Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31](Cl)=[O:32])[CH:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][S:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])=[O:39]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31]([N:44]3[CH2:45][CH2:46][N:41]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:42][CH2:43]3)=[O:32])[C@H:13]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)N1CCNCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(S(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-methylsulfonyl-piperazine (Aldrich) to give the title compound. LC-MS: 671.2 [(M+H)+]
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[OH-].[CH2:12]([N+:19](C)(C)C)[C:13]1C=CC=C[CH:14]=1>C(#N)C=C.C(OCC)C>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([O:10][CH2:14][CH2:13][C:12]#[N:19])=[CH:3][C:2]=1[CH3:1]
Reactant: COc1ccc(O)cc1C
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCOCC
Solvent: C=CC#N
Product: COc1ccc(OCCC#N)cc1C
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of 7.0 grams (0.050 mole) of 3-methyl-4-methoxyphenol (known compound) in 20 mL of acrylonitrile was stirred, and 0.4 mL of benzyltrimethylammonium hydroxide (Triton® B) was added. Upon completion of addition, the reaction mixture was warmed to reflux where it stirred during a 21 hour period. The reaction mixture was then cooled to ambient temperature and diluted with 100 mL of diethyl ether. The mixture was then first washed with three 50 mL portions of an aqueous solution of 10% potassium hydroxide, then with three 50 mL portions of aqueous 4N hydrochloric acid. The organic layer was dried with sodium sulfate, and the mixture was filtered. The filtrate was concentrated under reduced pressure, yielding 6.0 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][CH2:17][N:18]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH3:23])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[S:54](Cl)([C:57]1[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=1)(=[O:56])=[O:55]>C(Cl)Cl>[S:54]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:16][CH2:17][N:18]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH3:23])([C:57]1[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=1)(=[O:56])=[O:55]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CCN(CCN(CCCCCCO)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CCN(CCN(CCCCCCOS(=O)(=O)c1ccc(C)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 6.1 g amount of 7,10,13-tri (t-butoxycarbonyl)-7,10,13-triazapentadecanol, 100 mg of dimethylaminopyridine, and 4 ml of triethylamine in 100 ml of CH2Cl2 was stirred at 0° C. Dropwise, 2.64 of tosyl chloride in 20 ml of CH2Cl2 was added at 0° to 5° C. The reaction was then stirred overnight at room temperature and then 100 ml of CH2Cl2 was added. The reaction mixture was washed with 30 ml of 2N HCl, 30 ml of water and 30 ml of brine. The organic layer was dried over MgSO4 and was filtered. The solvent was evaporated and the residue from the filtrate was purified using a silica gel column and eluted with ethyl acetate/hexane (1:2 v/v). About 7.8 g of 7,10,13-tri(t-butoxycarbonyl)-7,10,13-triazapentadecanol tosylate was collected. The reaction is shown below:
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.Cl[Si](C)(C)[CH3:15]>CO>[Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH3:15])=[O:11])=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)Cc1ccc(CBr)cc1
Solvent: CO
Product: COC(=O)Cc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 434.3 %

