Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21])[CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.Cl.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21])[CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([C:35]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[O:42])[CH2:17][CH2:18]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](C(N)=O)N(CC1CCNCC1)S(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@H](C(N)=O)N(CC1CCN(C(=O)c2ccncc2)CC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.3 %

Procedure:
To a solution of (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(piperidin-4-ylmethyl)amino]-4-methyl-pentanoic acid amide (Example 126, 0.10 g, 0.22 mmol) and Et3N (0.06 mL, 0-5 mmol) in CH2Cl2 (3.0 mL) was added isonicotinoyl chloride hydrochloride (56 mg, 0.32 mmol). The reaction was stirred at rt for 18 h and then was poured into a mixture of EtOAc and sat. aq. NaHCO3. The organic solution was separated and washed with brine, dried over MgSO4, and concentrated to an oily residue. The residue was purified on a Biotage 10M (eluted with 80% EtOAc/hexanes) to give a white solid (36 mg, 30%). MS (ESI), (M+H)+ 509.20; 1H NMR (CDCl3, 500 MHz) δ 8.66 (br s, 2H), 7.80 (d, 1H, J=8.6), 7.73 (d, 2H, J=8.5), 7.51 (d, 2H, J=7.6), 7.41 (br s, 1H), 6.64 (br s, 1H), 5.35 (br s, 1H), 4-70 (br s, 1H), 4.10 (br s, 1H), 3.71 (br s, 1H), 3.33 (br s, 1H), 3.02 (dd, 2H, J=4.8, 16), 2.70-2.85 (br s, 1H), 1.50-2.09 (m, 5H), 1.18-1.33 (m, 4H), 0.73 (d, 3H, J=6.7), 0.68 (d, 3H, J=6.5).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9]I)=[N:6][CH:7]=1.[CH2:11]([O:13][C:14](=[O:22])[CH:15]([S:17]([CH2:20]C)(=[O:19])=[O:18])[CH3:16])[CH3:12].BrC1C=NC=CC=1.BrC1C=CC(CCC(C)(S(C)(=O)=O)C(OCC)=O)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:15]([CH3:16])([S:17]([CH3:20])(=[O:18])=[O:19])[C:14]([O:13][CH2:11][CH3:12])=[O:22])=[N:6][CH:7]=1
Reactant: Brc1ccc(CCI)nc1
Reactant: CCOC(=O)C(C)S(=O)(=O)CC
Agent: CCOC(=O)C(C)(CCc1ccc(Br)cc1)S(C)(=O)=O
Solvent: Brc1cccnc1
Product: CCOC(=O)C(C)(CCc1ccc(Br)cn1)S(C)(=O)=O
Yield: 48.5 %

Procedure:
The title compound (2030 mg, 49%) was prepared from 5-bromo-2-(2-iodoethyl)pyridine (3571 mg, 11.5 mmol) and (+/−)-2-ethanesulfonyl-propionic acid ethyl ester (2270 mg, 12.6 mmol) by a procedure analogous to that described for the preparation of compound (1) from Preparation 2, Step 2, i.e. (+/−)-ethyl 4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoate. MS (LC MS) m/z 364.0 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 (t, J=7.03 Hz, 3H) 1.68 (s, 3H) 2.28-2.39 (m, 1H) 2.54-2.76 (m, 2H) 2.83-2.95 (m, 1H) 3.05 (s, 3H) 4.24 (q, J=7.29 Hz, 2H) 7.05 (d, J=8.59 Hz, 1H) 7.71 (dd, J=8.20, 2.34 Hz, 1H) 8.56 (d, J=1.95 Hz, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([CH3:8])[CH2:5][CH2:4][N:3]1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N+:15]([O-])=O>CO.[Pd]>[CH3:1][CH:2]1[CH2:7][N:6]([CH3:8])[CH2:5][CH2:4][N:3]1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH2:15]
Reactant: CC1CN(C)CCN1c1ccncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC1CN(C)CCN1c1ccncc1N
Yield: 91.4 %

