Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:11][S:12][C:13]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:19]=2)=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(O)(=O)C>[OH:8][CH2:9][C:10]1[S:11][S:12][C:13]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:19]=2)=[CH:14][CH:15]=1
Reactant: CN(C)c1cccc(OCC2=CC=C(CO[Si](C)(C)C(C)(C)C)SS2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)c1cccc(OCC2=CC=C(CO)SS2)c1
Reaction time: 3 h
Yield: 84 %

Procedure:
To a stirred solution of the 3-[(tert-butyldimethylsilyloxy)methyl]-6-[[3-(N,N-dimethylamino)-phenyloxy]methyl]-1,2-dithiin obtained above (100 mg, 0.24 mmol) in 2 mL THF was added a mixture of 2.4 mL of 1M tetrabutylammonium fluoride in THF and 1.4 mL of acetic acid. The reation mixture was stirred for 3 h until TLC analysis showed the reaction to be complete, then concentrated in vacuo. The residue was partitioned between 40 mL of water and 60 mL ethyl acetate. The organic phase was washed with dilute aqueous sodium bicarbonate, water, dried over sodium sulfate, and then evaporated to a small volume. The residue was chromatographed over silica gel column (ethyl acetate-hexane, 1:1) to yield 60.5 mg (84.0%) of the title compound. Further purification was accomplished by reverse-phase HPLC (PRP-1 column, acetonitrile-water, 2:3); 1H-NMR (CDCl3) δ7.3 (bs, 1 H), 7.1 (bs, 1 H), 6.64 (s, 1 H), 6.55 (d, J=7.2, 1 H), 6.46(d, J=5.6, 1 H), 6.41 (d, J=5.6, 1 H), 4.65 (s, 2 H), 4.30 (s, 2 H), 2.69 (s, 6 H).
Reaction SMILES: C1C=CC2[C:17](=[O:18])[C:16]3C4C(C=CN=3)=CC=NC=4C=2C=1.[Br:19][C:20]1[C:29]2[C:24]3=[C:25]([C:30]4[C:35]([C:36](=[O:37])[C:23]3=[N:22][CH:21]=1)=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:26]=[CH:27][CH:28]=2.C1C=C[NH+]=CC=1.Br[Br-]Br>C(Cl)(Cl)Cl>[CH:32]1[CH:31]=[C:30]2[C:25]3[C:24]4[C:23]([C:36](=[O:37])[C:35]2=[CH:34][CH:33]=1)=[N:22][CH:21]=[C:20]([Br:19])[C:29]=4[CH:28]=[CH:27][N:26]=3.[CH3:16][CH2:17][O:18][C:21]1[N:22]=[C:23]2[C:24]3[C:25]([C:30]4[C:35]([C:36]2=[O:37])=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:26][CH:27]=[CH:28][C:29]=3[C:20]=1[Br:19]
Reactant: O=C1c2ccccc2-c2nccc3ccnc1c23
Agent: O=C1c2ccccc2-c2nccc3c(Br)cnc1c23
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CCOc1nc2c3c(nccc3c1Br)-c1ccccc1C2=O
Yield: 1 %

Procedure:
Electrophilic Bromination of Sampangine: Preparation of 4-Bromo-7H-naphtho[1,2,3-ij] [2,7]naphthyridin-7-one [4-Bromosampangine, 5] and 4-Bromo-5-ethoxy-7H-naphtho[1,2,3-ij][2,7]naphthyridin-7-one[4-Bromo-5-ethoxysampangine, 20]. A mixture of pyridinium bromide perbromide (4.80 g, 15.0 mmol) and sampangine (2.32 g, 10.0 mmol) in CHCl3 (100 mL) was heated at reflux for 24 h. After cooling, the mixture was poured into a separatory funnel and washed with saturated aqueous NaHCO3Solution (2×250 mL). The organic layer was dried (K2CO3) and concentrated to dryness. The residual solids were subjected to flash silica gel chromatography while eluting with CHCl3 to give pure 4-bromosampangine (5) (2.00 g, 64%) and 