Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH:21]([CH:23]2[CH:27]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=3)[CH2:26][NH:25][CH2:24]2)[CH3:22])=[N:18][CH:19]=1.N1C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH:21]([CH:23]2[CH:27]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=3)[CH2:26][N:25]([C:7]([Cl:10])=[O:6])[CH2:24]2)[CH3:22])=[N:18][CH:19]=1
Reactant: CC(Oc1ccc(Cl)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(Oc1ccc(Cl)cn1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 129.6 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (48 mg, 0.16 mmol) in CH2Cl2 (10 mL) at −78° C., was added a solution of 5-chloro-2-{(RS)-1-[(3SR,4RS)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-pyridine (intermediate XV-B-2) (150 mg, 0.40 mmol) and pyridine (0.072 mL, 0.88 mmol) in CH2Cl2 (5 ML) over 30 minutes. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Concentration under vacuo yielded and column chromatography (SiO2, EtOAc/H, 1:1) yielded 90 mg (50%) of the title compound as a viscous colorless oil.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].C([CH:14]1[N:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[NH:44][N:43]=[N:42][N:41]=3)=[CH:30][CH:29]=2)[C:17]2=[N:18][C:19](=S(=O)=O)[CH:20]=[C:21]([CH3:22])[C:16]2=[N:15]1)C.Cl>O.CN(C=O)C>[CH2:1]([O:5][C:14]1[N:26]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[NH:44][N:43]=[N:42][N:41]=3)=[CH:32][CH:33]=2)[C:17]2=[N:18][CH:19]=[CH:20][C:21]([CH3:22])=[C:16]2[N:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC1N=C2C(C)=CC(=S(=O)=O)N=C2N1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CCCCO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 0.08 h
Yield: 49 %

Procedure:
A mixture of 100 mg (1.3 mmol) of n-butanol, 400 mg (3.6 mmol) of potassium tert. butoxide and DMF was heated at 80 degree C. for 5 minutes. 300 mg (0.65 mmol) of 2-ethyl-sulfonyl-7-methyl-3[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazo[4.5-b]pyridine was added to the mixture. The resultant was heated for 2 hours. The reaction product mixture was mixed with water, neutralized with 2n HCl and extracted with dichloromethane. The dichloromethane phase was washed with a saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled out at a reduced pressure and the residue was treated with ether hexane-dichloromethane or re-crystallization to obtained 140 mg of the intended compound.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[F:27][C:28]1[C:29]([CH:43]=O)=[N:30][C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[C:33]([O:38][CH2:39][CH2:40][O:41][CH3:42])[CH:32]=2.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CCO.C(Cl)Cl>[F:26][C:2]([F:25])([F:1])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:43]([C:29]3[C:28]([F:27])=[CH:37][C:36]4[C:31](=[CH:32][C:33]([O:38][CH2:39][CH2:40][O:41][CH3:42])=[CH:34][CH:35]=4)[N:30]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: COCCOc1ccc2cc(F)c(C=O)nc2c1
Solvent: CCO
Solvent: Ic1ccccc1
Solvent: ClCCl
Product: COCCOc1ccc2cc(F)c(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
A mixture of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.080 g, 0.20 mmol) and 3-fluoro-7-(2-methoxyethoxy)quinoline-2-carbaldehyde (0.051 g, 0.20 mmol) in EtOH (10 mL) was stirred at ambient temperature for 3 hours. The solvent was removed. The residue obtained was dissolved in DCM (10 mL) and iodobenzene diacetate (0.078 g, 0.24 mmol) was added. The mixture was stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure. The residue obtained was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-90% CH3CN/water gradient; 25 CV)) to give tert-butyl (3S)-1-((1R)-2,2,2-trifluoro-1-(3-(3-fluoro-7-(2-methoxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.096 g, 0.159 mmol, 78% yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH:23][CH3:24])(=[O:22])=[O:21].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH:23][CH3:24])(=[O:22])=[O:21])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: CNS(=O)(=O)c1ccccc1N
Reactant: FC(F)(F)c1cnc(Cl)cc1I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1ccccc1Nc1cc(Cl)ncc1C(F)(F)F

