Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([OH:8])[CH2:5][CH:6]=[CH2:7].CCN(C(C)C)C(C)C.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.CCOCC>[CH2:5]([C:4]1([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[O:8][C:26](=[O:28])[NH:1][CH2:2][CH2:3]1)[CH:6]=[CH2:7]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCC(O)(CCN)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC1(c2ccc(F)cc2)CCNC(=O)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 265.7 %

Procedure:
A stirred solution of 1-amino-3-(4-fluorophenyl)hex-5-en-3-ol (53 mg, 0.25 mmol) and i-Pr2NEt (0.091 mL, 0.50 mmol) in CH2Cl2 (10 mL) was cooled in an ice bath and solid triphosgene (25 mg, 0.08 mmol) was added. The ice bath was allowed to melt and the mixture was stirred at rt for 6 h. The mixture was diluted with ether (80 mL), washed with 5% aq HCl (20 mL) and satd aq NaHCO3 (20 mL), and dried over MgSO4. Removal of the solvent afforded 6-allyl-6-(4-fluorophenyl)-1,3-oxazinan-2-one (50 mg, 84%) as an oil, which was used without further purification. LC-MS Method 1 tR=1.32 min, m/z=236.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]([O:12][CH3:13])=[O:11].[F:14][C:15]1[CH:16]=[C:17]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:34][CH2:33][NH:32][CH2:31]3)=[C:26]([CH3:35])[CH:25]=2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl>[CH3:13][O:12][C:10](=[O:11])[CH2:9][N:32]1[CH2:33][CH2:34][CH:30]([C:27]2[CH:28]=[CH:29][C:24]([S:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=3)(=[O:23])=[O:22])=[CH:25][C:26]=2[CH3:35])[CH2:31]1
Reactant: Cc1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCNC1
Reactant: COC(=O)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN1CCC(c2ccc(S(=O)(=O)c3cccc(F)c3)cc2C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.2 %

Procedure:
Triethylamine (0.387 mL, 1.533 mmol) and methyl bromoacetate (0.146 mL, 1.533 mmol) were added at 0° C. to a solution of 3-[4-(3-fluoro-benzenesulfonyl)-2-methyl-phenyl]-pyrrolidine (0.445 g, 1.393 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 4 hours, then concentrated under reduced pressure, and the crude residue was purified via flash chromatography (DCM/MeOH/NH4OH) to give 0.410 g (84% yield) of {3-[4-(3-fluoro-benzenesulfonyl)-2-methyl-phenyl]-pyrrolidin-1-yl}-acetic acid methyl ester as a yellow oil.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13](C3CCCCO3)[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([NH:27][C:28]2[C:29]([NH2:34])=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[F:41][C:42]([F:47])([CH3:46])[C:43](O)=O.CN(C)C=O.C(N(CC)C(C)C)(C)C.C(O)(=O)C>>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([N:27]2[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[N:34]=[C:43]2[C:42]([F:47])([F:41])[CH3:46])[N:15]=3)[CH2:7][CH2:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)N1CCN(Cc2nc3c(N4CCOCC4)nc(Nc4ccccc4N)nc3n2C2CCCCO2)CC1
Reactant: CC(F)(F)C(=O)O
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(F)(F)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C)CC3)[nH]c2n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
N1-(8-((4-tert-butylpiperazin-1-yl)methyl)-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl)benzene-1,2-diamine (0.085 g, 0.15 mmol) and 2,2-difluoropropanoic acid (0.019 g, 0.17 mmol) were dissolved in N,N-dimethylformamide (2 mL, 0.02 mol). N,N-Diisopropylethylamine (0.054 mL, 0.31 mmol) was added. The resulting solution was cooled at 0° C. for 20 minutes. N,N,N′N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.070 g, 0.00018 mol) was added and the reaction stirred overnight at room temperature. The reaction mixture was concentrated to dryness. Acetic acid (3.0 mL, 0.053 mol) was added to the crude residue and the reaction mixture was heated at 90° C. for 18 hours. The reaction mixture was cooled, filtered and concentrated to dryness. The crude was purified by reverse phase HPLC to give 457 (15.3 mg, 18%). [M+H]+=540.3
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([C@@H:22]3[O:30][CH2:29][C@H:24]([S:25]C(=O)C)[CH2:23]3)=[O:21])[CH2:16][CH2:15]2)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].CO>C(OCC)(=O)C.CCCCCC>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([C@@H:22]3[O:30][CH2:29][C@H:24]([SH:25])[CH2:23]3)=[O:21])[CH2:18][CH2:19]2)=[O:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1CO[C@@H](C(=O)N2CCN(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCN(C(=O)[C@H]2C[C@@H](S)CO2)CC1
Yield: 41.4 %

