Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]1([CH2:15][CH3:16])[CH2:14][O:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:20]([F:37])=[C:21](/[CH:25]=[C:26](/[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])\[C:27]#[N:28])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[CH:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[C:20]=2[F:37])[C:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])([C:27]#[N:28])[CH:9]([CH2:10][C:11]2([CH2:15][CH3:16])[CH2:12][O:13][CH2:14]2)[NH:8]1)=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC1(C/C=N/CC(=O)OC(C)(C)C)COC1
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: CCC1(CC2NC(C(=O)OC(C)(C)C)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)COC1
Yield: 58.5 %

Procedure:
In a manner similar to the method described in Example 100b, [2-(3-ethyl-oxetan-3-yl)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 113a (1.9 g, 7.8 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.9 g, 6.2 mmol) prepared in Example 52a, AgF (1.2 g, 9.5 mmol), and triethylamine (2.2 mL, 16 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (7.5 ml) in tert-butanol (10 mL) at 100° C. for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white solid (2 g, 58%).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH:19]=[C:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].C(OC(C1CC(C(OCC)=O)=C(C)NC=1C)=O)C>C1(C)C=CC=CC=1>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH2:19][CH:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][CH:16]=2)=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Oc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Reaction time: 5 h
Yield: 79.4 %

Procedure:
98 g (0.23 mole) 5-(4-[2-(4-methanesulfonyloxyphenyl)ethoxy]benzylidene)thiazolidine-2,4-dione and 89 g (0.35 mole) diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate was heated under reduced pressure until it melted (160° C.). The reaction mixture was allowed to stay at this temperature for 5 hours. The reaction mixture was then taken off the heat and toluene was added when the temperature was below 100° C. The crystals were collected and washed with diethyl ether and recrystallized in toluene to give 77 g (yield 79%) of the desired product.
Reaction SMILES: [C:1](N)(=O)[CH:2]([CH:4]([C:6](N)=O)[OH:5])O.[CH:11]1[CH:12]=[CH:13][C:14]2[C:15](=CC=CC=2O)[CH:16]=1>CO>[CH:2]1[C:1]2[C:12](=[CH:11][CH:16]=[CH:15][CH:14]=2)[CH:13]=[CH:6][C:4]=1[OH:5]
Reactant: NC(=O)C(O)C(O)C(N)=O
Reactant: Oc1cccc2ccccc12
Solvent: CO
Product: Oc1ccc2ccccc2c1
Yield: 36.8 %

Procedure:
4.80 g of (+)-tartaric acid diamide (VI) and 1.44 g of naphthol (α:β=1 : 1) were dissolved in 10 ml of methanol by heating, and the thus-obtained solution was allowed to stand for 12 hours at room temperature, with 2.3 g of a clathrate compound (colorless needle-like crystal, mp. 199-204° C.) containing tartaric acid diamide (VI) and 8 -naphthol in a ratio of 1 : 1 being crystallized. When the tartaric acid diamide (VI) was separated from the clathrate compound by column chromatography, 0.53 g of β-naphthol was obtained. (Function and Effect of the Invention)
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[C:19]([C:26]3[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=3)=[CH:18]2)(=O)=O)C=CC=CC=1>>[CH:1]1([NH:7][C:28]2[N:27]=[C:26]([C:19]3[C:20]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[NH:17][CH:18]=3)[CH:31]=[CH:30][N:29]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: NC1CCCCC1
Product: c1cnc2[nH]cc(-c3ccnc(NC4CCCCC4)n3)c2c1
Yield: 41.7 %

Procedure:
Using the procedure of example 1, cyclohexylamine (88 mg) was reacted with compound 1f (100 mg) to provide compound 13 (33 mg, 42%). 1H NMR (400 MHz, CD3OD) δ 8.91 (d, J=8.4 Hz, 1H), 8.26 (d, J=4.8 Hz, 1H), 8.16 (s, 1H), 8.10 (d, J=5.6 Hz, 1H), 7.22 (dd, J=8.0 Hz, 4.8 Hz, 1H), 6.97 (d, J=5.6 Hz, 1H), 3.86 (m, 1H), 2.13-1.27 (m, 10H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([S:11](Cl)(=[O:13])=[O:12])[S:8][C:9]=1[CH3:10].[NH3:15]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([S:11]([NH2:15])(=[O:13])=[O:12])[S:8][C:9]=1[CH3:10]
Reactant: N
Reactant: COCCc1cc(S(=O)(=O)Cl)sc1C
Solvent: ClCCl
Product: COCCc1cc(S(N)(=O)=O)sc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 118 %