Procedure:
Method B was applied to a mixture of 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (40 mg, 0.13 mmol), 2-amino-N-methylbenzenesulfonamide (22 mg, 0.12 mmol), Pd2(dba)3 (11 mg, 0.012 mmol), xantphos (12 mg, 0.021 mmol) and cesium carbonate (79 mg, 0.24 mmol) in dioxane (3.5 ml).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[Cl:18]N1C(=O)CCC1=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[C:6]([Cl:18])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)cc2c1c(Cl)cn2C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 100 ml round bottom flask was added methyl 6-bromo-1-(1-methylethyl)-1H-indole-4-carboxylate (1.100 g, 3.71 mmol) as a solution in THF and a magnetic stir bar. To the same was added 1-chloro-2,5-pyrrolidinedione (0.546 g, 4.09 mmol) and the system stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue dissolved in EtOAc (60 ml) and washed with saturated NaHCO3 (20 ml) and brine (8 ml). The organic layer was dried over Na2SO4, filtered and concentrated. Purification of the residue by column chromatography provided methyl 6-bromo-3-chloro-1-isopropyl-1H-indole-4-carboxylate (as a thick gold oil), which was used in the next step. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J=1.52 Hz, 1H), 7.93 (s, 1H), 7.50 (d, J=1.77 Hz, 1H), 4.90 (quin, J=6.63 Hz, 1H), 3.89 (s, 3H), 1.43 (d, J=6.57 Hz, 6H). MS(ES) [M+H]+ 332.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-:30].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[Br:30])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [Br-]
Reactant: CC1C(=O)NN=C2COc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CO
Product: CC1C(=O)NN=C2COc3cc(Br)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a solution of 4-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (Example #71, Step B, 0.50 g, 1.249 mmol) in DCM (5 mL) and MeOH (5 mL) was added tetrabutylammonium tribromide (0.662 g, 1.373 mmol) portionwise and the reaction mixture was stirred for 30 min at ambient temperature. Saturated aqueous Na2S2O3 solution (5 mL) was added and the pH was adjusted to 7 by the addition of saturated aqueous NaHCO3 solution. The mixture was extracted with DCM (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 20% EtOAc in petroleum ether) to give 4-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.34 g, 57%). LC/MS (Table 1, Method 2) Rt=1.289 min.; MS m/z: 479/481 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3]/[N:4]=[C:5](/[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)\[C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl[CH2:20][C:21]1[CH:40]=[CH:39][C:24]([O:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30][C:31]=2[CH3:32])=[CH:23][CH:22]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11](/[C:5](=[N:4]/[O:3][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:31]=3[CH3:32])=[CH:39][CH:40]=2)/[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:16][CH:15]=1
Reactant: CCOC(=O)/C(=N\O)c1ccc(OC)cc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(OC)cc1
Reaction time: 1 h
Yield: 94.1 %

Procedure:
Sodium hydride (60% in oil, 127 mg) was added under a nitrogen atmosphere to a solution of ethyl Z-2-hydroxyimino-2-(4-methoxyphenyl)acetate (711 mg) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) in N,N-dimethylformamide (10 ml) at room temperature and the mixture was stirred for 1 hour. After adding 1N HCl (5 ml), aqueous sodium bicarbonate was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl Z-2-(4-methoxyphenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate (1.50 g, yield: 94%) as crystals from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization was performed from ethyl acetate-hexane. m.p. 102-103° C.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=2)=[O:16])[C@@H:7]([CH3:24])[CH2:6]1)=[O:4].[CH3:25][O-:26].[Na+].CO.Cl>COCCOC>[CH3:25][O:26][C:20]1[N:19]=[CH:18][C:17]([C:15]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]([C:3]([OH:2])=[O:4])[CH2:6][CH:7]2[CH3:24])=[O:16])=[CH:22][CH:21]=1
Reactant: COC(=O)[C@@H]1C[C@H](C)N(C(=O)c2ccc(Cl)nc2)c2ccccc21
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: COc1ccc(C(=O)N2c3ccccc3C(C(=O)O)CC2C)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 32 %

