Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:15])[CH:14]=1)[O:5][CH2:6][CH2:7][C:8]([O:10]C)=O.FC(F)(F)S(O)(=O)=O>O>[F:15][C:13]1[CH:14]=[C:2]([F:1])[CH:3]=[C:4]2[C:12]=1[C:8](=[O:10])[CH2:7][CH2:6][O:5]2
Reactant: COC(=O)CCOc1cc(F)cc(F)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: O=C1CCOc2cc(F)cc(F)c21
Temperature: 80 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
A mixture of methyl 3-(3,5-difluorophenoxy)propanoate (11.6 g, 53.7 mmol, STEP 6) and trifluoromethanesulfonic acid (23.2 mL, 2.0 mL/g of substrate) was stirred at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (120 mL), and extracted with toluene (120 mL). The organic layer was washed successively with aqueous solution of potassium carbonate (50 mL), water (50 mL), and dried over magnesium sulfate. The organic mixture was concentrated in vacuum to afford the title compound (8.75 g, 88%) as a white solid, which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15]>C1COCC1.O>[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:13]([CH3:12])[S:14]([CH3:17])(=[O:16])=[O:15])[N:7]=1)#[N:9]
Reactant: N#Cc1ccnc(Cl)n1
Reactant: CNS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(c1nccc(C#N)n1)S(C)(=O)=O
Reaction time: 0.33 h

Procedure:
To a solution of 2-chloropyrimidine-4-carbonitrile (0.20 g, 1.43 mmol) in THF was 60% NaH (0.05 g, 2.00 mmol) in mineral oil. After 20 minutes, N-methylmethanesulfonamide (0.22 g, 2.00 mmol) was added. After 3 hours, the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 30% ethyl acetate in heptane. The major fractions were combined and the solvent was concentrated in vacuo to afford N-(4-cyano-pyrimidin-2-yl)-N-methyl-methanesulfonamide.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29][Si](C(C)C)(C(C)C)C(C)C)[CH:24]=1)(=[O:21])[CH3:20].Br[CH2:41][C:42](=[O:50])[CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46]>C1COCC1>[C:19]([O:22][C:23]1[CH:24]=[C:25]([S:29][CH2:41][C:42](=[O:50])[CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:26]=[CH:27][CH:28]=1)(=[O:21])[CH3:20]
Reactant: CCOC(=O)CCC(=O)CBr
Reactant: CC(=O)Oc1cccc(S[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)CSc1cccc(OC(C)=O)c1
Reaction time: 0.25 h
Yield: 63.1 %

Procedure:
Tetrabutylammonium fluoride (7 ml, 7.0 mmol, 1M in THF) was added to a solution of 3-[1,1-bis(Methylethyl)-2-methyl-1-silapropylthio]phenyl acetate (1.53 g, 4.7 mmol) in THF (10 ml) under argon at room temperature. The reaction was stirred for 15 minutes followed by addition of a solution of ethyl 5-bromo-4-oxopentanoate (1.15 g, 5.17 mmol) in THF (5 ml). After stirring for 3 hours, the solvent was removed under vacuum and the crude product was chromatographed over silica gel to yield 920 mg (73%) of ethyl 5-(3-acetyloxyphenylthio)-4-oxopentanoate. NMR 1H Cl3CD δ: 7.29 (t, 1H, J=8.0 Hz), 7.18 (dd, 1H, J=0.8, 7.6 Hz), 7.07 (t, 1H, J=1.6 Hz), 6.94 (dd, 1H, J=1.2, 8.0 Hz), 4.12 (c, 2H, J=7.2 Hz), 3.75 (s, 2H), 2.89 (t, 2H, J=6.8 Hz), 2.60 (t, 2H, J=6.8 Hz), 2.29 (s, 3H), 1.24 (t, 1H, J=7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:26]=[CH:25][C:16]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>S(Cl)(Cl)=O.C1COCC1>[C:17]([C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=2[Cl:1])=[CH:26][CH:25]=1)(=[O:18])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)c1ccc(NC(=O)c2cc(Cl)ccc2Cl)cc1
Yield: 84.3 %

Procedure:
Reaction of 2,5-dichlorobenzoic acid (300 mg, 1.50 mmol) in thionyl chloride (3.5 mL) then with 4-aminobenzophenone (100 mg, 0.51 mmol) in presence of triethylamine (90 μL) in THF (6 mL) according to method B gave N-(4-benzoyl-phenyl)-2,5-dichloro-benzamide (160 mg, 0.43 mmol, 84% yield) as a off-white powder after purification by chromatography on silica gel (eluent:EtOAc/exane 1/9 to 3/7).
