Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[S:9][C:5]=2[CH:4]=1)#[CH:2].[C:13]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([S:10][CH3:13])[S:9][C:5]=2[CH:4]=1)#[CH:2]
Reactant: O=C([O-])[O-]
Reactant: C#Cc1ccc2nc(S)sc2c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C#Cc1ccc2nc(SC)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 139.2 %

Procedure:
To a stirred solution of 6-ethynylbenzo[d]thiazole-2-thiol (4.0 g, 21 mmol) from Step 2 of this Example in 20 mL of DMF at 0° C. were added K2CO3 (7.25 g, 5.25 mmol), and MeI (5 mL). The mixture was stirred at rt for 2 h before it was partitioned between EtOAc and water, the organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 3:1 DCM/hexanes to afford 6-ethynyl-2-(methylthio)benzo[d]thiazole (1.5 g, 35%) as an off-white solid. LCMS (ESI) m/z 206 (M+H)+.
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][OH:8])[CH2:5][OH:6])[CH2:2][CH3:3].[CH2:9]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:24][C:23]([CH:25]=O)=[CH:22][CH:21]=2)=[CH:16][N:15]=1)[CH2:10][CH2:11][CH2:12][CH3:13].C(C1C=CC(C2SC=CC=2)=CN=1)CCCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1(C)C=CC=CC=1>[CH2:9]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:24][C:23]([C@H:25]3[O:8][CH2:7][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][O:6]3)=[CH:22][CH:21]=2)=[CH:16][N:15]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCc1ccc(-c2ccc(C=O)s2)cn1
Reactant: CCCC(CO)CO
Agent: CCCCCc1ccc(-c2cccs2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(-c2ccc([C@H]3OC[C@H](CCC)CO3)s2)cn1
Reaction time: 3 h

Procedure:
A mixture of 1.2 g of 2-propylpropane-1,3-diol, 2.59 g of 5-(2-pentyl-5-pyridyl)-2-formyl-thiophene (obtainable by formylation of 5-(2-pentyl-5-pyridyl)-thiophene via a Vilsmeier reaction), 0.01 g of p-toluenesulfonic acid and 15 ml of toluene is boiled for 3 hours, using a water separator, cooled, washed with water and evaporated. 5-(2-Pentyl-5-pyridyl)-2-(trans-5-propyl-1,3-dioxan-2-yl)-thiophene is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)#[N:2].S(Cl)(Cl)=O.[CH3:19]O>>[C:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][CH2:9][C:10]([O:12][CH3:19])=[O:11])=[CH:5][CH:4]=1)#[N:2]
Reactant: CO
Reactant: N#Cc1ccc(OCCC(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCOc1ccc(C#N)cc1
Yield: 79 %

Procedure:
A solution of 3.80 g (19.9 mmol) of 3-(4-cyanophenoxy)propanoic acid in 10 ml of methanol is cooled by an ice bath. 3 ml (40 mmol) of thionyl chloride are added drop by drop and then the reaction medium is agitated with solvent reflux for 2 hours. The reaction mixture is then concentrated under reduced pressure and the evaporation residue is purified by silica column chromatography eluting with the help of a dichloromethane/methanol mixture (99/1; v/v). The expected product is obtained in the form of a white solid with a yield of 79%.
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].[CH3:17][O:18][C:19](=[O:23])[CH2:20][NH:21][CH3:22].C([N:26](CC)CC)C>CN(C)C=O>[CH3:17][O:18][C:19](=[O:23])[CH2:20][N:21]([NH:26][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)[CH3:22]
Reactant: CCN(CC)CC
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: CNCC(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)CN(C)NC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 12.5 °C
Reaction time: 13 h

