Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:7]=[N:6][CH:5]=1.[Li+].[OH-]>CO.C1COCC1.CCOC(C)=O>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([S:10][C:8]3[CH:7]=[N:6][CH:5]=[C:4]([CH:9]=3)[C:3]([OH:22])=[O:2])=[C:12]([CH3:21])[NH:13]2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1cncc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1[nH]c2cc(Cl)ccc2c1Sc1cncc(C(=O)O)c1
Temperature: 50 °C

Procedure:
5-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-nicotinic acid methyl ester (0.050 g, 0.15 mmol) was dissolved in MeOH:THF (1:1, 4 mL) and LiOH (1 M aq., 1 mL) was added. The reaction was heated to 50° C. for 3.5 hours then cooled. The reaction was acidified with HCL (1 M aq., 1 mL), diluted with EtOAc, dried over MgSO4, then filtered and concentrated to supply the title compound. Mass spectrometric data: [M+H]+=319.
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[C:39]([O:43][C:44](=[O:51])[C@H:45]([CH2:47][C:48](=[O:50])[NH2:49])[NH2:46])([CH3:42])([CH3:41])[CH3:40]>C1COCC1>[C:39]([O:43][C:44](=[O:51])[C@H:45]([CH2:47][C:48](=[O:50])[NH2:49])[NH:46][C:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[O:13])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CC(N)=O
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1

Procedure:
Analogously to Example 100, 5.45 g (31.4 mmol) of quinaldic acid in 161 ml of THF are reacted with 7.08 g (34.3 mmol) of DCC, 4.63 g (34.3 mmol) of HOBT and 5.38 g (28.6 mmol) of (L)-asparagine tert-butyl ester (Bachem, Bubendorf/Switzerland). Filtration, extraction and column chromatography (SiO2, ethyl acetate/hexane 3:1) yields the pure title compound: TLC Rf (C')=0.15; tRet (V)=12.2 min; FAB-MS (M+H)+ =344.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([CH:15]=[CH2:16])(=[O:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:25]1C=CC=C1CC(O)=O.[CH3:34][CH2:35][O:36]CC>>[C:1]([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([CH:15]=[CH2:16])(=[O:13])=[O:14])([CH3:4])([CH3:2])[CH3:3].[C:1]([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([CH2:15][CH2:16][S:25][C:35](=[O:36])[CH3:34])(=[O:13])=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)Cc1cccs1
Reactant: CCOCC
Agent: C=CS(=O)(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Product: CC(=O)SCCS(=O)(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
N-(Vinylsulfonyl)-L-proline t-butyl ester (5.0 g, 0.0192 mole), triethylamine (2.8 ml, 0.02 mole) and thiolacetic acid (1.43 ml, 0.02 mole) are mixed in 100 ml of ether and allowed to stand overnight. The mixture is washed with 5% potassium bisulfate solution, saturated sodium bicarbonate solution and brine, then evaporated in vacuo to a yellow oil. The procedure is repeated using half of the above quantities of triethylamine and thiolacetic acid. Workup as in part (a) affords the crude product, N-[[2-(acetylthio)ethyl]sulfonyl]-L-proline t-butyl ester, which is filtered through a short silical gel column and crystallized from ether/hexane, m.p. 46°-50° (2.9 g, 45%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([CH3:19])[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27][C:28]4[CH:41]=[CH:40][C:31]5[C@H:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:33][O:34][C:30]=5[CH:29]=4)[CH:21]=3)=[C:15]([CH3:42])[CH:14]=2)[CH2:9]1.C(N(CC)CC)C.[CH:50]1([C:53](Cl)=[O:54])[CH2:52][CH2:51]1>ClCCl>[CH:50]1([C:53]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:14]=[C:15]([CH3:42])[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27][C:28]5[CH:41]=[CH:40][C:31]6[C@H:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:33][O:34][C:30]=6[CH:29]=5)[CH:21]=4)=[C:17]([CH3:19])[CH:18]=3)[CH2:9]2)=[O:54])[CH2:52][CH2:51]1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CNC5)cc4C)c3)ccc21
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CN(C(=O)C6CC6)C5)cc4C)c3)ccc21
Reaction time: 12 h
Yield: 94.4 %

