Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)/[CH:4]=[CH:5]/[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC>CCOCC>[CH:6]1(/[CH:5]=[CH:4]/[CH2:3][OH:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)/C=C/C1CCCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: CCCCCC
Product: OC/C=C/C1CCCCC1
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
29.25 g (0.174 mol) of (2E)-3-cyclohexylpropenoic acid methyl ester was dissolved in 200 ml of ether (dried over dry nap). Thereto was added 412 ml (0.383 mol) of diisobutylaluminum hydride (n-hexane solution, 0.93N) in an argon stream at -60° C. over a 15-minute period. The mixture was stirred at the same temperature for 30 minutes. n-Hexane and diethyl ether were added. The resulting mixture was washed with a saturated aqueous ammonium chloride solution, hydrochloric acid (0.2N) and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography (n-hexane/ethyl acetate=19/1 to 9/1) and distillation (57.0°-58.5° C./0.40-0.42 mmHg) to obtain 20.1 g (0.143 mol) of (2E)-3-cyclohexyl-2-propen-1-ol.
Reaction SMILES: [F:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:5][CH:4]=1.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:13][CH2:12][CH2:11][C:10]#[C:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][F:1])[N:8]=1)=[O:18]
Reactant: NCCC#Cc1cccc(CF)n1
Reactant: O=C(Cl)c1ccccc1Cl
Product: O=C(NCCC#Cc1cccc(CF)n1)c1ccccc1Cl
Yield: 19.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 184, from 4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn-1-amine (39 mg, 0.22 mmol, Example 189(D)) and 2-chlorobenzoyl chloride (50 mg, 0.28 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 13.5 mg (43 μmol, 19%) of 2-chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzamide as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]C)=[O:20])=[CH:14][C:13]=2[Cl:23])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:24])[NH:6]2.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1>[Cl:23][C:13]1[CH:14]=[C:15]([CH2:18][C:19]([OH:21])=[O:20])[CH:16]=[CH:17][C:12]=1[O:11][C:10]1[C:2]([NH:1][S:33]([C:27]2[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=2[Cl:25])(=[O:35])=[O:34])=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5](=[O:24])[CH2:4]2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)Cc1ccc(Oc2ccc3c(c2N)CC(=O)N3)c(Cl)c1
Solvent: c1ccncc1
Product: O=C(O)Cc1ccc(Oc2ccc3c(c2NS(=O)(=O)c2ccc(Cl)cc2Cl)CC(=O)N3)c(Cl)c1

Procedure:
23.2 (35 mg, 0.1 mmol) and 2,4-dichlorobenzenesulfonyl chloride (52 mg, 0.21 mmol) were stirred in pyridine (0.5 mL) at 25° C. for 4 h. The reaction mixture was loaded directly to a prepacked Redisep Column and flash chromatographed (gradient, 0-100% EtOAc in Hexanes) to give the sulfonamide, which was then hydrolyzed in MeOH/THF/water (0.3 mL each) with LiOH (7 mg, 0.3 mmol) at 25° C. for 2 h. Reverse phase HPLC (C18, 10-90% ACN in water with 0.1% TFA as eluant) of the reaction mixture afforded 23 as a yellow solid. MS ESI (pos.) m/e calcd for (M+H)+ 543.0.1. found 543.0. 1H NMR (500 MHz) (CDCl3) δ 12.45 (br. s, 1H); 10.47 (s, 1H); 10.08 (s, 1H); 7.73 (d, J=8.5 Hz, 1H); 7.58 (s, 1H); 7.34 (d, J=8.5 Hz, 1H); 7.33 (s, 1H); 7.04 (d, J=7.8, 1H); 6.71 (d, J=8.3 Hz, 1H); 6.54 (d, J=8.1 Hz, 1H); 6.43 (d, J=8.3 Hz, 1H); 3.57 (s, 2H); 3.56 (s, 2H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32](O)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@H:36]1[C@H:40]([OH:41])[CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][C@H:36]4[C@H:40]([OH:41])[CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]4)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Reactant: COc1ccc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CN(C(=O)OC(C)(C)C)C[C@H]4O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c5) and commercially available tert-butyl(3R*,4R*)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate the title compound is obtained as colorless foam.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[N:14][N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]3)[CH:16]=2)=[C:6]2[CH:10]=[C:9](Cl)[O:8][C:7]=12.O1CCOCC1.[F:32][C:33]1[CH:41]=[C:40]2[C:36]([C:37](B3OC(C)(C)C(C)(C)O3)=[CH:38][N:39]2[Si](C(C)C)(C(C)C)C(C)C)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[N:14][N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]3)[CH:16]=2)=[C:6]2[CH:10]=[C:9]([C:37]3[C:36]4[C:40](=[CH:41][C:33]([F:32])=[CH:34][CH:35]=4)[NH:39][CH:38]=3)[O:8][C:7]=12
Reactant: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(B2OC(C)(C)C(C)(C)O2)c2ccc(F)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5c[nH]c6cc(F)ccc56)cc34)cn2)CC1
Temperature: 25 °C
Yield: 28 %