Procedure:
To a solution of biotin in anhydrous dimethylformamide is added 1.1 equivalents of N-methylglycine methyl ester and 3 equivalents of triethylamine followed by the addition of 1.05 equivalents of BOP (benzotriazol-1-yloxy-tris (dimethylamine)phosphonium hexafluorophosphate). The mixture is stirred at 0-25° C. for 2-24 h and then concentrated. The residue is diluted with ethyl acetate and the resulting solution is washed with 1 N aqueous hydrochloric acid and then with saturated aqueous sodium bicarbonate. The organic phase is dried over magnesium sulfate, filtered and then concentrated via reduced pressure rotary evaporation. The residue is chromatographed on silica gel, eluting with 5-15% methanol/ethyl acetate. Chromatographic fractions containing product are combined and concentrated to afford the final product (4).
Reaction SMILES: [CH2:1]([C:4]1[CH:29]=[C:28]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[O:18]2)=[CH:13][CH:12]=1)[CH2:2][CH3:3].CN(C)P(N(C)C)(N(C)C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH2:59][CH2:60][CH3:61]>C1COCC1>[CH2:1]([C:4]1[CH:29]=[C:28]([O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:27]=[CH:26][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][C:17]([CH2:59][CH2:60][CH3:61])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[O:18]2)=[CH:13][CH:12]=1)[CH2:2][CH3:3]
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc2c(c1)OC(C(=O)OCC)CC2
Reactant: CCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc2c(c1)OC(CCC)(C(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
To a 2 ml THF solution of ethyl 7-(3-(2-propyl-4-phenoxyphenoxy)propoxy)-chromane-2-carboxylate (Example 1, Step B) (100 mg, 0.204 mmol) were added hexamethylphosphoramide (0.046 ml, 0.26 mmol) and sodium bis(trimethylsilyl)amide (1.0M THF solution) (0.265 ml, 0.265 mmol) upon cooling in a dry ice-acetone bath. After stirring at that temperature for 30min, to it was added iodopropane (0.06 ml, 6.2 mmol). The cooling bath was removed and the reaction mixture was gradually warmed to rt overnight. The solvent was removed under reduced pressure, diluted with AcOEt and water. The organic layer was separated. The aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel. Elution with 5% AcOEt/hexanes gave the title compound as a clear oil 33 mg (30%).
Reaction SMILES: CI.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([CH2:15][CH3:16])[CH:5]=1.[C:17](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:17])[S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([CH2:15][CH3:16])[CH:5]=1
Reactant: CCc1cc(Br)ccc1NS(C)(=O)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCc1cc(Br)ccc1N(C)S(C)(=O)=O
Reaction time: 24 h
Yield: 71.8 %

Procedure:
Methyl iodide (1.6 g, 0.0256M) was added to a mixture of N-(4-bromo-2-ethylphenyl)methanesulfonamide (4.77 g, 0.0171M) and potassium carbonate (3.5 g, 0.0256M) in dimethylformamide (50 ml) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for a further 24 hrs after which time it was partitioned between diethylether (100 ml) and water (100 ml). The aqueous was extracted further with diethyl ether (2×100 ml). The combined organics were dried over magnesium sulfate, filtered and the solvent concentrated in vacuuo to afford the title compound as a brown oil (3.6 g). 1H NMR (CDCl3): δ 1.12 (t, J=8.60 Hz, 3H), 2.94 (m, 5H), 3.02 (s, 3H), 6.71 (d, J=8.5 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 7.28 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:22]([O:24]CC3C=CC([N+]([O-])=O)=CC=3)=[O:23])=[C:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:15][S:16][C@:11]12[O:37][CH3:38])=[O:8].C1COCC1.CO>CCOC(C)=O.[Pd]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:22]([OH:24])=[O:23])=[C:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:15][S:16][C@:11]12[O:37][CH3:38])=[O:8]
Reactant: CO[C@]12SCC(COC(C)=O)=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2NC(=O)Cc1cccs1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CO[C@]12SCC(COC(C)=O)=C(C(=O)O)N1C(=O)C2NC(=O)Cc1cccs1
Yield: 74.6 %

Procedure:
A mixture of 5% Pd on charcoal (120 mg., prereduced in 1:1 THF-MeOH), the major isomer of p-nitrobenzyl 7-(2-thienylacetamido)-6-methoxy-3-acetoxymethyl-ceph-3-em-4-carboxylate (60 mg.), and 1:1 THF-MeOH (3 ml.) is hydrogenated at atmospheric pressure and room temperature for 3 hrs. The mixture is filtered and the filtrate is evaporated in vacuo. Trituration of the residue with Et2O provides a white solid (50 mg.). The solid is taken up in EtOAc (5 ml.) and filtered. The EtOAc filtrate is extracted with saturated aqueous NaHCO3 (3 × 2 ml.). The combined extracts are acidified to pH 2 with 10% HCl and extracted with EtOAc (4 × 3 ml.). The EtOAc extracts are washed with brine, dried over MgSO4, filtered, and evaporated in vacuo to yield 7-(2-thienylacetamido)-6-methoxy-3-acetoxymethyl-ceph-3-em-4-carboxylic acid (34 mg.) as a white solid.
Reaction SMILES: [CH:1](=[N:6][OH:7])[CH2:2][CH2:3][CH2:4][CH3:5].C(=NO)CCC.CN[C:16](NC)=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH2:21]([O:20][C:18]([C:17]1[C:1]([CH2:2][CH2:3][CH2:4][CH3:5])=[N:6][O:7][CH:16]=1)=[O:19])[CH3:22]
Reactant: CCCCC=NO
Reactant: CCOC(=O)C=C(NC)NC
Agent: CCCC=NO
Product: CCCCc1nocc1C(=O)OCC
Yield: 61 %

