Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH:5]=[N:4][C:3]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C([Sn](CCCC)(CCCC)[C:25]1[O:29][C:28]([Si](C(C)C)(C(C)C)C(C)C)=[N:27][CH:26]=1)CCC>C1(C)C(C)=CC=CC=1.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>[O:29]1[C:25]([C:2]2[N:7]=[C:6]([NH:8][C:9]([CH:11]3[CH2:13][CH2:12]3)=[O:10])[CH:5]=[N:4][C:3]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:26][N:27]=[CH:28]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc([Si](C(C)C)(C(C)C)C(C)C)o1
Reactant: O=C(Nc1cnc(-c2ccncc2)c(Cl)n1)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: O=C(Nc1cnc(-c2ccncc2)c(-c2cnco2)n1)C1CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
A mixture of N-(6-chloro-5-pyridin-4-ylpyrazin-2-yl)cyclopropanecarboxamide (100 mg, 0.36 mmol) and 5-(tributylstannyl)-2-(triisopropylsilyl)-1,3-oxazole (397 mg, 0.73 mmol) in xylene (3 mL) was degassed with argon. The catalyst Pd(PPh3)4 (25 mg, 0.022 mmol, 6 mol %) was added and degassing was repeated. The mixture was heated to 90° C. in a sealed tube and stirred overnight. The mixture was cooled and ethyl acetate and HCl 2N were added. The aqueous layer was washed with ethyl acetate and then neutralized with 6N NaOH. The cloudy solution was extracted with CH2Cl2. The organic layer was dried and concentrated. The residue was purified by flash silica gel chromatography (dichloromethane/methanol 95:5) to give the title compound (36 mg, 35%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2(O)[CH2:12][C:13](=[O:15])[CH3:14].C(OCC)(=O)C.O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:12][CH:13]([OH:15])[CH3:14]
Reactant: CC(=O)CC1(O)C(=O)Nc2ccc(F)cc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(O)Cc1c[nH]c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The aldol product 48 (10 mmol) was dissolved in absolute THF (20 ml) under an Ar atmosphere. BH3xTHF (30 ml, 1 M solution, 30 mmol) was then added to the mixture, while cooling with a water bath, and the mixture was stirred at room temperature for 4 h. The course of the reaction was monitored by TLC. When the reaction had ended, the reaction solution was added to a mixture of ethyl acetate (50 ml) and H2O (50 ml). After separation of the phases, the aqueous phase was extracted twice with ethyl acetate (30 ml each time). The combined organic phases were dried over Na2SO4 and concentrated under vacuo. The residue was filtered over silica gel with ethyl acetate. After removal of the solvent, the product was obtained in the form of a sufficiently pure oil and crystallizes spontaneously.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:9][C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:15]([CH:19]=1)[C:16](O)=[O:17])[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:68][C:69]([CH3:73])([CH3:72])[CH2:70][OH:71]>CN(C=O)C>[CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:9][C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:15]([CH:19]=1)[C:16]([NH:68][C:69]([CH3:73])([CH3:72])[CH2:70][OH:71])=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(=O)O)c1
Reactant: CC(C)(N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(=O)NC(C)(C)CO)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.2 %

Procedure:
To a solution of 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzoic acid (0.203 mmol, 94.9 mg), HBTU (0.203 mmol, 79.3 mg), diisopropyl ethyl amine (0.34 mmol, 0.0592 mL) in DMF (1 mL) was added 2-amino-2-methyl-propan-1-ol (0.45 mmol, 42.2 mg). It was stirred at room temperature for 20 min. The reaction mixture was partitioned between ethyl acetate (12 mL) and saturated aq. sodium bicarbonate solution (12 mL). The ethyl acetate layer was washed again with saturated aq. sodium bicarbonate solution (2×12 mL) and dried over sodium sulfate. The organic solvents were removed in vacuo to give 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzamide (87.7 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[N:6][CH:7]=1.[Cl:20][C:21]1[C:22](F)=[N:23][CH:24]=[C:25]([O:27][CH2:28][CH:29](OCC)OCC)[CH:26]=1.[CH3:37][NH:38][CH3:39].O1CCCC1>>[Cl:20][C:21]1[C:22]([O:19][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[CH:11][N:10]=[C:9]3[NH:8][C:5]2[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=2)=[N:23][CH:24]=[C:25]([O:27][CH2:28][CH2:29][N:38]([CH3:39])[CH3:37])[CH:26]=1
