Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6]2[C:7]([NH:26][C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)=[N:8][C:9]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][C:5]=2[CH2:4][NH:3]1.[Cl:34]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:34][C:10]1[C:5]2[CH2:4][NH:3][C:2](=[O:1])[C:6]=2[C:7]([NH:26][C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)=[N:8][C:9]=1[NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)c1
Solvent: ClCCl
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(Cl)c3c2C(=O)NC3)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A vial was charged with tert-butyl (1S,2R)-2-(3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (63 mg, 0.140 mmol) and N-chlorosuccinimide (18.63 mg, 0.140 mmol) in DCM (1.4 mL) to give a yellow solution. The solution was stirred for 1 h at RT. The crude reaction mixture was diluted with DCM (20 mL) and washed with saturated aq NaHCO3 (2×10 mL) followed by water (10 mL) and brine (10 mL). The organic layers were combined, dried over sodium sulfate, and concentrated to a residue which was purified by flash column chromatography. The collected fractions were concentrated to a brown residue to give the title compound as a cream colored solid upon drying (38.1 mg, 56%). [M+H] calc'd for C25H32ClN5O3, 486; found, 486.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.Cl.[CH2:26]([OH:28])[CH3:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:10]2[CH:11]=[CH:12][C:13]([C:16](=[NH:17])[O:28][CH2:26][CH3:27])=[CH:14][CH:15]=2)=[O:18])=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: CCO
Reactant: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Agent: Cl
Product: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
4-Chloro-3-(pyridin-2-yl)aniline (687 mg, 3.36 mmol) was dissolved in dichloromethane (8.0 ml) and THF (8.0 ml), treated with pyridine (0.33 ml, 4.0 mmol), and cooled to 0° C. 4-Cyanobenzoyl chloride (612 mg, 3.7 mmol) was added and the reaction was stirred for 1.0 hour. The reaction was diluted with dichloromethane and methanol was added to dissolve all solids. The solution was washed with water once, brine once, dried with MgSO4, and evaporated to an orange solid which was purified by silica gel flash column chromatography (50% ethyl acetate/50% hexanes) to afford 908 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-cyanobenzamide as a yellow solid. N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-cyanobenzamide (500 mg, 1.5 mmol) was slurried in ethanol (75 ml) and heated until just dissolved. The solution was cooled in an ice bath, and saturated with HCl gas. The solution was heated briefly to 70° C. to dissolve precipitated solids, cooled in an ice bath, and resaturated with HCl gas. The solution was then stored at 0° C. for 18 hours. The solution was saturated again with HCl gas, heated to 70° C. until all solids dissolved, cooled to 0° C., resaturated with HCl gas, and stored at 0° C. for 18 hours. Finally, nitrogen gas was bubbled through the solution for 1.0 hour, and the solution was evaporated to dryness. The residue was dissolved in methanol, treated with MP-carbonate (2.57 g) and stirred 30 min. The solution was filtered to afford a neutral, methanolic solution of ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate, which was diluted with enough methanol to make a 0.075 M solution.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1.[O:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([CH:31]5[CH2:32][CH2:33][O:28][CH2:29][CH2:30]5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1
Reactant: NC1CCC(CCN2CCN(c3nccc4ccoc34)CC2)CC1
Reactant: O=C(O)C1CCOCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccoc34)CC2)CC1)C1CCOCC1

Procedure:
The title compound, white solid (41 mg, 47%), MS (ISP) m/z=441.4 [(M+H)+], mp 211° C., was prepared in accordance with the general method of example 6 from 4-[2-(4-furo[2,3-c]pyridin-7-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and tetrahydropyran-4-yl-carboxylic acid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:9]=[O:10])[CH2:3][CH2:2]1.[O-:18][Mn](=O)(=O)=O.[K+].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:16])[F:17])[C:9]([OH:18])=[O:10])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 60 °C
Yield: 82.8 %

Procedure:
To a solution of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde (8.6 g, 35.5 mmol) in acetone (120 ml) and water (60 ml), KMnO4 (13.1 g, 70.8 mmol) was added and the reaction was heated at 60° C. for 1 h. K2CO3 (9 g, 65.2 mmol) and water (100 ml) were added, and the resulting mixture was filtered through a celite pad. The filtrate was acidified with HCl 37% (pH=1) and extracted twice with EtOAc. The organic phase was dried over Na2SO4 and the solvent was removed under vacuum affording 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid (7.6 g, 29.4 mmol, 83% yield). This product was used without any further purification.
Reaction SMILES: [C:1]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:49])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:48])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:47])[NH:34][CH2:35][CH2:36][CH2:37][N:38](C(OC(C)(C)C)=O)[CH3:39])=[CH:29][CH:28]=2)[CH3:19])[CH2:12][CH2:11]1.[ClH:56].CO.C1(C)C=CC=CC=1>ClCCl>[ClH:56].[ClH:56].[ClH:56].[C:1]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:49])[O:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[C:20](=[O:48])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33](=[O:47])[NH:34][CH2:35][CH2:36][CH2:37][NH:38][CH3:39])=[CH:31][CH:32]=2)[CH2:14][CH2:15]1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(C(=O)NCCCN(C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: CNCCCNC(=O)c1ccc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compound (135 mg, 0.178 mmol) obtained in Example 73d was dissolved in 2.0 mL of dichloromethane, 2.0 mL of a 2 N hydrochloric acid-methanol solution was added, and the mixture was stirred at room temperature for 16 hours. 10 mL of toluene was added to the reaction mixture, and then the solvent was evaporated under reduced pressure to give a crude title compound.
Reaction SMILES: Cl.[S:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:9]=2)[CH2:4][CH2:3]1.OO.C([O-])(=O)/C=C\C([O-])=[O:33].C(O)(C)C>S(=O)(=O)(O)O>[O:33]=[S:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:9]=2)[CH2:4][CH2:3]1
Reactant: O=C([O-])/C=C\C(=O)[O-]
Reactant: O=[N+]([O-])c1cccc2c(N3CCSCC3)nc(N3CCNCC3)cc12
Agent: Cl
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccc2c(N3CCS(=O)CC3)nc(N3CCNCC3)cc12
Yield: 41 %

Procedure:
1-(1-Oxido-thiomorpholino)-3-piperazino-5-nitro-isoquinoline was prepared analogous to Example 12 from 1-thiomorpholino-3-piperazino-5-nitro-isoquinoline hydrochloride by oxidation with hydrogen peroxide in dilute sulfuric acid. M.p. of its maleate: 231°-233°C (from isopropanol). Yield: 41% of theory.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[CH3:17].C1C(=O)N([Br:31])C(=O)C1>ClCCl.[Cl-].[Na+].O>[Br:31][C:21]1[CH:22]=[CH:23][C:18]([N:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[CH3:17])=[CH:19][CH:20]=1
Reactant: Cc1ccc(N(c2ccccc2)c2ccc(C)cc2C)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(N(c2ccc(Br)cc2)c2ccc(C)cc2C)c(C)c1
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of N-(2,4-dimethylphenyl)-2,4-dimethyl-N-phenylaniline (Compound 15) (12.4 g, 41 mmol) in dichloromethane (200 mL), was added NBS (8.01 g, 45 mmol) at 0° C. The whole was stirred for about 3 hours and worked up with brine. The organic phase was dried over Na2SO4, loaded on silica gel and purified by flash column using eluents of hexanes. After removal of solvents, a colorless oil (Compound 16) was obtained (15 g, in 96% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:40])([CH3:39])[CH:37]=[CH2:38])[NH:13]2)=[O:11])[CH2:4][O:3]1>C(OCC)(=O)C.O=[Pt]=O>[CH3:1][C:2]1([CH3:41])[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:40])([CH3:39])[CH2:37][CH3:38])[NH:13]2)=[O:11])[CH2:4][O:3]1
Reactant: C=CC(C)(C)CC1NC(C(=O)NCC[C@H]2COC(C)(C)O2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCC(C)(C)CC1NC(C(=O)NCC[C@H]2COC(C)(C)O2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reaction time: 1 h
Yield: 83.4 %