Procedure:
As described for example 1a except using valeraldehyde (12.4 mL, 116 mmol) instead of butyraldehyde, the penatnal oxime intermediate product (11.7 g, 99%) was obtained as a yellow solid and as a mixture of cis and trans isomers that was used directly without further purification. MS (EI): m/e=101.0 [M]+. Then as described for example 1b, except using (E and/or Z)-pentanal oxime (11.4 g, 113 mmol) instead of (E and/or Z)-butanal oxime, and using ethyl 3,3-dimethylaminoacrylate instead of ethyl (E)-3-(1-pyrrolidino)-2-butenoate, the title compound (13.6 g, 61%) was obtained as a yellow liquid after purification by chromatography (silica, 0 to 10% ethyl acetate in heptane). MS: m/e=198.1 [M+H]+.
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(OCC)=O.[CH2:29]([NH:36][C:37]([C:39]1[S:43][C:42]([N:44]2[CH2:48][CH2:47][N:46]([CH2:49][C:50]([O:52]CC)=[O:51])[C:45]2=[O:55])=[N:41][C:40]=1[CH3:56])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([NH:36][C:37]([C:39]1[S:43][C:42]([N:44]2[CH2:48][CH2:47][N:46]([CH2:49][C:50]([OH:52])=[O:51])[C:45]2=[O:55])=[N:41][C:40]=1[CH3:56])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)CN1CCN(c2nc(C)c(C(=O)NCc3ccccc3)s2)C1=O
Agent: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Product: Cc1nc(N2CCN(CC(=O)O)C2=O)sc1C(=O)NCc1ccccc1
Yield: 89 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 2-(3-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)acetate, the title compound was obtained as a colorless solid in 89% yield: 1H NMR (300 MHz, CDCl3) δ 7.37-7.27 (m, 5H), 6.06 (t, J=5.4 Hz, 1H), 4.56 (d, J=5.4 Hz, 2H), 4.17-4.07 (m, 4H), 3.70 (t. J=8.1 Hz, 2H), 2.59 (s, 3H); MS (ES+) m/z 258.2 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=1.[NH2:25][CH:26]1[CH2:30][CH2:29][O:28][CH2:27]1.F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:25][CH:26]2[CH2:30][CH2:29][O:28][CH2:27]2)=[O:22])=[CH:18][N:17]=1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Reactant: NC1CCOC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCOC1)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a solution of 6-(5-hydroxymethyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.21 mmol) in DMF (5 mL) was added 3-aminotetrahydrofuran (26 mg, 0.30 mmol), N,N,N′,N′-tetramethyl-O-(benzotriazole-1-yl)-uronium tetrafluoroborate (96 mg, 0.30 mmol) and N,N-diisopropyl ethylamine (0.15 mL, 0.84 mmol). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was partitioned (ethyl acetate/aqueous saturated sodium bicarbonate solution) and the organic phase was dried (Na2SO4) and concentrated. Chromatography (silica, dichloromethane:methanol=100:0 to 97:3) afforded the title compound (58 mg, 68%) as a colorless oil. MS: m/e=397.1 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:14][C:13]([NH2:15])=[N:12][C:11]2[C:7]=1[N:8]=[CH:9][N:10]=2.[CH:16]1([CH2:22][CH2:23]O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CN(C=O)C.C1COCC1>[CH:16]1([CH2:22][CH2:23][N:10]2[CH:9]=[N:8][C:7]3[C:11]2=[N:12][C:13]([NH2:15])=[N:14][C:6]=3[C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: OCCC1CCCCC1
Reactant: Nc1nc2ncnc-2c(-c2ccco2)[nH]1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccco2)c2ncn(CCC3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
