Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:36])([C:32]([CH3:35])([CH3:34])[CH3:33])[O:3][C@@H:4]([CH2:16][N:17](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:5][O:6][C:7]1[C:15]2[NH:14][CH:13]=[N:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][Si:2]([CH3:36])([C:32]([CH3:34])([CH3:33])[CH3:35])[O:3][C@@H:4]([CH2:16][NH2:17])[CH2:5][O:6][C:7]1[C:15]2[NH:14][CH:13]=[N:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H](COc1cccc2nc[nH]c12)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN)COc1cccc2nc[nH]c12

Procedure:
(S)-4-[2-(Dimethyl-tert-butylsilyl)oxy-3-(dibenzylamino)propoxy]benzimidazole (1.27g. 2.5mmol) was dissolved in methanol (140 mL) and treated with an excess of ammonium formate (1.64g, 25.0 mmol) followed by 10% palladium on carbon (410 mg). The resulting suspension was stirred at reflux for 1 hour. After cooling, the reaction mixture was filtered through a pad of celite. The filtrate was concentrated in vacuo to a brown oil (780 mg, 97%). NMR.
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[O:10][CH2:11][C:12](=[N:14][OH:15])[NH2:13].[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33](O)=O)=[O:27])([CH3:24])([CH3:23])[CH3:22].CCN=C=NCCCN(C)C.Cl>O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[O:10][CH2:11][C:12]1[N:13]=[C:33]([C@@H:29]2[CH2:30][CH2:31][CH2:32][N:28]2[C:26]([O:25][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:27])[O:15][N:14]=1
Reactant: COc1ccc(OCC(N)=NO)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(OCc2noc([C@@H]3CCCN3C(=O)OC(C)(C)C)n2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.6 %

Procedure:
To a CHCl3 (20 ml) solution of the compound (1.0 g) obtained in Example 12-(1) and (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.0 g), WSC.HCl (1.0 g) was added and the mixture was stirred at room temperature for 4 hours. Water was added, followed by extraction with CHCl3. After distilling off the solvent under reduced pressure, the residue was dissolved in toluene (20 ml), followed by refluxing for 2 hours. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (AcOEt/hexane) to give the titled compound (190 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=[C:19]3[C:18]2=[O:28])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:42][OH:43]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=[C:19]3[C:18]2=[O:28])[CH2:13][C:14]([NH:42][OH:43])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccc(O)cc3C2=O)ccc1OC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3ccc(O)cc3C2=O)ccc1OC
Yield: 43.2 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-(4-hydroxyphthalimido)propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(4-hydroxyphthalimido)propanoic acid (4.0 g, 10.4 mmol), carbonyldiimidazole (2.02 g, 12.46 mmol) and hydroxylamine hydrochloride (1.13 g, 16.3 mmol) in tetrahydrofuran (20 mL) to afford 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(4-hydroxyphthalimido)propionamide as a yellow solid (1.8 g, 44% yield): mp, 143.5-146.0° C.; 1H NMR (DMSO-d6) δ1.31 (t, J=6.9 Hz, 3H, CH3), 3.09 (d, J=7.9 Hz, 2H, CH2), 3.72 (s, 3H, CH3), 3.98 (q, J=6.9 Hz, 2H, CH2), 5.62 (t, J=7.9 Hz, 1H, NCH), 6.89 (br s, 2H, Ar), 7.01 (br s, 1H, Ar), 7.09-7.12 (m, 2H, Ar), 7.66-7.69 (m, 1H, Ar), 8.88 (br s, 1H, OH), 10.59 (br s, 1H, NH); 13C NMR (DMSO-d6) δ24.71, 44.39, 60.08, 65.47, 73.75, 119.72, 121.76, 122.36, 129.66, 130.53, 131.37, 135.32, 141.49, 144.08, 157.68, 158.51, 173.43, 176.09, 177.49; Anal Calcd for C20H20N2O7+0.35H2O: C, 59.07; H, 5.13; N, 6.89. Found: C, 58.84; H, 5.05; N, 7.26.
Reaction SMILES: [NH2:1][C:2](=[O:44])[CH2:3][C:4]1[CH:43]=[CH:42][CH:41]=[CH:40][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][C:20]=2[CH2:38][CH3:39])[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:38]([C:20]1[CH:21]=[C:22]([CH:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]2)[CH:23]=[CH:24][C:19]=1[NH:18][C:10]1[N:9]=[C:8]([CH2:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[CH2:3][C:2]([NH2:1])=[O:44])[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=1)[CH3:39]
Reactant: CCc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
tert-Butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-ethylphenyl)piperidine-1-carboxylate, (I44) (120 mg, 0.20 mmol) was dissolved in DCM (20 mL), TFA (2 mL) was added and the mixture stirred for 16 hours at room temperature. The mixture was concentrated and the residue suspended in 10% sodium hydroxide (10 mL) and brine (10 mL). The mixture was extracted with ethyl acetate (4×20 mL), the combined extracts washed with brine, dried (sodium sulphate) evaporated and the residue evaporated for ether to give the title compound (8) (93 mg, 93% yield) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 9.47 (s, 1H), 8.49 (s, 1H), 7.37 (s, 1H), 7.26-7.18 (m, 2H), 7.17-7.09 (m, 4H), 7.05 (dd, J=8.2, 1.9 Hz, 1H), 6.89 (s, 1H), 3.44 (s, 2H), 3.09-2.88 (m, 6H), 2.62-2.54 (m, overlaps with DMSO), 1.70 (d, J=11.4 Hz, 2H), 1.52 (qd, J=12.3, 3.7 Hz, 2H), 1.10 (t, J=7.5 Hz, 3H), LCMS Method C: 4.96 min; m/z 512.2 [M+H]+, 534.2 [M+Na]+; m/z 510.2 [M−H]−.
Reaction SMILES: [CH2:1]([CH:3]([C:9]([O:11]CC)=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(O)C.[OH-].[K+].Cl>O.C(OCC)C>[C:4]([CH:3]([CH2:1][CH3:2])[C:9]([OH:11])=[O:10])([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(CC)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(CC)C(=O)O

