Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:12]2[CH:11]([C:13]([OH:15])=O)[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[CH2:8][O:7][C:6]=2[C:5]([CH3:20])=[CH:4][CH:3]=1.[CH:21]([C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:25]=1[NH2:26])([CH3:23])[CH3:22]>>[CH:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:24]([CH:21]([CH3:23])[CH3:22])[C:25]=1[NH:26][C:13]([CH:11]1[C:10]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[CH2:8][O:7][C:6]2[C:5]([CH3:20])=[CH:4][CH:3]=[C:2]([CH3:1])[C:12]1=2)=[O:15])([CH3:33])[CH3:32]
Reactant: Cc1ccc(C)c2c1OCc1ccccc1C2C(=O)O
Reactant: CC(C)c1cccc(C(C)C)c1N
Product: Cc1ccc(C)c2c1OCc1ccccc1C2C(=O)Nc1c(C(C)C)cccc1C(C)C
Yield: 55.7 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.34 g of 6,11-dihydro-1,4-dimethyldibenz[b,e]oxepin-11-carboxylic acid obtained in Example 64 (Compound AC) in place of Compound A and 1.18 g of 2,6-diisopropylaniline in place of aniline to obtain 1.19 g of Compound 49.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[CH3:12].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)C>C(Cl)Cl>[Cl:1][CH2:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[CH3:12]
Reactant: Cc1c(F)cccc1CC(O)CCl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1c(F)cccc1CC(=O)CCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
0.867 g (35.67 mmol) of magnesium turnings were dried and suspended in 17 ml of anhydrous THF under argon. A solution of 1,2-dibromoethane (0.14 ml, 1.62 mmol) and 2-bromo-6-fluoro-toluene (6.74 g, 35.67 mmol) in 17 ml of anhydrous THF was then added dropwise so as to maintain a gentle reflux. Once the magnesium had been consumed, copper(I) iodide (0.432 g, 2.27 mmol) was then added, followed by a solution of epichlorohydrine (3.00 g, 32.42 mmol) in DMF (8 ml). The mixture was stirred for 3.5 h at room temperature and then quenched with a saturated solution of ammonium chloride (120 ml). The organic layer was separated, and the aqueous phase was extracted twice with EA. The combined organic phases were washed twice with a saturated solution of ammonium chloride, dried over sodium sulfate, filtered and evaporated to dryness. The product was purified by chromatography on silica gel (cyclohexane/EA, from 100:0 to 90:10) to give 6.89 g of 1-chloro-3-(3-fluoro-2-methyl-phenyl)-propan-2-ol. 3.92 g (16.23 mmol) of this alcohol were dissolved in DCM under argon, and 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane reagent; 7.57 g, 16.23 mmol) was added. The mixture was stirred at room temperature overnight and then diethyl ether (150 ml) was added. The mixture was washed three times with 1 N hydrochloric acid (70 ml) and twice with a saturated solution of sodium chloride, and extracted with ether. The extracts were dried over sodium sulfate, filtered and evaporated to dryness. 2.69 g of the title compound were obtained as a white powder.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:20][C:21]1[N:25]([CH2:26][C:27]([N:29]2[CH2:34][CH2:33][CH:32]([C:35]3[S:36][CH:37]=[C:38]([C:40](Cl)=[O:41])[N:39]=3)[CH2:31][CH2:30]2)=[O:28])[N:24]=[C:23]([C:43]([F:46])([F:45])[F:44])[CH:22]=1>ClCCl>[CH3:1][N:2]([CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[C:40]([C:38]1[N:39]=[C:35]([CH:32]2[CH2:33][CH2:34][N:29]([C:27](=[O:28])[CH2:26][N:25]3[C:21]([CH3:20])=[CH:22][C:23]([C:43]([F:44])([F:46])[F:45])=[N:24]3)[CH2:30][CH2:31]2)[S:36][CH:37]=1)=[O:41]
Reactant: CNC1CCCc2ccccc21
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)C3CCCc4ccccc43)cs2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
