Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10]([N:17]([CH3:28])[C@H:18]([C:20]([C@:22]([CH3:27])([OH:26])[C:23]([OH:25])=O)=[O:21])[CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl>[CH2:10]([N:17]([CH3:28])[C@H:18]([C:20]([C@:22]([CH3:27])([OH:26])[C:23]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:25])=[O:21])[CH3:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[C@@H](C(=O)[C@](C)(O)C(=O)O)N(C)Cc1ccccc1
Reactant: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](C(=O)[C@](C)(O)C(=O)N1CCCCC1)N(C)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
5.4 g (41.4 mmol) of N,N-diisopropylethylamine (Hünig's base) and 5.3 g (20.7 mmol) of bis(2-oxo-3-oxazolidinyl)-phosphonium acid chloride (BOP-Cl) are added at 0° C. to a solution of 5.0 g (18.8 mmol) of N-benzyl-N-methyl-L-alanyl-D-lactic acid and 1.6 g (20.7 mmol) of piperidine in 150 ml of methylene chloride, and the mixture is stirred at 0° C. for two hours and then at room temperature for 18 hours. The residual crude product is chromatographed on a silica gel column (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the eluent cyclohexane:ethyl acetate (3:1). 3.5 g (55.8% of theory) of N-benzyl-N-methyl-L-alanyl-D-lactic acid piperidide are obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[N:11]=[CH:10][CH:9]=1>CN(C=O)C>[Br:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[C:8]2[O:5][CH2:4][CH2:3][OH:6]
Reactant: OCCO
Reactant: Clc1ccnc2ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCOc1ccnc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57 %

Procedure:
To a suspension of sodium hydride (60% suspension, 40 mg, 0.99 mmol) in DMF (3 mL) under nitrogen atmosphere was added ethylene glycol dropwise. The reaction mixture was stirred for 20 min before adding 4-chloro-6-bromoquinoline (200 mg, 0.825 mmol) in one portion. The reaction mixture was stirred at 90° C. for 22 h. Another 20 mg of sodium hydride was added after 16 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in methanol and the solution was adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-10% methanol/dichloromethane afforded 127 mg of 2-(6-bromo-quinolin-4-yloxy)-ethanol as a white solid (57% yield): 1H NMR (DMSO-d6) δ 3.93 (q, 2H), 4.32 (t, 2H), 5.21 (t, 1H), 7.14 (d, 1H), 7.94 (m, 2H), 8.50 (d, 1H), 8.82 (d, 1H); MS (m/z) 268, 270 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][C:12](=[NH:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([CH3:3])[CH3:2].C([Li])CCC.Cl[P:27]([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29]>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][C:12](=[N:20][P:27]([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([CH3:3])[CH3:2]
Reactant: CC(C)P(Cl)C(C)C
Reactant: Cc1ccc(C(=N)Nc2c(C)cccc2C(C)C)cc1
Agent: [Li]CCCC
Product: Cc1ccc(C(=NP(C(C)C)C(C)C)Nc2c(C)cccc2C(C)C)cc1

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.33 g of N1-(2-isopropyl-6-methylphenyl)-4-methylbenzamidine (Amidine V, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.80 mL chlorodiisopropylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, a yellow semi-solid was isolated (1.86 g, 97%).
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[N:13]([CH2:16][C:17]1[CH:21]=[CH:20][O:19][CH:18]=1)=[N+:14]=[N-:15]>>[ClH:1].[O:19]1[CH:20]=[CH:21][C:17]([CH2:16][N:13]2[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]3[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=3)[N:15]=[N:14]2)=[CH:18]1
Reactant: [N-]=[N+]=NCc1ccoc1
Reactant: C#CCCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCCc2cn(Cc3ccoc3)nn2)c[nH]1
Yield: 58.1 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.063 g, 0.340 mmol) was reacted with 3-azidomethyl-furan (0.050 g, 0.406 mmol) following the general procedure for click reactions outlined above to produce 4-[3-(1-Furan-3-ylmethyl-1H-[1,2,3]triazol-4-yl)-propyl]-1Himidazol-2-ylamine hydrochloride (0.061 g, 58%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.70 (s, 1H), δ 7.56 (s, 1H), δ 7.41 (s, 1H), δ 6.44 (s, 1H), δ 6.35 (s, 1H), δ 5.35 (s, 2H), δ 2.65 (t, 2H), δ 2.45 (t, 2H), δ 1.86 (m, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 147.3, 147.3, 144.2, 141.6, 127.2, 122.1, 120.2, 109.9, 108.8, 44.7, 27.8, 24.2, 23.6 ppms; HRMS (ESI) calcd for C13H16N6O (M+) 272.1458. found 272.1462.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][CH2:11][S:12][CH3:13])[C:14]([O:16][CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)CC1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CSCCC(NC(=O)OC(C)(C)C)C(=O)OC1CCN(C)CC1
Yield: 56 %

