Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CS(C)=O.[OH:7][CH2:8][CH2:9][CH2:10][C:11]([O-:13])=[O:12].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCC.CCOCC>[CH2:15]([O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=C([O-])CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: CCOCC
Product: O=C(O)CCCOCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
4.0 g (60%, 0.1 mol) of sodium hydride were washed in hexane and mixed with 30 ml of dry DMSO, and the resulting admixture was stirred at 60° C. on an oil bath for 1 hour under a nitrogen gas flow. The mixture was stirred at room temperature, and dry DMSO containing 12.6 g (0.1 mol) of sodium 4-hydroxybutyrate (100 ml) was added. After stirring at room temperature for 2 hours, the reaction solution was cooled on an ice bath, 0.2 mol of benzyl bromide was added, and the reaction was carried out at room temperature for 2 hours. After solidification, 0.5 L of ether was added, the admixture was filtered, the resulting residue was washed with ether (300 ml×3), and the filtrate was concentrated under vacuum. The resulting residue was mixed with 100 ml of methanol, 100 ml of 8% sodium hydroxide were added, and the admixture was stirred at 60° C. for 15 hours. After drying under vacuum, the resulting concentrated residue was washed with ether (200 ml×2), and the ether layer was extracted with 1 N sodium hydroxide (50 ml). All aqueous layers were combined, neutralized with concentrated hydrochloric acid (pH<4) and then extracted with ether (100 ml×5). The ether layer was extracted with 2 N sodium hydroxide (50 ml×3), all water layers were neutralized with concentrated hydrochloric acid (pH<4), and further extracted with ether. The resulting product was washed with an aqueous saturated sodium chloride solution, dried on magnesium sulphate, and then concentrated under vacuum. 9.42 g of 4-benzyloxybutyric acid was obtained as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](=[O:40])[C@H:22]([NH:36][C:37](=[O:39])[CH3:38])[CH2:23][C:24]3[CH:29]=[CH:28][C:27](C4C=CC=CC=4)=[CH:26][CH:25]=3)=[O:15])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.N1CCC[C@H]1C(O)=O>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](=[O:40])[C@H:22]([NH:36][C:37](=[O:39])[CH3:38])[CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:15])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Agent: O=C(O)[C@@H]1CCCN1
Product: CC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Yield: 839.2 %

Procedure:
Using the procedure described for example 97f 0.125 g of 1-(2-(R)-acetylamino-3-phenyl)-propionyl)-pyrrolidin-2-(S)-carboxylic acid was converted into 0.90 g (47%) of the title compound. (+)-APCI-MS: 460 (MH+).
Reaction SMILES: [C:1]1([C@H:7]2[C@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][C:9]3([CH2:22][CH2:21][CH:20]([CH2:23]S(OC)(=O)=O)[CH2:19][CH2:18]3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:29].[Na+].O.C(OCC)(=O)C>CC(C)=O>[I:29][CH2:23][CH:20]1[CH2:21][CH2:22][C:9]2([O:8][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10]2)[CH2:18][CH2:19]1
Reactant: [I-]
Reactant: COS(=O)(=O)CC1CCC2(CC1)O[C@@H](c1ccccc1)[C@H](c1ccccc1)O2
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: ICC1CCC2(CC1)O[C@@H](c1ccccc1)[C@H](c1ccccc1)O2
Temperature: 25 °C
Yield: 64.2 %

Procedure:
To a solution of methyl [(2S,3S)-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-8-yl]methanesulfonate (58.6 g) in acetone (800 mL) was added sodium iodide (52.3 g) at room temperature. The mixture was heated under reflux overnight and again cooled to room temperature. To the reaction mixture were added water and ethyl acetate. The organic layer was separated, sequentially washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The crude product obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=1:0-50:1-30:1-10:1) to obtain (2S,3S)-8-(iodomethyl)-2,3-diphenyl-1,4-dioxaspiro[4.5]decane (40.6 g) as a pale yellow oily substance.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[C:8]1([CH2:14][CH2:15][CH2:16][OH:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:17][CH2:16][CH2:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCCCCCBr
Reactant: OCCCc1ccccc1
Product: BrCCCCCOCCCc1ccccc1

