Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH:11]=[CH:12][C:13](=O)[CH3:14].[C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:17].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:22]([O:21][C:19](=[O:20])[C:18]([C:16]#[N:17])=[C:13]([CH3:14])[CH:12]=[CH:11][C:3]1[CH:4]=[CH:5][C:6]([CH:8]([CH3:10])[CH3:9])=[CH:7][C:2]=1[Cl:1])[CH3:23]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)C=Cc1ccc(C(C)C)cc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=C(C)C=Cc1ccc(C(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 4-(2-chloro-4-isopropylphenyl)but-3-en-2-one (50 mmole), ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E- and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate/petroleum ether.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[H-].[Na+].[C:6]([C:8]([CH3:14])([CH3:13])[C:9](OC)=[O:10])#[N:7]>C1COCC1>[CH3:13][C:8]([CH3:14])([C:9](=[O:10])[CH2:2][C:1]#[N:3])[C:6]#[N:7]
Reactant: CC#N
Reactant: COC(=O)C(C)(C)C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C#N)C(=O)CC#N
Yield: 62.5 %

Procedure:
A solution of anhydrous acetonitrile (2.3 g, 56 mmol) in THF (100 mL) was added dropwise at 80° C. to a mixture of NaH (60%, 2.8 g, 70 mmol) and methyl 2-cyano-2-methylpropanoate (6 g, 47 mmol) in THF (100 mL). The resultant reaction mixture was heated at reflux for 8 hours. The solvent was removed in vacuo and the residue was diluted with EtOAc and washed with 10% HCl, water and brine. The organics were dried (MgSO4) and concentrated in vacuo to obtain crude 2,2-dimethyl-3-oxopentanedinitrile (4 g), which was used for the next step reaction without further purification.
Reaction SMILES: [Mg+2].[Cl-].[Cl-].[CH2:4](N(CC)CC)C.C(OC)(=O)CC(OC)=O.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32])[C:25](Cl)=[O:26].Cl>C1(C)C=CC=CC=1>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:25](=[O:26])[CH3:4])[CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32]
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: COC(=O)CC(=O)OC
Product: COc1cc(C(C)=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.1 %

Procedure:
A suspension of MgCl2 (932 mg, 9.8 mmol) in toluene (13 mL) was treated with triethylamine (4.65 mL, 33.4 mmol), dimethyl malonate (1.9 mL, 16.6 mmol), stirred for 1.5 hours, and treated portionwise over 30 minutes with 3-methoxy-4-nitrobenzoyl chloride (3 g, 13.9 mmol). The reaction mixture was stirred for 45 minutes, then carefully treated with concentrated HCl (4 mL). The layers were separated and the organic phase was dried (Na2SO4), filtered, and concentrated. The, residue was dissolved in DMSO (11.5 mL) and water (0.5 mL), heated to reflux overnight, cooled to room temperature, and partitioned between water and ethyl acetate. The organic phase was washed sequentially with saturated NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated to provide 1.63 g (60% yield) of the desired product. MS (ESI(−)) m/e 194 (M−H)−.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([CH3:7])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:7][C@H:6]1[C@H:2]([O:1][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:3][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(+/−)-(trans)-benzyl 3-hydroxy-4-methylpyrrolidine-1-carboxylate (9.2 g, 39.1 mmol) in pyridine (50 mL) at 5° C. was added tosyl chloride (9.69 g, 50.8 mmol) in one portion and the resulting mixture was allowed to warm to rt and stir overnight. The reaction mixture was concentrated and the residue was taken up in dichloromethane (400 mL) and washed with water (50 mL×2), 0.5 N HCl (50 mL×2), water, sat aq. sodium bicarbonate (50 mL×2), brine, then dried over magnesium sulfate, filtered and concentrated to give a dark oil as the crude title compound which was used directly without any further purification. HPLC (method B) retention time=3.60 min. LCMS (m+1)=390.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([OH:10])=O)[C:4](=[O:11])[CH2:3]1.[NH2:12][CH2:13][C:14]([N:16]1[CH:20]([CH3:21])[C:19](=[O:22])[NH:18][C:17]1([CH3:24])[CH3:23])=[O:15]>>[OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([NH:12][CH2:13][C:14]([N:16]2[CH:20]([CH3:21])[C:19](=[O:22])[NH:18][C:17]2([CH3:23])[CH3:24])=[O:15])=[O:10])[C:4](=[O:11])[CH2:3]1
Reactant: CC1C(=O)NC(C)(C)N1C(=O)CN
Reactant: O=C(O)CN1CC(O)CC1=O
Product: CC1C(=O)NC(C)(C)N1C(=O)CNC(=O)CN1CC(O)CC1=O

