Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:30]=[CH:29][C:14]2[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:31].C(O)C.C(=O)([O-])[O-].[NH4+:39].[NH4+]>ClCCl.C(O)C>[ClH:31].[CH2:1]([NH:8][C:9]([C:11]1[CH:30]=[CH:29][C:14]2[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:26](=[NH:39])[NH2:27])=[CH:24][CH:25]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)NCc3ccccc3)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)NCc3ccccc3)ccc21
Yield: 63 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-benzylamide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 63% of theory, C24H24N6O (412.5); Rf value: 0.76 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=413.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:10]2=[O:27])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[C:34](Cl)(=[O:42])[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCCC1.C(OCC)(=O)C>[C:23]([C:20]1[CH:19]=[CH:18][C:17]([N:11]2[C:12](=[O:16])[C:13]([CH3:15])([CH3:14])[N:9]([CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:34](=[O:42])[O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:7]=3)[C:10]2=[O:27])=[CH:22][CH:21]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(N)n3)C(C)(C)C2=O)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)Oc4ccccc4)n3)C(C)(C)C2=O)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 100 mg of 1-[(2-aminopyrimidin-4-yl)methyl]-3-(4-tert-butylphenyl)-5,5-dimethylimidazolidine-2,4-dione obtained in stage f) of Example 1, in 3 mL of tetrahydrofuran, are added, at 0° C., 0.034 mL of pyridine and 0.045 mL of phenyl chlorocarbonate. The reaction mixture is stirred for 4.5 hours at room temperature and then diluted with ethyl acetate and washed with twice 30 mL of aqueous 1N hydrochloric acid solution, then with twice 30 mL of water, with twice 30 mL of saturated aqueous sodium hydrogen carbonate solution and finally with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with an ethyl acetate/cyclohexane mixture (62/38 by volume) to give 70 mg of phenyl (4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl]methyl}pyrimidin-2-yl)carbamate in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4](Cl)=[O:5].C[Si](C)(C)[N:15]=[C:16]=[N:17][Si](C)(C)C>CC1C=CC(C)=CC=1C.[Sn](Cl)(Cl)(Cl)Cl>[C:16]([N:17]1[C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]2[C:1]1=[O:11])#[N:15]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cc1ccc(C)c(C)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Product: N#CN1C(=O)c2ccccc2C1=O
Temperature: 60 °C

Procedure:
N-Cyanophthalimide was prepared, as shown in Reaction 1, under a dry atmosphere from a 1:1 mixture of phthaloyl dichloride and 1,3-bis(trimethylsilyl) carbodiimide using 1,2,4-trimethylbenzene as solvent. Two drops of tin(IV) chloride were added as a catalyst before heating the mixture to 60° C. for six hours. The reaction mixture was cooled, filtered, and washed with chilled toluene giving yellow crystals as product. ##STR6##
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([C:14]([O:16][CH3:17])=[O:15])[NH:2]1.C(N(CC)CC)C.[C:25](=[S:27])=[S:26].[C:28]1(CCl)[S:32][CH:31]=[CH:30][CH:29]=1>CO>[S:32]1[CH:31]=[CH:30][CH:29]=[C:28]1[S:27][C:25]([N:2]1[C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:26]
Reactant: S=C=S
Reactant: ClCc1cccs1
Reactant: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=S)Sc1cccs1
Yield: 70 %

Procedure:
In the same manner as described in Example 53, methyl (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (5.00 g), triethylamine (2.61 g), carbon disulfide (1.57 ml), methanol (100 ml) and 2-thenyl chloride (3.45 g) are reacted and treated. The product is recrystallized from benzene-n-hexane to give the title compound (6.00 g, 70%) as pale yellow needles, m.p. 150°-152° C.
Reaction SMILES: [O-:1][Mn](=O)(=O)=O.[K+].[CH3:7][O:8][C:9]1[C:18]2[C:19](=[O:32])[C:20]3[CH:21]=[C:22]4[CH:31]=[CH:30][CH:29]=[CH:28][C:23]4=[N:24][C:25]=3[N:26]([CH3:27])[C:17]=2[C:16]2[CH:15]=[CH:14][C:13]([CH3:34])([CH3:33])[O:12][C:11]=2[CH:10]=1.[OH2:35]>CC(C)=O>[OH:35][CH:14]1[C:15](=[O:1])[C:16]2[C:17]3[N:26]([CH3:27])[C:25]4[N:24]=[C:23]5[CH:28]=[CH:29][CH:30]=[CH:31][C:22]5=[CH:21][C:20]=4[C:19](=[O:32])[C:18]=3[C:9]([O:8][CH3:7])=[CH:10][C:11]=2[O:12][C:13]1([CH3:34])[CH3:33]
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1cc2c(c3c1c(=O)c1cc4ccccc4nc1n3C)C=CC(C)(C)O2
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2c(c3c1c(=O)c1cc4ccccc4nc1n3C)C(=O)C(O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Over the course of 30 minutes, add a suspension of 1.28 g of KMnO4 in 15 ml of water dropwise to a solution of 0.5 g of the product of Example 2 dissolved in 25 ml of acetone. The reaction mixture is stirred at ambient temperature for 8 hours and then, following conventional extraction and treatment, the expected product is isolated by chromatography of the residue on silica gel (dichloromethane/methanol:98/2).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH2:6][C:7]([C:9](=[N:35][OH:36])[C:10]([NH:12][CH:13]1[C:33](=[O:34])[N:15]2[C:16]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]12)=[O:11])=O>C(O)C.O1CCCC1.O>[NH2:1][C:2]1[S:3][CH:6]=[C:7]([C:9](=[N:35][OH:36])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=4)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:4]=1
Reactant: O=C(CBr)C(=NO)C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: NC(N)=S
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1nc(C(=NO)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=CCS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.6 %