4-bromo-5-ethoxysampangine (20) (0.05 g, 1%). An analytical sample of 20 was obtained by crystallization from CHCl3. Compound 5: mp 244°-246° C.; IR (KBr) 1670, 1590, 1400, 1320, 1310, 1275, 1230, 980, 790, 755, 720 cm-1 ; 1H NMR (CDCl3) δ7.72 (ddd, 1 H, J=7.9, 7.9, 1.4 Hz), 7.86 (ddd, 1 H, J=7.9, 7.9, 1.4 Hz), 7.96 (d, 1 H, J=5.9 Hz), 8.46 (dd, 1 H, J=7.9, 1.4 Hz), 8.85 (dd, 1 H, J=7.9, 1.4 Hz), 8.99 (d, 1 H, J=5.9 Hz), 9.28 (s, 1H); 13C NMR (CDCl3) 118.3 (1), 120.5 (0), 123.7 (0), 125.8 (1), 128.7 (1), 131.8 (1), 132.3 (0), 135.0 (1), 135.1 (0), 138.6 (0), 146.7 (0), 148.6 (1), 150.2 (1), 151.7 (0), 181.6 (0) ppm; Anal. (exact mass, HREIMS) calcd for C15H7BrN2O m/e 309.9741, found 309.9747; Anal. calcd for C15H7BrN2O: C 57.90, H 2.27, N 9.00; found C 57.70, H 2.27, N 9.26. Compound 20: mp 200°-201° C.; IR (KBr) 1670, 1592, 1570, 1430, 1382, 1365, 1330, 1270, 1212, 1080, 1070, 1042, 980, 845, 762, 755, 720, 710, 635 cm-1 ; 1H NMR (CDCl3) δ1.56 (t, 3 H, J=7.1 Hz), 4.79 (q, 2 H, J=7.1 Hz), 7.67 (ddd, 1 H, J=7.3, 7.3, 1.4 Hz), 7.79 (ddd, 1 H, J=7.3, 7.3, 1.4, Hz), 7.82 (d, 1 H, J=6.1 Hz), 8.36 (dd, 1 H, J=7.3, 1.4 Hz), 8.72 (d, 1 H, J=6.1 Hz), 8.75 (dd, 1 H, J=7.3, 1.4 Hz); 13C NMR (CDCl3) 14.6 (3), 64.7 (2), 107.4 (0), 117.5 (0), 117.8 (1), 125.5 (1), 128.2 (1), 131.4 (1), 132.2 (0), 134.5 (1), 135.0 (0), 140.9 (0), 144.6 (0), 147.2 (1), 151.7 (0), 159.9 (0), 181.4 (0) ppm; Anal. calcd for C17H11BrN2O: C 57.48, H 3.12, N 7.88; found C 57.09, H 3.37, N 7.75.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][NH:35][CH2:36][CH2:37][CH2:38][OH:39]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:35]([CH2:36][CH2:37][CH2:38][OH:39])[CH2:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=2)=[O:26])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: OCCCNCc1ccccn1
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Product: CN(C)c1cccc(N(CC(=O)N(CCCO)Cc2ccccn2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with 3-[(pyridin-2-ylmethyl)-amino]-propan-1-ol
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH3:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9][CH2:8]1.[OH-].[NH4+]>S(=O)(=O)(O)O>[CH3:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([N+:1]([O-:4])=[O:2])=[CH:14][CH:15]=2)[CH:10]=[N:9][CH2:8]1
Reactant: O=[N+]([O-])[O-]
Reactant: CC1CN=Cc2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: CC1CN=Cc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
To a stirred solution of potassium nitrate (10 g) in conc-sulfuric acid (50 ml) was added slowly a solution of 3,4-dihydro-4-methylisoquinoline (12 g) in conc-sulfuric acid (50 ml) at -20°~-10° C. over a period of an hour. The reaction mixture was allowed to stir at ambient temperature for 3 hours and heated at 60° C. for 1.5 hours. The reaction mixture was poured onto ice, and adjusted to alkaline pH with 28% ammonium hydroxide under cooling. The resulting brown solid was filtered off, washed with water, and dried in vacuo to give 3,4-dihydro-4-methyl-7-nitroisoquinoline (14.63 g).
