Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[S:19][C:20]2[CH2:21][NH:22][CH2:23][CH2:24][C:25]=2[N:26]=1)=[O:17]>CN(C=O)C>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[S:19][C:20]2[CH2:21][N:22]([C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:23][CH2:24][C:25]=2[N:26]=1)=[O:17]
Reactant: Clc1ncccn1
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CNCC2
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1nc2c(s1)CN(c1ncccn1)CC2
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a solution of 2-chloro pyrimidine (1.2 eq) in DMF, N-(2-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide obtained from step VIII of example I (1.0 eq) was added and the reaction mixture was stirred at 100° C. for 15 h. Solvent was then evaporated under reduced pressure to afford crude product, which, on purification by column chromatography or preparative HPLC afforded the title compound.
Reaction SMILES: CN[C:3]([C:5]1[S:6][C:7]([CH3:19])=[C:8]([CH3:18])[C:9]=1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4].[OH-:20].[K+]>CO.O>[C:10]([C:9]1[C:8]([CH3:18])=[C:7]([CH3:19])[S:6][C:5]=1[C:3]([OH:20])=[O:4])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CNC(=O)c1sc(C)c(C)c1C(=O)c1ccccc1
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1sc(C(=O)O)c(C(=O)c2ccccc2)c1C

Procedure:
A solution of 16a (0.281 g, 1.03 mmole) in methanol-water 1:1 containing 10% KOH was heated at reflux for 12 hours, neutralized and extracted with ethyl acetate. The solid after evaporation was crystallized from ethanol. Yield 0.19 g, 71%.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C@H:10]([NH:19][CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[CH2:9][C@@H:8]1[CH3:35])=[O:6])([CH3:3])[CH3:2].[F:36][C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[C:40](Cl)=[O:41]>N1C=CC=CC=1>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C@H:10]([N:19]([CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[C:40](=[O:41])[C:39]2[CH:43]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:45]=[C:37]([F:36])[CH:38]=2)[CH2:9][C@@H:8]1[CH3:35])=[O:6])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Reactant: COc1ccc2c(n1)[C@H](NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C[C@H](C)N2C(=O)OC(C)C
Solvent: c1ccncc1
Product: COc1ccc2c(n1)[C@H](N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cc(F)cc(C(F)(F)F)c1)C[C@H](C)N2C(=O)OC(C)C
Yield: 85.2 %

Procedure:
Prepare the title compound by essentially following the procedure described for the synthesis of Example 47, using (+/−)-cis-4-(3,5-bis-trifluoromethyl-benzylamino)-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (0.210 g, 0.415 mmol), 3-fluoro-5-trifluoromethyl benzoyl chloride (0.095 mL, 0.631 mmol) and pyridine (0.10 mL). Purify using silica gel column chromatography (gradient eluent, 0-30% ethyl acetate in hexane) to provide the title compound (0.246 g, 88%). MS (ES+): 696 (M+H).
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[NH2:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19].[C-:30]#[N:31].[Na+]>O.[OH-].[Na+].CCOCC>[ClH:19].[NH2:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)[CH2:15][CH2:16][CH2:17][CH2:18][C:30]#[N:31]
Reactant: [C-]#N
Reactant: NCCON=C(CCCCCl)c1ccc(C(F)(F)F)cc1
Agent: O=C(O)/C=C\C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Cl
Product: N#CCCCCC(=NOCCN)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
10 Mmol (4.3 g) of 5-chloro-4'-trifluoromethylvalerophenone O-(2-aminoethyl) oxime maleate (1:1) (melting point 121.5°-122.5° C) were dissolved in 50 ml of water. 5 Ml of 50% sodium hydroxide solution at 0° C were added. Three extractions with 25 ml of CH2Cl2 were then carried out and this extract was washed with 5% sodium bicarbonate solution (1x) and water (1x). The solution was then dried on sodium sulphate and the CH2Cl2 was distilled off in vacuo. The residue was dissolved in 10 ml of dimethylsulfoxide (DMSO) and 25 mmol (1.2 g) of sodium cyanide were then added. The suspension was heated at a temperature of 50° to 70° C for 3 hours and then cooled to room temperature. Then there was diluted with 100 ml of 0.5 N sodium hydroxide solution and three extractions with 40 ml of ether were carried out. The ether extract was washed with water (1x), dried on sodium sulphate and evaporated in vacuo. The residue was purified chromatographically over silica gel with ethanol/ammonia (95:5) as an eluent. After evaporating the solvents, the residue was dissolved in absolute ethanol and acidified with ethanolic hydrochloric acid. After crystallization from ethanol/ether (1:3) the title compound having a melting point of 142°-143.5° C was obtained.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH:12]([CH2:13][CH:14]([CH:18]([CH3:20])[CH3:19])[CH2:15][CH2:16]O)[O:11][C:10]([CH3:22])([CH3:21])[N:9]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:30].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:32]([O:30][C@@:14]([CH:18]([CH3:19])[CH3:20])([CH2:15][CH3:16])[CH2:13][C@@H:12]1[O:11][C:10]([CH3:21])([CH3:22])[N:9]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[C@H:8]1[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)C(CCO)CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1CC1CCCCC1
Reactant: BrCc1ccccc1
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC[C@@](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1)(OCc1ccccc1)C(C)C
Yield: 75.9 %