Procedure:
A suspension of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 80d (0.4 g, 0.65 mmol) and PtO2 (0.2 g) in ethyl acetate (15 mL) was vigorously shaken under H2 atmosphere (30 psi) for 1 h. The mixture was filtered through a short pad of celite, and the filtrate was concentrated to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide as a white gum (0.33 g, 83%).
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:7][CH2:6][N:5]([C:8]2[O:9][CH2:10][C:11](=[O:18])[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:4][CH2:3]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:10]2[O:9][C:8]([N:5]3[CH2:6][CH2:7][S:2](=[O:1])(=[O:19])[CH2:3][CH2:4]3)=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]2=[O:18])=[CH:21]1
Reactant: CCOC(=O)C1=C(N2CCS(=O)(=O)CC2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(N2CCS(=O)(=O)CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 96.3 %

Procedure:
To a solution of ethyl 2-(1,1-dioxidothiomorpholino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.027 g, 0.092 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.014 g, 0.092 mmol) in ethanol (0.5 mL), piperidine (0.00092 mL, 0.0093 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.037 g, y. 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](=O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([BH3-])#[N:16].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH2:16])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: [BH3-]C#N
Reactant: COc1ccc(CC(C)=O)cc1OC
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CC(C)N)cc1OC
Temperature: 25 °C
Reaction time: 67 h
Yield: 96.5 %

Procedure:
A mixture of 3,4-dimethoxyphenylacetone (51.1 g, 0.26 m) is dissolved in methanol (780 ml), sodium cyanoborohydride (11.3 g, 0.18 m) is added and the mixture is stirred at room temperature for 67 hours. The reaction mixture is adjusted to pH 2 with concentrated HCl and the solvent is evaporated under reduced pressure. The residue is dissolved in H2 0 (250 ml), the aqueous layer is extracted with ether (3X) and then rendered alkaline with KOH and extracted with CH2Cl2 (3X). After drying, the solvent is evaporated under reduced pressure and the product is distilled at 112°-5°/0.5 mm to yield (VIII) (33.88 g, 67%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][CH2:27][C:28]([C:31]([O:33][CH3:34])=[O:32])([CH3:30])[CH3:29])/[C:9]1=[O:35])=O)(C)(C)C.[F:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:52])=[C:41]([CH:43]=[N:44][C:45]([O:47][Si](C)(C)C)=[CH2:46])[CH:42]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:35])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][C:28]([C:31]([O:33][CH3:34])=[O:32])([CH3:30])[CH3:29])[CH2:46][C:45](=[O:47])[NH:44][CH:43]3[C:41]3[CH:42]=[C:37]([F:36])[CH:38]=[CH:39][C:40]=3[CH3:52])[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: COC(=O)C(C)(C)COc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)COc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Yield: 5.6 %

Procedure:
In a manner similar to the method described in Example 1e, E/Z-6-chloro-3-[5-chloro-2-(2-methoxycarbonyl-2-methyl-propoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (4.5 g, 9 mmol) was reacted with 1-(5-Fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (63 mmol) in toluene to give title compound as a white solid (Yield: 300 mg, 5.5%).
Reaction SMILES: [CH3:1][S:2](/[CH:5]=[CH:6]/[C@@H:7]([NH:24]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:11][CH:10]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.C(Cl)Cl.Cl>O>[CH3:1][S:2](/[CH:5]=[CH:6]/[C@@H:7]([NH2:24])[CH2:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[CH:11][CH:10]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C[C@@H](/C=C/S(C)(=O)=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(C[C@H](N)/C=C/S(C)(=O)=O)cc1
Reaction time: 0.5 h