Reaction SMILES: C1C[O:4][CH2:3]C1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:18][C:19]1[C:28]([NH2:29])=[C:27]([NH:30][CH2:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.O>N1C=CC=CC=1>[Cl:18][C:19]1[C:28]2[N:29]=[C:3]([OH:4])[N:30]([CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: Nc1c(Cl)nc2ccccc2c1NCC1CCOCC1
Reactant: C1CCOC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: c1ccncc1
Product: Oc1nc2c(Cl)nc3ccccc3c2n1CC1CCOCC1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
THF (50 mL) and 1,1′-carbonyldiimidazole (4.2 g, 26 mmol) were sequentially added to a solution of 2-chloro-N4-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (5 g, 17 mmol) in pyridine (50 mL), and the reaction was heated at 90° C. overnight. The reaction was cooled to approximately 0° C., and water (400 mL) was added. The mixture was stirred for 30 minutes. A precipitate was present and was isolated by filtration and washed with water and diethyl ether to provide 4 g of 4-chloro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-ol. A small portion of the product was triturated with hot acetonitrile, isolated by filtration, and washed with cold acetonitrile and diethyl ether to provide beige needles with the following analytical data, mp greater than 275° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@H:19]2[CH2:23][CH2:22][O:21][CH2:20]2)[CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].[Cl:24][C:25]1[C:35]2[O:34][CH2:33][CH2:32][N:31]([CH3:36])[C:30](=[O:37])[C:29]=2[CH:28]=[CH:27][C:26]=1F>>[Cl:24][C:25]1[C:35]2[O:34][CH2:33][CH2:32][N:31]([CH3:36])[C:30](=[O:37])[C:29]=2[CH:28]=[CH:27][C:26]=1[O:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@H:19]2[CH2:23][CH2:22][O:21][CH2:20]2)[CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6]
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@H]3CCOC3)c2)cn1
Reactant: CN1CCOc2c(ccc(F)c2Cl)C1=O
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc4c(c3Cl)OCCN(C)C4=O)cc(O[C@H]3CCOC3)c2)cn1

Procedure:
The preparations of 3-hydroxy-N-(5-methylpyrazin-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide and 9-chloro-8-fluoro-4-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one were described earlier.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([C:16]3[CH:20]=[C:19]([CH3:21])[O:18][N:17]=3)=[CH:15][C:8]=2[CH2:7][CH2:6]1)=O.C([O-])([O-])=O.[K+].[K+].CO>O>[CH3:21][C:19]1[O:18][N:17]=[C:16]([C:14]2[CH:13]=[CH:12][C:9]3[CH2:10][CH2:11][NH:5][CH2:6][CH2:7][C:8]=3[CH:15]=2)[CH:20]=1
Reactant: Cc1cc(-c2ccc3c(c2)CCN(C(=O)C(F)(F)F)CC3)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc(-c2ccc3c(c2)CCNCC3)no1
Yield: 78 %

Procedure:
A mixture of 3-trifluoracetyl-7-(5-methyl-isoxazol-3-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine (7.1 g) and K2CO3 (12.1 g) in 1:1 methanol:water (400 ml) was heated at 50° C. for 1 h. The mixture was cooled, poured into water (500 ml) and extracted with dichloromethane. The combined organic layers were dried and evaporated in vacuo to give the title compound as a yellow oil (3.9 g).