Procedure:
To a stirred suspension of 2-(4-(bromomethyl)phenyl)acetic acid (5.00 g, 21.8 mmol, 1.0 eq.) in methanol (75 mL) was added chlorotrimethylsilane (0.64 mL, 5.02 mmol, 0.23 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 hr, at which time the reaction was a clear colorless solution. The volatile material was removed under reduced pressure, the residue dissolved in methanol (25 mL), and the volatile material was removed under reduced pressure. This process was repeated two additional times to afford methyl 2-(4-(bromomethyl)phenyl)acetate as an orange solid (5.30 g, quantitative yield). 1H NMR (CDCl3, 500 MHz) δ 7.37-7.33 (m, 2H), 7.26-7.24 (m, 2H), 4.48 (s, 2H), 3.69 (s, 3H), 3.62 (s, 2H). [Lit. J. Med. Chem. 2009, 52, 1180-9.]
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8](O)=[O:9])[N:3]=1.P(Cl)(Cl)([Cl:16])=O.CN(C)C=O>COCCOC>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([Cl:16])=[O:9])[N:3]=1
Reactant: CO/N=C(\C(=O)O)c1nsc(N)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)Cl)c1nsc(N)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 50.0 ml of 1,2-dimethoxyethane (DME), 10.0 g of 2- (5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetic acid were stirred at -20° C., followed by the dropwise addition of a chlorinating reagent, which had been prepared beforehand by gradually adding 8.4 g of phosphorus oxychloride at 5° C. to a mixture of 20 ml of DME and 4.0 g of N,N-dimethylformamide (DMF) and then reacting them for 30 minutes. After they were reacted for 5 minutes, the reaction mixture was poured into 160 ml of ice water to precipitate crystals. The resulting crystals were collected by filtration, washed with 200 ml of ice water and then stirred for 30 minutes in 120 ml of n-hexane. After filtration, the resulting crystals were dried under reduced pressure, whereby the title compound was obtained. Yield: 8.43 g (76.6%). Purity: 97.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2Cl)[N:3]=1.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[S:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[N:3]=[C:4]2[C:9]([C:8]([NH:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=3[S:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=3)=[CH:7][CH:6]=[N:5]2)=[CH:10][CH:11]=1
Reactant: Clc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)cc1
Product: CC(=O)Nc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(Cl)ccc23)cc1

Procedure:
The product from Example 13d (200 mg, 1.0 mmol) was reacted with the product from Example 18b (215 mg, 1.0 mmol) for 24 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (200 mg, 45%).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH2:12].[CH2:14]([CH2:16][NH2:17])[OH:15]>C(#N)C>[OH:15][CH2:14][CH2:16][NH:17][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH2:12]
Reactant: NCCO
Reactant: COC(=O)c1cc(Cl)cc(C)c1N
Solvent: CC#N
Product: Cc1cc(Cl)cc(C(=O)NCCO)c1N
Temperature: 70 °C
Yield: 88.3 %

Procedure:
To a 100 mL round-bottom flask, 0.1 mol of 2-amino-3-methyl-5-chlorobenzoic acid methyl ester having the structural formula of VIII-3, 100 mL of acetonitrile, 0.4 mol of ethanolamine were added, heated to 70° C. and reacted for 3 hours, after treatment 20.2 grams of N-hydroxyethyl-2-amino-3-methyl-5-chlorobenzamide having a structural formula of III-3 was obtained, and the yield was 88.4%; To a 50 mL round-bottom flask, 3.0 mmol of N-hydroxyethyl-2-amino-3-methyl-5-chlorobenzamide having the structural formula of III-3, 3.0 mmol of 1-(3,5-dichloropyridine-2-yl)-3-bromo-1H-pyrazole-5-carboxylic acid having a structural formula of II-3, 10 mL of acetonitrile were added, and 9.0 mmol of potassium carbonate and 0.2 gram of potassium iodide were added under stirring, cooled to −7° C. and a 3 mL acetonitrile solution of 12 mmol methanesulfonyl chloride was dripped, after dripping was completed reacted at 0° C. for 1.0 hour, reacted at 20° C. for 1.0 hour, 10 mL of water was added and stirred for 0.5 hour, filtered and dried to obtain 1.52 grams of 1-(3,5-dichloropyridine-2-yl)-3-bromo-N-(2-methyl-4-chloro-6-hydroxyethylaminocarbonyl)phenyl-1H-pyrazole-5-formamide having a structural formula of I-29 as a pale yellow solid, and the yield was 92.7%.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:36])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C:16]=3[N:17]=2)=[CH:8][CH:7]=1)[CH3:2].[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[CH2:1]([NH:3][C:4]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:21][CH2:20][NH:19][CH2:18][C:16]=3[N:17]=2)=[CH:10][CH:11]=1)=[O:36])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a stirred solution of (S)-tert-butyl 2-(4-(3-ethylureido)phenyl)-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (intermediate 5) (2.72 g, 5.5 mmol) in DCM (40 mL) was added TFA (20 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and the resulting residue was dissolved in the minimum MeOH and precipitated from Et2O to give a cream solid (2.35 g, 4.6 mmol, 84% yield).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li][CH2:15]CCC.IC.OC1O[C@@H](CO)[C@H](O)[C@H](O)[C@H]1O>>[CH3:15][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: OC[C@@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O
Solvent: CI
Product: CC1c2ccccc2-c2ccccc21