Procedure:
To a solution of the above prepared 4-(2-methoxy-ethyl)-5-methyl-thiophene-2-sulfonyl chloride (4.59 g, 18 mmol) in DCM (18 mL) were added 25% aqueous NH3 (9 mL, ˜120 mmol) and the biphasic reaction mixture was vigorously stirred at rt for 3 h. After the addition of DCM (120 mL) the reaction mixture was washed with H2O (2×120 mL) and the aqueous layers were extracted with DCM (50 mL). The combined organic layers were dried (Na2SO4) and evaporated affording 5.0 g crude product as a yellow viscous oil which was purified by chromatography over silica with hexane-ethyl acetate 2:1 providing 3.62 g (85% GC 96.3%) yellow viscous oil. ESI-MS (m/z) 253 (M+NH4+, 100).
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][CH:8]([C:11]([CH3:19])([CH3:18])[O:12][SiH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:29](Cl)([CH3:32])(=[O:31])=[O:30]>ClCCl.O.C(OCC)(=O)C>[C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][CH:8]([C:11]([CH3:19])([CH3:18])[O:12][SiH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][O:10][S:29]([CH3:32])(=[O:31])=[O:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[SiH2]OC(C)(C)C(CO)CO[Si](C)(C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[SiH2]OC(C)(C)C(CO[Si](C)(C)C(C)(C)C)COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.2 %

Procedure:
Ex-50A: To a solution of 3-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-silanyloxymethyl)-propan-1-ol (25.0 g, 74.3 mmol) and triethylamine (22.6 g, 223 mmol) in dichloromethane (150 mL) at 0° C. was added mesyl chloride (12.8 g, 111 mmol) and the resulting slurry was stirred at 0° C. for 15 min and allowed to warm to rt. The solution was stirred for an additional 3 h at rt and diluted with water (130 mL) and ethyl acetate (350 mL). The layers were separated and the aqueous was extracted with ethyl acetate (1×150 mL). The combined organic extracts were washed with a saturated sodium bicarbonate (1×200 mL), a 50% sodium chloride solution (2×200 mL), dried over sodium sulfate and concentrated to afford 29.5 g (97%) of the expected methanesulfonic acid 3-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-silanyloxymethyl)-propyl ester as a yellow oil, 97% yield. 1H-NMR (300 MHz, CDCl3) δ 4.29 (d, 2H, J=5.7 Hz), 3.61–3.68 (m, 4H), 2.99 (s, 3H), 2.04–2.11 (m, 1H), 0.88 (s, 18H), 0.049 (s, 12H). HRMS (ESI) Calcd. for C17H40O5SSi2: 413.2213. Found 413.2226.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]([O:10][CH2:11][C@H:12]([CH3:34])[O:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:22]=1)[C:17]([OH:19])=[O:18])([CH3:9])([CH3:8])[CH3:7]>CC(OC)(C)C>[C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]([O:10][CH2:11][C@H:12]([CH3:34])[O:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:22]=1)[C:17]([O:19][NH2+:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:18])([CH3:9])([CH3:8])[CH3:7]
Reactant: C[C@@H](COC(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Solvent: COC(C)(C)C
Solvent: CC(C)(C)N
Product: C[C@@H](COC(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O[NH2+]C(C)(C)C)c1
Temperature: 25 °C
Yield: 181.5 %