Procedure:
To a solution of cis-1-(6-chloro-pyridine-3-carbonyl)-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid methyl ester (620 mg, 1.8 mmol) in ethylene glycol dimethyl ether (6.00 mL) was added at 0° C. a 5M solution of sodium methoxide in methanol (3.3 mL, 16.2 mmol). The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was acidified to pH 1 by addition of aqueous 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to yield 1-(6-methoxy-pyridine-3-carbonyl)-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (190 mg, 32%).
Reaction SMILES: [CH:1]([CH:4]1[NH:8][C:7](=[O:9])[NH:6][C:5]1=[O:10])([CH3:3])[CH3:2].[Cl-].[Li+].[CH2:13]1[O:16][CH:14]1[CH3:15]>OS(O)(=O)=O.CN(C)C=O>[OH:16][CH:14]([CH3:13])[CH2:15][N:8]1[CH:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:10])[N:6]([CH2:13][CH:14]([OH:16])[CH3:15])[C:7]1=[O:9]
Reactant: CC(C)C1NC(=O)NC1=O
Reactant: CC1CO1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(O)CN1C(=O)C(C(C)C)N(CC(C)O)C1=O
Temperature: 50 °C

Procedure:
A mixture of 995.0 g of 5-isopropylhydantoin (7 mols), 2000 ml of dimethylformamide and 14.8 g of lithium chloride is stirred at 50° C. 1220 g of propene oxide (21 mols) are slowly added dropwise over the course of 6 hours. Thereafter the temperature is gradually raised at 70° C. and after a total of 15 hours the reaction mixture is allowed to cool. It is adjusted to pH = 7 with a few drops of 2 N H2SO4 and the pale yellow solution is filtered. The solution is completely concentrated at 90° C. bath temperature on a rotational evaporator under a waterpump vacuum and is subsequently treated at 90° C./0.1 mm Hg until constant weight is reached. 1654.5 g of a pale yellow highly viscous product (91.7% of theory) are obtained.
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1)[CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:37]([CH2:44][C:45](=O)[CH3:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O)(=O)C>O1CCCC1>[CH3:36][O:35][C:33]1[CH:32]=[C:11]([CH:12]=[C:45]([CH3:46])[CH2:44][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:10]=[C:9]([O:8][CH3:7])[CH:34]=1
Reactant: COc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1
Reactant: CC(=O)CCc1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(C=C(C)CCc2ccccc2)cc(OC)c1