Procedure:
The title compound is prepared by the procedure of Example 153 using 0.230 g of product from Example 157, 0.29 ml of 4N sodium hydroxide and 1.7 ml of methyl alcohol to give 0.086 g of the desired product after chromatography (silica gel: 10-100% ethyl acetate/hexane).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].[Cl-]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: COCCOCCOCCO
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOCCOCCOS(C)(=O)=O

Procedure:
A solution of non-polydispersed triethylene glycol monomethyl ether molecules (4.00 mL, 4.19 g, 25.5 mmol) and triethylamine (4.26 mL, 3.09 g, 30.6 mmol) in dry dichloromethane (50 mL) was chilled in an ice bath and place under a nitrogen atmosphere. A solution of methanesulfonyl chloride (2.37 mL, 3.51 g, 30.6 mmol) in dry dichloromethane (20 mL) was added dropwise from an addition funnel. Ten minutes after the completion of the chloride addition, the reaction mixture was removed from the ice bath and allowed to come to room temperature. The mixture was stirred for an additional hour, at which time TLC (CHCl3 with 15% MeOH as the elutant) showed no remaining triethylene glycol monomethyl ether.
Reaction SMILES: I.[F:2][C:3]1[CH:4]=[C:5]([NH:17][C:18](SC)=[NH:19])[CH:6]=[C:7]([O:15][CH3:16])[C:8]=1[N:9]1[CH:13]=[N:12][C:11]([CH3:14])=[N:10]1.[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=1)[C:28](O)=O.CN1CCOCC1.C(N(CC)C(C)C)(C)C.[NH2:58][NH2:59]>>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([C:28]1[NH:59][N:58]=[C:18]([NH:17][C:5]2[CH:6]=[C:7]([O:15][CH3:16])[C:8]([N:9]3[CH:13]=[N:12][C:11]([CH3:14])=[N:10]3)=[C:3]([F:2])[CH:4]=2)[N:19]=1)[C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([F:39])([F:40])[F:41])=[CH:33][CH:32]=1
Reactant: COc1cc(NC(=N)SC)cc(F)c1-n1cnc(C)n1
Reactant: O=C(O)C(CCCCCl)c1ccc(OC(F)(F)F)cc1
Reactant: NN
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCOCC1
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(OC(F)(F)F)cc3)n2)cc(F)c1-n1cnc(C)n1

Procedure:
Methyl 3-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydroiodide (0.575 g, 1.36 mmol, from preparation 5) and 6-chloro-2-(4-(trifluoromethoxy)phenyl)hexanoic acid (0.528 g, 1.70 mmol, from preparation AI) were coupled [N-methylmorpholine (0.747 mL, 6.79 mmol) was substituted for N,N-diisopropylethylamine] and then reacted with hydrazine (0.213 mL, 6.80 mmol) using a procedure analogous to Step A of Example 13. After an aqueous workup, 5-(5-chloro-1-(4-(trifluoromethoxy)phenyl)pentyl)-N-(3-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine was obtained as a brown solid. The crude product was used in the next step without purification. LC-MS (M+H)+ 554.2.
Reaction SMILES: [F:1][C:2]([F:14])([C:10]([O:12][CH3:13])=[O:11])[C:3]([F:9])([F:8])[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:16][CH2:17][OH:18].CS(C)=O.[H-].[Na+]>CCOCC.O>[CH3:7][O:6][C:4]1([C:3]([F:9])([F:8])[C:2]([F:14])([F:1])[C:10]([O:12][CH3:13])=[O:11])[O:18][CH2:17][CH2:16][O:5]1
Reactant: COC(=O)C(F)(F)C(F)(F)C(=O)OC
Reactant: OCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: COC(=O)C(F)(F)C(F)(F)C1(OC)OCCO1
Yield: 44.1 %

