Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH2:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH2:9]1[CH2:15][S:12](=[O:14])(=[O:13])[O:11][CH2:10]1>O1CCCC1.O>[C:6]([C@@H:2]([NH:1][CH2:10][CH2:9][CH2:15][S:12]([OH:14])(=[O:13])=[O:11])[CH:3]([CH3:5])[CH3:4])(=[O:7])[NH2:8]
Reactant: CC(C)[C@H](N)C(N)=O
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H](NCCCS(=O)(=O)O)C(N)=O
Temperature: 25 °C

Procedure:
To a solution of L-valinamide (1.57 g, 13.5 mmol) in tetrahydrofuran (20 mL) was slowly added 1,3-propane sultone (1.61 g, 12.9 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×25 mL). The crude product was dissolved in water (60 mL) and treated with ion exchange resin Dowex Marathon C (strongly acidic, 15 g). The mixture was stirred for 15 minutes. The resin was removed by filtration. The filtrate was poured into EtOH (250 mL). The solid product, after the completion of the precipitation, was collected by filtration, and dried in vacuo, to afford compound EQ (1.6 g, 51%). 1H NMR (D2O, 500 MHz) δ ppm 3.63 (d, 1H), 3.05 (m, 2H), 2.85 (m, 2H), 2.05 (m, 4H), 0.93 (d, 3H), 0.88 (d, 3H). 13C NMR (D2O, 125 MHz) δ ppm 170.24., 65.92, 48.16, 46.31, 29.59, 21.31, 18.02, 17.07. [α]D=+10.5° (c=0.0027 in water), ES-MS 237 (M−1).
Reaction SMILES: [CH:1]([C@H:3]1[C@@H:8]([CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][O:6][C@@H:5]([CH3:19])[O:4]1)=O.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH3:18][O:17][C:15]([CH2:14][CH2:13][CH2:12]/[CH:11]=[CH:10]\[CH2:9][C@H:8]1[CH2:7][O:6][C@@H:5]([CH3:19])[O:4][C@H:3]1[CH2:1][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[O:16]
Reactant: NCc1ccccn1
Reactant: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1CNCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2R,4R,5S)-4-formyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (200 mg) and 2-aminomethylpyridine (0.15 ml) in a mixture of methanol (4 ml) and acetic acid (1 ml) was added sodium cyanoborohydride (100 ml) and the solution was stirred at room temperature overnight. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The organic extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column (10 g) with a mixture of chloroform and methanol (30:1) as an eluent to give (2R,4R,5S)-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-4-(2-pyridylmethylaminomethyl)-1,3-dioxane (165 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[N:16]1([CH2:21][CH:22]2[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:28][C@H:25]1[CH2:24][CH2:23][C@H:22]([CH2:21][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:27][CH2:26]1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: NC1CCC(CN2CCCC2)CC1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN2CCCC2)CC1

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (220 mg, 0.92 mmol) was reacted with 4-(pyrrolidin-1-ylmethyl)cyclohexanamine (200 mg, 1.1 mmol) to afford the desired product (67 mg, 19%) as a brown solid: 1H NMR (300 MHz, CDCl3) δ 10.88 (br s, 1H), 8.93 (s, 1H), 8.07 (d, J=8.7 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 5.09-4.88 (m, 1H), 2.66 (br s, 7H), 2.46 (d, J=7.1 Hz, 2H), 2.37-2.25 (m, 2H), 2.08-1.76 (m, 6H), 1.72-1.55 (m, 1H), 1.51-1.12 (m, 4H); ESI MS m/z 387 [M+H]+
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:8]=1)(=O)=O.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>C(#N)C>[N:21]1([CH2:6][C:7]2[N:8]=[C:9]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][CH:12]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(COS(C)(=O)=O)n1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cccc(CN2CCCC2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.5 %

Procedure:
A mixture of (6-(tert-butoxycarbonylamino)pyridin-2-yl)methyl methanesulfonate 79 (1.30 g, 3.2 mmol), pyrrolidine 68 (0.46 g, 6.4 mmol) and K2CO3 (1.30 g, 9.6 mmol) in acetonitrile (15 mL) was stirred at room temperature for 12 h. Saturated aqueous NaHCO3 was added and the mixture was concentrated under reduced pressure. The resulting aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford 80 (0.75 g, 62% yield).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.Cl.[F:15][C:16]([F:21])([F:20])[CH2:17][CH2:18][NH2:19].CCN(C(C)C)C(C)C>CS(C)=O>[F:11][C:10]([F:13])([F:12])[C:4]1[CH:3]=[C:2]([NH:19][CH2:18][CH2:17][C:16]([F:21])([F:20])[F:15])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: NCCC(F)(F)F
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1ccc(NCCC(F)(F)F)cc1C(F)(F)F
Temperature: 200 °C
Yield: 60.8 %