To a stirred solution of 1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (145 mg, 0.9 mmol) and triethylamine (0.16 mL, 1.13 mmol) in dichloromethane (2 mL) at 0° C. was gradually added 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarbonyl chloride (316 mg, 0.75 mmol) (i.e. the product of Example 2, Step D). The reaction mixture was stirred at room temperature for 16 h and then diluted with dichloromethane (4 mL). The mixture was washed with water, 1 N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to provide crude product, which was purified by medium-pressure liquid chromatography on silica gel using 60-100% of ethyl acetate in hexanes as eluant to give 242 mg of the title compound as white foam.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15].C1(C)C=CC=CC=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:12])[CH2:8][N:9]2[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)OC(=O)Cl
Reactant: O=c1cnc2cc(Br)ccc2[nH]1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)OC(=O)N1CC(=O)Nc2ccc(Br)cc21
Yield: 97 %

Procedure:
To a solution of 7-bromo-3-oxo-3,4-dihydroquinoxaline (6.8 g, 30 mmol) in pyridine (50 ml) was added a solution of isopropyl chloroformate in toluene (35 ml, 1M, 35 mmol) over 30 minutes. The mixture was triturated with water/chloroform, the organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated to obtain crude isopropyl 7-bromo-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxylate(9.3 g, 97%). A sample was recrystallized from ethanol: mp. 159-161° C.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=O)[C:5]1=[O:29])[CH:2]=[CH2:3].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C1COCCN1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CCOCC2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 100 mg (0.225 mmol) of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (Example 91, Step C) in DCE (2420 μL) was added morpholine (200 μL, 2.297 mmol), acetic acid (1.288 μL, 0.023 mmol) and sodium triacetoxyborohydride (95 mg, 0.450 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with sat. sodium bicarbonate solution and extracted with DCM (2×10 mL). The combined organic layers were washed with sat NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford the crude title compound as an oil.
Reaction SMILES: [NH2:1]/[C:2](/OCC)=[CH:3]\[C:4](=O)[C:5]([F:8])([F:7])[F:6].Cl.[C:14]1([CH3:22])[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>>[C:14]1([CH3:22])[CH:19]=[CH:18][C:17]([N:20]2[C:2]([NH2:1])=[CH:3][C:4]([C:5]([F:6])([F:7])[F:8])=[N:21]2)=[CH:16][CH:15]=1
Reactant: CCO/C(N)=C/C(=O)C(F)(F)F
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nc(C(F)(F)F)cc2N)cc1
Temperature: 95 °C
Yield: 61.8 %

Procedure:
According to the procedure described in Example 161A Step 3, (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (2.747 g, 15 mmol), p-tolylhydrazine hydrochloride (2.379 g, 15 mmol) and triethylamine (2.03 g, 20 mmol) were heated at 95° C. for 8 hours. The crude product was purified by silica gel chromatography with 5-25% EtOAc/hexane as eluants to afford 1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-amine as solid (2.237 g, 62%). 1H NMR (300 MHz, CDCl3) δ 7.42 (d, 2H), 7.30 (d, 2H), 5.84 (s, 1H), 3.88 (br, 2H), 2.41 (s, 3H); LC-MS (ESI) m/z 242 (M+H)+.
Reaction SMILES: [C:1]([CH:3]1[CH2:21][CH2:20][N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:5]2[CH2:4]1)#[N:2]>O>[NH2:2][CH2:1][CH:3]1[CH2:21][CH2:20][N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:5]2[CH2:4]1
Reactant: N#CC1CCN2c3ccccc3Cc3ccccc3C2C1
Solvent: O
Product: NCC1CCN2c3ccccc3Cc3ccccc3C2C1

Procedure:
3 g of 2-cyano-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine (ax.), is dissolved in 27 ml of concentrated H2S04 and 0.3 ml of water. The solution is heated at a steambath for about 2 hours. The reaction mixture is then poured into 500 ml of water, whereupon the aqueous mixture obtained is extracted into ether.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=C>>[CH2:14]([O:13]/[CH:1]=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:15][CH2:16][CH3:17]
Reactant: C=COCCCC
Reactant: C=CCCCCCCCC
Product: CCCCCCCC/C=C\OCCCC
Reaction time: 2 h
Yield: 67.7 %

Procedure:
Following the general procedure, 1-decene (50.0 mg, 0.356 mmol) was treated with butyl vinyl ether (357 mg, 3.56 mmol) and 2.5 mol % of in situ-generated complex 1a (89.0 μL, 0.10 M, 8.90 μmol; final substrate concentration=4.0 M) and allowed to stir for 2 h. The unpurified product is 98% Z (as determined by 400 MHz 1H NMR analysis). The resulting brown oil was purified by neutral alumina chromatography (100% hexanes) to afford 8b (51.2 mg, 0.241 mmol, 68.0% yield, 98% Z isomer) as a colorless oil. IR (neat): 2958(s), 2923 (s), 2854 (s), 1664 (s), 1464 (m), 1375 (m), 1306 (w), 1259 (m), 1102 (s); 1H NMR (400 MHz, CDCl3): δ [diagnostic E isomer signal: 6.21 (1H, dt, J=12.8, 1.2 Hz)], 5.91 (1H, dt, J=6.4, 1.6 Hz), 4.32 (1H, td, J=7.2, 6.2 Hz), 3.70 (2H, t, J=6.4 Hz), 2.06 (2H, tdd, J=7.2, 7.2, 1.2 Hz), 1.63-1.55 (2H, m), 1.44-1.21 (14H, m), 0.93 (3H, t, J=7.6 Hz), 0.88 (3H, t, J=7.2 Hz); 13C NMR (100 MHz, CDCl3): δ 145.0, 107.1, 72.0, 32.1, 32.0, 30.0, 29.6, 29.5, 29.4, 24.1, 22.8, 19.2, 14.3, 14.0; HRMS (ESI+) [M+H]+ calcd for C14H29O: 213.2218, found: 213.2220.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]1=O)C.[CH3:13][NH:14]N.CC(O)=O>CC(O)(C)C>[CH3:13][N:14]1[C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:5]=2[CH:4]=[N:2]1
Reactant: CNN
Reactant: CN(C)C=C1C(=O)CCCC1=O
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: Cn1ncc2c1CCCC2=O
Yield: 44.4 %

Procedure:
To a solution of 2-((dimethylamino)methylene)cyclohexane-1,3-dione (55 g crude, 300 mmol) in t-BuOH (400 ml) was added methylhydrazine solution (35 g, 40% aqueous solution, 304 mmol) and AcOH (20 ml) at room temperature. The resulting mixture was heated to reflux for 3 h under nitrogen protection. After cooling, the mixture was concentrated in vacuo and the residue was purified by column chromatograph on silica gel (petroleum ether/ethyl acetate=1/1 v/v %) to give 1-methyl-6,7-dihydro-1H-indazol-4(5H)-one (20 g, two steps: 44%). MS-ESI (m/z): 151 (M+1)+ (Acq Method: 0-60AB_2 min; Rt: 0.90 min)
Reaction SMILES: [OH:1][CH:2]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[OH:14])[N:8]=[C:7](Cl)[N:6]=1.[C:36]1([CH2:44][NH2:45])[CH:41]=[CH:40][C:39]([CH2:42][NH2:43])=[CH:38][CH:37]=1>C1(C)C(C)=CC=CC=1>[OH:1][CH:2]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[OH:14])[N:8]=[C:7]([NH:43][CH2:42][C:39]2[CH:40]=[CH:41][C:36]([CH2:44][NH:45][C:7]3[N:8]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]4[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:23])([CH3:24])[CH2:16]4)[OH:14])[N:10]=[C:5]([NH:4][CH2:3][CH:2]([CH:26]4[CH2:27][C:28]([CH3:35])([CH3:34])[NH:29][C:30]([CH3:33])([CH3:32])[CH2:31]4)[OH:1])[N:6]=3)=[CH:37][CH:38]=2)[N:6]=1
Reactant: NCc1ccc(CN)cc1
Reactant: CC1(C)CC(C(O)CNc2nc(Cl)nc(NCC(O)C3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Solvent: Cc1ccccc1C
Product: CC1(C)CC(C(O)CNc2nc(NCc3ccc(CNc4nc(NCC(O)C5CC(C)(C)NC(C)(C)C5)nc(NCC(O)C5CC(C)(C)NC(C)(C)C5)n4)cc3)nc(NCC(O)C3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Temperature: 0 °C

Procedure:
2,4-Bis{2-hydroxy-N-(2,2,6,6-tetramethyl-4-piperidyl)ethylamino}-6-chloro-1,3,5-triazine (15.4 g) and p-xylylenediamine (1.4 g) were dissolved in xylene (50 ml) and the solution was heated to reflux for 5 hours. The reaction mixture was poured into ice water. After saturation with potassium carbonate, the mixture was extracted with a mixture of benzene (300 ml) and chloroform (500 ml). The extract was dried over anhydrous potassium carbonate and benzene and chloroform were distilled off. The resulting residue was treated with silica gel column chromatography (eluent=ethyl acetate:triethylamine:ethanol=3:1:1) to yield crystals, which were recrystallized from cyclohexane to give the desired product with a melting point of 151°-156° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][N:25]2[C:24](=[O:26])[C:23]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]3[C:21]2=[O:31])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A mixture of 1-tert-butoxycarbonyl-4-(2-mesyloxyethyl)piperidine (1.20 g) and potassium phthalimide (0.80 g) in N,N-dimethylformamide (15 ml) was stirred at 40° C. for 2 hours. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, and dried over magnesium sulfate and evaporated in vacuo to give N-[2-[1-tert-butoxycarbonylpiperidin-4-yl]ethyl]phthalimide (1.12 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([C:22]([F:33])([F:32])[F:21])[CH:28]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cccc(C(F)(F)F)c3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 3-trifluoromethyl-phenylboronic acid (44 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: C1COCC1.[H-].[Na+].[CH3:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH3:27])[C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1)[CH:12]=O.[CH3:28][CH2:29][O:30][C:31]([CH3:33])=[O:32]>O>[CH3:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:33]/[C:31]([O:30][CH2:29][CH3:28])=[O:32])[CH:14]=[C:15]([CH3:27])[C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1
Reactant: CCOC(C)=O
Reactant: Cc1cc(C=O)cc(C)c1Oc1ccc([N+](=O)[O-])cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cc(C)c(Oc2ccc([N+](=O)[O-])cn2)c(C)c1
Reaction time: 1 h

Procedure:
To a THF (100 mL) solution of triethyl phosphonoacetate (44.0 mL) was slowly added NaH (60% dispersion in mineral oil, 8.8 g) at 0° C. After stirring for 1 hour, a THF (200 mL) solution of 3,5-dimethyl-4-[(5-nitropyridin-2-yl)oxy]benzaldehyde (54.5 g) was added to the reaction mixture. After stirring at room temperature for 2 hours, AcOEt and H2O were added to the reaction mixture. The resulting precipitate was collected to give ethyl (E)-3-{3,5-dimethyl-4-[(5-nitropyridin-2-yl)oxy]phenyl}prop-2-enoate as a white powder (40.9 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:37]([N:39]1[N:59]=C2C3OC(C4C=CC=CC=4)=C(I)C(=O)C=3C=C[C:41]2=[CH:40]1)C>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[CH:25]=[CH:24][C:23]5[C:22](=[N:59][N:39]([CH2:40][CH3:41])[CH:37]=5)[C:21]=4[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCn1cc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c2n1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: CCn1cc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c2n1
Yield: 89 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 2-ethyl-7-iodo-8-phenyl-2H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one was reacted to give the title compound as a colourless gum (43.2 mg, 89%). LCMS (Method H): RT=4.24 min, [M+H]+=536.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[C:12]([C:20]#[N:21])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1.[Li].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CN1CCOCC1>[C:20]([C:12]1[C:13]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[N:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:1][C:34](=[O:35])[C:33]3[CH:32]=[CH:31][C:30]([CH2:29][N:26]4[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]4)=[CH:38][CH:37]=3)[CH:7]=[CH:6][CH:5]=2)=[N:10][CH:11]=1)#[N:21]
Reactant: N#Cc1cnc(Nc2cccc(N)c2)nc1-c1cccs1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Li]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4ncc(C#N)c(-c5cccs5)n4)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of N-3-aminophenyl-5-cyano-4-thien-2-ylpyrimidine-2-amine (300 mg, 1.0 mmol) and 4-(4-methylpiperazin-1-yl)methylbenzoic acid, lithium salt (300 mg, 1.0 mmol) in DMF (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (307 mg, 1.6 mmol), 1-hydroxybenzotriazole (216 mg, 1.6 mmol) and N-methylmorpholine (350 ml, 3.2 μmol) and the resulting mixture was stirred at ambient temperature for 48 h. The reaction was then concentrated under reduced pressure and the resulting residue partitioned between ethyl acetate and saturated brine. The organic phase was dried (MgSO4), concentrated under reduced pressure and the resulting residue recrystallised from ethyl acetate-ether-MeOH (4:4:1) to give the title compound (312 mg) as a colourless solid, m.p. 208-209°. δH (d6 DMSO) 10.48 (1H, bs), 10.23 (1H, s), 8.89 (1h,s), 8.28 (1H, d, J 3.5 Hz), 8.13 (1H, m), 7.98 (1H, d, J 4.8 Hz), 7.90 (2H, d, J 8.2 Hz), 7.60 (1H, bs), 7.43 (3H, d, J 8.2 Hz), 7.36-7.30 (2H, s), 3.52 (2H, s), 2.37 (8H, bs) and 2.15 (3H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C[Al](C)C.