Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][C:30]2=[O:36])[CH:26]=[CH:27][CH:28]=1.Cl>C(O)(C)C>[CH3:15][CH:14]([NH:13][C:11](=[O:12])[C:10]1[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=1[NH:8][C:6]1[C:5]([CH3:21])=[CH:4][N:3]=[C:2]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][C:30]3=[O:36])[CH:24]=2)[N:7]=1)[CH3:16]
Reactant: CN1CCN(c2cccc(N)c2)C(=O)C1
Reactant: Cc1cnc(Cl)nc1Nc1ccccc1C(=O)NC(C)C
Agent: Cl
Solvent: CC(C)O
Product: Cc1cnc(Nc2cccc(N3CCN(C)CC3=O)c2)nc1Nc1ccccc1C(=O)NC(C)C
Temperature: 25 °C
Yield: 27.1 %

Procedure:
2-[(2-Chloro-5-methyl-4-pyrimidinyl)amino]-N-(1-methylethyl)benzamide (103 mg, 0.337 mmol) and 1-(3-aminophenyl)-4-methyl-2-piperazinone (68.8 mg, 0.335 mmol) were stirred at 95° C. overnight in isopropanol (10 mL) with 12 N HCl (0.056 mL, 0.673 mmol). The reaction was cooled to room temperature and the solid was filtered off and washed with isopropanol. The solid was chromatographed using reverse phase HPLC eluting with 5-30% acetonitrile containing 0.1% formic acid to give a white solid (43 mg, 27%) after lyophilozation of the combined HPLC fractions. MS: M(C26H31N7O2)=473.57, (M+H)+=473.8.
Reaction SMILES: [C:1]([Si:5]([CH3:37])([CH3:36])[O:6][CH:7]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[C:23]([CH3:30])[CH:22]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH3:31])([CH3:4])([CH3:3])[CH3:2].[NH4+:38].[OH-]>>[C:1]([Si:5]([CH3:37])([CH3:36])[O:6][CH:7]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[S:25][C:24]([S:26]([NH2:38])(=[O:28])=[O:27])=[C:23]([CH3:30])[CH:22]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH3:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(S(=O)(=O)Cl)s1
Reactant: [NH4+]
Agent: [OH-]
Product: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Yield: 39 %

Procedure:
Using a procedure analogous to Example 134E, 5-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonyl chloride and NH4OH give the title compound (39%).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[C:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=O)[CH3:35]>>[CH2:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH:35]=[C:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(=CCc1ccccc1)c1ccccc1
Yield: 46.3 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (3.48 g, 7.78 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 4.9 mL, 7.78 mmol, 1.0 equiv.) and acetophenone (1.40 g, 11.7 mmol, 1.5 equiv.), 0.75 g (46%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[C:7]([CH:12]=[CH:13][O:14]CC)[CH:6]=2.Cl.[OH-].[Na+]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:12][CH:13]=[O:14])[CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: CCOC=Cc1cnc2cc(Br)cnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=CCc1cnc2cc(Br)cnc2c1
Yield: 95 %

