Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:29][NH:30][CH3:31].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:29][N:30]([CH3:31])[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(Cl)n1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Temperature: 140 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
To a solution of 6-chloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (40 mg, 0.10 mmol, prepared as described in Example 18) in DMSO (1 ml) was added dimethylamine (2M in THF, 0.052 ml, 0.10 mmol) and DIPEA (0.09 ml). The mixture was heated under microwave irradiation firstly at 140° C. for 1 h, then at 160° C. for 1 h and then at 180° C. for 1 h. Further dimethylamine (2M in THF, 0.052 ml, 0.10 mmol) was added and the mixture was heated under microwave irradiation at 160° C. for 2 h. The product was then purified by Mass Directed Automated Preparative HPLC (Method B), then further purified by chromatography using an SCX cartridge (1 g), which was eluted with MeOH (2 column volumes) and then ammonia in MeOH (2M, 1 column volume). The product-containing fractions were combined and blown down under a stream of nitrogen. Purification using an aminopropyl cartridge (1 g), which was eluted with MeOH (1 column volume), afforded the title compound (9.8 mg) as a pale orange gum.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]2[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:20]([F:23])[CH:21]=[CH:22][C:12]=2[N:11]=1)[CH3:9])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:23][C:20]1[CH:21]=[CH:22][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]=2[C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: COCCn1c([C@H](C)NC(=O)OC(C)(C)C)nc2ccc(F)c(-c3ccccn3)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCn1c([C@H](C)N)nc2ccc(F)c(-c3ccccn3)c21
Yield: 101.7 %

Procedure:
A solution of {(S)-1-[6-fluoro-1-(2-methoxyethyl)-7-pyridin-2-yl-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (231 mg, 0.56 mmol) in TFA (2 mL) and DCM (6 mL) was stirred for 45 min at RT. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH, followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford the title compound as a pale yellow oil (179 mg, 99%). Marfey's test: >99% de. LCMS (Method C): RT 1.76 min [M+H]+ 315. 1H NMR (CDCl3, 400 MHz): δ 8.75 (1H, ddd, J=5.0, 2.0, 1.0 Hz), 7.84 (1H, ddd, J=7.5, 7.5, 2.0 Hz), 7.73 (1H, dd, J=9.0, 5.0 Hz), 7.60-7.57 (1H, m), 7.38 (1H, ddd, J=7.5, 5.0, 1.0 Hz), 7.09 (1H, dd, J=10.0, 9.0 Hz), 4.33 (1H, q, J=6.5 Hz), 4.12 (1H, ddd, J=15.5, 5.5, 4.5 Hz), 4.02 (1H, ddd, J=15.5, 7.0, 5.0 Hz), 3.12-3.01 (2H, m), 3.06 (3H, m), 2.00 (2H, bs), 1.59 (3H, d, J=6.5 Hz).
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]([C:15]([O:17][CH3:18])=[O:16])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:7]=1.[Na].[F:20][C:21]([C:24]1[NH:28][N:27]=[N:26][N:25]=1)([F:23])[F:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:3]([CH2:2][N:26]2[N:27]=[N:28][C:24]([C:21]([F:23])([F:22])[F:20])=[N:25]2)[S:4][C:5]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: FC(F)(F)c1nnn[nH]1
Reactant: COC(=O)c1sc(CBr)nc1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CC#N
Product: COC(=O)c1sc(Cn2nnc(C(F)(F)F)n2)nc1-c1ccccc1Cl
Temperature: 60 °C
Reaction time: 6 h