Procedure:
(2.8 g), T.l.c. [K] Rf 0.44 from 1,5-dibromopentane (10.2 g) and benzenepropanol (2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C@@H:13]([CH3:17])[C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51](=[O:63])[CH2:52][C@H:53]([OH:62])[CH2:54][NH:55][CH2:56][CH:57]([O:60][CH3:61])[O:58][CH3:59].OS([O-])(=O)=O.[K+].CCOC(C)=O>CN(C=O)C>[CH3:49][O:50][C:51](=[O:63])[CH2:52][C@H:53]([OH:62])[CH2:54][N:55]([C:14](=[O:16])[C@@H:13]([NH:12][C:4]1[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([Cl:1])[CH:3]=1)[CH3:17])[CH2:56][CH:57]([O:58][CH3:59])[O:60][CH3:61]
Reactant: C[C@H](Nc1ccc(C(F)(F)F)c(Cl)c1)C(=O)O
Reactant: COC(=O)C[C@H](O)CNCC(OC)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)([O-])O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C[C@H](O)CN(CC(OC)OC)C(=O)[C@H](C)Nc1ccc(C(F)(F)F)c(Cl)c1
Yield: 122.9 %

Procedure:
To a solution of 0.915 g (3.4 mmol) of (S)-2-(3-chloro-4-trifluoromethyl-phenylamino)-propionic acid (26% ee) (intermediate 32) and 0.394 ml (3.6 mmol) of 4-methylmorpholine in 10.0 ml of DMF, was added at 0° C. 1.86 g (4.9 mmol) of HATU, followed after 30 min by 1.20 g (3.3 mmol) of (S)-4-(2,2-dimethoxy-ethylamino)-3-hydroxy-butyric acid methyl ester in 6.5 ml of DMF. The solution was stirred and warmed up over night. The reaction was poured on aqueous 10% KHSO4/EtOAc (3×). The organic phases were washed with aqueous 10% KHSO4, saturated NaHCO3, 10% NaCl and dried over Na2SO4 to yield 1.91 g (62%) of the titled compound as light brown oil. MS: 469.14 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][CH2:15][C@@H:16]([C:18](OC)=[O:19])[NH2:17].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[NH2:17][C@@H:16]([CH2:15][S:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[F:7])[CH2:18][OH:19]
Reactant: COC(=O)[C@@H](N)CSc1ccccc1F
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: N[C@H](CO)CSc1ccccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
In a round-bottom flask maintained under an inert atmosphere, 23.9 mL (23.9 mmoles) of lithium aluminum hydride (1M in THF) is introduced. The solution is cooled to 0° C. then 4.57 g (19.9 mmoles) of methyl S-(2-fluorophenyl)-L-cysteinate (3a-1) diluted in 21 mL of anhydrous THF is added. The solution is stirred at 0° C. for 1 hour then at ambient temperature for 30 minutes. The reaction medium is hydrolyzed by successive additions of 2.7 mL of water, 0.9 mL of 15% soda in water, then 0.9 mL of water. The suspension is stirred for 30 minutes at ambient temperature in the presence of sodium sulfate then filtered on a silica filter. The precipitate is washed with THF then the filtrate is concentrated under reduced pressure. A brown oil (3.56 g) is obtained that can be used without any additional purification in the following step.
Reaction SMILES: [CH2:1]([S:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([C:17]3[CH:18]=[N:19][N:20]([CH2:23][CH3:24])[C:21]=3[OH:22])=[O:16])[C:12]=2[CH3:14])[S:7](=[O:26])(=[O:25])[CH2:6][CH2:5]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:33]([S:36](Cl)(=[O:38])=[O:37])[CH2:34][CH3:35]>C(Cl)Cl.O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH2:1]([S:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([C:17]3[CH:18]=[N:19][N:20]([CH2:23][CH3:24])[C:21]=3[O:22][S:36]([CH2:33][CH2:34][CH3:35])(=[O:38])=[O:37])=[O:16])[C:12]=2[CH3:14])[S:7](=[O:26])(=[O:25])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCSC1CCS(=O)(=O)c2ccc(C(=O)c3cnn(CC)c3O)c(C)c21
Reactant: CCCS(=O)(=O)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCS(=O)(=O)Oc1c(C(=O)c2ccc3c(c2C)C(SCC)CCS3(=O)=O)cnn1CC
Yield: 59.9 %