Procedure:
A mixture of 43.6 g (0.20 mol) of dimethyl tetrafluorosuccinate, 16.1 g (0.20 mol) of 2-chloroethanol, and 100 mL of DMSO was stirred and maintained at 25°-35° while 9.6 g (0.20 mol) of 50% NaH in mineral oil were added portionwise. The resulting mixture was stirred overnight, and then poured into 500 mL of cold water. Ether (300 mL) was added, and the resulting mixture was shaken. After mixture separated into layers, the ether layer was separated, washed with 100 mL of water, dried over CaSO4, filtered and distilled to give 23.1 g (44%) of 2-methoxy-2-(2-methoxycarbonyltetrafluoroethyl)-1,3-dioxolane, b.p. 72°-72.5° at 13 Pa (0.1 mm). IR (neat) and NMR (CCl4) spectra of the product were consistent with the assigned structure. Anal.: Calcd. for C8H10F4O5 : C, 36.65; H, 3.85; F, 28.99. Found: C, 36.45; H, 3.95; F, 28.70.
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:9]([CH3:10])=[C:8]([CH2:11][C:12]([CH3:14])=[CH2:13])[C:7]([OH:15])=[C:6]([CH3:16])[C:5]=1[CH3:17])=[O:2].C([O-])(=O)C.[Na+].[Br:23]Br>C(O)(=O)C>[Br:23][CH2:13][C:12]1([CH3:14])[CH2:11][C:8]2[C:9]([CH3:10])=[C:4]([NH:3][CH:1]=[O:2])[C:5]([CH3:17])=[C:6]([CH3:16])[C:7]=2[O:15]1
Reactant: C=C(C)Cc1c(C)c(NC=O)c(C)c(C)c1O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C)c1NC=O)CC(C)(CBr)O2
Temperature: 0 °C
Yield: 67.1 %

Procedure:
4-Formylamino-2,3,5-trimethyl-6-(2-methyl-2-propenyl)phenol (50 g, 0.21 mol) and sodium acetate (30.5 g, 0.37 mol) were added to acetic acid (500 ml). Bromine (16.5 ml, 0.21 mol) was added dropwise to the mixture with stirring. After the reaction mixture was stirred for 30 minutes, the mixture was poured into ice water and the product was extracted with ethyl acetate. The extract was washed with aqueous saturated sodium bicarbonate solution, dried and then concentrated. The residue was dissolved in ethyl acetate again and insoluble materials were filtered off. The filtrate was concentrated and isopropyl ether was added to the residue. The crystals precipitated were filtered off to obtain the desired compound (44.0 g, yield: 65.7%), m.p. 157°-158° C.
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][C:8]1[C:9]([CH2:23][CH3:24])=[N:10][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]=1[CH2:13][CH3:14])(C)(C)C.[C:26](=[O:29])([O-:28])N>>[CH2:15]([O:28][C:26]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:11]2[C:12]([CH2:13][CH3:14])=[C:8]([CH2:7][C:6]([OH:5])=[O:25])[C:9]([CH2:23][CH3:24])=[N:10]2)=[CH:21][CH:20]=1)=[O:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCc1nn(Cc2ccc(N)cc2)c(CC)c1CC(=O)OC(C)(C)C
Reactant: NC(=O)[O-]
Product: CCc1nn(Cc2ccc(NC(=O)OCc3ccccc3)cc2)c(CC)c1CC(=O)O

