Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][CH:9]([O:12][CH2:13][CH3:14])[C:10]#[CH:11])[CH3:7].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH:20]=[O:21].[Cl-].[NH4+]>O1CCCC1.CCOCC>[CH2:6]([O:8][CH:9]([O:12][CH2:13][CH3:14])[C:10]#[C:11][C:20]([C:19]1[CH:22]=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:17]([O:16][CH3:15])[CH:18]=1)=[O:21])[CH3:7]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: C#CC(OCC)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(C#CC(=O)c1cc(OC)c(OC)c(OC)c1)OCC
Reaction time: 0.5 h

Procedure:
43.6 ml of n-butyllithium solution (1.6M in hexane) are added at -78° to a solution of 10 ml (69.8 mmol) of 3,3-diethoxy-1-propyne in 210 ml of absolute tetrahydrofuran. The mixture was stirred at -78° for 30 minutes and treated at -40° with 13.70 g (69.8 mmol) of 3,4,5-trimethoxybenzaldehyde in 60 ml of tetrahydrofuran. The reaction mixture was stirred at 0° for 1 hour and treated with 100 ml of saturated ammonium chloride solution and 150 ml of ether. The aqueous phase was extracted twice with ether. The combined organic phases were dried over magnesium sulphate and evaporated. The residue was dissolved in 100 ml of methylene chloride and added dropwise at 0° to a suspension of 176.8 g of manganese dioxide in 300 ml of methylene chloride. The reaction mixture was stirred at 0° for 20 minutes, filtered over magnesium sulphate and evaporated. The residue was crystallized from iso-octane at 0° and there is obtained 4,4-diethoxy-1-(3,4,5-trimethoxyphenyl)-2-butyn-1-one of melting point 52°-54°.
Reaction SMILES: C(O[C:4]([N:6]1[CH2:11][CH2:10][C:9]2[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[C:8]=2[CH2:7]1)=O)C.C(OC(N1CCC(=O)CC1)=O)C.C(N)C1C=CC=CC=1.ClC1C=CC(C=C[N+]([O-])=O)=CC=1>C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:22]([N:12]1[C:9]2[CH2:10][CH2:11][N:6]([CH3:4])[CH2:7][C:8]=2[C:14]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[CH:13]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)N1CCc2c(c(-c3ccc(Cl)cc3)cn2Cc2ccccc2)C1
Agent: CCOC(=O)N1CCC(=O)CC1
Agent: O=[N+]([O-])C=Cc1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: NCc1ccccc1
Solvent: Cc1ccccc1
Product: CN1CCc2c(c(-c3ccc(Cl)cc3)cn2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1-Benzyl-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid ethyl ester. To a stirred solution of 3.0 g of 4-oxo-piperidine-1-carboxylic acid ethyl ester in benzene (35 mL) was added 1.91 mL of benzylamine. The mixture was heated at reflux for 24 h using a Dean-Stark apparatus. The solvent was removed to give a pale yellow oil. A portion of the crude product (0.50 g) was dissolved in toluene (4 mL) and 0.35 g of 1-chloro-4-(2-nitro-vinyl)-benzene was added, followed by 0.7 g of 4 Å molecular sieves. The resulting mixture was stirred for 12 h at RT. The mixture was then filtered through diatomaceous earth and the filtrate was washed with satd. aq. NH4Cl (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on SiO2 (8% EtOAc/hexanes) afforded 0.25 g the title compound. TLC (SiO2, 25% EtOAc/hexanes): Rf=0.34. MS (ESI): exact mass calculated for C23H23ClN2O2, 394.14; found, m/z 395.2 [M+H]+, 397.2 [M+H]+, 417.1 [M+Na]+.
