Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:29][CH:28]=1)[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20]C2CCCCO2)=[CH:16][CH:15]=1)[CH3:13])(=[O:10])=[O:9].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([CH:12]([C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[CH3:13])[C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:31][CH:32]=1)(=[O:9])=[O:10]
Reactant: CC(c1ccc(OC2CCCCO2)cc1)N(c1ccc(OCCN2CCCC2)cc1)S(=O)(=O)c1ccccc1Cl
Agent: Cl
Solvent: CCO
Product: CC(c1ccc(O)cc1)N(c1ccc(OCCN2CCCC2)cc1)S(=O)(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.7 %

Procedure:
To a solution of 2-chloro-N-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-N-{1-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-ethyl}-benzenesulfonamide (0.088 g, 0.150 mmol) in absolute ethanol (4.0 mL) was added HCl (1.2N, 0.8 mL). The reaction was stirred at room temperature overnight. The reaction mixture was quenched with sat. sodium bicarbonate solution (ca. 10 mL) and extracted with methylene chloride (2×10 mL). The combined organic layers were dried (sodium sulfate), filtered and concentrated. The residue was purified by preparative TLC (SiO2, 10% methanol/ethyl acetate) to afford the title compound (0.007 g, 14.6 μmol). MS 501.4 (M+1)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:17][C:18](=[O:20])[CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: OC(Cc1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(Cc1ccc(Br)cc1)c1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
A mixture of 1,2-di(p-bromophenyl)-hydroxyethane (7.2 g, 0.02 mol), acetic anhydride (20 mL, 0.2 mol), pyridine (20 mL) was stirred at 60° C. for 30 min. The solution was then allowed to stand at room temperature for 2 days. The mixture was poured into ice water (250 g) and extracted with methylene chloride (150 mL). The organic phase was extracted with 5% aqueous sodium carbonate (100 mL×2), 5% aqueous hydrochloric acid (100 mL×2), water (100 mL×2), dried over sodium sulfate and concentrated to give an oil (5.5 g) which solidified upon standing. This was purified by passing through a short alumina column followed by recrystallization from hexanes to give the above white solid product (4.2 g): mp: 61-64° C.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]2[C:18](=O)[C:17](=[O:20])[C:16]=2[O:21]C)[N:9]=1)[C:2]([NH2:4])=[NH:3].[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.CO>CN(C)C=O>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]2[C:16](=[O:21])[C:17](=[O:20])[C:18]=2[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: COc1c(NCCSCc2csc(NC(=N)N)n2)c(=O)c1=O
Reactant: NCc1ccncc1
Solvent: CN(C)C=O
Solvent: CO
Product: N=C(N)Nc1nc(CSCCNc2c(NCc3ccncc3)c(=O)c2=O)cs1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of 1-[2-(2-guanidinothiazol-4-ylmethylthio)ethylamino]-2-methoxycyclobutene-3,4-dione (0.17 g), 4-aminomethylpyridine (0.054 g), methanol (5 ml) and dimethyl formamide (3 ml) was stirred at room temperature for seven days. Evaporation of the solution gave a yellow oil which crystallized on scratching; this was triturated with ethanol and filtered to give 1-[2-(2-guanidinothiazol-4-ylmethylthio)ethylamino]-2-(4-pyridylmethylamino)cyclobutene-3,4-dione, m.p. 172°-175°.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:44][S:45]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:18][CH2:19]1)(=[O:47])=[O:46]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)n1nc(C(=O)NCCN2CCC(NS(C)(=O)=O)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.330 g, 1 mmol) and triethylamine (0.15 mL, 1.05 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added dropwise methanesulfonyl chloride (0.08 mL, 1 mmol) and the resulting mixture was stirred 18 h at room temperature. The mixture was filtered and the filtrate was evaporated to 0.401 g oil. Flash chromatography [silica gel, methylene chloride/methanol (90/10)] yielded 0.147 g oil. Crystallization as the oxalate salt from ethyl acetate/methanol provided 0.149 g colorless crystals. Mp 204° C. Mass Spectrum, m+ =407. Exact mass theory, 408.2069; found, 408.2066.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]([O:18]C)=[O:17])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[OH-].[Na+].CCOC(C)=O.O>O1CCOCC1>[O:4]1[C:5]2([CH2:6][CH2:7][N:8]([C:11]([NH:13][C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]([OH:18])=[O:17])=[O:12])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: COC(=O)c1ccccc1NC(=O)N1CCC2(CC1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1NC(=O)N1CCC2(CC1)OCCO2
Reaction time: 1 h

