Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([OH:19])C#C.N1C=C[CH:23]=[CH:22][CH:21]=1.Cl>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:14][CH2:21][C:22]#[CH:23])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccncc1
Reactant: C#CCO
Reactant: O=C(Cl)CCCCCCc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: C#CCOC(=O)CCCCCCc1ccccc1
Yield: 81 %

Procedure:
544 Milligrams of 7-phenylheptanoyl chloride was added by drops to a mixture of 135 mg of propargyl alcohol, 191 mg of pyridine and 20 ml of dry toluene with stirring and ice-cooling. After dropwise addition, the resultant solution was stirred for additional 12 hours at room temperature. The thus stirred solution was poured into a dilute hydrochloric acid cooled with ice. The toluene layer was separated from the resulting mixture. The aqueous layer was extracted once with toluene. These toluene layers were combined, washed with water and then with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off from the dried layer under reduced pressure. The resulting residue was subjected to chromatography on silica gel to obtain 482 mg of propargyl 7-phenylheptanoate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[C:15](\[CH3:21])/[C:16](OCC)=[O:17])=[CH:10][CH:9]=2)[CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[C:15](\[CH3:21])/[CH2:16][OH:17])=[CH:12][CH:13]=2)[CH:2]=1
Reactant: CCOC(=O)/C(C)=C/c1ccc(Cc2cccnc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C/C(=C\c1ccc(Cc2cccnc2)cc1)CO
Yield: 72.3 %

Procedure:
In 33 ml of anhydrous tetrahydrofuran was dissolved 6.5 g of ethyl (E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylacrylate, and to the resulting solution was added 0.66 g of lithium aluminum hydride in small portions at room temperature. Further, the resulting mixture was subjected to reaction at the same temperature for one hour, and thereafter, 30 ml of ethyl acetate and then 2.5 ml of water were added in small portions with water-cooling. The insolubles were removed by filtration, and thereafter, the organic layer was dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: benzene:ethyl acetate (3:1 by volume)], to obtain 4.0 g (yield 72.3%) of colorless, oily (E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyl alcohol.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:9]2[C@@:5]([C:12]([O:14]C)=[O:13])([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[O:4][C@H:3]1[CH2:16][NH:17][C:18]([CH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][NH:27][C:28](=[O:70])[CH2:29][NH:30][C:31](=[O:69])[CH2:32][N:33]2[CH2:44][CH2:43][N:42]([CH2:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:41][CH2:40][N:39]([CH2:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[CH2:38][CH2:37][N:36]([CH2:61][C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:35][CH2:34]2)[CH2:22][CH2:21]1)=[O:19].O[Li].O>CO>[OH:1][C@@H:2]1[C@@H:9]2[C@@:5]([C:12]([OH:14])=[O:13])([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[O:4][C@H:3]1[CH2:16][NH:17][C:18]([CH:20]1[CH2:21][CH2:22][CH:23]([CH2:26][NH:27][C:28](=[O:70])[CH2:29][NH:30][C:31](=[O:69])[CH2:32][N:33]2[CH2:34][CH2:35][N:36]([CH2:61][C:62](=[O:63])[O:64][C:65]([CH3:66])([CH3:67])[CH3:68])[CH2:37][CH2:38][N:39]([CH2:53][C:54](=[O:60])[O:55][C:56]([CH3:57])([CH3:58])[CH3:59])[CH2:40][CH2:41][N:42]([CH2:45][C:46]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:52])[CH2:43][CH2:44]2)[CH2:24][CH2:25]1)=[O:19]
Reactant: COC(=O)[C@]12O[C@@H](CNC(=O)C3CCC(CNC(=O)CNC(=O)CN4CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC4)CC3)[C@H](O)[C@H]1OC(C)(C)O2
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCN(CC(=O)NCC(=O)NCC2CCC(C(=O)NC[C@@H]3O[C@]4(C(=O)O)OC(C)(C)O[C@@H]4[C@H]3O)CC2)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
To a solution of 19b (1.5 g, 1.5 mmol) in MeOH (4 mL) was added a solution of LiOHH2O (63 mg, 1.5 mmol, Aldrich). The resulting solution was stirred at room temperature for 4 h. 30 mg of LiOH.H2O was added and it was stirred at RT for 20 more hours. Solvents were evaporated to obtain crude product 20b (1.45 g; crude yield 99%). The material was used without further purification.
Reaction SMILES: [I:1]/[CH:2]=[CH:3]/[CH2:4][C:5]([OH:11])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9].N1C=CN=C1.CN(C)C=O.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>CCCCCC>[I:1]/[CH:2]=[CH:3]/[CH2:4][C:5]([CH3:10])([O:11][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(C)(O)C/C=C/I
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCCCC(C)(C/C=C/I)O[Si](C)(C)C
Reaction time: 8 h