Reaction SMILES: C(OC(=O)C)(=O)C.O[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[N:17][OH:18])[CH3:16].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[CH3:16][C:15]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:18][N:17]=1
Reactant: CC(=NO)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1noc2ccccc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
Acetic anhydride (7.1 mL, 75 mmol) was added to 24 (7.55 g, 50 mmol) in a 100 mL flask. The mixture was heated to 60° C. for 3 hours followed by evaporation to dryness. Potassium carbonate (8.7 g, 63 mmol) was partly dissolved in 40 mL DMF and added to the mixture. The mixture was stirred at room temperature overnight and finally heated to 100° C. for 30 minutes. Ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate and dichloromethane. The combined organic phases were dried over magnesium sulphate and evaporated to dryness to give 5.6 g of a yellow oil. Crude product was purified by column chromatography (100% dichloromethane), producing pure 25 (4.6 g). 1H NMR (CDCl3) δ2.6 (s, 3H), 7.3 (m, 1H), 7.55 (m, 2H), 7.65 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH2:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[N:22]=2)=[C:18]([Cl:34])[CH:17]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:15][C:16]2[CH:33]=[CH:32][C:19]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[N:22]=3)=[C:18]([Cl:34])[CH:17]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: Nc1ccc(Oc2ccnc(NCCCO)n2)c(Cl)c1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc(NCCCO)n2)c(Cl)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 8 h
Yield: 27.2 %

Procedure:
A solution of 205 mg (0.926 mmol) 4-chloro-3-trifluoromethyl-phenyl isocyanate in 3 ml THF was added within 10 min. to a solution of 273 mg (0.926 mmol) 3-[4-(4-amino-2-chloro-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in 3 ml THF and stirring continued overnight. The reaction mixture was evaporated and purified by chromatography on silica (dichloromethane/ethanol 97:3). The obtained material was stirred with dichloromethane. The precipitate was filtered and dried to yield 130 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.CO.[C:13]([O:17][C:18](=[O:36])[N:19]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][N:21]=1)([CH3:16])([CH3:15])[CH3:14].[OH-].[K+]>O>[C:13]([O:17][C:18](=[O:36])[N:19]([C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:5]2[C:4]3[C:8](=[N:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][CH:6]=2)[OH:27])=[CH:22][N:21]=1)[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1ccc(C=O)cn1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1ccc(C(O)c2c[nH]c3ncc(Br)cc23)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 5-bromo-7-azaindole (44, 198.0 mg, 1.01 mmol) in methanol (30.0 mL, 0.741 mol) were added (4-Chloro-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (43, 355.0 mg, 1.02 mmol) and potassium hydroxide (80.0 mg, 1.42 mmol). The reaction was stirred at room temperature 48 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 8% methanol in dichloromethane to give compound (45, 200.0 mg, 36.8%).
Reaction SMILES: [CH:1]([N:4]([CH3:46])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:35])[CH2:13][C:14]([NH:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[NH:27]C(=O)OC(C)(C)C)=[O:15])[C@H:7]([CH2:36][S:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:39])=[O:38])[CH2:6]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][C:18]1[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:24])[F:25])=[CH:22][C:17]=1[NH:16][C:14](=[O:15])[CH2:13][C:12]([NH:11][C@H:8]1[CH2:9][CH2:10][C@@H:5]([N:4]([CH:1]([CH3:2])[CH3:3])[CH3:46])[CH2:6][C@H:7]1[CH2:36][S:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:38])=[O:39])=[O:35]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)CC(=O)Nc2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)[C@H](CS(=O)(=O)c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)CC(=O)Nc2cc(C(F)(F)F)ccc2N)[C@H](CS(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(3-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexylamino)-3-oxopropanamido)-4-(trifluoromethyl)phenylcarbamate (10 mg, see procedure 35b) in CH2Cl2 (1.5 mL) was added TFA (0.5 mL) at 0° C. The reaction was warmed to RT and stirred for one hour at which time it was concentrated in vacuo. The title compound (presumed mono-TFA salt) was obtained as a white powder after reverse-phase HPLC and lyopholization. MS found: (M+H)+=569.32.