Procedure:
Fluorene (15.0 g, 90.4 mmol), n-BuLi (48.1 ml, 120 mmol, 2.5 M in hexane), RX=iodomethane (19.3 g, 136 mmol). 40 was isolated as a yellowish waxy solid (16.2 g, quant.). The analytical data were identical to those in the literature (M. A. Schmidt, H. G. Alt, W. Milius, J. Organomet. Chem. 1996, 525, 15).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Pd].C1COCC1.CO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1
Reactant: O=C(Nc1cc([N+](=O)[O-])ccc1F)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(F)c(NC(=O)c2ccccc2)c1
Yield: 91 %

Procedure:
A mixture of N-(2-fluoro-5-nitro-phenyl)-benzamide (4.86 g, 18.7 mmol) and 10% Pd/C, (486 mg) in a 1:1 mixture of THF-MeOH (80 ml) was hydrogenated at 23° C. After 25 h the reaction mixture was filtered through celite and concentrated to give N-(5-Amino-2-fluorophenyl)benzamide (3.92 g, 91%). MS (ESI+) [M+H]/z Calc'd 231, found 231.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:10]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C#CCCCCCCCCCCC
Reactant: O=Cc1ccncc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC#Cc1cnccc1C=O
Temperature: 105 °C
Reaction time: 19 h
Yield: 73 %

Procedure:
Palladium acetate (10.8 mg) was added to a stirred, deaerated solution of 3-bromopyridine-4-carboxaldehyde (0.80 g, 4.5 mmole; prepared as described by E. J. Corey, S. G. Pyne and A. I. Schafer, Tet. Letters, 3291, 1983), 1-tridecyne (1.4 g) and triphenylphosphine (36 mg) in anhydrous triethylamine (18 ml) maintained under an atmosphere of nitrogen. The mixture was stirred at 105° C. for 19 hours after which time it was cooled and the precipitated triethylamine hydrobromide filtered off. Chromatography of the evaporated filtrate on silica using dichloromethane as eluant afforded 0.93 g (73%) of the title compound as a white crystalline solid of mp (petroleum ether [bp. 40°-60° C.]) 38°-39° C., νmax (mull) 2230, 1710 cm-1 ; δ(CDCl3) 0.87 (3H, distorted t, terminal CH3), 1.12-1.76 (18H, m, alkylene chain), 2.48 (2H, t, J 6 Hz, CH2 --C≡C), 7.62 (1H, d, J 5 Hz, C-5H), 8.63 (1H, d, J 5 Hz, C-6H), 8.82 (1H, s, C-2H), 10.52 (1H, s, aldehyde C-H).
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([Cl:22])[N:8]=1.CN(CCN(C)C)C.[CH3:31][C:32]([CH3:34])=[O:33]>C1COCC1>[Cl:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([C:32]([OH:33])([CH3:34])[CH3:31])[N:13]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([Cl:22])[N:8]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: CC(C)=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)c1nc2c(Cl)nc(Cl)nc2n1C1CCCCO1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 61.8 %