Procedure:
Example 3.3 was prepared according to the method described for method 3.1, employing intermediate 2.1.2 instead of intermediate 1.1.3 in the carbamate formation step. The subsequent cleavage of the tert-butyl ester was performed under acidic conditions as described for example 2.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH:35]1[CH2:40][CH2:39][CH2:38][C@@H:37]([NH:41][C:42]2[N:47]=[CH:46][N:45]=[C:44]3[NH:48][N:49]=[CH:50][C:43]=23)[CH2:36]1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH:48]1[C:44]2=[N:45][CH:46]=[N:47][C:42]([NH:41][C@@H:37]3[CH2:38][CH2:39][CH2:40][N:35]([C:11](=[O:13])[CH2:10][NH:9][C:4]4[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH2:36]3)=[C:43]2[CH:50]=[N:49]1
Reactant: O=C(O)CNc1cc(F)cc(Cl)c1
Reactant: c1nc(N[C@@H]2CCCNC2)c2cn[nH]c2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNc1cc(F)cc(Cl)c1)N1CCC[C@@H](Nc2ncnc3[nH]ncc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
To a cooled solution of 2-(3-chloro-5-fluorophenylamino)acetic acid (70 mg, 0.34 mmol) at 0° C. in DMF (5 mL), HOBt (69 mg, 0.51 mmol) was added and the reaction mixture was stirred for 10 min. before EDCI (101 mg 0.51 mmol), (R)—N-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (75 mg, 0.34 mmol) and DIEA (104 mg, 0.80 mmol) were added in succession. The reaction mixture was allowed to warm to rt and was stirred overnight. After completion of the reaction as indicated by TLC the reaction mixture was diluted with EtOAc (50 mL) and was washed with water (3×20 mL). The EtOAc layer was then dried over Na2SO4 and evaporated in vacuo to give a residue that was purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford the titled compound (14 mg, 10%). 1H NMR (400 MHz, CD3OD): δ 8.52-8.43 (m, 1H), 6.45-6.08 (m, 4H), 4.49-3.82 (m, 5H), 3.31-2.95 (m, 2H), 1.96-1.63 (m, 4H). LC-MS: m/z [M+1]=404.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C:3]#[C:4][CH3:5].C(N(CC)CC)C.Cl[SiH:15]([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17]>CN(C)C1C=CN=CC=1.CCCCCC>[CH:16]([SiH:15]([CH:19]([CH3:21])[CH3:20])[O:6][CH2:1][CH2:2][C:3]#[C:4][CH3:5])([CH3:18])[CH3:17]
Reactant: CC(C)[SiH](Cl)C(C)C
Reactant: CC#CCCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC#CCCO[SiH](C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (0° C.) solution of 3-pentynol (5.880g, 70.0 mmol, 1.0 equiv), 4-dimethylaminopyridine (DMAP) (840 mg, 7.00 mmol, 0.10 equiv), and triethylamine (TEA) (9.80 ml, 71.0 mmol, 1.01 equiv) in 100 mL of dry hexane was added dropwise chlorodiisopropylsilane (11.0 g, 71.0 mmol, 1.01 equiv) over 20 minutes. The resulting white suspension was allowed to warm to room temperature and was stirred overnight. The reaction mixture was filtered through a short silica pad (10 g) and the solvent was then evaporated in vacuo to give a colorless liquid. Fractional distillation of this liquid afforded 11.2 g (81%) of A-7 as a colorless liquid. An analytical sample (0.48 g) was obtained by redistillation of a 0.50 g sample by Kugelrohr distillation.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][C:8]([CH3:15])=[C:9]([C:12](=[O:14])[CH3:13])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[CH:4]([CH3:18])[CH2:3]1.[Br:20]Br>C(O)(=O)C>[CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][C:8]([CH3:15])=[C:9]([C:12](=[O:14])[CH2:13][Br:20])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[CH:4]([CH3:18])[CH2:3]1
Reactant: BrBr
Reactant: CC(=O)c1cc2c(cc1C)C(C)(C)C(C)CC2(C)C
Solvent: CC(=O)O
Product: Cc1cc2c(cc1C(=O)CBr)C(C)(C)CC(C)C2(C)C