Procedure:
5.00 g (14.4 mmol) of methyl 2-(bromomethyl)-4-(2-chlorophenyl)-1,3-thiazole-5-carboxylate were added to a solution of 10.00 g (18.7 mmol) of trifluoromethyltetrazole sodium salt in 100 ml of acetonitrile. Then 600 mg (4.32 mmol) of potassium carbonate were added to the reaction solution, and the mixture was stirred at 60° C. for 6 hours. After cooling to room temperature, the reaction solution was filtered and the mother liquor was freed from the solvent under reduced pressure. 10 ml of water were added to the residue and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic phases were dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by chromatography. (logP: 3.60; MH+: 404; 1H-NMR (400 MHz, DMSO, ppm): 3.71 (s, 3H), 6.70 (s, 2H), 7.40-7.60 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:54])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH:35]([CH2:41][CH2:42]OS(C4C=CC(C)=CC=4)(=O)=O)[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:55])[CH:10]=1)#[N:2].CC(C)([O-])C.[K+].Cl>O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:54])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][C:35]4([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:42][CH2:41]4)[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:55])[CH:10]=1)#[N:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(CCOS(=O)(=O)c3ccc(C)cc3)C(=O)OCC)CC2)c2ncnn12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC3(C(=O)OCC)CC3)CC2)c2ncnn12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of ethyl 2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-4-{[(4-methylphenyl)sulfonyl]oxy}butanoate (0.42 g), potassium tert-butoxide (0.24 g) and tetrahydrofuran (5 mL) was stirred at 0° C. for 10 min. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.051 g, 15%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].[H-].[Na+].[F:14][C:15]([F:26])([F:25])[CH2:16]OS(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][C:15]([F:26])([F:25])[F:14])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(O)cn1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(F)(F)F)cn1
Temperature: 0 °C

Procedure:
Under an atmosphere of nitrogen a solution of 5-hydroxy-pyridine-2-carboxylic acid methyl ester (200 mg, 1.31 mmol) in N,N-dimethylformamide (2 ml) was treated at room temperature with sodium hydride (55% dispersion in oil, 64 mg). After the gas formation had ceased, the suspension was cooled to 0° C. and trifluoro-methanesulphonic acid 2,2,2-trifluoro-ethyl ester (364 mg, 1.57 mmol) was added. After stirring at room temperature for 2 hours about 50% of the starting material was left. Another 364 mg of trifluoro-methanesulphonic acid 2,2,2-trifluoro-ethyl ester were added and after 30 minutes the reaction was complete. For the workup, the reaction mixture was treated with a saturated solution of sodium carbonate, then extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulphate, and evaporated at reduced pressure. The crude product was purified by chromatography on silica gel using a 3:1-mixture of heptane and ethyl acetate as the eluent. The 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester was obtained as a white solid (216 mg, 70% of theory). MS (ISP): m/z=236.3 [M+H]+. b) 5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid Under an atmosphere of nitrogen a solution of 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester (216 mg, 0.92 mmol) in methanol (1 ml) was treated with a solution of lithium hydroxide monohydrate (78 mg, 1.84 mmol) in methanol (0.1 ml). After stirring for 2 hours the reaction mixture was evaporated at reduced pressure. The residue was treated with hydrochloric acid (1N), the solid material was filtered then washed with water, finally dried at high vacuum. The 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid was obtained as a white solid (125 mg, 61% of theory).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:51])[NH:4][C@@H:5]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:6](=[O:46])[NH:7][C@@H:8]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:9]([OH:38])[CH2:10][C@H:11]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH:28][CH:27]=1)[NH:12][C:13](=[O:24])[C@H:14]([C:20]([CH3:23])([CH3:22])[CH3:21])[NH:15][C:16](=[O:19])[O:17][CH3:18].[CH2:52]([S:54][CH2:55][CH3:56])[CH3:53].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH2:39]([C@H:8]([NH:7][C:6]([C@@H:5]([NH:4][C:3](=[O:51])[O:2][CH3:1])[C:47]([CH3:50])([CH3:49])[CH3:48])=[O:46])[C@@H:9]([O:38][CH:52]([S:54][CH2:55][CH3:56])[CH3:53])[CH2:10][C@@H:11]([NH:12][C:13](=[O:24])[C@H:14]([C:20]([CH3:23])([CH3:22])[CH3:21])[NH:15][C:16]([O:17][CH3:18])=[O:19])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH:28][CH:27]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CCSCC
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCSC(C)O[C@@H](C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Yield: 104.5 %