Procedure:
A mixture of 500 mg (1.2 mmol) of t-butyl 4-(cyclohexylmethyl)-5-(4-hydroxy-2-isopropylbutyl)-2,2-dimethyl-3-oxazolidinecarboxylate in 3 ml of toluene, 191 mg (0.5 mmol) of tetrabutylammonium iodide, 5.9 g (150 mmol) of sodium hydroxide in water (8.8 ml) and 1.16 ml (9.8 mmol) of benzyl bromide is stirred at room temperature for 24 hours. Thereafter, water is added thereto, the mixture is extracted with ether, the ether extracts are dried over sodium sulphate and evaporated to dryness under reduced pressure. Chromatography of the residue on silica gel with a 1:8 mixture of ether and petroleum ether yields 457 mg (78.5%) of t-butyl (4S,5S)-5-[(S)-2-(benzyloxy)-2-isopropylbutyl]-4-(cyclohexylmethyl)-2,2-dimethyl-3-oxazolidinecarboxylate as a pale yellow resin, MS: 486 (M-CH3)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][O-:12].[Na+]>CO>[CH3:11][O:12][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1ncccc1[N+](=O)[O-]
Yield: 75.2 %

Procedure:
2-Chloro-3-nitropyridine (25 g, 0.157 mol) was suspended in methanol (300 ml) and sodium methoxide (17 g, 0.315 mol) was added. The mixture was refluxed for 2 hr and part of the solvent removed under reduced pressure. The reaction mixture was diluted with water (1 litre) and the precipitate collected by filtration. The white solid obtained was washed with more water and dried under vacuum to give the title compound (18.2 g, 75%). 1H NMR (CDCl3): 8.42 (dd, J=5, 2 Hz, 1H); 8.28 (dd, J=8, 2 Hz, 1H); 7.06 (dd, J=8, 5 Hz, 1H); 4.13 (s, 3H)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.[N+](C=C(SC)SC)([O-])=O.[N+:20]([CH:23]=[C:24](SC)[NH:25][CH2:26]CCCC1N=CNC=1)([O-:22])=[O:21].CN>>[N+:20]([CH:23]=[C:24]([NH:25][CH3:26])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)([O-:22])=[O:21]
Reactant: NCCCCc1c[nH]cn1
Reactant: CSC(=C[N+](=O)[O-])NCCCCc1c[nH]cn1
Agent: CN
Agent: CSC(=C[N+](=O)[O-])SC
Product: CNC(=C[N+](=O)[O-])NCCCCc1c[nH]cn1

Procedure:
Reaction of 4-(4-aminobutyl)imidazole (from the dihydrobromide (3.6g) with 1-nitro-2,2-bis-methylthioethylene (2.0g) by the procedure of Example 4(i) and treatment of the resultant 1-nitro-2-methylthio-2-[4-(4-imidazolyl)butylamino]ethylene with methylamine according to the procedure of Example 3(ii) gives the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[CH:13]=[C:14]([C:20]2[NH:24][C@@H:23]3[CH2:25][CH2:26][CH2:27][CH2:28][C@H:22]3[N:21]=2)[C:15]([O:18][CH3:19])=[N:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[Br:11][C:12]1[CH:13]=[C:14]([C:20]2[NH:21][C:22]3[CH2:28][CH2:27][CH2:26][CH2:25][C:23]=3[N:24]=2)[C:15]([O:18][CH3:19])=[N:16][CH:17]=1
Reactant: COc1ncc(Br)cc1C1=N[C@@H]2CCCC[C@H]2N1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncc(Br)cc1-c1nc2c([nH]1)CCCC2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
To a solution of Oxalyl dichloride (10 ml) in dichloromethane (10 mL), was treated with DMSO (2 mL) in dichloromethane (10 mL) by dropwise at −78° C., the solution was stirred at −78° C. for another 10 min, then trans-2-(5-bromo-2-methoxypyridin-3-yl)-3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazole (1 g, 3.3 mmol) was added in one portion under N2 protection. The react solution was stirred at −60° C. for 30 min, triethylamine is added over 5 min and the mixture was stirred at R.T. overnight. The resulting solution was treated with ice-cold 1 M hydrochloric acid solution (10 mL), the two phases are separated, the aqueous phase was extracted with dichloromethane (2*30 mL), and the combined organic phases was washed with pH 7 aqueous phosphate buffer (2*20 mL), then dried with anhydrous sodium sulfate and concentrated under reduced pressure to provide 2-(5-bromo-2-methoxypyridin-3-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole (0.78 g, yield 78.8%) as a solid. 1HNMR (400 MHz, DMSO) δ 14.5 (br, 1H), 8.78 (d, J=2 Hz, 1H), 8.50 (d, J=2 Hz, 1H), 4.04 (s, 3H), 3.15 (s, 4H), 2.66 (s, 4H). MS (M+H)+: 310/312. MS (M+H)+: 308/310.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:30][CH3:31])[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:32][CH3:33])[CH:6]=1.CO.CO.C(Cl)(Cl)Cl>C(=O)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:30][CH3:31])[C:17]4[CH2:22][CH2:21][C@H:20]([C:23]5[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:32][CH3:33])[CH:6]=1
Reactant: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccc(Cl)cc1
Agent: O=C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CC[C@@H]2c1ccc(Cl)cc1

Procedure:
A racemic mixture of N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (37 mg, 0.077 mmol from Example 94) was purified using chiral SFC to afford 10.5 mg of peak A (Example 94A) and 13.6 mg of peak B (Example 94B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 35% methanol (0.1% diethylamine) in CO2, 35° C., flow rate 2.0 mL/min for 20 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solution in 50:50 methanol/chloroform (multiple stacked injections), tR (peak A)=5.3 min, tR (peak B) 14.9 min. The absolute stereochemistry of individual enantiomers (Examples 94A and 94B) was not determined LC-MS and 1H NMR analytical data for the separated enantiomers was identical to the racemate (Example 94).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([SH:12])[N:7]=1)[CH3:2].Cl[CH2:15][C:16](=[O:18])[CH3:17]>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH2:15][C:16](=[O:18])[CH3:17])[N:7]=1)[CH3:2]
Reactant: CC(=O)CCl
Reactant: CCOC(=O)Cc1cccc(S)n1
Product: CCOC(=O)Cc1cccc(SCC(C)=O)n1

Procedure:
Prepared according to the procedure described in Example 1, Step 3, using the following starting materials: (6-mercapto-pyridin-2-yl)-acetic acid ethyl ester and chloroacetone.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:21]>C1C=CC=CC=1>[CH3:1][O:2][N:3]=[C:4]([Cl:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CONC(=O)c1ccccc1SCc1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CON=C(Cl)c1ccccc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.7 %

Procedure:
To a suspension of 79 g of the product of Example 1 in 1500 ml of benzene under a N2 atmosphere, cooled at 20° to 30° C. with external cooling, was added, portionwise, 60.2 g of phosphorous pentachloride. After stirring at 25° C. for about 24 hours, the suspension was warmed at 40° C. for about four hours, then cooled to 25° C. and filtered. The filtrate was evaporated at less than 40° C. under vacuum, and residue was chromatographed on silica gel with methylene chloride at eluant to yield 47 g of the subject compound as a crude yellow oil.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][N:7]1[C:15]2[C:10](=[C:11]([Cl:17])[CH:12]=[C:13]([Cl:16])[CH:14]=2)[CH2:9][C:8]1=O.CN([CH:22]=[O:23])C>>[CH3:6][N:7]1[C:15]2[C:10](=[C:11]([Cl:17])[CH:12]=[C:13]([Cl:16])[CH:14]=2)[C:9]([CH:22]=[O:23])=[C:8]1[Cl:3]
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN1C(=O)Cc2c(Cl)cc(Cl)cc21
Product: Cn1c(Cl)c(C=O)c2c(Cl)cc(Cl)cc21

