Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5]O)(C)([CH3:3])[CH3:2].[CH3:7][C:8]([CH3:28])([CH3:27])[C:9]([O:11][CH2:12][C:13]1[NH:22][C:21](=[O:23])[C:20]2[C:15](=[CH:16][C:17]3CCC[C:18]=3[CH:19]=2)[N:14]=1)=[O:10]>C(Cl)Cl>[CH3:7][C:8]([CH3:28])([CH3:27])[C:9]([O:11][CH2:12][C:13]1[NH:22][C:21](=[O:23])[C:20]2[C:15](=[CH:16][C:17]3[CH2:18][CH2:3][C:1](=[O:5])[C:2]=3[CH:19]=2)[N:14]=1)=[O:10]
Reactant: CC(C)(C)C(=O)OCc1nc2cc3c(cc2c(=O)[nH]1)CCC3
Reactant: CC(C)(C)OO
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCc1nc2cc3c(cc2c(=O)[nH]1)C(=O)CC3
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.3 %

Procedure:
To a stirred solution of (Ph3SiO)2CrO2 (L. M. Baker and W. L. Carrick, J. Org. Chem. 1970, 35, 774) (10.6 mg, 0.017 mmol) in CH2Cl2 (5 ml) was added sequentially aqueous 70% tert-butyl hydroperoxide (0.18 ml, 1.3 mmol) and 2-(2,2-dimethylpropionyloxymethyl)-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (0.1 g, 0.33 mmol). The mixture was stirred at room temperature with protection from the light for 24 h. The solvents were removed in vacuo and the residue purified by column chromatography (20 g of silica gel) eluting with a gradient of 10-30% EtOAc in CHCl3 to yield 2-(2,2-dimethylpropionyloxymethyl)-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4,6-dione as a white solid (47 mg, 45%); m.p. 185-190° C.; 1H-NMR (DMSO-d6) δ 1.23 (s, 9H, CMe3), 2.72 (m, 2H, 7-H), 3.25 (m, 2H, 8-H), 5.00 (s, 2H, 2-CH2), 7.70 (s, 1H, 9-H), 8.29 (s, 1H, 5-H), 12.20 (br, 1H, NH); MS (FAB, m/z): Found 315 [(M+H)+, 100%], 337 [(M+Na)+, 75%]; HRMS: measured 315.1360; calculated for C17H19N2O4 (M+H)+: 315.1345; Found C, 64.18; H, 5.72; N, 8.81. C17H18N2O4.0.2H2O requires C, 64.23; H, 5.79; N, 8.82%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.CCOC(C)=O>[CH3:32][O:31][C:29](=[O:30])[CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:9])[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: Cc1nc(N(C)c2ccc(O)cc2)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Temperature: 60 °C