Procedure:
The same procedure of Example 11, starting from 4-hydroxy-2-oxo-1-pyrrolidineacetic acid and 1-(2-aminoacetyl)-2,2,5-trimethyl-4-imidazolidinone, gave the title compound as a diastereoisomeric mixture, m.p. 218°-220° C. Mass spectrum (E.I., 70 eV, 1.5 mA), m/z=269 (M.+ --C3H7N).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.CO.[CH2:21](N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[C:5]([O:7][CH3:21])=[O:6]
Reactant: CCN(CC)CC
Reactant: COc1ccc(Br)c(OC)c1C(=O)O
Solvent: ClCCl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c(OC)ccc(Br)c1OC
Temperature: 25 °C
Reaction time: 64 h
Yield: 78.9 %

Procedure:
3-Bromo-2,6-dimethoxybenzoic acid (5.0 g, 19.2 mmol) and thionyl chloride (10 ml) were heated to reflux for 2 h. The mixture was then concentrated in vacuo and diluted with CH2Cl2 (20 ml) and added to a solution of MeOH (614 mg, 38.4 mmol) and triethylamine (3.88 g, 38.4 mmol) in CH2Cl2 (100 ml) at 0° C. The resulting mixture was allowed to warm to RT and stirred for 64 h. The organics were washed with 10% HCl (50 ml), brine (50 ml) and dried (MgSO4) and purified by chromatography (0-50% EtOAC in heptane) to leave a white solid (4.17 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:13][CH3:14])=[C:11]([C:15]([OH:17])=O)[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:46]2[CH:47]=[CH:48][CH:49]=C[C:45]=2[N:44]=[N:43]1.NN1CCCCC1>CC#N.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:13][CH3:14])=[C:11]([C:15]([NH:43][N:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:17])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CSc1c(C(=O)O)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: NN1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: CSc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Reaction time: 40 h
Yield: 72 %