Procedure:
Prepared from POCl3 (11 ml), DMF (11 ml), (43) (8.4 g), yielding (48) 6.5 g as crude product sufficiently pure for the next synthesis. 1 H-NMR (DMSO-d6): δ 3.8 (s, 3H), 7.43 (d, 1H), 7.86 (d, 1H), 10.52 (s, 1H). In this reaction the reaction time was 24 h instead of 3 h.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=1)[O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:4].Br[CH2:19][C:20]1[O:21][C:22]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:24]=1>C1COCC1.[NH4+].[Cl-].CCOCC>[C:25]1([C:23]2[N:24]=[C:20]([CH2:19][N:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]3[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=3)[O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[O:21][C:22]=2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)COc1cccc(NC(=O)OC)c1
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)COc1cccc(N(Cc2nc(-c3ccccc3)c(-c3ccccc3)o2)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
NaH (0.34 g of a 50% dispersion in mineral oil, 3.5 mmol) was washed twice with hexanes and covered with dry THF (10 mL). A solution of methyl [3-[(methoxycarbonyl)amino]phenoxy]acetate (0.75 g, 3 mmol) in dry THF (10 mL) was added and the mixture stirred at room temperature. After about 30 minutes, a solution of 2-bromomethyl-4,5-diphenyl-oxazole (0.99 g, 3 mmol) in THF (7 mL) was added and the mixture stirred overnight at room temperature. The mixture was diluted with saturated NH4Cl solution and Et2O, the organic phase separated, washed with H2O and saturated NaCl solution and dried over MgSO4. The solvent was evaporated and the residue chromatographed on a column of silica gel using a mixture of hexanes and EtOAc (4:1) as eluent to give methyl [3-[[(4,5-diphenyl-2-oxazolyl)methyl](methoxycarbonyl) amino]phenoxy]acetate (0.71 g, 48%). IR (film) 1760, (CO2CH3), 1715 (NCO2CH3) cm-1 ; 1H NMR (CDCl3) δ3.73 (6H, s, CO2CH3), 4.58 (2H, s, OCH2CO2CH3), 4.99 (2H, s, CH2 -oxazole), 6.79 (1H, dd, J=9 Hz, J'=2 Hz, aromatic H), 7.02 (2H, m, aromatic H), 7.20 to 7.45 (7H, m, aromatic H), 7.50 to 7.65 (4H, m, aromatic H); MS m/z 473 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:20])([CH3:19])[CH2:9][C@@:10]([C:15]([F:18])([F:17])[F:16])([OH:14])[CH2:11][C:12]#[CH:13])=[C:4]([CH2:21][OH:22])[CH:3]=1.CS(C)=O.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:20])([CH3:19])[CH2:9][C@:10]([OH:14])([C:15]([F:17])([F:18])[F:16])[CH2:11][C:12]#[CH:13])=[C:4]([CH:3]=1)[CH:21]=[O:22]
Reactant: C#CC[C@](O)(CC(C)(C)c1ccc(F)cc1CO)C(F)(F)F
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CC[C@](O)(CC(C)(C)c1ccc(F)cc1C=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 15 g (0.040 mol) of (S)-6-(4-fluoro-2-hydroxymethylphenyl)-6-methyl-4-trifluoromethylhept-1-yn-4-ol in 150 mL DCM at 0° C. was added 21.3 mL of DMSO and 21.2 mL of triethylamine. The reaction was cooled to 0° C. then 19.1 g (0.12 mol) of Pyr-SO3 was added. The reaction mixture was stirred at 0° C. for 1 hour. The reaction was then quenched with 500 mL of water, acidified with 1 N HCl to pH=2, and the organic layer was separated. The aqueous phases were then extracted with DCM. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 5-fluoro-2-((S)-3-hydroxy-1,1-dimethyl-3-trifluoromethylhex-5-ynyl)benzaldehyde as a thick yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[CH:2].C(N(CC)CC)C.[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH:18]([Cl:22])[C:19]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:1]#[CH:2])=[CH:4][CH:5]=1)=[O:20]
Reactant: C#Cc1ccc(N)cc1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#Cc1ccc(NC(=O)C(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-Ethynylaniline (2.94 g, 25.1 mmol) was dissolved in anhydrous dichloromethane (20 mL) with triethylamine (4.55 mL, 32.6 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (2.42 mL, 25.1 mmol) in anhydrous dichloromethane (20 mL) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature for 12 h. The reaction mixture was then washed successively with water, 20% hydrochloric acid and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a brown solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[Na+].O>C(O)C>[CH2:25]([O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:13]1[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cccc(-c2ccccc2-c2ccccc2OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc(-c2ccccc2-c2ccccc2OCc2ccccc2)c1
Temperature: 50 °C

