Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([O:22]C(=O)CCl)[C@H:5]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.[OH-].[Na+].CO>O1CCOCC1>[C:18]([O:17][C:15]([NH:14][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)[C@H:4]([OH:22])[C:3]([OH:27])=[O:2])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)[C@@H](OC(=O)CCl)[C@@H](Cc1cccc(F)c1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](Cc1cccc(F)c1)[C@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
A mixture of (2S,3R)-3-tert-butoxycarbonylamino-2-(2-chloro-acetoxy)-4-(3-fluoro-phenyl)-butyric acid methyl ester (4.56 g, 11.3 mmol, 1 eq), 4N NaOH (6.5 mL, 25.9 mmol, 2.3 eq), MeOH (48 mL) and 1.4-dioxane (72 mL) was stirred at ambient temperature for 4 h after which the solvents were removed in vacuo and the residue was charged with H2O (50 mL) and washed with Et2O (100 mL). The aqueous layer was made acidic with 10% citric acid and extracted with EtOAc (2×75 mL). The combined EtOAc layers were washed with H2O (3×50 mL) brine (50 mL), dried (Na2SO4), concentrated, shaken with heptane and filtered to give the desired acid as a white solid (3.3 g, 94%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:14](=[CH:17][C:18]4[O:19][CH2:20][O:21][C:22]=4[C:23]=3[CH2:24][N:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:14](=[CH:17][C:18]4[O:19][CH2:20][O:21][C:22]=4[C:23]=3[CH2:24][N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:15]\2=[O:16])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c3c(cc4c2O/C(=C\c2n[nH]c5ccccc25)C4=O)OCO3)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1/C(=C/c2n[nH]c3ccccc23)Oc2c1cc1c(c2CN2CCNCC2)OCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
A solution of tert-butyl (Z)-4-({6-[(1H-indazol-3-yl)methylene]-7-oxo-6,7-dihydrobenzofuro[5,6-d][1,3]dioxol-4-yl}methyl)piperazine-1-carboxylate (0.019 g, 0.038 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped with toluene under reduced pressure to remove the solvent and hydrogen chloride. The residual solid was added with water, and then the mixture was adjusted to pH 9 with saturated aqueous sodium hydrogencarbonate, and extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (99:1→95:5)) to obtain (Z)-6-[(1H-indazol-3-yl)methylene]-4-(piperazin-1-ylmethyl)benzofuro[5,6-d][1,3]dioxol-7(6H)-one (0.005 g, 33%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][CH3:14])[C@@H:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH3:18]O>>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@H:10]([OH:15])[C@@H:11]([N:13]([CH3:18])[CH3:14])[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1O
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: CN(C)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1O
Reaction time: 1 h

Procedure:
This compound was prepared in the same manner as in Reference Example 25 (step 1), except that (3S,4S)-1-(t-butoxycarbonyl)-3-hydroxy-4-(methylamino)pyrrolidine (Tetrahedron: Asymmetry, 2001, 12, 2989-2997) was used, and that the reaction was conducted for 1 hour under ice cooling, the reaction solution was alkalified with a 1N aqueous sodium hydroxide solution and methanol was mostly distilled off under reduced pressure, followed by extraction with ethyl acetate twice.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[CH2:19][CH2:18][CH2:17][C:16]([C:20]([O:22]C)=[O:21])=[CH:15][C:14]=3[CH:24]=2)=[CH:6][CH:5]=1)[CH3:2].[OH-].[Na+].Cl>CO.C1COCC1>[CH2:1]([O:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[CH2:19][CH2:18][CH2:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:14]=3[CH:24]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCC3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(COc2ccc3c(c2)C=C(C(=O)O)CCC3)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To methyl 2-(4-ethoxybenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (296 mg, 0.84 mmol) dissolved in a mixed solvent of methanol (4 ml) and THF (4 ml) was added a 1N aqueous solution of sodium hydroxide (2.5 ml), and the resulting mixture was stirred at 50° C. for 4 hours. The reaction mixture was mixed with 1 N hydrochloric acid (2.5 ml) at 0° C., was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was washed with water, and was dried under reduced pressure to obtain 2-(4-ethoxybenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (283 mg, 0.84 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[S:17](=[O:20])(=[O:19])[NH2:18])=O)[CH3:2].P(Cl)(Cl)(Cl)=O>>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[S:17](=[O:20])(=[O:19])[N:18]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)Nc1ccc(OC)cc1S(N)(=O)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CC1=NS(=O)(=O)c2cc(OC)ccc2N1
Temperature: 25 °C
Yield: 79 %

Procedure:
A mixture of 10 (8.0 g, 28 mmol) in phosphorous oxychloride (150 mL, 1.64 mol) was heated to reflux for 2.5 hours, then cooled to room temperature and concentrated in vacuo. The residue was then dissolved in ethyl acetate and neutralized with saturated aqueous sodium bicarbonate. The organic phase was washed with 2 N hydrochloric acid and then brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The solid product was then triturated in diethyl ether to produce 6.6 g of the desired product (4a) as a brown solid in 79% yield. See procedure described in International Patent Application No. PCT/US03/16374. 1H NMR (400 MHz, DMSO-d6): δ12.20 (s, 1H), 7.27 (m, 2 H), 7.20 (s, 1H), 4.14 (q, 2H, J=7.2 Hz), 3.73 (s, 3H), 3.66 (s, 2H), 1.21 (t, 3H, J=7.6 Hz); LC-MS (ESI+): m/e=299.1 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[OH-].[K+].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([CH3:21])[N:15]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:17]=[C:16]([CH3:21])[N:15]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: COc1ccc(CO)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(Cl)nc(C)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Methoxybenzyl alcohol (1.66 g, 12 mmol) was dissolved in DMF (20 mL). Potassium hydroxide (2.31 g, 36 mmol, 87%) was added and stirred at room temperature for 10 min followed by cooling to 0° C. 4,6-dichloro-2-methylpyrimidine (2.15 g, 13.2 mmol) was dissolved in DMF (4 mL) and added to the solution drop-wise. The internal temperature was controlled under 2° C. The reaction solution was kept at 0° C. for 2 h, then allowed to warm slowly to 16° C. over 1 hr. The reaction was diluted with ethyl acetate (50 mL), washed with brine (50 mL×2), dried over MgSO4, filtered and concentrated i. vac. The crude mixture was purified by chromatography on silica gel (eluting 7.7% ethyl acetate/hexane) to yield the titled compound as a colorless oil. LC-MS (M+1): 265.51, (M+23): 287.52.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([C:12]1[N:20]2[C:15]([CH2:16][O:17][CH2:18][CH2:19]2)=[C:14]([C:21](=[O:32])[NH:22][C@@H:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][CH3:25])[CH:13]=1)=[O:11])=[O:4].COC(C1CCCN1C(C1N2C(COCC2)=C(C(=O)N[C@@H](C2C=CC=CC=2)CC)C=1)=O)=O.[OH-].[Na+].Cl>O1CCCC1.O>[C:26]1([C@H:23]([NH:22][C:21]([C:14]2[CH:13]=[C:12]([C:10]([N:6]3[CH2:7][CH2:8][CH2:9][C@@H:5]3[C:3]([OH:4])=[O:2])=[O:11])[N:20]3[CH2:19][CH2:18][O:17][CH2:16][C:15]=23)=[O:32])[CH2:24][CH3:25])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C(=O)OC)n2c1COCC2)c1ccccc1
Agent: CC[C@@H](NC(=O)c1cc(C(=O)N2CCCC2C(=O)OC)n2c1COCC2)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C(=O)O)n2c1COCC2)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of (R)-1-[8-((R)-1-phenyl-propylcarbamoyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbonyl]-pyrrolidine-2-carboxylic acid methyl ester (Comp. No. 16m) (171 mg, 0.389 mmol) in tetrahydrofuran (5 ml) and water (4 ml), and 2 M aqueous sodium hydroxide (1 ml, 2 mmol) was refluxed for 3 h, cooled to room temperature, acidified with excess aqueous hydrochloric acid, and extracted with dichloromethane. Solvents were evaporated to give 140 mg of (R)-1-[8-((R)-1-phenyl-propylcarbamoyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbonyl]-pyrrolidine-2-carboxylic acid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SiH](CC)(CC)CC>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][O:10][CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cc1ccccc1)OCCC1CCNCC1
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Product: c1ccc(CCOCCC2CCNCC2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 41.8 %

Procedure:
In a oven-dried flask, 4-[2-(phenylacetoxy)ethyl]piperidine (101 mg, 0.41 mmol) and InBr3 (290 mg, 0.82 mmol, 2 equiv.) were dissolved in toluene (2 mL). After degassing and replacement of the atmosphere with Ar, Et3SiH (260 μL, 1.64 mmol, 4 equiv.) was added. The mixture was stirred at 90° C. for 4 h. After cooling to room temperature, the reaction was quenched with 1N HCl. After the aqueous layer was washed with EtOAc, its pH was raised to 9-10. After extraction with CH2Cl2, the organic layer was dried with Na2SO4. The solvent was removed to afford 4-[2-(2-phenylethoxy)ethyl]piperidine (40 mg, 42%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:18]([OH:20])[CH3:19]>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4]([O:20][CH2:18][CH3:19])=[O:5]
Reactant: CCO
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Product: CCOC(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 2-chloro-3-nitro-5-trifluoromethylbenzoyl chloride (5.5 g; 18 mmol), obtained in step b) of Example 1, is dissolved in ethanol (50 ml) and stirred for 1 hour at room temperature. After evaporating to dryness, the pasty solid is purified by filtration on silica (eluent: dichloromethane). 4.2 g of ethyl 2-chloro-3-nitro-5-trifluoromethylbenzoate are obtained in the form of a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[F-].[K+].[O:22]1[CH2:27][CH2:26]OCC1>O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:8]1([C:7]2[C:2]([C:8]3[CH:9]=[CH:10][C:26]([CH:27]=[O:22])=[CH:6][CH:7]=3)=[N:3][C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1nc(-c2ccccn2)ncc1-c1ccccc1
Reactant: C1COCCO1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: O
Product: O=Cc1ccc(-c2nc(-c3ccccn3)ncc2-c2ccccc2)cc1

Procedure:
4-Chloro-5-phenyl-2-pyridin-2-ylpyrimidine (4-2; 0.15 g, 0.56 mmol), (4-formylphenyl)boronic (0.126 g, 0.840 mmol), bis(tri-t-butylphosphine)palladium(0) (0.014 g, 0.028 mmol) and anhydrous KF (0.107 g, 1.85 mmol) were stirred in 2 μl anhydrous dioxane under N2. The reaction was heated to reflux. After 15 min an additional sample of bis(tri-t-butylphosphine)palladium(0) (0.014 g, 0.028 mmol) was added and the reaction was heated at reflux overnight. The reaction was cooled and diluted with water. The mixture was extracted 3× with DCM. The combined organic phases was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (dissolved sample in DCM, eluted with 98:2 DCM/EA) and provided an impure sample of 4-(5-phenyl-2-pyridin-2-ylpyrimidin-4-yl)benzaldehyde (4-3) that was used directly in the next transformation.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65](=[O:76])[C:66]1[CH:71]=[CH:70][C:69]([NH2:72])=[C:68]([O:73][CH2:74][CH3:75])[CH:67]=1>>[CH3:63][O:64][C:65](=[O:76])[C:66]1[CH:71]=[CH:70][C:69]([NH:72][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[C:68]([O:73][CH2:74][CH3:75])[CH:67]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CCOc1cc(C(=O)OC)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(C(=O)OC)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.4 g, 0.69 mmol), was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with 4-amino-3-ethoxy-benzoic acid methyl ester (0.21 g, 1.1 mmol) to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-ethoxy-benzoic acid methyl ester as a white solid (Yield, 0.13 g, 29%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([NH:23][OH:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[N+:23]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[O-:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: ONC1CCCCC1
Product: [O-][N+](=Cc1ccc(OCc2ccccc2)cc1)C1CCCCC1

Procedure:
The title compound was prepared according to the procedure described in Example 42 using 4-benzyloxybenzaldehyde and N-cyclohexylhydroxylamine. The title compound was obtained in 81.2% yield as slightly yellowish solid, m.p. 129.0° C. (Rf=0.30 on a silica gel plate using hexanes:EtOAc, 1:1, v:v, as an eluant).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[Cl-].[F:13][C:14]([F:29])([F:28])[C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][C@@H:25]3[CH2:27][C@H:22]2[CH2:23][NH2+:24]3)[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C.C1COCC1>O1CCOCC1>[F:29][C:14]([F:13])([F:28])[C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][C@@H:25]3[CH2:27][C@H:22]2[CH2:23][N:24]3[C:2]2[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: FC(F)(F)c1cccc(N2C[C@@H]3C[C@H]2C[NH2+]3)c1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(N2C[C@@H]3C[C@H]2CN3c2cccc(C(F)(F)F)c2)s1
Yield: 95.3 %

Procedure:
A suspension of ethyl 2-bromothiazole-5-carboxylate (0.125 mL, 0.834 mmol), title compound 216 (425 mg, 1.525 mmol), and triethylamine (0.465 mL, 3.34 mmol) in dioxane (1.525 mL) was sonicated for 1 h. More THF (2 mL) was added and the mixture was sonicated for another 2 h. The mixture was partitioned between water and ethyl acetate and the organic layer was washed with water (×2) then with brine. The organic extract was dried (magnesium sulfate) and solvent evaporated. The residue was purified via ISCO (0-50% Hex/EtOAc; 40 g silica gel column) to obtain title compound 217 (316 mg, 95%) as a white foam. LRMS: (calc) 397.11 (found) 398.1 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:14]3=[C:15]([CH2:17][CH2:18][N:13]3[C@@H:12]3[CH2:19][CH2:20][NH:21][CH2:22][C@H:11]23)[CH:16]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][CH2:31][CH2:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)=[O:34]>CCC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:14]3=[C:15]([CH2:17][CH2:18][N:13]3[C@@H:12]3[CH2:19][CH2:20][N:21]([CH2:30][CH2:31][CH2:32][C:33]([C:35]4[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=4)=[O:34])[CH2:22][C@H:11]23)[CH:16]=1
Reactant: Clc1ccccc1-c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CC2
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(CCCN1CC[C@@H]2[C@H](C1)c1cc(-c3ccccc3Cl)cc3c1N2CC3)c1ccc(F)cc1
Temperature: 25 °C
Yield: 46.6 %

Procedure:
(±)-Cis-2-(2-chlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole (26.4 mg, 0.085 mmol) 0.7 ml of MEK. KI (14 mg, 0.085 mmol) and K2CO3 (22 mg, 0.26 mmol), and 4-chloro-4′-fluorobutyrophenone (22.2 mg, 0.11 mmol) were added. The suspension was refluxed for 48 h and then cooled to rt. The suspension was filtered and the residue was washed with CH2Cl2 (5 ml). The solution was concentrated in vacuo. The residue was purified by column chromatography (10% MeOH—CH2Cl2) to afford the title compound (18.8 mg, 47%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 8.00-8.04 (m, 2 H), 7.41 (dd, 1H, J=1.5, 7.3 Hz), 7.30 (dd, 1H, J=1.8, 7.3 Hz), 7.10-7.20 (m, 4H), 7.01 (s, 1H), 6.96 (s, 1H), 3.68 (bt, 1H, J=6.6 Hz), 3.30-3.50 (m, 2H), 3.10-3.30 (m, 2H), 2.92-3.08 (m, 3H), 2.60-2.92 (m, 2H), 2.38-2.58 (m, 3H), 2.27 (t, 1H, J=11.3 Hz), 1.70-2.05 (m, 4H) ppm. MS (CI, NH3): 475 (base, M+H).
Reaction SMILES: [C:1]1([CH3:10])[C:2]([N:7]=[C:8]=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([NH2:25])[C:16](=[CH:21][C:22]=1[O:23][CH3:24])[C:17](OC)=[O:18].C[O-].[Na+]>C1(C)C=CC=CC=1>[C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:17](=[O:18])[C:16]2[C:15](=[CH:14][C:13]([O:12][CH3:11])=[C:22]([O:23][CH3:24])[CH:21]=2)[NH:25][C:8]1=[O:9]
Reactant: Cc1ccccc1N=C=O
Reactant: COC(=O)c1cc(OC)c(OC)cc1N
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2[nH]c(=O)n(-c3ccccc3C)c(=O)c2cc1OC
Temperature: 90 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
A solution of o-tolyl isocyanate (13.3 g, 0.10 mol) in toluene (40 ml) is metered at room temperature into a solution of methyl 4,5-dimethoxyanthranilate (21.1 g, 0.10 mol) in toluene (70 ml). After addition is complete, the mixture is stirred at 90° C. for 2 hours. 1.80 ml of a 30% strength solution of methanolic sodium methoxide (0.010 mol) are metered in and the mixture is stirred at 90° C. for a further 1 hour, methanol being distilled off. After cooling, the product is filtered off with suction and washed with 3×30 ml of toluene. The toluene-moist precipitate is treated with dilute sulfuric acid and the residual toluene is removed by azeotropic distillation. The product is then filtered off with suction, washed with water and dried. 29.0 g of 3-(2-tolyl)-6,7-dimethoxy-2,4(1H,3H)-quinazolinedione (yield: 92.9% of theory) of melting point 282° to 284° C. are obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].[CH2:15]([O:17][C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1)=[O:19])[CH3:16].CCN=C=NCCCN(C)C>CCO.[Pd]>[CH2:15]([O:17][C:18]([CH:20]1[CH2:21][CH2:22][N:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32](=[O:33])[NH:12][C:9]3[CH:10]=[C:11]4[C:6]([CH:5]=[CH:4][N:3]4[CH2:1][CH3:2])=[CH:7][CH:8]=3)=[CH:30][CH:31]=2)[CH2:24][CH2:25]1)=[O:19])[CH3:16]
Reactant: CCn1ccc2ccc([N+](=O)[O-])cc21
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Solvent: CCO
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc4ccn(CC)c4c3)cc2)CC1
Reaction time: 8 h
Yield: 34.8 %

Procedure:
A slurry of 1-ethyl-6-nitro-1H-indole (100 mg, 0.52 mmol) and 10% Pd/C (21 mg) in EtOH was hydrogenated under 1 atm of H2 for 2 h. The mixture was filtered and concentrated and the intermediate amine was dissolved in CH2Cl2 (5 mL) and treated with 1-(4-carboxy-phenyl)-piperidine-4-carboxylic acid ethyl ester (110 mg, 0.39 mmol) and EDCI (228 mg, 1.19 mmol). After stirring overnight the reaction mixture was partitioned between EtOAc and water. The EtOAc layer was collected, filtered and concentrated. The residue was chromatographed with 20-60% EtOAc in hexanes to afford the product (57 mg, Yield: 34%). HRMS m/z calcd for C25H29N3O3 [M+H]+: 420.2282. Found: 420.2280.
Reaction SMILES: [Cl:1][C:2]1[C:12]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:11][C:10]2[O:9][CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][C:4]=2[CH:3]=1.[BrH:26].C(O)C>C(O)C>[BrH:26].[Cl:1][C:2]1[C:12]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[N:11][C:10]2[O:9][CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(N3CCOCC3)c(Cl)cc2C1
Agent: Br
Solvent: CCO
Product: Clc1cc2c(nc1N1CCOCC1)OCCNC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 25 %

Procedure:
To a solution of the compound (0.10 g) obtained in step 1 in ethanol (1 mL) was added hydrobromic acid-ethanol solution (1 mL), and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure, and the aqueous layer was made basic with ethyl acetate and aqueous sodium hydroxide solution. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and hydrobromic acid-ethanol solution was added. The precipitate was collected by filtration to give the title compound (0.03 g, 25%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23](=[N:26][CH3:27])SC)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(#N)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:22][C:23]([NH:26][CH3:27])=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:6]2[NH:5][CH:4]=[N:3][C:2]=2[CH3:1])(=[O:20])=[O:21])=[CH:17][CH:18]=1
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CN=C(NS(=O)(=O)c1ccc(Cl)cc1)SC
Solvent: CC#N
Product: CNC(=NCCSCc1[nH]cnc1C)NS(=O)(=O)c1ccc(Cl)cc1
Yield: 59.1 %

Procedure:
A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (3.33 g.) and N-(4-chlorobenzenesulphonyl)-N',S-dimethylisothiourea (5.40 g.) in acetonitrile was heated under reflux for 24 hours. Concentration, followed by recrystallisation from aqueous ethanol afforded N-(4-chlorobenzenesulphonyl)-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)-methylthio)ethyl]guanidine (4.6 g.), m.p. 153°-154°.