Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]([CH2:25][C:26]3[CH:37]=[CH:36][C:29]([O:30][CH2:31][C:32]([O:34]C)=[O:33])=[CH:28][CH:27]=3)[C:19]([NH:21][CH2:22][CH2:23][CH3:24])=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO.C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]([CH2:25][C:26]3[CH:37]=[CH:36][C:29]([O:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:28][CH:27]=3)[C:19]([NH:21][CH2:22][CH2:23][CH3:24])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)NCCC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)O)cc3)C(=O)NCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a solution of methyl [4-({{4-[(4-butylphenyl)ethynyl]benzyl}[(propylamino)carbonyl]-amino}methyl)phenoxy]acetate (47 mg, 0.089 mmol) in MeOH/THF (2 ml, (1/1)) was added an aqueous solution of NaOH (2 mL, 1N). The reaction mixture was stirred at rt for 2 hrs. Then an aqueous solution of HCl (7 mL, 1N) was added and extracted with Et2O (2×7 mL). The combined organic layers were dried over Na2SO4 and the solvents were removed under reduced pressure to give 42 mg (77%) of the title compound as a yellow oil. HPLC, Rt: 5.1 min (purity: 83.9%). LC/MS, M+(ESI): 513.4, M−(ESI): 511.4. 1H NMR (DMSO-d6) Ε: 7.49 (d, J=8.3 Hz, 2H), 7.44 (d, J=7.9 Hz, 2H), 7.22 (m, 4H), 7.11 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 6.53 (t, J=5.3 Hz, 1H), 4.63 (s, 2H), 4.37 (s, 2H), 4.31 (s, 2H), 3.03 (m, 2H), 2.60 (t, J=7.7 Hz, 2H), 1.58-1.22 (m, 6H), 0.89 (t, J=7.3 Hz, 3H), 0.78 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:5]=2[N:6]=1.[CH2:17]([O:24][C@@H:25]1[C@H:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:28]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:27][CH:26]1Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>CC#N.CCOC(C)=O>[Cl:1][C:2]1[N:3]([C@@H:26]2[O:27][C@H:28]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:29]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:25]2[O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1cc2nc(Cl)[nH]c2cc1[N+](=O)[O-]
Reactant: ClC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc2nc(Cl)n([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c2cc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
To a mixture of 0.541 g (2.23 mmol) of 2-chloro-5,6-dinitrobenzimidazole in 12 mL of MeCN, was added 0.558 mL (2.23 mmol) of BSA. The reaction mixture was stirred at 75° C. for 15 min to give a clear solution. This solution was treated with the above MeCN solution of 2,3,5-tri-O-benzyl-D-ribofuranosyl chloride and 0.56 mL (2.90 mmol) of TMSOTf at 75° C. for 30 min. The reaction mixture was cooled and diluted with EtOAc (50 mL). The EtOAc solution was washed with sat. NaHCO3 solution (50 mL×2), sat. NaCl solution (50 mL), dried (Na2SO4), and evaporated. The residue was chromatographed on a silica column (2.2×18 cm, eluted with 20% EtOAc/hexane). Evaporation of fractions 10-14 (20 mL per fraction) gave 0.502 g (35%) of 60 as a syrup. MS: (FAB) m/e 645 (1%, MH+ =645). 1H NMR (DMSO-d6): δ8.50, 8.49 (2×s, 2,7-H and 4-H), 7.34, 6.90 (2×m, 15, 3×Ph), 6.09 (d, 1,1'-H, J1'-2' =8.0 Hz), 4.73~4.27 (m, 9,2'-H, 3'-H, 4'-H, and 3×PhCH2), 3.77 (dd, 1,5'-H, J4'-5' =2.0 Hz, J5'-5" =11.0 Hz), 3.65 (dd, 1,5"-H, J4'-5" =2.5 Hz).
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][N:15]2[C:21](=[O:22])[CH2:20][CH2:19][NH:18][C@H:17]([CH3:23])[CH2:16]2)[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.C(N(CC)CC)C.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([F:41])=[C:36]([N:38]=[C:39]=[O:40])[CH:37]=1>ClCCl>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([F:41])=[C:36]([NH:38][C:39]([N:18]2[CH2:19][CH2:20][C:21](=[O:22])[N:15]([CH2:14][CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:6][CH2:7]4)[C@H:4]([OH:3])[CH2:11]3)[CH2:16][C@H:17]2[CH3:23])=[O:40])[CH:37]=1
Reactant: O=C=Nc1cc(Cl)ccc1F
Reactant: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1C(=O)Nc1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
0.022 g (purity: 76% corresponds to 0.04 mmol) of (R)-4-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-[1,4]diazepan-5-one dihydrochloride (example 58E) was suspended in 1 ml dichloromethane. The reaction mixture was treated at room temperature with 0.031 ml (0.22 mmol, 5 eq.) of triethylamine and at 0° C. with 8 mg (0.05 mmol, 1.1 eq.) 5-chloro-2-fluorophenyl isocyanate. The solution was stirred overnight and warmed up to room temperature. The solution was evaporated. The crude product was purified by flash chromatography (20 g amine-silica, ethyl acetate/n-heptane 1:1, 4:1, 9:1, 100%, ethyl acetate/ethanol 95:5, 9:1) to give 0.010 g (48%) of the title compound as white solid. MS: 467.4 (MH+, Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:32]([OH:37])[CH2:33][CH2:34][C:35]#[CH:36].CN(C=O)C>N(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:36]#[C:35][CH2:34][CH2:33][CH2:32][OH:37])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCCCO
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#CCCCO)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added 4-pentyn-1-ol (0.056 mL). Anhydrous DMF (20 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H20. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 100% CH2Cl2 (1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1L), and 2% MeOH in CH2Cl2 (5L)). Product-containing fractions are combined, concentrated, and recrystallized from hot acetonitrile to afford 117.5 mg (43%) of the desired product as a creme solid.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.Cl.[C:19]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)#[CH:20].[O-]S([O-])(=O)=O.[Mg+2]>>[N:24]1[CH:25]=[CH:26][C:21]([C:19]#[C:20][C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)=[CH:22][CH:23]=1
Reactant: C#Cc1ccncc1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: C(#Cc1cccc2c3c([nH]c12)C1CCN(CC1)C3)c1ccncc1