Procedure:
0.27 Gram (0.7 mmol) of 4-ethylthio-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide was dissolved in 3 ml of methylene chloride, and then a solution of 0.2 g (1.4 mmol) of potassium carbonate in 2 ml of water was added. Further, 0.16 ml (1.4 mmol) of n-propanesulfonyl chloride and 20 mg (0.08 mmol) of benzyltriethylammonium chloride were added, and the mixture was allowed to react at room temperature for 1 day. After the completion of the reaction, a methylene chloride layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 0.21 g (yield 60%) of 4-ethylthio-5-methyl-6-(1-ethyl-5-n-propanesulfonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](I)=[CH:11][C:10]([NH2:14])=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][O:30][CH2:31][C:32]([F:35])([F:34])[F:33])[CH:24]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:27]3[CH:28]=[CH:23][CH:24]=[C:25]([CH2:29][O:30][CH2:31][C:32]([F:33])([F:34])[F:35])[CH:26]=3)=[CH:11][C:10]([NH2:14])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1cc(I)n(-c2ccc(F)cc2)n1
Reactant: CC1(C)OB(c2cccc(COCC(F)(F)F)c2)OC1(C)C
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: COCCOC
Product: Nc1cc(-c2cccc(COCC(F)(F)F)c2)n(-c2ccc(F)cc2)n1
Temperature: 25 °C
Yield: 51 %

Procedure:
Under argon atmosphere, to a solution of 1-(4-fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine (70 mg) prepared in Preparation 18 in 1,2-dimethoxyethane (0.7 ml) were sequentially added 4,4,5,5-tetramethyl-2-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-[1,3,2]dioxaborolane (80 mg), a 2M aqueous solution of sodium carbonate (0.35 ml), tricyclohexylphosphine (13.0 mg) and palladium (II) acetate (5.2 mg) at room temperature, and the mixture was stirred at 100° C. for 2 hours. This reaction mixture was cooled to room temperature, filtered through Celite, and subjected to elution with ethyl acetate. The filtrate was extracted with ethyl acetate, the resulting organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to give the titled compound (43 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:19][CH2:18][C@:13]2([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[NH:14][O:15][C@@H:16]([CH3:17])[C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C@@]1(C2C=CC(F)=CC=2F)CO[C@@H](COCC2C=CC=CC=2)C[C@H]1CO>>[NH2:14][C@@:13]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[CH2:18][O:19][C@@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:11][C@H:12]1[C@@H:16]([OH:15])[CH3:17]
Reactant: C[C@@H]1ON[C@@]2(c3ccc(F)cc3F)CO[C@@H](COCc3ccccc3)C[C@@H]12
Agent: N[C@@]1(c2ccc(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Product: C[C@H](O)[C@@H]1C[C@H](COCc2ccccc2)OC[C@@]1(N)c1ccc(F)cc1F

Procedure:
The product, obtained as a yellow oil, was prepared from (3S,3aR,5R,7aS)-5-[(benzyloxy)methyl]-7a-(2,4-difluorophenyl)-3-methyl hexahydro-1H-pyrano[3,4-c][1,2]oxazole (C18) according to the general procedure for the synthesis of [(2R,4R,5S)-5-amino-2-[(benzyloxy)methyl]-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]methanol (C6) in Preparation P1. Yield: 13.96 g, 37.00 mmol, 98%. LCMS m/z 378.2 [M+H+]. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 7.65-7.78 (br m, 1H), 7.27-7.40 (m, 5H), 6.93-7.02 (br m, 1H), 6.80 (ddd, J=12.6, 8.5, 2.6 Hz, 1H), 4.06 (dd, J=11.7, 2.2 Hz, 1H), 3.53 (dd, J=10.2, 3.7 Hz, 1H), 2.50-2.61 (br m, 1H), 1.62 (ddd, J=14, 4, 2.5 Hz, 1H), 0.89 (d, J=6.6 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][OH:27])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1O)([CH3:4])([CH3:3])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>C1(C)C=CC=CC=1>[C:28]([O:27][CH2:26][CH2:25][N:18]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:24]2[C:16]([C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[C:9]([C:12]([CH3:14])([CH3:13])[CH3:15])[CH:8]=2)=[N:17]1)(=[O:30])[CH3:29]
Reactant: CC(C)(C)c1cc(-c2nn(CCO)c3ncccc23)cc(C(C)(C)C)c1O
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)OCCn1nc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)c2cccnc21
Temperature: 20 °C
Yield: 86.4 %