Procedure:
A solution of n-butyl lithium (29 ml. of 2.2 M) is added dropwise to 3,5-dimethoxybenzyl triphenylphosphonium bromide (31.5 g.) in tetrahydrofuran (200 ml.) with stirring and the resulting deep red solution is stirred for one-half hour. Benzyl acetone (9.4 g.) is added dropwise and the reaction mixture stirred for 12 hours. It is then adjusted to pH 7 by addition of acetic acid and concentrated under reduced pressure. The residue is extracted with methylene chloride and the extract evaporated to give crude 1-(3,5-dimethoxyphenyl)-2-methyl-4-phenyl-1-butene as an oil. It is purified by chromatography on silica gel (400 g.) and elution with benzene. Yield: 10 g. as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH2:14])=O)[CH:6]=[CH:5]2.N1C=CC=CC=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]#[N:14])[CH:6]=[CH:5]2
Reactant: NC(=O)c1ccc2cc(Br)ccc2c1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Product: N#Cc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
To 6-bromo-2-naphthamide (1 g, 4.00 mmol) in dioxane (8.00 ml) at 0° C. was added pyridine (0.647 ml, 8.00 mmol) and then TFAA (0.621 ml, 4.40 mmol) dropwise. The reaction was stirred at room temperature for 3 h. The mixture was quenched with H2O and extracted with EtOAc two times, dried over magnesium sulfate, filtered, concentrated. The title compound (653 mg, 70%) was isolated as a beige solid, and used as is for the next step.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C@H:9]1[C:26]([OH:28])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:36][OH:37].C(N(CC)CC)C.Cl>C(Cl)Cl.C(OCC)(=O)C.O.O1CCCC1.CN(C)C=O>[CH2:1]([C@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C@H:9]1[C:26]([NH:36][OH:37])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: COc1ccc(S(=O)(=O)N2CCCC[C@H](Cc3ccccc3)[C@@H]2C(=O)O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(S(=O)(=O)N2CCCC[C@H](Cc3ccccc3)[C@@H]2C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
cis-3-Benzyl-1-(4-methoxybenzenesulfonyl)-azepane-2-carboxylic acid (146 mg, 0.36 mmol) was dissolved in 4-mL of anhydrous methylene chloride. Dimethylformamide (10-μL) was added followed by oxalyl chloride (0.36-mL of a 2.0 M solution, 0.72 mmol). The reaction was allowed to stir at room temperature for 30 minutes. In a separate flask, 2.0-mL of tetrahydrofuran was used to suspend hydroxylamine hydrochloride (125 mg, 1.8 mmol). 0.2-mL of water was added to dissolve the mixture. The solution was cooled on ice then triethylamine (290 mg, 2.88 mmol) was added. This solution was stirred at 0° C. for 30 minutes. The acid chloride solution was then added and the reaction stirred at 0° C. for an additional 30 minutes. 20-mL of ethyl acetate was added followed by 20-mL of 0.25 M hydrochloric acid. The layers were separated and the aqueous phase was extracted with another 20-mL of ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated to leave a clear colorless oil which was chromatographed (silica gel, 0-1% methanol in methylene chloride) to afford the title compound ((M+H)+ 419.2, (M+NH4)+ 436.2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.CCN([CH2:16][CH3:17])CC>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2](/[CH:7]=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:16][CH3:17])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: CCN(CC)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Product: CCCCCC/C=C/c1ccc([N+](=O)[O-])cc1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 181.8 %

Procedure:
1-bromo-4-nitrobenzene (2.01 g, 10 mmol), 1-ocetene (7.8 mL, 50 mmol), and Pd(OAc)2 (50 mg, 0.2 mmol) were stirred for 10 min under nitrogen atmosphere. Then tri-o-tolylphosphine (24 mg, 0.8 mmol) was added to the mixture and stirred for 10 min. Et3N (5.5 mL, 40 mmol) was then added to the mixture. The mixture was heated to 110° C. for 18 h. Water was added to the mixture and extracted with EtOAc. The organic layer was concentrated and purified by silica gel chromatography using PE as eluent to give compound the title compound (2.121 g, 90%). 1H NMR (300 MHz, CDCl3) δ 8.097 (d, 2H), 7.235 (d, 2H), 6.442 (s, 1H), 5.976-5.377 (m, 1H), 2.231-2.052 (m, 2H), 1.710-1.246 (m, 8H), 0.850 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>O1CCCC1>[CH2:9]([O:8][C:6]1[CH:5]=[C:4]([CH3:11])[N:3]=[C:2]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[N:7]=1)[CH3:10]
Reactant: CCOc1cc(C)nc(Cl)n1
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Product: CCOc1cc(C)nc(-n2ccnc2)n1
Yield: 50.5 %