Procedure:
The crude (S)-methyl 2-(6-((4′-(azetidin-3-yloxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 2,2,2-trifluoroacetate 14c (40 mg, 0.09 mmol) was dissolved in 3 mL of dichloromethane, followed by addition of triethylamine (0.1 mL, 0.26 mmol) and cyclopropanecarbonyl chloride 15a (14 mg, 0.13 mmol). The reaction solution was stirred for 12 hours. The resulting solution was mixed with 10 mL of dichloromethane, washed with saturated sodium chloride solution (5 mL), dried with anhydrous magnesium sulphate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound (S)-methyl 2-(6-((4′-((1-(cyclopropanecarbonyl)azetidin-3-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 15b (46 mg) as a red oil, which was directly used in the next step without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[N:19][NH2:20])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2F)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:11]3[C:16](=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[NH:20][N:19]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=NN)c2ccc(Cl)cc2F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCC(c2n[nH]c3cc(Cl)ccc23)CC1
Temperature: 120 °C
Reaction time: 16 h
Yield: 20.8 %

Procedure:
A mixture of 19.6 g of 1-acetyl-4-(2-fluoro-4-chlorobenzoyl)piperidine hydrazone, 18.2 g of potassium carbonate and 200 ml of dimethylformamide was stirred, under nitrogen, at 120° C. for 16 hrs. After cooling to ambient temperature, the reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to an oil. Upon standing, a solid formed. The solid was triturated with ethyl acetate to yield 3.8 g (21%) of product. Recrystallization from acetonitrile gave the analytical sample, mp 172°-174° C.
Reaction SMILES: [C:1]1([S:7][CH2:8][S:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K].C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl>[C:1]1([S:7][CH2:8][S:9][CH2:10][C:11]([Cl:18])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CSCSc1ccccc1
Agent: [K]
Solvent: ClCCl
Product: O=C(Cl)CSCSc1ccccc1

Procedure:
5.1 gms. of [[(phenylthio)methyl]thio]acetic acid, potassium salt are treated with 5 gms. of oxalyl chloride in 10 ml. of methylene chloride at 0°-5° to obtain 3.4 gms. of [[(phenylthio)methyl]thio]acetyl chloride which is used further without purification.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[S:3]1.Cl.O.[NH:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>>[O:27]=[C:24]1[CH2:25][CH2:26][N:21]([S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:8][CH:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH2:22][CH2:23]1
Reactant: O=C1NC(=O)C(Cc2ccc(S(=O)(=O)Cl)cc2)S1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: O=C1CCN(S(=O)(=O)c2ccc(CC3SC(=O)NC3=O)cc2)CC1

Procedure:
The title compound was prepared from 4-(2,4-dioxo-thiazolidin-5-ylmethyl)-benzene-sulfonylchloride (J. Med. Chem. 1992, 35, 1853) and 4-piperidone monohydrate hydrochloride according to the procedure of Intermediate 22 as a white solid; 1H NMR (300 MHz, DMSO-d6) □ 2.40-2.50 (m, 4H), 3.20-3.40 (m, 5H), 3.50 (dd, J=14.1,4.7 Hz, 1H), 5.00 (dd, J=10.4, 4.7 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.4 Hz, 2H), 12.09 (s, 1H); MS (ES) m/z:368.9 (M++H); HRMS Calcd. for C15H16N2O5S2(M++H): 368.0501. Found: 368.0481. Anal. Calcd. for C15H16N2O5S2: C, 48.90; H, 4.38; N, 7.60. Found: C,48.63; H, 4.35; N, 7.38.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.O[NH:28][C:29]([C:31]1[N:35]=[C:34]([CH3:36])[N:33]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([N:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)[CH:39]=2)[N:32]=1)=[NH:30]>C(Cl)Cl>[CH3:36][C:34]1[N:33]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([N:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)[CH:39]=2)[N:32]=[C:31]([C:29]2[N:30]=[C:8]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:14])[F:13])=[CH:12][CH:11]=3)[O:10][N:28]=2)[N:35]=1
Reactant: Cc1nc(C(=N)NO)nn1Cc1cccc(N2CCN(C)CC2)c1
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1nc(-c2noc(-c3ccc(OC(F)(F)F)cc3)n2)nn1Cc1cccc(N2CCN(C)CC2)c1
Temperature: 45 °C
Reaction time: 6 h
Yield: 18 %

