Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[CH:8]1([Mg]Br)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[NH4+].[Cl-]>C1COCC1.CCOCC>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: BrCCCCCBr
Reactant: Br[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: BrCCCCCC1CCCCC1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To a solution of 1,5-dibromopentane (16 gm, 69.97 mmol) in THF (20 ml) was added a solution of (Li2CuCl4 in ether, 14 ml) under nitrogen at 5-10° C. and stirred for 25 minutes. Cyclohexyl magnesium bromide (10 gm, 69.97 mmol) was added dropwise with stirring for about 30 minutes. The reaction mixture was stirred at 0° C. for another 1 h and stirred at room temperature for 12 hr. The reaction mixture was cooled to 0° C. in ice, saturated NH4Cl solution (20 ml) was added and the resulting mixture was extracted with EtOAc (4×25 ml). The organic layer was separated, washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography using hexane as an eluent. The pure product was an oily liquid (12.84 gm).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([F:10])([F:9])[F:8])=[C:4]([CH2:11][OH:12])[CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:23][CH:22]([O:24][C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=2O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[CH2:23][CH:22]([O:24][C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=2[O:12][CH2:11][C:4]2[CH:3]=[C:2]([CH3:1])[O:6][C:5]=2[C:7]([F:10])([F:8])[F:9])[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Reactant: Cc1cc(CO)c(C(F)(F)F)o1
Product: Cc1cc(COc2ccc(Cl)cc2OC2CN(C(=O)OC(C)(C)C)C2)c(C(F)(F)F)o1

Procedure:
Synthesized from the title compound of Step A and 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester using general procedure 7. MS (ESI): mass calcd. for C21H23ClF3NO5, 461.1; m/z found, 485.9 [M+Na]+. 1H NMR 6.91 (dd, J=8.6, 2.3 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H), 6.55 (d, J=2.3 Hz, 1H), 6.22 (s, 1H), 5.07-5.00 (m, 2H), 4.90-4.81 (m, 1H), 4.30 (ddd, J=9.7, 6.5, 0.8 Hz, 2H), 4.06 (dd, J=9.8, 4.0 Hz, 2H), 2.34 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][C:10]#[N:11])[CH:5]=[CH:4][C:3]=1[OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24](N)[CH2:25][NH2:26].ClC1C=CC=CC=1Cl.Cl>C(O)(C)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][C:10]2[NH:26][CH2:25][CH2:24][N:11]=2)[CH:5]=[CH:4][C:3]=1[OH:12]
Reactant: NCCN
Reactant: N#CCSc1ccc(O)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Clc1ccccc1Cl
Solvent: CC(C)O
Product: Oc1ccc(SCC2=NCCN2)cc1Cl
Reaction time: 1.5 h

Procedure:
A mixture of 19.95 g of 2-chloro-4-(cyanomethylthio)-phenol, 23.3 g of ethylenediamine p-toluenesulfonate and 75 ml of 1,2-dichlorobenzene was heated at 160°-175° C. with stirring under a small flow of nitrogen for 1.5 hours. After cooling the reaction mixture, the 1,2-dichlorobenzene was decanted off. The residue was slurried in water and CH2Cl2 and then basified. The CH2Cl2 layer was separated from the mixture and an insoluble gum obtained. The gum was put in solution in isopropyl alcohol, acidified with hydrochloric acid in isopropyl alcohol and then cooled. The crude product was removed by filtering and recrystallized from isopropyl alcohol. Recrystallized 2-chloro-4-(((2-imidazolin-2-yl)methyl)thio)-phenol hydrochloride was found to have a m.p. of 181°-183° C.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].O=C[C@H]([C@H]([C@@H](CO)O)O)O>>[O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C[C@@H](O)[C@@H](O)[C@H](O)CO
Product: O=C[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
D-xylose and D-lyxose: 2.3%
Reaction SMILES: C1C=CC(C(Cl)(C2C(Cl)=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(C(C)C)CC)(C)C.C([NH:48][C@H:49]([C:54]([OH:56])=[O:55])[CH2:50][C:51](=[O:53])[NH2:52])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[C:57]([C:59]1[CH:86]=[CH:85][C:62]([CH2:63][C@@:64]2([CH3:84])[N:68]3[C:69]([C:72]([OH:74])=O)=[CH:70][N:71]=[C:67]3[N:66]([C:75]3[CH:80]=[C:79]([Cl:81])[CH:78]=[C:77]([Cl:82])[CH:76]=3)[C:65]2=[O:83])=[CH:61][CH:60]=1)#[N:58].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O.C(Cl)Cl>[C:57]([C:59]1[CH:86]=[CH:85][C:62]([CH2:63][C@@:64]2([CH3:84])[N:68]3[C:69]([C:72]([NH:48][C@H:49]([CH2:50][C:51]([NH2:52])=[O:53])[C:54]([OH:56])=[O:55])=[O:74])=[CH:70][N:71]=[C:67]3[N:66]([C:75]3[CH:80]=[C:79]([Cl:81])[CH:78]=[C:77]([Cl:82])[CH:76]=3)[C:65]2=[O:83])=[CH:61][CH:60]=1)#[N:58]
Reactant: NC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)O)n21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)N[C@H](CC(N)=O)C(=O)O)n21
Reaction time: 14 h
Yield: 73.2 %