Procedure:
To a stirred mixture of 24.5 g (55.6 mmoles) of 1-iodo-4-hydroxy-4-methyl-trans-1-octene (Example 130), 13.6 g (200 mmoles) of imidazole, and 75 ml of dimethylformamide is added 10.9 g (100 mmoles) of chlorotrimethylsilane. After standing overnight the mixture is poured into 250 ml of hexane. The mixture is washed thoroughly with water followed by brine and dried over magnesium sulfate. After removal of the solvent, the product is distilled to give a colorless liquid, bp 67.5°-68° C. (0.07 mm).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:15][CH2:14][CH2:13][O:12][C:9]=3[CH:10]=2)C(=O)N(CCCCl)N=1.COC1C=[C:25]([CH2:31][CH2:32][NH:33][CH3:34])C=CC=1OC.C(Cl)(Cl)Cl.CO>ClC1C=CC=CC=1>[CH3:34][N:33]([CH2:32][CH2:31][CH3:25])[CH2:1][CH2:2][C:11]1[CH:6]=[CH:7][C:8]([O:15][CH3:14])=[C:9]([O:12][CH3:13])[CH:10]=1
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: Cc1nn(CCCCl)c(=O)c2cc3c(cc12)OCCO3
Solvent: CO
Solvent: Clc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCN(C)CCc1ccc(OC)c(OC)c1

Procedure:
1-4-Methyl-6,7-ethylenedioxy-1(2H)-phthalazinone-2-yl]-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane was prepared analogous to Example 1 (b) by reaction of 1-[4-methyl-6,7-ethylenedioxy-1(2H)-phthalazinone-2-yl]-3-chloro-propane with N-(3,4-dimethoxy-phenylethyl)-N-methyl-amine in chlorobenzene. Yellow oil. Rf -value (chloroform/methanol = 9/1) : 0.7.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]([NH2:19])=[S:18])=[N:11][CH:12]=[C:13]([Br:15])N=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22](=O)[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26].[CH2:30](N(CC)CC)C>CO>[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:21]=[C:22]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[N:19]=2)=[N:11][CH:12]=[C:13]([Br:15])[CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=O)CBr
Reactant: NC(=S)Nc1ncc(Br)nc1OCc1ccccc1
Reactant: CCN(CC)CC
Solvent: CO
Product: COC(=O)CCc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Yield: 57 %