Procedure:
(4-Hydroxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine (468 mg, 1.41 mmol) and K2CO3 were dissolved in DMF (10 mL). Methyl bromoacetate (0.67 mL, 7.08 mmol) was added and the reaction was heated at 60° C. for 2 h. The mixture was cooled and diluted with EtOAc. The organics were washed with water (2×) and dried over MgSO4. The title compound was purified by preparative RPLC. 1H NMR (DMSO-d6) δ 7.64 (d, 1H), 7.59 (t, 1H), 7.20 (d, 2H), 7.05 (t, 1H), 7.0-6.9 (m, 3H), 4.85 (s, 2H), 3.71 (s, 3H), 3.50 (s, 3H), 2.58 (s, 3H); LC-MS (ESI+; 338 ([M+H]+)).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH2:23])[CH:16]=1.[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1.C([O-])(O)=O.[Na+].[O-][Cl:40].[Na+]>>[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH:23][C:30](=[N:31][Cl:40])[C:29]2[CH:32]=[CH:33][C:26]([Cl:25])=[CH:27][CH:28]=2)[CH:16]=1
Reactant: COC(=O)c1ccc(OC)c(N)c1
Reactant: [O-]Cl
Reactant: N#Cc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(OC)c(NC(=NCl)c2ccc(Cl)cc2)c1
Temperature: 160 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
Anhydrous p-toluene sulfonic acid (41.99 g, 220.76 mmol) was melted at 120° C. and 3-amino-4-methoxy benzoic acid methyl ester (20 g, 110.38 mmol) obtained in step 1 of Preparation Example 1 and 4-chlorobenzonitrile (22.78 g, 165.57 mol) were added thereto and stirred at 160° C. for 8 hours. The resulting solution was cooled to room temperature and the reaction was stopped by adding 1M NaHCO3 thereto. The resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO4 and concentrated under a reduced pressure. The concentrate was dissolved in 500 ml of 50% methanol and 5% NaOCl (197 Ml, 132.46 mmol) was added dropwise thereto. After 5 min, the resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chlomatography (eluent—MeOH:CDCl3=5:95, Merck, Silicagel 60) to obtain the title compound (19.43 g, 55.19 mmol) in a yield of 50%.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5](OC2CCN(C(OC(C)(C)C)=O)CC2)=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:31][CH:30]([C:32]([NH:34][C:35]3[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=3)=[O:33])[CH2:29]2)[N:23]=1.C(OC(N1CC(C(O)=O)C1)=O)C1C=CC=CC=1>>[C:2]1([NH:1][C:39]([C:38]2[CH:37]=[CH:36][C:35]([NH:34][C:32]([CH:30]3[CH2:29][N:28]([C:24]4[N:23]=[N:22][CH:27]=[CH:26][CH:25]=4)[CH2:31]3)=[O:33])=[CH:43][CH:42]=2)=[O:40])[CH:21]=[CH:20][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(NC(=O)C2CN(c3cccnn3)C2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Agent: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Product: O=C(Nc1ccccc1)c1ccc(NC(=O)C2CN(c3cccnn3)C2)cc1

Procedure:
The title compound was prepared as described in Example 1A, substituting aniline for tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate and 4-(1-(pyridazin-3-yl)azetidine-3-carboxamido)benzoic acid for 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6/D2O) δ ppm 8.53 (dd, J=4.4, 1.3 Hz, 1H), 7.98-7.92 (m, 2H), 7.77-7.65 (m, 5 H), 7.38-7.24 (m, 3 H), 7.15-7.07 (m, 1H), 4.49 (t, J=9.0 Hz, 2H), 4.46-4.38 (m, 2H), 4.00-3.81 (m, 1H); MS (ESI(+)) m/e 374 (M+H)+.
Reaction SMILES: CO[CH2:3][CH2:4][N:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6]1=[S:16]>Cl.O>[CH2:4]1[N:5]2[C:6](=[N:7][C@@H:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:9]2)[S:16][CH2:3]1
Reactant: COCCN1CC(c2ccccc2)NC1=S
Agent: Cl
Solvent: O
Product: c1ccc([C@H]2CN3CCSC3=N2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The 1-2(methoxyethyl)-4-phenylimidazolidin-2-thione product of Example VII in the amount of 0.78 g is suspended in 50 ml concentrated aqueous hydrochloric acid and maintained with stirring at 70°-75° C. for four hours. The solution is then cooled to room temperature and diluted with 50 ml water.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][SH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.Br[CH2:14][C:15]([OH:17])=[O:16].[OH-].[Na+]>C(O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][S:12][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: SCCc1ccc2c(c1)OCO2
Reactant: O=C(O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CSCCc1ccc2c(c1)OCO2
Yield: 93.2 %

Procedure:
100 g of 2-(1,3-benzodioxol-5-yl)ethanethiol and 75.1 g of bromoacetic acid were dissolved in 1 l of ethanol. A solution of 44 g of sodium hydroxide in 125 ml of water and then 2 l of ethanol were added thereto. The mixture was heated under reflux for 3 h. The reaction mixture was concentrated under reduced pressure. 2.5 l of water was added thereto. The mixture was made alkaline with a 1N sodium hydroxide solution, washed with 35% hydrochloric acid, extracted with ethyl acetate, washed with water four times and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 121 g of [{2-(1,3-benzodioxol-5-yl)ethyl}thio]acetic acid in the form of a faint yellow oil.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Cl[C:31]([O:33][CH3:34])=[O:32].O>O1CCCC1.CCCCCC>[C:31]([C:21]1[N:20]([C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=[CH:23][N:22]=1)([O:33][CH3:34])=[O:32]
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.7 %