A solution of 6-(2-furyl)-1H-purine-2-amine (25 mg, 0.12 mmol) in anhydrous DMF (0.5 mL) and anhydrous THF (2 mL) was treated with triphenylphosphine polystyrene (65 mg, 0.25 mmol) and 2-cyclohexylethanol (35 mg, 0.25 mmol), shaken at room temperature for 10 min, treated with di-tert-butyl azodicarboxylate (0.058 g, 0.25 mmol), shaken at room temperature for 16 h, filtered and concentrated in vacuo. The resulting oil was dissolved in CH2Cl2 (2 mL) and TFA (1 mL), shaken for 2 h and concentrated in vacuo. The resulting oil was dissolved in CH2Cl2 (3 mL), shaken with 1-M aq HCl (1 mL) for 15 min and the organic phase concentrated in vacuo and purified by chromatography (SiO2; EtOAc) to give the title compound (22 mg, 57%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:40][N:39]([CH3:41])[CH2:38][CH2:37][NH:36][S:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=1)(=[O:34])=[O:35]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN(C)CCNS(=O)(=O)c1cccc(Br)c1
Product: CN(C)CCNS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 3-bromo-N-(2-dimethylamino-ethyl)-benzenesulfonamide (example B.35) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (200 mg, 34%). MS (ISP) 582.2 [(M+H)+]; mp 146-147° C.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:18]([O:20][CH3:21])=[O:19].Cl>C1COCC1.C(OCC)C>[CH3:21][O:20][C:18]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:19]
Reactant: NCCc1ccccc1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a stirred solution of phenethylamine (75.2 mL, 0.6 mol) and triethylamine (83 mL, 0.6 mol) in THF (500 mL) was added slowly methyl chloroformate 46.2 mL, 0.6 mol) dissolved in THF (50 mL). After the reaction was stirred for an additional 1 h at room temperature, diethyl ether (2 L) and 1N HCl (800 mL) were added. The organic layer was washed with water, dried (MgSO4), filtered, and the filtrate was concentrated in vacuo to give a clear oil of pure title compound (102 g, 95%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Br[CH2:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[CH:8]=1>C(#N)C>[CH3:12][C:9]1[CH:8]=[C:7]([CH2:6][NH:3][CH2:2][CH2:1][NH2:4])[O:11][N:10]=1
Reactant: NCCN
Reactant: Cc1cc(CBr)on1
Solvent: CC#N
Product: Cc1cc(CNCCN)on1
Temperature: 20 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
Ethylenediamine (30 g) was dissolved in 120 g of acetonitrile, and a solution of 17.6 g of 5-bromomethyl-3-methylisoxazole in 30 ml of acetonitrile was added dropwise at 5° to 10° C. After the addition, the mixture was stirred for 1 hour with a care taken not to permit the temperature of the reaction system to rise above 20° C. Then, most of the volatile materials were removed under vacuum (less than 2 mmHg) while maintaining the bath temperature at 20° C. Ice water was added to the residue, and the mixture was extracted with dichloromethane. The dichloromethane layer was dehydrated, and dichloromethane was distilled off under reduced pressure to give 10.0 g of N-(3-methyl-5-isoxazolylmethyl)ethylenediamine (purity about 95%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.Cl.[CH3:23][O:24][CH2:25][C:26]1[N:30]=[C:29]([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[NH:28][N:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:35][C:34]3[CH:33]=[CH:32][C:31]([C:29]4[NH:28][N:27]=[C:26]([CH2:25][O:24][CH3:23])[N:30]=4)=[CH:37][CH:36]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: COCc1n[nH]c(-c2ccc(N)cc2)n1
Agent: Cl
Product: COCc1n[nH]c(-c2ccc(NC(=O)C(C)n3ccc(-c4cc(Cl)ccc4C#N)cc3=O)cc2)n1