Procedure:
A solution of 2,4-dimethyl-1-(3-nitro-4-pyridyl)piperazine (89 mg, 0.3767 mmol) in methanol (4 mL) and Pd on C (10%, wet, Degussa) (20 mg) was hydrogenated overnight at RT under an atmosphere of hydrogen (balloon). The catalyst was filtered off through a Celite cartridge, washed with methanol. The filtrate was concentrated under reduced pressure yielding 4-(2,4-dimethylpiperazin-1-yl)pyridin-3-amine (71 mg, 91%). MS (ES+) 207.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.CN1CCCN(C)C1=O.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].I[CH2:30][CH2:31][CH2:32][CH3:33]>O1CCCC1.C(OCC)(=O)C>[CH2:30]([NH:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[N:3]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCI
Reactant: Cc1cc(Cl)nc(N)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCCN(C)C1=O
Product: CCCCNc1nc(C)cc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To 2-amino-4-chloro-6-methylpyrimidine (10.0 g, 69.7 mmol) dissolved in 70 mL of anhydrous tetrahydrofuran was added 21 mL (2.5 equilvalents) of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) at ambient temperature. The solution was cooled to ~10° C. and 69.6 mL (1.0 equivalent) of 1M lithium hexamethyldisilazide in tetrahydrofuran was added. The solution was stirred at 0° C. for 30 minutes and then 7.92 mL (1.0 equivalent) of 1-iodobutane was added at 0° C., and the reaction was allowed to warm to ambient temperature. The reaction mixture was poured into ethyl acetate and washed with water (2×); the aqueous washes were back-extracted with ethyl acetate (2×). The combined organic extracts were dried over potassium carbonate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 13% ethyl acetate in hexane to afford 4.6 g (33%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ 0.93 (t, 3H), 1.40 (m, 2H), 1.57 (m, 2H), 2.30 (s, 3H), 3.41 (m, 2H), 5.12 (bs, 1H), 6.43 (s, 1H). MS (DCl/NH3) m/e 200 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C@H:7]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([F:21])[CH:15]=2)[O:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]1)=[O:4].[ClH:29].[CH:30]12[O:37][CH:34]([CH2:35][CH2:36]1)[CH2:33][NH:32][CH2:31]2>>[ClH:1].[ClH:29].[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C@@H:13]2[O:12][CH2:11][CH2:10][NH:9][CH2:8][C@H:7]2[CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:32]2[CH2:31][CH:30]3[O:37][CH:34]([CH2:35][CH2:36]3)[CH2:33]2)=[CH:15][C:16]=1[F:21]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNC(=O)CCl)C1
Reactant: C1CC2CNCC1O2
Agent: Cl
Product: O=C(CN1CC2CCC(C1)O2)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1

Procedure:
Using tert-butyl (6R,7R)-6-{[(chloroacetyl)amino]methyl}-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and 8-oxa-3-azabicyclo[3.2.1]octane monohydrochloride, and in the same manner as in Example 336, steps B and C, the title compound was obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].[Cl:7][CH2:8][C:9](=O)[CH2:10][C:11](OCC)=[O:12]>>[Cl:7][CH2:8][C:9]1[N:6]=[C:2]2[S:1][CH:5]=[CH:4][N:3]2[C:11](=[O:12])[CH:10]=1
Reactant: Nc1nccs1
Reactant: CCOC(=O)CC(=O)CCl
Product: O=c1cc(CCl)nc2sccn12

Procedure:
The intermediate 7-(chloromethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one was prepared from 2-thiazolamine and ethyl 4-chloroacetoacetate by the procedure described in EXAMPLE 1. The m.p. was 132°-136° C., and the structure was confirmed by NMR and IR.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][C:4]=1[N+:12]([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl>CCO>[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:12]
Reactant: COc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Product: COc1c(N)cccc1N
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A 2 L round bottomed flask was charged with 23 g (116 mmol) 2-methoxy-1,3-dinitrobenzene and 261 g (1.16 mol) tin chloride dihydrate. 160 mL EtOH was added, and the resulting suspension was stirred at 70° C. for 90 min. In the beginning, the reaction is very exothermic be careful! The solvent was removed and the reaction mixture was diluted with H2O and slowly added to about 500 mL of a 10 M NaOH solution. The suspension was cooled down to RT and extracted three times with EtOAc. The combined organic layers were dried over MgSO4, filtered and the solvent was removed under reduced pressure. The product was obtained as red oil and used without further purification.
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[CH3:19][N:20]1[C:28]2[C:23](=[C:24]([NH2:29])[CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1.[N:30]1([C:36]2[N:37]=[C:38]([CH2:43][C:44]([O-])=[O:45])[NH:39][C:40](=[O:42])[CH:41]=2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.[Na+]>CN(C)C=O>[CH3:19][N:20]1[C:28]2[C:23](=[C:24]([NH:29][C:44](=[O:45])[CH2:43][C:38]3[NH:39][C:40](=[O:42])[CH:41]=[C:36]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:37]=3)[CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: Cn1ccc2c(N)cccc21
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1ccc2c(NC(=O)Cc3nc(N4CCOCC4)cc(=O)[nH]3)cccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.6 %