Procedure:
Trityl protected amine 17 (0.54 g, 0.90 mmol) was treated with 1% v/v TFA/DCM (15 mL) at room temperature. To this yellow solution was added H2O (1 mL) which resulted in a colourless suspension. After stirring the mixture for 30 minutes, 10 mM aq. HCl (20 mL) was added and DCM was removed under reduced pressure. The aqueous layer was extracted with Et2O (3×) and basified with NaHCO3 until pH 9, after which it was extracted with DCM (3×). The latter combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting deprotected amine proved to be pure on LC-MS analysis and was subjected to the next step without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1)[C:5](=[O:21])[O:6][CH2:7][C@@:8]([OH:20])([CH3:19])[CH2:9][N:10]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[N:12]=[C:11]1Cl.O.C(OCC)(=O)C>CN(C=O)C>[CH3:3][N:4]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1)[C:5](=[O:21])[O:6][CH2:7][C@:8]1([CH3:19])[O:20][C:11]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:10]2[CH2:9]1
Reactant: CN(C(=O)OC[C@](C)(O)Cn1cc([N+](=O)[O-])nc1Cl)c1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C(=O)OC[C@@]1(C)Cn2cc([N+](=O)[O-])nc2O1)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Sodium hydride (0.48 g, 11.9 mmol) was added to a solution of (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl N-methyl-N-(4-trifluoromethoxyphenyl)carbamate prepared in Example 76 (4.50 g, 9.94 mmol) in DMF (13.5 ml) with cooling on ice-bath followed by stirring at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the precipitates were filtered off. The precipitates were recrystallized from isopropanol to afford (R)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl N-methyl-N-(4-trifluoromethoxyphenyl)carbamate (2.95 g, yield 71%) as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])(=[O:14])[CH3:13].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([C:12](=[O:14])[CH3:13])[CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1cccc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)c1cccc(C(=O)NCCNC(=O)OC(C)(C)C)c1
Reaction time: 2.5 h

Procedure:
N-(t-Butoxycarbonyl)ethylenediamine 2 (5 mmol, 800 mg) was weighed directly into a clean dry flask, which was then tightly stoppered. 3-Acetylbenzoic acid 3 (5 mmol, 820 mg) was added directly to the amine in the flask. Under an inert atmosphere dry dimethylformamide (15 mL) was added to the flask. Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (5 mmol, 2.21 g) was added to the solution, and subsequently N-methylmorpholine (15 mmol, 1.51 g, 1.7 mL) was added to the solution, and the mixture was allowed to stir for 2-3 hrs. The reaction mixture was quenched by the addition of 15 mL of water to the reaction flask, and partitioned between water (300 mL) and ethyl acetate (300 mL). The organic phase was washed successively with saturated sodium bicarbonate (200 mL), water (4×300 mL), and brine (200 mL) and then dried over anhydrous sodium sulfate. Filtering off the drying agent and concentration of the organic phase to ˜10-15 mL yielded a tan solid. Hexanes (˜30 mL) were added and the mixture gently heated to reflux. Upon cooling semicrystalline product was precipitated as a white powder. The product was collected by filtration and dried. Yield 775 mg, 51%.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[CH:16][N:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=4[C:21](=[O:29])[N:20]4[CH2:30][CH2:31][C@H:19]4[C:18]=23)[N:10]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]>C(OCC)(=O)C.[Pd]>[Cl:28][C:27]1[C:22]2[C:21](=[O:29])[N:20]3[CH2:30][CH2:31][C@H:19]3[C:18]3[N:17]([CH:16]=[N:15][C:14]=3[C:11]3[N:10]=[C:9]([CH2:8][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH3:7])[O:13][N:12]=3)[C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: C=CCN(CC=C)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)no1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)no1
Yield: 86.6 %

Procedure:
473 mg (1.1 mmol) of (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were hydrogenated in 10 ml of ethyl acetate in the presence of 20 mg of 5% palladium-on-charcoal at room temperature and normal pressure. After separating the catalyst the solution was concentrated. There was obtained 0.42 g (80%) of (S)-8-chloro-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 147°-153°.
Reaction SMILES: C([NH:4][C:5]1[N:6]=[C:7]([O:33][CH:34]([CH3:36])[CH3:35])[C:8]2[S:13][C:12](=[O:14])[N:11]([C@@H:15]3[O:27][C@H:26]([CH2:28][O:29]C(=O)C)[C@@H:21]([O:22]C(=O)C)[C@H:16]3[O:17]C(=O)C)[C:9]=2[N:10]=1)(=O)C.C([O-])([O-])=O.[K+].[K+].C1COCC1.C(Cl)(Cl)Cl>CO>[NH2:4][C:5]1[N:6]=[C:7]([O:33][CH:34]([CH3:36])[CH3:35])[C:8]2[S:13][C:12](=[O:14])[N:11]([C@@H:15]3[O:27][C@H:26]([CH2:28][OH:29])[C@@H:21]([OH:22])[C@H:16]3[OH:17])[C:9]=2[N:10]=1
Reactant: CC(=O)Nc1nc(OC(C)C)c2sc(=O)n([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)Oc1nc(N)nc2c1sc(=O)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 18 h