Procedure:
2-Chlorotrityl resin (0.536 g, 0.75 mmol/g) was placed in a dry glass fritted shaker flask. To the resin was added CH2Cl2 (10 mL), diisopropylethylamine (0.522 mL) and Fmoc-L-asparagine (0.265 g, 0.75 mmol) and the reaction was agitated on an orbital shaker for 14 h. The reaction solution was drained and the resin washed with CH2Cl2/MeOH/DIEA (17:2:1; 3×10 mL), CH2Cl2 (3×10 mL), DMF (3×10 mL), and CH2Cl2 (3×10 mL). The resin was swelled with DMF (2 mL) and the solvent drained. A solution of 50% piperidine in DMF (10 mL) was added to the resin and the reaction was agitated on an orbital shaker for 90 min. The reaction solution was drained and the resin washed with DMF (2×10 mL), CH2Cl2 (2×10 mL), DMF (2×10 mL), CH2Cl2 (2×10 mL), and DMA (1×2 mL). (R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (0.132 g, 0.30 mmol) and HATU (0.285 g, 0.75 mmol) were dissolved in DMA (2 mL), and the resulting solution added to the resin. Diisopropylethylamine (0.130 mL, 0.75 mmol) was added and the reaction agitated on an orbital shaker for 48 h. The reaction solution was drained and washed as described above. The resin was treated with 10% TFA in CH2Cl2 and agitated on an orbital shaker for 90 min. The reaction solution was collected and the resin washed with CH2Cl2 (4×3 mL). The filtrates were combined with the supernatant and the volatiles removed in vacuo at 40° C. The residue was dissolved in CH2Cl2 (5 mL) and washed with water (2×5 mL) and brine (5 mL). The organic layer was dried over anhydrous Na2SO4, the solution decanted, and the solvent removed in vacuo to afford 0.122 g (73%) of (R)-2-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-succinamic acid as an orange foam.
Reaction SMILES: C[C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][N:14]3[C:18]([Cl:19])=[C:17]([Cl:20])[N:16]=[C:15]3[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:9][CH:8]=2)[C:3]=1[C:25]([O-:27])=[O:26]>CO.[OH-].[Na+].O>[CH2:21]([C:15]1[N:14]([CH2:13][C:10]2[CH:11]=[CH:12][C:7]([N:4]3[CH:5]=[CH:6][CH:2]=[C:3]3[C:25]([OH:27])=[O:26])=[CH:8][CH:9]=2)[C:18]([Cl:19])=[C:17]([Cl:20])[N:16]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCc1nc(Cl)c(Cl)n1Cc1ccc(-n2ccc(C)c2C(=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1nc(Cl)c(Cl)n1Cc1ccc(-n2cccc2C(=O)O)cc1

Procedure:
A solution of 250 mg of the methyl ester from Example 1, Step (i) in 25 mL of methanol and 25 mL of sodium hydroxide in water (10%) was stirred at ambient temperature overnight. The methanol was removed in vacuo and the pH adjusted to 4 with hydrochloric acid which caused the acid to precipitate. The product was collected by filtration: m.p. 181°-182° C.; MS(FAB) m/e(rel intensity 392 (60, M+H+), 200(100); HRMS. Calcd for M+H: 392.0933; found: 392.0967.
Reaction SMILES: C([O:9][CH:10]([C:35]([NH:37][C@@H:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH3:39])=[O:36])[C@@H:11]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])(=O)C1C=CC=CC=1.[OH-].[Li+]>O1CCOCC1.O.C(OCC)(=O)C>[CH2:20]([O:19][C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:10]([OH:9])[C:35](=[O:36])[NH:37][C@@H:38]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH3:39])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@@H](NC(=O)C(OC(=O)c1ccccc1)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)C(O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 110.8 %