Procedure:
A solution of tert-butoxycarbonyl-L-methionine (5 g; 20 mmol), 4-hydroxy-1-methylpiperidine (3.3 g; 20 mmol); DMAP (2.44 g; 20 mmol) and EDC (4.6 g; 2.4 mmol) in dichloromethane (200 ml) was stirred at ambient temperature overnight. The mixture was extracted with dichloromethane. The organic phase was evaporated and purified by flash chromatography, eluting with dichloromethane/ethanol (97/3) to give 1-methylpiperidin-4-yl 2-tert-butoxycarbonylamino-4-methylsulfanylbutyrate. Yield 56%.
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]([CH2:20]O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:67]=[N+:68]=[N-:69])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[C:1]([O:7][CH2:8][CH:9]([CH2:20][N:67]=[N+:68]=[N-:69])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1ccc(CCC(CO)COC(=O)C(C)(C)C)cc1C
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(CCC(CN=[N+]=[N-])COC(=O)C(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
A mixture of alcohol (17) (10 mmol), triphenylphospine (20 mmol, 5.25 g), diethyl azodicarboxylate (20 mmol, 3.15 ml) in THF (70 ml) was treated with diphenylphosphorylazide (20 mmol, 4.32 ml) and stirred at room temperature for 18 h. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel with EtOAc/hexanes (1:10) as an eluant to give compound 19.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:26])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]2[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:27][N:28]=[C:29]=S.Cl>O1CCCC1>[OH:26][C:9]1([C:4]2[CH:5]=[CH:6][C:7]3[NH:8][C:27]([NH:28][CH3:29])=[N:1][C:2]=3[CH:3]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN=C=S
Reactant: Nc1ccc(C2(O)c3ccccc3C(=O)N2Cc2ccccc2)cc1N
Agent: Cl
Solvent: C1CCOC1
Product: CNc1nc2cc(C3(O)c4ccccc4C(=O)N3Cc3ccccc3)ccc2[nH]1
Temperature: 65 °C
Reaction time: 3 h
Yield: 3 %