Procedure:
1-(3-(Benzyloxy)-5-bromopyrazin-2-yl)thiourea (2.00 g, 5.91 mmol), methyl 5-bromo-4-oxopentanoate (1.48 g, 7.10 mmol) (prepared according to Synthetic Communications (1994) 2557-2562), and triethylamine (1.44 mL, 10.3 mmol) were heated in methanol (50 mL) at reflux for 3 hours according to the method of Example 2, Step C, to provide methyl 3-(2-(3-(benzyloxy)-5-bromopyridin-2-ylamino)thiazol-4-yl)propanoate (1.51 g, 57%) as a white powder: 1H NMR (DMSO-d6) δ 11.16 (bs, 1H), 8.02 (s, 1H), 7.59 (d, 2H), 7.36-7.44 (m, 3H), 6.71 (bs, 1H), 5.43 (s, 2H), 3.59 (s, 3H), 2.85 (t, 2H), 2.69 (t, 2H). Mass spectrum (esi) m/z=449 (96), 451 (100).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH2:3]1.[Br:14]Br>C(Cl)Cl>[Br:14][C:10]1[CH:11]=[CH:12][C:5]2[O:4][CH2:3][C:2]([CH3:13])([CH3:1])[CH2:8][O:7][C:6]=2[CH:9]=1
Reactant: BrBr
Reactant: CC1(C)COc2ccccc2OC1
Solvent: ClCCl
Product: CC1(C)COc2ccc(Br)cc2OC1
Temperature: 25 °C
Yield: 108.2 %

Procedure:
8.55 g of 3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepine (see Example 10) were dissolved in 70 ml of methylene chloride (CH2Cl2) and treated at 0° C. under an Argon atmosphere with a solution of 8.0 g of Br2 in 30 ml of CH2Cl2. The mixture was warmed to room temperature and left to react for 1 hour. It was then poured on to ice and extracted with ether. Washing with NaHCO3 solution and water, drying and evaporation yielded 13.35 g of 7-bromo-3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepine as a colorless oil which was 94.5% pure and which contained 4.7% of starting material; it was processed in the crude state.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.Br[CH2:15][C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[C:16]([CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1)#[N:17]
Reactant: COC(=O)c1ccc(O)cc1OC
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCC#N)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
Methyl 4-hydroxy-2-methoxy-benzoate (0.790 g, 4.34 mmol), 2-bromoacetonitrile (361 μL, 5.42 mmol), and potassium carbonate (900 mg, 6.51 mmol) were combined in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 mL of ethyl acetate and 25 mL of water. The layers were separated and the water layer was extracted with 50 mL of ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of sodium chloride (2×). The organic layer was then dried over sodium sulfate, filtered, and evaporated to dryness to yield methyl 4-(cyanomethoxy)-2-methoxy-benzoate (99%) as a brown oil. ESI-MS m/z calc 221.1, found 222.1 (M+1)+. Retention time: 1.08 minutes (3 min run).
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([NH:12][C:13]([C:15]2[CH:20]=[N:19][CH:18]=[CH:17][N:16]=2)=[O:14])[C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:22](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:46][C@:47]12[C@H]3C[C@H](C3(C)C)[CH2:58][C@H:48]1[O:49][B:50]([C@@H:52]([NH2:57])[CH2:53][CH:54]([CH3:56])[CH3:55])[O:51]2.C(N(CC)C(C)C)(C)C>CN(C)C=O>[O:49]1[CH2:48][CH2:58][NH:22][CH2:46][CH2:47][O:51][B:50]1[C@@H:52]([NH:57][C:9](=[O:11])[C@@H:8]([NH:12][C:13]([C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)=[O:14])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:53][CH:54]([CH3:56])[CH3:55]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cnccn1
Reactant: CC(C)C[C@H](N)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OCCNCCO1
Temperature: -25.5 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A 500 ml three neck round bottomed flask equipped with a stir bar, addition funnel, thermocouple, nitrogen inlet/outlet and cooling bath was charged with 11 g (99.9 mmol) of (S)-3-Phenyl-2-[(pyrazine-2-carbonyl)-amino]-propionic acid (the product of Step B), 15.5.0 g (40.6 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU), 12.2 g (40.6 mmol) of (1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylamine hydrochloride salt (87:13 mixture of isobutyl diastereomers (R:S)) and 165 mL of N,N-dimethylformamide (DMF). The pale yellow reaction solution was cooled to −35° C. where 12.6 g (17 mL, 97.3 mmol) of N,N-di-isopropyl ethyl amine was added dropwise over six minutes at −34° C. to −35° C. The resulting solution was then stirred overnight at −40 to −11° C. The reaction mixture was quenched onto 600 ml of a 1:1 cold water/ethyl acetate mixture. After transferring into a separatory funnel the layers were separated. The organic phase was then washed successively with 10% aqueous sodium hydrogen phosphate (1×200 mL), 8% aqueous sodium bicarbonate (2×200 mL) and saturated sodium chloride (1×200 mL). The product solution was dried over magnesium sulfate then filtered. The filtrate was evaporated to dryness in vacuo to give 19.57 g (37.7 mmol, 93%) of the title compound as a light brown foam with an HPLC purity of 92 A %. 1H NMR (d6-DMSO, 400 MHz) δ 9.15 (d, 1H, J=1.44 Hz), 8.87 (d, 1H, J=2.48 Hz), 8.7 (m, 3H), 7.25 (m, 4H), 7.18 (m, 1H), 4.89 (q, 1H, J=6.88, 15.4 Hz), 4.13 (dd, 1H, J=1.8, 8.56 Hz), 3.15 (d, 2H, J=6.88 Hz), 2.7 (m, b, 1H), 2.22 (m, b, 1H), 2.05 (m, b, 1H), 1.87 (t, 1H, J=5.40 Hz), 1.81 (s, b, 1H), 1.67 (d, b, 1H), 1.52 (m, b, 1H), 1.13-1.33 (m, 9H), 0.83 (dd, 6H, J=2.48, 6.56 Hz), 0.80 (s, 3H).
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([OH:17])=O)[CH2:10]2)=CC=1.C(OC([N:27]1[CH2:32][CH2:31]N[CH2:29][CH2:28]1)=O)(C)(C)C.[N+:33]([C:36]1[CH:49]=[CH:48][C:39]([CH2:40][O:41][C:42]([NH:44][C:45](=[NH:47])[CH3:46])=[O:43])=[CH:38][CH:37]=1)([O-:35])=[O:34]>>[SH:8][C@@H:9]1[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([N:27]2[CH2:32][CH2:31][N:47]([C:45](=[N:44][C:42]([O:41][CH2:40][C:39]3[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:49][CH:48]=3)=[O:43])[CH3:46])[CH2:29][CH2:28]2)=[O:17])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C)C2)cc1
Reactant: CC(=N)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCN(C(=O)[C@@H]2C[C@H](S)CN2C)CC1
Yield: 49.9 %

Procedure:
Following a procedure similar to that described in Preparation 1, but using 282 mg of (2S,4S)-4-(4-methoxybenzylthio)-1-methyl-2-pyrrolidinecarboxylic acid, 203 mg of 1-t-butoxycarbonylpiperazine and 258 mg of N-(4-nitrobenzyloxycarbonyl)acetamidine, 225 mg of the title compound were obtained as a viscous oil.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[C:13]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([OH:24])=O)=[N:20][CH:21]=2)[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[CH:5]=1)(O)=[O:2].[NH2:25][C:26]1[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=1>>[CH3:31][N:28]1[CH:29]=[CH:30][C:26]([NH:25][C:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][C:13]3[C:7]4[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=4[CH:5]=[C:4]([C:1](=[O:2])[NH:25][C:26]4[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=4)[CH:14]=3)=[CH:21][N:20]=2)=[O:24])=[N:27]1
Reactant: CC1(C)Cc2c(Oc3ccc(C(=O)O)nc3)cc(C(=O)O)cc2O1
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)Nc4ccn(C)n4)nc3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 149, from 5-(6-carboxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid (163b) (111 mg, 0.288 mmol) and 3-amino-1-methyl-pyrazole (56 mg, 0.576 mmol) to give a white solid (112 mg, 80% yield). 1H NMR (400 MHz, CDCl3) δ 10.19 (s, 1 H) 8.98 (s, 1 H) 8.30 (d, J=2.53 Hz, 1 H) 8.22 (d, J=8.59 Hz, 1 H) 7.28-7.38 (m, 2 H) 7.24-7.28 (m, 1 H) 7.07 (d, J=3.03 Hz, 2 H) 6.79 (d, J=2.02 Hz, 1 H) 6.83 (d, J=2.27 Hz, 1 H) 3.84 (s, 3 H) 3.74 (s, 3 H) 2.89 (s, 2 H) 1.49 (s, 6 H); LCMS for C25H25N7O4 m/z 488.20 (M+H+); Anal. Calcd. for C25H25N7O4.0.1 CHCl3: C, 59.50; H, 5.15; N, 19.35. Found: C, 59.77; H, 5.17; N, 18.96.
Reaction SMILES: C[O-].[Na+].C(OC)(=O)C.[CH3:9][O:10][C:11](=[O:29])[CH:12]=[C:13]1[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][CH:14]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1>CS(C)=O.C(OCC)(=O)C>[CH3:9][O:10][C:11](=[O:29])[CH2:12][C:13]1[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][C:14]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1
Reactant: COC(=O)C=C1CCC(C)(C)CC1c1cccc(OC)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: COC(C)=O
Product: COC(=O)CC1=C(c2cccc(OC)c2)CC(C)(C)CC1
Temperature: 100 °C
Yield: 100.2 %

Procedure:
Dissolve sodium methoxide (0.99 g, 18.4 mmol) in DMSO (37 ml) add methyl acetate (1 ml), add [2-(3-methoxy-phenyl)-4,4-dimethyl-cyclohexylidene]-acetic acid methyl ester (5.3 g, 18 mmol). Heat at 100° C. stirring over night. Dilute with ethyl acetate (50 ml), wash with brine 4× (30 ml), dry, and concentrate to give the title compound (5.2 g 98%): 1H NMR (CDCl3) δ 7.24-7.18 (m, 1H), 6.78-6.68 (m, 3H), 3.79 (s, 3H), 3.65 (s, 2H), 3.59 (s,1H), 2.95 (s,1H), 2.15-2.07 (m, 3H), 1.55(s, 3H), 1.49-1.46 (m,1H), 0.98 (s, 6H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:28])=[C:11]([NH:13][C:14]([C:16]3[S:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=4)=[CH:19][CH:20]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.C1(C)C=CC(S([O:38][CH2:39][C@H:40]2[CH2:44]OC(C)(C)[O:41]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.O.CO>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:28])=[C:11]([NH:13][C:14]([C:16]3[S:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:44][C@H:40]([OH:41])[CH2:39][OH:38])[CH:22]=4)=[CH:19][CH:20]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(-c2cccc(O)c2)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(-c2cccc(OC[C@H](O)CO)c2)s1
Temperature: 80 °C
Yield: 31.1 %

Procedure:
A mixture of N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-5-(3-hydroxyphenyl)thiophene-2-carboxamide (Example 144, 80 mg, 0.20 mmol), (R)-(−)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate (70 mg, 0.24 mmol) and K2CO3 (84 mg, 0.61 mmol) in DMF (0.3 mL) was stirred and heated at 80° C. for 17 h. After cooling to rt, the mixture was diluted with water (˜5 mL) and extracted with EtOAc (3×10 mL) and the combined extracts were washed with brine, dried over anhyd. Na2SO4, filtered, and concentrated under vacuum to afford a brown oil. This material was purified by reverse-phase Prep HPLC to isolate the major product which was dissolved in MeOH (˜3 mL) and 2 N aq HCl (0.3 mL) was added. The solution was warmed to 65° C. for 45 min then cooled to rt and concentrated under vacuum to remove most of the MeOH. The resulting heterogeneous mixture was diluted with water (˜2-3 mL) and stirred for 1 h. The resulting solid was collected by vacuum filtration, rinsed with water (˜5 mL), and air dried in funnel then under vacuum to afford 29 mg (30%) of an off-white solid as the title compound (Example 193). HPLC Ret. Time=2.90 min, LCMS [M+H]+ 467.29.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])O.[Na+].C(O)C.[C:21]([NH:29][C:30]1[CH:42]=[C:41](Br)[CH:40]=[CH:39][C:31]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.O>[C:21]([NH:29][C:30]1[CH:42]=[C:41]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:40]=[CH:39][C:31]=1[C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 18 %

