Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10](S(C)(=O)=O)[N:11]=[C:12]([CH3:13])[C:7]=2[CH:6]=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]1=[O:24])[CH3:2].[CH2:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)[CH3:26]>CS(C)=O>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:37][C:36]3[CH:35]=[CH:34][C:33]([N:30]4[CH2:29][CH2:28][N:27]([CH2:25][CH3:26])[CH2:32][CH2:31]4)=[CH:39][CH:38]=3)[N:11]=[C:12]([CH3:13])[C:7]=2[CH:6]=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]1=[O:24])[CH3:2]
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Reactant: CCn1c(=O)c(-c2ccccc2)cc2c(C)nc(S(C)(=O)=O)nc21
Solvent: CS(C)=O
Product: CCN1CCN(c2ccc(Nc3nc(C)c4cc(-c5ccccc5)c(=O)n(CC)c4n3)cc2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
8-Ethyl-4-methyl-2-(methylsulfonyl)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one (275 mg, 0.80 mmol) and 4-(4-ethylpiperazin-1-yl)aniline (197 mg, 1.2 equiv.) were added to dimethyl sulfoxide (5 mL) and the resulting mixture was heated to 100° C. and stirred overnight. After cooling to room temperature, the reaction was partitioned between aqueous and organic layers with ethyl acetate and H2O, organic layer was dried with anhydrous magnesium sulfate, filtered and evaporated, and directly applied to prep-LC to provide the title compound in (210.0 mg, 56% yield): 1H NMR (400 MHz, CDCl3): δ 7.80 (s, 1H), 7.62 (d, 2H), 7.60 (d, 2H), 7.40 (m, 2H), 7.18 (s, 1H), 6.95 (d, 2H), 4.50 (q, 2H), 3.22 (m, 4H), 2.70 (m, 4H), 2.60 (s, 3H), 2.50 (m, 2H), 1.40 (t, 3H), 1.20 (t, 3H); MS (EI) for C28H32N6O: 469.10 (MH+).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[N:4]1[CH2:10][C:11]([OH:13])=[O:12].O[N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[O:21]=[C:16]1[CH2:17][CH2:18][C:19](=[O:20])[N:15]1[O:12][C:11](=[O:13])[CH2:10][N:4]1[CH:3]([CH3:2])[CH2:8][CH2:7][CH2:6][CH:5]1[CH3:9]
Reactant: O=C1CCC(=O)N1O
Reactant: CC1CCCC(C)N1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC1CCCC(C)N1CC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.15 g (20 mMol) (2,6-dimethyl-piperidin-1-yl)-acetic acid hydrochloride (6), in 50 ml DMF, was added to 2.3 g (20 mMol) N-hydroxysuccinimide and 8.1 g (40 mMol) dicyclohexylcarbodiimide. The reaction mixture was stirred for 16 h at RT. The residue was filtered and the filtrate was evaporated under vacuum to dryness. After dissolving the residue in CH2Cl2, the solution was washed with NaHCO3, dried (sodium sulphate) and the solvent evaporated. The compound was then recrystallised from diisopropylether (A-Kohle).
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1[C:9](=[O:19])[O:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[OH:18])#[N:7].[H-].[Na+].[C:22]([O:25][CH2:26][CH2:27][CH2:28]Br)(=[O:24])[CH3:23]>O>[C:6]([C:8]1[C:9](=[O:19])[O:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[O:18][CH2:28][CH2:27][CH2:26][O:25][C:22](=[O:24])[CH3:23])#[N:7]
Reactant: N#Cc1cc2cccc(O)c2oc1=O
Reactant: CC(=O)OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCCOc1cccc2cc(C#N)c(=O)oc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 25 %

Procedure:
In 150 ml. of dry dimethylformamide was dissolved 9.35 g. of 3-cyano-8-hydroxycoumarin. To the resulting solution was added 2.5 g. of about 60% sodium hydride with agitation and ice-cooling, and after raising to room temperature, the solution was agitated for 20 minutes. After adding dropwise 9.05 g. of 3-acetoxypropyl bromide at a temperature of 80° to 90° C. with agitation, the reaction was carried out for 5 hours with agitation. After the completion of the reaction, the reaction mixture was poured into 200 ml. of water added with ice, and extracted with three 200 ml. portions of methylene chloride. The obtained extract was dried with magnesium sulfate, and the solvent was then distilled away under reduced pressure. The residue was purified by a silica-gel column chromatography (silica-gel: 350 g., eluent: methylene chloride) to give 3-cyano-8-(3-acetoxypropoxy)coumarin (yield: 25%). The product was further recrystallized from ethyl acetate to give light yellow needles having a melting point of 132° to 135° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16].C(N(CC)CC)C.Cl>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([C:15]([C:14]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:12]([F:11])[CH:13]=2)=[O:16])[C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2
Reactant: COc1ccc(C(=O)Cl)cc1F
Reactant: c1cc2c(cn1)NCCO2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCOc3ccncc32)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
In a 10 ml flask, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (50 mg, 0.441 mmol) and 3-fluoro-4-methoxy-benzoyl chloride (125 mg, 0.661 mmol) were dissolved in dichloromethane. Triethylamine (0.77 ml, 1.288 mmol) was added thereto and then stirred at room temperature for 2 hours. After neutralizing with 1N hydrochloric acid solution, the mixture was extracted with dichloromethane and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of ethyl acetate. The fractions containing the product were collected and evaporated to obtain white solid (42.1 mg, 33%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[CH:5][CH:4]=1>[Pd].CCO>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[O:21])=[CH:17][CH:16]=1
Reactant: COc1ccc(NC(=O)Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(NC(=O)Cc2ccc(N)cc2)cc1
Reaction time: 5 h
Yield: 95.2 %

Procedure:
A mixture of N-(4-Methoxy-phenyl)-2-(4-nitro-phenyl)-acetamide (859 mg, 3 mmol), 5% Pd on C (16 mg) and EtOH (20 mL) was stirred under a hydrogen atmosphere (1 atm) for 5 hr. Filtration of the catalyst and evaporation of the solvent afforded 2-(4-Amino-phenyl)-N-(4-methoxy-phenyl)-acetamide (732 mg, 95%).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([CH:14]=[CH:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[S:13][C:6]=12.[NH4+].[Cl-].O>CCO.[Fe]>[CH3:20][N:18]([CH3:19])[CH2:17][CH2:16]/[CH:15]=[CH:14]\[C:12]1[S:13][C:6]2[C:7](=[N:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]2[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:2]=2[F:1])[CH:11]=1
Reactant: CN(C)CCC=Cc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN(C)CC/C=C\c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reaction time: 0.67 h
Yield: 68.2 %

Procedure:
To a mixture of 4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-N,N-dimethylbut-3-en-1-amine (234) (171 mg, 0.44 mmol) and NH4Cl (20 mg, 0.37 mmol) in EtOH (4.4 mL)/water (2.2 mL) at 100° C., Fe (209 mg, 3.75 mmol) was added in one portion and the mixture was heated to reflux with vigorous stirring for 40 min. The mixture was filtered through Celiteg, the Celite® washed with EtOH and the combined organic solutions concentrated under reduced pressure. The residue was dissolved in MeOH and purified by preparative HPLC (gradient 40% to 95% MeOH in water, 45 min) giving title compound 235 as a yellow solid (122.8 mg, 0.3 mmol, 69% yield). MS (m/z): (M+1) 358.1 (100%).
Reaction SMILES: [C:1]1([CH:7]2[N:12](N)[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1(=O)[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH2:19]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]1([CH:7]2[N:12]3[C:11]4[C:14]([C:19]5[C:20](=[O:24])[CH2:21][CH2:22][CH2:23][C:18]=53)=[CH:15][CH:16]=[CH:17][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN1c2ccccc2OCC1c1ccccc1
Reactant: O=C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCCc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 110 °C
Yield: 34 %

Procedure:
To a mixture of 3-phenyl-2,3-dihydro4H-1,4-benzoxazin-4-ylamine (1.042 g, 4.6 mmol) in toluene (30 mL) is added, with stirring, cyclohexane-1,3-dione (0.538 g, 4.8 mmol). The mixture is heated to 85° C. for 15 min, at which time p-toluenesulfonic acid monohydrate (0.874 g, 4.6 mmol) is added and the temperature increased to 110° C. The mixture is refluxed for 24 h, cooled to room temperature and concentrated. The residue is partitioned between CH2Cl2/1N NaOH and the organic layer is washed with brine and dried over magnesium sulfate. Column chromatography (100 g silica gel) using (acetone/hexane (25/75)) as eluent gave 0.475g (34%) of 1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11](O)=[O:12])=[CH:3][CH:2]=1.[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31].CCN=C=NCCCN(C)C.Cl.ON1C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:19]([O:18][C:16](=[O:17])[NH:15][C@H:8]([CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:2][CH:3]=1)[CH2:9][C@@H:10]([CH3:14])[C:11]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[O:12])([CH3:22])([CH3:21])[CH3:20]
Reactant: CS(N)(=O)=O
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)NS(C)(=O)=O
Temperature: 25 °C
Yield: 55.4 %

Procedure:
To a solution of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid (500 mg, 1.304 mmol) in DMF (10 ml) at room temperature is added methyl sulfonamide (223 mg, 2.347 mmol), EDC.HCl (450 mg, 2.347 mmol), 1-hydroxy-7-azabenzotriazole (284 mg, 2.086 mmol) and DIPEA (0.501 ml, 2.87 mmol). The reaction mixture is stirred at room temperature over night. The reaction is quenched by brine and is extracted with EtOAc. The combined organic layer is washed with brine and is dried over anhydrous sodium sulfate, filtered and concentrated. Reverse phase HPLC [15 to 60% ACN—H2O (0.1% NH4OH) over 10 min by X-bridge phenyl column] provides ((1S,3R)-1-Biphenyl-4-ylmethyl-4-methanesulfonylamino-3-methyl-4-oxo-butyl)-carbamic acid tert-butyl ester (333 mg, 55%). HPLC retention time=1.03 minutes (condition D), MS (m−1)=495.5, MS (m−55)=405.3, MS (m−99)=361.3.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[O:45]1[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][O:53][C:54]2[N:59]=[CH:58][C:57]([NH2:60])=[CH:56][CH:55]=2)[CH2:47][CH2:46]1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:60][C:57]4[CH:58]=[N:59][C:54]([O:53][CH2:52][CH2:51][N:48]5[CH2:49][CH2:50][O:45][CH2:46][CH2:47]5)=[CH:55][CH:56]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: Nc1ccc(OCCN2CCOCC2)nc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(OCCN5CCOCC5)nc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 6-(2-morpholinoethoxy)pyridin-3-amine as the aniline component. (37%, MS=600.3 (M+H))
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([CH2:13][C:14]2[N:15]=[C:16]([NH2:19])[S:17][CH:18]=2)=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]=[C:22]=[O:23]>N1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([CH2:13][C:14]2[N:15]=[C:16]([NH:19][C:22]([NH:21][CH3:20])=[O:23])[S:17][CH:18]=2)=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN=C=O
Reactant: CC(C)(C)c1nnc(NC(=O)Cc2csc(N)n2)s1
Solvent: c1ccncc1
Product: CNC(=O)Nc1nc(CC(=O)Nc2nnc(C(C)(C)C)s2)cs1
Yield: 70.5 %

Procedure:
A reaction mixture comprising 3.0 g (0.01 mole) of 4-(5-tert-butyl-1,3,4-thiadiazol-2-ylcarbamoylmethyl)-2-aminothiazole, 50 ml of pyridine and 0.8 g (0.014 mole) of methyl isocyanate was heated at 35°-37° for four hours. The reaction solution was allowed to stand over the weekend at ambient temperature. Most of the pyridine was removed by employing a rotary evaporator. The residue was mixed with hexane and the crude solid was collected. The filter cake was well washed with ethyl acetate. There was obtained 2.5 g of product, m.p. 190° (dec.). N.M.R. (dimethyl-d6 sulfoxide) ∂ 1.4 [C(CH3)3 ], 2.6 (CH3, doublet), 3.7 (CH2), 6.7 (hetero-aromatic).
Reaction SMILES: [CH2:1]([N:5]([C:9]1[CH:18]=[CH:17][C:16]2[C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][C:12]([CH3:22])([CH3:21])[C:11]=2[CH:10]=1)[C:6](Cl)=[O:7])[CH2:2][CH2:3][CH3:4].[NH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH2:1]([N:5]([C:9]1[CH:18]=[CH:17][C:16]2[C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][C:12]([CH3:22])([CH3:21])[C:11]=2[CH:10]=1)[C:6](=[O:7])[NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCCCN(C(=O)Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Solvent: c1ccncc1
Product: CCCCN(C(=O)Nc1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 40 °C
Reaction time: 15 h
Yield: 52.9 %

Procedure:
A solution of butyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-carbamoyl chloride (9) (368 mg, 0.55 mmole) in 30 mL pyridine was treated with 272 mg of ethyl p-aminobenzoate (3 eq.) and stirred at 40° C. for 15 hours. The reaction mixture was concentrated in vacuo to provide an orange oil which was purified by flash chromatography (SiO2, 2.5% methanol/dichloromethane) which yielded 131 mg (54%) of ethyl 4-[3-butyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoate (11) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][C:31]=2[C:42]2[CH:47]=[CH:46][N:45]=[N:44][CH:43]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:32][C:31]=2[C:42]2[CH:47]=[CH:46][N:45]=[N:44][CH:43]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccccc4)cc3-c3ccnnc3)cc2F)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2ccc(-c3ccccc3)cc2-c2ccnnc2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.8 %

Procedure:
5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-[(3-pyridazin-4-ylbiphenyl-4-yl)oxy]-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 25, 124 mg, 0.18 mmol) was dissolved in trifluoroacetic acid (1 mL) and the solution stirred for 16 hours at room temperature. The reaction was concentrated in vacuo then purified by reverse phase column chromatography (ISCO™, 12 g, C18, 20:1 water:acetonitrile to 1:4 water:acetonitrile). The appropriate fractions were combined and concentrated in vacuo to afford the title compound as a white solid (61 mg, 63%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[N-:10]=[N+:11]=[N-:12].[Na+].O>CO>[N:10]([CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CCCBr
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CCCN=[N+]=[N-]
Yield: 98.5 %

Procedure:
A solution of ethyl 4-bromobutyrate (10.0 g, 51.3 mmol), NaN3 (6.66 g, 102 mmol) and 25 ml of water in 75 ml of MeOH was refluxed for 3.5 hrs. The MeOH was removed in vacuo and residue was partitioned between CHCl3 (200 ml) and water (50 ml). The organic. layer was separated and washed with water. After drying and evaporation of solvent, ethyl 4-azidobutyrate (7.94 g, 98.6%) was obtained as a colorless oil.
Reaction SMILES: [Si]([O:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=1)[CH2:10][NH:11][C@H:12]([CH3:35])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])=[O:24])=[CH:17]2)(C(C)(C)C)(C)C.[F-].[NH4+]>CO.O>[OH:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=1)[CH2:10][NH:11][C@H:12]([CH3:35])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])=[O:24])=[CH:17]2
Reactant: COc1ccccc1CNC(=O)c1cc2cc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)ccc2[nH]1
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COc1ccccc1CNC(=O)c1cc2cc(C[C@@H](C)NC[C@H](O)c3ccc(O)c(CO)c3)ccc2[nH]1
Temperature: 40 °C
Yield: 68.6 %

Procedure:
A solution of 5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-(2-methoxybenzyl)-1H-indole-2-carboxamide (Preparation 1, 67 mg, 0.11 mmol) in a mixture of methanol (4.0 ml) and water (2.4 ml) was treated with ammonium fluoride (40 mg, 1.08 mmol) and the resulting suspension heated at 40° C. for a period of 16 hours. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica gel eluting with dichloromethane:methanol 0.88 ammonia (95:5:0.5 changing to 85:15:1.5, by volume) to give the title compound as a colourless solid (38 mg).
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:3]1[CH:2]=[C:1]([C:11]([OH:13])=[O:12])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc2c1CCCC2
Product: O=C(O)c1cc([N+](=O)[O-])cc2c1CCCC2
Temperature: 2 °C

Procedure:
Fuming red nitric acid (150 ml.) was cooled to 2° C. and 27.3 g. of 5,6,7,8-tetrahydronaphthalene-1-carboxylic acid was added portionwise over 0.5 hour with stirring maintaining the temperature at 2°-6° C. After another 45 minutes at about 5° C. the mixture was poured into 1500 ml. of crushed ice. The precipitate was collected and washed well with 5 × 500 ml. portions of water. The dried precipitate was heated with about 200 ml. of benzene. The insoluble material was collected and recrystallized from ethyl acetate to give 3-nitro-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid, m.p. 209°-212° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][CH:3]=1.P(Br)(Br)[Br:12]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Br:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(O)c1ccc(Br)cc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CC(Br)c1ccc(Br)cc1
Yield: 75 %

Procedure:
A solution of 1-(4-bromo-phenyl)-ethanol (4.21 g, 20.9 mmol) in 15 mL of CH2Cl2 was reacted with 15 mL of 1.0M PBr3 in CH2Cl2 at room temperature for 4 h. Quenched by pouring into ice and adjusted to pH 9 with 5% aqueous NaHCO3. Extracted with CH2Cl2 and dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (4.1 g, 75%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:18]=[C:17]([C:19]([N:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:25](=O)[CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O.C(OCC)(=O)C>[CH3:7][O:8][C:9]1[CH:18]=[C:17]([C:19]([N:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:25](=[CH2:1])[CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1OC
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C1CCCN(C(=O)c2ccc(C(=O)OC)c(OC)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (607 mg) in N,N-dimethylformamide (10 ml) was added potassium-tert-butoxide (191 mg), and the mixture was stirred at room temperature for 30 minutes. Methyl 2-methoxy-4-(2,3,4,5-tetrahydro-5-oxo-1H-1-benzazepin-1-yl)carbonylbenzoate (300 mg) was added to the resulting solution, and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and the solution was washed successively with 1N hydrochloric acid, water and brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo to give an oil. The crude product was purified by silica gel column chromatography (10% ethyl acetate in hexane) to give methyl 2-methoxy-4-(2,3,4,5-tetrahydro-5-methylene-1H-1-benzazepin-1-yl)carbonylbenzoate (65 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[CH:17]=1)=[O:14].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13]([NH:12][C:7]2[C:8]3[C:3](=[C:2]([C:33]4[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=4)[CH:11]=[CH:10][CH:9]=3)[CH:4]=[CH:5][CH:6]=2)=[O:14])=[CH:17][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]1
Reactant: OB(O)c1cccnc1
Reactant: COc1ccc(NC(=O)Nc2cccc3c(Br)cccc23)cc1N1CCN(C)CC1
Product: COc1ccc(NC(=O)Nc2cccc3c(-c4cccnc4)cccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from N-[5-bromo-1- naphthyl]-N'-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl] urea (E19) and 3-pyridylboronic acid using a similar procedure to Example 4 as a white solid (28%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:27]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:18]([Cl:33])=[CH:17][N:16]=1>>[Cl:33][C:18]1[C:19]([NH:21][C:22]2[C:27]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: CS(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Product: CS(=O)(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl

Procedure:
Title compound was prepared from 8-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(2-fluoro-6-methanesulfonyl-phenyl)-amine in an analogous manner to Example 1221d. Product isolated as an off-white solid (52 mg, 41%). MP=242-245, LCMS 478.05 (M+H), HPLC purity 93%, 1H-NMR (DMSO-d6, 400 MHz) δ 9.50 (s, 1H), 9.19 (s, 1H), 8.89 (s, 1H), 8.20 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.75-7.72 (m, 1H), 7.67-7.64 (m, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.93 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 3.21 (s, 3H), 2.55-2.51 (m, 2H), 2.07-2.04 (m, 4H).