Reaction SMILES: C([O:8][C:9](=[O:61])[CH2:10][O:11][C:12]1[C:17]2[C@@:18]3([OH:55])[C@@:31]([O:35][CH3:36])([C@H:32]([OH:34])[CH2:33][C:16]=2[CH:15]=[C:14]([CH3:56])[C:13]=1[C:57]([O:59][CH3:60])=[O:58])[C:30](=[O:37])[C:29]1[C:20](=[CH:21][C:22]2[C:23](=[O:53])[C:24]([NH:40][C@@H:41]4[C@H:46]([O:47][CH3:48])[C@H:45]([OH:49])[C@@H:44]([O:50][CH3:51])[C@H:43]([CH3:52])[O:42]4)=[CH:25][C:26](=[O:39])[C:27]=2[C:28]=1[OH:38])[C:19]3=[O:54])C1C=CC=CC=1>C1COCC1.[Pd]>[OH:34][C@H:32]1[C@:31]2([O:35][CH3:36])[C@@:18]([OH:55])([C:19](=[O:54])[C:20]3[C:29]([C:30]2=[O:37])=[C:28]([OH:38])[C:27]2[C:26](=[O:39])[CH:25]=[C:24]([NH:40][CH:41]4[C@H:46]([O:47][CH3:48])[C@H:45]([OH:49])[C@@H:44]([O:50][CH3:51])[C@H:43]([CH3:52])[O:42]4)[C:23](=[O:53])[C:22]=2[CH:21]=3)[C:17]2[C:12]([O:11][CH2:10][C:9]([OH:61])=[O:8])=[C:13]([C:57]([O:59][CH3:60])=[O:58])[C:14]([CH3:56])=[CH:15][C:16]=2[CH2:33]1
Reactant: COC(=O)c1c(C)cc2c(c1OCC(=O)OCc1ccccc1)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1c(C)cc2c(c1OCC(=O)O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(NC1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A mixture of (6R,6aS,14aR)-methyl 1-(2-(benzyloxy)-2-oxoethoxy)-6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (22 mg, 0.024 mmol) and 10% Pd/C (10 mg) in THF (1 mL) was stirred under hydrogen (1 atm) at room temperature for 1 h. The reaction mixture was filtered and concentrated. The residue was purified by semi-preparative HPLC (45:55 acetonitrile/water with 0.05% TFA) to afford 2-((6R,6aS,14aR)-6,8,14a-trihydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-2-(methoxycarbonyl)-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracen-1-yloxy)acetic acid (13 mg, 66%) as an orange solid and as a mixture of diastereomers: 1H NMR (500 MHz, acetone-d6) δ 14.30 (br s, 1H), 8.21 (s, 0.5H), 8.17 (s, 0.5H), 7.19 (d, J=9.0 Hz, 0.5H), 7.08 (d, J=5.7 Hz, 0.5H), 6.99 (s, 0.5H), 6.91 (s, 0.5H), 6.17 (s, 0.5H), 6.00 (s, 0.5H), 5.30 (br s, 1H), 5.11 (d, J=4.8 Hz, 0.5H), 5.06 (d, J=4.8 Hz, 0.5H), 4.92-4.85 (m, 0.5H), 4.76-4.72 (m, 0.5H), 4.62 (br s, 0.5H), 4.60 (br s, 0.5H), 4.50-4.41 (m, 1H), 4.04 (d, J=5.1 Hz, 1H), 3.91-3.83 (m, 1H), 3.76 (s, 1.5H), 3.75 (s, 1.5H), 3.74 (br s, 3H), 3.54 (br s, 3H), 3.52 (s, 1.5H), 3.50 (s, 1.5H), 3.32-3.30 (m, 1H), 3.09-3.05 (m, 1H), 2.19 (s, 1.5H), 2.17 (s, 1.5H), 1.25 (d, J=6.2 Hz, 1.5H), 1.21 (d, J=6.3 Hz, 1.5H); MS (ESI+) m/z 756 (M+H); HPLC 98.5% (AUC), tR 11.48, 11.45 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([OH:20])[CH3:19])=[CH:10][CH:9]=1.N1C=CC=CC=1.FC(F)(F)C(O)=O.C1(N=C=NC2CCCCC2)CCCCC1.O.O.C(O)(=O)C(O)=O>CCOCC.CO.O.C1C=CC=CC=1.CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:20])[CH3:19])=[CH:10][CH:9]=1
Reactant: CC(O)CCCCc1ccc(-c2ccccc2F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C(=O)O
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC(=O)CCCCc1ccc(-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
20.0 Gm (0.0734 mol) of 6-(2'-fluoro-4-biphenylyl)-2-hexanol were dissolved in a mixture consisting of 110 ml of anhydrous dimethyl sulfoxide, 110 ml of absolute benzene, 5.9 ml (0.0732 mol) of pyridine and 2.95 ml (0.0397 mol) of trifluoroacetic acid. 45.5 Gm (0.22 mol) of N,N'-dicyclohexylcarbodiimide were added to the solution, and the mixture was stirred at room temperature for 14 hours. Then, the mixture was diluted with 2 liters of dry ether, a solution of 27.7 gm (0.22 mol) of oxalic acid dihydrate in 180 ml of methanol was added dropwise while stirring, and 2 liters of water were added after the gas evolution, lasting about 30 minutes, was compete. The insoluble N,N' -dicyclohexyl-urea was filtered off, and the aqueous and organic layers were separated. The organic layer was washed twice with aqueous 5% sodium bicarbonate solution and once with water, dried over sodium sulfate and evaporated. The residue was purified by chromatography on silicagel, using benzene as the eluant, and was subsequently recrystallized three times from petroleum ether. Yield: 7.0 gm (35% of theory) of colorless crystals, m.p. 37°-38°C.