Procedure:
2 ml of pyridine, 300 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 272 mg of 1-methyl-1H-indol-4-ylamine are added to a solution of 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 2 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 15 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 280 mg of N-(1-methyl-1H-indol-4-yl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a pinkish solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][S:8](=[O:22])(=[O:21])[C:9]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:10]=2[C:11]=1[OH:12])=[O:5])[CH3:2].[CH3:23]I>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:23])[S:8](=[O:21])(=[O:22])[C:9]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:10]=2[C:11]=1[OH:12])=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Product: CCOC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Yield: 82 %

Procedure:
4-Hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid ethyl ester-1,1-dioxide was prepared analogous to Example 1c from 4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid ethyl ester-1,1-dioxide and methyl iodide. Yield: 82% of theory; m.p. 163°-165° C.
Reaction SMILES: [CH2:1]([O:3][C:4]12[CH2:11][O:10][CH2:9][CH:8]1[S:7][C:6]([NH2:12])=[N:5]2)[CH3:2].[C:13]12([C:23](Cl)=[O:24])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>C(N(CC)CC)C>[CH2:1]([O:3][C:4]12[CH2:11][O:10][CH2:9][CH:8]1[S:7][C:6]([NH:12][C:23]([C:13]13[CH2:22][CH:17]4[CH2:16][CH:15]([CH2:21][CH:19]([CH2:18]4)[CH2:20]1)[CH2:14]3)=[O:24])=[N:5]2)[CH3:2]
Reactant: CCOC12COCC1SC(N)=N2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Product: CCOC12COCC1SC(NC(=O)C13CC4CC(CC(C4)C1)C3)=N2

Procedure:
The product of Example 72B, triethylamine, and adamantane-1-carbonyl chloride were processed according to the method of Example 1A to afford the title compound. MS (ESI+) m/z 351 (M+H)+.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=2)[CH:9]=1>C1COCC1.O>[F:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:28]=1[S:25]([C:22]1[CH:21]=[CH:20][C:19]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=3)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]=2[CH3:18])=[CH:24][CH:23]=1)(=[O:26])=[O:27]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3c(F)cccc3F)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)c2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
Lithium hydroxide monohydrate (0.011 g, 0.26 mmol) was added to a stirred solution of {4-[4-(2,6-difluorobenzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.031 g, 0.064 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {4-[4-(2,6-difluorobenzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (0.024 g, 80%) as a solid. The final product was isolated with a significant amount of water as an impurity. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.17 (d, J=7.91 Hz, 2 H), 8.01 (dd, J=9.23, 6.22 Hz, 1 H), 7.91 (s, 1 H), 7.80-7.88 (m, 1 H), 7.58 (d, J=8.48 Hz, 2 H), 7.39 (t, J=9.04 Hz, 3 H), 6.64 (d, J=11.87 Hz, 1 H), 3.83 (s, 2 H), 2.04 (s, 3 H). MS calcd. for C25H16F3O4S [(M−H)−] 469, obsd. 469.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17]C(OCC2C=CC=CC=2)=O)=[CH:9][CH:8]=1)[CH3:2].[H][H]>[Pd].CO>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:9][CH:8]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)COc1ccc(CCCCN)cc1
Yield: 88.4 %

Procedure:
A suspension of 42 (1.11 g, 2.88 mmol) and 10% palladium on carbon (0.40 g, wet) in methanol (50 mL) was stirred at room temperature for 2 h under atmospheric pressure of hydrogen. The mixture was then filtered through a silica gel pad. The solvent was evaporated to provide 43 (0.64 g, 88%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.21 (m, 3H), 1.30-1.63 (m, 6H), 3.13 (m, 2H), 4.17 (m, 2H), 4.72 (br s, 2H), 6.84 (m, 2H), 7.10 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][CH2:12][C:13]#[CH:14])=[N:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[N:7]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:3]2[N:4]([C:13]([CH3:14])=[CH:12][N:11]=2)[CH:5]=[C:6]([C:8]([OH:10])=[O:9])[N:7]=1
Reactant: C#CCNc1ncc(C(=O)O)nc1Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc2c(Cl)nc(C(=O)O)cn12