Procedure:
To a solution of 3-(3,4-diaminophenyl)-3-hydroxy-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one (100 mg, 0.289 mmol) and methyl isothiocyanate (31 mg, 0.434 mmol) in tetrahydrofuran (30 mL) was added 1-[3-dimethylamino)propyl]-3-ethylcarbodiimmide hydrochloride (89 mg, 0.462 mmol) at room temperature. The reaction mixture was heated to 65° C. and stirred for 3 h, at which time it was cooled to room temperature and partitioned with water and a mixture of acetonitrile-ethyl acetate (1:9, 200 mL). The organic layer was washed with water and brine then dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography (SiO2, methanol/dichloromethane) to afford 3-hydroxy-3-[2-(methylamino)-1H-benzimidazol-5-yl]-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one (3.3 mg). 1H NMR (400 MHz, CD3OD): 7.79 (d, 1H), 7.54-7.48 (m, 2H), 7.29-7.26 (m, 2H), 7.18-7.16 (m, 2H), 7.11-7.01 (m, 4H), 6.86 (dd, 1H), 4.57 (d, 1H), 4.34 (d, 1H), 2.96 (s, 3H); MS (EI) for C23H20N4O2: 385 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=2)=[CH:11][C:10]([CH:21]=O)=[N:9]1.[CH3:23][NH2:24].CO.CO>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=2)=[CH:11][C:10]([CH2:21][NH:24][CH3:23])=[N:9]1
Reactant: CN
Reactant: Cc1ccc(Sc2cc(C=O)nn2-c2ccccc2Cl)nc1
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1cc(Sc2ccc(C)cn2)n(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of 1-(2-chlorophenyl)-5-[(5-methylpyridin-2-yl)thio]-1H-pyrazole-3-carbaldehyde (422 mg) in tetrahydrofuran (4 mL) were added 40% methylamine-methanol solution (1.3 mL) and methanol (4 mL) at 0° C. The mixture was stirred at room temperature for 16 hr, and concentrated under reduced pressure. The residue was dissolved in methanol (4 mL), sodium borohydride (60 mg) was added at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 433 mg, 98%).
Reaction SMILES: [CH3:1][C:2]([C:9]1[C:17]2[O:16][CH:15]=[CH:14][C:13]=2[CH:12]=[C:11]([F:18])[CH:10]=1)([CH3:8])[C:3](OCC)=[O:4].C([NH2:21])=O.C[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]([C:9]1[C:17]2[O:16][CH:15]=[CH:14][C:13]=2[CH:12]=[C:11]([F:18])[CH:10]=1)([CH3:8])[C:3]([NH2:21])=[O:4]
Reactant: NC=O
Reactant: CCOC(=O)C(C)(C)c1cc(F)cc2ccoc12
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C(N)=O)c1cc(F)cc2ccoc12
Temperature: 100 °C
Yield: 43.7 %

Procedure:
A mixture of 0.156 gm (0.62 mMol) ethyl 2-methyl-2-(5-fluorobenzofur-7-yl)propionate, 0.095 gm (2.12 mMol) formamide, and 0.44 mL (0.44 mMol) sodium methoxide (1.0 M in methanol) in 3 mL dimethylformamide was heated at 100° C. for 45 minutes. The reaction mixture was diluted with ethyl acetate and the organics washed sequentially with water and saturated aqueous sodium chloride. The organics were then concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with 2:1 hexane:ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.060 gm (25%) of the desired compound.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[C:8]([I:17])=[N:7]1.[CH2:28]([N:30]([CH2:41][CH3:42])[CH2:31][CH2:32][N:33]([CH3:40])[C:34]1[S:35][CH2:36][C:37](=[O:39])[N:38]=1)[CH3:29]>>[F:1][C:2]([F:26])([F:27])[C:3]1[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:36]3[S:35][C:34]([N:33]([CH2:32][CH2:31][N:30]([CH2:41][CH3:42])[CH2:28][CH3:29])[CH3:40])=[N:38][C:37]3=[O:39])=[CH:12][CH:13]=2)[C:8]([I:17])=[N:7]1
Reactant: O=Cc1ccc2c(c1)c(I)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: CCN(CC)CCN(C)C1=NC(=O)CS1
Product: CCN(CC)CCN(C)C1=NC(=O)C(=Cc2ccc3c(c2)c(I)nn3Cc2ccc(C(F)(F)F)cc2C(F)(F)F)S1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazol-5ylmethylene]-2-[(2-diethylamino-ethyl)-methyl-amino]-thiazol-4-one was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazole-5-carbaldehyde and 2-[(2-Diethylamino-ethyl)-methyl-amino]-thiazol-4-one following General Procedure E.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:13][C@H:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[S:22]([CH3:25])(=[O:24])=[O:23])[C:11]2[C:10](=[O:26])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1.I[CH2:38][C:39]#[N:40]>O1CCCC1.O>[C:39]([CH2:38][N:13]1[C@H:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[S:22]([CH3:25])(=[O:24])=[O:23])[C:11]2[C:10](=[O:26])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:36])[F:34])[CH:28]=2)[C:4]1=[O:3])#[N:40]
Reactant: N#CCI
Reactant: CS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(C#N)ccc1[C@@H]1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1CC#N

