Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)[CH:21]=[C:22]1[S:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]>>[F:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][CH:35]([NH:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]2[C:14]3[NH:13][C:12](=[O:15])[NH:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:34][CH2:33]1)[CH:21]=[C:22]1[S:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1CCN(c2ccc(C=C3SC(=O)NC3=O)cc2F)CC1
Product: O=C1NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)c(F)c2)S1

Procedure:
The title compound was prepared from 4-((2S)-3-amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one (U.S. Pat. No. 5,786,356/1998) and 5-[3-fluoro-4-(4-oxo-piperidin-1-yl)-benzylidene]-thiazolidine-2,4-dione (which was obtained in Example 62) according to the procedure of Example 63 as an olive green solid; mp 162–164° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.66–1.74 (m, 2H), 2.07–2.17 (m, 2H), 2.74–2.83 (m, 2H), 3.12–3.15 (m, 2H), 3.43–3.48 (m, 1H), 3.52–3.56 (m, 2H), 3.98–4.11 (m, 1H), 5.63 (brs, 1H), 6.62 (m, 2H), 6.87 (t, J=8.1 Hz, 1H), 7.18 (t, J=9.1 Hz, 3H), 7.27–7.35 (m, 1H), 10.60 (s, 1H), 10.7 (s, 1H); MS (ES) m/z: 527.9 (MH+); HRMS Calcd. for C25H28FN5O5S (MH+): 528.1716. Found: 528.1702.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S:12]([C:14]2[N-:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=3[N:15]=2)=[O:13])=[N:4][CH:3]=1.[CH3:25][C:26]1[C:31]([O:32][CH3:33])=[C:30]([CH3:34])[C:29]([CH2:35][S:36]([C:38]2[N-:42][C:41]3[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:40]=3[N:39]=2)=[O:37])=[N:28][CH:27]=1.O.O.O.[Mg+2:52]>CO>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:13])[C:14]2[N-:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=3[N:15]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[CH3:25][C:26]1[CH:27]=[N:28][C:29]([CH2:35][S+:36]([O-:37])[C:38]2[N-:42][C:41]3[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:40]=3[N:39]=2)=[C:30]([CH3:34])[C:31]=1[O:32][CH3:33].[Mg+2:52]
Reactant: COc1ccc2[n-]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Mg+2]
Solvent: O
Solvent: CO
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 61.9 %

Procedure:
Esomeprazole magnesium trihydrate (20 g) was dissolved in methanol (200 ml) at 25-30° C. Any undissolved material was filtered off and triethylamine (0.2 ml) was added to the filtrate. The clear solution thus obtained was subjected to spray drying with an inlet temperature of 65-68° C. and an outlet temperature of 22-42° C. The solid was further dried under vacuum at 60-65° C. for 14 to 15 hours to yield 11.5 g of esomeprazole magnesium of amorphous form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][N:12]=[C:11](C)[C:10]=1C#N.S(=O)(=O)(O)O.N([O-])=O.[Na+].[CH3:26][C:27](=[O:31])[O:28]CC>>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][N:12]=[C:11]([CH3:10])[C:26]=1[C:27]([OH:28])=[O:31]
Reactant: CCOC(C)=O
Reactant: Cc1ccc(-c2snc(C)c2C#N)c(F)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1ccc(-c2snc(C)c2C(=O)O)c(F)c1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Into a 25-mL round-bottom flask, was placed 5-(2-fluoro-4-methylphenyl)-3-methyl-1,2-thiazole-4-carbonitrile (200 mg, 0.86 mmol, 1.00 equiv). This was followed by the addition of sulfuric acid (conc.) (10 mL). The mixture was stirred for 1 h at 120° C. To this was added NaNO2 (aq) (201 mg) at 0-5° C. The resulting solution was stirred for 30 min at 50° C. The resulting solution was diluted with 50 mL of EA. The organic phase was washed with 1×20 mL of 2N HCl and 1×20 mL brine. The mixture was dried over anhydrous sodium sulfate and concentrated. This resulted in 180 mg (crude) of 5-(2-fluoro-4-methylphenyl)-3-methyl-1,2-thiazole-4-carboxylic acid as a yellow oil.
Reaction SMILES: OO.C(O)(=[O:5])C.[C:7]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)(=[O:9])[CH3:8].C([O-])([O-])=O.[K+].[K+]>CC(O)C>[C:7]([C:10]1[CH:11]=[N+:12]([O-:5])[CH:13]=[CH:14][CH:15]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)O
Reactant: CC(=O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CC(C)O
Product: CC(=O)c1ccc[n+]([O-])c1
Temperature: 25 °C