Procedure:
28.0 g (45.0 mmol) of (2S)-6-{[(Benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]-1-({[(1R)-1-phenylethyl]amino}carbonyl)hexyl benzoate was dissolved in 200 mL of dioxane, and a solution of 2.47 g (174 mmol) of lithium hydroxide in 100 mL of water was added. The resulting mixture was stirred for 24 h at room temperature. It was then diluted with 500 mL of ethyl acetate, and washed with 300 mL of 1N hydrochloric acid. The aqeous layer was back-extracted with two 100 mL portions of ethyl acetate. The extracts were then combined with the original ethyl acetate layer, washed with three 200 mL aliquots of saturated aqueous sodium bicarbonate, followed by 100 mL of saturated aqueous sodium chloride, and dried over magnesium sulfate. Volatiles were then removed under vacuum to afford 25.61 g (quantitative crude yield) of tert-butyl (1S)-5-{[(benzyloxy)carbonyl]amino}-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate as a waxy light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 7.98-7.88 (m, 1H); 7.68-7.63 (m) and 7.49-7.42 (m) total 1H; 7.35-7.10 (m, 10H); 6.31 (d, J=9 Hz) and 6.02 (d, J=9 Hz) total 1H; 5.62-5.53 (br s) and 5.53-5.42 (br s) total 1H; 4.94 (s, 2H), 4.91-4.83 (m, 1H); 3.87 (br s) and 3.79 (br s) total 1H; 3.72-3.58 (m, 1H); 2.99-2.76 (m, 2H); 1.47-1.10 (m, 18H). ES-LCMS m/z 514 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][N:9]1[CH2:13][CH2:12][C@H:11]([O:14][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NN1CC[C@H](O)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NN1CC[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.2 %

Procedure:
(S)-1-(tert-Butoxycarbonylamino)-3-hydroxypyrrolidine (40 g, 0.21 mol) was dissolved in anhydrous methylene chloride (400 mL), in the presence of N,N-diisopropyl-ethylamine (73 mL, 0.42 mol, 2 equiv.) and cooled using an ice bath. This solution was treated with methanesulfonyl chloride (18 mL, 0.23 mol, 1.1 equiv.) over a 30 min. period and was then allowed to stir at room temperature for 4 h. The solution was concentrated and the residue dissolved in ethyl acetate (250 mL). The resulting organic solution washed with 5% NaHCO3 and then with brine. The organic extract was dried over magnesium sulfate, filtered and concentrated to give (S)-1-(tert-butoxycarbonyl-amino)-3-methanesulfonyloxypyrrolidine as a dark oil (39 g) which was used directly without further purification.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29].[Cl-].[NH4+]>ClCCl>[NH3:7].[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH:20][C:28](=[O:30])[CH3:29])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)Cl
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(N)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(NC(C)=O)c1
Product: N
Temperature: 25 °C
Reaction time: 8 h
Yield: 198.8 %

Procedure:
To a solution of 3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 12, 1.30 g, 4.8 mmol) and triethylamine (3.34 ml, 24.0 rnuol) in dichloromethane (30 ml) at room temperature was slowly added acetyl chloride (0.48 ml, 6.72 mmol). The mixture was stirred at room temperature overnight and then saturated ammonium chloride solution (50 ml) was added. The two layers were separated and the aqueous layer was extracted with dichloromethane (3×20 ml). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica column chromatography eluting with ethyl acetate:methanol:ammonia solution (0.880) (90:10:1) to afford the title compound (1.5 g, 100%) as a colourless gum.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH3:9][C:10]1[S:11][C:12]([CH3:19])=[CH:13][C:14]=1[S:15](Cl)(=[O:17])=[O:16]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:14]1[CH:13]=[C:12]([CH3:19])[S:11][C:10]=1[CH3:9])(=[O:17])=[O:16]
Reactant: Cc1noc(N)c1Br
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)s1
Product: Cc1cc(S(=O)(=O)Nc2onc(C)c2Br)c(C)s1
Yield: 55 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-2, 5-dimethylthiophene-3-sulfonamide was prepared in the same manner as described in Example 1 from 5-amino-4-bromo-3-methylisoxazole and 2, 5-dimethylthiophene-3-sulphonyl chloride in 55% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 77-80° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.[Mg].Cl[P:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH:27]O>C1COCC1.II.O>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([P:14](=[O:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: OO
Reactant: COc1cc(Br)cc(OC)c1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)cc(P(=O)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
1-Bromo-3,5-dimethoxybenzene (10 g, 46.1 mmol) in THF (60 ml) was added to a Schlenk flask (250 ml) with magnesium (1.2 g, 49.9 mmol), I2 (10 mg) and THF (40 ml). The mixture was reflux for 2 h. It was cooled to RT. The resulting light brown solution was transferred to another flask (250 ml) and it was cooled to −78° C. Chlorodiphenylphosphine (11 g, 49.9 mmol) in THF (30 ml) was added at −78° C. The mixture was stirred at −78° C. for 1 h, then it was slowly warmed up to RT and stirred at RT for 1 h. To the resulting reactions, water (50 ml) was added, then H2O2 (30%, 13 ml) was added dropwise at 0° C. The resulting mixture was stirred for 30 min. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 ml×2). The combined organic layer was washed thoroughly with NaHSO3 (100 ml×3) and brine (100 ml×2) and dried over MgSO4. It was filtered and the solvent was removed to give a viscous oil which was purified with crystallization (CH2Cl2/Hexane=1:20) to give the product as a colorless solid (15.2 g, Yield: 97.5%). 1H NMR (300 Mhz, CD2Cl2) δ: 7.72-7.64 (m, 4H), 7.60-7.54 (m, 2H), 7.52-7.45 (m, 4H), 6.79 (dd, J1=2.1 Hz, 13.2 Hz, 2H), 6.64 (t, J=2.1 Hz, 1H), 3.77 (s, 6H). 31P NMR (121.5 MHz, CD2Cl2) δ: 29.03. 13C (75 MHz, CD2Cl2) δ: 161.18 (d, J=17.6 Hz), 135.17 (d, J=102 Hz), 132.99 (d, J=103 Hz), 132.12 (d, J=2.9 Hz), 132.11 (d, J=9.8 Hz), 109.87 (d, J=10.9 Hz), 103.91 (d, J=2.3 Hz), 55.74.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Br:10][C:11]1[C:20]2[C:15](=[C:16]([Br:25])[CH:17]=[C:18]([C:21]([O:23]C)=O)[CH:19]=2)[N:14]=[CH:13][CH:12]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:21]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([Br:25])[CH:17]=2)[N:14]=[CH:13][CH:12]=[C:11]3[Br:10])[OH:23])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(Br)c2nccc(Br)c2c1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1cc(Br)c2nccc(Br)c2c1
Reaction time: 2 h

Procedure:
A solution of (4-chlorophenyl)magnesium bromide (2.02 mL, 1.0 M in THF) was dropwise added to a suspension of methyl 4,8-dibromoquinoline-6-carboxylate (0.2 g, 0.58 mmol) in THF (5 mL) at room temperature. The resulting mixture was slowly dissolved and became a clear solution after 30 min. During this period of time, cooling was needed, when the temperature of the reaction mixture rose above room temperature. After 2 hr, the reaction was quenched with ice water and saturated NH4Cl followed by EtOAc. The aqueous layer was extracted with EtOAc. The combined organics were concentrated and purified by silica column (25-30% EtOAc/hexanes) chromatography to yield bis(4-chlorophenyl)(4,8-dibromoquinolin-6-yl)methanol. (M+H)+: 536, 540, 541
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[OH-].[Li+]>C1COCC1.CCO>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: COC(=O)CCc1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(F)c(-c2cc(COc3ccc(CCC(=O)O)cc3)ccc2C(C)(C)C)c1
Reaction time: 16 h
Yield: 83.4 %