Procedure:
Thiourea (0.18 g.) was added to a suspension of 4-nitrobenzyl 7-[2-(2-bromoacetyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 1.05 g.) in ethanol (25 ml.), tetrahydrofuran (25 ml.) and water (5 ml.), and stirred at room temperature for 4 hours. The resultant solution was concentrated under reduced pressure and cooled. The residue was crystallized by treating with a mixture of tetrahydrofuran and ethyl acetate, and collected by filtration to give 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 0.95 g.), colorless crystals, mp 172° to 175° C. (dec.)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:14]S[C:16](=[N:19][C:20]#[N:21])[S:17][CH3:18]>C(O)C>[CH2:3]([OH:2])[CH3:8].[CH3:4][CH2:3][O:2][CH2:1][CH3:14].[C:20]([NH:19][C:16](=[N:13][CH2:12][CH2:11][S:10][CH2:9][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=1)[S:17][CH3:18])#[N:21]
Reactant: CSC(=NC#N)SC
Reactant: COc1cccnc1CSCCN
Solvent: CCO
Product: CCOCC
Product: COc1cccnc1CSCCN=C(NC#N)SC
Reaction time: 8 h
Yield: 149.6 %

Procedure:
A solution of 2-(3-methoxy-2-pyridylmethylthio)-ethylamine (2.1 g) in ethanol (15 ml) was added over one hour to a stirred solution of dimethyl-N-cyanodithioimidocarbonate (1.5 g) in ethanol (15 ml) and the mixture was allowed to stand overnight, to yield on recrystallisation from ethanol/ether N-cyano-N'-[2-(3-methoxy-2-pyridylmethylthio)ethyl]-S-methylisothiourea (2.2 g), m.p. 102°-103° C.
Reaction SMILES: C(O)(=O)C(O)=[O:3].C([O:15][CH2:16][CH2:17][CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([CH2:30][C@H:31]([NH:33][CH2:34][CH2:35][O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH2:44][C:45]([F:48])([F:47])[F:46])[CH3:32])=[CH:25][C:26]=2[C:28]#[N:29])[CH2:21][CH2:20]1)(=O)C1C=CC=CC=1.[OH-].[K+:50].O>CO>[OH-:3].[K+:50].[OH:15][CH2:16][CH2:17][CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([CH2:30][C@H:31]([NH:33][CH2:34][CH2:35][O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH2:44][C:45]([F:48])([F:46])[F:47])[CH3:32])=[CH:25][C:26]=2[C:28]#[N:29])[CH2:21][CH2:20]1
Reactant: O=C(O)C(=O)O
Reactant: C[C@H](Cc1cc(C#N)c2c(c1)CCN2CCCOC(=O)c1ccccc1)NCCOc1ccccc1OCC(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H](Cc1cc(C#N)c2c(c1)CCN2CCCO)NCCOc1ccccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.6 %