Procedure:
A mixture of 4-fluoro-2-(trifluoromethyl)benzonitrile (0.158 g, 0.84 mmol), (3,3,3-trifluoropropyl)amine hydrochloride (0.125 g, 0.84 mmol) and DIEA (0.326 g, 2.52 mmol) in 1.5 mL of DMSO was heated in a microwave at 200° C. for 20 min. Upon cooling, the mixture was partitioned between Et2O and 0.1N HCl. The organic phase was washed with 0.1N HCl (×2) and brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (10-80% EtOAc-hexanes gradient) and the product crystallized from Et2O-hexanes to give 0.144 g (61% yield) of the title compound: 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J=8.6 Hz, 1H), 6.87 (d, J=2.4 Hz, 1H), 6.71 (dd, J=8.6, 2.4 Hz, 1H), 4.56 (bs, NH), 3.53 (q, J=6.5 Hz, 2H), 2.51-2.40 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([NH2:6])([CH3:5])[C:3]#[CH:4].Br[CH2:8][CH:9]=[O:10].[OH-].[Na+]>CO>[CH3:1][C:2]([NH:6][CH2:8][CH:9]=[O:10])([CH3:5])[C:3]#[CH:4]
Reactant: C#CC(C)(C)N
Reactant: O=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CC(C)(C)NCC=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1,1-Dimethylprop-2-ynylamine (2.0 mole), the diethyl acetal of 2-bromoacetaldehyde (1.0 mole) and methanol (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 6 hours. After this time the reaction mixture is cooled to room temperature and sodium hydroxide (20 grams) is added. The reaction mixture is then stirred for an additional period of about 16 hours. The mixture is then filtered and the filtrate is distilled to yield the desired product the diethyl acetal of 2-(1,1-dimethylprop-2-ynylamino)acetaldehyde.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH2:14])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[F:15][C:16]([F:21])([F:20])[C:17](O)=[O:18].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH:14][C:17](=[O:18])[C:16]([F:21])([F:20])[F:15])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(N)cc2C1
Reactant: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCc2ccc(NC(=O)C(F)(F)F)cc2C1
Yield: 92.5 %

Procedure:
A solution of 14 (3.0 g, 17 mmol), trifluoroacetic acid (2 ml, 28 mmol) and trifluoroacetic anhydride (4 ml, 28 mmol) in CH2Cl2 is refluxed for 15 minutes, cooled, and the mixture is poured onto ice, extracted twice with CH2Cl2 and evaporated. The mixture is chromatographed on silica gel to give 4.5 g of compound 15 (94% yield). 1H NMR [300 MHz, (CD3)2SO], a 3:2 mixture of amide conformers doubling most signals, δ 11.24 (0.8H, s, NH), 11.21 (1.2H, s, NH), 7.55-7.40 (2H, m, H5.8), 7.22 (0.6H, s, H-6), 7.20 (0.4H, s, H-6), 4.64 (0.8H, s, ArCH2N), 4.57 (1.2H, s, ArCH2N), 3.65 (2H, t, ArCH2CH2N), 2.84 (1.2H, t, ArCH2CH2N), 2.73 (0.8H, t, ArCH2CH2N), 2.06 (1.2H, s, COCH3), 2.05 (1.8H, s COCH3).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][CH:11]([CH3:15])[C:12](=[O:14])[N:13]=1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.CC1(C2C=CC(C#N)=CC=2)SC(N[C@H](C2C=CC=CC=2C(F)(F)F)C)=NC1=O.[Li]N([Si](C)(C)C)[Si](C)(C)C>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:11]([CH3:15])([C:21]2[CH:20]=[CH:19][N:18]=[CH:17][CH:22]=2)[C:12](=[O:14])[N:13]=1
Reactant: Brc1ccccn1
Reactant: CC1SC(NC2CC3CCC2C3)=NC1=O
Agent: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccccc1C(F)(F)F
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Product: CC1(c2ccncc2)SC(NC2CC3CCC2C3)=NC1=O