Procedure:
A solution of 1,1,3,4,4,6-Hexamethyl-7-acetyl-1,2,3,4-tetrahydronaphthalene(33 g.) in 40 ml. glacial acetic acid was treated slowly with 20 g. bromine. Warming was necessary to initiate the reaction, evidenced by disappearance of the red colouration. When all the bromine had been added,the mixture was cooled and poured onto ice to give a pale green gum. The whole was extracted with ether, the ethereal extracts washed with dilute Na2CO3, water and finally dried over MgSO4. Evaporation ofthe ether gave a pale green solid which was recrystallised from EtOH to give the title compound 27.6 g. (64%), m.p. 68° C. Analysis : Calculated for C18H25OBr, C, 64.09%; H, 7.47%. Found : C, 64.40%; H, 7.65%.
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)#[N:2].[C:23](Cl)(=[O:27])[CH2:24][CH2:25][CH3:26]>>[C:23]([N:8]1[CH2:9][CH2:10][C:11]2[C:3]([C:1]#[N:2])=[C:4]([NH:12][C:13](=[O:22])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[S:5][C:6]=2[CH2:7]1)(=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: COc1cccc(C(=O)Nc2sc3c(c2C#N)CCNC3)c1
Reactant: CCCC(=O)Cl
Product: CCCC(=O)N1CCc2c(sc(NC(=O)c3cccc(OC)c3)c2C#N)C1

Procedure:
Prepared according to general procedure A starting from N-(3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-methoxybenzamide (compound B3) and butyryl chloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[N:20]([CH3:21])[N:19]=[N:18][N:17]=1.C(N(CC)CC)C.C(O)CCC>O>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:16]2[N:20]([CH3:21])[N:19]=[N:18][N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nnnc1Cl
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCCCO
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1nnnc1N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
Piperidin-4-yl-carbamic acid tert-butyl ester (30.0 g, 0.189 mol), 5-chloro-1-methyl-1H-tetrazole (28.8 g, 0.242 mol) and triethylamine (80 mL, 0.573 mol) were added to a mixture of n-butanol (80 mL) and water (80 mL) and the reaction mixture heated to 80° C. for 5 hours. The reaction was cooled to room temperature and stirred at this temperature overnight. The resulting precipitate was filtered off and washed with water (2×25 mL) and then dried to give tert-butyl[1-(1-methyl-1H-tetrazol-5-yl)-piperidin-4-yl]-carbamate as a white powder (41.8 g). 1H NMR (300 MHz, DMSO-d6) ppm 1.39 (s, 9H) 1.44-1.65 (qd, J=12, 4 Hz, 2H) 1.75-1.92)dd, J=13, 3 Hz, 2H) 2.95-3.16 (td, J=13, 3 Hz, 2H) 3.34-3.50 (broad s, 1H) 3.50-3.65 (dt, J=13, 3 Hz, 2H) 3.85 (s, 3H) 6.83-7.04 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][CH3:14])(=[NH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:16]([O:18][CH:19]1[CH:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:22][CH:21]([CH3:28])[CH2:20]1)=[O:17].[Na+].[Cl-]>N1C=CC=CC=1>[CH2:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)(=[N:12][C:16]([O:18][C@@H:19]1[CH2:20][C@H:21]([CH3:28])[CH2:22][CH2:23][C@H:24]1[CH:25]([CH3:27])[CH3:26])=[O:17])=[O:11])[CH3:14]
Reactant: CC1CCC(C(C)C)C(OC(=O)Cl)C1
Reactant: CCS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCS(=O)(=NC(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 mg (0.47 mmol) of (RS)—S-(4-nitrophenyl)-S-ethyl sulfoximide in 4.40 ml of pyridine is mixed drop by drop at room temperature with 0.46 ml (2.17 mmol) of (+) menthyl chloroformate. The batch is stirred for 4 hours at room temperature and then added to dilute NaCl solution. It is extracted from ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate 1:1). 161 mg (0.41 mmol, corresponding to 87% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([SH:30])[C@@H:28]([C:31]([CH3:39])([CH3:38])[O:32][SiH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:27]1=[O:40])=[P:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH: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)[CH:2]=[CH2:3].[Cl:42][CH2:43][C:44](Cl)=[O:45]>[Ag]>[CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([S:30][C:44](=[O:45])[CH2:43][Cl:42])[C@@H:28]([C:31]([CH3:39])([CH3:38])[O:32][SiH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C:27]1=[O:40])=[P:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C(N1C(=O)[C@H](C(C)(C)O[SiH2]C(C)(C)C)[C@H]1S)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)CCl
Agent: [Ag]
Product: C=CCOC(=O)C(N1C(=O)[C@H](C(C)(C)O[SiH2]C(C)(C)C)[C@H]1SC(=O)CCl)=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
In a manner analogous to that described in Example 7, 30 g of the silver salt of 2-[(3S,4R)-3-(tert.-butyl-dimethyl-silyloxymethyl)-4-mercapto-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester are reacted with 5.04 ml of chloroacetyl chloride to form the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9](O)[CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].S(Cl)([Cl:23])=O.O>C(Cl)(Cl)Cl>[Cl:23][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=1)[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCc1ccc(C(Cl)COc2ccc(C=O)cc2)nc1
Yield: 76.7 %