Procedure:
To a stirred solution of 12.4 g (40 mmol.) of 1-tritylimidazole in 250 mL of tetrahydrofuran, under argon, at 0° C. was added 20 mL (48 mmol.) of a solution of n-butyl-lithium in hexane. After the solution was allowed to warm to ambient temperature, it was stirred for 1 hour and then 3.4 mL (50 mmol.) of methyl chloroformate was added dropwise. The mixture was stirred for 20 hours at 25° C., 100 mL of water was added and then the mixture was concentrated in vacuo. The residue was extracted with ether. After the extracts were dried (MgSO4) and concentrated, the residue was chromatographed on 200 g of silica using 1:3 ethyl acetate: hexane, followed by 1:1 ethyl acetate: hexane, and finally ethyl acetate to give 3.2 g of colorless product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19].[H-].[Na+].[Cl:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]Cl.O>CN(C=O)C>[Cl:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]([CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[C:11]1=[O:19]
Reactant: O=c1[nH]c2ccccc2n1CCOC1CCCCO1
Reactant: ClC/C=C\CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(C/C=C\CCl)c2ccccc2n1CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
To a solution of 1-[2-(tetrahydro-2H-pyran-2yloxy)ethyl]-1,3-dihydro-2H-benzimidazol-2-one (12 g, 46 mmoles) in DMF (120 ml) was added 80% sodium hydride (1.7 g, 55 mmoles) and the mixture was stirred at room temperature for 1 hour. Cis-1,4-dichloro-2-butene (5.8 ml, 55 mmoles) was added dropwise and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was taken to dryness and the residue was purified by flash chromatography (cyclohexane-ethyl acetate 70-30) to give 2.8 g of the title compound as a thick oil which was used without any further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25]>>[ClH:19].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH:25][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: CN(C)CCCN
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCCN(C)C)s2)c(C)[nH]c1=O
Product: Cl
Yield: 64 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 3-dimethylaminopropylamine as described in Step 5, Example 24 to give the title compound as a solid (64% yield). LC/MS: RT 1.98 min; m/e 384 (M+H); 1H NMR (δ, ppm): 11.84 (1H, br s), 8.06 (1H, t), 7.57 (1H, d), 7.34 (1H, s); 7.17 (1H, d), 2.94 (4H, m), 2.70 (6H), 2.36 (2H, q), 2.32 (3H, s), 1.82 (2H), 1.07 (3H, t).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([OH:9])[CH3:8].CCN(CC)CC.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([O:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)c1ccccn1
Reaction time: 1.17 h
Yield: 105.3 %

Procedure:
To a stirred solution of 1-pyridin-2-yl-ethanol (156 mg, 1.27 mmol) (Mandal, S. K. et al. J. Org. Chem. 2003, 68, 4600-4603) and Et3N (0.27 mL, 1.94 mmol) in CH2Cl2 (5 mL) was added methanesulphonyl chloride (0.11 mL, 1.29 mmol) and the solution was stirred for 70 minutes. The solution was diluted with CH2Cl2 (20 mL) and washed with saturated aqueous NaHCO3 (2×15 mL) and brine (1×15 mL). The combined aqueous phase was extracted with CH2Cl2 (1×15 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to give crude methanesulphonic acid 1-pyridin-2-yl-ethyl ester as a yellow oil (269 mg, 100%). 1H NMR (CDCl3) δ 1.77 (d, 3H, J=6.6 Hz), 2.94 (s, 3H), 5.79 (q, 1H, J=6.6 Hz), 7.28 (ddd, 1H, J=7.4, 7.1, 1.3 Hz), 7.47 (d, 1H, J=7.9 Hz), 7.76 (td, 1H, J=7.6, 1.7 Hz), 8.61 (d, 1H, J=4.9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH2:34][CH3:35])[C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([CH3:36])[CH:21]=3)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:11]=2)[CH:6]=1)=[O:4].[BH4-].[Na+].C(Cl)Cl.CCOC(C)=O.C(Cl)Cl>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([CH2:16][CH3:17])([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH2:34][CH3:35])[CH:28]([OH:33])[C:29]([CH3:30])([CH3:31])[CH3:32])=[C:22]([CH3:36])[CH:21]=3)[CH2:18][CH3:19])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: CCC(Oc1ccc(C(CC)(CC)c2ccc3cc(C(=O)OC)ccc3c2)cc1C)C(=O)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(Oc1ccc(C(CC)(CC)c2ccc3cc(C(=O)OC)ccc3c2)cc1C)C(O)C(C)(C)C
Yield: 8 %