Procedure:
The title compound was prepared from the reaction of 2-(bicyclo[2.2. 1]heptan-2-ylamino)-5-methylthiazol-4(5H)-one with bromopyridine using the procedure described for 2a. 4.0 equivalent of LiN(SiMe3)2 was used. MS (ESI, pos. ion) m/z: 302 (M+1). % de (chiral LC): 20%
Reaction SMILES: S(O[CH2:12][C@H:13]([C@@H:15]([CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O)[OH:16])[OH:14])(C1C=CC(C)=CC=1)(=O)=O.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH2:29]([N:36]1[CH2:12][C@@H:13]([OH:14])[C@H:15]([OH:16])[CH2:17]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](O)COS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Yield: 45.8 %

Procedure:
To a 1,4-dioxane (20 mL) solution of 1,4-di-O-tosyl-D-threitol (9.15 g, 21.25 mmol), benzylamine (9.29 mL, 85.0 mmol) was added, and the mixture was heated to reflux under a nitrogen stream for 4 days while stirring. The reaction liquor was returned to room temperature, and then a saturated aqueous solution of sodium hydrogen carbonate (50 mL) was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography using silica gel [NH(basic)-silica gel 100 g, ethyl acetate to chloroform/methanol (10/1)], to obtain the title compound (1.88 g, 46%) as an oily matter.
Reaction SMILES: [CH2:1]([C:4]1[C:9]2[O:10][C@@H:11]([CH2:14][OH:15])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:2]=[CH2:3].C(N(CC)C(C)C)(C)C.[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:43][C:33]1[CH:38]=[CH:37][C:36]([S:39]([O:15][CH2:14][CH:11]2[O:10][C:9]3[C:4]([CH2:1][CH:2]=[CH2:3])=[C:5]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:6]=[CH:7][C:8]=3[O:13][CH2:12]2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCc1c(OCc2ccccc2)ccc2c1O[C@@H](CO)CO2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCc1c(OCc2ccccc2)ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 15.6 g (50.0 mmole) of [(2S)-8-allyl-7-(benzyloxy)-2,3-dihydro-1,4-benzodioxin-2-yl]methanol in 100 mL of methylene chloride was added 26.3 mL (0.15 mole) of N,N-diisopropylethylamine, 0.63 g (5 mmole) of 4-dimethylaminopyridine and 14.25 g (75.0 mmole) of p-toluenesulfonyl chloride. The mixture was stirred at room temperature under nitrogen for 15 hours. The solvent was then removed in vacuum and the residue column chromatographed on silica gel with methylene chloride as eluant. Combination of the product fractions and concentration in vacuum gave 18.0 g (77%) of the (R)-enantiomer of the title compound as a white solid, m.p. 76-77° C.
Reaction SMILES: [S:1]=[C:2]1[NH:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=2)[NH:3]1.[CH3:16]I>CCO>[CH3:16][S:1][C:2]1[NH:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COC(=O)c1ccc2c(c1)NC(=S)NC2
Reactant: CI
Solvent: CCO
Product: COC(=O)c1ccc2c(c1)N=C(SC)NC2
Yield: 84.6 %

Procedure:
To a suspension of methyl 2-thioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (110 mg, 0.5 mmol) in anhydrous EtOH (5 mL) was added MeI (0.125 mL, 2 mmol). The reaction mixture was stirred at reflux for 1 hr. After cooling, the solid was isolated by filtration to afford methyl 2-(methylthio)-3,4-dihydroquinazoline-7-carboxylate (100 mg).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[N:6][CH:5]=1.[BH4-].[Na+]>CO>[CH3:11][O:10][C:7]1[N:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(OC)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CO)cn1
Temperature: 25 °C