Procedure:
To a mixture of the product from Example 153C (0.25 g, 0.89 mmol) in 15 mL of THF was added 1.5 mL of HCl (6N). The mixture was heated to reflux for 5 hr, cooled and the pH adjusted to 8.0 with NaOH. The mixture was diluted with 75 mL of CH2Cl2 and washed successively with a saturated solution of sodium bicarbonate, brine and water. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to give the desired product in 95% yield. 1H NMR (CDCl3, 300 MHz) δ 3.75 (m, 2H), 8.25 (m, 1H), 8.60 (m, 1H), 8.85 (m, 1H), 9.00 (m, 1H), 9.90 (s, 1H). MS (ESI) [M+H]+ at 252.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5](=[O:15])[CH:4]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:2].ClC1C(=O)C(C#N)=[C:26](C#N)[C:27](=[O:30])C=1Cl>C(OC(C)=C)(=O)C.C(Cl)Cl>[C:27]([O:15][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2)[CH:12]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:30])[CH3:26]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: CCC1Cc2cc(OC)ccc2C(=O)C1c1ccccc1
Agent: C=C(C)OC(C)=O
Solvent: ClCCl
Product: CCc1cc2cc(OC)ccc2c(OC(C)=O)c1-c1ccccc1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
3-Ethyl-6-(methyloxy)-2-phenyl-3,4-dihydro-1(2H)-naphthalenone (55) (0.84 g, 3.00 mmol) was dissolved in isopropenyl acetate (30 mL). pTsOH monohydrate (100 mg) was added. The mixture was refluxed under nitrogen for 3 days. Cooled to room temperature, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.74 g, 7.50 mmol) was added. The resulting mixture was refluxed under nitrogen overnight. Cooled to room temperature and diluted with CH2Cl2 (150 mL). The mixture was washed with 0.2 N NaOH (4×20 mL), water (2×20 mL), brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a dark brown tar. The crude product was purified by flash chromatography over SiO2 with hexanes:acetone (50:1) to give 0.61 g (64%) of the title compound (56) as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.11 (t, J=7.5 Hz, 3H), 1.97 (s, 3H), 2.55 (q, J=7.5 Hz, 2H), 3.93 (s, 3H), 7.10-7.16 (m, 2H), 7.20-7.25 (m, 2H), 7.30-7.45 (m, 3H), 7.57 (s, 1H), 7.62 (d, J=8.9 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:24][CH2:23][CH2:22][N:12]2[C:13]=1[C:14]1[N:15]=[N:16][C:17]([NH:20][NH2:21])=[CH:18][CH:19]=1.CO.O=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:24][CH2:23][CH2:22][N:12]2[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]2[N:16]([C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:21][N:20]=2)[N:15]=1
Reactant: CCOC(=O)C=O
Reactant: NNc1ccc(-c2c(-c3ccc(F)cc3F)nc3n2CCC3)nn1
Solvent: Ic1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4n3CCC4)nn12
Temperature: 70 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
A 250 mL pear flask was charged with 2-(2,4-difluorophenyl)-3-(6-hydrazinylpyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (7.90 g, 24.1 mmol) and MeOH (70 mL). To the flask was added ethyl 2-oxoacetate (Fluka, 5.72 mL, 28.9 mmol) and the mixture was heated to about 70° C. for about 1 h, at which point the starting material was consumed. The suspension was cooled to ambient temperature and the MeOH was removed under reduced pressure to give a brown solid. To the flask was added DCM (70 mL) and iodobenzene diacetate (10.1 g, 31.3 mmol) resulting in the formation of a dark solution. After about 1 h, the solution was poured into additional DCM (100 mL) and washed with water and brine. The layers were separated and the organic solution was dried over MgSO4, filtered, and concentrated to give a dark brown solid. The solid was triturated with Et2O (about 30 mL) and a brown solid was collected by vacuum filtration. A second trituration was carried out with Et2O/MeOH (9:1, 45 mL) to give the title compound as a light brown solid (7.25 g, 73%): LC/MS (Table 1, Method h) Rt=1.27 min; MS m/z: 411.1 (M+H)+.
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.Cl>N1C=CC=CC=1>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCCCCCCCCCO
Agent: Cl
Solvent: c1ccncc1
Product: C=CCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
4.32 g (54.0 mM) of dry pyridine was added to 3.40 g (20.0 mM) of 10-undecene-1-ol, followed by stirring for 10 minutes at 0° C. Into the solution was added 3.80 g (20.0 mM) of p-toluenesulfonyl chloride, followed by stirring for 4 hours at room temperature. After the reaction, 2M-hydrochloric acid was added to acidify the reaction liquid, followed by extraction with ether. Into the extract liquid was added anhydrous sodium sulfate, followed by drying and distilling-off of the ether to obtain 6.20 g (19.1 mM) of 10-undecenyl p-toluenesulfonate. Yield: 95.5%.
Reaction SMILES: Cl[C:2](OCC1C=CC=CC=1)=[O:3].[CH3:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([NH2:33])([CH2:31][OH:32])[CH2:29][OH:30])=[CH:24][CH:25]=1.Cl.Cl>[OH-].[Na+]>[OH:32][CH2:31][C:28]1([CH2:27][CH2:26][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12])=[CH:25][CH:24]=2)[CH2:29][O:30][C:2](=[O:3])[NH:33]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCCCCCCc1ccc(CCC(N)(CO)CO)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCc1ccc(CCC2(CO)COC(=O)N2)cc1

Procedure:
Benzyl chloroformate (0.45 ml; 3.2 mmol) is added to a suspension of FTY720.HCl (1.03 g, 3 mmol) in 2N NaOH (20 ml). The reaction is kept at RT over night and in order to complete the reaction further benzyl chloroformate (0.9 ml; 6.4 mmol) is added. After 2 days at RT the reaction is acidified with 1N HCl, extracted with methylenechloride and purified on a silica gel column using methylenechloride/methanol/acetic acid50% (9/1/0.125) as mobile phase.
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[C:16]=2[F:24])=[CH:11][C:10]1=[O:25])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1>[F:24][C:16]1[C:17]([O:22][CH3:23])=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:26])=[O:2])[C:10](=[O:25])[CH:11]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2c(F)ccc(OC)c2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Temperature: 5 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
To a solution containing (S)-2-[4-(2,6-difluoro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.254 g, 0.001 mol) in tetrahydrofuran (10 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 3 mL, 0.002 mol). The mixture was stirred at 5° C. for 3 h, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-[4-(2,6-difluoro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid, (0.212 g, 87%), as a light brown solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[H-].[Na+].[CH2:10](Br)[CH:11]=[CH2:12]>CN(C=O)C>[CH2:12]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7])[CH:11]=[CH2:10]
Reactant: O=C1CCCCN1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CCCCC1=O

Procedure:
2-Piperidinone is deprotonated with NaH in DMF solution and reaction with allyl bromide, and 1-allyl-2-piperidinone is obtained by distillation. Ozonolysis in MeOH solution at -78° C., followed by reductive workup with Me2S, gives the aldehyde derivative, which is reductively aminated using diethylamine hydrochloride and NaBH4 to give the title compound.
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[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][CH3:17].[C:28]([C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>N1C=CC=CC=1>[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:41][S:38]([C:35]2[CH:36]=[CH:37][C:32]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:33][CH:34]=2)(=[O:39])=[O:40])=[O:24])=[CH:21][CH:20]=1)[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][CH3:17]
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
A solution of 21.1 g. of 4-(hexadecylamino)benzoyl chloride hydrochloride and 10.8 g. of p-tert-butylbenzenesulfonamide in 250 ml. of pyridine was stirred under reflux for 2 hours and evaporated. The residue was partitioned between 1N hydrochloric acid and CH2Cl2 and the organic layer was separated, washed with water, dried (MgSO4), and evaporated. Crystallization of the residual glass from CH2Cl2 hexane afforded a white solid, melting point 173°-176° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]([C:17]([OH:19])=O)[CH2:15][CH2:14][CH2:13][CH:12]1[C:20]([OH:22])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OC(=O)C)(=O)C>O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:16]1[C:17](=[O:19])[N:33]([CH2:32][CH2:31][CH2:30][CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20]2=[O:22])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCCc1ccccc1
Reactant: O=C(O)C1CCCC(C(=O)O)N1C(=O)OCc1ccccc1
Solvent: C1COCCO1
Solvent: CC(=O)OC(C)=O
Product: O=C1C2CCCC(C(=O)N1CCCCc1ccccc1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Anhydride 2 (0.54 g, 1.89 mmol, prepared from Compound 1) was dissolved in 1 mL of dioxane. 4-Phenylbutylamine (0.28 g, 1.89 mmol) was added from the top. The mixture was stirred at room temperature for 1 hour. After this time, acetic anhydride (0.62 mL, 3.78 mmol) was added, and the reaction was refluxed for 5 hours. The dioxane was evaporated, and flash chromatographic purification of the residue (40% EtOAc/hexanes) gave Compound 13 (0.75 g, 95% yield) as a colorless thick oil. Rf=0.66 (40% EtOAc/hexanes); IR: 2935, 2863, 1710, 1688, 1430, 1341, 1311, 1256, 1126, 1096, 1069, 749, 699 cm−1; 1H NMR: δ 1.41-2.04 (m, 8H), 2.61 (t, 2H, J=6.9), 3.79 (t, 2H, J=6.9), 4.96 (s, 2H), 5.14 (s, 2H), 7.14-7.37 (m, 10H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[C:28](Cl)(=[O:32])[CH2:29][CH2:30][CH3:31]>N1C=CC=CC=1>[CH:27]1[CH:26]=[CH:25][N:17]2[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:14]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([C:3]4[CH:4]=[CH:5][N:1]([C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[N:2]=4)=[CH:7][CH:8]=3)=[O:13])[CH2:15][C:16]=12
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCC(=O)n1ccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)n1
Yield: 63.5 %

Procedure:
In the manner of Example 32, employing [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.71 g) in dry pyridine (10 ml) and butyryl chloride (0.32 g), the title compound (0.54 g) was obtained as a solid, m.p. 105-110° C.; MS, m/z: 424 (M)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:14]([O:16]CC)=[O:15])=[CH:11][NH:12][CH:13]=1.[OH-].[K+]>O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:14]([OH:16])=[O:15])=[CH:11][NH:12][CH:13]=1
Reactant: CCOC(=O)c1c[nH]cc1-c1cccc(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1c[nH]cc1-c1cccc(Cl)c1Cl
Yield: 97.4 %

Procedure:
A mixture of ethyl 4-(2,3-dichlorophenyl)pyrrole-3-carboxylate (5.95 g, 21 mmol) and potassium hydroxide (6.5 g, 85%, 99 mmol) is heated at reflux for 6 hours, cooled, diluted with water and washed with diethyl ether. The aqueous phase is acidified with hydrochloric acid and filtered to obtain a solid. The solid is washed with diethyl ether and petroleum ether and dried to give the title product as a white solid (5.24 g) which is identified by 1H and 13C NMR spectral analyses.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][CH2:13][CH2:14][NH:15][C:16]1[N:17]=[C:18]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[F:41])[C:19]2[CH:25]=[CH:24][C:23](=[O:26])[N:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[C:20]=2[N:21]=1)OC1C=CC=CC=1)#[N:2].[NH3:42]>C(O)(C)C>[C:1]([NH:3][C:4]([NH:12][CH2:13][CH2:14][NH:15][C:16]1[N:17]=[C:18]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[F:41])[C:19]2[CH:25]=[CH:24][C:23](=[O:26])[N:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[C:20]=2[N:21]=1)=[NH:42])#[N:2]
Reactant: N
Reactant: N#CNC(=NCCNc1nc(-c2ccc(F)cc2F)c2ccc(=O)n(-c3ccccc3F)c2n1)Oc1ccccc1
Solvent: CC(C)O
Product: N#CNC(=N)NCCNc1nc(-c2ccc(F)cc2F)c2ccc(=O)n(-c3ccccc3F)c2n1
Reaction time: 144 h
Yield: 60 %

Procedure:
To a solution of phenyl N-cyano-N′-(2-{[4-(2,4-difluorophenyl)-8-(2-fluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}-ethyl)imidocarbamate in isopropanol (2 mL) was added a 2M solution of ammonia in isopropanol (2 mL). The mixture was irradiated with microwave at about 60° C. for about 20 min. LC/MS showed a mixture containing approximately 25% product and 75% starting material. The mixture was kept in a sealed tube for 6 days. LC/MS showed 100% product. The solvent was evaporated and the residue was purified to give the title compound (20 mg, 60%). LC-MS m/z 479 (M+H)+, 2.84 min (ret time).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C@@H:12]([CH3:17])[CH2:13][C:14]([NH2:16])=[O:15])[CH2:9][CH3:10])=[C:4]([F:18])[C:3]=1[C:19]([C:21]1[CH:26]=[CH:25]C(C#N)=[CH:23][CH:22]=1)=[O:20].Cl.CC[O:32][C:33]([CH3:35])=[O:34]>>[C:14]([CH2:13][C@@H:12]([NH:11][C@@H:8]([C:5]1[C:4]([F:18])=[C:3]([C:19]([C:21]2[CH:26]=[CH:25][C:35]([C:33]([OH:32])=[O:34])=[CH:23][CH:22]=2)=[O:20])[C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][CH3:10])[CH3:17])(=[O:15])[NH2:16]
Reactant: CC[C@@H](N[C@@H](C)CC(N)=O)c1ccc(Cl)c(C(=O)c2ccc(C#N)cc2)c1F
Reactant: CCOC(C)=O
Agent: Cl
Product: CC[C@@H](N[C@@H](C)CC(N)=O)c1ccc(Cl)c(C(=O)c2ccc(C(=O)O)cc2)c1F
Reaction time: 48 h

Procedure:
To (3S)-3-{[(1R)-1-{4-chloro-3-[(4-cyanophenyl)carbonyl]-2-fluorophenyl}propyl]amino}-butanamide (compound of Example 91) (0.024 g, 0.06 mmol) added EtOAc (0.1 ml) and 6M HCl (0.1 ml)stirred at ambient 48 hours, evaporated down, residue dissolved in DMSO (0.1 ml) treated with K2CO3 (spatula end) stirred ambient for 16 hours, some primary amide product visible, further DMSO (0.1 ml) and 2M NaOH (0.2 ml) added stirred ambient 16 hours to give predominantly the acid. Reaction products purified by Prep HPLC to give 4-({3-[(1R)-1-{[(2S)-1-carbamoylpropan-2-yl]amino}propyl]-6-chloro-2-fluorophenyl}carbonyl)-benzoic acid (0.09 g).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([OH:11])=O)[CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CN(C=O)C>[Br:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[O:11])[CH:3]=1
Reactant: O=C(O)c1c[nH]c(=O)c(Br)c1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2c[nH]c(=O)c(Br)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-bromo-6-oxo-1,6-dihydropyridine-3-carboxylic acid (500 mg, 2.294 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (1044 mg, 2.75 mmol) in DMF (6 mL) was added 1-methylpiperazine (0.382 mL, 3.44 mmol). The mixture was stirred at room temperature for 2 hours and was purified via preparative HPLC, eluting with a gradient of 10-50% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA). The product-containing fractions were dried under vacuum to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([C:32]#[N:33])[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N-:35]=[N+:36]=[N-:37].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([C:32]5[NH:37][N:36]=[N:35][N:33]=5)[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OC1(c2ccc(Cl)cc2)CCN(CCC=C2Cc3c(cccc3-c3nnn[nH]3)Oc3ncccc32)CC1
Temperature: 100 °C
Reaction time: 36 h
Yield: 73.3 %

Procedure:
To a solution of the product of Example 364 (1.0 g) in DMF (10 ml) were added sodium azide (0.69 g) and ammonium chloride (0.56 g) and the mixture stirred at 100° C. for 36 hour. Water was added to the reaction mixture, and the precipitate was filtered and washed with ethanol to give the titled compound (800 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]#[CH:21].O>C(#N)C>[Cl:1][C:2]1[C:3]([O:12][CH2:21][C:20]#[CH:19])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C#CCOc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of 2-chloro-4-fluoro-5-nitrophenol (19.1 g) in acetonitrile (100 ml), there was added anhydrous potassium carbonate (8 g). After stirring at room temperature for several minutes, propargyl bromide (14 g) was added thereto, and the resultant mixture was heated under reflux for 3 hours. After being allowed to cool to room temperature, water was added thereto, and the reaction mixture was extracted with ether. The ether extract was washed with a 5% aqueous sodium hydroxide solution and water in this order, dried over anhydrous magnesium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol to obtain 13.5 g of 4-chloro-2-fluoro-5-(2-propynyloxy)nitrobenzene. M.P., 88°-89° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([NH2:11])[CH:10]=1)[CH3:2].C(N(CC)CC)C.[C:20](Cl)([CH3:22])=[O:21]>C(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([NH:11][C:20](=[O:21])[CH3:22])[CH:10]=1)[CH3:2]
Reactant: CCOCc1ccc(C)c(N)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1ccc(C)c(NC(C)=O)c1

Procedure:
N-(5-ethoxymethyl-2-methyl-phenyl)-acetamide VII-e was prepared as described for intermediate II-i using 5-ethoxymethyl-2-methyl-phenylamine I-e (5 g, 30.26 mmol), dry triethylamine (12.23 mL), DCM (60 mL) and AcCl (4.32 mL) to give the desired intermediate VII-e as a white solid (5.39 g, 86%). 1H NMR (300 MHz, CDCl3) δ 7.69 (s, 1H), 7.15 (d, J=7.7 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 4.46 (s, 2H), 3.53 (q, J=7.0 Hz, 2H), 2.23 (s, 3H), 2.18 (s, 3H), 1.23 (t, J=7.0 Hz, 3H).