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[H-].[Na+].[CH2:12](Br)[CH:13]=[CH2:14]>CN(C=O)C.CCOCC>[CH2:14]([O:9][C:3]1([C:1]#[CH:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH:13]=[CH2:12]
Reactant: C#CC1(O)CCCCC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C#CC1(OCC=C)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
A solution of 1-ethynylcyclohexanol (2.28 g, 18.36 mmol) in DMF (25 ml) was cooled (0° C. ice bath) and treated with 60% NaH (0.890 g, 22.25 mmol). The reaction was stirred for 30 min, then warmed to room temperature and stirred for 1 hr. To this was added allyl bromide (4.8 ml, 55.5 mmol) over 5 min and continued stirring for 16 h. The reaction was diluted with Et2O (75 mL), washed with water (4×50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated to give the product, 1-(allyloxy)-1-ethynylcyclohexane (2.873 g, 12.24 mmol, 66.7% yield) as a pale yellow mobile oil. 1H NMR consistent with expected product, consists of approx 3:1 product/SM. Used as-is without further purification 1H NMR (CDCl3) δ: 5.94-6.04 (m, 1H), 5.33 (dq, J=17.2, 1.7 Hz, 1H), 5.17 (dq, J=10.3, 1.5 Hz, 1H), 4.15 (dt, J=5.6, 1.5 Hz, 2H), 2.50 (s, 1H), 2.49 (s, 1H), 1.91-1.98 (m, 3H), 1.49-1.77 (m, 12H), 1.24-1.38 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@:12]([F:15])([CH3:14])[CH2:11][N:10]1[C:16](=[O:38])[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([O:27]CC3C=CC=CC=3)=[CH:24][CH:25]=2)[C:20]([C:35](=[O:37])[CH3:36])=[CH:19]1)=[O:8].C(O)(C(F)(F)F)=O.C1(SC)C=CC=CC=1>>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@:12]([F:15])([CH3:14])[CH2:11][N:10]1[C:16](=[O:38])[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([OH:27])=[CH:24][CH:25]=2)[C:20]([C:35](=[O:37])[CH3:36])=[CH:19]1)=[O:8]
Reactant: CC(=O)c1cn(CC(=O)N2C[C@](C)(F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(OCc3ccccc3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: CC(=O)c1cn(CC(=O)N2C[C@](C)(F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(O)cc12

Procedure:
The title compound was prepared in a similar manner as described above for Example 577 from (2S,4R)-1-[2-(3-acetyl-5-benzyloxy-indol-1-yl)-acetyl]-4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide (57.0 mg, 0.096 mmol), TFA (3 mL), and thioanisole (0.114 mL, 0.960 mmol). Solid. MS (LC/MS): 504 [M+H]+; tR (HPLC, conditions k): 3.22 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-])=[O:2].C(N)CC>C1(C)C=CC=CC=1.[Pt]>[C:5]1([CH3:10])[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH:1][OH:2]
Reactant: Cc1ccccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCCN
Solvent: Cc1ccccc1
Product: Cc1ccccc1NO
Temperature: 6.5 °C
Reaction time: 1.67 h

Procedure:
41.1 g (0.3 mol) of o-nitrotoluene in 600 ml of toluene were initially taken with 5.1 g of active carbon, with stirring, in a 1.5 l hydrogenation flask having a gas inlet tube. After cooling to about 5-8° C., 67.4 g (1.1 mol) of n-propylamine and 3 g of platinum on carbon (5%) (CF 105 XRS from Degussa) were added and the reaction vessel was flushed at 5° C. with nitrogen and then with hydrogen. The hydrogenation was carried out at a constant hydrogen pressure of 100 mbar gauge pressure. According to HPLC analysis, the reaction was complete after 100 minutes.
Reaction SMILES: [CH3:1][N+:2]1([CH2:23][CH:24]2[CH2:26][CH2:25]2)[C@@H:19]2[CH2:20][C:7]3=[CH:8][CH:9]=[C:10]([OH:22])[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=43)[CH2:4][CH2:3]1)=[O:15].C1C2C[C@H]3N(CC4CC4)CC[C@]45[C@H](C(CC[C@@]34O)=O)OC(C=25)=C(O)C=1.C[I:53]>CC(C)=O>[I-:53].[CH3:1][N+:2]1([CH2:23][CH:24]2[CH2:26][CH2:25]2)[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([OH:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15]
Reactant: CI
Agent: C[N+]1(CC2CC2)CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Agent: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Solvent: CC(C)=O
Product: [I-]

Procedure:
U.S. Pat. No. 4,176,186 discloses that methylnaltrexone is prepared by reacting naltrexone as raw material with methyl iodide in acetone as solvent in a closed vessel at 70° C. for 4 days to produce an iodide of MNTX after quaternization, and then performing an ion exchange. The two-step reaction has a yield of about 54%. The disadvantages of this method lie in that the raw material would not react completely; the raw material would form a salt and precipitate out during the process of the reaction; a qualified product would not be not ease to be obtained even after refining; moreover; and phenol alkylation byproducts would be generated.
Reaction SMILES: [N:1]([N:3]1[CH2:10][CH2:9][CH2:8][C@H:4]1[C:5]([OH:7])=[O:6])=O>[Zn].C(O)(=O)C>[NH2:1][N:3]1[CH2:10][CH2:9][CH2:8][C@H:4]1[C:5]([OH:7])=[O:6]
Reactant: O=NN1CCC[C@H]1C(=O)O
Agent: [Zn]
Solvent: CC(=O)O
Product: NN1CCC[C@H]1C(=O)O
Reaction time: 0.25 h

Procedure:
A solution of 10 g. of N-nitroso-L-proline in 500 ml. of 50% acetic acid is cooled in an ice bath and 40 g. of zinc dust is added gradually, with vigorous stirring, at a rate that the temperature of the reaction mixture is maintained below 10°. The addition requires about 15 minutes. The unreacted zinc dust is removed by filtration and the filtrate treated with hydrogen sulfide to precipitate the zinc as zinc sulfide. The precipitated zinc sulfide is removed by filtration and the filtrate evaporated to dryness. The residue is dissolved in 30 ml. of absolute ethanol and the solution allowed to remain overnight at 5°. The N-amino-L-proline, a yellow crystalline solid is removed by filtration and melts at 153°-154° after drying.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=2)=[CH:12][C:11]=1[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[BH4-].[Na+].Cl>C(O)C.O.C(OCC)(=O)C>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=2)[OH:28])=[CH:12][C:11]=1[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(C(=O)c2cccc(C(=O)OCC)c2)cc1CC(=O)OCC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc(C(O)c2cccc(C(=O)OCC)c2)cc1CC(=O)OCC
Reaction time: 3 h
Yield: 86 %

Procedure:
To a solution of 220 mg of 2-(octyloxy)-5-[3-(ethoxycarbonyl)benzoyl]benzeneacetic acid, ethyl ester, in 25 ml of ethanol were added 20 mg of sodium borohydride. After 3 hours of stirring, 5 ml of water and 2 ml of hydrochloric acid were added. After stirring for 15 minutes, additional water was added until the solution turned cloudy. The mixture was poured into ethyl acetate and water. The layers were separated, the organic layer was washed three times with water, and the combined water extracts were back extracted with ethyl acetate. The ethyl acetate extracts were combined, dried over magnesium sulfate, and concentrated to dryness providing 190 mg of the desired title product as a colorless oil. NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:14]2[NH:35][C:17]3=[N:18][C:19]([N:22]4[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)=[O:29])[CH2:23]4)=[CH:20][CH:21]=[C:16]3[N:15]=2)[N:13]=1)[C:6]([O:8]CC)=[O:7].[OH-].