Procedure:
A solution of methyl6-methoxy-nicotinate (50 mmol) in anhydrous methanol (60 mL) was treated with sodium borohydride (122 mmol) at 0° C., warmed to ambient temperature for 18 h, then heated to reflux for 6 h. The incomplete reaction product was concentrated to dryness in vacuo, dissolved in anhydrous 1,4-dioxane (70 mL), treated with more sodium borohydride (122 mmol), and heated to reflux for 18 h. After cooling to ambient temperature, the reaction was quenched with methanol, filtered over a coarse glass frit, solids washed with methanol, and the filtrate concentrated. The residue was repeatedly dissolved in methanol, filtered, and concentrated in vacuo until no solids remained, then triturated with 10% MeOH/CH2Cl2, filtered, and concentrated. The impure product was then adsorbed onto silica gel, poured onto a 9.5×5.5 cm plug of silica gel, and eluted with a gradient of 0 to 15% MeOH/CHCl3, and the pure fractions concentrated in vacuo giving the title compound as a pale yellow oil. 1H NMR (CDCl3) δ 8.08 (1H, d, J=2.5 Hz), 7.61 (1H, dd, J=8.5 Hz, 2.4 Hz), 6.74 (1H, d, J=8.5 Hz), 4.60 (2H, s), 3.92 (3H, s).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[C:20]3=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]3[CH2:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.Cl>CO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[C:20]3=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]3[CH2:18][CH2:17][CH2:16]2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CCCN3CCS(=O)(=O)N=C23)cc1
Agent: Cl
Solvent: CO
Product: O=S1(=O)CCN2CCC[C@H](c3ccc(O)cc3)C2=N1
Temperature: 60 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A mixture of (9R)-9-(4-((tert-butyldimethylsilyl)oxy)phenyl)-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (11.8 g) and 6 M HCl aq. (15.0 mL) in MeOH (100 mL) was stirred at 60° C. for 2 hr. After cooling to room temperature, the precipitate was collected and washed with MeOH to give the title compound (8.04 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:19]([CH2:20][N:21]2[CH2:41][CH2:40][C:24]3([O:29][CH2:28][CH2:27][N:26]([C:30]([C:32]4[N:33]=[C:34]([CH:37]([CH3:39])[CH3:38])[S:35][CH:36]=4)=[O:31])[CH2:25]3)[CH2:23][CH2:22]2)=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]([O:11]C(C)(C)C)=[O:10].FC1C(CN2CCC3(OCCN(C(C4N=C(C(C)C)SC=4)=O)C3)CC2)=CC=CC=1CCOCCC([O-])=O>>[Cl:1][C:2]1[C:19]([CH2:20][N:21]2[CH2:22][CH2:23][C:24]3([O:29][CH2:28][CH2:27][N:26]([C:30]([C:32]4[N:33]=[C:34]([CH:37]([CH3:38])[CH3:39])[S:35][CH:36]=4)=[O:31])[CH2:25]3)[CH2:40][CH2:41]2)=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)OC(C)(C)C)c4Cl)CC3)C2)cs1
Agent: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)[O-])c4F)CC3)C2)cs1
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)O)c4Cl)CC3)C2)cs1

Procedure:
Prepared by the method of Example 7, step d using tert-butyl 3-(2-chloro-3-((4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoate [Example 27, step c] (0.93 g) in place of tert-butyl. 3-(2-fluoro-3-((4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoate. Yield 0.76 g.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([O:12]CC)=O.O.[CH:16]([NH2:18])=O>>[N:1]1[C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][C:4]=3[C:3]=2[C:10](=[O:12])[NH:18][CH:16]=1
Reactant: NC=O
Reactant: CCOC(=O)c1c(N)sc2c1CCC2
Solvent: O
Product: O=c1[nH]cnc2sc3c(c12)CCC3

Procedure:
A suspension of 11.37 g ethyl 2-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate in 40 mL formamide was heated for 4 h to 190° C. using a heating mantle, then cooled and poured into 400 mL water. The mixture was then filtered to remove the solid product. The solids were washed successively with 30 mL EtOAc and 200 mL diethyl ether, air dried overnight, then vacuum oven dried for 3 h. The material was used in the subsequent reactions without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)CC)C.O>ClCCl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
A mixture of 2-chloro-5-nitro-pyridine (5 g, 31 mmol), morpholine (13 mL, 155 mmol), and triethylamine (10 mL) in dichloromethane (30 mL) was stirred at room temperature for 3 hr. After the reaction, the reaction mixture was mixed with water, and two layers were separated. The aqueous layer was extracted with CH2Cl2 two times. Organic layers were collected, combined, washed with brine, dried over sodium sulfate, filtered, and concentrated to give 4-(5-nitro-pyridin-2-yl)-morpholine (6.48 gm, 100%) as a yellow solid. LCMS calcd for C9H11N3O3 (m/e) 209, obsd 210 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:15]2[CH2:20][CH2:19][C:18](O)([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([C@H:15]2[CH2:16][CH2:17][C@H:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=3[CH3:28])[CH2:19][CH2:20]2)[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(C2CCC(O)(c3ccc(C)cc3C)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1N1CCN([C@H]2CC[C@H](c3ccc(C)cc3C)CC2)CC1
Reaction time: 8 h