Procedure:
To a solution of 40 g of the compound of Example 43 in 320 ml of toluene is added 22 g of acetic anhydride under stirring, and refluxed for 8 hours. After completion of the reaction, the reaction mixture is cooled to 20° C., washed with 300 ml of water twice and dried over anhydrous sodium sulfate. The toluene is concentrated and the residue is recrystallized from ethanol and dried to give 37 g of 1-(2-acetoxyethyl)-3-(3,5-di-tertiary butylphenyl)-1H-pyrazolo[3,4-b]pyridine, melting at 115°-116° C.
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][N:4]1[CH:9]([NH:10]S(C2C=CC(C)=CC=2)(=O)=O)[CH:8]=[CH:7][C:6]([O:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:38])=[C:26]([NH:28][C:29]([C:31]3[N:35]([CH3:36])[N:34]=[C:33]([CH3:37])[CH:32]=3)=[O:30])[CH:27]=2)=[CH:5]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[N:10]=[C:9]2[CH:8]=[CH:7][C:6]([O:21][C:22]3[CH:23]=[CH:24][C:25]([Cl:38])=[C:26]([NH:28][C:29]([C:31]4[N:35]([CH3:36])[N:34]=[C:33]([CH3:37])[CH:32]=4)=[O:30])[CH:27]=3)=[CH:5][N:4]2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NC2C=CC(Oc3ccc(Cl)c(NC(=O)c4cc(C)nn4C)c3)=CN2CC(N)=O)cc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4c3)ccc2Cl)n(C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.1 %

Procedure:
A mixture of N-{5-[(1-(2-amino-2-oxoethyl)-6-{[(4-methylphenyl)sulfonyl]amino}-1,6-dihydropyridin-3-yl)oxy]-2-chlorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (300 mg, 0.527 mmol), trifluoroacetic anhydride (2 mL) and dichloromethane (2.5 mL) was stirred at room temperature for 5 hr. The reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution (10 mL) and ethanol (10 mL) were added to the residue, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate) and recrystallized from ethyl acetate-hexane to give N-{5-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]-2-chlorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (134 mg, 64%) as a white solid. To a solution of N-{5-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]-2-chlorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (130 mg, 0.328 mmol) thus-obtained and triethylamine (136 μL, 0.984 mmol) in tetrahydrofuran (4 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (38.7 μL, 0.426 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=50/50→0/100) and recrystallized from ethyl acetate-tetrahydrofuran to give the title compound (83.0 mg, 54%) as a white solid.
Reaction SMILES: N.[C:2]1(=[O:18])[N:6]([CH:7]([CH3:12])[CH2:8][CH2:9][C:10]#[N:11])[C:5](=[O:13])[C:4]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:3]12.[SH2:19]>CO>[C:5]1(=[O:13])[N:6]([CH:7]([CH3:12])[CH2:8][CH2:9][C:10]([NH2:11])=[S:19])[C:2](=[O:18])[C:3]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:4]12
Reactant: CC(CCC#N)N1C(=O)c2ccccc2C1=O
Reactant: S
Agent: N
Solvent: CO
Product: CC(CCC(N)=S)N1C(=O)c2ccccc2C1=O

Procedure:
Liquid ammonia (20 g) and 4-phthalimidovaleronitrile (67 g) is added to a cooled solution of hydrogen sulphide (50 g) in methyl alcohol (500 ml). The sealed reaction vessel is the heated at 40° for 3 days with stirring. Concentration followed by recrystallization from isopropyl acetate yields 4-phthalimidothiovaleramide, m.p. 143°-146° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:21])(=O)C.[CH3:22][NH:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.[OH-].[Na+]>C1COCC1.CO>[C:28]([C:27]1[CH:30]=[CH:31][C:24]([N:23]([C:13](=[C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][C:5]2=[O:21])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:22])=[CH:25][CH:26]=1)#[N:29]
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccccc21
Reactant: CNc1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(=C1C(=O)Nc2ccccc21)c1ccccc1)c1ccc(C#N)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and 4-methylamino-benzonitrile in THF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)C1C=CC=CC=1.[CH3:24][C:25]([CH3:29])([CH3:28])[CH:26]=[CH2:27]>>[CH3:24][C:25]([CH3:29])([CH3:28])[CH2:26][CH2:27][C:13]1[CH:12]=[CH:11][C:10]([N:16]2[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:23])[CH2:17]2)=[C:9]([OH:8])[CH:14]=1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C=CC(C)(C)C
Product: CC(C)(C)CCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one and 3,3-dimethylbut-1-ene analogous to Example 300: (M−1)−=311; HPLC retention time=1.20 min (method A).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17]O)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:19](Br)[C:20]#[CH:21]>O1CCCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:21][C:20]#[CH:19])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCCCN1CCN(C(=O)OC(C)(C)C)CC1
Yield: 108.5 %