Procedure:
Sodium hydride (60% in mineral oil, 11 mg, 0.28 mmol) is added to a solution of (S)-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-(methylsulfonyl)benzonitrile (example 18A, 50 mg, 0.10 mmol) in tetrahydrofuran (3 mL), and the mixture is stirred at room temperature for 20 min 2-Iodoacetonitrile (7 μL, 0.10 mmol) is added, and the mixture is stirred over night. Another portion of 2-iodoaceto-nitrile (7 μL, 0.10 mmol) is added, and the mixture is stirred over night. Another portion of 2-iodoacetonitrile (14 μL, 0.20 mmol) is added, and the mixture is stirred for 2 h, diluted with water and purified by preparative HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 6 mg; ESI mass spectrum [M+H]+=529; Retention time HPLC: 1.05 min (Z018_S04).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([C@H:23]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:24]1)=[N+]=[N-].O>O1CCCC1>[NH2:20][C@H:23]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[C@H:25]([CH2:35][O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:24]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])C[C@H]1COCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](N)C[C@H]1COCc1ccccc1
Yield: 53.6 %

Procedure:
Triphenylphosphine (421 mg) was added to a solution of tert-butyl (2S,4R)-4-azido-2-[(benzyloxy)methyl]pyrrolidine-1-carboxylate (455 mg) [see Preparation 33] in dry tetrahydrofuran (10 ml). The reaction mixture was then stirred until the evolution of nitrogen gas had ceased, water (0.036 ml) was added, the mixture was then stirred for a further 72 hours. The solvent was then removed under reduced pressure and the residue was dissolved in diethyl ether and hexane added until the mixture became cloudy. The supernatant liquid was separated and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 90:10, by volume, dichloromethane:methanol to afford tert-butyl (2S,4R)-4-amino-2-[(benzyloxy)methyl]pyrrolidine-1-carboxylate (225 mg) as a colourless oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OCC)C3)cc1

Procedure:
Compound dy was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with ethyl chloroformate. LC-MS: m/z=+469 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[CH:19]([CH2:20][CH3:21])[S:18][C:17](=[O:22])[NH:16][N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11].[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1)([O-:25])=[O:24]>>[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:16]2[N:15]=[C:14]([C:5]3[CH:6]=[CH:7][C:8]([O:9][C:10]([F:12])([F:13])[F:11])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:19]([CH2:20][CH3:21])[S:18][C:17]2=[O:22])=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: CCC1SC(=O)NN=C1c1ccc(OC(F)(F)F)c(OC)c1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Product: CCC1SC(=O)N(Cc2ccc([N+](=O)[O-])cc2)N=C1c1ccc(OC(F)(F)F)c(OC)c1

