Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[CH:10]=[C:11]2[CH:17]=[CH:16][N:15]([CH3:18])[C:12]2=[N:13][CH:14]=1>>[CH3:18][N:15]1[C:12]2=[N:13][C:14]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=[C:11]2[CH:17]=[CH:16]1
Reactant: Cn1ccc2cc(Br)cnc21
Reactant: Nc1ccccc1
Product: Cn1ccc2ccc(Nc3ccccc3)nc21

Procedure:
The procedure is in accordance with the protocol of Step B of Preparation 1″ using aniline and 5-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine (obtained in accordance with a protocol from the literature: Heterocycles, 60(4), 865, 2003).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[CH2:12][C:13]([OH:15])=O.[C:18]([CH:21]1[CH2:26][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH2:24][CH2:23][NH:22]1)(=[O:20])[NH2:19].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[F:11][C:9]1[CH:8]=[CH:7][C:6]([CH2:12][C:13]([N:22]2[CH2:23][CH2:24][N:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[CH2:26][CH:21]2[C:18](=[O:20])[NH2:19])=[O:15])=[C:5]([O:4][CH2:3][C:2]([F:1])([F:17])[F:16])[CH:10]=1
Reactant: Cc1ccccc1N1CCNC(C(N)=O)C1
Reactant: O=C(O)Cc1ccc(F)cc1OCC(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1N1CCN(C(=O)Cc2ccc(F)cc2OCC(F)(F)F)C(C(N)=O)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 2-(2,2,2-trifluoroethoxy)-4-fluorophenylacetic acid (0.15 g, 0.60 mmol) from Step 5 above and 2-carbamoyl-4-(2-methylphenyl)piperazine (0.13 g, 0.66 mmol) from Step 4 of Example 1 in DMF (3 mL) was added HOBT (0.11 g, 0.78 mmol), EDC (0.17 g, 0.9 mmol), and DIEA (0.16 mL, 0.9 mmol). The solution was stirred at ambient temperature for 14 h and the solvent was removed under reduced pressure. The residue was partitioned between EtOAc (50 mL) and 0.25 M aqueous citric acid (25 mL). The organic phase was separated and washed with H2O (10 mL) and saturated aqueous NaHCO3 (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 5:95 MeOH:CH2Cl2 as eluant. Evaporation of the product-containing fractions gave the title compound as an amorphous solid. HPLC retention time=9.16 min (method A) TLC Rf =0.25 (5:95 MeOH:CH2Cl2); FAB MS: m/z=454 (M+ +H), 0.4 CH2Cl2 ; combustion analysis: C22H23F4N3O3, 0.4 CH2Cl2 ; Calculated C, 57.43; H, 5.12; N, 8.97; Found C, 57.44; H, 4.89; N, 9.22
Reaction SMILES: [NH:1]([CH2:3][C:4]([NH:6][C@H:7]([C:19]([N:21]([CH2:23][C:24]([NH:26][C@H:27]([C:36]([NH2:38])=[O:37])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)=[O:25])[CH3:22])=[O:20])[CH:8](CC1C=CC=CC=1)[C:9](=[O:11])[OH:10])=[O:5])[CH3:2].C1(C[O:46][C:47]([C@@:49](C(Cl)=O)([CH2:51][CH2:52][CH2:53][NH:54][C:55](=[NH:57])[NH2:56])[NH2:50])=O)C=CC=CC=1>C(O)(=O)C.O.[Pd]>[NH2:50][C@H:49]([C:47]([N:1]([CH2:3][C:4]([NH:6][C@H:7]([C:19]([N:21]([CH2:23][C:24]([NH:26][C@H:27]([C:36]([NH2:38])=[O:37])[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=1)=[O:25])[CH3:22])=[O:20])[CH2:8][C:9](=[O:11])[OH:10])=[O:5])[CH3:2])=[O:46])[CH2:51][CH2:52][CH2:53][NH:54][C:55](=[NH:56])[NH2:57]
Reactant: N=C(N)NCCC[C@](N)(C(=O)Cl)C(=O)OCc1ccccc1
Reactant: CNCC(=O)N[C@H](C(=O)N(C)CC(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O)C(Cc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: CN(CC(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O)C(=O)[C@H](CC(=O)O)NC(=O)CN(C)C(=O)[C@@H](N)CCCNC(=N)N
Reaction time: 15 h
Yield: 50.4 %