Procedure:
Hydrogen peroxide (20.9 ml, 0.61453 moles, Baker) and acetic acid (125 ml, Baker) were combined and stirred at room temperature (RT). The 3-acetylpyridine (50 ml, 0.40984 moles, Aldrich), distilled prior to use (94° C., 2.00 mm Hg), was added and then, the reaction mixture was stirred overnight (O/N) at 95° C. Next, the reaction mixture was cooled to RT and then, neutralized with saturated K2CO3 (400 ml). Then, 5 g of KSO3 was added to destroy the remaining hydrogen peroxide. Next, methanol (750 ml) was added and the resultant cloudy solution was filtered. The filtrate was then evaporated to dryness using a rotary evaporator. The semi-solid was extracted repeatedly with hot CH2Cl2 (4×500 ml) and combined. Next, the solvent was removed leaving approximately 44 g of a crude, pale yellow solid. The crude solid was dissolved in hot 2-propanol (150 ml) and stirred until cool in an icebath. The white solid which precipitated was collected, washed with 2-propanol (100 ml) and dried in a vacuum dessicator O/N at 50° C. The air-dried weight was 41 g. HPLC analysis of the recrystallized sample (m.p. 146°-147° C.) showed a single principal peak 96% by area.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[O:9][CH2:8]1.[O:10]1CCCC1.Cl(O)(=O)(=O)=O>O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([OH:9])[CH2:8][OH:10]
Reactant: BrCCCCCC1CO1
Reactant: C1CCOC1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: OCC(O)CCCCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
42 g of 1-bromo-6,7-epoxyheptane were introduced into a mixture of 400 ml of tetrahydrofuran and 235 ml of water, which had been adjusted to pH 2 with perchloric acid, at room temperature. After stirring at room temperature for 8 hours, the mixture was neutralized, evaporated under reduced pressure and the residue was extracted with methylene chloride. After removal of the solvent, 41.5 g of crude 1-bromo-6,7-dihydroxyheptane were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH3:9])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[N:34][CH:35]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:30]1[CH:35]=[N:34][C:33]([Cl:36])=[CH:32][CH:31]=1
Reactant: Clc1ccc(Br)cn1
Reactant: COc1ccccc1N(C)C(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccccc1N(C)C(=O)c1ccc(Cl)c(-c2ccc(Cl)nc2)c1
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-N-(2-methoxy-phenyl)-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (60 mg, 0.15 mmol), 5-bromo-2-chloro-pyridine (29 mg, 0.15 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol), K2CO3 (41 mg, 0.3 mmol) in dioxane (1 mL), was heated at 100° C. for 12 hrs. The mixture was filtered and purified by prep. LCMS to yield 4-chloro-3-(6-chloro-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide 2-1.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].[C:14](Cl)(=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:16]([O:15][C:14]([NH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(C(=O)O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NC(C(=O)O)c1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.5 %

Procedure:
To a solution of 2-amino-2-phenylacetic acid (500 mg, 3.31 mmol) in 2N sodium hydroxide (1.65 ml, 3.31 mmol) stirred at 0° C., benzyl carbonochloridate (512 μl, 3.64 mmol) and 2N sodium hydroxide (1.82 ml, 3.64 mmol) were simultaneously added dropwise from two different syringes. The reaction was stirred at RT for 45 minutes, and a precipitate appeared. Water was added, and the solution was extracted with Et2O. The aqueous phase was acidified with 1N HCl and the desired product was extracted again with Et2O. The combined organic phases were dried over Na2SO4, filtered and evaporated to obtain 2-(benzyloxycarbonylamino)-2-phenylacetic acid (855 mg; 91% yield).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@@H:8]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:12]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:11]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@:10]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH3:56])=[C:50]([F:57])[C:49]=3[F:58])[CH:41]=2)([O:38][CH3:39])[O:9]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[CH2:15]([O:14][C@H:13]1[C@H:12]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:11]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@:10]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH3:56])=[C:50]([F:57])[C:49]=3[F:58])[CH:41]=2)([O:38][CH3:39])[O:9][C@@H:8]1[CH2:7][OH:6])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.3 %

