30]=[CH:31][N:32]=2)[CH:24]=[CH:23][CH:22]=[N:21]1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OC
Reactant: O=Cc1ccnc(-n2cccn2)c1
Product: COc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccnc(-n2cccn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate with 2-(1H-pyrazol-1-yl)isonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.79 min.; [M+H]+: 381.04 g/mol.
Reaction SMILES: C(OC([NH:8][CH:9](C1C=CC=CC=1)[CH2:10][CH:11]=C)=O)(C)(C)C.[ClH:19].[C:20]1([CH3:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1>[ClH:19].[NH2:8][C@H:9]([CH:10]=[CH2:11])[CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccccc1
Reactant: C=CCC(NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: C=C[C@@H](N)Cc1ccccc1

Procedure:
A solution of 5.00 g (20.21 mmol) of (S)-2-(tert-butoxycarbonylamino-1-phenylbut-3-ene [J. R. Luly et al., J. Org. Chem. 52, 1487 (1987)] in 100 ml of a 4N solution of gaseous hydrogen chloride in anhydrous dioxane was stirred at room temperature for 30 min. 15 ml of toluene were then added and the mixture was concentrated in vacuo. This process was repeated twice more, then the residue was triturated with a little ether, filtered off with suction and dried in a high vacuum over KOH. 3.69 g (99% of theory) of the title compound were obtained as colourless crystals.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[H-].[Na+].[CH3:14]I.O>C1COCC1>[I:1][C:2]1[C:3](=[O:11])[N:4]([CH3:14])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cnc(O)c(I)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc([N+](=O)[O-])cc(I)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3-iodo-5-nitropyridin-2-ol (2.66 g, 10.0 mmol) in THF (30 mL) was cooled to −20° C. NaH (60% dispersion in mineral oil, 0.600 g, 15.0 mmol) was added cautiously in three portions. After being stirred for 30 min at this temperature, methyl iodide (6.23 mL, 100.0 mmol) was added dropwise through a syringe. The resulting mixture was allowed to warm to rt during a 30 min period. Stirring was continued for 18 h at rt. Water (15 mL) was added with caution to quench the reaction. THF was removed under reduced pressure and methylene chloride (80 mL) was added to the aqueous phase. Layers were separated and the aqueous phase was extracted with methylene chloride (2×50 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated to afford the desired product as a yellow crystalline solid. 1H-NMR (CDCl3, 400 MHz): δ=3.73 (s, 3H), 8.65 (d, J=2.8 Hz, 1H), 8.74 (d, J=2.8 Hz, 1H). MS (ES+): m/z 280.96 [MH+]. HPLC: tR=2.55 min (ZQ2000, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10](/[N:12]=[C:13]2\[NH:14][CH2:15][C:16]3([CH2:23][CH:22]4[NH:24][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[NH:17]\2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:56][C:57]1[CH:62]=[CH:61][C:60]([CH2:63][CH2:64][C:65](O)=[O:66])=[CH:59][CH:58]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.CN1CCOCC1>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:10](/[N:12]=[C:13]2\[NH:14][CH2:15][C:16]3([CH2:23][CH:22]4[N:24]([C:65](=[O:66])[CH2:64][CH2:63][C:60]5[CH:61]=[CH:62][C:57]([O:56][CH2:49][C:50]6[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=6)=[CH:58][CH:59]=5)[CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[NH:17]\2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CC4CCC(C3)N4)N2)nc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CC4CCC(C3)N4C(=O)CCc3ccc(OCc4ccccc4)cc3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(E)-3,5-diamino-6-chloro-N-(8-azaspiro[bicyclo[3.2.1]octane-3,4′-imidazolidine]-2′-ylidene)pyrazine-2-carboxamide (prepared as described for Ex. 252) (280 mg, 0.798 mmol) is dissolved in DMF (8 ml) along with HATU (303 mg, 0.798 mmol) and 3-(4-benzyloxy-phenyl)-propionic acid (205 mg, 0.798 mmol). N-Methyl morpholine (0.263 ml, 2.394 mmol) is added and the solution stirred at room temperature for 6 hours. The mixture is then concentrated in vacuo. EtOAc (100 ml) is added and the solution washed with water (100 ml). The organic phase is dried (MgSO4) and concentrated. The residue is dissolved in MeOH (20 ml) and dry loaded onto silica (5 g). Purification by flash chromatography (SiO2, DCM/MeOH) gives the title compound as a tan solid; [M+H]+ 589.20, 591.19 for Cl isotopes.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([N:6]1[CH:10]=[C:9]([CH:11](O)[C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[N:8]=[CH:7]1)(=[O:5])=[O:4].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH3:18][N:2]([CH3:1])[S:3]([N:6]1[CH:10]=[C:9]([CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[N:8]=[CH:7]1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)n1cnc(C(O)c2cccs2)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)S(=O)(=O)n1cnc(Cc2cccs2)c1
Yield: 93.2 %

Procedure:
2-(tert-butyl-dimethyl-silanyl)-4-(hydroxy-thiophen-2-yl-methyl)-imidazole-1-sulfonic acid dimethylamide (Intermediate-E1) (2.5 g, 6.2 mmol) in THF (60 mL) was treated with tetrabutylammonium fluoride (TBAF) (6.9 mL of a 1M soln) at 0° C. for 1 h and at rt for 3 h. The reaction mixture was subjected to an aqueous work-up and the product was purified by chromatography on silica gel with EtOAc to give 4-(hydroxy-thiophen-2-yl-methyl)-imidazole-1-sulfonic acid dimethylamide as a white solid, 1.43 g. 4-(Hydroxy-thiophen-2-yl-methyl)-imidazole-1-sulfonic acid dimethylamide (0.5 g, 1.74 mmol) in dichloromethane (25 mL) was reacted with trifluoroacetic acid (4.3 mL, 56 mmol) and triethylsilane (TES) (2.2 mL, 14 mmol) at rt for 18 h. The mixture was quenched with water and solid NaHCO3. This material was subjected to an aqueous work-up and the residue was purified by chromatography on silica gel with 50% EtOAc: hexane to yield 4-thiophen-2-ylmethyl-imidazole-1-sulfonic acid dimethylamide (Intermediate-E2) 0.44 g.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11]([O:13]CC)=O)=O.O.[NH2:17][NH2:18]>CCO>[NH2:17][N:18]1[C:3](=[O:2])[C:5]2[S:6][CH:7]=[CH:8][C:9]=2[NH:10][C:11]1=[O:13]
Reactant: CCOC(=O)Nc1ccsc1C(=O)OC
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nn1c(=O)[nH]c2ccsc2c1=O
Temperature: 90 °C
Yield: 61.9 %

Procedure:
To a solution of 3-ethoxycarbonylamino-thiophene-2-carboxylic acid methyl ester (3.43 g, 15.0 mmol) in EtOH (100 mL) was added hydrazine monohydrate (7.98 mL, 164.6 mmol). After heating at 90° C. for 12 h, the mixture was filtered to afford a fine yellow powder (1.70 g), which was used in the next step without further purification. MS: 184.2. 1H NMR (400 MHz, CD3OD) δ ppm 7.93 (d, J=5.3 Hz, 1H), 6.95 (d, J=5.3 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[NH2:11][C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[Br:8][C:6]1[CH:7]=[C:2]([NH:11][C:12]2[N:17]=[N:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nn2)CC1
Product: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nn2)c1=O
Yield: 60.2 %

Procedure:
Following Example 188c, 3,5-dibromo-1-methylpyridin-2(1H)-one (536 mg, 2.0 mmol) and 330a (558 mg, 2.0 mmol) were reacted to give 330b as a yellow solid (560 mg, 60%). MS: [M+H]+ 467
Reaction SMILES: [CH:1]1([CH2:5][C:6]2([CH3:23])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8](C(OCC)=O)[C:7]2=[O:22])[CH2:4][CH2:3][CH2:2]1>O1CCOCC1.Cl.O>[CH:1]1([CH2:5][C:6]2([CH3:23])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[CH:8][C:7]2=[O:22])[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)C1=C(O)c2ccccc2C(C)(CC2CCC2)C1=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC1(CC2CCC2)C(=O)C=C(O)c2ccccc21
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of Example 55E (0.055 g, 0.174 mmol) in 4 mL of dioxane and 4 mL of 1N HCl was refluxed for 3 hours. The solution was cooled to room temperature, diluted with water and extracted with 3× ethyl acetate. The combined organic layers were dried over MgSO4, and concentrated in vacuo to yield the title compound (0.035 g, 83% yield) as an oil that solidifies on standing. 1H NMR (300 MHz, DMSO-d6): δ ppm 1.16 m, 3 H) 1.48 (s, 3H) 1.70 m, 3 H) 2.04 m, 2 H) 2.21 m, 1 H) 5.76 m, 1 H) 7.30 m, 1 H) 7.44 (m, 1 H) 7.63 m, 1 H) 8.00 (d, J=8.09 Hz, 1 H). MS (ESI+) m/z=243 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][CH2:19][C:20](N)=[O:21])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[OH-:29].[Na+]>O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][CH2:19][C:20]([OH:29])=[O:21])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1
Reactant: [OH-]
Reactant: NC(=O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
26 ml of concentrated hydrochloric acid are added dropwise to a suspension of 25.2 g (0.065 mole) of dextrorotatory (+)-2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetamide (prepared at point 10 above) in 70 ml of water, causing the temperature of the mixture to rise to 38° C. The mixture is then heated at 50° C. for 17 hours. The reaction mixture is then cooled in an ice bath and the pH brought to a value of between 4 and 5 by addition of a 4N aqueous solution of sodium hydroxide. The resulting solution is extracted successively with 100 ml, then twice with 50 ml of dichloromethane. The organic phases are combined and dried over magnesium sulfate. They are filtered and the solvent is evaporated. The residual oil is dissolved in 243 ml of acetone and the solution is treated with 3.5 g of Norit and filtered through Celite, which is then washed with 35 ml of acetone. The solution is heated at reflux temperature and 198 ml (0.13 mole) of concentrated hydrochloric acid are added dropwise thereto. The mixture is cooled in an ice bath and allowed to stand for one hour. The precipitate which forms is filtered off, washed with 100 ml of acetone and dried under vacuum at 50° C. 24.1 g of the levorotatory dihydroshloride of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid are obtained.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([C:31]([O:33][CH3:34])=[O:32])[C:7]=2[C:10]2[C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]([O:25][CH3:26])=[C:14]([O:16]C(=O)C3C=CC=CC=3)[CH:15]=2)[O:2]1.[H][H]>O1CCCC1.CO.[C].[Pd]>[CH2:1]1[O:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([C:31]([O:33][CH3:34])=[O:32])[C:7]=2[C:10]2[C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]([O:25][CH3:26])=[C:14]([OH:16])[CH:15]=2)[O:2]1
Reactant: COC(=O)c1cc(OC)c(OC(=O)c2ccccc2)cc1-c1c(C(=O)OC)ccc2c1OCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(OC)c(O)cc1-c1c(C(=O)OC)ccc2c1OCO2
Yield: 96.4 %