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:14]=[C:15]([CH2:19][C:20]#[N:21])[CH:16]=[CH:17][CH:18]=3)=[CH:10][CH:11]=2)[N:6]([CH3:22])[C:5]1=[O:23].[CH3:26]I>C1COCC1.CO>[CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:14]=[C:15]([CH:19]([CH3:26])[C:20]#[N:21])[CH:16]=[CH:17][CH:18]=3)=[CH:10][CH:11]=2)[N:6]([CH3:22])[C:5]1=[O:23]
Reactant: CI
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(CC#N)c3)nc21
Solvent: C1CCOC1
Solvent: CO
Product: CC(C#N)c1cccc(-c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask, {3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl}acetonitrile (14-48) (45 mg, 0.14 mmol) was added and dissolved in THF (1.3 ml) under nitrogen and cooled to −78° C. 1 M Sodium bis(hexamethylsilyl)amide (0.18 ml, 0.18 mmol) was added slowly to the cooled solution, followed by Methyl iodide (25 mg, 0.18 mmol). The cooled solution was stirred for 30 minutes, allowed to warm to room temperature and stirred for 10 minutes. The reaction was diluted with methanol, and passed through a syringe filter. The solution was purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile) and the desired fractions were collected and concentrated to produce 2-{3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl}propanenitrile (33-1), HRMS (M+H)+: observed=349.2032, calculated=349.2023 and 2-{3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl}-2-methylpropanenitrile (33-2); HRMS (M+H)+: observed=363.2186, calculated=363.2179.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[N:8]=[N:9][C:10]([Cl:13])=[CH:11][CH:12]=1.[OH:14][CH2:15][C:16](C)([CH3:19])[CH:17]=O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>O>[Cl:6][C:7]1[N:8]=[N:9][C:10]([Cl:13])=[CH:11][C:12]=1[C:16]([CH2:15][OH:14])([CH3:19])[CH3:17]
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(C=O)CO
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: CC(C)(CO)c1cc(Cl)nnc1Cl
Reaction time: 1 h

Procedure:
Ten ml. of water and 0.33 ml. of sulfuric acid were heated to 80°, and to it were added 0.75 g. of 3,6-dichloropyridazine and 2.55 g. of 3-hydroxy-2,2-dimethylpropanaldehyde. Then a solution of 5.7 g. of ammonium persulfate in 15 ml. of water was added dropwise over 10 minutes. The temperature of the mixture reached 100° during the addition. The mixture was stirred for one hour, and then 0.51 g. of the aldehyde and 1.1 g. of ammonium persulfate were added, and the mixture was stirred one hour more at 90°. It was then cooled and extracted twice with 30 ml. portions of dichloromethane. The organic layers were combined, washed with 30 ml. of water and then with 30 ml. of saturated aqueous sodium bicarbonate, and dried with sodium sulfate. The solvent was removed under vacuum to obtain 1.38 g. of oil, which was chromatographed on 100 g. of silica gel, eluting with one liter of 3:7 ethyl acetate:hexane and then with 2:3 ethyl acetate:hexane. The product-containing fractions were combined and evaporated under vacuum to obtain 0.43 g. of the desired product in crude form, about 80% pure by nuclear magnetic resonance analysis. The spectrum, taken in CDCl3 on a 90 mmHz instrument, showed the following characteristic features: δ7.59 (s, 1H); 4.02 (broad s, 3H); 1.46 (s, 6H).