Procedure:
To a solution of tert-butyl-dimethyl-[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]silane 23i (16.29 g, 18.95 mmol) in tetrahydrofuran (100 mL) was added tetrabutylammonium fluoride (37.9 mL, 37.9 mmol, 1 M in tetrahydrofuran) at room temperature. The mixture was stirred at room temperature for 12 hours, and then ethyl acetate (200 mL) was added. The resulting mixture was washed with saturated aqueous sodium chloride (100 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=15/1 to give the title compound 23j as a yellow solid (4.42 g, 31%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.29 (m, 10H), 7.22 (s, 2H), 7.5 (m, 4H), 6.95 (m, 2H), 6.76 (m, 1H), 6.51 (m, 1H), 4.92 (m, 3H), 4.66 (d, 1H), 4.47 (d, 1H), 4.14 (m, 1H), 4.03 (m, 3H), 3.88 (m, 3H), 3.77 (m, 1H), 3.66 (m, 2H), 3.27 (d, 1H), 3.05 (s, 3H), 1.39 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[N:7]=[C:8]([NH:10][CH:11]=[C:12]([C:18]([O:20]CC)=[O:19])[C:13](OCC)=[O:14])[S:9][C:5]=2[CH:4]=1.[OH-:25].[Na+].O>C(O)C>[SH:9][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:24]=[CH:23][C:6]=1[N:7]1[C:13](=[O:14])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][NH:10][C:8]1=[O:25]
Reactant: CCOC(=O)C(=CNc1nc2ccc(OC)cc2s1)C(=O)OCC
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-n2c(=O)[nH]cc(C(=O)O)c2=O)c(S)c1

Procedure:
25 g. Diethyl N-(6-methoxybenzthiazol-2-yl)-aminomethylenemalonate are introduced into a solution of 36 g. sodium hydroxide, 360 ml. water and 120 ml. ethanol which has been heated to 70° C. and the reaction mixture is heated under reflux for 30 minutes. A part of the ethanol is then removed in vacuo, filtered and, after cooling, the filtrate is acidified with 2 N hydrochloric acid. 1-(2-Mercapto-4-methoxyphenyl)-5-carboxypyrimidine-2,6-dione is obtained in a yield of 14.7 g. (70% of theory). According to the melting point and the IR, UV and NMR spectra, the product is identical with the compound prepared according to Variant I.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[OH:21][CH:22]1[CH2:26][CH2:25][NH:24][CH2:23]1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:24]4[CH2:25][CH2:26][CH:22]([OH:21])[CH2:23]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: OC1CCNC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(O)C3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.2 %

Procedure:
A mixture of 2.1 g (7.8 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 20 ml acetonitrile, 1.2 g (7.8 mmole) 1,8-diazobicyclo[5.4.0]undec-7-ene and 0.7 g (7.8 mmole) of 3-hydroxypyrrolidine was refluxed for 2.5 hours. The reaction was allowed to cool and stirred at room temperature for 48 hours. The resulting precipitate was filtered, washed with diethyl ether, then taken up in isopropyl alcohol. The solid was filtered and washed with ether until dry to give 2.0 g of the title compound, mp 276°-278° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C@@H:12]1[CH2:16][C@@H:15]([S:17]([CH2:20][CH:21]2[CH2:23][CH2:22]2)(=[O:19])=[O:18])[CH2:14][NH:13]1)=[O:11].[C:24](OC(C)(C)C)(=[O:29])[CH2:25][C:26]([CH3:28])=[O:27]>C(N(CC)CC)C>[CH3:8][O:9][C:10]([C@@H:12]1[CH2:16][C@@H:15]([S:17]([CH2:20][CH:21]2[CH2:23][CH2:22]2)(=[O:18])=[O:19])[CH2:14][N:13]1[C:24](=[O:29])[CH2:25][C:26](=[O:27])[CH3:28])=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1C(=O)CC(C)=O