Procedure:
A solution of tert-butylamine was prepared by charging tert-butylamine (0.31 L, 2.94 mol) to a reaction vessel containing MTBE (2.27 L). The solution was stirred at ambient temperature and then charged into a second reaction vessel containing 3-[(1S)-2-tert-butoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]benzoic acid (1.13 Kg, 267 mol) and MTBE (2.54 L). The temperature was maintained between 20-30° C. during the addition, the residual tert-butylamine was washed in with MTBE (0.57 L). The reaction mixture was heated to 38-40° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to 18-25° C. over 1-2 hours and then held until crystallisation occurred. The product was isolated by filtration washed twice with MTBE (2.28 L), and dried in a vacuum oven at 38-40° C. This resulted in (1.32 Kg, 100% yield) of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[C:10]([Cl:13])[CH:11]=2)[NH:6][C:5]=1[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[N:22]([CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[C:10]([Cl:13])[CH:11]=2)[NH:6][C:5]=1[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(Cl)cc2c1CCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(Cl)cc2c1CCN=[N+]=[N-]
Temperature: 70 °C
Reaction time: 4 h
Yield: 100.3 %

Procedure:
A mixture of 3-(2-bromoethyl)-5,6-dichloro-2-(triethylsilyl)-1H-indole (0.548 g; 1.35 mmol) and sodium azide (0.262 g; 4.04 mmol) in DMF (8 mL) was stirred at 70° C. for 4 hours and concentrated under reduced pressure. The residue was diluted in ethyl acetate, washed with brine, dried and concentrated under reduced pressure to afford 0.500 g (quantitative yield) of the title compound as a brown oil.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29](O)=[O:30])[CH2:19][C:20]3[CH:25]=[C:24]([Br:26])[C:23]([OH:27])=[C:22]([Br:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:67][S:68]([N:71]1[CH2:76][CH2:75][CH:74]([CH:77]2[CH2:82][CH2:81][NH:80][CH2:79][CH2:78]2)[CH2:73][CH2:72]1)(=[O:70])=[O:69]>C1COCC1.CCOC(C)=O>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:21]=[C:22]([Br:28])[C:23]([OH:27])=[C:24]([Br:26])[CH:25]=3)[C:29]([N:80]3[CH2:79][CH2:78][CH:77]([CH:74]4[CH2:73][CH2:72][N:71]([S:68]([CH3:67])(=[O:70])=[O:69])[CH2:76][CH2:75]4)[CH2:82][CH2:81]3)=[O:30])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1
Reactant: CS(=O)(=O)N1CCC(C2CCNCC2)CC1
Reactant: O=C(O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(C2CCN(C(=O)[C@@H](Cc3cc(Br)c(O)c(Br)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 130 mg (0.21 mmol) of (R)-1-carboxy-2-(3,5-dibromo-4-hydroxy-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 80 mg (0.25 mmol) TBTU and 50 μL (0.27 mmol) ethyldiisopropylamine in 10 mL THF was stirred for 50 min at RT. Then 60 mg (0.24 mmol) 1-methanesulphonyl-[4,4′]bipiperidinyl were added and the reaction mixture was stirred overnight at RT. The reaction solution was diluted with 50 mL EtOAc, extracted twice with 30 mL 15% K2CO3 solution, the organic phase was separated off and dried over MgSO4. After the desiccant and solvent had been eliminated the residue was triturated with water and filtered. The solid was combined with 5 mL 1 M HCl and stirred overnight. Further purification of the crude product was carried out by chromatography (silica gel, gradient DCM to DCM/MeOH/NH3 50:45:5). The fractions containing the product were combined, evaporated down i.vac., triturated with DIPE, suction filtered and dried at 40° C.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:29][CH:30]1[CH:35]=[C:34]([CH3:36])[CH2:33][CH2:32][CH:31]1[CH:37]=O>>[CH3:29][CH:30]1[CH:35]=[C:34]([CH3:36])[CH2:33][CH2:32][CH:31]1[CH:37]=[CH:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC1=CC(C)C(C=O)CC1
Agent: [Br-]
Product: CC1=CC(C)C(C=CCc2ccccc2)CC1
Yield: 61.4 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (3.67 g, 8.20 mmol, 1.0 equiv.), n-Buli (1.6 M in hexanes, 5.1 mL, 8.20 mmol, 1.0 equiv.) and 2,4-dimethylcyclohex-3-enecarbaldehyde (1.70 g, 12.3 mmol, 1.5 equiv.), 1.14 g (61%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane).
Reaction SMILES: N1C2CCNCCC=2C=C[CH:2]=1.[Br:12][C:13]1[CH:14]=[N:15][C:16]2[N:17]([N:19]=[C:20]([C:22]([N:24]3[CH2:30][CH2:29][C:28]4[N:31]=[CH:32][NH:33][C:27]=4[CH2:26][CH2:25]3)=[O:23])[CH:21]=2)[CH:18]=1.CI.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:12][C:13]1[CH:14]=[N:15][C:16]2[N:17]([N:19]=[C:20]([C:22]([N:24]3[CH2:30][CH2:29][C:28]4[N:31]=[CH:32][N:33]([CH3:2])[C:27]=4[CH2:26][CH2:25]3)=[O:23])[CH:21]=2)[CH:18]=1
Reactant: c1cnc2c(c1)CCNCC2
Reactant: O=C(c1cc2ncc(Br)cn2n1)N1CCc2nc[nH]c2CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cnc2c1CCN(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
75.0 mg (0.21 mmol) 6 (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl)-methanone, 13.0 μL (0.21 mmol) methyliodide, 35.0 mg (0.25 mmol) potassium carbonate in 1.0 mL DMF were stirred at RT overnight. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 12 mg (15% of theory). ESI-MS: m/z=375 (M+H)+; Rt(HPLC): 0.71 min. (Method K).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][O:10][CH2:11][O:12][CH3:13].[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)#[N:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)=[CH:4][C:3]=1[CH2:9][O:10][CH2:11][O:12][CH3:13]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: COCOCc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOCc1cc(OCc2ccc(C#N)cc2)ccc1Br
Temperature: 70 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
A mixture of 4-bromo-3-(methoxymethoxymethyl)phenol (2.47 g, 10.0 mmol), 4-cyanobenzyl bromide (1.88 g, 9.50 mmol), and potassium carbonate (1.66 g, 12.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 70° C. for overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 4-[4-bromo-3-(methoxymethoxymethyl)phenoxymethyl]benzonitrile (1.88 g, 95%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([O:9][CH2:10][CH2:11]Br)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:15]1([N:21]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:22](=[O:25])[CH2:23][CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([O:9][CH2:10][CH2:11][N:29]2[CH2:28][CH2:27][CH:26]([N:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:22](=[O:25])[CH2:23][CH3:24])[CH2:31][CH2:30]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(OCCBr)cc1
Reactant: CCC(=O)N(c1ccccc1)C1CCNCC1
Product: CCC(=O)N(c1ccccc1)C1CCN(CCOc2ccc(NC(C)=O)cc2)CC1