Procedure:
Alpha-Phenylmethoxycarbonyl-L-Arginyl(HCl)-Sarcosyl-beta-benzyl-L-Aspartyl-Sarcosyl-L-Tyrosine amide (1.0 g) was dissolved in 100 ml of 75% aqueous acetic acid and reduced with 0.5 g of 10% Pd/C at 50 p.s.i. for 15 hours. The catalyst was removed by filtration and the solution lyophilized to give 0.8 g. The material was dissolved in 7 ml water, filtered through a 3μ multipore filter, adjusted to pH 5 with NH4OH(conc.) and chromatographed in an SP-C-25 column (2.5×100 cm) with 0.20 M NH4OAc, pH 5.0, 100 ml/hr, 20 ml/tube. Tubes 71 to 78 were pooled and lyophilized to give 0.35 g of Arg-Sar-Asp-Sar-Tyr-NH2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:29](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:29])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(CC(c1ccc(Br)cc1)c1ccc(Cl)cc1F)c1ccc(=O)[nH]c1
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccc(Cl)cc2F)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-3-(4-chloro-2-fluoro-phenyl)-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless solid, MS (ESI+): m/z=450.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[NH:8][CH2:7][CH2:6][CH2:5]2.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.O.[Cu]I>[CH3:14][O:13][CH:12]([O:15][CH3:16])[C:11]1[N:10]=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][NH:8]2)=[CH:3][C:2]=1[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)c1nc2c(cc1-n1ccnc1)CCCN2
Temperature: 120 °C

Procedure:
A suspension of 6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 12, 200 mg, 0.696 mmol), imidazole (66 mg, 0.969 mmol), Cs2CO3 (454 mg, 1.393 mmol) and CuI (27 mg, 0.142 mmol) in DMF (1.4 ml) was heated to 120° C. for 19 h. The reaction mixture was diluted with ethyl acetate and water, layers were separated and the aqueous layer was extracted with ethyl acetate (7×). Organic layers were combined, washed with water and brine, dried using Na2SO4, filtered, evaporated and dried to yield the title compound as a yellow solid. (UPLC-MS 3) tR 0.45 min, ESI-MS 275.1 [M+H]+.
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH2:8][CH2:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])[CH2:4][C:5]1=[O:11].[CH3:13]O>[Na+].Cl[Au-](Cl)(Cl)Cl>[CH3:13][O:12][C:3]1[CH:2]2[CH:6]([CH:7]3[O:10][CH:1]2[CH2:9][CH2:8]3)[C:5](=[O:11])[CH:4]=1
Reactant: O=C1CC(=O)C2C3CCC(O3)C12
Reactant: CO
Agent: Cl[Au-](Cl)(Cl)Cl
Agent: [Na+]
Product: COC1=CC(=O)C2C3CCC(O3)C12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a suspension of 10-oxa-tricyclo[5.2.1.0*2,6*]decane-3,5-dione (9.97 g, 60 mmol) in methanol (200 ml) is added sodium tetrachloroaurate (597 mg, 1.5 mmol) and the reaction mixture is heated to 60° C. for 7 hours. The reaction mixture is allowed to cool down to room temperature and left to stand overnight. The reaction mixture is concentrated under reduced pressure, dissolved in ethyl acetate (200 ml) and washed with aqueous 2N sodium carbonate (100 ml), followed by saturated brine (100 ml). The organic layer is then dried over magnesium sulphate and concentrated under reduced pressure to give 5-methoxy-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one (8.62 g)
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[C:15]([O:24][CH3:25])[CH:14]=1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][CH2:12][C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[C:15]([O:24][CH3:25])[CH:14]=1
Reactant: COc1cc(CNC(=O)OCc2ccccc2)ccc1OCC(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc(CN)ccc1OCC(=O)O
Yield: 55 %

Procedure:
A solution of 16 (0.276 g, 0.8 mmol) in MeOH (5 mL) was treated with 10% palladium on carbon (30 mg) and hydrogenated under a balloon of hydrogen for 30 min. The reaction mixture was filtrated and the filtrate was concentrated to give 17 as white solid (0.093 g, 55%) which was used to next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:15][C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[CH2:24][OH:25]>>[CH3:12][N:11]1[C:4]2[N:5]([C:6](=[O:8])[N:7]=[C:2]([O:25][CH2:24][C:17]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=3[F:15])[CH:3]=2)[CH2:9][C:10]1([CH3:14])[CH3:13]
Reactant: OCc1cc(F)c(F)cc1F
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3cc(F)c(F)cc3F)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (2,4,5-trifluorophenyl)methanol.
Reaction SMILES: [N:1]([C@@H:4]1[O:41][C@H:40]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[C@@H:15]([O:16][C@@H:17]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]2[O:19][C:20](=[O:22])[CH3:21])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]1[O:6][C:7](=[O:9])[CH3:8])=[N+]=[N-]>C(OCC)(=O)C.[Pd]>[NH2:1][C@@H:4]1[O:41][C@H:40]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[C@@H:15]([O:16][C@@H:17]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]2[O:19][C:20](=[O:22])[CH3:21])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]1[O:6][C:7](=[O:9])[CH3:8]
Reactant: CC(=O)OC[C@H]1O[C@@H](N=[N+]=[N-])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](N)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 99.4 %

Procedure:
A solution of 35 (0.67 g) in ethyl acetate (15 ml) was hydrogenated in the presence of Pd-C (0.3 g) at atmospheric pressure for one hour. Pd-C was filtered, and the solvent was evaporated to give 1-amino-1-deoxy-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-(1→4)-2,3,6-tri-O-acetyl-β-D-glucopyranose (36, 0.64 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:20])=[C:4]([F:23])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:30][O:31][C:32](Cl)=[O:33].O>C1COCC1>[C:32](=[O:33])([O:31][CH3:30])[O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[CH:9][C:8](=[O:20])[N:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][C:4]=3[F:23])[CH:12]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)Cl
Reactant: O=c1ccc(-c2ccc(O)cc2)cn1Cc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Oc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
According to Scheme 14 Method B: A suspension of 1-(4-chloro-2-fluorobenzyl)-5-(4-hydroxyphenyl)pyridin-2(1H)-one (1 eq, 0.61 mmol, 0.20 g, Example 20 Step 2), K2CO3 (10 eq, 6.10 mmol, 0.84 g) and methylchloroformate (4 eq, 2.43 mmol, 0.19 mL) in THF (10 mL) was stirred overnight at room temperature. Water was added to the reaction mixture, then the aqueous phase was extracted with AcOEt. The organic phase was dried over MgSO4, filtered and evaporated. The resulting crude oil was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 109 SiO2) using CH2Cl2/AcOEt 90/10 then washed with Et2O and was dried to afford 4-(1-(4-chloro-2-fluorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl methyl carbonate (0.36 mmol, 139 mg, 59%) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10].[F:13][C:14]1[C:19]([C:20]2[CH:21]=[C:22]3[C@@:33]4([CH2:38][CH2:37][O:36][C:35](/[N:39]=C/N(C)C)=[N:34]4)[C:32]4[C:27](=[N:28][CH:29]=[C:30]([OH:44])[CH:31]=4)[O:26][C:23]3=[CH:24][CH:25]=2)=[CH:18][CH:17]=[CH:16][N:15]=1>CN(C=O)C>[F:13][C:14]1[C:19]([C:20]2[CH:21]=[C:22]3[C@@:33]4([CH2:38][CH2:37][O:36][C:35]([NH2:39])=[N:34]4)[C:32]4[C:27](=[N:28][CH:29]=[C:30]([O:44][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:31]=4)[O:26][C:23]3=[CH:24][CH:25]=2)=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CC(C)(C)CI
Reactant: CN(C)/C=N/C1=N[C@@]2(CCO1)c1cc(-c3cccnc3F)ccc1Oc1ncc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)COc1cnc2c(c1)[C@]1(CCOC(N)=N1)c1cc(-c3cccnc3F)ccc1O2
Temperature: 100 °C
Reaction time: 6 h
Yield: 1.3 %

Procedure:
In a 35-mL resealable vessel, cesium carbonate (0.621 g, 1.905 mmol), 1-iodo-2,2-dimethylpropane (0.211 mL, 1.587 mmol), and crude (S,E)-N′-(7-(2-fluoropyridin-3-yl)-3-hydroxy-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-yl)-N,N-dimethylformimidamide (0.344 g, 0.794 mmol) were taken up in DMF (8 mL). The vessel was sealed and heated in a 100° C. oil bath. After 6 h, the reaction was concentrated. The residue was taken up in 10% MeOH/DCM (120 mL) and the organic layer was extracted with water (2×10 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was taken up in dioxane (8 mL), and a dioxane solution of HCl (4 M, 2 mL) was added. The vessel was sealed and heated in a 60° C. oil bath. After 1 h, the reaction was concentrated. The residue was diluted with water (30 mL) and the aqueous phase was extracted with 10% MeOH/DCM (3×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated. The material was purified by chromatography using 65:35:0.5:1 EtOAc-hexane-MeOH-Et3N to afford (S)-7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (4.5 mg, 0.010 mmol). MS (m/z) 449 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)#[N:2].[NH2:12][C@@H:13]([CH3:29])[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[CH:21]=2)=[N:16]1>>[Cl:28][C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][N:15]([CH2:14][C@@H:13]([NH:12][C:9]([C:7]3[N:8]=[C:4]([CH2:3][C:1]#[N:2])[S:5][CH:6]=3)=[O:11])[CH3:29])[N:16]=2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: N#CCc1nc(C(=O)O)cs1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(CC#N)n1
Yield: 1 %