Procedure:
A solution of methyl 2-(1,4-dioxa-8-azaspiro[4.5]decan-8-ylcarbonyl)aminobenzoate (2.00 g, 6.25 mmol) in dioxane (30 mL) was treated with 5 N NaOH (12.5 mL). After 1 h, the mixture was poured into EtOAc and water, and the aqueous layer was washed with EtOAc. The pH of the aqueous layer was then adjusted to 2–3 by addition of 5 N HCl and washed with EtOAc (3×). The combined organic layers were washed with brine, dried with sodium sulfate, and concentrated, yielding the title compound; which was used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][C:12](=[O:33])[C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([C:28](=[O:32])[CH2:29]2)[C@:25]2([CH3:26])[C@H:20]([CH2:21][CH:22]=[CH:23][CH2:24]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)(=O)C.O>CO>[OH:10][CH2:11][C:12](=[O:33])[C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([C:28](=[O:32])[CH2:29]2)[C@:25]2([CH3:26])[C@H:20]([CH2:21][CH:22]=[CH:23][CH2:24]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1
Reactant: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@]12CC=CC[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CO)[C@@]3(C)CC(=O)[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of potassium carbonate in methanol (190 ml; 0.19M) was added to a suspension of (5α)-21-(acetyloxy)pregn-2-ene-11,20-dione and its 3-ene-isomer (18.8 g) in methanol (188 ml). The resulting solution was stirred at room temperature for 30 min and poured into water (3.7 l). The mixture was extracted with dichloromethane and the organic phase was washed with water, dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel to give a mixture (3:1) (15.3 g) of (5α)-21-hydroxypregn-2-ene-11,20-dione and its 3-ene-isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][C:7]2[N:8]=[C:9]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:10]3[N:15]=[C:14]([C:16]4[CH:30]=[C:29]([CH3:31])[C:19]([O:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[C:18]([CH3:32])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:10]3[N:15]=[C:14]([C:16]4[CH:17]=[C:18]([CH3:32])[C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[C:29]([CH3:31])[CH:30]=4)[O:13][C:11]=3[N:12]=2)=[CH:37][CH:38]=1
Reactant: Cc1cc(-c2nc3c(CC(C)C)nc(Cc4ccc(Cl)cc4)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2nc3c(CC(C)C)nc(Cc4ccc(Cl)cc4)nc3o2)cc(C)c1OCC(=O)O
Yield: 100 %

Procedure:
Analogously to example 1 (j), the reaction of 784 mg of tert-butyl {4-[5-(4-chlorobenzyl)-7-isobutyloxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenoxy}acetate with trifluoroacetic acid gave 702 mg (100%) of the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][NH:12][C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:23]([F:26])([F:25])[F:24].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:22]=4[C:23]([F:26])([F:25])[F:24])[C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: FC(F)(F)c1ccncc1Br
Reactant: O=C1NCCN1c1ccc2ncsc2c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2ccc3ncsc3c2)CCN1c1cnccc1C(F)(F)F
Yield: 2.8 %

Procedure:
Using the same reaction conditions as in Example 14, 1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 150 mg, 0.684 mmol) was reacted with 3-bromo-4-trifluoromethyl-pyridine (185.75 mg, 0.822 mmol), 1,4-dioxane (10 mL), copper iodide (12.99 mg, 0.0684 mmol), trans-1,2-diamino cyclohexane (23.37 mg, 0.205 mmol) and potassium phosphate (435 mg, 2.052 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in CHCl3), followed by preparative HPLC afforded 7 mg of the product (12.04% yield).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[C:13]12([CH2:23][NH:24][CH2:25][CH2:26][CH:27]([OH:32])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.CCN(CC)CC>C(Cl)Cl>[C:13]12([CH2:23][N:24]3[CH2:25][CH2:26][CH:27]([CH2:28][CH:29]([CH3:30])[CH3:31])[O:32][C:2]3=[O:4])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)CC(O)CCNCC12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC1CCN(CC23CC4CC(CC(C4)C2)C3)C(=O)O1
Reaction time: 1 h
Yield: 218.3 %