Procedure:
Dimethyl 5,6-methylenedioxy-4'-methoxy-5'-benzoyloxy-2,2'-biphenyldicarboxylate (1.15 g) is dissolved in tetrahydrofuran (50 ml) and methanol (50 ml), and the solution is stirred under 40 psi hydrogen gas atmosphere in the presence of palladium-carbon (0.2 g) for 16 hours. After the reaction, the catalyst is filtered off, and the filtrate is evaporated into dryness under reduced pressure. The residue is treated with methanol to give dimethyl 5,6-methylenedioxy-4'-methoxy-5'-hydroxy-2,2'-biphenyl-dicarboxylate (0.86 g) as colorless crystal. M.p. 172°-173° C.
Reaction SMILES: [CH:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=2[C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C>[CH:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][C:7]=2[C:14]([F:15])([F:16])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=Cc1ccc(C2CCCC2)c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(C2CCCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of 4-cyclopentyl-3-(trifluoromethyl)benzaldehyde (0.25 g, 1.032 mmol) in ethanol (2.5 mL) was added sodium borohydride (0.047 g, 1.238 mmol) and the mixture was stirred in room temperature for 2 h. The mixture was quenched with water, acidified with 6N HCl, diluted with more water and extracted with CH2Cl2. The CH2Cl2 layer was washed with water, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (0.22 g). LCMS m/z=227.5 [M−H2O+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54-1.72 (m, 4H), −1.77-1.89 (m, 2H), 1.93-2.05 (m, 2H), 3.19-3.28 (m, 1H), 4.52 (d, J=6 Hz, 2H), 5.28 (t, J=5.6 Hz, 1H), 7.52-7.6 (m, 3H).
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:8]=[N:9][C:10](Cl)=[CH:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH:14][C:15]1[CH:16]=[C:17]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:29]=1)[C:18]([NH:20][C:21]1[CH:25]=[CH:24][N:23]([CH3:26])[N:22]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:1]1([C:5]([C:7]2[N:8]=[N:9][C:10]([O:14][C:15]3[CH:16]=[C:17]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:29]=3)[C:18]([NH:20][C:21]3[CH:25]=[CH:24][N:23]([CH3:26])[N:22]=3)=[O:19])=[CH:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: O=C(c1ccc(Cl)nn1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)nn2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
A mixture of 3-(azetidin-1-ylcarbonyl)-6-chloropyridazine (45 mg, 0.23 mmol), 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (70 mg, 0.23 mmol) and potassium carbonate (63 mg, 0.46 mmol) in acetonitrile (3 mL) was stirred in a Smith Creator microwave at 130° C. for 1 hour. The solid was filtered off and the solvent was removed in vacuo. The residue was purified by reverse phase preparative HPLC, eluting with 5-95% acetonitrile in water (+0.2% TFA), followed by passage through a Silicycle Si-Carbonate cartridge, eluting with methanol, to give the desired product as a colourless solid (97 mg). 1H NMR δ (CDCl3): 1.34 (3H, d), 1.66 (3H, s), 2.33-2.41 (2H, m), 3.40 (3H, s), 3.48-3.52 (1H, m), 3.56-3.60 (1H, m), 3.79 (3H, s), 4.27 (2H, d), 4.58-4.62 (1H, m), 4.76 (2H, t), 6.79 (1H, d), 6.97 (1H, t), 7.25-7.29 (3H, m), 7.35-7.36 (1H, m), 8.26-8.28 (1H, m), 8.49 (1H, s); m/z 467 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[F:42][C:43]([F:49])([F:48])[S:44](Cl)(=[O:46])=[O:45]>ClCCl>[F:42][C:43]([F:49])([F:48])[S:44]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:46])=[O:45]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reaction time: 0.8 h
Yield: 92.9 %

Procedure:
4-Hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.173 mmol) was suspended in dichloromethane (4.8 mL), and the suspension was added with triethylamine (0.072 mL, 0.52 mmol) and trifluoromethanesulfonyl chloride (0.022 mL, 0.21 mmol) under ice-cooling, followed by stirring for 0.8 hour. The reaction mixture was filtered and the filtrate was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (95.4 mg, yield 93%).