Procedure:
Diethyl ethylmalonate was stirred overnight with 95% ethanol in the presence of 1M KOH. The white precipitate that forms was filtered out of solution, and the filtrate was concentrated under reduced pressure (e.g., on a rotary evaporator). The yellowish oil obtained upon concentration of the filtrate was added to the precipitate and the mixture was dissolved in a minimum amount of water. After acidification with dilute aqueous HCl to a pH of 2, an oil separates from the solution. The oil was taken up into diethyl ether and the aqueous layer was extracted three times with further with diethyl ether. The ether extracts were combined, dried over magnesium sulfate and filtered. A quantitative yield of 2-carboethoxybutyric acid was obtained as a yellowish oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=3)[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([Sn]([N:35]=[N+:36]=[N-:37])(CCCC)CCCC)CCC.[OH-].[Na+]>C1(C)C=CC=CC=1>[N:21]1[NH:35][N:36]=[N:37][C:20]=1[C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[C:11]2[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COc1ccc(-c2n[nH]c3ccc(C#N)cc23)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2n[nH]c3ccc(-c4nn[nH]n4)cc23)cc1OC
Reaction time: 14 h
Yield: 52.5 %

Procedure:
To a solution of 3-(3,4-dimethoxyphenyl)-1H-indazole-5-carbonitrile (190 mg, 0.68 mmol) in toluene (10 mL) was added tributyltin azide (930 μL, 3.4 mmol). The solution was heated to reflux for 12 hours when 3 N NaOH (80 mL) was added and the solution extracted with ethyl acetate (2×20 mL). The aqueous layer was then acidified with 4 N HCl to pH<1 and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried (Na2SO4) and concentrated to an oil. After remaining at room temperature for 14 hours, the product crystallized from solution to recover, after filtration and drying, the title compound (115 mg, 53% yield). 1H NMR (DMSO-d6) δ 13.4 (s, 1H), 8.70 (s, 1H), 8.04 (d, 1H), 7.75 (d, 1H), 7.54 (d, 1H), 7.49 (s, 1H), 7.12 (d, 1H), 3.85 (s, 3H), 3.81 (s, 3H); ES-MS (m/z) 323 [M+1]+.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:12]([NH:14][C@@H:15]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@H:16]([OH:31])[CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[C:24]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:13])[CH2:10][SH:11])=O)(C)(C)C>FC(F)(F)C(O)=O>[C:27]([NH:26][C:24]([C@@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][N:18]1[CH2:17][C@@H:16]([OH:31])[C@@H:15]([NH:14][C:12](=[O:13])[C@H:9]([CH2:10][SH:11])[NH2:8])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CS
Yield: 85.4 %

