Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][S:7](Cl)(=[O:9])=[O:8])=[O:5])[CH3:2].C[Si](C)(C)[NH:13][Si](C)(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH2:6][S:7]([NH2:13])(=[O:9])=[O:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)CS(=O)(=O)Cl
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: ClCCl
Product: CCOC(=O)CS(N)(=O)=O

Procedure:
A solution of 54.6 g (0.29 mole) ethoxy carbonyl methanesulfonyl chloride in 250 ml methylene chloride is stirred at 0° under a nitrogen atmosphere while 46.8 g (0.29 mole) hexamethyldisilazane is added dropwise. The resulting cloudy solution is allowed to warm to 25° over one hour and then evaporated in vacuo to an oil which crystallizes: yield of the title product is 48.4 g (100%), mp 63°-67°; lit.1 mp 67°-68°, lit2 mp 66°-68°.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:19]2[CH:20]=[CH:21][C:16]([C:14](=[O:15])[CH3:13])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: Oc1ccc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)c1ccc(Oc2ccc(Cl)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 35.6 g of 4-chloro-1-naphthol, 27.62 g of 4-fluoroacetophenone, and 55.2 g of potassium carbonate in 250 ml of N,N-dimethylacetamide are heated under Argon with vigorous stirring at 150°-155° C overnight. After cooling to room temperature, 500 ml of water is added and the mixture is extracted with three 150 ml portions of benzene. The combined extracts are washed with two 150 ml portions of 5% NaOH, three 150 ml portions of 10% HCl, two 150 ml portions of water, 150 ml of saturated NaHCO3, 150 ml of saturated brine and dried over MgSO4. Evaporation of the solvent at reduced pressure affords a light brown solid, which is extracted with 800 ml of hot hexane to give the product as a tan solid, mp 98°-105° C. Recrystallization from 15:1 hexane-chloroform gives cream colored plates, mp 100°-104.5° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=2)[CH:18]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]([NH:5][C:4]3[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=3[C:2]([F:10])([F:11])[F:1])=[O:23])[N:21]=2)[CH:18]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: Nc1ccccc1C(F)(F)F
Product: O=C(Nc1ccccc1C(F)(F)F)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using 2-(trifluoromethyl)aniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][CH2:6][CH2:7][CH:8]1[C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9]1.CCOCC.O>CS(C)=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]2[O:10][CH2:9][CH:8]([CH2:7][CH2:6][CH2:5][C:1]#[N:2])[C:12]=2[CH:13]=1
Reactant: Fc1ccc2c(c1)C(CCCCl)CO2
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: N#CCCCC1COc2ccc(F)cc21
Temperature: 80 °C
Yield: 49.8 %

Procedure:
Sodium cyanide (12 g) was suspended in dimethyl sulfoxide (180 ml) and heated to 80° C. A solution of 3-(3-chloro-1-propyl)-2,3-dihydro-5-fluoro-benzofuran (42 g) in 40 ml of dimethyl sulfoxide was added dropwise followed by heating to 140° C. for 15 min. After cooling ether and water were added, the ether phase separated, washed with water and dried over magnesium sulfate. Removal of solvent in vacuo left a viscous oil which was applied to a silica gel column giving 4-(2,3-dihydro-5-fluoro-benzofuran-3-yl)butyronitrile as an oil (20 g).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[OH:12])[O:5][C:4](=[O:13])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+].[I-].[K+].[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34]Cl)[CH2:29][CH2:28]1>C(Cl)(Cl)Cl.C(C(C)=O)C(C)C>[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[OH:12])[O:5][C:4](=[O:13])[C:3]=2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:29][CH2:28]1
Reactant: ClCCN1CCOCC1
Reactant: O=c1oc2cccc(O)c2c(O)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)CC(C)C
Product: O=c1oc2cccc(O)c2c(OCCN2CCOCC2)c1-c1ccccc1
Temperature: 60 °C
Yield: 44.5 %