Procedure:
A solution of 4-(trifluoromethoxy)benzoic acid (85 mg, 0.41 mmol) and CDI (66 mg, 0.41 mmol) in DCM (2 mL) was stirred at RT for 4 h before being added to a solution of N-hydroxy-5-methyl-1-(3-(4-methylpiperazin-1-yl)benzyl)-1H-1,2,4-triazole-3-carboximidamide (66 mg, 0.2 mmol) in DCM (1 mL). The reaction was then stirred at 45° C. for 6 h. The solvent was removed under reduced pressure, DMF (2 mL) was added and the reaction was stirred at 135° C. for 2 h. The reaction was then diluted with H2O (10 mL), extracted with 4:1 CHCl3:iPrOH (3×10 mL), dried with MgSO4 and concentrated under reduced pressure. The crude product was purified by pre-HPLC (Mobile phase: A=0.1% CF3CO2H/H2O, B=MeCN; Gradient: B=10%-40% in 30 min; Column: Waters C18) to afford 3-(5-methyl-1-(3-(4-methylpiperazin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-5-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (18 mg, 18%) as a yellow oil. MS (ES+) C24H24F3N7O2 requires: 499. found: 500 [M+H]+; 1H-NMR (600 MHz, CDCl3) δ ppm 8.34 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H), 7.23 (t, J=7.6 Hz, 1H), 6.86 (d, J=8.1 Hz, 1H), 6.77 (s, 1H), 6.67 (d, J=7.5 Hz, 1H), 5.40 (s, 2H), 3.18 (m, 4H), 2.54 (m, 4H), 2.49 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([Si:4]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[O:5]C/C(/C)=C/C(OCC)=O)[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:27]1[CH2:31][O:30][CH2:29][CH2:28]1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>CCOCC>[CH3:17][CH:15]([Si:4]([CH:18]([CH3:20])[CH3:19])([CH:2]([CH3:3])[CH3:1])[O:5]/[C:27](/[CH3:31])=[CH:28]/[CH2:29][OH:30])[CH3:16]
Reactant: CCOC(=O)/C=C(\C)CO[Si](C(C)C)(C(C)C)C(C)C
Reactant: C1CCOC1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: C/C(=C\CO)O[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of (E)-ethyl 4-[tris-(1-methylethyl)silyloxy]-3-methylbut-2-enoate (5 g, 17.6 mmol) in dry Et2O was added a solution of lithium aluminum hydride (17.6 mL, 17.6 mmol, 1 M in Et2O). After 30 minutes, the reaction mixture was neutralized by dropwise addition of THF followed by addition of a saturated solution of potassium sodium tartrate. The reaction mixture was stirred overnight and then diluted with Et2O. The organic layer was separated and washed with water, dried over MgSO4 and concentrated in vacuo to afford (E)-3-[tris-(1-methylethyl)silyloxy]but-2-en-1-ol as a colorless oil which was used directly into the next reaction.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:17])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15]C)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([OH:17])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1Cc1cccc(Cl)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccccc1Cc1cccc(Cl)c1O
Temperature: 25 °C

Procedure:
(3-Chloro-2-hydroxyphenyl)(2-methoxyphenyl)methane (3.98 g, 16 mmol) was dissolved in 100 ml of methylene chloride and 24 ml of 1M boron tribromide in methylene chloride (24 mmol) was added under nitrogen with stirring at ambient temperature. The mixture was allowed to react for 4 hours and then 100 ml of water was added slowly at ambient temperature. The organic layer was recovered and extracted with 2 N sodium hydroxide. The alkaline extract was acidified with 6 N hydrochloric acid and extracted with ether. The ether extract was dried over magnesium sulfate and concentrated by evaporation under reduced pressure to obtain 2.7 g (72 percent of theory) of the title compound. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: OC1C(C)=NC([Br:9])=CN=1.O[C:11]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][C:14]([Br:23])=[CH:13][N:12]=1>>[Br:9][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][C:14]([Br:23])=[CH:13][N:12]=1
Reactant: Cc1nc(Br)cnc1O
Reactant: Oc1ncc(Br)nc1-c1ccccc1
Product: Brc1cnc(Br)c(-c2ccccc2)n1

Procedure:
By replacing the 2-hydroxy-3-methyl-5-bromopyrazine used in Step A of Preparation 87 by an equivalent quantity of 2-hydroxy-3-phenyl-5-bromopyrazine and following substantially the same procedure there is obtained 2,5-dibromo-3-phenylpyrazine.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:11][C:12](=[O:27])[NH:13][C:14]2[C:15]([CH3:26])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH3:10])=[CH:5][CH:4]=1.[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:12]([O:11][CH:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:29])([F:28])[F:1])=[CH:4][CH:5]=4)[CH3:10])=[O:27])=[CH:20][CH:21]=3)=[CH:40][CH:39]=2)[CH2:36][CH2:37]1)=[O:34])[CH3:31]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)c4ccc(C(F)(F)F)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(4-trifluoromethyl-phenyl)-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester; the isolated material was then purified by preparative HPLC, using a chiral column (95:5 hexanes:EtOAc) to provide enantiomer A and enantiomer B. Enantiomer A had a retention time of 30 minutes, enantiomer B had a retention time of 50 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]([CH3:11])[N:4]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[F:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([F:46])=[C:24]([NH:23][C:8]([C:7]5[C:3]([O:2][CH3:1])=[N:4][N:5]([CH3:11])[CH:6]=5)=[O:10])[CH:25]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: COc1nn(C)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1nn(C)cc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 27.6 %