Procedure:
A solution of 930 mg of 1-[3(S)-[[N-(tert.butoxycarbonyl)-L-cysteinyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-2(S)-piperidinecarboxamide in 7 ml of trifluoroacetic acid was stirred at 20° C. for 1 hour. The mixture was then evaporated to dryness and the residue was partitioned between dichloromethane and aqueous sodium bicarbonate solution. The organic phasewas evaporated to give 650 mg of N-tert.butyl-1-[3(S)-[(L-cysteinyl)amino]-2(R)-hydroxy-4-phenylbutyl]-2(S)-piperidinecarboxamide as a colourless gum; MS: m/e [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1.[OH:11]O.C=O>C(O)(=O)C>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N+:2]=1[O-:11]
Reactant: OO
Reactant: c1cc2c(cn1)CCCC2
Agent: C=O
Solvent: CC(=O)O
Product: [O-][n+]1ccc2c(c1)CCCC2
Temperature: 97.5 °C
Yield: 86 %

Procedure:
5,6,7,8-Tetrahydroisoquinoline (13.3 g, 100 mmole) is dissolved in 35 ml glacial acetic acid in a 200 ml one neck round bottom flask. The solution is warmed to 95-100° C. and is treated dropwise with 30% hydrogen peroxide (28 ml). The reaction is stirred at 95-100° C. for 6h, is treated portionwise with paraformaldehyde until negative to starch iodide paper, and the volatiles are removed in vacuo. The residue is azeotroped with 2×100 ml toluene and the crude material is chromatographed over 500 g silica gel (230-400 mesh), eluting with 4 l 6% methanol/dichloromethane followed by 1 l 10% methanol/dichloromethane while collecting 50 ml fractions. Fractions 39-82 are combined and concentrated to afford 12.8 g (86%) of 5,6,7,8-tetrahydroisoquinoline-N-oxide.
Reaction SMILES: [C:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]([CH2:26][CH2:27][CH3:28])=[N:5][C:4]=1[N:29]1[CH:33]=[CH:32][CH:31]=[CH:30]1)#N.[OH-:34].[K+].Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:40]>>[CH2:26]([C:6]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:13][CH:14]=2)[C:3]([C:1]([OH:40])=[O:34])=[C:4]([N:29]2[CH:30]=[CH:31][CH:32]=[CH:33]2)[N:5]=1)[CH2:27][CH3:28]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: [OH-]
Reactant: CCCc1nc(-n2cccc2)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Agent: [K+]
Product: CCCc1nc(-n2cccc2)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
5-Cyano-2-propyl-4-(1H-pyrrol-1-yl)-1-[(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]-1H-imidazole (Example 22, 2.2 g) was treated with 2N KOH (75 mL) and heated at reflux for 12 hours. The resulting solution was cooled on an ice bath and treated dropwise with concentrated aqueous HCl (8 mL) followed by dropwise addition of aqueous 10% citric acid (50 mL). The resulting precipitate was collected by filtration and then it was partitioned between ethyl acetate and 10% citric acid. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator, keeping the temperature below 25° C. to give a foam. This foam was dissolved in ether-CH2Cl2 (1:1) and diluted to turbidity with hexanes. Evaporation of solvents as above gives the title compound as a colorless powder. MS (FAB, thioglycerol) 454 (m+1), 410 (m-CO2 +1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:27]CC#N)[C:25](=[O:31])[CH2:24][O:23][C:22]=4[N:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O=C1COC2N=[C:48](C3C=CC(C4(NC(=O)OC(C)(C)C)CCC4)=CC=3)[C:49](C3C=CC=CC=3)=[CH:50][C:43]=2[NH:42]1.BrCCCCC#N>>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:20][C:21]4[N:26]([CH2:27][CH2:48][CH2:49][CH2:50][C:43]#[N:42])[C:25](=[O:31])[CH2:24][O:23][C:22]=4[N:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCC#N)C(=O)CO4)cc2)CCC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: N#CCCCCBr
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCCCC#N)C(=O)CO4)cc2)CCC1

