Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:11])[CH2:8][CH2:9][NH2:10].C1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([NH:10][CH2:9][CH2:8][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])(=[O:26])[CH3:25]
Reactant: CC(CCN)c1ccccc1-c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)NCCC(C)c1ccccc1-c1ccccc1
Reaction time: 3 h

Procedure:
A mixture of 2.25 g of 3-p-biphenylyl-butylamine, 20 ml of benzene, 1 ml of pyridine and 1 ml of acetic anhydride is stirred for 3 hours at 25°. 1-Acetamido-3-p-biphenylylbutane is obtained after working up in the customary manner.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([OH:9])=O)[CH3:2].O[NH:17][C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23]2)=[NH:19].C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7]2[O:9][N:17]=[C:18]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23]4)[N:19]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: CCOc1ccc(C(=O)O)cc1OCC
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C(=N)NO)cc2C1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2nc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)C4)no2)cc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.6 %

Procedure:
A mixture of 3,4-diethoxybenzoic acid (0.19 g; 0.904 mmol), a product of Step D (0.25 g; 0.904 mmol) and EDC (0.27 g; 1.4 mmol) in anhydrous DMF (2 ml) was stirred at ˜60° C. for 1 h, then cooled to room temperature and diluted to 20 ml with EtOAc. This was washed with H2O (2×5 ml), brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness. The residue was diluted to 3 ml with anhydrous diglyme and 1M TBAF in THF (0.5 ml) was added and the resulting mixture was stirred at ˜80° C. for 1 h, then solvents were removed in vacuo. The residue was purified by crystallization from MeOH, to give the title compound (0.084 g; 20%) as greyish solid. 1H-NMR (CDCl3) 1.4-1.6 (m, 15H+H2O); 4.14-4.24 (m, 4H); 4.7-4.76 (m, 4H); 6.97 (d, 1H, J=6 Hz); 7.32-7.4 (m, 1H); 7.66 (d, 1H, J=3 Hz); 7.78 (dd, 1H, J=3, 9 Hz); 8.02-8.08 (m, 2H).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(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>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
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: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccccc2Cl)C1
Yield: 82.7 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 2-chlorophenylboronic acid (143 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml) and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) were stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (180 mg, 82.5%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:27]([CH3:30])([CH3:29])[OH:28])[CH:5]=[C:6]([O:25][CH3:26])[C:7]=1[O:8][C:9]1[C:14]([NH2:15])=[C:13]([NH:16][CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[N:12]=[C:11]([CH3:24])[N:10]=1.[N:31]([O-])=O.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:27]([CH3:30])([CH3:29])[OH:28])[CH:5]=[C:6]([O:25][CH3:26])[C:7]=1[O:8][C:9]1[C:14]2[N:15]=[N:31][N:16]([CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[C:13]=2[N:12]=[C:11]([CH3:24])[N:10]=1
Reactant: CCCC(CCC)Nc1nc(C)nc(Oc2c(Br)cc(C(C)(C)O)cc2OC)c1N
Reactant: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCCC(CCC)n1nnc2c(Oc3c(Br)cc(C(C)(C)O)cc3OC)nc(C)nc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-bromo-5-methoxy-α,α-dimethyl-4-[[5-amino-2-methyl-6-[(1-propylbutyl)amino]-4-pyrimidinyl]oxy]benzene-methanol (0.70 g) in 35 mL of glacial acetic acid, 0.10 g of sodium nitrite in 1 mL of water was added dropwise. The mixture was stirred at room temperature for 20 minutes and then diluted with water, basified with 1 N NaOH and extracted three times with ethyl acetate. The combined extracts were dried over MgSO4 and stripped of the solvent under reduced pressure to yield the title compound as viscous liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[C:32]1(B(O)O)[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(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>[CH2:1]([O:3][C:4](=[O:31])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:40]4[C:41]5[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH:37]=[CH:38][CH:39]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)[CH3:6])[CH3:2]
Reactant: OB(O)c1cccc2ccccc12
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)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: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cccc5ccccc45)cc3)oc2C)cc1
Temperature: 25 °C