Reaction SMILES: [CH:1]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:9][CH2:10][CH2:11][C:12](O)=[O:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:1]1([O:8][C:12](=[O:13])[CH2:11][CH2:10][SH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCS
Reactant: OC1CCCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(CCS)OC1CCCCCC1

Procedure:
Into a 100 ml reaction flask equipped with stirrer, thermometer, reflux condenser and hot plate are placed 45.6 grams of cycloheptanol; 16 grams of 3-mercaptopropionic acid and 0.5 grams of paratoluene sulfonic acid. The reaction mass is heated to reflux and refluxed for a period of 12 hours. At the end of the 12 hour period, the reaction mass is cooled and distilled on a micro distillation apparatus yielding the compound having the structure: ##STR146## as confirmed by GLC, IR, NMR and mass spectral analyses.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][CH2:8][C:9]#[C:10][CH2:11]Cl.[CH:13]1([C:17]2[C:22]([O:23]CC#N)=[N:21][N:20]3[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:28][N:29]=[C:19]3[CH:18]=2)[CH2:16][CH2:15][CH2:14]1>CN(C=O)C>[Cl:7][CH2:8][C:9]#[C:10][CH2:11][O:23][C:22]1[C:17]([CH:13]2[CH2:16][CH2:15][CH2:14]2)=[CH:18][C:19]2[N:20]([C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:28][N:29]=2)[N:21]=1
Reactant: ClCC#CCCl
Reactant: N#CCOc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCC#CCOc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Reaction time: 2 h

Procedure:
Potassium carbonate (311 mg, 2.2 mmol) and 1,4 dichloro-2-butyne (275 mg, 2.2 mol) in DMF (3 ml) were heated to 50° C. prior to the dropwise addition of the product from Example 185, Step a (200 mg, 0.75 mmol) in DMF (2 ml). The reaction mixture was left to stir for 2 hours. Cooled and partitioned (ethyl acetate/water). The organic layer was washed (H2O, brine), dried MgSO4) and evaporated in vacuo. Purified via silica gel chromatography using 50/50 ethyl acetate/hexane to elute. 1H NMR (250 MHz, CDCl3) δ1.93 (1 H, m), 2.11-2.16 (3 H, m), 2.42 (2 H, m), 4.2 (2 H, m), 5.10 (2 H, m), 7.50-7.59 (3 H, m), 7.84 (1 H, s), 8.47 (2 H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:20][CH3:21])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CCO
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
A solution of 4-chloro-3-trifluoromethyl benzoic acid (10 g, 44.5 mmol) in ethanol (10 ml) was split equally between two microwave vials. Concentrated sulfuric acid (0.75 ml) was added to each vial (1.5 ml in total). The reactions were heated in the microwave at 120° C. for 30 minutes in total. The reaction mixtures were combined and concentrated in vacuo. The residue was partitioned between EtOAc (100 ml) and aq. sodium bicarbonate (100 ml), the organic phase was separated, washed with aq. sodium bicarbonate (100 ml) and water (2×100 ml) and then dried (phase separator) and the solvent removed in vacuo to give the title compound (4.126 g) as a colourless oil. δH (400 MHz, methanol-d4) 1.40 (3H, t), 4.41 (2H, quart), 7.76 (1H, d), 8.22 (1H, dd), 8.34 (1H, d).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([O:18]C)=[O:17])[CH:14]=2)[C:9](=[O:20])[N:8]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:7]=1[CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=2)[C:9](=[O:20])[N:8]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:7]=1[CH2:25][NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC2CC2)c(=O)c2ccc(C(=O)OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC2CC2)c(=O)c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a solution of methyl 4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylate (2.98 g, 6.5 mmol) in tetrahydrofuran (10 mL) and methanol (10 mL) was added 1N sodium hydroxide (10 mL). The obtained mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylic acid (2.62 g, 90.7%) as crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11](=[O:42])[NH:12][C@H:13]([CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:14](=[O:32])[N:15]1[CH2:20][CH2:19][N:18]2[C:21](=[O:24])[CH2:22][CH2:23][C:17]2([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:16]1)([CH3:10])[CH3:9])(C)(C)C.Cl>CCOCC>[NH2:7][C:8]([CH3:10])([CH3:9])[C:11]([NH:12][C@H:13]([CH2:33][O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:14](=[O:32])[N:15]1[CH2:20][CH2:19][N:18]2[C:21](=[O:24])[CH2:22][CH2:23][C:17]2([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:16]1)=[O:42]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCN2C(=O)CCC2(Cc2ccccn2)C1