Procedure:
To a nitrogen degassed solution of 1-{4-[4-(7-amino-2-chloro-furo[2,3-c]pyridin-4-yl)-pyrazol-1-yl]-piperidin-1-yl}ethanone (0.050 g, 0.14 mmol) in 4:1 1,4-dioxane:water (10 mL) was added 6-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-indole (0.060 g, 0.143 mmol), potassium carbonate (0.047 g, 0.34 mmol), dichlorobis(triphenylphosphine)palladium (16 mg, 0.023 mmol). The mixture was heated at reflux for 3 h, then cooled to room temperature and concentrated. The residue was suspended in water and extracted with ethyl acetate (3×50 mL). The combined organic fractions were washed with water (15 mL), dried, and evaporated. Purification by flash chromatography (5% MeOH:DCM) afforded 18 mg (28%) of the title compound as a solid. 1H NMR (300 MHz, CDCl3): δ 1.99-2.14 (m, 2H), 2.17 (s, 3H), 2.24-2.34 (m, 2H), 2.81 (t, J=12 Hz, 1H), 3.29 (m, 1H), 4.02 (d, J=14.7 Hz, 1H), 4.40-4.48 (m, 1H), 4.78 (br. s, 2H), 4.78-4.82 (m, 1H), 6.97 (s, 1H), 7.07 (dt, J=9 Hz, 2.4 Hz, 1H), 7.16 (dd, J=9 Hz, 2.4 Hz, 1H), 7.70 (s, 1H), 7.78 (d, J=2.7 Hz, 1H), 7.87 (s, 1H), 7.92-7.97 (m, 2H), 8.94 (brs, 1H); MS (ESI): 459 [M+H]+.
Reaction SMILES: [CH:1]1(O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]3=2)[CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]3=2)[CH:3]=[CH:2]1
Reactant: OC1CCc2ccc3ccccc3c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C1=Cc2ccc3ccccc3c2C1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To the crude product of benzindanol dissolved in 200 ml of toluene was added 1.2 g (6.3 mmole) of p-toluenesulfonic acid, and the mixture was stirred at 80° C. for 15 minutes. The reaction was terminated with a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with toluene, and the organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product of benzindene was obtained in an amount of 12.6 g, which was purified by column chromatography (Merck; solvent, hexane-ethyl acetate 0-1%). The product was obtained in an amount of 9.66 g (yield 85%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([CH2:52][CH2:53][CH3:54])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[N:32](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:31]=[N:30][N:29]=4)=[CH:18][CH:17]=3)[C:12]=2[CH:13]=[O:14])[C:4]([CH3:7])=[CH:5][CH:6]=1.C.N>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([CH2:52][CH2:53][CH3:54])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:29][N:30]=[N:31][N:32]=4)=[CH:18][CH:17]=3)[C:12]=2[CH:13]=[O:14])[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: CCCc1nc(-n2c(C)ccc2C)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C
Agent: N
Product: CCCc1nc(-n2c(C)ccc2C)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared from 4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-propyl-1-[[2'-(N-triphenylmethyl-tetrazol-5-yl)-1,1'-biphenyl-4-yl]methyl]-1H-imidazole-5-carboxaldehyde according to the procedure of Example 52. MS (EI, CH4 +NH3) 465 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.[N-:17]=[C:18]=[O:19].[K+]>CO.O.O.CO>[CH3:15][O:14][C:12](=[O:13])[CH2:11][N:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:17][C:18]1=[O:19]
Reactant: COC(=O)CNCC(=O)c1ccc(Cl)cc1
Reactant: [N-]=C=O
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)Cn1cc(-c2ccc(Cl)cc2)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.41 g (12.27 mmol) of the compound from Example 231A in 14 ml methanol/water (7:3) is added dropwise to a solution of 995 mg (12.27 mmol) of potassium isocyanate in 11 ml methanol/water (7:3). This is stirred for 1 hr at RT. The thick suspension is diluted with 7.4 ml water and 39 ml methanol to facilitate stirring, then heated under reflux for 1 hr and then left to stand overnight at RT. After cooling to 0° C., the precipitate is filtered off, washed with ice-cold water and dried overnight in the drying cabinet at 60° C. 2.84 g (76% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C@H:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[C:24]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:23])[C@@H:5]([NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:24])=[CH:18][CH:17]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
N-Benzoyl-L-tyrosine ethyl ester (0.054 g, 0.17 mmol) was dissolved in DMF (1 mL). K2CO3 (1 eq, 0.17 mmol, 0.024g) was added, followed by methyl iodide (1 eq, 0.17 mmol, 0.011 mL). The slightly cloudy mixture was allowed to stir at room temperature under nitrogen for 3.5 hours. An additional 2 eq K2CO3 was added and the mixture was allowed to stir overnight. Water was poured into the flask, causing cloudiness. Precipitation was completed via refrigeration. The resulting white solid was filtered, washed well with water and dried in air (0.030 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:23]I>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CI
Reactant: COc1ccc(Nc2nc(Cl)nc3ccccc23)c(OC)c1
Product: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)c(OC)c1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(2,4-dimethoxy-phenyl)-amine and methyl iodide by a procedure similar to Example 36 (91% yield). 1H NMR (CDCl3): 7.70-7.73 (m, 1H), 7.54 (ddd, J=8.7, 6.3 and 2.1 Hz, 1H), 7.10 (d, J=8.7 Hz, 1H), 6.93-7.23 (m, 2H), 6.50-6.57 (m, 2H), 3.87 (s, 3H), 3.67 (s, 3H), 3.52 (s, 3H).
Reaction SMILES: C(O[C:9]([N:11]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])C)=O)C1C=CC=CC=1.[ClH:20]>[Pd].CO>[ClH:20].[CH3:9][NH:11][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CCN(C)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)CCNC