Procedure:
To a slurry of the compound of Example 2D (2.00 g, 2.84 mmol) and ethyl sulfide (8.0 mL, 74.06 mmol) in acetonitrile (28.0 mL) at room temperature was added benzoyl peroxide (4.95 g, 20.45 mmol) in three portions over 2 hours. The reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with ethyl acetate to give the title compound (2.35 g, 84% yield).
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2)[NH2:2].CN(/[CH:16]=[C:17](/[C:22](=O)[CH:23]1[CH2:25][CH2:24]1)\[C:18]([O:20][CH3:21])=[O:19])C>>[CH3:21][O:20][C:18]([C:17]1[CH:16]=[N:2][N:1]([C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][CH:7]=[N:8]3)[C:22]=1[CH:23]1[CH2:25][CH2:24]1)=[O:19]
Reactant: NNc1cccc2ncccc12
Reactant: COC(=O)/C(=C\N(C)C)C(=O)C1CC1
Product: COC(=O)c1cnn(-c2cccc3ncccc23)c1C1CC1

Procedure:
combining 5-hydrazinoquinoline made by a method of this invention with α-[(dimethylamino)methylene]-β-oxo-cyclopropanepropanoic acid, (αZ)-methyl ester to form 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid methyl ester; and
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4](Cl)[CH:3]=1.[CH3:10][NH:11][CH3:12]>>[CH3:10][N:11]([CH3:12])[C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH2:1])[CH:3]=1
Reactant: Cc1cc(Cl)cc(N)n1
Reactant: CNC
Product: Cc1cc(N(C)C)cc(N)n1
Temperature: 130 °C

Procedure:
To 6-amino-4-chloro-2-picoline (500 mg, 3.51 mmol) in a vial under nitrogen was added dimethylamine (40% in water, 17.5 ml, 35.0 mmol). The reaction mixture was sealed and heated at 130° C. in a microwave for 2.5 hours. The reaction mixture was cooled, concentrated under reduced pressure, and purified by silica gel chromatography (2-10% methanol/DCM with 1% ammonium hydroxide, linear gradient) to give N4,N4,6-trimethylpyridine-2,4-diamine. MS ESI calc'd. for C8H14N3 [M+H]+ 152. found 152. 1H NMR (500 MHz, DMSO-d6) δ 6.15 (s, 2H), 6.02 (s, 1H), 5.54 (s, 1H), 2.90 (s, 6H), 2.18 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH:12]1[CH2:11][CH2:10][CH:9]([S:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(SC2CCNCC2)cc1
Yield: 72 %

Procedure:
tert-Butyl 4-(4-aminophenylthio)piperidine-1-carboxylate (9.27 mmol, 2.859 g) was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (10 mL) and the reaction mixture stirred at room temperature for 30 minutes. The reaction mixture was purified via SCX column chromatography to afford the title compound (1.39 g).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[C:8]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:18])/[CH:9]=[CH:10]\[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12]>>[CH2:20]([O:19][C:8]([CH:9]([S:1][C:2]1[S:3][C:4]([S:7][CH:9]([C:8]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])[CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])=[N:5][N:6]=1)[CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])=[O:18])[CH2:21][CH2:22][CH3:23]
Reactant: Sc1nnc(S)s1
Reactant: CCCCOC(=O)/C=C\C(=O)OCCCC
Product: CCCCOC(=O)CC(Sc1nnc(SC(CC(=O)OCCCC)C(=O)OCCCC)s1)C(=O)OCCCC
Temperature: 55 °C