Procedure:
In anhydrous tetrahydrofuran, 173 mg of 2-chloro-4-ethoxy-6-methylpyrimidine was substituted with 68 mg of imidazole. The reaction mixture was treated according to the procedure of Example 5 to yield 103 mg of 4-ethoxy-2-(1-imidazolyl)-6-methylpyrimidine, recrystallized from a mixture of n-hexane and ethyl acetate, having a melting point of 115.5°-116° C.
Reaction SMILES: [CH:1]1[C:9]2[C:10]3[C@@H:15]([CH2:16][C:7]4[C:8]=2[C:4]([NH:5][CH:6]=4)=[CH:3][CH:2]=1)[NH:14][CH2:13][C@H:12]([C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])[CH:11]=3.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])=[C:25]=[O:26].[N-]=C=O>O1CCCC1>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[NH:24][C:25]([N:14]1[C@H:15]2[C:10]([C:9]3[CH:1]=[CH:2][CH:3]=[C:4]4[C:8]=3[C:7](=[CH:6][NH:5]4)[CH2:16]2)=[CH:11][C@@H:12]([C:17]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)=[O:18])[CH2:13]1)=[O:26]
Reactant: COc1ccccc1N=C=O
Reactant: O=C([C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2NC1)N1CCCC1
Agent: [N-]=C=O
Solvent: C1CCOC1
Product: COc1ccccc1NC(=O)N1C[C@H](C(=O)N2CCCC2)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 25 °C

Procedure:
5.087 g (16.54 mmol) of the product of step 2 is dissolved in 80 ml tetrahydrofurane and 1.79 ml (16.5 mmol) 1-isocyanato-2-methoxy-benzene is added and stirred at room temperature. In order to trap excess isocyanate 0.3 equivalent 3-amino-1,2-propanediol is added and stirred for 2.5 hours. Then the reaction mixture is washed with saturated sodium hydrogen carbonate solution and brine, dried with Na2SO4 and partially evaporated. Crystallization give (6aR,9R)-9-(Pyrrolidine-1-carbonyl)-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-7-carboxylic acid (2-methoxy-phenyl)-amide. MS/ES: 457 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2B(O)O)[CH:7]=1.Br[C:26]1[N:31]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:26]2[N:31]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=[CH:28][CH:27]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1-c1cc(Cl)ccc1OCc1ccccc1
Reactant: CCOC(=O)c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2OCc2ccccc2)n1
Temperature: 90 °C
Yield: 83.4 %

Procedure:
A mixture of {5′-chloro-2′-[(phenylmethyl)oxy]-2-biphenylyl}boronic acid (1.32 g, 3.9 mmol), ethyl 6-bromopicolinate (851 mg, 3.7 mmol), potassium carbonate (2.76 g, 20 mmol) and tetrakis(triphenylphosphine)palladium(0) (232 mg, 0.2 mmol) in 1:1 toluene/ethanol (25 ml) was stirred and heated at 90° C. under nitrogen for 1.5 hours. After cooling and dilution with diethyl ether/water the organic phase was separated, dried (magnesium sulphate) and evaporated. The residue was chromatographed on silica eluting with ethyl acetate/iso-hexane (3:17) to give 1.37 g of white solid. LC/MS t=3.76, [MH+] 444.3
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([N:15]([CH2:21][C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17][C:18]([OH:20])=O)[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[C:39]1([S:45]([NH2:48])(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1CCN2C(=NCCC2)CC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([N:15]([CH2:21][C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17][C:18]([NH:48][S:45]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:47])=[O:46])=[O:20])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(-c2csc(N(CCC(=O)O)Cc3cccs3)n2)cc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)c1ccc(-c2csc(N(CCC(=O)NS(=O)(=O)c3ccccc3)Cc3cccs3)n2)cc1

Procedure:
N-(3-{[4-(4-isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amino}-propionyl)-benzenesulfonamide was prepared following procedure K using 3-{[4-(4-isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amino}-propionic acid (Prepared in Example 35) (50 mg, 0.125 mmol), CDI (62 mg, 0.39 mmol), DBU (30 μl, 0.2. mmol), and benzene sulfonamide (41 mg, 0.26 mmol). Purification (Silica gel, ethyl acetate/hexane 1:4) provided the product (10 mg). LCMS m/z: 527 (M+1)+.