[F:14][C:15]1[C:24]([F:25])=[C:23]([F:26])[C:22]([F:27])=[C:21]2[C:16]=1[C:17]([OH:33])=[C:18]([C:28](OCC)=[O:29])[CH:19]=[N:20]2.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:28]([C:18]2[CH:19]=[N:20][C:21]3[C:16]([C:17]=2[OH:33])=[C:15]([F:14])[C:24]([F:25])=[C:23]([F:26])[C:22]=3[F:27])=[O:29])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2c(F)c(F)c(F)c(F)c2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)c(F)c(F)c(F)c2c1O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of 4-chlorobenzylamine (0.080 mL) in 5 mL of toluene is added 0.70 mL of a 2.0 M solution of trimethylaluminum in toluene. The solution is stirred for 5 min at 0° C. and then a suspension of 0.20 g of ethyl 5,6,7,8-tetrafluoro-4-hydroxy-3-quinolinecarboxylate (U.S. Pat. No. 4,940,710) in 5 mL of toluene is added. The solution is stirred at 0° C. for an additional 10 min and then it is stirred 3 h at 90° C. The mixture is cooled to 25° C. and it is poured onto a mixture of 10 mL of 3 M hydrochloric acid and 10 mL of crushed ice. After stirring the mixture vigorously for 20 min it is filtered. The solid is dissolved in 50 mL of warm glacial acetic acid and distilled water is added to the resulting solution until it is cloudy. The mixture is then allowed to stand for several h at 5° C. Filtration of this mixture gives the desired amide as 0.12 g of a solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][S:8][C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]1=2.[CH:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1)=O.CC[O-].[Na+].Cl>C1COCC1>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])/[C:9](=[CH:20]/[C:22]2[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)/[S:8][C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]1=2
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: O=C1CSc2ccccc2N1Cc1ccccc1F
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(/C=C2\Sc3ccccc3N(Cc3ccccc3F)C2=O)cc1
Temperature: 70 °C
Yield: 76.1 %

Procedure:
4-(2-fluorobenzyl)-2H-benzo[b][1,4]thiazin-3(4H)-one (1 g, 3.66 mmole) and methyl 4-formylbenzoate (1.2 g) were dissolved in THF (20 mL) and to the solution was added NaOEt (1 g). The reaction solution was heated at 70 ° C. overnight and aqueous HCl (5%, 10 mL) was added to quench the reaction. The mixture was extracted with EtOAc (50 mL) twice and combined organic layers were dried over anhydrous magnisum sulfate. After filtration, the solvent was removed under vacuum to give 4-((Z)-(4-(2-fluorobenzyl)-3,4-dihydro-3-oxobenzo[b][1,4]thiazin-2-ylidene)methyl)benzoic acid (1.13 g, 71%).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3](=O)[CH2:4][C:5](=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:15][NH:16][NH2:17]>CCO>[CH2:9]([O:8][C:6]([C:5]1[N:16]([CH3:15])[N:17]=[C:3]([C:2]([CH3:14])([CH3:13])[CH3:1])[CH:4]=1)=[O:7])[CH3:10]
Reactant: CNN
Reactant: CCOC(=O)C(=O)CC(=O)C(C)(C)C
Solvent: CCO
Product: CCOC(=O)c1cc(C(C)(C)C)nn1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 5,5-dimethyl-2,4-dioxo-hexanoate (1.02 g, 5.09 mmol) was dissolved in absolute EtOH (20 mL). CH3NHNH2 (0.270 mL, 5.09 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 2 h. The resulting mixture was warmed to 80° C. for 4 h, and then cooled to room temperature. The solvent was removed under reduced pressure, and the resulting residue was chromatographed using a 70-g pre-packed SiO2 column eluting with 1:19 EtOAc-hexanes to yield the title compound as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ: 6.68 (s, 1H), 4.33 (q, J=7.2 Hz, 2H), 4.12 (s, 3H), 1.38 (t, J=7.1 Hz, 3H), 1.30 (s, 9H).