Procedure:
3-{7-Cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}-propyl benzoate monooxalate(10.0 g) was dissolved. in methanol (40 mL), then an aqueous potassium hydroxide solution, which was prepared from potassium hydroxide (2.93 g) and water (10 mL) was added little by little, and the mixture was stirred at room temperature for overnight. To the reaction mixture, water (150 mL) was added and extracted with ethyl acetate (150 mL and 50 mL) successively. The combined ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]-ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile (7.86 g).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[C:30]1[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[C:33]([F:39])=[C:32]([OH:40])[C:31]=1[O:41][CH3:42]>C(Cl)Cl>[Br:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=1[C:30]1[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[C:33]([F:39])=[C:32]([O:40][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[C:31]=1[O:41][CH3:42]
Reactant: COc1c(-c2ccc(C(F)(F)F)cc2CBr)cc(C(C)C)c(F)c1O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COc1c(-c2ccc(C(F)(F)F)cc2CBr)cc(C(C)C)c(F)c1OC1CCCCO1
Reaction time: 8 h

Procedure:
3,4-Dihydro-2H-pyran (51.9 mg, 56 μL, 0.617 mmol) was added to a stirred solution of p-toluenesulfonic acid (2.3 mg, 0.0123 mmol) and 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol (52.0 mg, 0.123 mmol) in dry CH2Cl2 (6.1 mL) at room temperature under N2 and the reaction was stirred overnight. The reaction mixture was diluted with CH2Cl2 (45 mL) and washed with saturated NaHCO3 (5 mL) and 30% saturated Na2SO3 (5 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-40% EtOAc in hexanes gradient) to afford 2-{[2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]oxy}tetrahydro-2H-pyran. Rf=0.59 (20% EtOAc in hexanes). 1H NMR (600 MHz, CDCl3) δ 7.82 (s, 1H), 7.60 (d, J=7.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H), 5.77 (s, 1H), 4.97 (dd, J=4.9, 2.9 Hz, 1H), 4.49 (d, J=9.8 Hz, 1H), 4.37 (d, J=9.8 Hz, 1H), 3.89-3.87 (m, 1H), 3.61-3.49 (m, 1H), 3.46 (s, 3H), 3.27-3.21 (m, 1H), 1.89-1.83 (m, 1H), 1.78-1.70 (m, 1H) 1.64-1.48 (m, 3H), 1.26 (d, J=6.8 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](=[O:15])[N:6]([CH:12]([CH3:14])[CH3:13])[CH2:7][C:8]=1C(O)=O)[CH3:2].[N+:16]([O-])([OH:18])=[O:17].C(=O)=O>S(=O)(=O)(O)O>[CH:12]([N:6]1[CH2:7][C:8]([N+:16]([O-:18])=[O:17])=[C:4]([O:3][CH2:1][CH3:2])[C:5]1=[O:15])([CH3:14])[CH3:13]
Reactant: CCOC1=C(C(=O)O)CN(C(C)C)C1=O
Reactant: O=[N+]([O-])O
Agent: O=C=O
Agent: O=S(=O)(O)O
Product: CCOC1=C([N+](=O)[O-])CN(C(C)C)C1=O
Temperature: -5 °C
Reaction time: 3 h

Procedure:
3-Ethoxy-1-isopropyl-2-oxo-3-pyrroline-4-carboxylic acid (5b, 8 g, 0.0376 mol) in powdered form was added in small portions through a seive to a stirred mixture of 70 mL of concentrated sulfuric acid and 4.7 mL of white fuming nitric acid (90%) that had been cooled to -5° C. prior to the start of the addition of 5b. The rate of addition of 5b was controlled so as to keep the temperature of the reaction mixture from rising above -3° C. and to minimize accumulation of undissolved lumps of starting material in the mixture. Stirring was continued for 3 h at -3° C. Effervescence caused by carbon dioxide evolution began after the mixture had been stirred for a few minutes and virtually ceased after an hour of two. When the mixture was poured slowly into a stirred suspension of 1 L of crushed ice, the product separated as a white crystalline precipitate. It was collected by filtration as soon as the ice was melted and washed on the filter with a small amount of cold water. The yield was 4.9 g (61%), mp 47°-47° C. Recrystallization from acetone or benzene and petroleum ether (bp 30°-60° C.) raised the melting point to 49°-50° C.: 1H NMR (CDCl3) δ4.90 (q, 2H, OCH2CH3, J=7 Hz), 4.40 (septet, 1H, NCH(CH3)2, J=7 Hz), 4.15 (s, 2H, CH 2 of pyrroline), 1.55-1.20 (t+d, 9H, overlap of --OCH2CHc and NCH(CH3)2, J=7 Hz); IR (thin film) 3.34, 3.39, 3.47, 5.87, 6.08, 6.69, 6.92, 7.17, 7.3, 7.30, 7.38, 7.67, 7.93, 8.10, 8.40, 8.55, 8.75, 8.87, 9.05 μm; UV (95% EtOH) 293 nm (ε9800).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([OH:16])=O>ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([N:3]([O:4][CH3:5])[CH3:2])=[O:16]
Reactant: CNOC
Reactant: O=C(O)Cc1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)Cc1ccccc1Cl
Temperature: 22.5 °C
Reaction time: 20 h
Yield: 93.4 %