Procedure:
Following the procedure described in Example 2; treat 6-{1-[4-(3,3-dimethyl-1-ethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}naphthalene-2-carboxylic acid methyl ester with NaBH4 in THF at 0 C. Chromatograph the residue (CH2Cl2 to 2% EtOAc/CH2Cl2) to give diastereomeric isomer pair 1 of the title compound as a glassy foam (1.004 g, 77%) and diastereomeric isomer pair 2 of the title compound as a glassy foam (102 mg, 8%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][N:7]=[C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11](=[O:18])[C:10]=1[C:9]=23.[CH3:19][NH:20][CH3:21]>N1C=CC=CC=1>[CH3:19][N:20]([CH3:21])[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][N:7]=[C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11](=[O:18])[C:10]=1[C:9]=23
Reactant: CNC
Reactant: O=C1c2ccccc2-c2n[nH]c3ccc(Cl)c1c23
Solvent: c1ccncc1
Product: CN(C)c1ccc2[nH]nc3c2c1C(=O)c1ccccc1-3
Temperature: 100 °C

Procedure:
A mixture of 5-chloroanthra[1,9cd]pyrazol-6(2H)-one (Example 1-B) and dimethylamine in pyridine is heated at 100° C. for 16 hours. The mixture is cooled and evaporated. The residue is chromatographed on silica gel to give the desired compound as yellow solids.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:10](O)=[O:11])[CH2:6][CH:7]([CH3:9])[CH3:8])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH:28](Cl)[C@H:29]([C:34]([O:36][CH3:37])=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32].Cl>C1COCC1>[NH:4]([C:1]([CH3:2])=[O:3])[C@H:5]([C:10]([NH:28][C@H:29]([C:34]([O:36][CH3:37])=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:11])[CH2:6][CH:7]([CH3:8])[CH3:9]
Reactant: COC(=O)[C@H](CC(C)C)NCl
Reactant: CC(=O)N[C@@H](CC(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(C)=O
Reaction time: 0.33 h