Procedure:
2,5-Dimercapto-1,3,4-thiadiazole (50.09 g, 0.33 mol) and dibutyl maleate (157.0 g, 0.69 mol) were charged in a reaction flask and heated to 55° C. for 4 hours. The reaction product was filtered warm using filter aid.
Reaction SMILES: Br.[NH2:2][C:3]1[C:4](=[O:17])[N:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1>>[CH2:10]([O:9][N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([NH:2][S:31]([C:28]2[CH:27]=[CH:26][C:25]([C:22]3[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=3)=[CH:30][CH:29]=2)(=[O:32])=[O:33])[C:4]1=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: Nc1cccn(OCc2ccccc2)c1=O
Agent: Br
Product: O=c1c(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3)cc2)cccn1OCc1ccccc1

Procedure:
The titled compound was prepared from 3-amino-1-benzyloxy-1H-pyridin-2-one hydrogen bromide salt from Step E and 4′-chloro-biphenyl-4-sulfonyl chloride according to the procedure described in Example 32 Step A. MS 467 (M+H)+.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1.[BH4-].[Na+]>CCO>[OH:10][CH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=Cc1cccc(CO)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of isophthalaldehyde (1.77 g, 13.0 mmol) in EtOH (30 ml) at 0° C., was added sodium borohydride (135 mg, 3.5 mmol). The reaction was stirred at 0° C. for 1 h. The solvent was evaporated and the residue purified by silica chromatography using DCM followed by DCM:MeOH (19:1) to yield 3-hydroxymethyl-benzaldehyde (1.14 g, 64%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:19]([O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>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.C(=O)([O-])[O-].[Na+].[Na+]>[C:7]([C:6]1[CH:9]=[C:2]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:31][CH:32]=2)[CH:3]=[CH:4][C:5]=1[O:10][C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])#[N:8]
Reactant: CCCCCCCCCCOc1ccc(B(O)O)cc1
Reactant: CCCCCC[C@@H](C)Oc1ccc(Br)cc1C#N
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+]
Product: CCCCCCCCCCOc1ccc(-c2ccc(O[C@H](C)CCCCCC)c(C#N)c2)cc1

Procedure:
Quantities: compound 42 (1.50 g, 4.84 mmol), compound 87 (1.61 g, 5.81 mmol), aqueous sodium carbonate (2 M, 20 ml), tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.24 mmol),
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=O)[CH2:10][CH2:11][CH:12]([NH:20][C:21]([CH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH:30][C:31](=[O:57])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:25][CH2:24]1)=[O:22])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:59][C@H:60]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[CH2:61][CH2:62][C:63](=[O:65])[OH:64]>C1COCC1.O>[C:69]([O:68][C:66](=[O:67])[CH:60]([NH:59][C:9](=[O:8])[CH2:10][CH2:11][CH:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:20][C:21]([CH:23]1[CH2:24][CH2:25][CH:26]([CH2:29][NH:30][C:31](=[O:57])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]([O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:51])[CH2:27][CH2:28]1)=[O:22])[CH2:61][CH2:62][C:63]([OH:64])=[O:65])([CH3:72])([CH3:71])[CH3:70]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NCC1CCC(C(=O)NC(CCC(=O)ON2C(=O)CCC2=O)C(=O)OC(C)(C)C)CC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NCC1CCC(C(=O)NC(CCC(=O)NC(CCC(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Yield: 83.6 %