Procedure:
2-(Cyanomethyl)thiazole-4-carboxylic acid (280 mg, 0.10 mmol) was coupled with (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile using the method of Example 34(d). Crude product was purified twice by CombiFlash (1st column: silica, eluent: 0-100% EtOAc in heptane; 2nd column: C-18 silica, eluent: 0-100% MeCN in water) to obtain 4.9 mg (1%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.26 (d, 3H), 4.13 (s, 2H), 4.31 (dd, 1H), 4.43 (dd, 1H), 4.55-4.67 (m, 1H), 6.63 (d, 1H), 7.49 (d, 1H), 7.70 (d, 1H), 7.79 (dd, 1H), 7.84 (d, 1H), 7.97 (d, 1H), 8.12 (d, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:16]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])C)[CH:12]=[C:11]([Cl:23])[C:10]=1[F:24])(C)(C)C.Cl>O1CCOCC1>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([Cl:23])[C:10]=1[F:24])[CH2:15][NH:16][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21]
Reactant: CN(C)CCN(C)Cc1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)CCNCc1cc(Cl)c(F)c(CN)c1

Procedure:
was prepared according to Scheme C2 (step D) from (3-chloro-5-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-2-fluoro-benzyl)-carbamic acid tert-butyl ester (165 mg, 0.46 mmol) and 4N HCl in dioxane (3 mL). MS (LC-MS): 260.0 [M]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[NH:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].S(Cl)(Cl)=O>>[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[N:24]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:12](=[O:14])[CH2:11][NH:10][C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:15]
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: CC(C)(C)OC(=O)CNc1cccc(Cl)c1Cl
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2cccc(Cl)c2Cl)c1
Yield: 12.9 %

Procedure:
Using a procedure similar to that described in Example 17, but starting with 2-[3-(3-methylphenyl)ureido]acetic acid (1.04 g), tert-butyl 2-[(2,3-dichlorophenyl)amino]acetate (1.4 g) and sulphinyl chloride (0.6 g), and after recrystallisation in acetonitrile, tert-butyl 2-{N-(2,3-dichlorophenyl)-2-[3 -(3-methylphenyl)ureido]acetamido}acetate (0.3 g), m.p. 135° C., is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([O:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH2:5][C:6]3=[O:11])=[N:14][CH:15]=1
Reactant: O=C1CCc2c(O)cccc21
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CCc2c(Oc3ccc(C(F)(F)F)cn3)cccc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
A mixture of 4-hydroxyindan-1-one (2.94 g, 19.8 mmol), 2-chloro-5-(trifluoromethyl)pyridine (3.00 g, 16.5 mmol), potassium-carbonate (6.84 g, 49.5 mmol) and N,N-dimethylformamide (40 mL) was stirred under a nitrogen atmosphere at 100° C. for 8 hr. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5-hexane/ethyl acetate=60/40) to give the title compound (2.74 g, yield 69%) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]2[CH:12]([CH:13]([NH:18]CC3C=CC=CC=3)[CH2:14][CH2:15][CH2:16]2)[NH:11][C:10](=[O:26])[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[NH2:18][CH:13]1[CH2:14][CH2:15][CH2:16][CH:17]2[CH:12]1[NH:11][C:10](=[O:26])[C:9](=[O:27])[N:8]2[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC2C(NCc3ccccc3)CCCC2N(Cc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: NC1CCCC2C1NC(=O)C(=O)N2Cc1ccccc1

Procedure:
(4aRS,5SR,8aRS)-1-Benzyl-5-(benzylamino)perhydroquinoxaline-2,3-dione (1.19 g, 3.28 mmol) was dissolved in methanol (40 ml) and NH4HCO2 (2.07 g, 32.8 mmol) was added. 120 mg of palladium-on-carbon (Merck) was furthermore added. The mixture was heated under reflux for 2 hours. The catalyst was then filtered off and the mixture was evaporated in vacuo. The residue was taken up in CH2Cl2 and the mixture was washed three times with 0.1 N NaOH. The organic phase was dried over Na2SO4 and evaporated in vacuo. A colorless solid was obtained.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[NH:4][C:5]([C:23](F)([F:25])[F:24])=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C1CCN2C(=NCCC2)CC1>C1COCC1>[F:25][CH:23]([F:24])[C:5]1[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:7]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:3]([C:2]([F:28])([F:1])[F:27])[N:4]=1
Reactant: CCOC(=O)C1=C(C(F)(F)F)NC(C(F)(F)F)=C(C(=O)OCC)C1CC(C)C
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1CC(C)C
Yield: 50.3 %