Procedure:
In the same manner as in Example 259 and using 3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid (93 mg, 0.60 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (61 μL, 0.72 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (59 mg, 28%) was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[OH:20][CH2:19][C:15]1[CH:14]=[C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:17][CH:16]=1
Reactant: C1CNCCN1
Reactant: O=Cc1c(Cl)n(-c2cccc(CO)c2)c2ccccc12
Product: O=Cc1c(N2CCNCC2)n(-c2cccc(CO)c2)c2ccccc12
Yield: 32 %

Procedure:
2-Chloro-1-(3-hydroxymethylphenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-(3-hydroxymethylphenyl)-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde (32% yield) as a red solid. ESI/MS 336 (M+H); RT=2.37 min.
Reaction SMILES: C([O:8][CH2:9][C@H:10]([O:12][C:13]1[C:18]([Br:19])=[CH:17][CH:16]=[CH:15][N:14]=1)[CH3:11])C1C=CC=CC=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:19][C:18]1[C:13]([O:12][C@H:10]([CH3:11])[CH2:9][OH:8])=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[C@H](COCc1ccccc1)Oc1ncccc1Br
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](CO)Oc1ncccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (R)-2-((1-(benzyloxy)propan-2-yl)oxy)-3-bromopyridine (2.4 g, 7.5 mmol) in dry DCM (10 mL) was added BBr3 (7.5 mL, 22 mmol, 3 M in DCM) at −78 Celsius in a drop-wise manner and stirring continued for 3 h. The reaction mixture was warmed to rt and the pH adjusted to −7-8 with sat. NaHCO3 (30 mL). The mixture was extracted with DCM (2×10 mL), and the combined extracts dried over Na2SO4, filtered, concentrated to dryness. The crude product was purified by FCC to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.05-7.99 (m, 1H), 7.84-7.75 (m, 1H), 6.83-6.71 (m, 1H), 5.25-5.12 (m, 1H), 3.78 (d, J=5.1, 2H), 3.29 (s, 1H), 1.37 (d, J=6.4, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH:9]1[C:13]2([CH3:30])[CH:14]([OH:29])[CH2:15][CH:16]3[C:21]4([CH3:27])[CH2:22][CH2:23][CH:24]([OH:26])[CH2:25][CH:20]4[CH2:19][CH:18]([OH:28])[CH:17]3[CH:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1.CC(OC)(C)C.Cl>N1C=CC=CC=1.O>[OH:28][C@@H:18]1[CH2:19][C@H:20]2[C@:21]([CH3:27])([CH2:22][CH2:23][C@@H:24]([O:26][S:37]([C:34]3[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=3)(=[O:39])=[O:38])[CH2:25]2)[C@@H:16]2[C@@H:17]1[C@H:12]1[C@:13]([CH3:30])([C@@H:14]([OH:29])[CH2:15]2)[C@@H:9]([C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[CH2:10][CH2:11]1
Reactant: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(O)CCC4(C)C3CC(O)C12C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: -8 °C

Procedure:
To a solution of cholic acid methyl ester (1000.0 g, 2.366 mol) in pyridine (2250 mL) at −10° C. was added a solution of p-toluenesulfonyl chloride (654.2 g, 2.431 mol) in pyridine (650 mL) dropwise over 2.5 hours while maintaining the reaction temperature at −10 to −6° C. The solution was mixed at −10° C. for an additional 12.5 hours, diluted with water (61.8 g) with continued cooling. The mixture at −7.5° C. was added over a period of 43 minutes to a mixture of MTBE (5 L) and 6N HCl (6.2 L). The layers were separated and the organic phase was washed with 7% NaHCO3 (2 L), followed by 2% NaCl (2 L), and finally with pH 7 phosphate buffer (2 L). The organic phase was filtered, concentrated under reduced pressure with MTBE (3×200 mL) to give 1608.93 g of a very viscous pale-straw colored oil (95.3% potency adjusted yield) that was used directly in the next step. 1H NMR (CDCl3, 400 MHz) δ 7.79 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.6 Hz, 2H), 4.40-4.31 (m, 1H), 3.97 (br s, 9H), 3.83 (br s, 1H), 3.68 (s, 3H), 2.60-2.50 (m, 1H), 2.45 (s, 3H), 2.43-1.34 (m, 25H), 0.99 (d, J=6.3 Hz, 3H), 0.88 (s, 3H), 0.69 (s, 3H). MS (ESI) Expected=576; base=594.2 (576+NH4+).
Reaction SMILES: [I-].[Li+].[Si:3]([O:10][C@@H:11]([CH2:16][O:17][CH:18]1[CH2:21][CH2:20][CH2:19]1)[C:12]([O:14]C)=[O:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>C(OCC)(=O)C>[Si:3]([O:10][C@@H:11]([CH2:16][O:17][CH:18]1[CH2:21][CH2:20][CH2:19]1)[C:12]([OH:14])=[O:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: COC(=O)[C@H](COC1CCC1)O[Si](C)(C)C(C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](COC1CCC1)C(=O)O
Temperature: 75 °C
Yield: 90.4 %