Procedure:
Using the procedure of Example I step B and starting from (4-acetamidophenoxyethyl) bromide and 4-(N-phenyl N-propionylamino) piperidine, N-[(4-acetamidophenoxy) ethyl] 4-(N'-phenyl N'-propionylamino) piperidine is obtained which melts at 78°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH:21]([CH3:24])[CH2:22][CH3:23]>CC(C)=O>[CH3:20][CH:21]([CH2:22][CH3:23])[CH2:24][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: CCC(C)CI
Reactant: COC(=O)c1cc([N+](=O)[O-])c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(C)Cn1cc([N+](=O)[O-])cc1C(=O)OC
Temperature: 25 °C
Yield: 70 %

Procedure:
Methyl 3-nitropyrrole-2-carboxylate (22) (2.7 g, 15.9 mmol), potassium carbonate (6.5 g), and iodo-2-methylbutane (5.2 ml) were dissolved in 100 ml of acetone and refluxed for 10 hours. The reaction mixture was then cooled to room temperature, concentrated in vacuo, partitioned between 200 ml of dichloromethane and 200 ml of water and extracted with dichloromethane (2×200 ml). The combined organic layers were dried (sodium sulfate) and concentrated in vacuo. The resulting yellow oil was purified by flash chromatography to provide the substituted nitro pyrrole 23 (2.5 g, 70% yield). 1H NMR (DMSO-d6) δ 8.30 (d, 1 H, J=2.0 Hz), 7.33 (d, 1 H, J=1.9 Hz), 4.15 (d, 2 H, J=7.4 Hz), 3.77 (s, 3 H), 2.03 (m, 1 H, J=3.1 Hz), 0.80 (d, 6 H, J=6.7 Hz); 13C NMR (DMSO-d6) δ 160.30, 134.79, 129.80, 122.40, 112.76, 105.00, 56.63, 52.41, 29.72, 19.73; FABMS, 226.096 calcd, 226.095 found.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]2[CH2:15][C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7]2)=[CH:4][CH:3]=1.Cl>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7]2)=[CH:17][CH:18]=1
Reactant: O=C1CC(c2ccc(Cl)cc2)Oc2ccccc21
Agent: Cl
Solvent: CC(=O)O
Product: Clc1ccc(C2CCc3ccccc3O2)cc1
Reaction time: 1 h