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-4-cyclopropylmethanesulfonyl-pyrrolidine-2-carboxylic acid methyl ester trifluoroacetate was reacted with tert-butyl acetoacetate in the presence of triethylamine to give the title compound as brown solid. MS (ESI): m/z=332.2 [M+H]+.
Reaction SMILES: FC(F)(F)COP([CH2:13][C:14]([O:16][CH3:17])=[O:15])(OCC(F)(F)F)=O.C1OCCOCCOCCOCCOCCOC1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:48][C:49]1[C:54]([CH:55]=O)=[C:53]([Cl:57])[N:52]=[CH:51][N:50]=1>C1COCC1>[Cl:48][C:49]1[C:54](/[CH:55]=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])=[C:53]([Cl:57])[N:52]=[CH:51][N:50]=1
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)/C=C\c1c(Cl)ncnc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 125 %

Procedure:
To a solution of methyl 2-(bis(2,2,2-trifluoroethoxy)phosphoryl)acetate (2.460 mL, 11.63 mmol) in 70 mL of THF at −78° C. was added 18-CROWN-6 (9.14 g, 34.6 mmol). Added KHMDS (23.05 mL, 11.53 mmol) dropwise over 15 min and allowed the resulting mixture to stir at −78° C. for 30 min. Then 4,6-dichloropyrimidine-5-carbaldehyde (1.7 g, 9.61 mmol) was added in 20 mL of THF and the resulting mixture was allowed to stir at −78° C. for 1.5 h. The reaction was quenched with about 25 mL sat'd NH4Cl, allowed to warm to RT and then most of the THF was removed by rotary evaporator. The resulting mixture was diluted with 1:1 hexane/ethyl acetate, washed with 1N HCl, sat'd aq sodium bicarbonate and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford an oil (2.8 g). The residue was purified by silica gel chromatography (80 g ISCO cartridge, 0-80% ethyl acetate/hexane) to afford Example 116A (1.55 g, 69%) as an oil, which was contaminated with ˜10% of the (E)-olefin isomer. The material was used without further purification. LRMS (ESI): 233.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].C(O[C:31]1(O[Si](C)(C)C)[CH2:33][CH2:32]1)C.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH:31]1([N:17]2[CH2:18][CH2:19][N:14]3[C:13]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:12][C:11]([C:9]([NH:8][C@@H:3]([C:2]([CH3:27])([CH3:26])[CH3:1])[C:4]([NH:6][CH3:7])=[O:5])=[O:10])=[C:15]3[CH2:16]2)[CH2:33][CH2:32]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CNCC2)C(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C1CC1)CC2)C(C)(C)C
Temperature: 60 °C

Procedure:
Compound 2 (60 mg, 0.16 mmol) was dissolved in methanol and (1-ethoxycyclopropoxy)trimethylsilane (170 mg, 0.94 mmol) was added followed by sodium cyanoborohydride (46 mg, 0.73 mmol) and acetic acid (98 mg, 1.62 mmol). The reaction mixture was heated at 60° C. overnight, cooled down to room temperature, filtered and concentrated.
Reaction SMILES: Cl[CH2:2][N:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[CH2:15]([OH:18])[CH2:16][OH:17].C(N(CC)CC)C>C(OCC)(=O)C>[OH:17][CH2:16][CH2:15][O:18][CH2:2][N:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: CN(C)C(=O)N(CCl)c1ccccc1
Reactant: OCCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)C(=O)N(COCCO)c1ccccc1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
212 g (1 mole) of 1-chloromethyl-1-phenyl-3,3-dimethylurea were dissolved in 100 ml of anhydrous ethyl acetate and 63 g (1.0 mole) of ethylen glycol and 60 g (1.0 mole) of triethylamine were added dropwise whilst cooling with ice. After stirring for 2 hours at 10° to 15°C, the triethylamine hydrochloride used was filtered off and the solvent was distilled off. 238 g of 1-β-hydroxyethoxymethyl-1-phenyl-3,3-dimethylurea were obtained as an oil, in quantitative yield.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].O.[N+:9]([C:12]1[CH:21]=[C:20]2[C:15]([NH:16][C:17](=[O:23])[C:18](=[O:22])[NH:19]2)=[CH:14][C:13]=1[S:24](Cl)(=[O:26])=[O:25])([O-:11])=[O:10]>>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:24]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:12]=1[N+:9]([O-:11])=[O:10])[NH:19][C:18](=[O:22])[C:17](=[O:23])[NH:16]2)(=[O:25])=[O:26]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(S(=O)(=O)Cl)cc2[nH]c1=O
Reactant: OCCNCCO
Solvent: O
Product: O=c1[nH]c2cc([N+](=O)[O-])c(S(=O)(=O)N(CCO)CCO)cc2[nH]c1=O
Reaction time: 16 h
Yield: 52 %