Procedure:
A solution of 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl-propionic acid ethyl ester (0.907 mmol) (see Ex. 2, part B) and 1-naphthaleneboronic acid (0.998 mmol) in toluene:ethanol (18.2 mL of a 1:1 solution) was treated with Na2CO3 (aq) (0.906 mL of a 2M solution). A nitrogen atmosphere was applied, Pd(PPh3)4 (52.5 mg) was added, and the orange mixture was heated at reflux for 2 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate (20 mL) and H2O (30 mL). The layers were separated, and the aqueous phase was back-extracted with ethyl acetate (2×10 mL). Combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (20 g SiO2, 3:7 ethyl acetate:hexanes) to give the desired product in 87% as an orange oil; Rf=0.46 in 1:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ8.09 (d, J=8Hz, 2H), 7.92-7.82 (m, 3H), 7.59-7.40 (m, 6H), 6.81-6.72 (m, 4H), 4.22-4.17 (m, 4H), 2.98 (t, 2H), 2.38 (s, 3H), 1.46 (s, 6H), 1.22 (t, 3H); MS (EI) 536.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][CH:9]([CH2:12][OH:13])[CH2:10][O:11][C:3]=12.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:13][CH2:12][C@H:9]1[O:8][C:4]2=[N:5][CH:6]=[CH:7][C:2]([Br:1])=[C:3]2[O:11][CH2:10]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1COc2c(Br)ccnc2O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1COc2c(Br)ccnc2O1
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To a mixture of intermediate (42) (0.0014 mol) and triethylamine (0.0028 mol) in DCM (5 ml), methanesulfonyl chloride (0.0021 mol) was slowly added at room temperature. The reaction mixture was stirred for 16 hours and was then extracted with water. The separated organic layer was dried, filtered and the solvent was evaporated, yielding 0.42 g of (S)-8-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-3-methanol methanesulfonate (ester) (intermediate (43).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.C[Si](C)(C)[N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20].[CH:23]1[N:24]=[CH:25][N:26]2[CH2:31][CH2:30][CH2:29][C:28](=[O:32])[C:27]=12>O1CCCC1>[OH:32][C:28]1([CH:17]2[CH2:18][CH2:19][NH:15][C:16]2=[O:20])[CH2:29][CH2:30][CH2:31][N:26]2[CH:25]=[N:24][CH:23]=[C:27]12
Reactant: O=C1CCCn2cncc21
Reactant: C[Si](C)(C)N1CCCC1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C1NCCC1C1(O)CCCn2cncc21
Reaction time: 0.5 h

Procedure:
1.25 ml of n-butyllithium (1.6M in hexane) are added dropwise to a solution to 0.29 ml of diisopropylamine and 2 ml of tetrahydrofuran at −78° C. After 30 minutes, a solution, cooled to −78° C., of 0.31 g of 1-trimethylsilanylpyrrolidin-2-one and 5 ml of tetrahydrofuran is added dropwise. The mixture is stirred for a further 30 minutes and then a solution of 0.27 g of 6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one [426219-51-4] and 5 ml tetrahydrofuran is added dropwise. The reaction mixture is stirred at −78° C. for 1 hour and then at 0° C. for 2 hours. The mixture is quenched with saturated aqueous ammonium chloride solution/water (1:1), the tetrahydrofuran is evaporated, and the residue is extracted with dichloromethane (3×). The combined organic phases are dried with sodium sulphate and evaporated. The title compound is identified from the residue by flash chromatography (SiO2 60F) on the basis of the Rf.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:20]([NH:22][CH2:23][C:24]([N:26]([CH2:43][CH3:44])[C@H:27]([C:35]([NH:37][NH:38][C:39]([CH2:41][CH3:42])=[O:40])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])=[O:21])[CH2:15][CH2:16][S:17]([CH3:19])=[O:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O.N[C@H](C(O)=O)CCSC.N[C@H](C(O)=O)CC1C=CC(O)=CC=1>>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:20]([NH:22][CH2:23][C:24]([N:26]([CH2:43][CH3:44])[C@H:27]([C:35]([NH:37][NH:38][C:39]([CH2:41][CH3:42])=[O:40])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])=[O:21])[CH2:15][CH2:16][S:17]([CH3:19])=[O:18])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CCC(=O)NNC(=O)[C@H](Cc1ccccc1)N(CC)C(=O)CNC(=O)[C@@H](CCS(C)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: CSCC[C@H](N)C(=O)O
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCC(=O)NNC(=O)[C@H](Cc1ccccc1)N(CC)C(=O)CNC(=O)[C@@H](CCS(C)=O)NC(=O)[C@@H](N)Cc1ccc(O)cc1
Reaction time: 0.17 h