Reactant: Cc1cnc(Nc2ncnc3ccc(O)cc23)cn1
Reactant: CNC
Reactant: CCOC(COc1cnc(F)c(Cl)c1)OCC
Solvent: C1CCOC1
Product: Cc1cnc(Nc2ncnc3ccc(Oc4ncc(OCCN(C)C)cc4Cl)cc23)cn1

Procedure:
Using 4-[(5-methylpyrazin-2-yl)amino]quinazolin-6-ol, 3-chloro-5-(2,2-diethoxyethoxy)-2-fluoropyridine and 2 M dimethylamine/tetrahydrofuran solution, and in the same manner as in Example 32 or according to a method similar to it or according to a combination thereof with an ordinary method, the entitled compound (14 mg) was obtained as a pale yellow amorphous solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH2:24][CH2:25][C:26](=[O:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Na+].[Cl-].[Na+]>CCOCC>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH2:24][CH2:25][CH:26]([OH:28])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCC(C)(C)c1ccc(CCC(C)=O)c(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1ccc(CCC(C)O)c(OCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a -15° C. solution of 0.5 g. (1.31 mmols.) of 4-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-butanone in 5 ml. of methanol was added 50 mg. (1.31 mmols.) of sodium borohydride. The reaction mixture was stirred for 30 minutes and then added to 100 ml. of saturated sodium chloride 150 ml. ether. The ether extract was washed once with 100 ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated in an oil. The oil was purified via column chromatography on 100 g. of silica gel eluted with 1:1 ether:cyclohexane to yield 419 mg. (84%) of the title compound as an oil.
Reaction SMILES: C1C2C(C[O:15][C:16]([N:18]([CH2:34][C:35]3[N:39](C)[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH2:19][CH2:20][NH:21][C@@H:22]([C@@H:30]([CH3:33])[CH2:31][CH3:32])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=O)C3C(=CC=CC=3)C=2C=CC=1.[CH2:45](NCC)C.[N+](C1C=CC(OC(=O)OC2C=CC([N+]([O-])=O)=CC=2)=CC=1)([O-])=O>CN(C)C=O.ClCCCl>[CH3:33][C@@H:30]([CH2:31][CH3:32])[C@H:22]([N:21]1[CH2:20][CH2:19][N:18]([CH2:34][C:35]2[N:39]([CH3:45])[C:38]3[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=3[N:36]=2)[C:16]1=[O:15])[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24]
Reactant: CC[C@H](C)[C@H](NCCN(Cc1nc2ccccc2n1C)C(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Reactant: CCNCC
Agent: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CCN(Cc2nc3ccccc3n2C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A solution of the product of Example 96A (0.81 mmol) in N,N-dimethylformamide (5 mL) was treated with diethylamine (0.8 mL), stirred at 25° C. for 2 hours and concentrated. A solution of the residue in 1,2-dichloroethane (16 mL) was treated with bis-(p-nitrophenyl)carbonate (0.296 g, 0.973 mmol), stirred at 60° C. for 16 hours and concentrated. The residue was chromatographed on silica gel, eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.192 g, 59% yield).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:11])[CH3:10]>CN(C=O)C.C(Cl)Cl>[C:9]([C:12]1[C:13]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:14][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:16]([Br:1])[CH:17]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(C(C)=O)c(OCc2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)Nc1cc(OCc2ccccc2)c(C(C)=O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