Procedure:
To a magnetically stirred suspension of 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methylsulfanyl-1H-imidazole-4-carboxylic acid (1.72 g, 4.16 mmol) in anhydrous CH3CN (45 ml) was successively added N,N-diisopropylethylamine (Hunig's base) (1.60 ml, 9.20 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (1.89 g, 4.99 mmol) and 1-aminopiperidine (0.54 ml, 5.01 mmol). After stirring for 40 h, water was added and the resulting mixture was extracted with dichloromethane. The dichloromethane layer was successively twice washed with an 1N HCl solution and water, dried over MgSO4, filtered and concentrated to give a crude oil. This oil was further purified by flash chromatography (silicagel, EtOAc) and triturated with diethyl ether to give 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methylsulfanyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide in 72% yield, mp 170° C. (dec);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH:11]2[C:17]([OH:19])=O)=[CH:4][CH:3]=1.C1CN([P+](O[N:37]2N=[N:44][C:39]3C=CC=C[C:38]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.NCC#N.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:38]([CH2:39][NH:44][C:17]([CH:11]1[CH2:12][CH:13]([CH3:16])[CH2:14][CH2:15][CH:10]1[CH2:9][S:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:19])#[N:37]
Reactant: CC1CCC(CSc2ccc(F)cc2)C(C(=O)O)C1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1CCC(CSc2ccc(F)cc2)C(C(=O)NCC#N)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To (1R/S,3R/S,6R/S)-2-{[(4-fluorophenyl)sulfanyl]methyl}-5-methylcyclohexanecarboxylic acid and (1R/S,3S/R,6R/S)-2-{[(4-fluorophenyl)sulfanyl]methyl}-5-methylcyclohexanecarboxylic acid (1:1 mixture, 52 mg, 0.18 mmol), PyBOP (144 mg, 0.28 mmol), and aminoacetonitrile hydrochloride (34 mg, 0.37 mmol) was added dry dimethylformamide (2 mL) under an atmosphere of dry nitrogen followed by triethylamine (103 μL, 0.74 mmol) and the reaction mixture was stirred for 5 h at room temperature. The reaction mixture was poured into aqueous saturated sodium hydrogen carbonate, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was concentrated in vacuo and the crude product was purified by flash chromatography over silica gel (ethyl acetate/hexanes, 30/70 to 50/50) to yield (1R/S,3R/S,6R/S)-N-(cyanomethyl)-2-{[(4-fluorophenyl)sulfanyl]-methyl}-5-methylcyclohexanecarboxamide and (1R/S,3S/R,6R/S)-N-(cyanomethyl)-2-{[(4-fluorophenyl)sulfanyl]methyl}-5-methylcyclohexanecarboxamide as a 1:1 mixture of diastereomers.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12](=[O:39])[NH:13][CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH:21]([OH:38])[CH:22]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([O:35][CH3:36])[C:32]=3[F:34])[N:27]=[CH:26][C:25]=2Cl)[OH:23])[O:16][CH2:15]1)([CH3:10])([CH3:9])[CH3:8].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.CCCCCC>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[C:7]([O:11][C:12](=[O:39])[NH:13][C@@H:14]1[CH2:19][CH2:18][C@@H:17]([CH2:20][CH:21]2[O:38][C:25]3[CH:26]=[N:27][C:28]4[CH:29]=[CH:30][C:31]([O:35][CH3:36])=[C:32]([F:34])[C:33]=4[C:24]=3[CH:22]2[OH:23])[O:16][CH2:15]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: COc1ccc2ncc(Cl)c(C(O)C(O)CC3CCC(NC(=O)OC(C)(C)C)CO3)c2c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc2ncc3c(c2c1F)C(O)C(C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)CO1)O3
Temperature: 100 °C
Reaction time: 16 h
Yield: 56.3 %

Procedure:
Potassium tert-butoxide (231 mg, 2.06 mmol, 2.0 eq) is added at room temperature to a stirred solution of (3R,6S)-{[6-[3-(3-chloro-5-fluoro-6-methoxy-quinolin-4-yl)-2,3-dihydroxy-propyl]-tetrahydro-pyran-3-yl}-carbamic acid tert-butyl ester (500 mg, 1.03 mmol, 1.0 eq) in dioxane (50 mL), followed by palladium(II) acetate (93 mg, 0.41 mmol, 0.4 eq) and racemic-2-di-tert-butylphosphino-1,1′-binaphthyl (164 mg, 0.41 mmol, 0.4 eq). After 16 hours stirring at 100° C., the reaction mixture is cooled down to room temperature and filtered through decalite. The filtrate is concentrated and the crude product is purified by column chromatography (silica gel, eluent: n-hexane:ethyl acetate, 5:1, v/v) to afford (3R,6S)-[6-(9-fluoro-1-hydroxy-8-methoxy-1,2-dihydro-furo[2,3-c]quinolin-2-ylmethyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester as a yellow solid (260 mg, 56% yield).
Reaction SMILES: Cl.C([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#N.[OH-].[K+].C1(C)C=CC=CC=1>O>[C:10]1([CH:4]2[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#CC1(c2ccccc2)CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(C2CCNCC2)cc1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
4-Cyano-4-phenylpiperidine HCl (10.0 g, 45.0 mmol) was combined with KOH pellets and stirred vigorously under Ar at 160° C. for 4 h. The reaction mix was cooled to RT and dissolved into toluene (100 ml) and H2O (100 ml). After separation of the layers, the aqueous layer was back-extracted two times with toluene. The combined organic layer was dried over Na2SO4, concentrated in vacuo, and dried under high vacuum, yielding a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH:20]C(=O)C1C=CC=CC=1)=[N:9]2.C1CCN2C(=NCCC2)CC1>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH2:20])=[N:9]2
Reactant: CO[C@@H]1CC[C@]2(c3ccccc3F)N=C(NC(=O)c3ccccc3)SC[C@@H]2C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CO[C@@H]1CC[C@]2(c3ccccc3F)N=C(N)SC[C@@H]2C1
Temperature: 25 °C