Procedure:
To a solution of 1-(2-methoxyphenyl)-4-[1-hydroxy-1-(2,4-dimethylphenyl)cyclohex-4-yl]piperazine in dichloromethane (anhydrous) at room temperature was added trifluoroacetic acid (8 equivalents). The solution was stirred overnight. Excess trifluoroacetic acid was removed under vacuo and the residue poured into sodium bicarbonate solution. The neutralised aqueous layer was extracted with dichloromethane, washed with salt solution, dried (MgSO4) and filtered. The solvent was removed and the residue purified by silica gel pressure column chromatography using hexane/ether (2/1) as eluant. The solid residue was recrystallised from ether to give the title compound which was converted to its dihydrochloride, m.p. 219° C. (dec.).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]2[NH:12][C:13](=[O:16])[CH2:14][O:15][C:10]=2[CH:9]=[C:8]([F:17])[C:7]=1[N:18]1[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]1=[O:30])=[O:4].[I-].[K+].C(N(CC)C(C)C)(C)C.O>C(#N)C>[CH3:29][N:20]1[C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][C:23](=[O:24])[N:18]([C:7]2[C:6]3[NH:5][C:3](=[O:4])[CH2:2][N:12]4[C:13](=[O:16])[CH2:14][O:15][C:10]([C:11]=34)=[CH:9][C:8]=2[F:17])[C:19]1=[O:30]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc3c(c2NC(=O)CCl)NC(=O)CO3)c1=O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc3c4c2NC(=O)CN4C(=O)CO3)c1=O

Procedure:
3-[5-(2-Chloroacetylamino)-7-fluoro-2H-1,4-benzoxazine-3(4H)-on-6-yl]-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (271 mg, 0.60 mmol was dissolved in anhydrous acetonitrile (10 ml) and potassium iodide (14 mg, 0.08 mmol) and N,N-diisopropylethylamine (100.8 mg, 0.78 mmol) were added. Solution was refluxed for 2 hr. added to water and extracted with ethyl acetate. Product was purified by flash chromatography on silica gel with hexane-ethyl acetate (1:1) as eluent (218.6 mg, 0.53 mmol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1.COC(C1C(C)=CC(C2C=CC=C(C(F)(F)F)C=2)=C(Cl)N=1)=O.CC1C(C(O)=O)=NC=C(C2C=CC=C(C(F)(F)F)C=2)C=1.[N:64]1([CH:69]2[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]2)[CH2:68][CH2:67][CH2:66][CH2:65]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([N:72]2[CH2:73][CH2:74][CH:69]([N:64]3[CH2:68][CH2:67][CH2:66][CH2:65]3)[CH2:70][CH2:71]2)=[O:10])[C:5]([CH3:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)O
Agent: COC(=O)c1nc(Cl)c(-c2cccc(C(F)(F)F)c2)cc1C
Agent: Cc1cc(-c2cccc(C(F)(F)F)c2)cnc1C(=O)O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 1, 6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid [prepared from 6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester (intermediate 2) by saponification in analogy to the procedure described for intermediate 1B] was reacted with 4-pyrrolidin-1-yl-piperidine to give the title compound as light brown solid. MS: 452.1 (MH+, 1Cl).
Reaction SMILES: OC(C)(C)[C:3]#[C:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1.[OH-].[K+]>C1C=CC=CC=1>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([C:6]#[C:5][C:4]#[CH:3])[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc(C#CC#CC(C)(C)O)c1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: C#CC#Cc1cccc(OC)c1
Yield: 73.7 %

Procedure:
800 mg of the thus-obtained diacetylene compound were dissolved in 200 ml of benzene, and 300 mg of potassium hydroxide were added to the reaction mixture, followed by reflux under heating for 15 minutes. After filtration, the solvent was evaporated, and the residue was purified by silica-gel chromatography using as hexane as an eluent to obtain 430 mg of 1-(3-methoxyphenyl)-1,3-butadiyne.