Procedure:
BuLi (20 mL, 40.0 mmol, 2 M in pentane) was added dropwise to a solution of 2,6-dichloro-9-(tetrahydro-pyran-2-yl)-9H-purine (8.0 g, 29.3 mmol) and TMEDA (6.4 mL, 42.4 mmol) in anhydrous THF (100 mL) at −78° C. The resulting dark solution was stirred at −78° C. for 45 min, then acetone (4 mL, 54.5 mmol) was added and the reaction mixture was stirred at −78° C. for 30 min, then at RT for 30 min. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0 to 20% ethyl acetate in cyclohexane) affording 2-[2,6-Dichloro-9-(tetrahydro-pyran-2-yl)-9H-purin-8-yl]-propan-2-ol as a dark solid (6.0 g, 62%). 1H NMR (400 MHz, CDCl3); δ 6.19 (1H, dd, J=11.2, 2.8 Hz), 4.26 (1H, m), 3.77 (1H, m), 2.87 (1H, m), 2.09 (1H, m), 1.90-1.71 (11H, m).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26](O)=[O:27])[C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][N:19]=[CH:20]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][N:19]=[CH:20]3)[CH2:25][C:26]([N:31]([CH2:32][CH3:33])[CH2:29][CH3:30])=[O:27])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCNCC
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2cccc3cnccc23)cc1
Product: CCN(CC)C(=O)CN(c1cccc2cnccc12)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-isoquinolin-5-yl-amino]-acetic acid with diethylamine
Reaction SMILES: C(CC(C)(C)C)(C)C.C([O:12]C(C)C)(C)C.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24]C(O)=O)=[C:19]([N+:28]([O-])=O)[CH:18]=1.Cl>>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]2[S:23][C:24](=[O:12])[NH:28][C:19]=2[CH:18]=1
Reactant: Cc1ccc(SCC(=O)O)c([N+](=O)[O-])c1
Reactant: CC(C)OC(C)C
Agent: Cl
Solvent: CC(C)CC(C)(C)C
Product: Cc1ccc2sc(=O)[nH]c2c1
Yield: 74 %

Procedure:
Analogous to Example 2(a), 2-acetyl-5-methyl-2-(3H)-benzothiazolone, m.p. 86°-88° C. (from isooctane/diisopropyl ether), was prepared with a yield of 51% of theory, starting from [(4-methyl-2-nitrophenyl)thio]-acetic acid. This intermediate was subsequently treated with 5 N hydrochloric acid analogous to Example 2(b). 5-Methyl-2(3H)-benzothiazolone was obtained with a yield of 74% of theory; m.p. 178°-180° C. (from ethanol/water 1:1).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].S(=O)(=O)(O)O.[CH2:10]1[CH2:20][C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1>O.C(Cl)(Cl)Cl>[NH:1]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:20][C:18]1=[O:19]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCCc2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1CCCc2ccccc2N1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
A solution of sodium azide (25 g, 370 mmol) in water (13 mL) and chloroform (160 mL) is cooled to 0° C. and treated dropwise with concentrated sulfuric acid (11 mL). Stirring is continued for 30 min and the layers separated. The organic layer is dried over anhydrous sodium sulfate, filtered, and α-tetralone (20 g, 137 mmol) is added in one protion with stirring. The resulting solution is heated at 40° C. and concentrated sulfuric acid (38 mL) is added dropwise to maintain the internal temperature at 40-45° C. and stirring continued for 1 h, then cooled to 20° C. and poured into a sepratory funnel. The bottom layer is added dropwise with stirring to ise water (900 mL). The resulting solids are collected by filtration, and dried in vacuo at 40° C. to give 19.7 g of an off-white solid (89%), mp 139-140° C.; MS (ESI+) m/z 162 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:28]([OH:30])=O)[CH2:7][CH2:6]1)=[O:4].S(Cl)(Cl)=O.[CH3:35][N:36]([CH:38]=O)[CH3:37]>>[CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:20][CH:21]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:28]([NH:5][C:11]2[CH:12]=[CH:13][C:14]([CH2:38][N:36]([CH3:35])[CH:37]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:15][CH:10]=2)=[O:30])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CCC(C(=O)O)=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc21
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)N1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In DMF (8 ml) was dissolved 1-methoxycarbonyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.15 g). To the solution was added, under ice-cooling, thionyl chloride (0.07 ml), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was suspended in THF (25 ml). The suspension was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.12 g) and triethylamine (0.26 ml) in THF (5 ml), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature for 4 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column chromatography (elution solvent: methanol/triethylamine/ethyl acetate) to give crude crystals, which were recrystallized from ethyl acetate/hexane to give 1-methoxycarbonyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.14 g) as colorless crystals.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:9][CH:8]=1)C.[CH3:29][NH:30][CH3:31]>>[CH2:21]([O:20][C:18](=[O:19])[NH:17][CH2:16][CH2:15][CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4](=[O:3])[N:30]([CH3:31])[CH3:29])=[CH:8][CH:9]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reactant: CNC
Product: CN(C)C(=O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Temperature: 55 °C
Yield: 52 %

