Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[Br:22][C:23]1[CH:28]=[C:27]([CH2:29]Br)[CH:26]=[CH:25][C:24]=1[I:31]>O1CCCC1>[Br:22][C:23]1[CH:28]=[C:27]([CH2:29][CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:8])[CH:26]=[CH:25][C:24]=1[I:31]
Reactant: BrCc1ccc(I)c(Br)c1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)C(Cc1ccc(I)c(Br)c1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
A solution of deoxybenzoin (26.4 mg, 0.134 mmol) in tetrahydrofuran (0.66 mL) was cooled to −78° C. and potassium tert-butoxide (0.15 mL, 0.15 mmol, 1.0 M in tetrahydrofuran) was added dropwise. The reaction mixture was stirred at −78° C. for 10 minutes and 2-bromo-4-(bromomethyl)-1-iodobenzene (50.0 mg, 0.133 mmol) in tetrahydrofuran (1 mL) was added dropwise. The reaction mixture was warmed to 25° C. and quenched with saturated ammonium chloride (5 mL) and extracted with ethyl acetate (2×5 mL). The combined organic extracts were washed with brine (5 mL), dried with magnesium sulfate, filtered, and concentrated to a crude yellow oil which was purified by flash column chromatography to yield the desired product (65 mg, 42%). LCMS found for C21H17BrIO (M+H)+: m/z=491, 493.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12](=[O:21])[CH:13]([P:15]([O:19][CH3:20])([O:17][CH3:18])=[O:16])[NH2:14].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.[Br:56][C:57]1[CH:65]=[C:64]([C:66]([NH:68][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([OH:76])[CH:71]=2)=[O:67])[CH:63]=[CH:62][C:58]=1[C:59](O)=[O:60]>CN(C)C=O>[CH3:10][O:11][C:12](=[O:21])[CH:13]([P:15]([O:17][CH3:18])([O:19][CH3:20])=[O:16])[NH:14][C:59](=[O:60])[C:58]1[CH:62]=[CH:63][C:64]([C:66]([NH:68][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([OH:76])[CH:71]=2)=[O:67])=[CH:65][C:57]=1[Br:56]
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)O)c(Br)c1
Reactant: COC(=O)C(N)P(=O)(OC)OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br)P(=O)(OC)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
Diisopropylethylamine (1.81 g, 14 mmol) was added to a solution of rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125) freshly prepared from rac.-N-benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (5.00 g, 15.1 mmol), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (5.20 g, 13.7 mmol), 1-hydroxybenzotriazole (1.85 g, 13.7 mmol) and 2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoic acid (Example 79; 4.80 g, 13.7 mmol) in N,N-dimethylformamide (50 mL). After the reaction was stirred for 4 h at 25° C., the volatiles were removed in vacuo. A solution of the residue in ethyl acetate (200 mL) was washed with 1N hydrochloric acid solution (100 mL), saturated aqueous sodium bicarbonate solution (100 mL), water (100 mL) and brine (100 mL). The organic layer was dried over MgSO4, filtered, concentrated and the resulting residue was flash chromatographed over silica gel (ethyl acetate-3% methanol in ethyl acetate) to give rac.-N-[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (5.50 g, 76% yield) as a colorless foam.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)=[CH:23][CH:22]=1
Reactant: NCc1ccc(F)cc1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: Fc1ccc(CNc2nccc(-n3cnc4ccccc43)n2)cc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 4-fluorobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 320.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.60 (s, 1H); 8.43 (br s, 1H); 8.07 (br s, 1H); 7.86 (m, 1H); 7.38 (m, 5H); 7.07 (t, J=8.7 Hz, 1H); 6.85 (d, J=5.5 Hz, 1H); 5.79 (br s, 1H); 4.72 (d, J=5.7 Hz, 2H).
Reaction SMILES: O=C(C)CCCC[N:7]1[C:16](=[O:17])[C:15]2[NH:14][CH:13]=[N:12][C:11]=2[N:10]([CH3:18])[C:8]1=[O:9].CN1C2N=CNC=2C(=O)NC1=O.[H-].[Na+].Cl[CH2:35][CH2:36][C:37]([CH3:42])([CH3:41])[C:38]([O-])=[O:39]>CS(C)=O.O>[CH3:18][N:10]1[C:11]2[N:12]=[CH:13][N:14]([C:38](=[O:39])[C:37]([CH3:42])([CH3:41])[CH2:36][CH3:35])[C:15]=2[C:16](=[O:17])[NH:7][C:8]1=[O:9]
Reactant: CC(=O)CCCCn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: CC(C)(CCCl)C(=O)[O-]
Agent: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCC(C)(C)C(=O)n1cnc2c1c(=O)[nH]c(=O)n2C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
This example illustrates a method for synthesis of CT1505 (1-(5-oxohexyl)-3-methylxanthine). A mixture of 3-methylxanthine (1.00 g, 6.0 mmol) and NaH (145 mg, 6.0 mmol) in DMSO (dimethyl sulfoxide) (20 ml) was stirred until homogeneous (about 30 min). Chloromethylpivalate (865 μl, 904 mg, 6.0 mmol) was added and the reaction mixture was stirred for 18 hrs. The reaction mixture was poured into 70 ml of water and extracted with 25% ethanol/dichloromethane (4×60 ml). The combined organic extracts were combined, dried with sodium sulfate, and then evaporated in a rotoevaporator to a volume of 40 ml. The solution was cooled in ice water and it formed a thick, white precipitate. The solid was filtered off under suction and dried under vacuum to give the 3-methyl-7-(methylpivaloyl)xanthine (1.43 g, 5.4 mmol, 90% yield).
Reaction SMILES: [C:1]([NH:9][CH:10]([C:18](=O)[CH3:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:30]2)=CC=1>C1COCC1>[CH3:19][C:18]1[S:30][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(=O)C(NC(=O)c1ccccc1)C(=O)OC(C)(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Cc1sc(-c2ccccc2)nc1C(=O)OC(C)(C)C
Yield: 62.1 %

Procedure:
A solution of tert-butyl 2-benzamido-3-oxobutanoate (842 mg, 3.04 mmol) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson's reagent) (1.88 g 6.07 mmol) in THF (20 ml) was heated at reflux for 6 h. The mixture was evaporated in vacuo and purified by flash chromatography to give tert-butyl 5-methyl-2-phenylthiazole-4-carboxylate as a yellow solid (520 mg, 62% yield).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11](Cl)=[O:12].[NH2:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[C:17]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[N:16]=1>C(Cl)Cl>[NH2:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[C:17]([N:29]2[CH2:34][CH2:33][N:32]([C:11]([CH:2]3[CH2:3][CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[O:1]3)=[O:12])[CH2:31][CH2:30]2)[N:16]=1
Reactant: O=C(Cl)C1CCc2ccccc2O1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: ClCCl
Product: COc1cc2nc(N3CCN(C(=O)C4CCc5ccccc5O4)CC3)nc(N)c2cc1OC
Temperature: 20 °C
Reaction time: 16 h
Yield: 29.2 %

Procedure:
A solution consisting of chroman-2-carbonyl chloride (1.13 g.) in dry methylene chloride (20 ml.) was added dropwise to a stirred suspension of 4-amino-6,7-dimethoxy-2-piperazinoquinazoline (1.38 g.) in dry methylene chloride (30 ml.) with ice bath cooling. The resulting reaction mixture was then stirred at room temperature (20° C.) overnight (approximately 16 hours), and the solid product so obtained was subsequently partitioned between aqueous sodium carbonate solution (30 ml., 1.0 N) and chloroform (220 ml.). The chloroform layer which separated was subsequently evaporated in vacuo and the resulting residue (2.5 g.) was thereafter chromatographed on silica gel (100 g.), eluting first with chloroform (200 ml.) and then with chloroform-methanol (800 ml., 97.5:2.5 parts by volume). The appropriate fractions were then collected and subsequently combined and evaporated in vacuo, and the resulting final product thereafter recrystallized from ethyl acetate to give pure 4-amino-2-[4-(chroman-2-carbonyl)piperazino]-6,7-dimethoxyquinazoline (yield, 625 mg.), m.p. 165°-167° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[C:11]([Cl:12])=[C:10]([NH:13][CH2:14][CH2:15][OH:16])[C:9]([Cl:17])=[C:8]([Cl:18])[N:7]=1>C(O)(=O)C>[Cl:5][C:6]1[C:11]([Cl:12])=[C:10]([NH:13][CH2:14][CH2:15][O:16][C:1](=[O:3])[CH3:2])[C:9]([Cl:17])=[C:8]([Cl:18])[N:7]=1
Reactant: CC(=O)Cl
Reactant: OCCNc1c(Cl)c(Cl)nc(Cl)c1Cl
Solvent: CC(=O)O
Product: CC(=O)OCCNc1c(Cl)c(Cl)nc(Cl)c1Cl
Temperature: 40 °C
Yield: 92.7 %

Procedure:
A solution of 34.4 ml (490 mmol) acetyl chloride in 250 ml glacial acetic acid was added dropwise to a suspension of 105 g (380 mmol) 2-(2,3,5,6-tetrachloropyridin-4-ylamino)-ethanol in 860 ml glacial acetic acid. During this the temperature increased to 40° C. After 2 h it was poured onto ice water, filtered, washed with water, the residue was dissolved in 500 ml ethyl acetate, dried over sodium sulfate, filtered and the solvent was removed in a vacuum. 112 g (93%) acetic acid-2(2,3,5,6-tetrachloropyridin-4-ylamino)-ethyl ester was obtained and was reacted without further purification. MS (m/e)=316.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]2([CH3:15])[CH:6]1[CH2:7][CH2:8][C:9]2=[O:16])[CH:2]=C.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:26].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:15][C:10]12[C:9](=[O:16])[CH2:8][CH2:7][CH:6]1[CH:5]([O:4][CH2:1][CH:2]=[O:26])[C:13](=[O:14])[CH2:12][CH2:11]2
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCOC1C(=O)CCC2(C)C(=O)CCC12
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Solvent: O
Product: CC12CCC(=O)C(OCC=O)C1CCC2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A commercial 4% w/w solution of osmium tetraoxide (10 mL, 0.82 mmol, 0.005 eq) was added to a stirred mixture of 4-allyloxy-7a-methyl-hexahydro-indene-1,5-dione (36.4 g, 164 mmol), 2,6-lutidine (57.2 mL, 246 mmol, 1.5 eq) and sodium periodate (210.6 g, 492 mmol, 3 eq) in dioxane (900 mL) and water (300 mL) at 0° C. The reaction mixture was then allowed to warm slowly to room temperature, and stirred for 24 h. The reaction mixture was cooled to 0° C., and then filtered through a fritted funnel. DCM (1 L) was used to wash to salt cake, and the filtrate was used to extract the separated aqueous solution (4×250 mL). The combined organic layer was dried with magnesium sulfate. The resulting mixture was filtered, condensed and the resulting residue purified by flash chromatography using 20-90% ethyl acetate in hexane yield the title compound as a light yellow foam.
Reaction SMILES: [CH2:1]([OH:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1>[C:11]([O:10][CH2:1]/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC/C=C/CO
Solvent: c1ccncc1
Product: CCCCCC/C=C/COC(C)=O

Procedure:
Pyridine (100 ml) and trans-2-nonen-1-ol (28.4 g, 0.2 mole) are heated to 110°C and acetic anhydride (30.6 g, 0.3 mole) is added dropwise. The reaction mixture is maintained at 110°-115° for 2 hours and 120°-125°C for 3 hours. The mixture is cooled and washed with water, 5% sulfuric acid, and finally water. The solution is dried over sodium sulfate. Trans-2-nonenyl acetate, 33.0 g is obtained by vacuum distillation, b.p. 70°-5°C/50-55 mm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:9][OH:10])N)=[N:4][O:5][N:6]=1.[ClH:11].[Cl-].[Na+].N([O-])=O.[Na+]>O.C(O)(=O)C>[NH2:1][C:2]1[C:3]([C:7]([Cl:11])=[N:9][OH:10])=[N:4][O:5][N:6]=1
Reactant: Cl
Reactant: NC(=NO)c1nonc1N
Agent: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nonc1C(Cl)=NO
Temperature: 43.5 °C
Yield: 53.4 %

Procedure:
4-Amino-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (422 g, 2.95 mol) was added to a mixture of water (5.9 L), acetic acid (3 L) and 6 N hydrochloric acid (1.475 L, 3 eq.) and this suspension was stirred at 42-45° C. until complete solution was achieved. Sodium chloride (518 g, 3 eq.) was added and this solution was stirred in an ice/water/methanol bath. A solution of sodium nitrite (199.5 g, 0.98 eq.) in water (700 mL) was added over 3.5 hrs while maintaining the temperature below 0° C. After complete addition stirring was continued in the ice bath for 1.5 hrs and then the reaction mixture was allowed to warm to 15° C. The precipitate was collected by filtration, washed well with water, taken in ethyl acetate (3.4 L), treated with anhydrous sodium sulfate (500 g) and stirred for 1 hr. This suspension was filtered through sodium sulfate (200 g) and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in methyl t-butyl ether (5.5 L), treated with charcoal (40 g), stirred for 40 min and filtered through Celite. The solvent was removed in a rotary evaporator and the resulting product was dried in a vacuum oven (45° C.) to give the desired product (256 g, 53.4%). LCMS for C3H4ClN4O2 (M+H)+: m/z=162.9. 13C NMR (100 MHz, CD3OD): δ 155.8, 143.4, 129.7.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)[CH:13]=1
Reactant: Brc1cccnc1
Reactant: Cc1ccc(B(O)O)cc1
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+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2cccnc2)cc1
Yield: 88.6 %

Procedure:
To a mixture of 4-tolylboronic acid (38 g, 0.28 mol), 3-bromopyridine (44 g, 0.28 mol), Na2CO3 (200 g) in toluene (500 ml) and water (500 ml) was added Pd(PPh3)4 (16 g, 0.014 mol), and refluxed for 16 h. The reaction mixture was cooled, and the separated organic layer was washed with water and brine, and dried. The solvent was removed to give 4-(3-pyridyl)toluene (42 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:29][C:30]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30](=[O:31])[N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)N1CCCCC1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C1OC2(CCN(C(=O)c3cn(CC(=O)N4CCCCC4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure V as described hereinabove, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (the preparation of which has been described in example 16) with commercially available 2-chloro-1-piperidin-1-yl-ethanone as electrophile, the title compound was obtained as a white powder.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[S:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[CH:33]=[C:32]1[S:40](Cl)(=[O:42])=[O:41]>O1CCCC1.[Cl-].[Na+].O>[S:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[CH:33]=[C:32]1[S:40]([N:11]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:9]([CH:12]=[O:13])=[CH:10]1)(=[O:42])=[O:41]
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cc3ccccc3s2)c1
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To a solution (10 mL) of 5-phenyl-1H-pyrrole-3-carbaldehyde (100 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 47 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (257 mg) was added dropwise and the mixture was stirred for 30 min, 2-benzothiophenesulfonyl chloride (204 mg) was added, and the mixture was further stirred for 1 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→3:2) to give the title compound as a colorless oil (yield 180 mg, 84%).
Reaction SMILES: [N:1]1([C:5]([C:7]2[O:8][C:9]3[C:15]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.Br[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:1]1([C:5]([C:7]2[O:8][C:9]3[C:15]([N:16]4[CH2:17][CH2:18][N:19]([CH2:23][CH2:24][C:25]5[CH:26]=[C:27]6[C:31](=[CH:32][CH:33]=5)[N:30]([C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]6)[CH2:20][CH2:21]4)=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)N1CCc2cc(CCBr)ccc21
Reactant: O=C(c1cc2cccc(N3CCNCC3)c2o1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)N1CCc2cc(CCN3CCN(c4cccc5cc(C(=O)N6CCC6)oc45)CC3)ccc21
Temperature: 120 °C

Procedure:
The reaction mixture of azetidin-1-yl(7-(piperazin-1-yl)benzofuran-2-yl)methanone (0.070 g, 0.25 mmol) (Example 45c), 1-(5-(2-bromoethyl)indolin-1-yl)ethanone (0.099 g, 0.37 mmol) and potassium carbonate (0.068 g, 0.49 mmol) in acetonitrile (1 mL) was heated by microwave irradiation at 120° C. for 15 min. The mixture was cooled and the solvent was removed in vacuo. The product was purified by flash chromatography (SiO2; DCM/MeOH; gradient 0-5%) to give the title compound. Yield: 0.056 g (48%).