Procedure:
3-Chloro-2-(2-propyn-1-ylamino)pyrazine-5-carboxylic acid is dissolved in 100 ml trifluoroacetic acid containing 1 g of mercuric oxide and the mixture is heated 4 hours on the steam bath and concentrated under vacuum. The residue is dissolved in aqueous sodium bicarbonate and 8-chloro-3-methylimidazo[1,2-a]pyrazine-6-carboxylic acid precipitated with acetic acid by adjusting the pH to approximately 7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([F:11])[CH:3]=1.CO.S(Cl)([Cl:17])(=O)=O.C(=O)(O)[O-].[Na+]>CCCCCCC>[Cl:17][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[F:11])=[O:10]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)c1ccc(Cl)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCCCCCC
Product: O=C(CCl)c1ccc(Cl)cc1F
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
In a 1 L round bottom flask combine 4′-chloro-2′-fluoroacetophenone (40 g, 231.8 mmol), heptane (120 mL), and methanol (16 mL). Cool to 0° C. and place under nitrogen. Dissolve sulfuryl chloride (21.5 mL, 1.15 equiv.) in heptane (120 mL) and charge to an addition funnel Add drop-wise to the reaction over 60 min. Stir for 2.5 h at 0° C.; a white precipitate forms during this time. Charge the addition funnel with 1 M sodium bicarbonate (400 mL) then add to the reaction drop-wise. After all gas evolution stops, filter the biphasic suspension to collect the title compound (38.18 g, 80%) as white needles. 1H NMR (DMSO-d6) δ 5.00 (d, 2H, J=2.5 Hz), 7.43 (m, 1H), 7.63 (m, 1H), 7.89 (t, 1H, J=8.4 Hz).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH:18]([CH3:22])[C:19](O)=[O:20])[CH3:2].[CH3:23][O:24][C:25](=[O:36])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=1[CH3:35].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:23][O:24][C:25](=[O:36])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:19](=[O:20])[CH:18]([C:4]2[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:15])[F:17])=[CH:10][CH:9]=3)[S:7][C:3]=2[CH2:1][CH3:2])[CH3:22])=[CH:30][C:29]=1[CH3:35]
Reactant: CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)C(=O)O
Reactant: COC(=O)CCc1ccc(N)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)C(=O)Nc1ccc(CCC(=O)OC)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionic acid (0.35 mmol), 3-(4-Amino-2-methyl-phenyl)-propionic acid methyl ester (0.35 mmol), and DMAP (0.01 g, 0.082 mmol) in CH2Cl2 (5 mL) is added EDCI (0.08 g, 0.42 mmol). After stirring for 2 h at RT, the mixture is concentrated. The residue is redissolved in EtOAc, and the organics are washed with 1N HCl (1×), 2N NaOH (2×), water, and brine, and dried with MgSO4. The crude material is purified by flash chromatography to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:4]1[N:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(Br)n1
Reactant: OB(O)c1ccccc1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1cccc(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
2-Amino-6-bromopyridine (1 g) and 2-chlorophenylboronic acid (1.039 g) were dissolved in toluene/ethanol (30 mL/3 mL) and at RT under an argon atmosphere treated with 2N aqueous sodium carbonate solution (6.13 mL). The mixture was stirred for 30 minutes at RT then treated with tetrakis(triphenylphosphine) palladium(0), 0.267 g, and heated to reflux for 24 h. The mixture was then cooled to RT and partitioned between AcOEt and water, the layers were separated and the organic layer dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (heptane/AcOEt 4:1) to give 6-(2-chloro-phenyl)-pyridin-2-ylamine as white solid (0.632 g). MS (EI): 204 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:15])[CH2:11][CH2:12][CH2:13]Br)([O-:3])=[O:2].C([N-]C(C)C)(C)C.[Li+].C1CCCCC1.[NH4+].[Cl-]>O1CCCC1>[CH:11]1([C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[O:15])[CH2:13][CH2:12]1
Reactant: O=C(CCCBr)c1ccccc1[N+](=O)[O-]
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: O=C(c1ccccc1[N+](=O)[O-])C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A solution of 1 (o-nitrophenyl)-4-bromo-1-butanone (0.75 g, 2.75 mmol) in dry tetrahydrofuran (THF) under nitrogen is cooled to -78° C. with stirring, cautiously treated with 2.21 ml of 1.5M lithium diisopropylamide (LDA) in cyclohexane (3.3 mmol LDA), held at -78° C. for 1 hour, allowed to warm to 0° C. for 2 hours and poured onto a saturated NH4Cl solution. The resultant mixture is extracted with ethyl acetate. The extracts are combined, washed with brine, dried over Na2SO4 and concentrated in vacuo to give a residue. The residue is purified by flash column chromatography (silica gel; gradient 15%→25% ethyl acetate in hexane as eluent) to give the title product as a yellow oil, 0.34 g, 64% yield, identified by NMR and mass spectral analyses.
Reaction SMILES: [CH:1]([C:7]1[CH:8]=[C:9]([N+:13]([O-])=O)[CH:10]=[CH:11][CH:12]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[H][H]>C(O)C.[Pd]>[CH2:1]([C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [H][H]
Reactant: CCCCC=Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCc1cccc(N)c1
Yield: 90.5 %