N-Bromosuccinimide (0.756 g, 4.27 mmol) was added portionwise to a solution of N-(4-acetyl-3-benzyloxy-phenyl)-acetamide (1.2 g, 4.24 mmol) in DMF (24 ml) and the reaction stirred overnight at room temperature. The reaction mixture was diluted with DCM, washed with water and dried over MgSO4 to afford a white solid (1.03 g, 67%). LC/MS: RT=2.609 min. 362/364 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[NH:27]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]1>C(Cl)Cl.CO>[CH3:16][C:11]1([CH3:17])[C:12]([CH3:15])([CH3:14])[O:13][B:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:27]3[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]3)=[CH:4][CH:5]=2)[O:10]1
Reactant: O=S1(=O)CCNCC1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CC1(C)OB(c2ccc(CN3CCS(=O)(=O)CC3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1 eq) and DIPEA (2 eq) were dissolved in DCM/MeOH (5:1 v:v) under N2 and thiomorpholine 1,1-dioxide (2 eq) was added portion wise. The resulting solution was stirred at room temperature for 16 h. After this time, the reaction was complete. The solvent was evaporated. The compound was extracted with EtOAc and water, washed with brine and dried over anhydrous MgSO4. Organic layers were filtered and evaporated. The final compound was isolated without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][CH:28]1[C:34](=[NH:36])[NH2:35]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:24][N:36]=[C:34]([C:28]4[CH:29]=[CH:30][CH:31]=[C:32]([CH3:33])[N:27]=4)[N:35]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: CC1=CC=CC(C(=N)N)N1O
Product: CCc1ccc(C2CC(c3nc(-c4cccc(C)n4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 33 mg (0.22 mmol, 1.1 eq.) of 1-hydroxy-6-methylpyridine-2-carboximidamide were reacted according to the General Method 1. Yield: 44 mg (47% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:4]=1[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:6].Br[C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH3:36][C:30]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][NH:7][C:5](=[O:6])[C:4]3[C:23]([O:27][CH3:28])=[CH:24][CH:25]=[CH:26][C:3]=3[O:2][CH3:1])=[CH:15][CH:14]=2)=[CH:17][CH:18]=1)([CH3:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: COc1cccc(OC)c1C(=O)NCCc1ccc(-c2ccc(O)cc2)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)c3c(OC)cccc3OC)cc2)cc1
Yield: 20 %

Procedure:
Ethyl 2-methyl-2-{4-[2-(2,6-dimethoxy-benzamido)-ethyl]-biphenyl-4'-oxy]-propionate was prepared from 4-[2-(2,6-dimethoxy-benzamido)-ethyl]-4'-hydroxy-biphenyl and ethyl 2-bromo-2-methyl-propionate analogous to Example 31. Yield: 20% of theory; m.p. < 20° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[C:31](=[O:35])[N:30]([C@@:36]1([CH3:44])[CH2:41][CH2:40][C:39](=[O:42])[NH:38][C:37]1=[O:43])[C:29]2=[O:45].CC#N>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:24][CH2:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[C:31](=[O:35])[N:30]([C@@:36]2([CH3:44])[CH2:41][CH2:40][C:39](=[O:42])[NH:38][C:37]2=[O:43])[C:29]3=[O:45])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: C[C@]1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: C[C@]1(N2C(=O)c3ccc(CNC(=O)c4ccc(Br)cn4)cc3C2=O)CCC(=O)NC1=O
Temperature: 40 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
A mixture of 5-bromopicolinic acid (0.40 g, 2.0 mmol) and CDI (0.36 g, 2.2 mmol) in DMF (20 mL) was stirred under nitrogen at 40° C. for 2 hours. Then, 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidin-3-yl]-isoindole-1,3-dione hydrochloride (0.67 g, 2.0 mmol) was added, and the mixture was stirred at this temperature for an additional 2 hours. The mixture was cooled to room temperature, and the solvent was evaporated under vacuum. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (2×100 mL). The organic phase was evaporated. The residue was chromatographed on silica gel using methylene chloride as the mobile phase. A pale red solid was obtained; this material was triturated in 10 mL of acetonitrile for 16 hours. The solid was filtered and washed with an additional 7 mL of acetonitrile. The product was dried under vacuum, providing 0.55 g (57% yield) as a white solid; mp 260-262° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 45/55 CH3CN/0.1% H3PO4, 3.61 (96.62%); 1H NMR (DMSO-d6) δ 1.88 (s, 3H), 2.00-2.08 (m, 1H), 2.49-2.62 (m, 2H), 2.65-2.73 (m, 1H), 4.62 (d, J=6.3 Hz, 2H), 7.76-7.82 (m, 3H), 7.97 (dd, J=8.4 Hz, J=0.6 Hz, 1H), 8.26 (dd, J=8.4 Hz, J=2.3 Hz, 1H), 8.81 (dd, J=2.3 Hz, J=0.6 Hz, 1H), 9.63 (t, J=6.3 Hz, 1H), 11.00 (s, 1H); 13C NMR (DMSO-d6) δ 21.0, 28.5, 29.1, 42.4, 58.7, 121.8, 123.1, 123.5, 123.9, 129.6, 131.3, 133.6, 140.5, 147.1, 148.5, 149.3, 163.5, 167.7, 167.8, 172.0, 172.1; Anal. Calcd for C21H17BrN4O5: C, 51.97; H, 3.53; N, 11.55. Found: C, 52.05; H, 3.44; N, 11.39.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=1>CC(N(C)C)=O.O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=2)=[CH:3][C:2]=1[NH2:1]
Reactant: Nc1cc(O)ccc1F
Reactant: CSc1nccc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CSc1nccc(Oc2ccc(F)c(N)c2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
In DMA (10 mL) was placed 3-amino-4-fluorophenol (500 mg, 3.93 mmol), potassium t-butoxide (441 mg, 3.93 mmol) and 4-chloro-2-(methylthio)pyrimidine (632 mg, 3.93 mmol). The mixture was warmed to 50° C. and stirred overnight. The mixture was cooled to RT and diluted with water (30 mL), extracted with ethyl acetate (2×25 mL) and the combined organic phases washed with brine, dried (Na2SO4) and concentrated to yield a dark oil. The oil was purified by column chromatography to yield 2-fluoro-5-(2-(methylthio)pyrimidin-4-yloxy)benzenamine (841 mg, 85% yield) as an oil which was used without further purification. MS (ESI) m/z: 252.0 (M+H+).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([O:19][CH3:20])=[CH:9][CH:10]=[C:11]3[C:16]=2[O:15][C:14](=[O:17])[CH:13]=[C:12]3O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:41]>C(Cl)(Cl)Cl>[Cl:41][C:12]1[C:11]2[C:16](=[C:7]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]([O:19][CH3:20])=[CH:9][CH:10]=2)[O:15][C:14](=[O:17])[CH:13]=1
Reactant: COc1ccc2c(O)cc(=O)oc2c1OC1CCCC1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(Cl)cc(=O)oc2c1OC1CCCC1
Temperature: 80 °C

Procedure:
A mixture of 8-(cyclopentyloxy)-4-hydroxy-7-methoxy-2H-chromen-2-one (415 mg, 1.5 mmol, Example 1, Step 2), triphenylphosphine (787 mg, 3.0 mmol), CCl4 (0.75 mL, 7.8 mmol), and chloroform (2 mL) was heated at 80° C. in a sealed vial for 4.5 h and then allowed to cool to rt. The reaction was concentrated and purified by silica gel chromatography (1:0→4:1; hexanes:ethyl acetate) to give 4-chloro-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one: MS (ESI): 294.8.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][CH2:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[CH:10][CH:9]=1)[CH3:5].I[CH:18]([CH3:20])[CH3:19]>CN(C=O)C>[NH3:4].[CH3:3][N:4]([CH2:6][CH2:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][N:14]2[CH:18]([CH3:20])[CH3:19])=[CH:10][CH:9]=1)[CH3:5]
Reactant: CC(C)I
Reactant: CN(C)CCc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1ccc2ccc(CCN(C)C)cc21
Product: N
Temperature: 0 °C
Reaction time: 1 h
Yield: 32.8 %
Yield: 7 %

Procedure:
Sodium hydride (12.7 mg, 0.531 mmol) was added to an ice-cooled solution 6-(2-(N,N-Dimethylamino)ethyl)-1H-indole (50 mg, 0.265 mmol) in DMF (1 ml). After stirring for 1 h at 0° C., 2-iodopropane (52.9 μL, 0.530 mmol) was added and the mixture stirred at 100° C. overnight. The reaction mixture was then partitioned between water and dichloromethane, the organic layer washed sequentially with water and brine, dried over sodium sulfate and the solvent was removed in vacuo. Flash chromatography (silica gel, 7% methanolic ammonia in dichloromethane) gave the title product (10 mg, 16%).