Procedure:
A solution of triphosgene (35 mg, 0.12 mmol) in anhydrous CH2Cl2 (500 μL) was added slowly to a solution of 1-(1-adamantylmethylamino)-5-methylhexan-3-ol (100 mg, 0.36 mmol) and Et3N (50 μl, 0.257 mmol) in anhydrous CH2Cl2 (2 mL) at 0° C. The reaction mixture was stirred for 1 h. Solvent was removed and the residue was purified by preparative TLC to give 3-((1-adamantyl)methyl)-6-isobutyl-1,3-oxazinan-2-one (80 mg, 74%). 1H NMR (MeOD, 400 MHZ): δ=0.93-0.98 (q, 6H), 1.35-1.44 (m, 1H), 1.50-2.08 (m, 18H), 2.87-2.94 (d, 1H), 3.12-3.20 (d, 1H), 3.30-3.40 (m, 1H), 3.49-3.61 (m, 1H), 4.35-4.45 (m, 1H); MS m/z=306.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4].[CH2:15]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)C>[CH2:15]([CH:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)=[O:4])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1ccc([N+](=O)[O-])cc1

Procedure:
The title compound is prepared from 2-chloro-N-(4-nitro-phenyl)-acetamide [J. Amer. Chem. Soc. 45, 1997. (1923)] and 4-benzyl-piperidine according to the method described in Example 142b. Melting Point: 126-128° C. (diethylether)
Reaction SMILES: O[C@@:2]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([C:21]([NH:23][CH3:24])=[O:22])[CH:15]=[CH:14]2)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH2:3][CH2:4]O.C(N(C(C)C)C(C)C)C.CS(Cl)(=O)=[O:36].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.C(OCC)(=O)C>[OH:36][C:10]1[N:9]=[CH:8][N:7]2[CH2:4][CH2:3][C@@H:2]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[CH:17]=[C:16]([C:21]([NH:23][CH3:24])=[O:22])[CH:15]=[CH:14]4)[C:6]=12
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)c1ccc2cc([C@@](O)(CCO)c3c[nH]cn3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2cc([C@@H]3CCn4cnc(O)c43)ccc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
To a solution of 6-[(1S)-1,3-dihydroxy-1-(1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide (1.0 g, 3.1 mmol) in tetrahydrofuran (100 mL) were added N-ethyldiisopropylamine (2.39 g, 18.4 mmol) and methanesulfonyl chloride (2.11 g, 18.4 mmol) at room temperature. The mixture was stirred at the same temperature for 3 hr. To the reaction mixture was added a solution of sodium carbonate (1.31 g, 12.3 mmol) in water (3 mL). The mixture was heated to 60° C. and stirred for 5 hr. After the reaction mixture was allowed to cool to room temperature, ethyl acetate (25 mL) was added thereto. The organic layer was separated and concentrated under reduced pressure. Methanol (16.7 mL) and water (6.4 mL) were added to the residue. The mixture was heated to 65° C., and activated carbon (45 mg) was added thereto. After stirring at the same temperature for 30 min, the activated carbon was filtered off and washed with methanol (1.1 mL). Water (6.4 mL) was added to the filtrate at 55° C. The resulting mixture was allowed to cool to room temperature and stirred for 30 min. To the mixture was added water (6.4 mL) at the same temperature, and the mixture was stirred for 2 hr. The mixture was cooled to 0° C. and stirred for 2 hr. The obtained precipitated crystals were collected by filtration, washed with 45% aqueous methanol (3 mL), and dried under reduced pressure to give 6-((7S)-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide (540 mg, 1.8 mmol). yield 57%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH2:39]([O:38][C:36](=[O:37])[C:28]1[CH:29]=[C:30]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:25])[C:10]([C:16]3[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)([OH:15])[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=2)[CH:31]=[CH:32][C:27]=1[Cl:26])[CH3:40]
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Reactant: CCOC(=O)c1cc(B(O)O)ccc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Oc2ccc(C(C)C(O)(c3cc(C)c(=O)n(C)c3)C(F)(F)F)c(Cl)c2)ccc1Cl

Procedure:
In analogy to Example 151, step 8, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5) was reacted with 4-chloro-3-ethoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as an off-white solid. MS (m/e)=558.2 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:35](OCC)[O:36]CC)=[C:5]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9]>CC(C)=O.Cl>[CH3:1][C:2]1[NH:3][C:4]([CH:35]=[O:36])=[C:5]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9]
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(=O)OCCOCc2ccccc2)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCCOCc2ccccc2)C1c1ccccc1[N+](=O)[O-]
Yield: 94.3 %

