Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[C:35]3[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:34]=3[O:33][C:32]2=[O:41])=[CH:27][CH:26]=1)(O)=[O:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:40][C:37]1[CH:38]=[CH:39][C:34]2[O:33][C:32](=[O:41])[CH:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][CH2:23][C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:21])=[CH:30][CH:29]=3)[C:35]=2[CH:36]=1
Reactant: Cc1ccc2c(c1)C(c1ccc(OCC(=O)O)cc1)C(=O)O2
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)COc1ccc(C2C(=O)Oc3ccc(C)cc32)cc1
Temperature: 200 °C
Reaction time: 1 h

Procedure:
A mixture of 5.0 g (18.5 mmol) of 1-octadecanol, 5.0 g (16.8 mmol) of 3-(4-carboxymethoxyphenyl)-5-methylbenzofuran-2-one (Compound (101), Example 1) and 1.0 g (5.3 mmol) of p-toluenesulfonic acid is stirred at 200° C. under a slight vacuum (150 mmHg) for about 1 hour. The reaction mixture is then diluted with 60 ml of ligroin and cooled with ice/water. The precipitated product is filtered. Crystallisation of the residue due from ligroin given 7.5 g (81%) of 5-methyl-3-(4-n-octadecyloxycarbonylmethoxyphenyl)benzofuran-2-one, melting pint 85°-87° C. (Compound (105), Table 1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[C:4]([C:8]([N+:13]([O-:15])=[O:14])=[C:9]([F:12])[C:10]=1[F:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:20])=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[C:3]([F:16])=[C:4]([C:8]([N+:13]([O-:15])=[O:14])=[C:9]([F:12])[C:10]=1[F:11])[C:5]([Cl:20])=[O:6]
Reactant: O=C(O)c1c(F)c(Cl)c(F)c(F)c1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1c(F)c(Cl)c(F)c(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a suspension of 25.6 g (100 mmol) of 3-chloro-2,4,5-trifluoro-6-nitrobenzoic acid in 75 ml of dichloromethane was added 14.0 g (110 mmol) of oxalyl chloride. This mixture was treated with four drops of dry N,N-dimethylformamide, and the rapidly bubbling solution was stirred overnight at room temperature. The mixture was concentrated to give 27.0 g of the title compound which was used without purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:4][C:3]=1[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:15]=2[N:14]=1.C(N(CC)CC)C.[CH3:32][C:33]([CH3:35])=O.C([BH3-])#N.[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH:33]([CH3:35])[CH3:32])[CH:5]=[CH:4][C:3]=1[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:15]=2[N:14]=1
Reactant: CC(C)=O
Reactant: NC(=O)c1cccc2[nH]c(-c3ccc(C4CCCN4)cc3F)nc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)N1CCCC1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 50F (80 mg) in methanol (3 mL) was added triethylamine (67 mL) and acetone (35 mL). This solution was stirred at ambient temperature for 1 hour, treated with sodium cyanoborohydride (30 mg), stirred at 50° C. for 18 hours and concentrated. The concentrate was purified by HPLC (Zorbax, C-18, 250×2.54 column, mobile phase A: 0.1% TFA in water; B: 0.1% TFA in CH3CN; 0-100% gradient). 1H NMR (CD3OD) δ 1.33 (d, J=6.71 Hz, 3H), 1.35 (d, J=6.71 Hz, 3H), 2.25-2.34 (m, 3H), 2.58-2.64 (m, 1H), 3.47-3.61 (m, 2H), 3.67-3.74 (m, 1H), 4.72-4.79 (m, 1H), 7.45 (t, J=7.78 Hz, 1H), 7.63 (d, J=8.24 Hz, 1H), 7.66 (d, J=11.90 Hz, 1H), 7.86 (d, J=8.24 Hz, 1H), 8.00 (d, J=7.32 Hz, 1H), 8.48 (t, J=7.78 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16](=[O:29])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH2:30][OH:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[S:39](Cl)([CH3:42])(=[O:41])=[O:40].Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16](=[O:29])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:26])([F:27])[F:28])[CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH2:30][O:31][S:39]([CH3:42])(=[O:41])=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1cccc(OC(F)(F)F)c1)[C@@H]1CC[C@H](CO)N1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CC[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2R,5S)-2-hydroxymethyl-5-(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (500 mg, 1.14 mmol) in CH2Cl2 (5 mL) was added at 0° C. under nitrogen atmosphere Et3N (350 μl, 2.5 mmol) and mesylchloride (197 μl, 2.5 mmol) and the mixture was further stirred at RT for 3 h. CH2Cl2 and HCl 0.1N were added, the layers were separated and the aqueous one re-extracted with CH2Cl2. The crude organic extracts were washed with brine dried over Na2SO4, filtered and concentrated. The crude material was used without further purification in the next step. MS (LC-MS): 517 [MH−Boc]+; tR (HPLC conditions b) 5.15 min.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[C:17]([F:22])[CH:18]=[CH:19][CH:20]=5)[NH:15][CH2:14][C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C.[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1>[C:41]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[N:12]2[CH:11]=[N:10][C:9]([C:6]3[N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[O:8][N:7]=3)=[C:13]2[CH2:14]1)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Fc1cccc2c1NCc1c(-c3noc(C4CC4)n3)ncn1-2
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1)N1Cc2c(-c3noc(C4CC4)n3)ncn2-c2cccc(F)c21
Reaction time: 5 h

Procedure:
To 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-6-fluoro-4,5-dihydroimidazo[1,5-a]quinoxaline (XXXIII, EXAMPLE 103, 0.438 g), diisopropylethylamine (0.26 ml), and dimethylamino-pyridine (0.018 g) in THF (20 ml) is added benzoyl chloride (0.19 ml). After stirring for 5 hr, additional benzoyl chloride (0.20 ml) is added. The reaction is stirred at 20°-25° for 2 hr, then stored over the weekend in the freezer. It is then stirred again at 20°-25° for 24 hr, after which the THF solvent is removed under reduced pressure and replaced with dichloromethane. After stirring for a final 7 hr, the reaction is partitioned between dichloromethane and aqueous sodium bicarbonate. The phases are separated and the organic phase is filtered through sodium sulfate, concentrated, and the crude product chromatographed on silica gel (300 ml) eluting with ethyl acetate/dichloromethane (20/80). The appropriate fractions are pooled and concentrated to give the product which is recrystallized from dichloromethane and hexane to give the title compound, nip 234.5°-235.5°; MS m/z at 401; IR (mineral oil) 1660, 1502, 1366, 786 and 1247 cm-1 ; NMR (CDCl3) 1.21, 2.20, 5.32, 6.98, 7.3-7.5 and 8.19 δ.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([F:23])=[CH:20][CH:21]=3)[CH:16]=[C:15]2[CH2:24][CH3:25])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C>CO>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([F:23])=[CH:20][CH:21]=3)[CH:16]=[C:15]2[CH2:24][CH3:25])[CH2:10][CH2:9]1
Reactant: CCc1cc2cc(F)ccc2n1C1CCN(Cc2ccccc2)CC1
Solvent: CC(=O)O
Solvent: CO
Product: CCc1cc2cc(F)ccc2n1C1CCNCC1
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
A solution of 1-(1-benzyl-piperidine-4-yl)-2-ethyl-5-fluoro-1H-indole (11.9 g) and acetic acid (4.1 ml) in methanol (250 ml) was hydrogenated for 8 h (50° C./1013 mbar). The mixture was then filtered and concentrated in vacuo. CH2Cl2 (250 ml), NaHCO3 (100 ml) and water (300 ml) were added and the mixture stirred for 10 min. The organic layer was extracted with CHCl3 and this was dried (MgSO4) and concentrated in vacuo. 6.4 g of pure product (73%) as colourless crystals was obtained by recrystallisation from ether/petroleum ether.
Reaction SMILES: [H][H].[C:3]([O:6][CH:7]=[CH:8][C:9]1([CH3:14])[NH:12][C:11](=[O:13])[CH2:10]1)(=[O:5])[CH3:4]>[Pd]>[C:3]([O:6][CH2:7][CH2:8][C:9]1([CH3:14])[NH:12][C:11](=[O:13])[CH2:10]1)(=[O:5])[CH3:4]
Reactant: [H][H]
Reactant: CC(=O)OC=CC1(C)CC(=O)N1
Agent: [Pd]
Product: CC(=O)OCCC1(C)CC(=O)N1

Procedure:
A solution of 4-(2-acetoxyvinyl)-4-methyl-2-azetidinone (10.0 g) 200 ml ethyl acetate containing 100 mg of 10% Pd/C is hydrogenated on a Parr shaker at 25° C. under 40 psi hydrogen for 15 minutes. The mixture is filtered through a bed of Supercel and washed with additional ethyl acetate. The combined filtrate is evaporated in vacuo to give 4-(2-acetoxyethyl)-4-methyl-2-azetidinone.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].[F:10][C:11]1[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:12]=1[CH2:13]Br>C(O)C>[F:10][C:11]1[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:12]=1[CH2:13][S:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Sc1ncccn1
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Fc1c(F)c(F)c(CSc2ncccn2)c(F)c1F
Reaction time: 0.75 h

Procedure:
To a mixture of 0.47 g of 2-mercapto-pyrimidine in 15 ml 95% ethanol was added 0.18 g of NaOH. The mixture was stirred 45 min. until an amber solution resulted; then 1 g of 2,3,4,5,6-pentafluorobenzyl bromide was added. The adduct precipitated within five minutes. Stirring continued for one hour. Filtration of the mixture yielded 0.26 g, mp 89°-92° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]2[N:6]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][O:24]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: C1=COCCC1
Reactant: Cc1cc(Br)cc2nc[nH]c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Br)cc2ncn(C3CCCCO3)c12
Yield: 94.7 %

Procedure:
A mixture of 74 (1.09 g, 5.19 mmol), TsOH.H2O (98 mg, 0.51 mmol), 3,4-dihydro-2H-pyran (2.4 mL, 26 mmol) in THF (15 mL) was degassed and then heated to reflux overnight. The solvent was removed in vacuo. The residue was partitioned between with DCM (300 mL) and water (50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated. The crude product was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (0.5% to 1% MeOH) to afford 1.45 g (95%) of 5-bromo-7-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole (76) as yellow solid: MS (ESI) m/z=295.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]12[CH2:9][N:8](C(OCC)=O)[CH2:7][CH:6]1[N:5]([CH3:15])[CH2:4][CH2:3]2>Cl>[Cl:1][C:2]12[CH2:9][NH:8][CH2:7][CH:6]1[N:5]([CH3:15])[CH2:4][CH2:3]2
Reactant: CCOC(=O)N1CC2N(C)CCC2(Cl)C1
Agent: Cl
Product: CN1CCC2(Cl)CNCC12

Procedure:
9.3 g (40 mmol) of ethyl 5-chloro-2-methyl-2,7-diazabicyclo[3.3. 0 ]octane-7-carboxylate are refluxed overnight together with 50 ml of concentrated hydrochloric acid. The mixture is concentrated, the concentrate is taken up in 30 ml of water, and this mixture is rendered alkaline using potassium carbonate and extracted five times using 50 ml portions of chloroform. The extracts are dried over potassium carbonate, concentrated and distilled.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:13][CH:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccccc2)C1
Reaction time: 1 h
Yield: 110.5 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)-3-hydroxy-pyrrolidine (430 mg, 2.30 mmol) in N,N-dimethylformamide (3 ml) was added to a solution of sodium hydride (60% dispersion in mineral oil, 137 mg, 3.43 mmol) and the mixture was stirred for one hour. A solution of benzyl bromide (562 mg, 3.29 mmol) in N,N-dimethylformamide (1 ml) was added to the solution and the mixture was stirred overnight. Reaction was quenched with water and the reaction mixture was extracted with diethyl ether. The organic layer was washed with water and dried over sodium sulfate. Removal of solvent afforded crude 3-benzyloxy-1-(tert-butoxycarbonyl)-pyrrolidine (705 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:20]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:10]1=[O:29])[CH2:6][CH2:7][OH:8].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:32].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:20]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:10]1=[O:29])[CH2:6][C:7]([OH:32])=[O:8]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: COC(=O)CC(CCO)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC(CC(=O)O)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Reaction time: 20 h
Yield: 64.4 %

Procedure:
5-Hydroxy-3-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]pentanoic acid methyl ester (70 mg, 0.17 mmol) is dissolved in DMF (1.5 mL) at room temperature and pyridinium dichromate (250 mg, 0.66 mmol) is added into it. The mixture is stirred for 20 hr and water (25 mL) is added. The pH of the solution is adjusted to pH 5 by adding acetic acids and the mixture is extracted with EtOAc (3×50 mL). The organic layers are combined, dried and concentrated to give crude product. Purification by preparative TLC using 80% EtOAc in Hexanes with 1% acetic acid affords 48 mg (66%) of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-pentanedioic acid monomethyl ester. LCMS (ESMS): m/z 439.17 (M+H+).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[Br:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1>N1CCCCC1.C(O)C>[Br:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19](=[CH:11][C:8]3[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=3[CH3:13])[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2cc(Br)ccc21
Yield: 92.3 %

Procedure:
4-(2-carboxyethyl)-2-formyl-3-methylpyrrole (90 mg), 106 mg 6-bromo-2-oxindole, and 3 drops piperidine in 3 mL of ethanol were heated at 90° C. for 4 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 172 mg (92%) of the title compound as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]=[C:21]3[NH2:26])[CH2:9]1)=O)(C)(C)C.[ClH:27].CO>>[ClH:27].[NH2:26][C:21]1[C:22]2[C:17](=[C:16]([O:15][CH2:14][CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)[CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:19][N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(COc2cccc3c(N)nccc23)C1
Agent: Cl
Solvent: CO
Product: Nc1nccc2c(OCC3CCCNC3)cccc12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 23 (179 mg) and 10% hydrogen chloride/methanol solution (2.5 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (0.5 ml) and diethyl ether (1.5 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (132 mg) as white powdery solid.
Reaction SMILES: [C:1]([CH:3]([NH:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[NH:28][C:27]2=[O:36])[CH2:22][CH2:21]1)=[O:19])[CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([CH2:14][CH3:15])[CH:13]=1)[NH:10][N:9]=[C:8]2[CH3:16])#[N:2].[N:37]([Sn](C)(C)C)=[N+:38]=[N-:39]>O1CCCC1>[CH2:14]([C:12]1[CH:13]=[C:5]([CH2:4][CH:3]([NH:17][C:18]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[CH2:24][CH2:25]2)=[O:19])[C:1]2[NH:39][N:38]=[N:37][N:2]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[C:8]2[CH3:16])[CH3:15]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCc1cc(CC(C#N)NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)cc2c(C)n[nH]c12
Solvent: C1CCOC1
Product: CCc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nnn[nH]2)cc2c(C)n[nH]c12

Procedure:
A stirred solution of 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-cyano-2-(7-ethyl-3-methyl-1H-indazol-5-yl)-ethyl]-amide (0.25 g, 0.5 mmol) in tetrahydrofuran (6 mL) was treated with azidotrimethyltin (0.16 g, 0.77 mmol). The resulting suspension was heated at reflux overnight. The solvents were evaporated, dissolved in ethyl acetate and washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography afforded the desired tetrazole. 1H-NMR (CD3OD) δ 1.3 (t, J=7.6, 3H), 1.45-1.70 (m, 4H), 1.87 (m, 1H), 2.0 (s, 3H), 2.75-2.90 (m, 4H), 3.42 (m, 1H), 3.72 (d, J=6.6, 1H), 4.12 (m, 4H), 4.88 (m, 1H), 5.48 (dd, J=7.0, 7.9, 1H), 6.77 (d, J=7.9, 1H), 6.94 (m, 1H) 6.98 (s, 1H), 7.09 (d, J=7.3, 1H), 7.14 (dd, J=7.9, 7.6, 1H), 7.30 (s, 1H). Mass spec.: 529.26 (MH)+.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([O:13][CH3:14])=[CH:6][C:5]=1F.[C:16]([O:23][CH3:24])(=[O:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19].Cl>CN1CCCC1=O.O>[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([O:13][CH3:14])=[CH:6][C:5]=1[CH:17]([C:16]([O:23][CH3:24])=[O:22])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CC(=O)OC
Reactant: COc1cc(F)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)C(C(=O)OC)c1cc(OC)c([N+](=O)[O-])cc1Cl
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
Sodium hydroxide (4.49 g, 112.3 mmol) was added at room temperature to a stirred solution of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene (11.0 g, 53.5 mmol) and dimethyl malonate (8.976 g, 67.9 mmol) in N-methylpyrrolidinone (110 mL). The mixture was heated to 80° C. for 2 hours then cooled to 5° C. The pH of the mixture was adjusted to 2 using aq. 1N HCl solution then water (600 mL) was added gradually with stirring over 15 minute at 5° C. The precipitated solid was collected by filtration and washed with water (2×20 mL). The filtered solid was dissolved in dichloromethane (150 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound (15.5 g, 91%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=O.O.[NH2:20][NH2:21].NN>O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([C:8]#[N:9])[CH:4]=3)[NH:21][N:20]=2)=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(F)c(C(=O)c2ccc(F)cc2)c1
Reactant: NN
Solvent: O
Product: N#Cc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reaction time: 8 h