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([NH2:18])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH2:33][C:34](O)=[O:35])[CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:20]>>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH2:33][C:34]([NH:18][CH:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:35])[CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:20]
Reactant: NC(CC1CC1)c1ccccc1N1CCCCC1
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Product: CCOC(=O)c1ccc(CC(=O)NC(CC2CC2)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
Prepared analogously to Example 47 from α-cyclopropylmethyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[O:6][CH:7]([CH3:11])[C:8]([OH:10])=O)([O-:3])=[O:2].[N+]([O-])(O)=O.[O:20]([CH2:24][CH2:25][NH2:26])[N+:21]([O-:23])=[O:22].C(OC(C)C)(C)C>>[O:20]([CH2:24][CH2:25][NH:26][C:8](=[O:10])[CH:7]([O:6][C:5]1[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:11])[N+:21]([O-:23])=[O:22]
Reactant: NCCO[N+](=O)[O-]
Reactant: CC(Oc1ccccc1[N+](=O)[O-])C(=O)O
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: CC(Oc1ccccc1[N+](=O)[O-])C(=O)NCCO[N+](=O)[O-]
Yield: 42.4 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.75 g of 2-(2-nitrophenoxy)propionic acid and 0.6 g of 2-nitroxyethylamine nitrate, 0.45 g of the title compound was obtained as pale yellow needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([C:20]3[NH:21][C:22]([C:25]4[S:26][CH:27]=[CH:28][N:29]=4)=[CH:23][CH:24]=3)[CH:17]=[C:16]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:15]=2)=[C:9]([F:36])[CH:8]=1)(=O)[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:47]2)=CC=1.N1C=CC=CC=1>C1(C)C=CC=CC=1.C(#N)C>[F:36][C:9]1[CH:8]=[C:7]([C:6]2[S:47][C:1]([CH3:2])=[N:4][N:5]=2)[CH:12]=[CH:11][C:10]=1[O:13][C:14]1[CH:19]=[C:18]([C:20]2[NH:21][C:22]([C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[CH:23][CH:24]=2)[CH:17]=[C:16]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:15]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)NNC(C)=O)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC[C@H](C)Oc1cc(Oc2ccc(-c3nnc(C)s3)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 70.5 %

Procedure:
N′-Acetyl-3-fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzohydrazide (40 mg, 0.076 mmol) synthesized in Example (49a) was dissolved in a mixed solvent of toluene (4.0 mL) and acetonitrile (2.0 mL), and 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (45 mg, 0.111 mmol) and pyridine (0.03 mL, 0.372 mmol) were added, followed by stirring at 100° C. for 4 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-80%) to afford the desired compound (28 mg, yield 70%) as a yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:4]=1[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1)=[O:6].CNCCCCCC.Cl.O>CS(C)=O>[CH3:23][O:22][C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:4]([C:5]([NH:7][C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)=[O:6])=[C:3]([OH:2])[CH:21]=1
Reactant: CCOC(=O)c1csc(NC(=O)c2cc(OC)c(OC)cc2OC)n1
Agent: CCCCCCNC
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1csc(NC(=O)c2cc(OC)c(OC)cc2O)n1
Temperature: 0 °C
Yield: 72.8 %

Procedure:
A suspension (6 ml) of 2-[N-(2,4,5-trimethoxybenzoyl)amino]-4-(ethoxycarbonyl)-1,3-thiazole (3.0 g) in dimethyl sulfoxide was dissolved with heat, and N-methyl-N-hexylamine (2.3 g) was added dropwise to the solution, refluxed for 2 hours. The reaction mixture was allowed to cool, poured into a mixture of 1 N hydrochloric acid (30 ml) and ice water (30 ml), and further, water was added thereto. Crystals so precipitated were collected by filtration, washed with water, and air-dried to thereby obtain crude crystals. The crystals were followed by recrystallization from 1,4-dioxane, 2.1 g of 2-[N-(4,5-dimethoxy-2-hydroxybenzoyl)amino]-4-(ethoxycarbonyl)-1,3-thiazole was obtained (yield: 64.6%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1)=[O:3].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:13]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[O:11][CH3:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
A solution of 4-hydroxy-3-methoxyacetophenone (40 g, 240 mmol), benzyl bromide (31.4 mL, 260 mmol) and potassium carbonate (99.6 g, 360 mmol) in DMF (800 mL) was heated to 40° C. overnight. The solution was cooled to room temperature, poured over ice and the resultant solid was filtered. This material was washed with water and dried to give 1-(4-benzyloxy-3-methoxyphenyl)ethanone (61 g, 99%).