Procedure:
The 3-(1-hexenyl)nitrobenzene (11.0 g, 0.054 m) was dissolved in absolute ethanol (500 ml), treated with 1.1 g of 10% palladium on charcoal catalyst and hydrogenated on a Parr apparatus at about 45 psi for 21/2 hours. Hydrogen uptake had ceased. The reaction mixture was filtered to remove catalyst, concentrated under vacuum, and then resulting oil purified by Kuglrohr distillation (BP 75°-85° C. at 0.05 mm Hg) to yield 3-hexylaniline (8.6 g, 90% yield) as a clear colorless oil.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].[C:10](O)(=[O:22])[C:11]1[CH:21]=[C:18]([O:19][CH3:20])[C:16]([OH:17])=[C:13]([O:14][CH3:15])[CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:10]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:22])[C:11]1[CH:12]=[C:13]([O:14][CH3:15])[C:16]([OH:17])=[C:18]([O:19][CH3:20])[CH:21]=1
Reactant: CCCCC(CC)CO
Reactant: COc1cc(C(=O)O)cc(OC)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCC(CC)COC(=O)c1cc(OC)c(O)c(OC)c1

Procedure:
To 13.2 g (0.1 mol) 2-ethyl-1-hexanol in a flask equipped with reflux condenser connected to a Dean-Stark trap was added 9.9 g (0.05 mol) syringic acid, 0.2 g p-toluenesulfonic acid and 75 ml toluene. The mixture was refluxed for 20 h. Excess alcohol and toluene were distilled off under slight vacuum. The dark liquid residue was diluted with CH2Cl2 and extracted with 2% NaHCO3 +15% aqueous NaCl followed by neutral 15% aqueous NaCl solution. The organic layer was dried with anhydrous Na2SO4 and distilled. After removal of all unreacted 2-ethylhexanol the product distilled over as a viscous, colorless liquid, b.p. 204°-209° C./4×102Pa, which crystallized on standing at room temperature to a fine white solid, mp 35°-36° C. Yield: 10.1 g, 65%.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]12[CH2:25][CH:24]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH3:26])[C:16](=[O:27])[CH:15]1[CH:11]([CH2:12][CH:13]([O:28][C:29]3[C:38]4[C:33](=[C:34]([CH3:41])[C:35]([O:39][CH3:40])=[CH:36][CH:37]=4)[N:32]=[C:31]([C:42]4[N:43]=[C:44]([CH:47]5[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]5)[S:45][CH:46]=4)[CH:30]=3)[CH2:14]1)[C:10](=[O:53])[NH:9]2)=[O:7])C>CO.C1COCC1.O>[CH:47]1([C:44]2[S:45][CH:46]=[C:42]([C:31]3[CH:30]=[C:29]([O:28][CH:13]4[CH2:12][CH:11]5[CH:15]([C:16](=[O:27])[N:17]([CH3:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH:23][CH:24]6[C:8]([C:6]([OH:7])=[O:5])([NH:9][C:10]5=[O:53])[CH2:25]6)[CH2:14]4)[C:38]4[C:33](=[C:34]([CH3:41])[C:35]([O:39][CH3:40])=[CH:36][CH:37]=4)[N:32]=3)[N:43]=2)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]1
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4csc(C5CCCCC5)n4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3csc(C4CCCCC4)n3)nc2c1C
Temperature: 50 °C
Reaction time: 19 h
Yield: 95 %

Procedure:
An aqueous solution of LiOH (1M, 5 mL) was added to a solution of 17-[2-(2-cyclohexylthiazol-4-yl)-7-methoxy-8-methyl-quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid ethyl ester (121) in MeOH (10 mL), THF (20 mL) and water (5 mL). The resulting solution was stirred at 50° C. for 19 h. Then, the pH of the reaction mixture was adjusted to 6 with myriatic acid (3M, 1.7 mL). The resulting solution was evaporated on silica and purified by column chromatography (AcOEt/MeOH/AcOH, 74:25:1) to give 273 mg (95%) of the title compound 122 as a white powder: m/z=687 (M+H)+.