Procedure:
Starting from a mixture of an oil (2.5 g) of 2-benzyloxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate in acetone (25 ml) and 6N hydrochloric acid (2 ml) was obtained a reddish oil (2.05 g) of 2-benzyloxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate, in a substantially similar manner to that of Example 2-(6).
Reaction SMILES: Cl[C:2]1([C:15]([NH2:17])=[O:16])[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]3OCO[C:8]3=[CH:9]2)=[N:4][CH2:3]1.[NH2:18][C:19]1[C:20]([CH3:27])=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][OH:23].C(O)(=O)C>CN(C=O)C.O>[OH:23][CH2:22][C:21]1[C:20]([CH3:27])=[C:19]([CH:26]=[CH:25][CH:24]=1)[NH:18][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:15]([NH2:17])=[O:16]
Reactant: NC(=O)C1(Cl)C=c2cc3c(cc2=NC1)OCO3
Reactant: Cc1c(N)cccc1CO
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CO)cccc1Nc1c(C(N)=O)cnc2ccccc12
Yield: 87.5 %

Procedure:
A mixture of 3-Chloro-6,7-methylenedioxy-3-quinolinecarboxamide (106 mg, 0.42 mmol); 3-amino-2-methylbenzylalcohol (72 mg, 0.52 mmol) and acetic acid (100 μL) in DMF (2 ml) was heated at 100° C. for 6 h. After cooling, the mixture was diluted with water (20 ml) and washed twice with ethyl acetate. The aqueous phase was made alkaline with 1 M NaOH and the resulting precipitate was collected by filtration, washed with water and dried to give the title compound (113 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:37])=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:15](=[O:33])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH2:27][CH2:28][OH:29])[CH:24]=2)[N:19]([C:30]([NH2:32])=[O:31])[CH:18]=1)=[O:8].CCN(CC)CC.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl>[C:30]([N:19]1[C:20]2[C:25](=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][S:46]([CH3:45])(=[O:48])=[O:47])=[CH:22][CH:21]=2)[C:17]([CH2:16][C:15]([N:10]2[C@H:9]([C:7](=[O:8])[NH:6][CH2:5][C:4]3[CH:34]=[CH:35][CH:36]=[C:2]([Cl:1])[C:3]=3[F:37])[CH2:14][C@@H:13]3[C@H:11]2[CH2:12]3)=[O:33])=[CH:18]1)(=[O:31])[NH2:32]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)n1cc(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(OCCO)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccc2c(c1)c(CC(=O)N1[C@@H]3C[C@@H]3C[C@H]1C(=O)NCc1cccc(Cl)c1F)cn2C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 453: 3-{2-[(1R,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl}-5-(2-hydroxy-ethoxy)-indole-1-carboxylic acid amide (45 mg, 0.08 mmol) and Et3N (56 μL, 0.41 mmol) in CH2Cl2 (1 mL) at 0° C. was added methanesulfonyl chloride (31 μL, 0.41 mmol) and the white suspension was stirred at RT under nitrogen overnight. Et3N (56 μL, 0.41 mmol) and methanesulfonyl chloride (31 μL, 0.41 mmol) were added and the mixture was further stirred for 1.5 h to complete the reaction. The reaction mixture was quenched by addition of saturated aqueous NaHCO3, extracted with CH2Cl2, dried (Na2SO4) and evaporated in vacuo. The crude residue was purified by column chromatography on silica gel (eluent: EtOAc to EtOAc/acetone 1-1). TLC, Rf (EtOAc)=0.2; MS (UPLC/MS): 607.4/609.3 [M+H]+, 629.2/631.2 [M+Na]+, 562.2/564.1 [M−CONH2]−, 651.3/653.3 [M+HCOO]−; tR (HPLC conditions f): 1.88 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[Li]CCCC.[O:20]1[CH2:23][C:22](=[O:24])[CH2:21]1>C1COCC1>[N:10]1([N:9]=[N:8][C:5]2[CH:6]=[CH:7][C:2]([C:22]3([OH:24])[CH2:23][O:20][CH2:21]3)=[CH:3][CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C1COC1
Reactant: Brc1ccc(N=NN2CCCC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(N=NN3CCCC3)cc2)COC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
To a solution of 1-((4-bromophenyl)diazenyl)pyrrolidine (500 mg, 1.97 mmol) in anhydrous THF (20 mL) was added n-BuLi (1.8 mL, 4.33 mmol) dropwise at −78° C. under N2. The solution was stirred at −78° C. for 1 h, followed by the addition of oxetan-3-one (326 mg, 4.53 mmol). The resultant mixture was stirred at RT for 18 h. The reaction was quenched by saturated aqueous NH4Cl aq. (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic layers were concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (DCM:MeOH=20:1) to afford the title compound (500 mg, yield 97%) as a light yellow solid. MS (ES+) C13H17N3O2 requires: 247, found 248 [M+H]+, purity: 90%.
Reaction SMILES: C([Mg]Br)C.[CH3:5][CH:6]([CH2:9][CH3:10])[C:7]#[CH:8].[CH3:11][C:12]([CH3:22])([C:14](=[O:21])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[CH3:13].[Cl-].[NH4+]>C(OCC)C.ClCCl>[CH3:13][C:12]([CH3:22])([C:14]([OH:21])([C:8]#[C:7][CH:6]([CH3:5])[CH2:9][CH3:10])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[CH3:11]
Reactant: CC(C)(C)C(=O)Cn1cncn1
Reactant: C#CC(C)CC
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(C)C#CC(O)(Cn1cncn1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
10 To a solution of ethyl magnesium bromide (20 ml) of a 3M solution in diethyl ether) in dry diethyl ether (30 ml) under N2 at room temperature was added a solution of 3-methyl-1-pentyne (5 g, 0.06 mol) in diethyl ether (20 ml). The resulting mixture was heated under reflux for 1 hour, and then cooled to 0° C. To this mixture was added slowly a solution of 2,2-dimethyl-4-(1,2,4-triazol-1-yl)-butane-3-one (8.4 g, 0.05 mol) in dry dichloromethane (150 ml), and the mixture stirred for 45 minutes, a gelatinous precipitate formed. Ammonium chloride solution was added to the mixture, and the organic layer separated and washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica eluting with diethyl ether (20-100%) in petrol gave 2,2-dimethyl-3-hydroxy-3-(3-methyl-pent-1-yne-1-yl)-4-(1,2,4-triazol-1-yl)-butane) as a white solid (4.29 g) (mpt=59°-60° C.).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].O.O.O.O.O.O.Cl([O-])(=O)(=O)=O.[La+3].Cl([O-])(=O)(=O)=O.Cl([O-])(=O)(=O)=O.C1(C)C=CC=CC=1.[CH2:37]([CH:39]1[O:41][CH2:40]1)Cl>C(Cl)Cl.C(O)(=O)C>[CH2:37]([O:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][OH:6])[CH:39]1[O:41][CH2:40]1
Reactant: ClCC1CO1
Reactant: OCCOCCO
Agent: [La+3]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: OCCOCCOCC1CO1
Temperature: 105 °C
Reaction time: 14 h