Procedure:
A mixture of 10.0 g (0.0240 mole) of diethyl 2,6-bis(trifluoromethyl)-l,4-dihydro-4-isobutyl-3,5-pyridinedicarboxylate, 3.65 g (0.0240 mole) of DBU and 150 ml of THF is held at reflux for 18 hours and concentrated. The residue is dissolved in ether and washed with diluted hydrochloric acid, dried (MgSO4) and concentrated. The residue is kugelrohr distilled at 0.1 torr to give 4.80 g (50%) of the desired product as an oil, nD25 1.4436.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH:15]([CH3:17])[CH3:16])[C:11]([Cl:18])=[CH:10][C:9]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH:15]([CH3:16])[CH3:17])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)Nc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)Nc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl

Procedure:
The title compound was prepared from (4-chloro-5-isopropylamino-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example C37) (3.75 g, 11.3 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as a brown solid (2.90 g, 86%).
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[C:7]2[C:11](=[O:12])[N:10]([CH:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]3=[O:20])[C:9](=[O:21])[C:8]=12)([O-])=O>C1COCC1.[Pd]>[NH2:1][C:4]1[S:5][CH:6]=[C:7]2[C:11](=[O:12])[N:10]([CH:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]3=[O:20])[C:9](=[O:21])[C:8]=12
Reactant: O=C1CCC(N2C(=O)c3csc([N+](=O)[O-])c3C2=O)C(=O)N1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1scc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 38.7 %

Procedure:
0.309 g of 1-nitro-5-(2,6-dioxopiperidin-3-yl)-5H-thieno(3,4-c)pyrrole-4,6-dione was dissolved in 40 mL of THF, and 0.309 g of 10% Pd/C were added. The reaction mixture was reacted under an atmosphere of hydrogen at room temperature for 4 h, filtered to remove the catalyst, evaporated to dryness. The reaction mixture was purified by silica gel column chromatography to obtain the title compound as a solid (0.108 g). 1H NMR (DMSO-d6): δ 11.00 (s, 1H), 7.62 (s, 2H), 7.19 (s, 1H), 4.91 (dd, 1H, J=3 Hz, J=3 Hz), 2.89-2.73 (m, 1H), 2.58-2.40 (m, 2H), 1.99-1.91 (m, 1H); MS (m/z): 278 (M−1)+.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:17]([NH:20][C:21]4[CH:42]=[CH:41][C:24]([C:25]([NH:27][C@H:28]([C:36]([O:38]CC)=[O:37])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:26])=[CH:23][CH:22]=4)(=[O:19])=[O:18])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>C(O)C.[OH-].[Na+]>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:17]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([C:25]([NH:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:26])=[CH:41][CH:42]=4)(=[O:19])=[O:18])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(NS(=O)(=O)c2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc3ccc(S(=O)(=O)Nc4ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc4)cc3c2c(=O)[nH]1
Yield: 100.4 %

Procedure:
A solution of diethyl N-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)sulfonamido)benzoyl)-L-glutamate (0.22 g, 0.37 mmol) in ethanol (3 ml) and 0.25 N NaOH (12 ml) was stirred at room temperature for 3 hours. The solution was slowly acidified to pH 3 with 1N HCl and the resulting precipitate filtered, washed with water, and dried under high vacuum to give N-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)sulfonamido)benzoyl)-L-glutamic acid as a white solid (0.20 g). 1H NMR (DMSO-d6, 200 MHz) δ: 1.73-2.15 (m, 2H, gluCH2), 2.27 (t, J=7 Hz, 2H, gluCH2), 2.43 (s, 3H, CH3), 4.22-4.36 (m, 1H, gluCH), 7.20 (d, J=9 Hz, 2H, Ar), 7.69 (d, J=9 Hz, 2H, Ar), 7.76 (d, J=9 Hz, 1H, Ar), 7.90 (dd, J=9, 2 Hz, 1H, Ar), 8.18 (d, J=9 Hz, 1H, Ar), 8.28 (d, J=9 Hz, 1H, Ar), 8.39 (d, J=8 Hz, 1H, gluNH), 10.44 (d, J=2 Hz, 1H, Ar), 10.86 (br s, 1H, SO2NH), 12.32 (br s, 2H, CO2H's), 12.75 (br s, 1H, N2H). Anal. Calculated for C25H22N4O8S.4/5H2O): C, 54.30; H, 4.30; N, 10.13; S. 5.80. Found: C, 54.29; H, 4.25; N, 10.13; S. 5.72.