Procedure:
A mixture of [4-(4-benzyloxycarbonylaminobutyl)phenoxy]acetic acid ethyl ester 23 (0.50 g, 1.3 mmol) and dimethylamine (2.0 M in THF, 10 mL, 20 mmol) in a sealed tube was heated at 55° C. for 48 h. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/CH2Cl2, 1:4, 1:3, v/v) to provide [4-(4-dimethylcarbamoylmethoxyphenyl)butyl]carbamic acid benzyl ester 28 (0.26 g, 52% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.55 (m, 4H), 2.55 (m, 2H), 2.90 (s, 3H), 3.05 (s, 3H), 3.20 (m, 2H), 4.65 (s, 2H), 5.08 (s, 2H), 6.80 (d, 2H), 7.05 (d, 2H), 7.35 (m, 5H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([N:18]([CH3:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:47][C:48]1[CH:52]=[CH:51][N:50]([CH2:53][C:54]([CH3:57])([OH:56])[CH3:55])[N:49]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([N:18]([CH3:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:13]=[N:12]2)[C:8]([NH:47][C:48]2[CH:52]=[CH:51][N:50]([CH2:53][C:54]([OH:56])([CH3:55])[CH3:57])[N:49]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CN(c1ccccc1)c1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(c1ccccc1)c1cnn(C(CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)c(=O)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 45.7 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(methyl-phenyl-amino)-6-oxo-6H-pyridazin-1-yl]-propionic acid (assume 0.18 mmol) in methylene chloride (1.8 mL, 0.1M) at 25° C. was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (34 μL, 0.19 mmol) followed by 1-hydroxybenzotriazole (26.3 mg, 0.19 mmol). The resulting solution was stirred at 25° C. for 3.5 h. After this time, the reaction was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1, 36.8 mg, 0.23 mmol). The resulting solution was stirred at 25° C. for 2 d. After this time, the reaction was diluted with methylene chloride (25 mL) and was washed consecutively with a saturated ammonium chloride solution (1×25 mL), a saturated sodium bicarbonate solution (1×25 mL), water (1×25 mL) and a saturated aqueous sodium chloride solution (1×25 mL). The organics were then dried over magnesium sulfate, filtered, rinsed and concentrated in vacuo. Silica gel column chromatography (AnaLogix 8 g, 50-100% ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(methyl-phenyl-amino)-6-oxo-6H-pyridazin-1-yl]-propionamide (39.4 mg, 44% over two steps) as a yellow solid; ES+-HRMS m/e calcd for C26H34N6O3 [M+H+] 479.2765, found 479.2764. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.04 (s, 3H) 1.05 (s, 3H) 1.06-1.11 (m, 1H) 1.16-1.33 (m, 1H) 1.37-1.74 (m, 7H) 1.84-1.99 (m, 1H) 2.17-2.30 (m, 1H) 3.33 (s, 3H) 3.88 (s, 2H) 4.66 (s, 1H) 5.39 (dd, J=10.5, 4.8 Hz, 1H) 6.40 (d, J=2.1 Hz, 1H) 6.71 (d, J=4.9 Hz, 1H) 6.96-7.03 (m, 2H) 7.03-7.11 (m, 1H) 7.22-7.31 (m, 2H) 7.51 (d, J=2.1 Hz, 1H) 7.82 (d, J=4.9 Hz, 1H) 10.55 (s, 1H).