[Li+]>O1CCCC1.CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:14]2[NH:35][C:17]3=[N:18][C:19]([N:22]4[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)=[O:29])[CH2:23]4)=[CH:20][CH:21]=[C:16]3[N:15]=2)[N:13]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1cc(OC)nc(-c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)cc(-c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-ethyl 2-methoxy-6-(5-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)isonicotinate (Example 96, 50 mg, 0.1 mmol) in tetrahydrofuran (1.0 mL) was added a solution of lithium hydroxide (14.9 mg, 0.6 mmol) in methanol (1.0 mL) and water (1.0 mL). The resulting suspension was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. To the residue was added a saturated solution of ammonium chloride in water (10 mL). The pH of the mixture was adjusted to 3 using aqueous hydrochloric acid (1N). The mixture was extracted with ethyl acetate (20 mL×3). The organics were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 451.1; HPLC retention time 2.21 min (Method A).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=O.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].CS(O)(=O)=O>[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7]2[NH:19][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]=2)[CH:10]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc(Br)cc1-c1nc2ccccc2[nH]1
Temperature: 170 °C
Reaction time: 5 h

Procedure:
Method 2—Step a Into a one necked round bottomed flask equipped with a magnetic stirrer, 5-bromo-2-chlorobenzoic acid (70.0 g, 297.3 mmol), o-phenylenediamine (64.3 g, 594.6 mmol) and methansulfonic acid (140 mL) were placed and heated to 170° C. in order to melt the solids. The system was stirred 5 h at this temperature, then left to come rt. The blue solid was treated with NaOH 35% (200 mL) obtaining a violet suspension (pH 5) that was filtered and washed with NaOH 0.5 M (2 L) and H2O (2 L). The product was dried under vacuum (60° C.), to give 61.6 g of a pure violet solid. (67%).
Reaction SMILES: [CH:1]([N:14]1[CH:19]=[C:18](I)[C:17](=[O:21])[NH:16][C:15]1=[O:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1>>[CH:1]([N:14]1[CH:19]=[C:18]([C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)[C:17](=[O:21])[NH:16][C:15]1=[O:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1I
Reactant: OB(O)c1cccnc1
Product: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1-c1cccnc1
Yield: 23.9 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 14 (Step 2), starting from 1-benzhydryl-5-iodo-pyrimidine-2,4-dione (0.81 g, 2 mmol) and 3-pyridylboronic acid (0.370 g, 3 mmol). The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 30:70) to afford the title compound (0.17 g, 24%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.14 (s, 1H), 7.20-7.24 (m, 4H), 7.29-7.33 (m, 2H), 7.36-7.46 (m, 6H), 7.93 (dt, J=8.1, 2.0 Hz, 1H), 8.41 (d, J=1.7 Hz, 1H), 8.45 (s, 1H), 8.52 (dd, J=4.9, 1.6 Hz, 1H). MS (ESI) m/z: 356 [M-H]+.
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:11])(=[NH:10])[CH2:6][CH2:7][CH2:8][CH3:9].[Cl:12][C:13]1[CH:14]=[C:15]([N:19]=[C:20]=[S:21])[CH:16]=[CH:17][CH:18]=1>C(O)C>[Cl:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]([NH:10][C:5](=[NH:11])[CH2:6][CH2:7][CH2:8][CH3:9])=[S:21])[CH:16]=[CH:17][CH:18]=1
Reactant: S=C=Nc1cccc(Cl)c1
Reactant: CCCCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCC(=N)NC(=S)Nc1cccc(Cl)c1

Procedure:
To a stirred, ice bath chilled solution of 5.4 g. of sodium methoxide in 100 ml. of absolute ethyl alcohol was added slowly 13.69 g. of valeramidine hydrochloride. Stirring was continued for ten minutes and then 16.9 g. of 3-chlorophenyl isothiocyanate was added dropwise and stirring was continued an additional hour. The solvent was evaporated under reduced pressure, the resulting residue was taken up in 100 ml. of dry ether and the ether solution was extracted several times with water and the combined water wash was extracted with 50 ml. dry ether. The combined ether extract was dried and then acidified by addition of 50 ml. 2-N ethereal hydrogen chloride. The resulting precipitate was filtered to give, after recrystallization from acetonitrile, 9.6 g. of 1-(3-chlorophenyl)-3-(pentanimidoyl)-2-thiourea hydrochloride; m.p. 142°-145°C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH2:10][CH2:11][NH:12][C:13]2[C:14]3[N:15]([N:27]=[C:28]([C:30]([O:32]CC)=[O:31])[CH:29]=3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[N:18]=2)=[N:7][CH:8]=1)#[N:2].O.