Procedure:
90 mg (purity 93%, 0.28 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) (Example 2.2B) and 80 mg (0.33 mmol) of 4-[3-(methoxymethyl)-1H-1,2,4-triazol-5-yl]aniline monohydrochloride were reacted according to General Method 1. Yield: 45 mg (33% of theory)
Reaction SMILES: [CH3:1][N:2]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=O)[CH2:5][CH2:4]1.C(Cl)(=O)C(Cl)=O.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][NH:35][CH3:36]>C(Cl)Cl.CN(C=O)C>[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][N:35]([CH3:36])[C:9]([C@H:6]1[CH2:5][CH2:4][C@H:3]([N:2]([CH3:1])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=2)(=[O:13])=[O:14])[CH2:8][CH2:7]1)=[O:11]
Reactant: CNCCN(C)C
Reactant: CN([C@H]1CC[C@H](C(=O)O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)CCN(C)C(=O)[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 1.5 h

Procedure:
A solution of 0.137 g (0.375 mmol) of trans-4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexanecarboxylic acid in 2 mL of CH2Cl2 was treated at RT with 1 drop of DMF, followed by 0.035 mL (0.412 mmol, 1.1 eq) of oxalyl chloride within 5 min, and stirring was continued for 90 min. The solution was evaporated, redissolved in 2 mL of CH2Cl2 and treated with 0.058 mL (0.450 mmol, 1.2 eq) of N,N,N′-trimethylethylenediamine at 0° C. The reaction was kept at RT for 2 h, then partitioned between Et2O (×3)/aqueous saturated NaHCO3. The organic phases were washed once with 10% aqueous NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on 8 g of silica gel (CH2Cl2:MeOH 99:1 to 9:1) gave 0.088 g (53%) of pure trans-4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexanecarboxylic acid (2-dimethylamino-ethyl)-methyl-amide, MS: 450 (MH+), MP: 83° C.
Reaction SMILES: [CH3:1][C:2](=[C:4]([CH3:6])[CH3:5])[CH3:3].[N+](=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N-]>>[CH3:1][C:2]1([CH3:3])[C:4]([CH3:6])([CH3:5])[CH:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CC(C)=C(C)C
Reactant: CCOC(=O)C=[N+]=[N-]
Product: CCOC(=O)C1C(C)(C)C1(C)C

Procedure:
The method of Mesheheryakov, Chem. Abstr., 54, 24436d (1960) was employed. To a mixture of 19 g. (0.226 mole) of 2,3-dimethyl-2-butene and 2 g. of cupric sulfate is added at reflux a mixture of 51 g. (0.447 mole) ethyl diazoacetate and 19 g. of 2,3-dimethyl-2-butene. The resulting mixture is heated at reflux for 3 hours, cooled, filtered and distilled to afford 19.8 g. (26%) of the desired cyclic ester, B.P. 76°-77° (15 mm.).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH:10]([C:13]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]2[C:14]=1[C:15](=[O:28])[NH:16][S:17]2(=[O:19])=[O:18])([CH3:12])[CH3:11].[C:29]1([S:35][CH2:36]Cl)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O.C(OCC)(=O)C>[C:29]1([S:35][CH2:36][N:16]2[C:15](=[O:28])[C:14]3[C:20](=[C:21]([O:26][CH3:27])[C:22]([O:24][CH3:25])=[CH:23][C:13]=3[CH:10]([CH3:12])[CH3:11])[S:17]2(=[O:18])=[O:19])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: ClCSc1ccccc1
Reactant: COc1cc(C(C)C)c2c(c1OC)S(=O)(=O)NC2=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(C)C)c2c(c1OC)S(=O)(=O)N(CSc1ccccc1)C2=O
Temperature: 80 °C
Yield: 49 %

Procedure:
Diisopropylethylamine (0.5 mL) was added to a solution of 4-isopropyl-6,7-dimethoxysaccharin (0.5 g) in dimethylformamide (3 mL). After 15 minutes chloromethyl phenyl sulfide (0.35 g) was added. The mixture was heated at 80° C. for 16 hours, diluted with ethyl acetate, washed with aqueous sodium carbonate solution, hydrochloric acid (3N) and saturated aqueous sodium chloride solution, dried over sodium sulfate, and stripped of solvents. Purification of the residue by flash chromatography on silica gel using dichloromethane as eluant gave 2-phenylthiomethyl-4-isopropyl-6,7-dimethoxysaccharin (0.35 g), chlorination of which with sulfuryl chloride (0.1 mL) in dichloromethane (3 mL) and purification of the product by trituration with hexane gave 2-chloremethyl-4-isopropyl-6,7-dimethoxysaccharin, 0.3 g.
Reaction SMILES: C([N:8]1[CH2:13][C:12](=[CH2:14])[CH2:11][C@H:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:9]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])C1C=CC=CC=1.Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>>[CH2:14]=[C:12]1[CH2:13][N:8]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[C@H:9]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[C@@H:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1
Reactant: C=C1C[C@H](C(=O)OC(C)(C)C)[C@@H](C(=O)OCc2ccccc2)N(Cc2ccccc2)C1
Reactant: O=C(Cl)OCc1ccccc1
Product: C=C1C[C@H](C(=O)OC(C)(C)C)[C@@H](C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C1
Temperature: 65 °C
Reaction time: 28 h

Procedure:
A mixture of 2-benzyl 3-tert-butyl(2S,3S)-1-benzyl-5-methylenepiperidine-2,3-dicarboxylate from step 1d (2.3 g) and benzyl chloroformate (3 mL) was stirred at 65° C. for 28 h. The excess of the benzyl chloroformate was removed under reduced pressure. The residue was purified through Combiflash (hexane and ethyl acetate: gradient 0 to 10% during 12 min) to give the desired compound 1,2-dibenzyl 3-tert-butyl(2S,3S)-5-methylenepiperidine-1,2,3-tricarboxylate (1.40 g). MS (ESI): 488.1 (M+Na+); 366.1 (M+H+−COO(t-Bu)).