Agent: Cl
Solvent: CCOCC
Product: CC(C)(N)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCN2C(=O)CCC2(Cc2ccccn2)C1

Procedure:
Compound of Example 202, Step E (12 mg, 0.020 mmol) was deprotected as described in General Procedure C to provide, after trituration with ether, Example 202, Step F as its HCl salt (5 mg, 50%): +APcl MS (M+1)+ 494; 1H NMR (400 MHz, CD3OD) δ: 8.90-7.15 (arom series of m, 9 H), 5.31 (m, 0.5H), 5.15 (m, 0.5H), 2.86 (d, 0.5H), 2.77 (d, 0.5H), 1.60 (Me, M, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].[CH3:26][C:27]1[N:28]=[CH:29][O:30][C:31]=1[C:32](O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:32]([C:31]5[O:30][CH:29]=[N:28][C:27]=5[CH3:26])[N:24]([CH3:25])[C:3]=4[CH:4]=3)[C:9](=[O:23])[CH:10]=2)=[CH:21][CH:20]=1
Reactant: CNc1cc(-n2ccc(OCc3ccc(F)cc3)cc2=O)ccc1N
Reactant: Cc1ncoc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ncoc1-c1nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (100 mg), 4-methyl-1,3-oxazole-5-carboxylic acid (37.5 mg), HATU (118 mg) and N,N-diisopropylethylamine (0.154 ml) in DMF (2 ml) was stirred at room temperature for 2 h. The mixture was poured into saturated NaHCO3 solution and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting residue was dissolved in AcOH (2 ml), and the mixture was stirred at 80° C. for 2 h. The mixture was concentrate in vacuo, and purified by NH silica gel column chromatography (MeOH/EtOAc). The resulting solid was washed with EtOAc/hexane to give the title compound (63.4 mg) as a white solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:10][O:9][C:7]([C:4]1[S:3][C:2]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][OH:11])[CH2:15][CH2:16]2)=[N:6][CH:5]=1)=[O:8]
Reactant: COC(=O)c1cnc(Br)s1
Reactant: OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cnc(N2CCN(CCO)CC2)s1
Temperature: 80 °C
Yield: 68.2 %

Procedure:
To a solution of methyl 2-bromothiazole-5-carboxylate 1 (222 mg, 1.00 mmol) in acetonitrile (20 mL) were added N-(2-hydroxyethyl)piperazine 14c (156 mg, 1.20 mmol) and potassium carbonate (152 mg, 1.10 mmol) under a N2 atmosphere. The reaction mixture was heated to reflux at 80° C. for 10 h. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 15c (185 mg, 68.2%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:24]2[C:29](=[O:30])[CH2:28][CH:27]([C:31](F)(F)F)[CH2:26][C:25]=2[O:35][CH2:36][CH3:37])[NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[O:12])=[CH:5][CH:4]=1)#[N:2].C(C1C=CC(C(C2C(=O)CC(C3[CH:73]=[C:72]([O:74][CH3:75])[C:71]([O:76][CH3:77])=[C:70]([O:78][CH3:79])[CH:69]=3)CC=2O)NC(NC2C=CC=C(C(F)(F)F)C=2)=O)=CC=1)#N>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:24]2[C:29](=[O:30])[CH2:28][CH:27]([C:31]3[CH:69]=[C:70]([O:78][CH3:79])[C:71]([O:76][CH3:77])=[C:72]([O:74][CH3:75])[CH:73]=3)[CH2:26][C:25]=2[O:35][CH2:36][CH3:37])[NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: COc1cc(C2CC(=O)C(C(NC(=O)Nc3cccc(C(F)(F)F)c3)c3ccc(C#N)cc3)=C(O)C2)cc(OC)c1OC
Reactant: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC(C(F)(F)F)C1
Product: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC(c2cc(OC)c(OC)c(OC)c2)C1

Procedure:
The title compound is prepared in analogy to 1-((4-cyanophenyl)(2-ethoxy-6-oxo-4-(tri-fluoromethyl)cyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 13), using 1-((4-cyanophenyl)(2-hydroxy-6-oxo-4-(3,4,5-trimethoxyphenyl)cyclohex-1-enyl)-methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 18, 680 mg, 1.14 mmol) as starting material. Yield: 684 mg; ESI mass spectrum [M+H]+=624, Retention time HPLC: 1.27 min (V011_S01).