Procedure:
76.3 g. (0.3 mol) of 4,5-dihydroxy-3-phenyl-coumarin (Example 23a), 25.2 g. (0.3 mol) of sodium bicarbonate, 3 g. of potassium iodide and 800 ml. of methyl isobutyl ketone are brought over one hour to 80° C. The mixture is then cooled to 60° C., whereafter 48.4 g. (0.324 mol) of 2-morpholino-1-chlorethane are added dropwise and the temperature is brought over 8 hours to 100° C. It is then left at room temperature for one night and filtered. The precipitate obtained is taken up in 1 liter of chloroform. The light, insoluble substance obtained is filtered and the chloroform is evaporated under vacuum. The residue obtained is recrystallised from 700 ml. of methyl isobutyl ketone. 50 g. of a white product are isolated. M.P. 206° C.; yield 44.5% (theoretical yield 110.2 g.).
Reaction SMILES: [O:1]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][CH2:16][C:17](Cl)=[O:18].C(N(CC)C(=O)COC1C=CC(C(=O)CCl)=CC=1)C>>[Cl:15][CH2:16][C:17]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][CH:4]=1)=[O:18]
Reactant: CCOC(=O)C(C)Oc1ccccc1
Reactant: O=C(Cl)CCl
Agent: CCN(CC)C(=O)COc1ccc(C(=O)CCl)cc1
Product: CCOC(=O)C(C)Oc1ccc(C(=O)CCl)cc1

Procedure:
Ethyl 2-phenoxypropionate was reacted with chloroacetyl chloride as described for N,N-diethyl-4-(chloroacetyl)phenoxyacetamide, used as a starting material for Example 7, to give ethyl 2-[4-(chloroacetyl)phenoxy]-propionate as a white solid, having a satisfactory analysis (found: C, 57.7, H, 5.5, N, 13.0; required: C, 57.7; H, 5.6; N, 13.1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[CH2:3][OH:4].[N:14]#[C:15]Br>>[Cl:13][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][C@H:2]2[CH2:3][O:4][C:15]([NH2:14])=[N:1]2)[CH:12]=[CH:11][CH:10]=1
Reactant: N[C@H](CO)CCc1cccc(Cl)c1
Reactant: N#CBr
Product: NC1=N[C@@H](CCc2cccc(Cl)c2)CO1

Procedure:
In analogy to example 1b (S)-2-amino-4-(3-chloro-phenyl)-butan-1-ol was reacted with cyanogen bromide to give (S)-4-[2-(3-chloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine. Light yellow viscous oil. MS (ISP): 227.2 ([{37Cl}M+H]+), 225.1 ([{35Cl}M+H]+).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:41])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:39])(=[O:38])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:40])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:40][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:41])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:24]=[CH:23][C:22]([S:25](=[O:39])(=[O:38])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)Nc3ccc(OC(F)(F)F)cc3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)Nc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
Lithium hydroxide monohydrate (0.009 g, 0.21 mmol) was added to a stirred solution of {6-chloro-3-methyl-4-[4-(4-trifluoromethoxy-phenylsulfamoyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.030 g, 0.05 mmol) in a 3:1 mixture of THF—H2O mixture (5 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded {6-chloro-3-methyl-4-[4-(4-trifluoromethoxy-phenyl-sulfamoyl)-phenyl]-naphthalen-2-yl}-acetic acid (0.02 g, 69%) as a solid. 1H NMR (DMSO-d6) δ: 12.49 (br. s, 1H), 10.56 (br. s, 1H), 7.82-8.03 (m, 4H), 7.38-7.54 (m, 3H), 7.27-7.35 (m, 2H), 7.19-7.27 (m, 2H), 6.82 (s, 1H), 3.84 (s, 2H), 1.99 (s, 3H). MS calcd. for C26H18ClF3NO5S [(M−H)−] 548, obsd. 548.0.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH:20](OCC)O)=[CH:15][C:10]=1[C:11]([O:13]C)=O)C1C=CC=CC=1.[CH3:26][C:27]([NH2:44])([CH3:43])[CH2:28][CH2:29][N:30]1[C:34]([CH3:35])=[N:33][C:32]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)=[N:31]1>>[CH3:43][C:27]([NH:44][CH2:20][CH:19]([C:16]1[CH:17]=[CH:18][C:9]([OH:8])=[C:10]([CH2:11][OH:13])[CH:15]=1)[OH:25])([CH3:26])[CH2:28][CH2:29][N:30]1[C:34]([CH3:35])=[N:33][C:32]([C:36]2[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=2)=[N:31]1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(C(=O)OC)c1
Reactant: Cc1ccc(-c2nc(C)n(CCC(C)(C)N)n2)cc1
Product: Cc1ccc(-c2nc(C)n(CCC(C)(C)NCC(O)c3ccc(O)c(CO)c3)n2)cc1