Procedure:
To a refluxing solution of 1.67 g of sodium hydride in 20 mL of tetrahydrofuran was added dropwise a solution of 9.00 g of 1-tert-butoxycarbonyl-4-(2-hydroxyethyl)piperazine in 15 mL of tetrahydrofuran and then 5.63 g of propargyl bromide was added dropwise to the resultant mixture. After completion of the reaction, the mixture was concentrated, poured into ice-water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated to give 10.70 g of the title compound.
Reaction SMILES: C([O-])=O.[NH4+].Cl[C:6]1[C:15]2[O:14][CH:13]([CH3:16])[N:12]([CH3:17])[C:11](=[O:18])[C:10]=2[CH:9]=[CH:8][C:7]=1[O:19][C:20]1[CH:21]=[C:22]([CH:32]=[C:33]([O:35][C@@H:36]([CH3:40])[CH2:37][O:38][CH3:39])[CH:34]=1)[C:23]([NH:25][C:26]1[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=1)=[O:24]>C(O)C.[Pd]>[CH3:16][CH:13]1[N:12]([CH3:17])[C:11](=[O:18])[C:10]2[CH:9]=[CH:8][C:7]([O:19][C:20]3[CH:21]=[C:22]([CH:32]=[C:33]([O:35][C@@H:36]([CH3:40])[CH2:37][O:38][CH3:39])[CH:34]=3)[C:23]([NH:25][C:26]3[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=3)=[O:24])=[CH:6][C:15]=2[O:14]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc3c(c2Cl)OC(C)N(C)C3=O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OC(C)N(C)C3=O)cc(C(=O)Nc2ccn(C)n2)c1

Procedure:
Ammonium formate (122 mg, 1.9 mmol) was added in one portion to a solution of 3-[(8-chloro-2,3-dimethyl-4-oxo-3,4-dihydro-2H-1,3-benzoxazin-7-yl)oxy]-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (100 mg, 0.19 mmol) in ethanol (3 mL). The reaction was blanketed with argon and 10% palladium on carbon (20 mg) was added. The mixture was heated to 140° C. for 10 minutes in a Smith Creator microwave after which complete conversion to desired product was observed. The reaction mixture was filtered through diatomaceous earth and the filter pad was washed well with ethyl acetate. The filtrate was evaporated in vacuo and the residue purified by column chromatography on silica, eluting with 60-100% ethyl acetate in hexanes, and then by chromatography on alumina, eluting with 20-60% ethyl acetate in hexanes, to afford the title compound as a colourless oil which foamed under high vacuum (50 mg).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][OH:7].S(OC)(OC)(=O)=O.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C@H:22]([N:26]1[CH2:31][CH2:30][C:29]2[S:32][CH:33]=[CH:34][C:28]=2[CH2:27]1)[C:23](N)=[O:24]>ClCCl.O>[CH3:6][O:7][C:23](=[O:24])[C@@H:22]([N:26]1[CH2:31][CH2:30][C:29]2[S:32][CH:33]=[CH:34][C:28]=2[CH2:27]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[Cl:15]
Reactant: CO
Reactant: NC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: ClCCl
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 45 °C

Procedure:
Concentrated sulfuric acid (˜98%; 496 ml; 9.30 mol) was charged into methanol (1.75 l) with sting between 25-38° C. followed by dimethyl sulfate (250 ml; 2.636 mol). The contents were heated to reflux for 3 hours, after which the reaction mixture was cooled to 40-50° C. and (+)-(S)-2-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5yl)acetamide (500 g; 1.55 mol) was charged. The reaction mixture was heated to 65° C. and maintained between 65-66° C. for a period of 60 hours. The reaction mixture was cooled to 25-30° C. and poured into water (10.0 l) with stirring. Dichloromethane (5.0 l) was added, stirred for 1 hour, after which the organic layer was separated. To the aqueous layer dichloromethane (2.5 l) was added and stirred for 1 hour and the separated organic layer was combined with the earlier separated layer and washed with water (2.5 l). 5% (w/v) aqueous sodium bicarbonate solution (2.5 l) was added to this organic layer and stirred for a period of an hour and the separated organic layer was washed with 0.25% sulfuric acid (2.5 l) followed by water (2.5 l) and treated with activated carbon (40.0 g) for a period of 3 hours with stirring. The activated carbon was removed by filtration through a celite bed and the celite bed was washed with dichloromethane (1.0 l). This washing was coupled with the filtrate and the solvent removed under vacuum to yield (+)-(S)-2-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetic acid methyl ester as a pale yellow oil. Yield: 380 g (73.0% by theory). The product was identified by IR spectrum, 1H and 13C NMR investigation.