Procedure:
Under a nitrogen atmosphere, 26.53 g of diethylene glycol, 0.25 g of lanthanum perchlorate hexahydrate and 50 ml of toluene are placed as the initial charge in a 350 ml sulfonating flask equipped with an intensive condenser and a propeller stirrer and heated to 105° C. After reaching an internal temperature of 105° C., with the temperature remaining constant 21.3 g of epichlorohydrin are added dropwise in the course of 70 minutes. After subsequently stirring for 14 hours at 105° C., 30 ml of toluene are added to the reaction mixture, in order then to remove by azeotropic distillation any water still present. At normal pressure about 30 ml of azeotrope are distilled off. After cooling to from 48 to 50° C., about 19 g of diazobicycloundecene are added dropwise in the course of 30 minutes and the mixture is subsequently stirred for 2 hours. After cooling to room temperature, the lower phase of the two-phase reaction mixture is adjusted to pH 5 to 8 using acetic acid, diluted with methylene chloride and extracted 3 times with approximately 100 ml of brine each time. After drying with magnesium sulfate, the crude product so obtained is concentrated to dryness and 27.1 g (73% of theory) of a slightly yellowish, viscous oil are obtained. 12 g of the crude product are purified by means of flash chromatography (800 g of silica gel 60 F; ethyl acetate 95: methanol 5). The desired product is obtained in the form of a slightly yellowish oil of approximately 85% purity (determined by GC). According to 1H-NMR spectrum, the by-product (15%, determined by GC) is the following compound: