Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[C:5]([O:12][CH:13]([CH3:15])[CH3:14])=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.[BH4-].[Na+]>CO>[Cl:3][C:4]1[C:5]([O:12][CH:13]([CH3:15])[CH3:14])=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][CH2:1][NH2:2]
Reactant: CC(C)Oc1c(Cl)cccc1C=O
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)Oc1c(Cl)cccc1CCN
Reaction time: 72 h
Yield: 93 %

Procedure:
Methylamine (10.3 mL of a 2.0 M solution in MeOH, 20.6 mmol) was added to 3-chloro-2-isopropoxybenzaldehyde (0.500 g, 2.52 mmol) and the mixture was stirred for 72 h. The solution was concentrated under reduced pressure. The resulting light yellow oil was dissolved in EtOH (10.3 mL) and treated with NaBH4 (0.095 g, 2.52 mmol). After stirring for 18 h, the reaction mixture was concentrated under reduced pressure, dissolved in 1 N NaOH (20 mL) and extracted with Et2O (3×50 mL). The combined organics were washed with brine (2×75 mL), dried (Na2SO4) and concentrated to give the title compound (0.50 g, 93%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.40-7.31 (m, 2H), 7.08 (t, J=7.8 Hz, 1H), 4.42 (q, J=6.1 Hz, 1H), 3.66 (s, 2H), 2.25 (s, 3H), 2.02 (br s, 1H), 1.25 (d, J=6.1 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[Si]([O:27][K])(C)(C)C>C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([OH:27])=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)O[K]
Reactant: Clc1ccc(-c2c(Cl)nnc(Cl)c2-c2ccc(Cl)cc2)cc1
Solvent: C1CCOC1
Product: Oc1nnc(Cl)c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a round bottom flask was added 3,6-dichloro-4,5-bis(4-chlorophenyl)pyridazine (1000 mg, 2.710 mmol), THF (20 ml) and TMSOK (869 mg, 6.775 mmol). The reaction was stirred at 80° C. for 8 hrs. After this time, the reaction mixture was concentrated. The residue was diluted with water (15 ml). The pH of the resulting solution was adjusted to 4 using 1N HCl. During addition, a solid precipitated. The solid was collected by filtration to give product 6-chloro-4,5-bis(4-chlorophenyl)pyridazin-3-ol as white solid (760 mg, 80% yield). HPLC retention time (method A) 3.535 min; LCMS (M+H)=351.1.
Reaction SMILES: FC1C=C(C2N3C(C(O)CCC3)=C3N(C)C(=O)N(C)C(=O)C=23)C=CC=1.FC1C=C(C2N3C(C(=O)CCC3)=C3N(C)C(=O)N(C)C(=O)C=23)C=CC=1.[F:51][C:52]1[CH:53]=[C:54]([C:58]2[N:66]3[C:61]([C:62](=[O:68])[CH2:63][CH:64]([CH3:67])[CH2:65]3)=[C:60]3[N:69]([CH3:76])[C:70](=[O:75])[N:71]([CH3:74])[C:72](=[O:73])[C:59]=23)[CH:55]=[CH:56][CH:57]=1>>[F:51][C:52]1[CH:53]=[C:54]([C:58]2[N:66]3[C:61]([CH:62]([OH:68])[CH2:63][CH:64]([CH3:67])[CH2:65]3)=[C:60]3[N:69]([CH3:76])[C:70](=[O:75])[N:71]([CH3:74])[C:72](=[O:73])[C:59]=23)[CH:55]=[CH:56][CH:57]=1
Reactant: CC1CC(=O)c2c3c(c(-c4cccc(F)c4)n2C1)c(=O)n(C)c(=O)n3C
Agent: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(=O)CCC3
Agent: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(O)CCC3
Product: CC1CC(O)c2c3c(c(-c4cccc(F)c4)n2C1)c(=O)n(C)c(=O)n3C

Procedure:
The title compound was prepared analogously to Intermediate L using by replacing 5-(3-fluorophenyl)-1,3-dimethyl-8,9-dihydropyrimido[4,5-a]indolizine-2,4,10(1H,3H,7H)-trione in (step 2) with 5-(3-fluorophenyl)-1,3,8-trimethyl-8,9-dihydropyrimido[4,5-a]indolizine-2,4,10(1H,3H,7H)-trione.
Reaction SMILES: C1COCC1.[CH2:6]([N:9]([CH2:32][CH2:33][CH3:34])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:23][NH:24][CH2:25][C:26]3[NH:27][CH:28]=[CH:29][N:30]=3)[CH:20]=2)[C:15]1=O)[CH2:7][CH3:8]>CO>[NH:27]1[CH:28]=[CH:29][N:30]=[C:26]1[CH2:25][NH:24][CH2:23][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([CH2:13][CH2:12][CH2:11][CH2:10][N:9]([CH2:6][CH2:7][CH3:8])[CH2:32][CH2:33][CH3:34])[CH2:22]2
Reactant: CCCN(CCC)CCCCN1Cc2cc(CNCc3ncc[nH]3)ccc2C1=O
Solvent: CO
Solvent: C1CCOC1
Product: CCCN(CCC)CCCCN1Cc2ccc(CNCc3ncc[nH]3)cc2C1
Temperature: 0 °C
Yield: 53.3 %

Procedure:
A THF solution (2.0 ml) containing the compound (24.3 mg) obtained in Example 7-7 was added with a 1 mol/l borane-THF complex/THF solution (0.41 ml). The whole was refluxed under heating for 16 hours. After having been cooled to 0° C., the solution was added with methanol to stop the reaction and concentrated. The residue was added with a 1 mol/l hydrochloric acid (4.0 ml) and the whole was refluxed under heating for 3 hours. After having been left standing for cooling, the resultant was added with a 1 mol/l sodium hydroxide aqueous solution (5 ml) and the whole was subjected to extraction with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried with anhydrous sodium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (12.5 mg) as a colorless oily substance.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.Br[CH2:15][C:16]([O:18]CC)=[O:17].[OH-].[Na+].Cl>CN(C=O)C.CCO>[CH3:3][C:4]1[N:5]([CH2:15][C:16]([OH:18])=[O:17])[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: Cc1ccc2[nH]c(C)cc2c1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1ccc2c(c1)cc(C)n2CC(=O)O
Reaction time: 0.33 h

Procedure:
60% sodium hydride/oil (0.64 g) was added to a solution of 2,5-dimethyl-1H-indole (2.0 g) in DMF (15 ml). After 15 min ethyl bromoacetate (2.7 ml) was added quickly and the reaction stirred for 20 min. The mixture was quenched with 1% aqueous acetic acid (100 ml), extracted with ethyl acetate (2×100 ml) and washed with water (2×50 ml) and brine (20 ml). The extracts were dried (MgSO4), filtered and evaporated in vacuo to yield a brown solid. The solid was dissolved in EtOH (20 ml) and aqueous sodium hydroxide (1M,10 ml) added. After 1 h the solution was adjusted to pH6 with aqueous hydrochloric acid (1M,˜10 ml), and then evaporated in vacuo. The residue was purified by flash column chromatography (gradient 1-10% methanol in dichloromethane). The sub-title compound was obtained as a red/brown solid (1.3 g).
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]4[N:29]=[C:30]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[O:31][C:32]=4[C:33]([F:36])([F:35])[F:34])=[O:27])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])=CC=1)([O-])=O.C[O:44][C:45]([CH:47]1[CH2:51][CH2:50][NH:49][CH2:48]1)=[O:46]>>[C:37]1([C:30]2[O:31][C:32]([C:33]([F:35])([F:36])[F:34])=[C:28]([C:26]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([CH:16]4[CH2:15][CH2:14][N:13]([C:11]([N:49]5[CH2:50][CH2:51][CH:47]([C:45]([OH:46])=[O:44])[CH2:48]5)=[O:12])[CH2:18][CH2:17]4)=[CH:24][CH:23]=3)=[O:27])[N:29]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Nc1ccc(C2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: COC(=O)C1CCNC1
Product: O=C(Nc1ccc(C2CCN(C(=O)N3CCC(C(=O)O)C3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to above, 1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-pyrrolidine-3-carboxylic acid was prepared from 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carboxylic acid 4-nitro-phenyl ester and pyrrolidine-3-carboxylic acid methyl ester. LCMS calcd for C28H27F3N4O5 (m/e) 556, obsd 557 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][CH:15]=[C:16]([C:18]([OH:20])=[O:19])[CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O=P(Cl)(Cl)[Cl:23].O>C(O)(=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:23])=[C:6]2[CH:5]=[N:4]1)=[CH:14][CH:15]=[C:16]([C:18]([OH:20])=[O:19])[CH:17]=3)[CH3:2]
Reactant: CCn1nccc1Nc1cc(C(=O)O)ccc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CCn1ncc2c(Cl)c3ccc(C(=O)O)cc3nc21