Procedure:
Following the procedure for tert-butyl(1-(4-(1-(2-cyanoethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate, tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (100 mg, 0.212 mmol) was reacted with 5-bromopentanenitrile (103 mg, 0.636 mmol) to afford the title compound (82 mg. 1H NMR (500 MHz, CDCl3): 7.20-7.33 (10H, m), 5.03 (1H, br), 4.91 (2H, s), 4.05 (2H, t), 2.45-2.51 (6H, m), 2.05-2.10 (1H, m), 1.88-1.94 (2H, m), 1.67-1.85 (3H, m), 1.27-1.38 (9H, br).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH3:14])[CH:5]=[C:4]([CH2:15]I)[N:3]=1.[CH3:17][S-:18].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH3:14])[CH:5]=[C:4]([CH2:15][S:18][CH3:17])[N:3]=1
Reactant: C[C@@H]1COCCN1c1cc(CI)nc(Cl)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCc1cc(N2CCOC[C@H]2C)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
Lithium iodide (17.57 g, 131.27 mmol) was added to (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate (19.2 g, 59.67 mmol) in dioxane (300 ml) and heated to 100° C. for 2 hours under nitrogen. The reaction mixture was quenched with water (200 ml) and extracted with EtOAc (3×200 ml). The organic layers were combined and washed with 2M sodium bisulfite solution (400 ml), water (400 ml), brine (400 ml) dried over MgSO4 and then evaporated. The residue was triturated with Et2O to afford (R)-4-(2-chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (13.89 g, 66%); 1H NMR (400 MHz, CDCl3) 1.32 (3H, d), 3.28 (1H, td), 3.54 (1H, td), 3.69 (1H, dd), 3.78 (1H, d), 3.98-4.02 (2H, m), 4.21 (2H, s), 4.29 (1H, br s), 6.41 (1H, s); m/z: (ESI+) MH+ 354.31. The mother liquors were concentrated down and triturated with Et2O to afford a further crop of (R)-4-(2-chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (2.46 g, 12%); 1H NMR (400 MHz, CDCl3) 1.32 (3H, d), 3.28 (1H, td), 3.54 (1H, td), 3.69 (1H, dd), 3.78 (1H, d), 3.98-4.02 (2H, m), 4.21 (2H, s), 4.30 (1H, s), 6.41 (1H, s); m/z: (ESI+) MH+, 354.31. Alternatively, this step can be carried out as follows: (R)-(2-Chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate (80 g, 248.62 mmol) and lithium iodide (83 g, 621.54 mmol) were dissolved in dioxane (300 ml) and then heated at 107° C. for 1 hour. The reaction mixture was quenched with water (250 ml), extracted with EtOAc (3×250 ml), the organic layer was dried over MgSO4, filtered and evaporated. The residue was dissolved in DCM and Et2O was added, the mixture was passed through silica (4 inches) and eluted with Et2O. Fractions containing product were evaporated and the residue was then triturated with Et2O to give a solid which was collected by filtration and dried under vacuum to afford (R)-4-(2-chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (75 g, 86%); m/z: (ESI+) MH+, 354.27. e) (R)-4-(2-Chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (17.0 g, 48.08 mmol) was dissolved in DMF (150 ml), to this was added sodium methanethiolate (3.37 g, 48.08 mmol) and the reaction was stirred for 1 hour at 25° C. The reaction mixture was quenched with water (50 ml) and then extracted with Et2O (3×50 ml). The organic layer was dried over MgSO4, filtered and then evaporated. The residue was purified by flash chromatography on silica, eluting with a gradient of 50 to 100% EtOAc in iso-hexane. Pure fractions were evaporated to afford (R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine (12.63 g, 96%); m/z: (ES+) MH+, 274.35.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11]S(O)(=O)=O.[O:16]=[S:17](=[O:19])=[O:18].OS(O)(=O)=O>>[OH2:9].[OH2:11].[Cl:1][C:2]1[C:7]([S:17]([OH:19])(=[O:18])=[O:16])=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: O=S(=O)=O
Product: O
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)O)c1

Procedure:
158.4 parts by weight of a sulfonation mixture (density 1.64 g/ml) which is obtained by reacting 63.0 parts by weight of 4-chloronitrobenzene with 86.3 parts by weight of 65% strength oleum (=65 parts of SO3 and 35 parts of H2SO4) and 9.1 parts by weight of H2SO4 is mixed, in an enameled dilution and precipitation vessel which is equipped with an anchor stirrer and cooling means, with 180.0 parts by weight of 11% strength sulfuric acid (or dilute sulfuric acid filtrate from the 2nd precipitation) at 50°-60° C., with high-speed stirring and moderate external cooling. After a residence time of about 2 hours at 50°-60° C. with stirring, the thin suspension is run into an enameled after stirring vessel which is equipped with an anchor stirrer and cooling means and where, after a residence time of at least 5 hours at 15° C., crystallization is brought to completion, again with stirring. The thin suspension, which has a solid content of 31%, is filtered to isolate the solids. About 163.0 parts by weight are obtained of industrially moist 6-chloro-3-nitrobenzenesulfonic acid dihydrate, containing 103.0 parts by weight of 6-chloro-3-nitrobenzenesulfonic acid and 21.0 parts by weight of H2SO4 (each calculated as 100% pure).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH:5]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[OH-:27].[K+]>O1CCCC1.O>[S:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH:5]=[C:4]1[CH2:3][CH:2]([N:17]1[CH2:18][CH2:19][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:16]1)[OH:27]
Reactant: BrC(Br)=Cc1cc2ccccc2s1
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(O)Cc2cc3ccccc3s2)CC1
Temperature: 70 °C
Yield: 65.3 %