Procedure:
Acetyl-Leucine (5.0 g) was dissolved in 150 mL of distilled THF under argon and the resulting solution was cooled to -15°. Next one equivalent of N-methyl morpholine followed by one equivalent of isobutyl chloroformate was added and the reaction was allowed to activate 20 minutes and then another equivalent of N-methyl morpholine followed by HCl-LeuOMe (5.25 g). The reaction is allowed to slowly come to room temperature and stir overnight. The reaction was then poured into 150 mL of 1N HCl and extracted with ethyl acetate (2×150 mL). The combined organic fractions were washed with 1N HCl (15 mL), brine (50 mL), and dried over MgSO4, filtered and the solvent was removed under reduced pressure and then high vacuum. TLC (silica gel, CHCl3 /isopropanol:95:5) showed the product Ac-Leu-Leu-OCH3 to be a single spot Rf 0.36. NMR (100 MHz) δ 0.95 (d, 12H), 1.5 (bs, 6H), 2.0 (s, 3H), 3.7 (s, 3H), 4.5 (q, 2H), 6.6 (d, 1H), 6.8 (d, 1H).
Reaction SMILES: [N+]([O-])(O)=O.[NH2:5][C:6]([NH2:8])=[NH:7].[H-].[Na+].[H][H].Cl[C:14]1[S:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[N:17][N:18]=1>CN(C)C=O.O>[NH:7]([C:14]1[S:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[N:17][N:18]=1)[C:6]([NH2:8])=[NH:5]
Reactant: [H][H]
Reactant: N=C(N)N
Reactant: O=[N+]([O-])c1ccc(-c2nnc(Cl)s2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=[N+]([O-])O
Solvent: O
Product: N=C(N)Nc1nnc(-c2ccc([N+](=O)[O-])cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
24.13 gm of guanidine nitrate were added in small portions over a period of 30 minutes to 6.5 gm of a 50% sodium hydride oil dispersion in 200 ml of dimethylformamide. After the evolution of hydrogen had ceased, a solution 15.8 gm of 2-chloro-5-(4-nitro-phenyl)-1,3,4-thiadiazole in 300 ml of dimethylformamide was added dropwise to the mixture, which was then stirred at room temperature for 2 hours, and then at 90° C. for 30 minutes. After cooling and dilution with water, the precipitate formed thereby was filtered off and dissolved in ethanol. Hydrogen chloride was added to this solution, and the hydrochloride which separated out was filtered off and dissolved in water, and then aqueous solution was made alkaline with 10% sodium hydroxide. The free base was filtered off, washed with water and dried, yielding 9.5 gm of the title compound, m.p. 295°-297° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C@H:8]1[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:1][S:2]([O:6][CH2:7][C@H:8]1[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CO)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCO[C@H](COS(C)(=O)=O)C1
Reaction time: 1.5 h

Procedure:
Methanesulfonyl chloride (12 mL, 0.15 mol) was added to a solution of (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (28 g, 0.13 mmol) in CH2Cl2 (172 mL) and triethylamine (23.4 mL, 0.17 mol) at 0° C. The resulting mixture was stirred at a temperature of from 0° C. to room temperature over 1.5 hr. The mixture was then diluted with water (35 mL), and the phases were separated. The aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, and filtered on a pad of silica gel, which was rinsed with CH2Cl2. The filtrate was concentrated under reduced pressure to the title product (37.7 g, 99%) as an oil. 1H NMR (300 MHz, CDCl3) δ ppm 1.55 (s, 9H), 2.77-2.91 (m, 1H), 2.97-3.09 (m, 1H), 3.14-3.15 (m, 3H), 3.57-3.67 (m, 1H), 3.73-3.81 (m, 1H), 3.85-4.10 (m, 3H), 4.31 (d, J=4.79 Hz, 2H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[CH2:25][C@H:24]2[CH2:26][C@H:22]([C:23]2([CH3:28])[CH3:27])[CH:21]1[NH2:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:32]=[C:33]2[C:39]([C:40]3[N:45]=[C:44](S(C)=O)[C:43]([F:49])=[CH:42][N:41]=3)=[CH:38][N:37]([S:50]([C:53]3[CH:59]=[CH:58][C:56]([CH3:57])=[CH:55][CH:54]=3)(=[O:52])=[O:51])[C:34]2=[N:35][CH:36]=1.C(N(C(C)C)CC)(C)C.[NH4+].[Cl-]>CN(C=O)C>[Si:1]([O:18][CH2:19][C@H:20]1[CH2:25][C@H:24]2[CH2:26][C@H:22]([C:23]2([CH3:28])[CH3:27])[C@@H:21]1[NH:29][C:42]1[C:43]([F:49])=[CH:44][N:45]=[C:40]([C:39]2[C:33]3[C:34](=[N:35][CH:36]=[C:31]([Cl:30])[CH:32]=3)[N:37]([S:50]([C:53]3[CH:59]=[CH:58][C:56]([CH3:57])=[CH:55][CH:54]=3)(=[O:52])=[O:51])[CH:38]=2)[N:41]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)[C@H]2C[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(N)[C@@H]1C2
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@@H]4[C@@H](CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)C[C@H]5C[C@@H]4C5(C)C)n3)c3cc(Cl)cnc32)cc1
Temperature: 75 °C