Procedure:
The product of Example 1B (100 mg, 0.34 mmol), 4-ethynylpyridine hydrochloride (144 mg, 1.03 mmol; Aldrich) and MgSO4 (83 mg, 0.69 mmol) were combined and processed as described in Example 3 to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.05-2.16 (m, 4 H), 3.03-3.14 (m, 2 H), 3.18-3.22 (m, 1 H), 3.22-3.29 (m, 2 H), 4.26 (s, 2 H), 7.03 (t, J=7.6 Hz, 1 H), 7.29 (dd, J=7.5, 0.8 Hz, 1 H), 7.41 (dd, J=7.9, 0.9 Hz, 1 H), 7.62-7.66 (m, 2 H), 8.53-8.58 (m, 2 H); MS (APCI) m/z 314 (M+H)+.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1.CCN(CC)CC>C1COCC1>[CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C1CCC(=O)O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 82.8 %

Procedure:
To a solution of 4.13 mL (4.32 g, 40 mmol) of benzyl alcohol and 4.40 g (44 mmol) of succinic anhydride in 100 mL of THF at 0° C. was added at once 12.24 mL (8.90 g, 88 mmol) of Et3N. The mixture was allowed to come to room temperature and stirred for 18 h at which time it was concentrated under vacuum to a viscous oil and partitioned between 100 mL of 1 N HCl and 100 mL of EtOAc. The EtOAc layer was extracted with 84 mL of 5% NaHCO3 solution. The aqueous layer was acidified with concentrated HCl solution to pH 1 and extracted with two 50 mL portions of EtOAc. The EtOAc layers were combined and washed with brine, dried (MgSO4), filtered, and concentrated to give 6.9 g (83%) of 21 as a white chunky solid: 1H NMR (CDCl3) 2.70 (s, 4H), 5.22 (s, 2H), 7.38 (s, 5H).
Reaction SMILES: [C:1]1([C:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=3)[C:8]=2[CH:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:35].[C:36](OCC)(=O)C>>[ClH:35].[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=3)[C:8]=2[CH2:19][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:36]3)=[CH:23][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc2c(c1)CCC(c1ccccc1)=C2C(O)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Product: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3)ccc2c1
Reaction time: 0.01 h
Yield: 89 %