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-4-carboxyanthranilic acid (2.5 g) and POCl3 (20 ml) is refluxed overnight. The reaction mixture is poured into water, acidified with acetic acid, and the solids which form are collected by filtration. The solid is taken up in 10% NaOH, washed with ether and then the aqueous layer is acidified with concentrated HCl. The mixture is extracted with ether, the ether layer is dried over MgSO4 filtered and evaporated to afford 1 g of 1-ethyl-4-chloro-7-carboxy-1H-pyrazolo[3,4-b]quinoline, as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[C:4](C(C)(C)C)[CH:3]=1.BrC1C=CC(O)=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O1C=CCCC1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1cc(Br)ccc1OC1CCCCO1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Oc1ccc(Br)cc1
Solvent: ClCCl
Product: Brc1ccc(OC2CCCCO2)cc1
Temperature: 25 °C

Procedure:
Using the same general procedure as for the preparation of 4-bromo-2-t-butyl-1-(2-tetrahydropyranoxy)benzene (Compound H), but instead using 15.00 g (86.7 mmol) of 4-bromophenol, 2.18 g (8.7 mmol) of pyridinium p-toluenesulfonate and 10.94 g (11.9 ml, 130.1 mmol) of 3,4-dihydro-2H-pyran and 75 ml of dichloromethane produced a clear, slightly yellow oil. Purification by flash chromatography (silica, 5% ethyl acetate in hexane) yielded a mixture of 4-bromophenol and the desired THP-ether. This mixture was separated by diluting with 300 ml of 1N aqueous NaOH solution, stirring at room temperature followed by ether extraction. The organic phase was dried over K2CO3, filtered and concentrated in vacuo to give the title compound as a white solid. PMR (CDCl3): d 1.5-2.1 (6H, m), 3.5-3.7 (1H, m), 3.8-3.95 (1H, m), 5.37 (1H, t, J=3.2 Hz), 6.9-6.96 (2H, m), 7.34-7.39 (2H, m).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]([NH:27][C:28](=[O:41])[CH2:29][N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])[C:21]=1[CH3:42])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:45]I.O>CN(C)C=O.C(OCC)(=O)C>[Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]([N:27]([CH3:45])[C:28](=[O:41])[CH2:29][N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])[C:21]=1[CH3:42])([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)CN2C(=O)c3ccccc3C2=O)c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(N(C)C(=O)CN2C(=O)c3ccccc3C2=O)c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
To a suspension of 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethyl-3-(phthalimidoacetylamino)benzene (57.4 g) and sodium hydride (4.78 g) in N,N-dimethylformamide (287 ml) was dropwise added methyl iodide (15.5 g) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature and for 2 hours at ambient temperature. Water and ethyl acetate were added thereto, and the resulting precipitate was collected by filtration and washed with water and ethyl acetate to give l-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethyl-3-[N-methyl-N-(phthalimidoacetyl)amino]benzene (28.18 g) as colorless crystals.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH2:3][OH:4].[N:15]#[C:16]Br>>[F:14][C:11]1[CH:10]=[CH:9][C:8]([S:7][CH2:6][CH2:5][C@H:2]2[CH2:3][O:4][C:16]([NH2:15])=[N:1]2)=[CH:13][CH:12]=1
Reactant: N[C@H](CO)CCSc1ccc(F)cc1
Reactant: N#CBr
Product: NC1=N[C@@H](CCSc2ccc(F)cc2)CO1