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]([CH3:8])=[O:7])C.[C:10]([CH2:12][C:13]([NH2:15])=[O:14])#[N:11].P(Cl)(Cl)(Cl)=O>>[C:10]([C:12]1[C:13]([OH:14])=[N:15][CH:8]=[C:6]([OH:7])[C:5]=1[CH3:4])#[N:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#CCC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(O)cnc(O)c1C#N

Procedure:
Amine was generated by the condensation of ethylacetoacetate with cyanoacetamide followed by reaction with phosphorus oxychloride to provide 3-cyano-2,5-dihydroxy-4-methylpyridine. Hydrogenation with palladium dichloride gave the 3-cyano-4-methylpyridine which was hydrogenated with Raney nickel in ammonia and ethanol to afford the desired amine (J. Org. Chem. 1959, 25, 560.).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[O:31])=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: C1COCCN1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)N2CCOCC2)cc1
Yield: 67.1 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with morpholine (available from Aldrich Chemical Company, Inc.; 54 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(morpholine-4-carbonyl)-biphenyl-2-carboxylic acid (76 mg, 69%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br s, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.44-7.51 (m, 4H), 3.60-3.67 (m, 4H), 3.26-3.30 (m, 4H).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:27])([CH3:26])[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2CN[C@@H]2CCCC[C@H]2NCC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([SiH2:5][O:6][C:7]([CH3:27])([CH3:26])[C:8]1[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[CH:10][C:9]=1[C@H:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[OH:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(C(F)(F)F)ccc1C(=O)C1CCCCC1
Agent: [K+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2CN[C@@H]2CCCC[C@H]2NCc2ccccc2P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)O
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(C(F)(F)F)ccc1[C@@H](O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
A mixture of [IrHCl2(COD)]2 (33 mg, 0.044 mmol) and (1R,2R)—N,N′-bis[2-(diphenylphosphino)benzyl]cyclohexane-1,2-diamine (29 mg, 0.044 mmol) in isopropanol (37 ml) was stirred at room temperature for 30 minutes. A solution of [2-(tert-butyl-dimethyl-silanyloxymethyl)-4-trifluoromethyl-phenyl]-cyclohexyl-methanone (1.6 g, 4 mmol) in isopropanol (5 ml) was added to mixture followed by potassium hydroxide (28 mg, 0.5 mmol) and stirred for 16 hours. Isopropanol was removed in vacuo and the residue was purified by chromatography over 25+M Biotage silica column eluted with ethyl acetate in heptanes 0% (1 CV), 2-20% (10CV), 20% (2CV) to yield the title compound (1.4 g, 87%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.09 (s, 6H) 0.9 (s, 9H) 1.2 (m, 3H) 1.6 (d, J=7.4 Hz, 1H) 1.7 (m, 4H) 2.0 (m, 1H) 2.2 (m, 1H) 2.4 (m, 1H) 4.5 (m, 1H) 4.7 (d, J=13.7 Hz, 1H) 4.8 (d, J=13.7 Hz, 1H) 7.5 (d, J=1.2 Hz, 2H) 7.6 (s, 1H). Chiral SFC, Retention timet=1.93 min. indicates product is 95.0% ee. [α]D20=−12.99 deg (c=9.5 mg/mL, acetone)
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.O.[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:2]1[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=1
Reactant: Nc1ccccc1Cl
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1nc(Cl)nc(Nc2ccccc2Cl)n1
Temperature: 20 °C
Reaction time: 0.42 h
Yield: 82.1 %

Procedure:
272.0 g of cyanuric chloride, 730 ml of water and 552 ml of toluene are mixed in a stirred glass beaker at 5° C. 188.2 g of o-chloroaniline are added in the course of 15 minutes without cooling or heating the mixture. The mixture is subsequently stirred for 25 minutes and the temperature is thereby allowed to rise to 35° C. The mixture is then cooled to 20° C. in the course of 30 minutes. The product is filtered off, washed acid-free with water and dried at 60° C. under a waterpump vacuum. 333.6 g of 2-(2-chlorophenylamino)-4,6-dichloro-s-triazine with a content of 97.8% are obtained, which corresponds to a yield of 81.1%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].C([Mg]Cl)(C)C.[C:21](=[O:23])=[O:22].O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:21]([OH:23])=[O:22]
Reactant: O=C=O
Reactant: Fc1cc(Br)ccc1C(F)(F)C(F)(F)F
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(F)(F)C(F)(F)F)c(F)c1
Temperature: -10 °C
Reaction time: 2.5 h

Procedure:
A solution of 16.0 g (99% by weight; 54.1 mmol) of 3-fluoro-4-(pentafluoroethyl)-bromobenzene in 110 ml of THF was cooled to −10° C. Added dropwise over the course of 30 minutes were 36.8 ml of a 2M (73.6 mmol) solution of isopropyl-magnesium chloride. The mixture was stirred at −10° C. for 2.5 hours and then cautiously poured onto an excess of dry ice. For working up, 130 ml of water were added, and the mixture was subsequently extracted once with 10 ml of diethyl ether. The aqueous phase was acidified with half-concentrated hydrochloric acid and then extracted with four times 150 ml of diethyl ether. The combined organic phases were dried and the filtrate was freed from the solvent. The residue was recrystallized from CHCl3, giving 10.7 g of product with a purity of 98% by weight.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:3]=1[CH:4]=O.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:3]=1[CH2:4][N:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1c(Cl)cccc1N1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(Cl)cccc2N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
A 100 mL round-bottom flask was charged with 2-chloro-6-(pyrrolidin-1-yl)benzaldehyde (1.40 g, 6.68 mmol, 1.10 equiv), tert-butyl piperazine-1-carboxylate (1.13 g, 6.07 mmol, 1.00 equiv), 1,2-dichloroethane (20 mL). The mixture was stirred 30 min at room temperature. Sodium triacetoxyborohydride (3.85 g, 18.2 mmol, 2.99 equiv) was added. The resulting solution was stirred overnight at room temperature and diluted with 1,2-dichloroethane (20 mL). The resulting solution washed with H2O (2×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (3/7) to yield 1.95 g (77% yield) of tert-butyl 4-[[2-chloro-6-(pyrrolidin-1-yl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 380 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6](=[NH:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[N:4]=1)[CH3:2].[C:27]12[C:35](=[O:36])[O:34][C:32](=[O:33])[C:28]=1[CH2:29][CH2:30][CH2:31]2.O>CN(C)C=O>[CH2:1]([C:3]1[S:7][C:6](=[N:8][C:35]([C:27]2[CH2:31][CH2:30][CH2:29][C:28]=2[C:32]([OH:34])=[O:33])=[O:36])[N:5]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=N)s1
Reactant: O=C1OC(=O)C2=C1CCC2
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=NC(=O)C2=C(C(=O)O)CCC2)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.4 %

Procedure:
To a solution of 5-ethyl-2-imino-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3,4-thiadiazoline (3.63 g) in N,N-dimethylformamide (30 ml) was added 1-cyclopentene-1,2-dicarboxylic anhydride (1.44 g), and they were stirred at room temperature for 6 hours. To the reaction mixture was added water (200 ml), and powders so precipitated were collected by filtration. The powders so obtained were washed successively with water and methanol and then dried, whereby 4.53 g of the title compound was obtained.