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[F:14][C:15]1[CH:16]=[C:17]([CH:29]=[CH:30][CH:31]=1)[CH2:18][C:19]1[S:23][C:22]([CH:24]2OCC[O:25]2)=[CH:21][CH:20]=1.O.C(OCC)(=O)C>CO>[F:14][C:15]1[CH:16]=[C:17]([CH:29]=[CH:30][CH:31]=1)[CH2:18][C:19]1[S:23][C:22]([CH:24]=[O:25])=[CH:21][CH:20]=1
Reactant: Fc1cccc(Cc2ccc(C3OCCO3)s2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Cc2cccc(F)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
An aqueous solution of saturated citric acid (20 mL) was added to a solution of 2-(5-(3-fluoro-benzyl)thiophen-2-yl)-[1,3]dioxolane described in Preparation Example 52 (670 mg, 2.53 mmol) in methanol (20 mL), and the solution was stirred at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction solution, which was then partitioned, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, and the title compound (485 mg, 2.2 mmol, 87.0%) was obtained as a brown oil.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:37])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[N:26]=[CH:25]3)=[C:13](\[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[CH2:14][CH3:15])=[CH:8][CH:7]=1.C(C(CCCC)[CH2:41][O:42]C(Cl)=O)C.N1C=CC=CC=1>CN(C=O)C>[C:16]1(/[C:13](/[CH2:14][CH3:15])=[C:12](\[C:9]2[CH:8]=[CH:7][C:6](/[CH:5]=[CH:4]/[C:3]3[NH:37][C:41](=[O:42])[O:1][N:2]=3)=[CH:11][CH:10]=2)/[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[N:26]=[CH:25]3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC/C(=C(/c1ccc(/C=C/C(N)=N/O)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1
Reactant: CCCCC(CC)COC(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC/C(=C(/c1ccc(/C=C/c2noc(=O)[nH]2)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
To a solution of (1Z,2E)-N′-hydroxy-3-(4-((E)-2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylimidamide (51 mg, 0.1 mmol) in anhydrous DMF (0.4 mL) was added 2-ethylhexylchloroformate (20 μL, 0.1 mmol) followed by pyridine (9 μL, 0.11 mmol). The reaction mixture was stirred at 0° C. for 1 h and then partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (2×), and the combined organics were dried over MgSO4 and concentrated. The residue was dissolved in xylenes (1 mL), heated at 130° C. for 2 h, and then concentrated to afford 25 mg of the title compound. LCMS: 519 (M+H)+.
Reaction SMILES: C([O:8][C:9]([C:11]1([C:42]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[O:43])[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:28]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[C:31]([F:41])[CH:30]=4)[O:26][N:25]=3)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1>C(OCC)(=O)C.O1CCCC1.C(O)C.[Pd]>[F:41][C:31]1[CH:30]=[C:29]([C:27]2[O:26][N:25]=[C:24]([C:21]3[CH:20]=[CH:19][C:18]([CH2:17][N:14]4[CH2:13][CH2:12][C:11]([C:42]([N:44]5[CH2:45][CH2:46][O:47][CH2:48][CH2:49]5)=[O:43])([C:9]([OH:10])=[O:8])[CH2:16][CH2:15]4)=[CH:23][CH:22]=3)[N:28]=2)[CH:34]=[CH:33][C:32]=1[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(OCc1ccccc1)C1(C(=O)N2CCOCC2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)C1(C(=O)N2CCOCC2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pd/C (0.13 g) is added to a solution of 1-{4-[5-(2-fluoro-biphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]-benzyl}-4-(morpholine-4-carbonyl)-piperidine-4-carboxylic acid benzyl ester (0.43 g, 0.0006 mol) in a mixture of ethyl acetate:tetrahydrofuran:ethanol (3:2:3, 45 mL). Hydrogen gas is bubbled through the reaction mixture under stirring at room temperature for 2 hrs. The reaction mixture is filtered through a celite bed, washed with MDC:MeOH (80:20, 100 mL) and the filtrate is concentrated under reduced pressure to get solid mass, which is purified by column chromatography (silica gel 230-400 mesh, MDC:MeOH 8:2) to get 1-{4-[5-(2-fluoro-biphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]-benzyl}-4-(morpholine-4-carbonyl)-piperidine-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:3]=1[F:21].C(N(C(C)C)CC)(C)C.C(OCC)C.[S:36](Cl)(Cl)=O>C1(C)C=CC=CC=1>[F:21][C:3]1[C:2]2[C:11](=[N:12][S:36][N:1]=2)[CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: COC(=O)c1cc(N)c(N)c(F)c1Nc1ccccc1C
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2nsnc2c(F)c1Nc1ccccc1C

Procedure:
To a stirring solution comprised of methyl 4,5-diamino-3-fluoro-2-(2-methyl-phenylamino)-benzoate (from Step e, Example 1) and diisopropylethylamine (2 equiv.) in an appropriate solvent like diethyl ether or toluene is added a reagent like N-thioaniline or thionyl chloride (1.35 equiv.). The reaction mixture is brought to reflux for one hour. The mixture is quenched with dilute aqueous hydrochloric acid. The organic phase is washed with saturated aqueous sodium bicarbonate and brine, is dried (MgSO4), and is concentrated in vacuo to afford the desired product. The product may be recrystallized with an appropriate solvent like chloroform or ethanol, or may be chromatographed if further purification is necessary.