Procedure:
In analogy to example 1d (S)-2-amino-4-(4-fluoro-phenylsulfanyl)-butan-1-ol was reacted with cyanogen bromide to give (S)-4-[2-(4-fluoro-phenylsulfanyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine. Colourless oil. MS (ISP): 241.2 ([M+H]+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([NH:29]C(OCC2C3CC4C(=CC=CC=4)C=3C=CC=2)=O)=[C:6]([CH:28]=1)[C:7]([C:9]1[CH:27]=[CH:26][C:12](OCC2C=CC(OCC(O)=O)=CC=2)=[CH:11][CH:10]=1)=[O:8].O.OC1C2N=NNC=2C=CC=1.C(N=C=NC(C)C)(C)C.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>CN(C=O)C>[NH2:29][C:5]1[CH:4]=[CH:3][CH:2]=[CH:28][C:6]=1[C:7]([C:9]1[CH:27]=[CH:26][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(O)COc1ccc(COc2ccc(C(=O)c3cc(Cl)ccc3NC(=O)OCc3cccc4c3Cc3ccccc3-4)cc2)cc1
Agent: CC(C)N=C=NC(C)C
Agent: O=C1c2ccccc2C(=O)C1(O)O
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccccc1C(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a 30 mL peptide reaction flask was added 4-(4-(5-chloro-2-fluorenylmethoxycarbonylamino-benzoyl)-phenoxymethyl)phenoxyacetic acid (1.52 g, 2.4 mmol, 2.0 equivalents), aminomethyl resin (1.99 g, 1.19 mmol of 1% crosslinked divinylbenzene-styrene, 100 mesh size, substitution level 0.60 milliequivalents/g), and hydroxybenzotriazole monohydrate (0.808 g, 5.28 mmol, 4.4 equivalents). Anhydrous DMF (12 mL) was added to the flask and the mixture was vortexed for 0.5 hour to fully solvate the resin. Diisopropylcarbodiimide (808 mg, 5.28 mmol, 4.4 equivalents) was added by syringe. The reaction flask was stoppered and then vortexed for 24 hours at which point the ninhydrin test on approximately 10 mg of the solid support demonstrated that coupling was complete. The solvent and reagents were filtered away from the solid support and the support was rinsed five times with 2.0 mL DMF and five times with 20 mL CH2Cl2 (for each rinse the mixture was vortexed for at least 30 seconds before filtering off the solvent) and then dried in vacuo for 12 hours to give 5.
Reaction SMILES: C(OC(=O)NCC(=O)[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34]C=C(F)C=2)=[C:24]([Cl:37])[CH:23]=1)(C)(C)C.C(OC([N:47]1CC[CH2:49][C@H:48]1C(O)=O)=O)(C)(C)C>>[Cl:37][C:24]1[CH:23]=[C:22]([NH:21][C:14]2[C:13]3[C:18](=[CH:19][CH:20]=[C:11]([NH2:10])[CH:12]=3)[N:17]=[CH:16][N:15]=2)[CH:27]=[CH:26][C:25]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:49]=[CH:48][N:47]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Product: Nc1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1

Procedure:
The procedure of (1-5) of Example 1 was repeated except for using 414 mg of (2S)-pyrrolidine-1,2-dicarboxylic acid-1-t-butylester instead of 2-t-butoxycarbonylamino-ethanoic acid and 368 mg of the compound obtained in (145-2) to obtain the title compound (200 mg, 35%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:33][CH2:34]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f3) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([C:16]([O:18][CH2:19][C:20](=[O:40])[C:21]2[CH:22]=[CH:23][C:24]3[C:33]4[CH:32]=[C:31]5[CH2:34][CH2:35][CH2:36][C:37](=[O:38])[C:30]5=[CH:29][C:28]=4[O:27][CH2:26][C:25]=3[CH:39]=2)=[O:17])[CH2:5]1.[Br-:41].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.CO>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[C@H:6]([C:16]([O:18][CH2:19][C:20]([C:21]2[CH:22]=[CH:23][C:24]3[C:33]4[CH:32]=[C:31]5[CH2:34][CH2:35][CH:36]([Br:41])[C:37](=[O:38])[C:30]5=[CH:29][C:28]=4[O:27][CH2:26][C:25]=3[CH:39]=2)=[O:40])=[O:17])[CH2:5]1
Reactant: COC[C@H]1C[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCCC4=O)N(C(=O)OC(C)(C)C)C1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CO
Product: COC[C@H]1C[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(Br)C4=O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
(2S,4S)-1-tert-Butyl 2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl) 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (7.66 g, 13.9 mmol) was dissolved in a solution of DCM (100 mL) and MeOH (40 mL), then treated with pyridinium tribromide (4.90 g, 15.3 mmol). After stirring at RT for 1.75 h, the reaction mixture was diluted with DCM and washed successively with 10% HCl, saturated aqueous NaHCO3 and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure and the crude material was carried on without further purification.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:20]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:18]=[C:17]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:16]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Br:33]N1C(=O)CCC1=O>CN(C)C=O>[Br:33][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]([C:15]2[CH:20]=[C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:16]=2)=[C:14]2[C:5]=1[CH:4]=[CH:3][CH:2]=[CH:1]2
Reactant: c1ccc(-c2cc(-c3c4ccccc4cc4ccccc34)nc(-c3ccccc3)n2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Brc1c2ccccc2c(-c2cc(-c3ccccc3)nc(-c3ccccc3)n2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Dissolving 19 g (47 mmol) of 4-anthracen-9-yl-2,6-diphenyl-pyrimidine obtained in the foregoing step (2) into 200 milliliter of N,N-dimethylformamide, and adding 9.2 g (52 mmol) of N-bromosuccinimide, stirred at room temperature for 8 hours. After completion of the reaction, precipitated solids were separated by filtration and washed with water and methanol, thereby obtaining 14.9 g of 4-(10-bromo-anthracen-9-yl)-2,6-diphenyl-pyrimidine (yield: 66%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C@@H:17]2[CH2:21][O:20][CH2:19][C@H:18]2[OH:22])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].Cl[CH2:24][C:25]([OH:27])=[O:26].[K].Cl>C(O)(C)(C)C>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([S:16][C@@H:17]2[CH2:21][O:20][CH2:19][C@H:18]2[O:22][CH2:24][C:25]([OH:27])=[O:26])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: O=C(O)CCl
Reactant: CC(C)(C)c1cc(S[C@@H]2COC[C@H]2O)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [K]
Solvent: CC(C)(C)O
Product: CC(C)(C)c1cc(S[C@@H]2COC[C@H]2OCC(=O)O)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
The compound of Example 2 (3.6 g, 0.011 mole) and chloroacetic acid (2.04 g, 0.022 mole) were added to t-butyl alcohol (40 ml) to which had been added potassium (1.39 g, 0.033 mole) and the reaction mixture was refluxed for 36 hours. The reaction mixture was cooled to room temperature, and 1 N hydrochloric acid (50 ml) was added slowly. The reaction mixture was extracted twice with 100 ml of diethyl ether. The combined diethyl ether extracts were washed with saturated sodium bicarbonate (2×100 ml), 1 N hydrochloric acid (10 ml) and brine (20 ml) dried over anhydrous sodium sulfate, filtered and concentrated in a rotary evaporator to give the crude product as an oil. The product was purified by silica gel chromatography and recrystallized from ethyl acetate-hexane. The structure was supported by NMR and infrared spectroscopy and elemental analysis.
Reaction SMILES: [CH2:1]1[CH:12]2[CH:4]([NH:5][C:6]3[C:7]([C:13]([NH:15][C@H:16]([CH3:21])[C:17]([O:19]C)=[O:18])=[O:14])=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1.[OH-].[Li+]>C1COCC1>[CH2:1]1[CH:12]2[CH:4]([NH:5][C:6]3[C:7]([C:13]([NH:15][C@H:16]([CH3:21])[C:17]([OH:19])=[O:18])=[O:14])=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1
Reactant: COC(=O)[C@@H](C)NC(=O)c1cccc2c1NC1CCCC21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)c1cccc2c1NC1CCCC21)C(=O)O