Procedure:
To a stirred solution of 2.2 (0.0421 g, 0.0934 mmol) in THF (2.00 mL) and EtOH (2.00 mL) at 23° C. was added 1N lithium hydroxide (2.00 mL, 2.00 mmol). Stirring continued for 16 hours. The reaction mixture was concentrated in vacuo. 1N HCl was added to reach pH 1, and the resulting mixture was extracted with EtOAc (3×10 mL), dried over MgSO4 and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-20% EtOAc in hexanes) to give a clear oil (0.034 g, 82% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.59 (1H, d, J=8.2 Hz), 7.41 (1H, dd, J=8.6, 2.2 Hz), 7.22 (1H, dd, J=9.0, 7.4 Hz), 7.11 (1H, d, J=2.2 Hz), 7.00 (1H, t, J=8.6 Hz), 6.88-6.79 (5H, m), 5.01 (2H, s), 3.79 (3H, s), 2.94 (2H, t, J=7.8 Hz), 2.68 (2H, t, J=7.8 Hz), 1.24 (9H, s). MS ESI (neg.) m/e: 871.3 (2M−H)+, 435.1 (M−H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(Cl)([Cl:16])(=O)=O>C(OC(C)C)(C)C>[Cl:16][CH2:11][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Solvent: CC(C)OC(C)C
Product: O=C(CCl)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
3′-Nitroacetophenone (2.00 g) was dissolved in diisopropyl ether (12.1 ml) and sulfuryl chloride (6.70 g) was added all at once thereto at 22° C. and refluxed for 6.5 hours. The reaction mixture was allowed to cool to room temperature while stirring, and the precipitated solids were filtered and washed with diisopropyl ether. Drying under reduced pressure yielded the desired 2-chloro-3′-nitroacetophenone (2.01 g; 83.1%).
Reaction SMILES: FC(F)(F)C([N:5]([CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9])=O.C(N(CC)CC)C.C([O:40][C:41](=[O:45])[C@H:42]([CH3:44])[NH2:43])C>CCOCC>[CH2:15]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:43][C@H:42]([C:41]([OH:45])=[O:40])[CH3:44])=[O:9])[CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCOC(=O)[C@H](C)N
Reactant: CCCCCCCCCCCCC=CN(C(=O)C(F)(F)F)c1ccccc1C(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCC=CCCCNc1ccccc1C(=O)N[C@@H](C)C(=O)O

Procedure:
A solution pf 4.75 g. of N-trifluoroacetyl-2-(tetradecenylamino)benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solvent is evaporated from the combined filtrate and washings. After treatment of the residue with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered and dried. Crystallization from acetone yields the product as a white, crystalline solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:15]=[CH:14][C:13]([C:24]#[N:25])=[C:12]2O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:29])=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:15]=[CH:14][C:13]([C:24]#[N:25])=[C:12]2[Cl:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOc1cc2ncc(C#N)c(O)c2cc1OCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: COCCOc1cc2ncc(C#N)c(Cl)c2cc1OCc1ccccc1
Yield: 67 %

Procedure:
Following the procedure used to prepare Reference Example 12, reaction of 6-benzyloxy-4-hydroxy-7-(2-methoxyethoxy)-3-quinolinecarbonitrile with phosphorous oxychloride provides 6-benzyloxy-4-chloro-7-(2-methoxyethoxy)-3-quinolinecarbonitrile in 67% yield, mp 142-145° C.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[O:22][CH3:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=[CH:40][NH:41]2)C1C=CC=CC=1)C>>[CH3:23][O:22][C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:5][C:4]([NH:41][CH3:40])=[O:3])[CH:14]=2)[NH:18][N:17]=1
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]nc(OC)c2c1
Product: CNC(=O)C=C(c1ccccc1)c1ccc2[nH]nc(OC)c2c1

Procedure:
The amide compound CCXII was prepared from 3-(3-methoxy-1H-indazol-5-yl)-3-phenyl-acrylic acid ethyl ester using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:18]([CH2:22][CH3:23])[C:19]([OH:21])=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:30]1[CH:34]=[N:33][N:32]=[C:31]1[NH2:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:18]([CH2:22][CH3:23])[C:19]([NH:35][C:31]4[S:30][CH:34]=[N:33][N:32]=4)=[O:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCC(C(=O)O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: Nc1nncs1
Product: CCC(C(=O)Nc1nncs1)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 35 %

Procedure:
Example 142 was prepared from 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)butanoic acid (180 mg, 0.26 mmol) and 1,3,4-thiadiazol-2-amine using General Coupling Method B to give 75 mg (35% yield). MS found: (M+H)+=472.