Procedure:
Under ice-cooling, N,O-dimethylhydroxylamine hydrochloride (3.42 g) was added to a mixture of (2-chlorophenyl)acetic acid (3.41 g) and WSCD (2.05 g) in dichloromethane (30 mL). The mixture was stirred at 0-10° C. for an hour and at 20-25° C. for 20 hours, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by silica gel (chromatorex NH) (hexane-AcOEt 50:50 v/v) to give 2-(2-chlorophenyl)-N-methoxy-N-methylacetamide as oil (3.99 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][P:14]([CH3:21])(=[O:20])[O:15][CH2:16][CH:17]([CH3:19])[CH3:18].[F:22][C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[N+:31]([O-:33])=[O:32])=[CH:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]([CH2:30][N+:31]([O-:33])=[O:32])[CH2:13][P:14]([CH3:21])(=[O:20])[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:27][CH:28]=1
Reactant: CC(C)COP(C)(C)=O
Reactant: O=[N+]([O-])/C=C/c1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)COP(C)(=O)CC(C[N+](=O)[O-])c1ccc(F)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 8.1 g of diisopropylamine in 50 ml of dry tetrahydrofuran at -78° C. under an atmosphere of nitrogen are added 50.0 ml of a 1.6M solution of n-butyllithium in hexane. This solution is then stirred for a period of 10 minutes at this temperature, after which time a solution of 10.0 g of isobutyl P,P-dimethyl-phosphinate is added. This mixture is stirred at -78° C. for a period of 1 hour, after which time a solution of 11.1 g of trans-1-(4-fluorophenyl)-2-nitro-ethene in 50 ml of tetrahydrofuran is added. This mixture is then allowed to warm to room temperature when 40 ml of a saturated ammonium chloride solution is added. The aqueous layer is then extracted with 2×25 ml of diethyl ether and the organic extracts are combined and dried over magnesium sulphate. The solvent is then evaporated under reduced pressure and the crude product purified by chromatography on silica gel using 5 parts ethyl acetate to 1 part ethanol as eluent. The fractions containing product are combined and concentrated under reduced pressure to give isobutyl 2-(4-fluorophenyl)-3-nitro-propyl-(methyl)phosphinate as a viscous oil, 31P-N.M.R. spectrum: δ=+51.0 and +50.6 ppm (CDCl3).
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH:10]12[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]1[CH2:13][NH:12][CH2:11]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([N:12]2[CH2:11][CH:10]3[CH:14]([CH:15]3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC1
Reactant: CCOC(=O)C1C2CNCC21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1C2CN(C3CCC3)CC21
Temperature: 0 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
A mixture of cyclobutanone (157 mg, 2.19 mmol) in acetic acid (0.11 mL, 1.56 mmol) was added to a stirred solution of ethyl 3-aza bicyclo[3.1.0]hexane-6-carboxylate (243 mg, 1.56 mmol, obtained in the above step) in dichloromethane, cooled at 0° C. Solid sodium triacetoxy borohydride (727 mg, 3.43 mmol) was added portion wise over a period of 15 minutes. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. The reaction mixture was cooled to 0° C. and basified with saturated sodium bicarbonate solution (pH: 7.5). The two layers were separated, the organic layer was washed with brine, dried over anhydrous sodium sulfate and the volatiles were removed under reduced pressure to obtain ethyl 3-cyclobutyl-3-aza bicyclo[3.1.0]hexane-6-carboxylate (219 mg).
Reaction SMILES: [Cl:1]CC([NH:5][C:6]1([CH3:12])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=O.NC(N)=S>C(O)C.C(O)(=O)C>[ClH:1].[CH3:12][C:6]1([NH2:5])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: CC1(NC(=O)CCl)CCOCC1
Agent: NC(N)=S
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(N)CCOCC1
Product: Cl

Procedure:
To a solution of 2-chloro-N-(4-methyltetrahydro-2H-pyran-4-yl)acetamide obtained in Example 7-2 (630 mg) in ethanol/acetic acid (5/1, 6 mL), was added thiourea (275 mg) at room temperature. The reaction mixture was heated at reflux for 2 hrs.
Reaction SMILES: [CH3:1][N:2]([C@@H:15]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]1)[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([F:13])([F:12])[F:11]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][N:2]([C@@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([F:13])([F:11])[F:12]
Reactant: CN(C(=O)c1ccccc1C(F)(F)F)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)c1ccccc1C(F)(F)F)[C@@H]1CCNC1