Procedure:
(±)-N-[(4aR*,6R*,8aS*)-8a-(2-Fluorophenyl)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide obtained in Preparation Example 59-(8) (1.65 g) was dissolved in methanol (60 mL). Then, DBU (1.24 mL, specific gravity: 1.018 g/cm3) was added, and the mixture was stirred with heating under reflux for 13 hours and 30 minutes. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (1.16 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[CH2:3][OH:2])[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)c1ccncc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2cnccc2CO)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.1 %

Procedure:
A solution of 3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-4,1′-dicarboxylic acid 1′-t-butyl ester 4-methyl ester (3.3 g, 8.2 mmol, 1.0 eq.) in THF (50 mL) was added dropwise to a solution of LiAlH4 (590 mg, 15.5 mmol, 1.5 eq.) in THF (50 mL) at 0° C. under nitrogen. The resulting solution was stirred for 10 minutes at 0° C. The reaction was then quenched with water (0.6 mL) and 15% NaOH (1.8 mL). The solids were filtered. The mixture was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:1) to yield the title compound (1.8 g) as a white solid. MS m/z: [M+H]+ calcd for C16H25N2O3, 293. found 293.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][CH2:5][O:4][C:3]1=[O:7].[OH-:9].[K+:10]>C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.CCO.O>[OH:4][CH2:5][CH2:6][C:2]([CH3:8])([CH3:1])[C:3]([O-:9])=[O:7].[K+:10]
Reactant: [OH-]
Reactant: CC1(C)CCOC1=O
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(CCO)C(=O)[O-]
Temperature: 105 °C
Reaction time: 3.5 h
Yield: 71.1 %

Procedure:
A mixture of dihydro-3,3-dimethyl-2(3H)-furanone (10 mmol; 1.14 g), aqueous 1 M KOH solution (10 mmol) and one drop of phenolphthalein indicator (0.5% w/v in EtOH/water (1:1)) is stirred at 105° C. for 3.5 hours. The mixture is cooled to ambient temperature and concentration under reduced pressure. To the residue is added 10 mL of EtOH. To the solution is added 50 ml of Et2O, and the solid isolated by filtration and dried under 100 mbar at 50° C. to give potassium 4-hydroxy-2,2-dimethylbutyrate (1.21 g, 71%).
Reaction SMILES: O.O.O.[CH2:4]([N:6]([CH2:10][CH3:11])[C:7](=[S:9])[S-:8])[CH3:5].[Na+].[CH:13]([C:15]1[CH:22]=[CH:21][C:18](CCl)=[CH:17][CH:16]=1)=[CH2:14].O>C(O)C>[CH:13]([C:15]1[CH:22]=[CH:21][C:18]([S:9][C:7](=[S:8])[N:6]([CH2:10][CH3:11])[CH2:4][CH3:5])=[CH:17][CH:16]=1)=[CH2:14]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: CCN(CC)C(=S)[S-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=Cc1ccc(SC(=S)N(CC)CC)cc1
Reaction time: 0.5 h