Procedure:
A mixture of ethyl 3-(N-benzyloxycarbonyl-N-methylamino)propionate (8 g), 10% palladium on carbon (1.6 g, 50% wet), conc.-hydrochloric acid (5.1 ml) in methanol (160 ml) was stirred for 5 hours at room temperature under hydrogen atmosphere. Catalyst was removed by filtration and mother liquor was concentrated in reduced pressure to give ethyl 3-(methylamino)propionate hydrochloride (4.31 g).
Reaction SMILES: [C:1]1([C:7](=[O:11])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[N+]([O-])([O-])=O.[Ag+:18]>CO>[C:1]1([C:7](=[O:11])[C:8]([O-:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Ag+:18]
Reactant: O=C(O)C(=O)c1ccccc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C([O-])C(=O)c1ccccc1
Reaction time: 1 h

Procedure:
In 20 g of methanol was dissolved 3.9 g of phenylglyoxylic acid (Aldrich), and 0.9 g of sodium hydroxide (Wako Pure Chemical Industries, Ltd.) was added thereto little by little (generation of heat caused by neutralization was observed). After stirring for 1 hour, 10.4 g of 1 mol/L aqueous silver nitrate solution (Wako Pure Chemical Industries, Ltd.) was added thereto. Then a precipitated gray solid was collected by filtration, washed with methanol, and dried, so that 4.4 g of silver phenylglyoxylate (gray solid) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11](C2C=C(Cl)C=CC=2COC(=O)C)[C@H](C)CCCBr)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S-]CC.[Na+]>CN(C=O)C>[C:5]1([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: CC(=O)OCc1ccc(Cl)cc1N([C@H](C)CCCBr)S(=O)(=O)c1ccc(Cl)cc1
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccccc1
Temperature: 22 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
To a solution of 4-chloro-N-[5-chloro-2-(acetoxymethyl)phenyl}-N-[(R)-1-methyl-4-bromobutyl]benzenesulfonamide (1.00 g, 1.91 mmol) in DMF (4 mL) was added sodium thioethoxide (0.535 g, 7.63 mmol) under nitrogen at 0° C. The mixture was stirred overnight at 22° C. The mixture was quenched with H2O (3 mL), extracted with ethyl ether (2×20 mL), dried over Na2SO4, and filtered. The organic solvent was concentrated under reduced pressure. Silica gel chromatography (1:9 ethyl acetate:hexanes) afforded 0.123 g of 4-ethylthio-N-[5-chloro-2-(hydroxymethyl)phenyl]-N-[4-(ethylthio)]-1-(R)-methylbutyl]benzenesulfonamide as a yellow oil in 14% yield. MS (ESI+), 488 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[SH-:13].[Na+]>CN(C=O)C>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([SH:13])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(S)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 105.7 %