Procedure:
To a solution of 10,5 g (0.1 mole) of diethanolamine in 40 ml of water 6.11 g (0.02 mole) of 1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxalinesulfonyl chloride are added under stirring, the reaction mixture is stirred at room temperature for 6 hours and then allowed to stand for 16 hours. The separated crystals are filtered off, washed with water, dried and recrystallized from acetone. Thus 3.90 g (52%) of N,N-bis(2-hydroxyethyl)-1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: 310-321° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)[C:8]#N)=[CH:4][CH:3]=1.[CH:22]([CH:24]=C)=O>>[F:1][C:2]1[CH:21]=[CH:20][C:5]([N:6]2[CH:24]=[CH:22][CH:8]=[C:7]2[C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: N#CC(Nc1ccc(F)cc1)c1ccc(S(N)(=O)=O)cc1
Reactant: C=CC=O
Product: NS(=O)(=O)c1ccc(-c2cccn2-c2ccc(F)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-fluoroanilino)-α-(4-sulfamoylphenyl)acetonitrile [prepared as described in step (ii) above] and acrolein as starting materials, the title compound was obtained as a white powder (yield 48%), melting at 160-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:70][CH2:71][CH2:72][OH:73]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:25](=[O:26])[NH:70][CH2:71][CH2:72][OH:73])([CH3:28])[CH3:27])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)CO)C12C(=O)Nc1cc(Cl)ccc12
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NCCO)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxy-1,1-dimethyl-ethoxy)phenyl]-2′-[5-fluoro-2-methylphenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (35 mg, 0.06 mmol), EDCl (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (1 mL) was added 2-amino-ethanol (11 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (9 mg).
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1.[H][H]>[Ni].O1CCCC1>[OH:1][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: CCOC(=O)N1CCC(CCC=O)CC1
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(CCCO)CC1
Yield: 98.3 %

Procedure:
A mixture of 36 parts of ethyl 4-(3-oxopropyl)-1-piperidinecarboxylate and 450 parts of tetrahydrofuran was hydrogenated at normal pressure and at 20° C. with 2 parts of Raney nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in 260 parts of dichloromethane. The organic layer was washed with 100 parts of a diluted hydrochloric acid solution, dried, filtered and evaporated, yielding 36 parts (98.3%) of ethyl 4-(3-hydroxypropyl) -1-piperidinecarboxylate as a residue (int. 47).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)=[O:4].[NH:15]1[CH:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:16]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][O:13][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:16]2[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=[N:15]2)[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc(C(=O)CBr)cc1OC
Reactant: CCOC(=O)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccnn1CC(=O)c1ccc(OC)c(OC)c1
Reaction time: 8 h

Procedure:
To a mixture of 2-bromo-1-(3,4-dimethoxyphenyl)ethanone (1.95 g, 7.53 mmol) and ethyl 1H-pyrazole-3-carboxylate (1.22 g, 8.72 mmol) in acetone (36 mL) at room temperature was added potassium carbonate (1.28 g, 9.23 mmol). Mixture stirred vigorously overnight and then was concentrated under reduced pressure. Resulting residue was taken up in ethyl acetate and washed with 4:1 water/brine. Layers were separated and aqueous was extracted with ethyl acetate. Combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. Resulting residue was purified by silica gel column chromatography (10-60% ethyl acetate in hexanes) to yield ethyl 1-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-1H-pyrazole-5-carboxylate 5.01.