Procedure:
Lithium iodide (1.986 g, 14.84 mmol) was added to (S)-methyl 2-(tert-butyldimethylsilyloxy)-3-cyclobutoxypropanoate (Intermediate R3) (1.07 g, 3.71 mmol) in ethyl acetate (15 mL). The resulting suspension was protected from light and stirred at reflux (75° C.) for 6 hours. The reaction mixture was diluted with ethyl acetate (75 mL) washed sequentially with 1M sodium metabisulphite (25 mL), water (25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4) and evaporated to afford the crude product (0.920 g, 90%) that was used without further purification. 1H NMR (400 MHz, DMSO) δ 0.09 (d, 6H), 0.91 (s, 9H), 1.40-1.54 (m, 1H), 1.59-1.71 (m, 1H), 1.75-1.90 (m, 2H), 2.10-2.22 (m, 2H), 3.40-3.57 (m, 2H), 3.90-4.02 (m, 1H), 4.25-4.31 (m, 1H), 12.55 (s, 1H); m/z (EI+) M+=274; GC tR=11.09 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([C:23]#N)=[CH:22][C:16]=3[N:15]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].C([Al+]CC(C)C)C(C)C.C1C[O:40]CC1>O.CC(=O)OCC>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([CH:23]=[O:40])=[CH:22][C:16]=3[N:15]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(Cc2nc3cc(C#N)ccc3[nH]2)cc1
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(Cc2nc3cc(C=O)ccc3[nH]2)cc1
Reaction time: 1 h
Yield: 46 %

Procedure:
To a stirred solution of 2-(4-(heptyloxy)benzyl)-1H-benzo[d]imidazole-5-carbonitrile INT-46 (1.22 g, 3.51 mmol) in THF (20 mL) at 0° C. was added diisobutylaluminum hydride (12.3 mL, 12.3 mmol, 1 M in toluene). After 2 h the reaction mixture was poured onto Rochelle's salt (7.91 g, 28.0 mmol) in water (100 mL) and EA (50 mL) and stirred for 1 h. The layers were split and the aqueous layer was further extracted with EA (2×30 mL). The combined organics were washed with brine (20 mL) dried over MgSO4 and evaporated. The crude material was purified by chromatography (EA/isohexanes) to afford 571 mg (46%) of 2-(4-(heptyloxy)benzyl)-1H-benzo[d]imidazole-5-carbaldehyde INT-47 as a brown oil. LCMS-ESI (m/z) calculated for C22H26N2O2: 350; found 351 [M+H]−, tR=2.34 min (Method 5).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[CH2:24][CH:13]2[C:14]3[CH:15]=[C:16]([O:22][CH3:23])[CH:17]=[CH:18][C:19]=3[C:20](=[O:21])[CH:12]2[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[CH2:24][CH:13]2[C:14]3[CH:15]=[C:16]([O:22][CH3:23])[CH:17]=[CH:18][C:19]=3[CH:20]([OH:21])[CH:12]2[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc2c(c1)C1CN(Cc3ccccc3)CC1C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)C1CN(Cc3ccccc3)CC1C2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
NaBH4 (0.27 g, 6.8 mmol) was added to a solution of 2-benzyl-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (from Example 1, Step C) (1.0 g, 3.4 mmol) in MeOH (17 mL), and stirred for 2 hours at room temperature. The reaction solution was concentrated via rotary evaporation and the residue dissolved in EtOAc. The organic solution was washed with a saturated aqueous NaHCO3 solution and brine, dried over MgSO4, and concentrated. The crude product was obtained without further purification. MS calculated for C19H21NO2+H: 296, observed: 296.