Procedure:
2-Benzyloxy-[1,1′;2′,1″]terphenyl-3″-carboxylic acid ethyl ester (84 mg, 0.206 mmol) was dissolved in ethanol (2 ml) and 2M sodium hydroxide (0.5 ml) added. The mixture was stirred and heated to 50° C. for 4 h. Water was added and the mixture extracted with isohexane. The aqueous layer was acidified with 2M hydrochloric acid and extracted with diethyl ether (2×10 ml). The combined organic phases were washed with water, dried (MgSO4) and evaporated. The oil was triturated with isohexane and the resulting white solid filtered, washed with isohexane and dried in vacuo. (42 mg, 54%).
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:10](C#N)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N-:24]=[N+:25]=[N-:26].[Na+].O.C([OH:32])(C)C>[Br-].[Zn+2].[Br-]>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:10]([OH:11])=[O:32])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[NH:1]1[CH:14]=[N:26][N:25]=[N:24]1
Reactant: N#CC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CC(C)O
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Product: c1nnn[nH]1
Temperature: 25 °C

Procedure:
Cbz-Phe-CN (2.54 g, 9.06 mmole) with sodium azide (1.18 g, 18.12 mmole) and zinc bromide (1.02 g, 4.53 mmole) in a 2:1 mixture of water/isopropanol (90 ml) was then refluxed for 16 hr. The mixture was removed from heat and allowed to cool to room temperature. 1M HCL (14 ml) was added to the mixture, causing the formation of a white precipitate. Ethyl Acetate (30 ml) was then added and the mixture was stirred until the precipitate disappeared. The aqueous phase was separated and washed with ethyl acetate (70 ml). The combined organic layers were then washed with 100 ml of water containing 150 μL of 1 mM DTPA in PBS. The organic layer were dried over magnesium sulfate, filtered, and concentrated in vacuo to give Cbz-Phe-tetrazole as a white solid. (2.96 g, 91%) HPLC analysis: 99% at 6.6 min; ESMS m/z 324.24 (MH)+, 346.25 (M+Na)+
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.Cl[C:56]1[S:57][C:58]2[CH:64]=[CH:63][CH:62]=[CH:61][C:59]=2[N:60]=1>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[S:57]1[C:58]2[CH:64]=[CH:63][CH:62]=[CH:61][C:59]=2[N:60]=[C:56]1[N:50]1[CH2:51][CH2:52][CH:47]([CH2:46][C:45]([NH:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])=[O:53])[CH2:48][CH2:49]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Clc1nc2ccccc2s1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(c2nc3ccccc3s2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 11 %

Procedure:
A solution of N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) (10 mg, 0.0144 mmol), 2-chloro-benzothiazole (20.7 mg, 0.122 mmol) was heated at 80° C. for 1 hour. Then the solution was diluted with MeOH and purified on LC/MS using pH2 buffer to give the desired compound in 11% yield. LCMS for C31H30ClN8OS (M+H)+: m/z=597.2.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([O:22][CH2:23][C:24]2[C:28]4[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=4[O:26][CH:25]=2)[CH:18]=[CH:17][CH:16]=3)=[O:12])=[CH:6][CH:5]=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[N:34]1([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[C:19]([O:22][CH2:23][C:24]3[C:28]5[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=5[O:26][CH:25]=3)[CH:18]=[CH:17][CH:16]=4)=[O:12])=[CH:6][CH:5]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: C1CCNCC1
Reactant: O=C(Nc1ccc(CCO)cc1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1
Product: O=C(Nc1ccc(CCN2CCCCC2)cc1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1

Procedure:
This compound is synthesized analogously to example 150 from 4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid [4-(2-hydroxy-ethyl)-phenyl]-amide (193, preparation see below) and piperidine.