Procedure:
To 0.50 g of BOC-Tyr-(D)-Met(O)-Gly-EtPhe-NHNHCOCH2CH3 were added 0.5 ml of anisole and 5 ml of TFA, and the mixture was shaken for 10 minutes. The solvent was distilled off, and ether was added to recover by filtration the product in the form of powder. The product was subjected to ion exchange on Amberlite IRA 410 (acetic acid type), and then poured on a column (2.2×120 cm) of Cephadex LH-20. The elution was conducted with 0.1 N acetic acid, and the fractions of 300 to 350 ml were collected and lyophilized. Yield: 0.35 g [α]D24 +18.5° (c=0.49, MeOH), Rf2, 0.24. Amino Acid analysis (4% thioglycolic acid/6 N hydrochloric acid hydrolysis): Gly 1.00(1), Met 1.05(1), Tyr 0.97(1).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[O:3][C:4]1[CH:32]=[CH:31][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][NH:16][CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:11])=[CH:6][CH:5]=1.Cl[C:36]1[S:37][C:38]2[CH:43]=[N:42][NH:41][C:40](=[O:44])[C:39]=2[N:45]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[F:34][C:2]([F:1])([F:33])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:36]3[S:37][C:38]4[CH:43]=[N:42][NH:41][C:40](=[O:44])[C:39]=4[N:45]=3)[CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:11])=[CH:31][CH:32]=1
Reactant: O=c1[nH]ncc2sc(Cl)nc12
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CNCCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3c(=O)[nH]ncc3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
To a mixture of the compound (87 mg) obtained in Example 983, Step 2 and the compound (32 mg) obtained in Step 5 in isopropanol (0.9 ml) was added N,N-diisopropylethylamine (30 μl) at room temperature. After stirring overnight at room temperature, and the mixture was stirred with heating under reflux for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (methanol:chloroform=5:95) to give the title compound (84 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][N:11]=1.[N+](C1C=C[C:26]([O:29][P:30]([CH3:42])(=[S:41])OC2C=CC([N+]([O-])=O)=CC=2)=CC=1)([O-])=O.N12CCCN=C1CCCCC2.CO>ClCCl>[CH3:26][O:29][P:30]([CH3:42])(=[S:41])[O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Reactant: CP(=S)(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COP(C)(=S)Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.7 %

Procedure:
The compound methylphosphonothioic acid O-[3-(1H-indol-2-yl)-1H-indazol-5-yl]ester O-methyl ester is prepared according to procedure F using 200 mg of 3-(1H-indol-2-yl)-H-indazole-5-ol (intermediate B) in solution with 284 mg of methylphosphonothioic acid O,O—bis-(4-nitrophenyl)ester in 6 ml of dichloromethane (stabilized with amylene), to which 120 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in solution in 1 ml of dichloromethane are added. After stirring at ambient temperature for 4 h 30 min, 325 μl of methanol and 120 μl of DBU in solution in 1 ml of dichloromethane are added. The mixture is left at ambient temperature overnight and the solvent is then evaporated off and the crude is purified by flash chromatography on 35-70 μm silica, eluent: cyclohexane/ethyl acetate 90/10 to 50/50. The fractions obtained are concentrated and purified by preparative LC/MS to obtain 47.7 mg of methylphosphonothioic acid O-[3-(1H-indol-2-yl)-1H-indazol-5-yl]ester O-methyl ester.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl[CH:19]([OH:21])[CH3:20].[Cl:22]CCl>>[Cl:22][CH2:20][CH2:19][O:21][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: CC(O)Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
p-Toluenesulfonyl chloride (172 g, 0.884 mol) and pyridine (59 g, 0.75 mol) were added to 180 mL dichloromethane (DCM) in a 1 L round-bottom flask (RBF) which was placed in an ice bath for ca. 5 min. 1-Chloroethanol (40.3 g, 0.496 mol) was added slowly, and the RBF was taken out of the ice bath and left to stir at room temperature (r.t.) for 15 hrs. The reaction mixture was poured into a 1 L separatory funnel, washed twice with 300 mL water+50 mL pyridine, and again with 300 mL water+75 mL 36% wt aq. HCl (discarding the aqueous phase after each wash). Removal of the solvent at reduced pressure yielded analytically pure 1 as a faint yellow, thick syrup (116 g, 0.494 mol, 100% yield). 1H NMR: δ=7.81 (d, 2 aromatic H meta to CH3, J=8.3 Hz), 7.37 (d, 2 aromatic H ortho to CH3, J=8.3 Hz), 4.23 (t, OCH2, J=5.9 Hz), 3.66 (t, CH2Cl, J=5.9 Hz), 2.46 (s, CH3).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)=[CH:13][C:12]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:11][N:10]=2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[Na+].[Na+].[C:35]1([N:41]=[C:42]=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(#N)C>[Cl:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:14]1[C:9]([N:6]2[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:42]([NH:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:43])[CH2:8][CH2:7]2)=[N:10][CH:11]=[C:12]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:13]=1)=[O:24]
Reactant: O=C=Nc1ccccc1
Reactant: CS(=O)(=O)c1cnc(N2CCC(CN)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CS(=O)(=O)c1cnc(N2CCC(CNC(=O)Nc3ccccc3)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 0 %