Procedure:
To a solution of (1R,3S,5R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-6,6-dimethyl-bicyclo[3.1.1]heptan-2-amine, 77e, (0.20 g, 0.46 mmol) and 5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.14 g, 0.30 mmol) in DMF (1.5 mL) was added diisopropylethylamine (0.11 mL, 0.61 mmol). The reaction was heated to 75° C. for 18 hours. The mixture was diluted into aqueous saturated NH4Cl solution and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-5% MeOH/CH2Cl2 gradient) to afford 78 mg of the desired product.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:25]C(OC(Cl)C)=O>ClCCCl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][C:16]=1[C:21]([F:24])([F:22])[F:23].[ClH:25]
Reactant: CC(Cl)OC(=O)Cl
Reactant: FC(F)(F)c1cc(C2CCN(Cc3ccccc3)CC2)ccc1Cl
Solvent: ClCCCl
Product: Cl
Product: FC(F)(F)c1cc(C2CCNCC2)ccc1Cl
Yield: 882.2 %

Procedure:
A solution of 1-Benzyl-4-(4-chloro-3-trifluoromethyl-phenyl)-piperidine (1.1 g) in 1,2-dichloroethane (50 ml) was cooled to 0° C. Then α-chloroethyl chloroformate (1.5 g) dissolved in 1,2-dichloroethane (30 ml) was added dropwise at 0° C. The reaction mixture was then brought to reflux for 2 days. The volatiles were evaporated in vacuo and the residue triturated with methanol. The mixture was brought to reflux for 4 hours. The solvent was evaporated to afford the title compound as HCl salt (light brown crystals, 1.0 g) MS m/z (relative intensity, 70 eV) 263 (M+, 34), 262 (22), 83 (22), 57 (60), 56 (bp).
Reaction SMILES: C([NH:3][CH:4]([C:12]([OH:14])=[O:13])[C:5]([SH:11])([CH3:10])[CH:6]=C(C)C)=O.C[C@H](N)[C@H](O)C1C=CC=CC=1>CC(C)=O>[NH2:3][C@@H:4]([C:12]([OH:14])=[O:13])[C:5]([SH:11])([CH3:10])[CH3:6]
Reactant: CC(C)=CC(C)(S)C(NC=O)C(=O)O
Agent: C[C@H](N)[C@H](O)c1ccccc1
Solvent: CC(C)=O
Product: CC(C)(S)[C@@H](N)C(=O)O

Procedure:
The procedure of Example 1 was followed, however, using 21.8 grams (0.1 mole) of N-formyl-isopropylidene-D,L-penicillamine and 15.1 grams (0.1 mole) of 1-norephedrine and using 150 ml of acetone as the solvent. There were obtained 28.5 grams (equal to 78%) of the adduct (1) having a melting point of 200°-204°C. and [α]D20 + 31°.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C([Li])CCC.[F:16][C:17]([F:21])=[C:18](F)[F:19].Cl>CCCCCC.C(OCC)C>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:18]([F:19])=[C:17]([F:21])[F:16])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(I)cc1
Reactant: FC(F)=C(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCc1ccc(C(F)=C(F)F)cc1
Temperature: -80 °C
Yield: 59.9 %

Procedure:
In 1 l four-necked flask having a gas supplying tube, 200 ml of n-hexane, 75 ml of dry diethyl ether and 24.6 g (0.1 mol) of 4-(n-propyl)iodobenzene were introduced under a nitrogen atmosphere, and then 86.2 ml of a hexane solution of n-butyl lithium (1.16 mol) was dropwise added thereto under stirring at -80° C. Then, while the reaction system was maintained at -80° C., 10 g (0.1 mol) of tetrafluoroethylene was introduced under vigorously stirring in 30 minutes. The reaction solution was stirred further for one hour and poured into ice water and neutralized with dilute hydrochloric acid, and then the organic layer was separated. The aqueous layer was extracted with methylene chloride, and the extract was combined to the organic layer, followed by drying. The solvent was distilled off to obtain 12 g (yield: 60%) of 1-(4-n-propylphenyl)-1,2,2-trifluoroethylene.