Procedure:
To a solution of the product of Example 7 (8.7 g, 18.5 mmol) stirring in ethyl acetate (100 mL) was added a saturated solution of hydrochloric acid gas in ethyl acetate (250 mL). After 0.5 min, the resulting solution was concentrated to give 8.0 g (89%) of the desired product as a white foam which was used without further purification: 1H-NMR (300 MHz, DMSO) δ 7.70-7.85 (m, 4H), 7.30-7.50 (m, 7H), 7.10 (s, 1H), 6.80-7.00 (m, 2H), 4.25-4.40 (m, 4H), 4.00-4.20 (br s, 3H), 3.35-3.55 (m, 4H), 2.85-3.55 (m, 2H), 1.70-1.90 (m, 4H), 1.30-1.45 (m, 2H); Anal. Calc'd for: C, 76.29; H, 7.02; N, 2.87. Found: C, 76.56; H, 7.18; N, 2.91; MS (FD) m/e 452 (M+-hydrochloric acid).
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[C:5]2=[CH:6][S:7][CH:8]=[C:4]2[C:3](=O)[NH:2]1.N1C=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>O>[S:1]1(=[O:11])(=[O:10])[C:5]2=[CH:6][S:7][CH:8]=[C:4]2[C:3](=[S:19])[NH:2]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1NS(=O)(=O)c2cscc21
Solvent: O
Solvent: c1ccncc1
Product: O=S1(=O)NC(=S)c2cscc21
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 40 %

Procedure:
To a mixture of 5.6 g. (0.03 mole) of thieno[3,4-d]isothiazol-3(2H)-one-1,1-dioxide in 50 ml. of dry pyridine is added 5.6 g. (0.016 mole) of phosphorus pentasulfide portionwise over 3 minutes. The viscous mixture is slowly heated in an oil bath under an atmosphere of nitrogen. The temperature of the oil bath is slowly increased to 80° C. after 30 minutes. The temperature of the oil bath is then kept at 80° C. for 25 minutes, the internal temperature reading 63° C. The solution is cooled to 50° C. and is added dropwise over 5 minutes to 200 ml. of water and cooled in an ice bath. The precipitate which forms is collected and discarded. The filtrate is cooled in ice and acidified with concentrated hydrochloric acid to pH 1. The precipitate which forms is collected to yield 40% of material. In another experiment, a sample is recrystallized from water to obtain an analytical sample, m.p. 196°-8° (dec.).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([OH:18])=[O:17])[CH2:14][O:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:23]O>>[CH3:23][O:17][C:16]([C@@H:15]1[CH2:14][O:13][CH2:12][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:18]
Reactant: O=C(O)[C@@H]1COCN1C(=O)OCc1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1COCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (s)-(−)-3-(Benzyloxycarbonyl)-4-oxazolidinecarboxylic acid 9 (1.75 g, 6.96 mmol) in anhydrous methanol (15 mL) was added thionyl chloride (1.02 mL, 13.9 mmol) at 0° C. After 30 minutes, the ice/water bath was removed and the reaction mixture continued to be stirred at room temperature for 3.5 hours. The reaction was quenched by addition of saturated sodium bicarbonate and diluted with dichloromethane (100 mL) and water (50 mL). The mixture was separated and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The solvents were removed under reduced pressure and the residue was purified by silica gel chromatography (Hexanes/AcOEt, 1.5:1) to give (s)-(−)-3-(Benzyloxycarbonyl)-4-oxazolidinecarboxylic methyl ester 10 as colorless oil (1.84 g, y=99%). 1H NMR (400 Hz, CDCl3): the compound appears as a pair of distinct rotomers. δ 7.35 (bs, 5H), 5.22-4.99 (m, 4H), 4.53-4.45 (m, 1H), 4.22-4.09 (m, 2H), 3.76 (s, 1.5H), 3.65 (s, 1.5H); MS (m/z): found 288.0 (M+Na)+.
Reaction SMILES: [H-].[K+].[NH2:3][C:4]1[N:8]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:7]=[C:6]([C:21]#[N:22])[C:5]=1[S:23]([CH3:25])=[O:24].[CH2:26]([S:28]([CH:31]=[CH2:32])(=[O:30])=[O:29])[CH3:27].[Cl-]>CN(C)C=O>[Cl:20][C:10]1[CH:11]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:13]=[C:14]([Cl:15])[C:9]=1[N:8]1[C:4]([NH:3][CH2:27][CH2:26][S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])=[C:5]([S:23]([CH3:25])=[O:24])[C:6]([C:21]#[N:22])=[N:7]1
Reactant: CS(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: C=CS(=O)(=O)CC
Agent: [Cl-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)CCNc1c(S(C)=O)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 31.1 %