Procedure:
0.11 g of 4-nitrophenylboronic acid, 0.11 g of sodium hydrogen carbonate, 1.2 mL of ethanol, 0.6 mL of water and 31 mg of tetrakis(triphenylphosphine)palladium(0) were added to 4.0 mL of toluene solution containing 0.20 g of tert-butyl 2-(benzamido)-4-bromobenzoate, and the resulting mixture was heated to reflux under nitrogen atmosphere for 3 hours. A saturated sodium hydrogen carbonate aqueous solution was added after the reaction mixture was cooled to room temperature. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate=10:1] to obtain 40 mg of tert-butyl 2-(benzamido)-4-(4-nitrophenyl)benzoate as white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([Cl:22])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]#[N:24])[CH:8]=2)[N:3]=1.[NH:25]1[CH2:33][CH2:32][CH:28]([C:29]([OH:31])=[O:30])[CH2:27][CH2:26]1.CN1CC[CH2:37][C:36]1=O>O>[CH2:36]([O:30][C:29]([CH:28]1[CH2:32][CH2:33][N:25]([C:2]2[CH:11]=[C:10]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([Cl:22])[CH:15]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:23]#[N:24])[CH:8]=3)[N:3]=2)[CH2:26][CH2:27]1)=[O:31])[CH3:37]
Reactant: CN1CCCC1=O
Reactant: O=C(O)C1CCNCC1
Reactant: COc1ccc(CNc2cc(Cl)nc3ccc(C#N)cc23)cc1Cl
Solvent: O
Product: CCOC(=O)C1CCN(c2cc(NCc3ccc(OC)c(Cl)c3)c3cc(C#N)ccc3n2)CC1
Temperature: 130 °C

Procedure:
A mixture comprising 750 mg of 2-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinoline, 1.6 ml of isonipecotic acid and 5 ml of N-methyl-2-pyrrolidone was heated on an oil bath at 130° C. for 3 hours and cooled, followed by the addition of water. The resulting mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (20 to 40% ethyl acetate/hexane) and thereafter recrystallized from ethyl acetate/hexane to give 860 mg of the title compound.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:35])[C:9]=1[NH:10][C:11]1[C:20]2[C:15](=[C:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[NH:14][C:13](=[O:34])[CH:12]=1.CO>O1CCCC1>[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:35])[C:9]=1[NH:10][C:11]1[C:20]2[C:15](=[C:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[NH:14][C:13](=[O:34])[CH:12]=1
Reactant: CCOC(=O)CCCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCC(=O)O
Reaction time: 24 h

Procedure:
Lithium hydroxide (2.0 mL, 1M, 2.0 mmol) was added to a solution of ethyl 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)hexanoate (100 mg, 0.20 mmol), methanol (2 mL), and tetrahydrofuran (8 mL). The mixture was stirred for 24 h, quenched with 1N HCl (30 mL), and extracted with ethyl acetate (40 mL×2). The organic extracts were dried, filtered, and concentrated to give 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)hexanoic acid: 1H NMR (400 MHz, DMSO-d6): δ 10.10 (s, 1H), 8.88 (s, 1H), 8.77 (s, 2H), 7.89 (d, 1H), 7.06 (d, 1H), 4.80 (s, 1H), 3.95 (t, 2H), 3.90 (s, 3H), 2.22 (t, 2H), 1.76 (m, 2H), 1.55 (m, 2H), 1.39 (m, 2H); MS (ESI): 465.8.