Procedure:
To a stirred solution of 5 g (0.018 mol) 4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde dissolved in chloroform was added 2.63 g (0.022 mol) thionyl chloride at 55-60° C. Reaction mixture was refluxed for 1 hr. Progress of the reaction was monitored by TLC and after completion of reaction, subsequent work-up in alkaline water yielded 4 g (75%) of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:19])[N:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10](=[O:19])[N:11]([CH2:15][C:16]([O:18][N:21]2[C:25](=[O:26])[CH2:24][CH2:23][C:22]2=[O:27])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)Cn1cccc(OCc2ccccc2)c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(Cn1cccc(OCc2ccccc2)c1=O)ON1C(=O)CCC1=O
Reaction time: 8 h
Yield: 82.2 %

Procedure:
3-Benzyloxy-1-carboxymethylpyrid-2-one (2 g) is dissolved in dimethylformamide (DMF) (25 ml) and to this solution is added N-hydroxysuccinimide (1 g). The resultant solution is cooled and to it is added dicyclohexylcarbodiimide (DCCI) (11.8 g) in DMF (5 ml). The mixture is allowed to stand overnight to give a brown supernatant and a white precipitate. The precipitate is filtered off, washed with a little DMF and then evaporated to dryness under high vacuum. The crude product is dissolved in a minimum volume of dichloromethane and diethyl ether is added to this solution until it becomes cloudy. The solution is then cooled and the resultant precipitate is filtered off and washed with a little diethyl ether to give 3-benzyloxy-1-(succinimidooxycarbonylmethyl)-pyrid-2-one (2.26 g, 82%), m.p. 187°-188° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:3]=12.[C:17]([Cl:20])(=[O:19])[CH3:18]>>[ClH:20].[C:17]([N:15]1[CH2:14][CH2:13][CH2:12][C:4]2=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]([CH3:1])=[C:3]2[CH2:16]1)(=[O:19])[CH3:18]
Reactant: Cc1c2c(nc3ccccc13)CCCNC2
Reactant: CC(=O)Cl
Product: CC(=O)N1CCCc2nc3ccccc3c(C)c2C1
Product: Cl
Yield: 75 %

Procedure:
2-Acetyl-2,3,4,5-tetrahydro-11-methyl-1H-azepino[4,3-b]quinoline hydrochloride was prepared from 2,3,4,5-tetrahydro-11-methyl-1H-azepino[4,3-b]quinoline and acetyl chloride analogous to Example 63.