[OH-].[Na+].Cl>COCCOC>[ClH:25].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH2:10][CH2:11][NH:12][C:13]2[C:14]3[N:15]([N:27]=[C:28]([C:30]([OH:32])=[O:31])[CH:29]=3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[N:18]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)c1cc2c(NCCNc3ccc(C#N)cn3)nc(-c3ccc(Cl)cc3Cl)cn2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cn3nc(C(=O)O)cc23)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
80 mg (0.16 mmol) of ester (Example 3) were dissolved in 5 ml of 1,2-dimethoxyethane, and 2.5 ml of water and 0.43 ml (0.4 mmol) of 1N sodium hydroxide solution were added. The solution was stirred at RT for 2 h. 20 ml of dilute hydrochloric acid (pH 3) were initially charged, and the reaction solution was slowly added dropwise. The mixture was stirred for another 30 min, and the product was filtered off and washed with diethyl ether. This gave, after drying under high vacuum, 70 mg (84% of theory) of the product as a solid.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8](O)=[O:9])(=[O:4])=[O:3].S(Cl)([Cl:17])=O>CN(C=O)C>[Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8]([Cl:17])=[O:9])(=[O:4])=[O:3]
Reactant: O=C(O)c1ccc(F)c(S(=O)(=O)Cl)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)c(S(=O)(=O)Cl)c1

Procedure:
3-(Chlorosulfonyl)-4-fluorobenzoic acid (1, 2.50 g, 10.5 mmol), thionyl chloride (10 mL) and DMF (1 drop) were heated at 90° C. for 1 hour and then the mixture evaporated to dryness. The material was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Nc1ccc(S(=O)(=O)c2cc(-c3ccccc3F)nc(N3CCCC3)c2)cc1
Yield: 65.4 %

Procedure:
A mixture of 191 mg (0.5 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 77 mg (0.55 mmole) 2-fluorophenylboronic acid, 18 mg bis(triphenylphosphine)-palladium(II)-chloride is refluxed for 3 hours in 7 ml toluene and 2 ml 2N aqueous potassium carbonate. The solvents are removed in vacuo. Flash chromatography (silicagel, ethyl acetate/hexane 1/1) of the residue yields 130 mg (65%) pure 4-[2-(2-fluoro-phenyl)-6-pyrrolidine-1-yl-pyridine-4-sulfonyl]-phenylamine as a pale yellow solid mp.: 246-248° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH2:8][N:9]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:10][CH:11]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26](=[O:39])[C@@H:27]([NH2:38])[CH2:28][CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.COC(=O)C(N1C(=O)CCN(C(=O)/C=C/C2C=CC(Cl)=C(Cl)C=2)CC1)CC(O)=O.C(N(CC)CC)C.B.N1C=CC=CC=1>ClCCCl.C(O)C.C(O)(=O)C>[CH3:24][O:25][C:26](=[O:39])[C@@H:27]([NH:38][CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:23])[CH2:28][CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)[C@@H](N)CCOCc1ccccc1
Reactant: CC(C)(C)OC(=O)CCN(CC=O)C(=O)OCc1ccccc1
Agent: B
Agent: COC(=O)C(CC(=O)O)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCOCc1ccccc1)NCCN(CCC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
3.71 g (11.55 mmol) of 3-[benzyloxycarbonyl-(2-oxo-ethyl)-amino]-propionic acid tert-butyl ester and 3.00 g (11.55 mmol) of (S)-2-amino-4-benzyloxy-butyric acid methyl ester; hydrochloride (intermediate 7) were dissolved in 1,2-dichloroethane/ethanol 1:1 80 ml) and treated with 1.93 ml (13.86 mmol) of triethylamine, 3.03 ml of acetic acid and 3.03 ml (24.25 mmol, 8 M in pyridine) of pyridine-borane complex (cooling with a water bath to room temperature). The reaction was stirred at room temperature over 1¼ h, then partitioned between aq. sodium hydrogencarbonate solution and diethyl ether (3×). The organic phases were washed with sat. aq. sodium hydrogencarbonate solution, 10% aq. sodium chloride solution, dried over Na2SO4 evaporated and purified by flash silica gel column (dichloromethane/n-heptane 1:1 to dichloromethane, then dichloromethane/ethyl acetate 4:1 to ethyl acetate) to yield 4.81 g (79%) of the titled compound as colorless oil. MS: 529.2 (MH+).