Procedure:
The compound is prepared analogously to the general working method A from 241 mg (0.7 mmol) of methyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 181 mg (0.7 mmol) of 1,1-dimethyl-3-(5-methyl-3-p-tolyl-[1,2,4]triazol-1-yl)-propylamine.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40].N1C=CC=CC=1>ClCCl>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([NH:8][C:7]1[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)[C:2]=1[F:1])(=[O:41])=[O:40]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccccc1Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 2-chloro benzene-1-sulfonyl chloride (15 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8](C(C3C=CC=CC=3)=O)[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=O)C>CO>[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)n1ccc2ccc(Cl)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Clc1ccc2cc[nH]c2n1

Procedure:
A solution of (Intermediate C3) (3.12 mmol) in MeOH (90 mL) was treated with 1 M NaOH (30 mL) at rt for 18 h. The solution was freed of MeOH under reduced pressure and ethyl acetate was added to the aqueous layer. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with sat. NaHCO3, and dried over Na2SO4. The mixture was filtered and the solvent was evaporated to give a solid 6-chloro-1H-pyrrolo[2,3-b]pyridine (Intermediate C4).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: CN(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc2c(c1)CCCC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-hydroxy-1-tetralone (Aldrich, 1.0 g, 6.17 mmol, 1.0 eq), N,N-dimethylethanolamine (Aldrich, 0.93 mL, 9.26 mmol, 1.5 eq), and triphenylphosphine (Aldrich, 2.43 g, 9.26 mmol, 1.5 eq) in THF (10 mL) was added diethyl azodicarboxylate (Aldrich, 1.94 mL, 12.34 mmol, 2.0 eq) at 0° C. The reaction mixture was gradually warmed to RT and continued to stir overnight. The solvent was evaporated in vacuo. The residue was purified by silica gel chromatography (3%-5% MeOH—CH2Cl2) to provide the product as orange oil. MS (ESI): 234 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH2:23])=[CH:10][C:11]=3[C:12]2([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1.[CH2:24]([C:28]1([CH2:42][CH2:43][CH2:44][CH3:45])[C:40]2[CH:39]=[C:38](I)[CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:25][CH2:26][CH3:27]>>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([N:23]([C:9]4[CH:8]=[CH:7][C:6]5[C:5]6[C:13](=[CH:14][CH:2]=[CH:3][CH:4]=6)[C:12]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[C:11]=5[CH:10]=4)[C:31]4[CH:32]=[CH:33][C:34]5[C:35]6[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=6)[C:28]([CH2:42][CH2:43][CH2:44][CH3:45])([CH2:24][CH2:25][CH2:26][CH3:27])[C:29]=5[CH:30]=4)=[CH:10][C:11]=3[C:12]2([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1
Reactant: CCCCC1(CCCC)c2cc(N)ccc2-c2ccc(Br)cc21
Reactant: CCCCC1(CCCC)c2ccccc2-c2ccc(I)cc21
Product: CCCCC1(CCCC)c2ccccc2-c2ccc(N(c3ccc4c(c3)C(CCCC)(CCCC)c3ccccc3-4)c3ccc4c(c3)C(CCCC)(CCCC)c3cc(Br)ccc3-4)cc21