Procedure:
To a suspension of 35% potassium hydride in oil (0.7 g) in dry N,N-dimethylformamide (DMF) was added a solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(methylsulfinyl)-1H-pyrazole-3-carbonitrile (10.0 g) in dry DMF dropwise at 4° C. over 10 minutes. After stirring for 20 minutes, vinyl ethyl sulfone (3.13 g) in dry DMF was added during 5 hours at 4° C. The mixture was stirred overnight under nitrogen with warming to 20° C. Ammnonium chloride was added at 4° C., and the mixture extracted (ethyl acetate), washed twice with water, dried (sodium sulfate) and evaporated. Crystallization from ethyl acetate/methanol/hexane gave 1-[2,6-dichlor-4-(trifluoromethyl)phenyl]-5-[2-(ethylsulfonyl)ethylamino]-4-(methylsulfinyl)-1H-pyrazole-3-carbonitrile (4.08 g), m.p.131-132° C. By proceeding in a similar manner the following compounds were prepared:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[C:17](O)(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[OH:24])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccncc1
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccncc1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and isonicotinic acid (pyridine-4-carboxylic acid)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1>>[F:17][C:16]([F:18])([F:19])[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)=[CH:11][CH:12]=1
Reactant: O=C1CCNCC1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Product: O=C1CCN(Cc2ccc(C(F)(F)F)cc2)CC1

Procedure:
1-(4-Trifluoromethylbenzyl)-4-piperidone is prepared from 4-piperidone and α′-chloro-α,α,α-trifluoro-p-xylene essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](Cl)=[N:10][C:9](=[O:14])[N:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].[N-:20]=[N+:21]=[N-:22].[Na+]>C(O)C>[CH2:1]([N:4]1[C:12]2[C:11]3=[N:20][N:21]=[N:22][N:10]3[C:9](=[O:14])[N:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cnc2c1c(Cl)nc(=O)n2CCCCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: C=CCn1cnc2c1c1nnnn1c(=O)n2CCCCC
Yield: 3.5 %

Procedure:
A mixture of 7-allyl-6-chloro-3-pentyl-3,7-dihydro-2H-purin-2-one (0.65 g, 2.3 mol) and sodium azide (0.98 g, 15 mmol) in ethanol (20 mL) was refluxed overnight. The reaction mixture was concentrated under vacuum. The residue was diluted with water and EtOAc. The organic phase was separated and the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative LCMS to provide the desired product as a white powder (0.15 g, 22.6%). LCMS calculated for C13H18N7O (M+H): 288.2; found: 288.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[C:11]1([CH3:14])[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:14][CH:11]1[CH2:13][CH2:12]1
Reactant: Oc1ccc(F)cc1Br
Reactant: CC1(Br)CC1
Product: Fc1ccc(OCC2CC2)c(Br)c1

Procedure:
Starting from commercially available 2-bromo-4-fluoro-phenol and commercially available bromo-methyl-cyclopropane the title compound is obtained as colorless oil after distillation at 5×10−3 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=1.[CH3:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[NH2:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:14]([NH:21][C:20]([CH3:23])([CH3:22])[C:19]([O:18][CH3:17])=[O:24])=[O:16])[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)c1cccc(-c2ccccc2Cl)n1
Reactant: COC(=O)C(C)(C)N
Product: COC(=O)C(C)(C)NC(=O)c1cccc(-c2ccccc2Cl)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(2-chlorophenyl)-2-pyridinecarboxylic acid (CAN 887982-21-0) and 2-methyl-alanine methyl ester as starting materials, MS (LC/MS): 333.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]#[N:13])[C:5]([O:7][CH3:8])=[O:6].OO.C(=O)([O-])[O-:17].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([NH2:13])=[O:17])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(C#N)c(Br)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(C(N)=O)c(Br)c1
Temperature: 25 °C
Reaction time: 18.5 h