Reaction SMILES: Cl.Cl.Cl.[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@@H:10]([N:14]1[CH2:19][CH2:18][N:17]([C:20]3([CH3:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH2:16][C@@H:15]1[CH3:27])[C@H:9]([O:28][CH2:29][CH3:30])[CH2:8]2.[CH3:31][C:32]1[C:37]([C:38](O)=[O:39])=[C:36]([CH3:41])[N:35]=[CH:34][N:33]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.CO.CCOC(C)=O>[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([N:14]1[CH2:19][CH2:18][N:17]([C:20]3([CH3:26])[CH2:21][CH2:22][N:23]([C:38]([C:37]4[C:32]([CH3:31])=[N:33][CH:34]=[N:35][C:36]=4[CH3:41])=[O:39])[CH2:24][CH2:25]3)[CH2:16][C@@H:15]1[CH3:27])[C@H:9]([O:28][CH2:29][CH3:30])[CH2:8]2
Reactant: Cc1ncnc(C)c1C(=O)O
Reactant: CCO[C@@H]1Cc2cc(Br)ccc2[C@H]1N1CCN(C2(C)CCNCC2)C[C@@H]1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCO[C@@H]1Cc2cc(Br)ccc2[C@@H]1N1CCN(C2(C)CCN(C(=O)c3c(C)ncnc3C)CC2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a slurry of (2S)-1-[(1R,2R)-5-bromo-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-2-methyl-4-(4-methylpiperidin-4-yl)piperazine trihydrochloride (50 mg, 0.0916 mmol) in methylene chloride (6 mL) were added 4,6-dimethyl-pyrimidine-5-carboxylic acid (27.88 mg, 0.183 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (21.07 mg, 0.11 mmol), 1-hydroxybenzotriazole (13.62 mg, 0.101 mmol) and triethylamine (0.0894 mL, 0.641 mmol). The reaction mixture was stirred at room temperature overnight. Direct chromatography on silica gel with 10% MeOH/EtOAc (1% NH4OH) afforded the desired product (42 mg, 80%). LC-MS [M+1]=570.10; 572.05.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2[CH:24]=[CH:23][N:22]([CH2:25][C@@H:26]([NH2:28])[CH3:27])[N:21]=2)[CH:16]=[CH:17][C:18]=1[Cl:19]>>[C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:28][C@@H:26]([CH3:27])[CH2:25][N:22]2[CH:23]=[CH:24][C:20]([C:15]3[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([Cl:12])[CH:14]=3)=[N:21]2)=[O:11])[NH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(Cl)c(Cl)c2)n1
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(Cl)c(Cl)c3)n2)[nH]n1
Yield: 12.61 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 3-acetyl-1H-pyrazole-5-carboxylic acid (71.9 mg, 0.466 mmol) and (S)-1-(3-(3,4-dichlorophenyl)-1H-pyrazol-1-yl)propan-2-amine (126 mg, 0.466 mmol). The product was purified by recrystallization from acetonitrile. Yield 12.61%. 1H-NMR (400 MHz; DMSO-d6): δ 1.05-1.25 (m, 3H), 4.18-4.53 (m, 3H), 6.79 (s, 1H), 7.31 (s, 1H), 7.57-7.85 (m, 3H), 7.89-7.98 (m, 1H), 8.39-8.54 (m, 1H), 14.05& 14.12 (2 broad s, 1H).