Procedure:
A solution of (R)-tert-butyl 3-(N-methyl-2-(trifluoromethyl)benzamido)pyrrolidine-1-carboxylate (1 mmol) in TFA (2 mL) and DCM (2 mL) was stirred at room temperature for 2 hours, concentrated and diluted with water. It was then basified with aqueous NaHCO3 solution till pH=˜9, and extracted with EtOAc. The combined extracts were dried, filtered, and concentrated to give (R)—N-methyl-N-(pyrrolidin-3-yl)-2-(trifluoromethyl)benzamide.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:11]=[C:12](O)[C:13]2[CH:19]=[CH:18][CH:17]=[N:16][C:14]=2[N:15]=1.S(Cl)([Cl:23])=O.CN(C=O)C>C(Cl)(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:11]=[C:12]([Cl:23])[C:13]2[CH:19]=[CH:18][CH:17]=[N:16][C:14]=2[N:15]=1
Reactant: O=S(Cl)Cl
Reactant: Oc1nc(-c2cc3ccccc3s2)nc2ncccc12
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Clc1nc(-c2cc3ccccc3s2)nc2ncccc12
Temperature: 25 °C

Procedure:
To a suspension of 2-(1-benzothien-2-yl)pyrido[2,3-d]pyrimidin-4-ol (150 mg, 0.54 mmol) in chloroform (10 mL) was added thionyl chloride (0.47 mL, 6.4 mmol) and a catalytic amount of DMF. The reaction was heated to reflux for 4 h and allowed to cool to rt. The solvent was removed under reduced pressure and the resultant product was (18.2 mg, 12%) used directly in the next step without further purification. HPLC/MS: (M+H)+ 298.2 m/z; Retention time (LC-MS)=3.76 min; 1H NMR (DMSO)-D6): 9.24(1H, m); 8.73(1H, d); 8.55(1H, s); 8.10(2H, t); 7.86(1H, m); 7.50(2H, m).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][C:15]([C:17]2[S:18][C:19]([CH3:28])=[C:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][CH2:22][C:21]=23)=[O:16])=[CH:8][C:7]=1[CH3:29].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:12][C:11]1[CH:10]=[C:9]([CH2:13][CH2:14][C:15](=[O:16])[C:17]2[S:18][C:19]([CH3:28])=[C:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][CH2:22][C:21]=23)[CH:8]=[C:7]([CH3:29])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][O:1][S:40]([CH3:39])(=[O:42])=[O:41]
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1OCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1OCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a solution of 3-[4-(3-hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (170 mg, 0.411 mmol) in DCM (10 mL) and DIPEA (0.15 mL, 0.89 mmol) is added methane sulfonylchloride (0.04 mL, 0.49 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is diluted with DCM, washed with 0.1 N aq. NaOH followed by 10% aq. citric acid solution, dried over MgSO4 and evaporated to give methanesulfonic acid 3-{2,6-dimethyl-4-[3-oxo-3-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propyl]-phenoxy}-propyl ester (200 mg) as a yellow oil; LC-MS: tR=1.18 min, [M+1]+=493.26.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Li].[Br:7][C:8]1S[CH:10]=[CH:11][CH:12]=1.C([Li])CCC.BrCCCCBr>>[Br:7][CH2:8][CH2:12][CH2:11][CH2:10][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccs1
Reactant: [Li]c1cccs1
Agent: [Li]CCCC
Solvent: BrCCCCBr
Product: BrCCCCc1cccs1

Procedure:
2-Thienyl lithium can be generated from 2-bromothiophene (Aldrich Chemical Co.) and n-butyl lithium (Aeros Organics, Pittsburgh, Pa.). 2-Thienyl lithium is allowed to react with 1.5 equivalents of 1,4-dibromobutane (Aeros Organics, Pittsburgh, Pa.) to give bromobutyl thiophene. The bromine is then replaced by an azide ion. The thienyl butyl azide thus obtained is reduced by sodium borohydride to yield the amine, 2-thienyl butyl amine (Scheme 5). The 2-thienyl butyl amine dissolved in water is added dropwise to a solution of thiophosgene in dichloromethane. In another dropping funnel a solution of 10% sodium hydroxide is introduced slowly to maintained alkalinity of the reaction mixture. The reaction is allowed to stand at room temperature for an additional hour with stirring. The organic layer is separated and washed with water, saturated sodium chloride solution, water, and dried over anhydrous magnesium sulfate. The solvent is removed in vacuo and the product, 2-TBITC, obtained by vacuum distillation.