Procedure:
To a flask containing 4-fluoro-3-{(4-fluorophenyl)carbonyl}benzenecarbonitrile (4.2 g, 0.017 mmol) was added hydrazine monohydrate (15 mL) and anhydrous hydrazine (10 mL). In an addition flask the procedure was repeated. Both flasks were allowed to stir overnight exposed to the atmosphere. LCMS confirmed the reactions were complete. To the flasks were added an excess amount of water. The reactions were allowed to stir for two hours. The product of the reactions was collected via a flitted funnel by filtration and combined to yield the title compound. The product was allowed to dry under vacuum and taken on crude into the next step of the synthesis. 1H NMR (DMSO-d6) 8.7 (s, 1H), 8.1 (m, 2H), 7.7–7.8 (m, 2H), 7.3–7.4 (t, 2H), ES-MS m/z 238 [M+1]+
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:18])=O)[CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1.[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([NH:28][C:16]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]2[CH2:5][CH2:4][CH:3]([N:2]([CH3:1])[CH3:19])[CH2:15][C:14]3=2)=[O:18])=[CH:24][CH:23]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(C(=O)O)cc3c2C1
Reactant: COc1ccc(N)cn1
Product: COc1ccc(NC(=O)c2ccc3[nH]c4c(c3c2)CC(N(C)C)CC4)cn1
Yield: 14 %

Procedure:
Beginning with 7.4 mg (0.029 mMol) 3-dimethylamino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxylic acid and 6-methoxy-3-aminopyridine, 1.8 mg (14%) of the title compound were recovered.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([Br:16])=[CH:11][C:10]=2[F:17])[N:5]=[C:4]([C:18]([O:20]C)=[O:19])[C:3]=1[Cl:22].CO.[OH-].[Na+]>CC(C)=O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([Br:16])=[CH:11][C:10]=2[F:17])[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1[Cl:22]
Reactant: COC(=O)c1nc(-c2cc(F)c(Br)cc2F)c(F)c(N)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: Nc1c(F)c(-c2cc(F)c(Br)cc2F)nc(C(=O)O)c1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a solution of methyl 4-amino-6-(4-bromo-2,5-difluorophenyl)-3-chloro-5-fluoropicolinate (0.160 g, 0.404 mmol) in a 1:1 mixture of MeOH (0.674 mL) and acetone (0.674 mL) was added a 2 N aqueous solution of sodium hydroxide (0.607 mL, 1.213 mmol). The reaction mixture was stirred at 20° C. overnight. The reaction mixture was concentrated, poured into a 2 N aqueous solution of HCl, and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered, concentrated and dried in vacuo to afford the title compound as a light brown solid (126 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7](=[O:20])[CH:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][O:32][C:33](=[O:35])[CH3:34]>CN(C)C=O.C(OCC)(=O)C>[C:33]([O:32][CH2:31][CH2:30][N:6]1[C:5]2[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][C:4]=2[C:10](=[O:11])[NH:9][CH:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]1=[O:20])(=[O:35])[CH3:34]
Reactant: O=C1NC(Cc2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCCN1C(=O)C(Cc2ccccc2Cl)NC(=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 7-chloro-3-(2-chlorobenzyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (0.5 g, 1.5 mmol) in N,N-dimethylformamide (10 mL), was added powdered potassium carbonate (0.31 g, 2.2 mmol) followed by 2-bromoethylacetate (0.17 mL, 1.6 mmol). The mixture was stirred at ambient temperature overnight. After 20 hours, more 2-bromoethylacetate (0.05 mL, 0.5 mmol) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (3×50 mL), washed with brine (50 mL), dried with anhydrous sodium sulfate, decanted, and concentrated to yield crude 2-(7-chloro-3-(2-chlorobenzyl)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)ethyl acetate, which was used directly in the next step without further purification. MS (m/z): 421.1 (M+H)+.