Procedure:
As shown in Scheme 3, 7-bromo-9H-fluoren-2-ylamine is reacted with 1-iodobutane to form 7-bromo-9,9-dibutyl-9H-fluoren-2-ylamine (31); and 2-Iodo-9H-fluorene is reacted with 1-iodobutane to form 9,9-dibutyl-2-iodo-9H-fluorene (32). Then, 7-bromo-9,9-dibutyl-9H-fluoren-2-ylamine (31) is reacted with 9,9-dibutyl-2-iodo-9H-fluorene (32) by Ullman coupling reaction to obtain (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-bis-(9,9-dibutyl-9H-fluoren-2-yl)amine (33). Next, (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-bis-(9,9-dibutyl-9H-fluoren-2-yl)amine (33) is reacted with 5-formyl-2-thiopheneboronic acid by Suzuki coupling reaction to obtain 5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophene-2-carbaldehyde (34a). Finally, in acetonitrile, 5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophene-2-carbaldehyde (34a) is reacted with cyanoacetic acid by using piperidine as a catalyst, to obtain 3-(5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophen-2-yl)-2-cyano-acrylic acid (35a).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:23]=3)[O:19][N:18]=2)=[CH:12][C:11]=1[CH2:35][CH3:36])(=O)=O.[NH3:37]>CO>[CH:30]1([C:24]2[CH:23]=[C:22]([C:20]3[O:19][N:18]=[C:17]([C:13]4[CH:14]=[C:15]([CH3:16])[C:10]([O:9][CH2:8][CH2:7][CH2:6][NH2:37])=[C:11]([CH2:35][CH3:36])[CH:12]=4)[N:21]=3)[CH:27]=[C:26]([O:28][CH3:29])[N:25]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: N
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCCOS(C)(=O)=O
Solvent: CO
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCCN

Procedure:
A solution of 3-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)propyl methanesulfonate (1.30 g, 2.52 mmol) in 7 N NH3 in methanol (30 mL) is stirred at 55° C. for 24 h. The mixture is concentrated and dried to give crude 3-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)propan-1-amine (1.24 g) as a pale yellow foam; LC-MS: tR=0.95 min, [M+H]+=437.33.
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Cl:16][CH2:17]I.C(N(CC)CC)C>CN(C=O)C>[Cl:16][CH2:17][O:14][C:13](=[O:15])[CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: ClCI
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CNC(=O)OCc1ccccc1)OCCl

Procedure:
A solution of N-carbobenzoxy-glycine (4.2 g), chloroiodomethane (6.0 ml), and triethylamine (3.5 ml) in DMF (10 ml) was stirred for 2 hours at room temperature. The mixture was worked up and purified in the same way as described in Example 6A to yield the desired compound as a slightly yellowish oil.
Reaction SMILES: [OH:1][CH:2]1[CH:6]([CH2:7][OH:8])[O:5][CH:4]([C:9]2C(O)=[N:11][C:12](O)=[C:13]([Cl:15])[N:14]=2)[CH2:3]1.N([O-])=O.[Na+].[NH2:22][C:23]([NH2:25])=O>C(O)(=O)C>[OH:1][CH:2]1[CH:6]([CH2:7][OH:8])[O:5][CH:4]([C:9]2[C:23]([NH2:25])=[N:22][C:12]([NH2:11])=[C:13]([Cl:15])[N:14]=2)[CH2:3]1
Reactant: NC(N)=O
Reactant: OCC1OC(c2nc(Cl)c(O)nc2O)CC1O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nc(N)c(C2CC(O)C(CO)O2)nc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.2 %