Procedure:
To a solution of 2-({4-[(19-tert-butoxycarbonylnonadecanoylamino)methyl]cyclohexanecarbonyl}-amino)pentanedioic acid 1-tert-butyl ester 5-(2,5-dioxopyrrolidin-1-yl)ester (5.0 g) in THF (100 ml) was added a solution of H-Glu-OtBu (1.36 g) in water (25 ml). After stirring over night the mixture was concentrated in vacuo. The residue was precipitated from water and filtered off and dried in vacuo to give the title compound (4.63 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]2[CH2:13][O:12]2)=[CH:5][CH:4]=1.S(=O)(=O)(O)[OH:15].CC(=O)C.C(=O)(O)[O-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH:11]([OH:15])[CH2:13][OH:12])=[CH:7][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(CCC2CO2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(CCC(O)CO)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 12 parts of 2-[2-(4-methoxyphenyl)-ethyl]oxirane in 1.8 parts of sulfuric acid and 160 parts of 2-propanone are added 100 parts of water. The whole is stirred for 2 days at room temperature. The reaction mixture is stirred with a sodium bicarbonate solution and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 1-[2-(4-methoxyphenyl)ethyl]-1,2-ethanediol as a residue.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[C:7]([CH:19]=[CH:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:25])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1cccc(C)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1cccc(C)c1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3-methylphenyl)-5-(pent-1-enyl)pyridine (Example 139) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): δ 0.77 (t, J=7.0 Hz, 3 H), 1.0-1.40 (m, 19 H), 2.25 (m, 2 H), 2.39 (s, 3 H), 3.23 (m, 1 H), 3.44 (m, 1 H), 4.34 (s, 2 H), 6.97 (m, 2 H), 7.18-7.34 (m, 2 H). FAB-MS: calculated for C24H35NO 354; found 354 (M+H, 100 %). Rf=0.34 (10% ethyl acetate/n-hexane). mp 88-90° C.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[S:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.O>C1(C)C=CC=CC=1>[S:4]1[C:11]2([CH2:12][CH2:13][S:8][CH2:9][CH2:10]2)[NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3]1
Reactant: O=S1CCCCC1
Reactant: N[C@@H](CS)C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)[C@@H]1CSC2(CCSCC2)N1
Yield: 74.4 %

Procedure:
5.22 g of L-cysteine and 5 g of tetrahydrothiopyranone are suspended in 50 ml of toluene and the suspension is boiled, using a water separator, until the theoretical amount of water has been separated off. When the suspension is cooled, the product separates out as a light yellow precipitate, which is recrystallized from methanol/water to give 6.9 g of light yellow crystals of melting point 196° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.[F:32][C:33]1[CH:43]=[CH:42][CH:41]=[CH:40][C:34]=1[O:35][CH2:36][CH2:37][CH2:38]Cl.[I-].[Na+]>C(O)C>[F:32][C:33]1[CH:43]=[CH:42][CH:41]=[CH:40][C:34]=1[O:35][CH2:36][CH2:37][CH2:38][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1
Reactant: O=C(NCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Reactant: Fc1ccccc1OCCCCl
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NCC1CCN(CCCOc2ccccc2F)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
To a solution of 0.58 g (1.5 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (7.5 mM) of triethylamine in ethanol were added 0.37 g (2.0 mM) of 3-(2-fluorophenoxy)-propyl chloride and 0.28 g (1.9 mM) of sodium iodide at room temperature and the mixture was refluxed under nitrogen for 20 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (methanol/ethyl acetate 30-50%) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1N.S(=O)(=O)(O)O.C(O)(C)C.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)c1cc(Cl)cc(Cl)c1
Yield: 90 %

Procedure:
206 parts of 3,5-dichloroanthranilic acid are introduced into 500 parts of 45 percent strength by weight sulfuric acid and 400 parts of isopropanol. A solution of 100 parts of sodium nitrite in 140 parts of water is run in over 5 hours at 80° C.; nitrogen is evolved. The mixture is cooled, 1,000 parts of water are added and the product is filtered off. 172 parts (90% of theory) of 3,5-dichlorobenzoic acid of melting point 175°-178° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([CH:24]=1)[CH2:7][NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]1.[Cl:27][C:28]1[C:29]2[C:39]([F:40])=[CH:38][CH:37]=[C:36]([F:41])[C:30]=2[S:31][C:32]=1[C:33](Cl)=[O:34]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:33]([C:32]1[S:31][C:30]2[C:36]([F:41])=[CH:37][CH:38]=[C:39]([F:40])[C:29]=2[C:28]=1[Cl:27])=[O:34])[CH:9]1[CH2:10][CH2:11][CH:12]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])[CH2:13][CH2:14]1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(Br)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(Br)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 219 (0.50 g, 1.17 mmol) is treated with acid chloride 8 (344 mg, 1.29 mmol) using Method D to give the title compound.