Procedure:
In analogy to Example 1, the reaction of 5-(3-methoxy-4-trifluoromethoxyphenyl)-6-ethyl-3,6-dihydro-1, 3,4-thiadiazin-2-one with 4-nitrobenzyl chloride ("C") gives 3-(4-nitrobenzyl)-5-(3-methoxy-4-trifluoromethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:27](Cl)([Cl:29])=[O:28]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:27]([Cl:29])=[O:28])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cl)OC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
1-Benzyloxycarbonyl-4-hydroxypiperidine (15 g., 0.0638 mole) and N,N-diisopropylethylamine (12.3 ml., 9.13 g., 0.0707 mole) were dissolved in toluene (150 ml.), and the solution was added over 30 min. to a solution of phosgene (12.63 g., 0.128 mole) in toluene (150 ml.). The reaction mixture was protected from atmospheric moisture (drying tube), stirred magnetically, and kept at ambient temperature in a water bath during the addition. When the addition was complete the mixture was filtered and the solid residue washed with toluene (ca. 50 ml.). The solvent in the combined filtrate and washings was evaporated in vacuo (1 mm. pressure, solid CO2 cold finger condenser) to give 1-benzyloxycarbonyl-4-chlorocarbonyloxypiperidine, I.R. λmax 1775 cm.-1 and 1700 cm.-1.
Reaction SMILES: O1CCOCC1.Cl.C(OC([N:15]1[CH2:19][C@@H:18]([S:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:17][C@H:16]1[C:30](=[O:33])[NH:31][CH3:32])=O)(C)(C)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][S:20][C@@H:18]2[CH2:19][NH:15][C@H:16]([C:30](=[O:33])[NH:31][CH3:32])[CH2:17]2)=[CH:27][CH:26]=1
Reactant: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
52.5 ml of a 4N dioxane solution of hydrogen chloride were added, whilst ice-cooling, to a solution of 4.00 g of (2S, 4S)-1-(t-butoxycarbonyl)-4-(4-methoxybenzylthio)-2-methylcarbamoylpyrrolidine [prepared as described in step (3) above] dissolved in 50 ml of ethyl acetate. The mixture was stirred at 0° to 50° C. for 30 minutes and then at room temperature for 2 hours. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate to make it weakly basic, and it was then extracted with ethyl acetate. The aqueous layer was saturated with ammonium chloride and then extracted with tetrahydrofuran. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluted with a 5:1 mixture by volume of ethyl acetate and methanol), to afford 2.34 g of the title compound as colorless crystals, melting at 53°-54° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])(=[O:3])[CH3:2].[CH3:13][C:14]([CH:16]([O:19][CH3:20])[O:17][CH3:18])=O.N1CCCC1>C1(C)C=CC=CC=1>[CH3:18][O:17][CH:16]([O:19][CH3:20])[C:14]1([CH3:13])[CH2:2][C:1](=[O:3])[C:4]2[CH:5]=[C:6]([C:7]#[N:8])[CH:9]=[CH:10][C:11]=2[O:12]1
Reactant: COC(OC)C(C)=O
Reactant: CC(=O)c1cc(C#N)ccc1O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: COC(OC)C1(C)CC(=O)c2cc(C#N)ccc2O1
Yield: 85.7 %

Procedure:
In 100 ml of toluene were dissolved 8.06 g (50 mmole) of 3-acetyl-4-hydroxybenzonitrile and 7.68 g (65 mmole) of pyruvic aldehyde dimethyl acetal; and, 1.67 ml (20 mmole) of pyrrolidine was added at room temperature thereto. 30 Minutes thereafter, the reactants were heated to reflux for 8 hours using Dean-Stark apparatus. The solvent was removed under reduced pressure; and, 50 ml of 2N HCl solution was added to the residue so obtained. The resultant solution was stirred for 30 minutes at room temperature, extracted with ethyl acetate (100 ml×2), washed with 50 ml of water and then with 50 ml of saturated sodium chloride aqueous solution and purified by silica gel column chromatography using as an eluent a mixture of hexane and ethyl acetate (4:1) to obtain 11.19 g (yield 86%) of the title compound as a white solid.
Reaction SMILES: CS(OC[CH:7]([C:16]1[CH:17]=[N:18][C:19]([NH:22][C:23]([C:25]2([C:28]3[CH:36]=[CH:35][C:31]4[O:32][CH2:33][O:34][C:30]=4[CH:29]=3)[CH2:27][CH2:26]2)=[O:24])=[CH:20][CH:21]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])(=O)=O.C[O:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.O1C2C=CC(C3(C(NC4C=CC(C(N(C)C)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:32]1[C:31]2[CH:35]=[CH:36][C:28]([C:25]3([C:23]([NH:22][C:19]4[CH:20]=[CH:21][C:16]([CH:7]([N:44]5[CH2:45][CH2:46][N:41]([CH2:40][CH2:39][OH:38])[CH2:42][CH2:43]5)[C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=5[O:14][CH3:15])=[CH:17][N:18]=4)=[O:24])[CH2:26][CH2:27]3)=[CH:29][C:30]=2[O:34][CH2:33]1
Reactant: COCCN1CCNCC1
Reactant: COc1ccccc1C(COS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Agent: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N(C)C
Product: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N1CCN(CCO)CC1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((4-(2-hydroxyethyl)piperazin-1-yl)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from (6-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)ethyl methanesulfonate and 1-(2-methoxyethyl)piperazine in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((dimethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.