Procedure:
Methyl 3-bromo-4-cyanobenzoate (prepared as described in Wang, G. T. et al. Bioorg. Med. Chem. Lett. 2005, 15(1), 153(1) (130 mg, 0.54 mmol) was dissolved in DMSO (1.5 mL) and was cooled in a cold water bath. 30% aqueous hydrogen peroxide (0.1 mL) and potassium carbonate (23.9.0 mg, 0.17 mmol) were added and the mixture was stirred at room temperature for 18.5 h. The reaction mixture was partitioned between ethyl acetate and 10% aqueous lithium chloride. The aqueous portion was extracted with ethyl acetate. The combined organic portions were dried over sodium sulfate, filtered and concentrated to afford methyl 3-bromo-4-(aminocarbonyl)benzoate (quantitative yield) as a yellow oil. GCMS for C9H8BrNO3: 257, 259 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13].[Li]CCCC.CN([CH:23]=[O:24])C>>[Cl:12][C:10]1[CH:11]=[C:2]([CH:23]=[O:24])[CH:3]=[C:4]2[C:9]=1[S:8][CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13]
Reactant: CN(C)C=O
Reactant: CC1(C)CCSc2c(Cl)cc(Br)cc21
Agent: [Li]CCCC
Product: CC1(C)CCSc2c(Cl)cc(C=O)cc21

Procedure:
Using essentially the same procedure as Example 5-20, Step 3, 6-bromo-8-chloro-4,4-dimethyl-3,4-dihydro-2H-thiochromene (954 mg, 3.27 mmol), n-BuLi (1.57 mL, 3.93 mmol) and DMF (1.01 mL, 13.1 mmol) afforded the desired product as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([I:9])[CH:3]=1.[Si]([O:17][CH2:18][CH:19]=O)(C(C)(C)C)(C)C.FC(F)(F)C(O)=O.[BH3-]C#N.[Na+]>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:19][CH2:18][OH:17])=[C:4]([I:9])[CH:3]=1
Reactant: Nc1cnc(Cl)cc1I
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: OCCNc1cnc(Cl)cc1I
Temperature: 25 °C
Reaction time: 12 h
Yield: 190.5 %

Procedure:
To a solution of 6-chloro-4-iodopyridin-3-amine (6.5 g, 25.5 mmol) in CH3OH (1500 mL) was added 2-(tert-butyldimethylsilyloxy)acetaldehyde (18.0 g, 103 mmol). Then trifluoroacetic acid (150 mL) and NaBH3CN (8.0 g, 127 mmol) were added slowly at 0° C. The mixture was allowed to warm to 25° C. and the stirring was continued for an additional 12 hours. The mixture was concentrated under reduced pressure and treated with NaOH (3M) to pH=8. The aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. The solvent was concentrated in vacuo to afford crude product 2-(6-Chloro-4-iodopyridin-3-ylamino)ethanol (14.5 g), that was used in the next step without further purification.
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.O.[CH3:19]O>>[CH3:19][O:4][C:3](=[O:5])[CH:2]([Br:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12]
Reactant: CO
Reactant: O=C(O)C(Br)c1ccccc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)C(Br)c1ccccc1Cl

Procedure:
α-Bromo-2-chlorophenyl acetic acid (350.0 gm) was dissolved in methanol (1.18 Liter) and concentrated sulphuric acid (53.20 gm) was added. The reaction mixture was refluxed for 4 hours. After completion of the reaction, the reaction mixture was distilled out to get a syrupy mass. To the residual mass, water (560 ml) was added and the product was extracted into chloroform (560 ml). The chloroform layer was separated and was treated with 10% aqueous sodium bicarbonate solution (1.12 Litre). The chloroform extract was finally washed with water and chloroform was distilled out to get a syrupy mass to get the titled compound.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([N+:37]([O-:39])=[O:38])=[C:14]([N:17]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:25][CH2:24]4)=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:40])[C:8]1=[O:41])=[O:5])C.[OH-].[Li+]>>[C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([N+:37]([O-:39])=[O:38])=[C:14]([N:17]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:25][CH2:24]4)=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:40])[C:8]1=[O:41])([OH:5])=[O:3]
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccc(CN4CCN(CCc5ccccc5)CC4)c3)cc21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccc(CN4CCN(CCc5ccccc5)CC4)c3)cc21

Procedure:
20 0.6 g (1.1 mmol) of Example 39 were hydrolyzed with lithium hydroxide as in method 1i.