Procedure:
A 50 mL round bottom flask was charged with 2-(2,2-dibromo-vinyl)-benzo[b]thiophene (1.0 g, 3.17 mmol), tert-butyl 1-piperazinecarboxylate (0.09 g, 4.76 mmol) and potassium hydroxide (0.71 g, 12.5 mmol). A solution of tetrahydrofuran:water (4:1) was added and the solution was heated to 70° C. for 18 hours. At the end of this time the solution was concentrated and the residue was diluted with a 2N aqueious solution of hydrochloric acid and extracted 3 times with ethyl acetate. The ethyl acetate was dried and concentrated and the residue subjected chromatography via Biotage (FLASH 40 M, silica, 60% ethyl acetate/hexane) to yield 0.75 g (65%) of tert-butyl 4-[2-(1-benzothien-2-yl)-1-hydroxyethyl]piperazine-1-carboxylate as an off white solid. MS (ES) m/z 305.1; HRMS: calcd for C19H26N2O3S, 362.1664; found (ESI, [M+H]+), 361.1569.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.[CH3:8][NH:9][C:10](=[S:13])[NH:11][NH2:12].FC(F)(F)C(F)=O>>[F:1][C:2]([F:7])([F:6])[C:3]1[N:9]([CH3:8])[C:10]([SH:13])=[N:11][N:12]=1
Reactant: CNC(=S)NN
Reactant: O=C(O)C(F)(F)F
Agent: O=C(F)C(F)(F)F
Product: Cn1c(S)nnc1C(F)(F)F

Procedure:
This exemplified compound may be readily synthesized by the reaction of methyl isocyanate with hydrazine to give 4-methyl-3-thiosemicarbazide followed by cyclocondensation with trifluoroacetic acid as described in U.S. Pat. No. 4,477,459. This compound may also be prepared by the reaction of 4-methyl-3-thiosemicarbazide with trifluoroacetylfluoride and heat (U.S. Pat. No. 3,780,052).
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].COP(O[C:15](=[C:22]([F:24])[F:23])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])(OC)=O>COC(C)(C)C>[CH:1]([N:4]([CH:5]([CH3:7])[CH3:6])[C:15](=[C:22]([F:24])[F:23])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(OP(=O)(OC)OC)=C(F)F
Reactant: CC(C)NC(C)C
Solvent: COC(C)(C)C
Product: CCOC(=O)CC(=C(F)F)N(C(C)C)C(C)C
Temperature: 25 °C
Yield: 70.6 %

Procedure:
Diisopropylamine (15.2 g, 0.15 mol) is added dropwise over 10 min to a solution of ethyl 3-[(dimethoxyphosphoryl)oxy]-4,4-difluorobut-3-enoate (IV-1) (14.2 g, 97%, 0.05 mol) in 100 ml methyl-tert-butyl ether. After 19 h heating under reflux the reaction mixture is cooled to room temperature, washed twice with 10 ml 10% sodium chloride solution each time, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was distilled for further use. 8.8 g (95%, 67.4% of theory) of ethyl 3-(diisopropylamino)-4,4-difluorobut-3-enoate are obtained (boiling point 55-57° C. at 0.5 hPa).
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].C[C:18](C)([O-:20])C.[K+].C(OCC)=O.O>CN(C)C=O>[C:1]([CH:3]([CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)[CH:18]=[O:20])#[N:2]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)CC1
Agent: [K+]
Solvent: O
Solvent: CCOC=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(C#N)C=O)CC1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
Under an argon atmosphere, tert-butyl 4-(cyanomethyl)piperidine-1-carboxylate (2.24 g, 10 mmol) and potassium tert-butoxide (6.73 g, 60 mmol) were dissolved in anhydrous N,N-dimethyl formamide (15 mL), and a solution of ethyl formate (4.44 g, 60 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added dropwise under ice-cooling. The temperature was gradually raised to room temperature, and then the resultant mixture was stirred overnight. Water was added to the reaction liquid, followed by extraction with ethyl acetate. 1 N hydrochloric acid was added to the obtained aqueous layer until it reached a pH of 6, and then the resultant mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure to give tert-butyl 4-(1-cyano-2-oxoethyl)piperidine-1-carboxylate (2.35 g) as a crude product.