Procedure:
1-Fluoro-4-(methylsulfonyl)-benzene (1.74 g) and sodium hydrosulphide hydrate (0.67 g) were dissolved in DMF (10 ml) and stirred at room temperature for 24 hours. The reaction was quenched with water, acidified with 2M hydrochloric acid (20 ml) and extracted with ethyl acetate (2×50 ml). The combined extracts were then washed with water (2×25 ml) and brine (20 ml). The organic solution was dried (MgSO4), filtered and evaporated in vacuo to yield the sub-title compound as a white solid (1.8 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH3:27])([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([OH:19])=[O:18])=[CH:11][C:10]=1[O:28][CH3:29])C1C=CC=CC=1>CCO.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH3:27])([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:17]([OH:19])=[O:18])=[CH:11][C:10]=1[O:28][CH3:29]
Reactant: COc1cc(CC(C)(Oc2ccccc2)C(=O)O)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(CC(C)(Oc2ccccc2)C(=O)O)ccc1O
Reaction time: 2 h

Procedure:
A solution of 3-(4-benzyloxy-3-methoxyphenyl)-2-methyl-2-phenoxypropionic acid (6.86 g, 17.5 mmol) in EtOH (175 mL) was added to 5% Pd/C (186 mg, 10 wt %). The mixture was purged first with nitrogen, then with H2, which was then applied at 45 p.s.i. for 2 h. Pd/C was subsequently filtered off through celite, and the filtrate was concentrated to a crude oil (5.42 g, in excess of theory). MS (EI) 301.2 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1.[CH:26]([Mg]Cl)([CH3:28])[CH3:27].[NH4+].[Cl-]>C1COCC1.CN1C(=O)CCC1>[F:18][C:14]1[CH:13]=[C:12]([CH2:11][NH:10][C:8]([C:7]2[C:2]([CH:26]([CH3:28])[CH3:27])=[N:3][C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:5][C:6]=2[CH3:19])=[O:9])[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(N2CCOCC2)nc(Cl)c1C(=O)NCc1cccc(F)c1
Reactant: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1cc(N2CCOCC2)nc(C(C)C)c1C(=O)NCc1cccc(F)c1
Temperature: -30 °C
Yield: 36.1 %

Procedure:
A solution of 300 mg (0.83 mmol) 2-chloro-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 9) in THF/NMP (6:1 v/v, 14 ml) was cooled to −30° C. At this temperature were successively added 58 mg (0.16 mmol) Fe(acac)3 and 6 ml (12.0 mmol, 2M in THF) iso-propyl-magnesium-chloride. The RM was then allowed to warm to 0° C. within 1 h. Then sat. aq. NH4Cl sol. was added the mixture was extracted with EtOAc (3×20 ml). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 7:3) provided 110 mg (0.30 mmol, 36%) N-[(3-Fluorophenyl)-methyl]-2-isopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 23). [M+H]+ 372.2.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:13]=[C:12]([C:15]5[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:17][C:18]6[O:22][C:21]([C:23]7[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=7)=[C:20]([C:30]([NH:32][CH3:33])=[O:31])[C:19]=6[CH:34]=5)[CH:11]=[CH:10][C:9]=4[CH2:8][CH:7]([CH2:41]O)[N:6]3[C:43]=2[CH:44]=[CH:45][CH:46]=1.CCN(S(F)(F)[F:53])CC>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:13]=[C:12]([C:15]5[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:37])=[O:38])=[CH:17][C:18]6[O:22][C:21]([C:23]7[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=7)=[C:20]([C:30]([NH:32][CH3:33])=[O:31])[C:19]=6[CH:34]=5)[CH:11]=[CH:10][C:9]=4[CH2:8][CH:7]([CH2:41][F:53])[N:6]3[C:43]=2[CH:44]=[CH:45][CH:46]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CO)C4)cc12
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CF)C4)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
5-(11-fluoro-6-(hydroxymethyl)-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (40 mg, 0.062 mmol) was dissolved in DCM (2 ml) and cooled to 0° C., followed by addition of DAST (0.025 ml, 0.187 mmol). The mixture was stirred at 0° C. for 1 h, then at RT for 30 min and then concentrated in vacuo. Preparative TLC (50% DCM in ethyl acetate) gave 5-(11-fluoro-6-(fluoromethyl)-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (14 mg, yield: 35%). MS (M+H)+: 645.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]#[N:13].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:24][O:25][CH2:26]Cl.[Cl-].[NH4+]>C1COCC1.O>[CH3:24][O:25][CH2:26][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]#[N:13]
Reactant: Cc1c(C#N)cnc2ccccc12
Reactant: COCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COCCc1c(C#N)cnc2ccccc12
Reaction time: 1 h
Yield: 40.3 %