Procedure:
264 mg (1 mmol) 3-(4-Hydroxy-5-hydroxymethyl-tetrahydrofuran-2-yl)-2,6-dihydroxy-5-chloro-pyrazine from example 10 was subjected to a deamination reaction in a mixture of 50 ml 80% acetic acid and 700 mg (10 mmol) NaNO2. After standing for 5 hours at RT, the reaction was almost complete according to TLC. 2 g urea was added to the reaction mixture to destroy excess nitrite and stirred for a further three hours at RT. Afterwards the solution was applied to an activated carbon column (Carboraffin C, ca. 50 ml volume), adequately washed and the desired product was eluted with ethanol/water/ammonium. 230 mg (ca. 87%) of a viscous oil resulted after evaporation which was used in the next stage without further purification.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][C:28]=1[OH:29])[CH2:20][C@@H:21]([C:23]([OH:25])=[O:24])[NH2:22]>>[C:23]([C@@H:21]([NH:22][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:20][C:19]1[CH:26]=[CH:27][C:28]([OH:29])=[C:17]([Cl:16])[CH:18]=1)([OH:25])=[O:24]
Reactant: N[C@@H](Cc1ccc(O)c(Cl)c1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(O)c(Cl)c1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 3-chloro-4-hydroxy-L-phenylalanine to provide the title compound in good yield.
Reaction SMILES: C([NH:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]([CH2:26][CH3:27])([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)[C:12]1=[O:28])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:26]([C:13]1([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)[CH2:14][CH2:15][CH2:16][CH2:17][N:11]([CH2:10][CH2:9][NH:8][C:6]([NH2:5])=[O:7])[C:12]1=[O:28])[CH3:27]
Reactant: CCC1(c2cccc(OC)c2)CCCCN(CCNC(=O)NC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC1(c2cccc(OC)c2)CCCCN(CCNC(N)=O)C1=O
Reaction time: 72 h

Procedure:
To a solution of 1-tert-butyl-3-{2-[3-ethyl-3-(3-methoxy-phenyl)-2-oxo-azepan-1-yl]-ethyl}-urea (as described above in Step A) (0.35 g, 0.93 mmol) in CH2Cl2 (2.0 mL) was added TFA (6.0 mL) and the solution was stirred for 72 hr. The solvents were removed in vacuo to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:4][CH:3]=1.Br[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([N+:29]([O-:31])=[O:30])=[CH:24][N:23]=1.N1C=CC=CC=1C1C=CC=CN=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.C(OCC)(=O)C.[Cu]I>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:22]4[C:27]([CH3:28])=[CH:26][C:25]([N+:29]([O-:31])=[O:30])=[CH:24][N:23]=4)[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:4][CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Br
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc([N+](=O)[O-])cc1C
Temperature: 150 °C
Reaction time: 16 h
Yield: 39.7 %

Procedure:
A mixture of 10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole (Reference Example 72; 292 mg, 1.00 mmol), 2-bromo-3-methyl-5-nitropyridine (651 mg, 3.00 mmol), copper(I) iodide (190 mg, 1.00 mmol), 2,2′-bipyridyl (312 mg, 2.00 mmol) and cesium carbonate (652 mg, 2.00 mmol) in 1-methyl-2-pyrrolidinone (3.0 mL) was stirred at 150° C. for 16 hr. The mixture was diluted with ethyl acetate, filtered through a pad of celite, washed with 1N hydrochloric acid and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 5-30% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a solid, which was recrystallized from n-hexane/ethyl acetate to give the title compound (170 mg, 0.397 mmol, 40%) as a yellow solid.
Reaction SMILES: [N+](=[C:3]([C:17](=[O:41])[CH2:18][C@@H:19]1[C@H:22]([C:23]([CH3:39])([O:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)=[O:27])[CH3:24])[C:21](=[O:40])[NH:20]1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>C1C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[O:41]=[C:17]1[CH2:18][C@H:19]2[N:20]([C:21](=[O:40])[C@H:22]2[C:23]([CH3:39])([O:25][C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=2)=[O:27])[CH3:24])[C@H:3]1[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)=[O:5]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N[C@@H]1CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Temperature: 25 °C
Yield: 98.9 %

Procedure:
A mixture of 4-nitrobenzyl 2-diazo-4-[(2R,3R)-3-{1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl}-4-oxoazetidin-2-yl]-3-oxobutanoate (1.00 g) and rhodium (II) acetate (5 mg) in benzene (50 ml) was refluxed for 25 minutes. After cooling to ambient temperature, the mixture was filtered through cellulose powder. The filtrate was evaporated to give 4-nitrobenzyl (2R, 5R, 6R)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (0.94 g) as an amorphous solid.