Procedure:
Compound 27 (600 mg, 1.14 mmol) was dissolved in methanol (15 ml) under a dry nitrogen atmosphere. K2CO3 (31.5 mg, 0.2 mmol) was added and the mixture was stirred for 18 h periodically being monitored by TLC (1:1 THF:Chloroform). The reaction mixture was concentrated under vacuum and purified by flash column chromatography (3% methanol in chloroform). The isolated solid was triturated with ethyl ether yielding 210 mg (51%) of pure 28 as a white solid: 1H NMR (400 MHz, d6-DMSO) δ 6.83 (s, 2H), 5.86 (d, J=5.2 Hz, 1H), 5.34 (m, 1H), 5.26 (d, J=5.6 Hz, 2H), 4.95 (d, J=5.6 Hz, 1H), 4.77 (m, 1H), 4.67 (m, 1H), 4.09 (m, 1H), 3.75 (m, 1H), 3.58 (m, 1H), 3.43 (m, 1H), 1.29 (d, J=6.4 Hz, 6H); MS (+)-ES [M+H]+ m/z 359, [2M+H]+ m/z 717.3. Rf=0.2 (50% THF—CHCl3). Elemental analysis for C13H18N4O16S: calc'd: C, 43.57; H, 5.06; N, 15.63; S, 8.95. Found: C, 43.39; H, 5.07; N, 15.45; S, 8.82.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C@H:7]([CH2:17][CH:18]=[CH:19][CH3:20])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.Cl>O1CCCC1>[CH2:10]([O:9][CH2:8][C@H:7]([O:6][CH2:5][CH:4]=[O:3])[CH2:17][CH:18]=[CH:19][CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC=CC[C@H](COCc1ccccc1)OCC(OCC)OCC
Agent: Cl
Solvent: C1CCOC1
Product: CC=CC[C@H](COCc1ccccc1)OCC=O
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a solution of ({[(2R)-2-(2,2-diethoxyethoxy)hex-4-en-1-yl]oxy}methyl)benzene (C10) (350 g from the previous step, ≦0.64 mol) in tetrahydrofuran (1.4 L) was added aqueous hydrochloric acid (2 M, 700 mL), and the reaction mixture was stirred at 75° C. for 1 hour. Solvent was removed in vacuo and the aqueous residue was extracted with ethyl acetate (2.0 L). The combined organic layers were washed with saturated aqueous sodium chloride solution (3×500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was obtained as a pale brown oil (210 g, ≦0.64 mol), which was taken directly to the following step.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([O:34][CH3:35])=[CH:16][CH:17]=[C:18]2[C:23]=1[O:22][C:21](=[O:24])[CH:20]=[C:19]2[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=1[Cl:33]>>[Cl:33][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([Cl:32])[C:26]=1[NH:25][C:19]1[C:18]2[C:23](=[C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:15]([O:34][CH3:35])=[CH:16][CH:17]=2)[O:22][C:21](=[O:24])[CH:20]=1
Reactant: C1COCCN1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCN1CCOCC1

Procedure:
The title compound was prepared from morpholine and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6): δ 9.52 (br s, 1H), 8.80 (s, 2H), 7.94 (d, 1H), 7.19 (d, 1H), 4.62 (s, 1H), 3.98 (t, 2H), 3.91 (s, 3H), 3.55 (br, 4H), 2.51-2.15 (br, 6H), 1.69 (m, 2H), 1.47 (m, 4H); MS (ESI): 507.9.