Procedure:
4'-Chloroflavanone (4.0 g.) was dissolved in acetic acid (150 ml.) and concentrated hydrochloric acid (20 ml.) and added to wet zinc amalgam (prepared from zinc powder (80 g.) and mercuric chloride (6.4 g.)). The reaction mixture was stirred for 1 hr. then allowed to stand overnight. The residual zinc was filtered off and washed with water, and the filtrate and washings combined and diluted with water. The oily product was extracted into ether, and the extract washed with water and saturated sodium bicarbonate solution; it was dried with magnesium sulphate, filtered and evaporated, and the residue chromatographed on alkaline alumina, eluting with toluene. The eluate was evaporated and the residue recrystallised from ethanol, to give 4'-chloroflavan, m.p. 76°-77° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[F:13][C:14]1[CH:15]=[C:16]([CH:20]=O)[CH:17]=[N:18][CH:19]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)[CH:17]=[N:18][CH:19]=1
Reactant: O=Cc1cncc(F)c1
Reactant: O=C(O)CNC(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(c2cccs2)=NC1=Cc1cncc(F)c1
Temperature: 90 °C
Yield: 68.1 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 5-fluoro-3-pyridinecarboxaldehyde (41 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 56 mg of the above-captioned compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][CH2:25][CH2:26][C:27](OCC)=[O:28].[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:26]([CH2:25][CH2:24][C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)[C:27]2=[O:28])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCCc1cccs1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCc2cccs2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 4-(2-thienyl)butanoate (1.5 eq., prepared in Synthetic Example 17) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[2-(2-thienyl)ethyl]-1,8-naphthyridin-2(1H)-one, mp 175 to 176° C./DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: C(N(CCCC)CCCC)CCC.[OH:14]N1C2C=CC=CC=2N=N1.[CH:24]1([N:30]=[C:31]=[N:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:31]([NH:30][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)([NH:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:14]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: On1nnc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
[3S-[3α(Z),4β]]-3-[[(2-Amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (2.18 g), 0.93 g of tributylamine, 0.1 g of N-hydroxybenzotriazole and 0.05 g of 4-dimethylaminopyridine were dissolved in 20 ml of dimethylformamide and a solution of 1.06 g of dicyclohexylcarbodiimide in 5 ml of dimethylformamide was added. After stirring for 15 minutes at room temperature, a solution of 0.94 g Girard Reagent P in 20 ml of dimethylformamide was added. After 3 hours of stirring, formed dicyclohexylurea was filtered off and the dimethylformamide of the filtrate was distilled off. Addition of 50 ml of tetrahydrofuran to the residue yielded 1.8 g of crude product, which was purified by column chromatography on HP-20 using water as an eluent, yielding 0.63 g of product, melting point 235° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:13]1([S:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NS(=O)(=O)c2ccccc2)cc1
Reaction time: 3 h
Yield: 78.9 %

Procedure:
5 g (30.3 mmol) of ethyl 4-aminobenzoate were dissolved in 100 ml of pyridine and admixed dropwise at 0° C. with 4.1 ml (31.8 mmol) of benzenesulfonyl chloride. The mixture was stirred for 3 h. The mixture was then concentrated under reduced pressure and the residue was recrystallized from ethanol. 7.3 g (85%) of the product were obtained.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:35])[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: O=C(N[C@@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: CCOC(=O)N1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A142) and ethyl chloroformate the title compound is obtained as colorless solid.