Procedure:
Following the procedure of method 1D, methyl (2R)-2-[(1,2,3,3a,4,8b-hexahydrocyclopenta[b]indol-5-ylcarbonyl)amino]propanoate (2.7 mmol, 0.77 g) was hydrolyzed to the acid using 1 M aqueous lithium hydroxide (5.9 mL) in THF (20 mL) to yield an orange oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2Cl.[CH3:16][NH:17][CH:18]([CH3:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:17]([CH:18]([CH3:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH3:16]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: CNC(C)Cc1ccccn1
Product: COc1cc2ncnc(N(C)C(C)Cc3ccccn3)c2cc1OC

Procedure:
Reaction of 6,7-dimethoxy-4-chloroquinazoline with 2-(2-[N-methylamino]prop-1-yl)pyridine, according to the procedure of Example I, yielded the title compound, isolated as its dihydrochloride dihydrate, m.p. 242°-5°C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:33]([F:36])([F:35])[F:34])[C:25]([N:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:28])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[Cl-].[CH2:42]([NH:46][CH3:47])[CH:43]([CH3:45])[CH3:44]>C(Cl)Cl.CN(C=O)C>[CH2:29]([N:27]([CH3:28])[C:25]1[C:24]([C:33]([F:35])([F:36])[F:34])=[CH:23][C:18]2[NH:19][C:20](=[O:22])[CH2:21][C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([C:7]4[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][N:46]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH3:47])[CH:8]=4)[CH:10]=3)=[N:16][C:17]=2[CH:26]=1)[CH:30]([CH3:31])[CH3:32]
Reactant: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2
Reactant: CNCC(C)C
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)CN(C)Cc1cc(-c2cccc(C3=Nc4cc(N(C)CC(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from 4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-(isobutyl-methyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 366) (248 mg, 0.50 mmol) by reaction with thionylchloride in CH2Cl2 and subsequent treatment of the corresponding crude chloride with isobutyl-methyl-amine in DMF according to the general procedure of Example 288. Obtained as an off-white solid (176 mg, 45%).