Procedure:
4-methyl-quinoline-3-carbonitrile (600 mg, 3.567 mmol) was dissolved in 10 mL of anhydrous THF, added with LHMDS (1M solution in THF, 3.9 mL, 3.924 mmol) at −78° C. under the nitrogen atmosphere and then stirred for about 1 hour at the same temperature. The mixture was dropwisely added with chloromethyl methyl ether (0.30 mL, 3.924 mmol) and then stirred for about 1 hour at −50° C., and then for about 1 hour at 0° C. The above mixture, while being stirred at 0° C., was added with 5 mL of a saturated solution of ammonium chloride and 10 mL of distilled water and then extracted twice with 50 mL of EtOAc. The resulting organic layer was washed with a saturated solution of sodium chloride, dried with anhydrous sodium sulfate and filtered. A silica gel column chromatography (30% EtOAc/Hexanes) was performed on the residue resulted by concentration of the above filtrate and obtained 305 mg (40%) of 4-(2-methoxy-ethyl)-quinoline-3-carbonitrile in pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([CH2:13][C:14]([O:16]N3C(=O)CCC3=O)=O)[C:10](=[O:24])[CH2:9]2)=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][C:26]1=[O:31]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([CH2:13][C:14]([N:28]3[CH2:29][CH2:30][NH:25][C:26](=[O:31])[CH2:27]3)=[O:16])[C:10](=[O:24])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C1CNCCN1
Reactant: O=C(CN1CC(c2ccc(F)cc2)CC1=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)CN2CC(c3ccc(F)cc3)CC2=O)CCN1

Procedure:
10 g (30 mmol) of N-[4-(p-fluorophenyl)-2-oxopyrrolidin-1-ylacetoxy]-succinimide and 3.0 g (30 mmol) of piperazin-2-one (ketopiperazine) are stirred at room temperature in 100 ml of dimethylformamide for 16 hours. The whole is concentrated to dryness by evaporation at 70° under reduced pressure, extracted at boiling temperature with trichloromethane, allowed to cool, filtered with suction and allowed to dry in the air. 1-[4-(p-fluorophenyl)-2-oxopyrrolidin-1-ylacetyl]-3-oxopiperazine having a melting point of 200°-203° is obtained.
Reaction SMILES: C(OC([N:8]1[CH2:18][CH2:17][C:11]2([CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Br[C:20]1[CH2:24][O:23][C:22](=[O:25])[CH:21]=1.O=C1OCC(N2CCCC3(CCNCC3)C2=O)=C1>>[O:25]=[C:22]1[O:23][CH2:24][C:20]([N:14]2[C:13](=[O:16])[CH2:12][C:11]3([CH2:10][CH2:9][NH:8][CH2:18][CH2:17]3)[CH2:15]2)=[CH:21]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)C2
Reactant: O=C1C=C(Br)CO1
Agent: O=C1C=C(N2CCCC3(CCNCC3)C2=O)CO1
Product: O=C1C=C(N2CC3(CCNCC3)CC2=O)CO1

Procedure:
The title compound was prepared from 3-oxo-2,8-diaza-spiro[4,5]decane-8-carboxylic acid tert-butyl ester and 4-bromofuran-2(5H)-one in two steps in an analogous fashion to that described for 2-(5-oxo-2,5-dihydrofuran-3-yl)-2,9-diazaspiro[5.5]undecan-1-one (I-18) above. LC/MS: [(M+1)]+=237