Procedure:
A solution of sodium diethyldithiocarbamate trihydrate (3.5 g, 1.55×10−2 mol) in 20 mL of ethanol was added to a flask equipped with a stirrer, dropping funnel and a reflux condenser. To this solution was added a solution of 4-vinylbenzyl chloride (3.0 g, 1.96×10−2 mol) and ethanol (5 mL), dropwise, over a period of 0.5 h at a temperature of 0° C. The resultant solution was stirred at room temperature for 24 h before pouring into a large volume of water and extracting with diethyl ether. The ether phase was washed three times with water, dried over sodium sulphate, before finally removing the diethyl ether by evaporation. The residue was recrystallised three times from methanol, giving a yield of 2.6 grams (83%). 1H NMR (CDCl3) δ7.36 (s, 4H, C6H4), 6.70 (dd, J=11.6 and 17.5 Hz, 1H, CH═CH2), 5.73 (d, J=17.5 Hz, 1H, CH═CH2), 5.24 (d, J=11.5 Hz, 1H, CH═CH2), 4.54 (s, 2H, CH2S), 4.04 (q, J=7.3 Hz, 2H, NCH2), 3.73 (q, J=6.6 Hz, 2H NCH2), 1.19 (t, J=ca.7.0 Hz, 6H CH2CH3).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl.[Cl:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[ClH:28].[N:31]1([CH2:30][CH2:29][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]4[CH:24]=[CH:25][CH:26]=[C:20]4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Reactant: ClCCN1CCCCC1
Agent: Cl
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCN3CCCCC3)cc12

Procedure:
6-(2-Piperidin-1-yl-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, hydrochloride was prepared in 27% overall yield using the method described in example 85, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 81A) and 1-(2-chloroethyl)-piperidine hydrochloride.
Reaction SMILES: N#N.[CH3:3]/[C:4](=[CH:8]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)/[C:5]([NH2:7])=[O:6].C([O-])(O)=O.[Na+].[CH2:20]([O:22][C:23](=[O:28])[C:24](=O)[CH2:25]Br)[CH3:21].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[C:9]1(/[CH:8]=[C:4](/[C:5]2[O:6][CH:25]=[C:24]([C:23]([O:22][CH2:20][CH3:21])=[O:28])[N:7]=2)\[CH3:3])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C/C(=C\c1ccccc1)C(N)=O
Reactant: CCOC(=O)C(=O)CBr
Agent: N#N
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)c1coc(/C(C)=C/c2ccccc2)n1

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of (E)-2-methyl-3-phenylacrylamide (29.4 g, 182 mmol) and NaHCO3 (68.72 g, 820 mmol) in THF (500 mL) was treated with 3-bromo-2-oxo-propionic acid ethyl ester (45.74 mL, 309 mmol) and the reaction mixture was heated at reflux for 20 h. 3-Bromo-2-oxo-propionic acid ethyl ester (10.0 mL, 68 mmol) was added again and the reaction mixture was stirred at reflux for 10 h. The reaction mixture was then filtered over celite and the solvents were evaporated under reduced pressure. The residue was dissolved in THF (500 mL) and treated at 0° C., dropwise, with trifluoroacetic anhydride (78.0 mL, 555 mmol). The reaction mixture was then stirred at rt overnight. Sat. aq. Na2CO3 (250 mL) was added and the mixture was extracted with EA (4×250 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (0:1→1:9 EA-Hept) gave the title compound as a brown oil. TLC:rf (1:9 EA-Hept)=0.13.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[C:27]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([C:31]1[CH:32]=[CH:33][C:34]([CH2:35][NH:36][C:3]2[C:4]3[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6][C:5]=3[CH:17]=[CH:18][C:2]=2[Cl:1])=[CH:37][CH:38]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: CC(C)(C)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 78.1 %

Procedure:
Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (300 mg, 0.7 mmol) with 4-(tert-butyl)benzyl amine (375 μL, 2.1 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (95:5) followed by SCX chromatography to give 6-(4-tert-butylbenzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil (240 mg, 78%). MS (ES+) m/z: 439 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17][OH:18])[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[CH3:27][C:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[CH:30][N:29]=1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C@:13]2([CH2:16][CH2:17][OH:18])[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:32]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:27])[CH:33]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:20][CH:21]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCO)(c4ccc(F)cc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 75 Step 1. LC-MS Method 2 tR=0.945 min, m/z=435.5; 1H NMR (CD3OD) 1.56 (d, 3H), 1.92 (m, 1H), 2.01 (m, 1H), 2.17 (m, 2H), 2.36 (m, 2H), 2.48 (m, 1H), 2.56 (m, 3H), 3.12 (m, 1H), 3.62 (m, 1H), 5.62 (m, 1H), 7.05 (m, 4H), 7.30 (m, 2H), 7.44 (m, 1H), 7.54 (m, 3H), 8.39 (s, 2H).