Procedure:
To 0.028 g (0.066 mmol) of N-(4-aminomethyl-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl)-3-chloro-benzamide in a mixture of acetonitrile (0.5 mL) and saturated aqueous sodium carbonate (0.5 mL) is added 0.0086 mL (0.11 mmol) of phenylisocyanate. The mixture is stirred at room temperature for 6 hours then concentrated under reduced pressure. The residue is diluted with water causing a gummy solid to form. The aqueous phase is decanted off and the solid is rinsed and decanted with water and then dried. The residue is purified by preparative thin layer chromatography to give 0.016 mg (44%) of the title compound (110) as a clear resin. [M+H]+=542.7.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:25]2[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:26]=2[OH:32])[NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17](F)=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)=[O:12])=[CH:5][CH:4]=1)#[N:2].[F:33]C1C=C(NC(N)=O)C=C(C(F)(F)F)C=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:25]2[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:26]=2[OH:32])[NH:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([C:21]([F:24])([F:22])[F:23])[CH:17]=[C:18]([F:33])[CH:19]=2)=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(NC(=O)Nc2ccc(F)c(C(F)(F)F)c2)C2=C(O)CCCC2=O)cc1
Reactant: NC(=O)Nc1cc(F)cc(C(F)(F)F)c1
Product: N#Cc1ccc(C(NC(=O)Nc2cc(F)cc(C(F)(F)F)c2)C2=C(O)CCCC2=O)cc1

Procedure:
The title compound is prepared in analogy to 1-((4-cyanophenyl)(2-hydroxy-6-oxocyclohex-1-enyl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea (intermediate 44), using 1-(3-fluoro-5-(trifluoromethyl)phenyl)urea (intermediate 43, 630 mg, 1.99 mmol) as starting material. Yield: 378 mg; ESI mass spectrum [M+H]+=448; Retention time HPLC: 1.07 min (Z018_S04).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][C:11]([C:17]([O:19][CH3:20])=[O:18])=[C:12]([CH2:14][O:15][CH3:16])[N:13]=1.[Cl:21]C1C=C(C(OCC)=O)NC=1C>CC#N>[CH3:20][O:19][C:17]([C:11]1[S:10][C:9]([Cl:21])=[N:13][C:12]=1[CH2:14][O:15][CH3:16])=[O:18]
Reactant: CCOC(=O)c1cc(Cl)c(C)[nH]1
Reactant: COCc1nc(N)sc1C(=O)OC
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: COCc1nc(Cl)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl nitrite (2.2 ml, 18.6 mmol) and cuprous chloride (1.5 g) were suspended in anhydrous CH3CN (100 ml). Methyl 2-amino-4-(methoxymethyl)-1,3-thiazole-5-carboxylate (2.5 g) prepared as described in (Kennedy, Alan R. et al. Acta Crystallographica, Section C: Crystal Structure Communications (1999, C55 (7) 2) was added in one portion. The mixture was stirred at room temperature for 2 h and the temperature was raised to 70° C. for 1 h. The mixture was cooled to room temperature and filtered. The filtrate was poured into 6 N HCl, extracted with EtOAc, dried with MgSO4 and concentrated to a black oil. Flash purification on silica gel with gradient elution (hexane to EtOAc) yielded product as a yellow liquid (0.82 g). NMR: 3.31 (s, 3H), 3.85 (s, 3H), 4.71 (s, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:16]2[C:17]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][CH:9]=1.C(O)C(N)(CO)CO.C(N(CC)CC)C.[F:43][C:44]([F:59])([F:58])[C:45]1[CH:46]=[C:47]([N:55]=[C:56]=[O:57])[CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1>O1CCCC1>[F:43][C:44]([F:58])([F:59])[C:45]1[CH:46]=[C:47]([NH:55][C:56]([N:25]2[CH2:26][CH2:27][N:22]([C:17]3[C:16]([O:15][CH2:14][C:11]4[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=4)=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:23][CH2:24]2)=[O:57])[CH:48]=[C:49]([C:51]([F:54])([F:52])[F:53])[CH:50]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: c1cnc(N2CCNCC2)c(OCc2ccncc2)c1
Agent: NC(CO)(CO)CO
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2ncccc2OCc2ccncc2)CC1
Reaction time: 1 h
Yield: 3.1 %

Procedure:
The crude 1-[3-(Pyridin-4-ylmethoxy)pyridin-2-yl]-piperazine trifluoroacetic acid salt (˜500 mg) was dissolved in 25 mL of tetrahydrofuran along with 2 g of trisamine resin. The suspension was stirred for 1 hr and the resin was removed by filtration. The filtrate was concentrated under vacuum. The free-based material was dissolved in 5 mL of dichloromethane. To this solution was added triethylamine (150 μL, 1.08 mmol) and 3,5-bis(trifluoromethyl)phenyl isocyanate (150 μL, 0.864 mmol). The reaction was stirred at room temperature for 1 hr. The reaction mixture was concentrated under vacuum and re-dissolved in 25 mL ethyl acetate. The reaction mixture was washed 3 times each with 25 mL portions of water, 0.05 M HCl and saturated aqueous sodium chloride. The organic fraction was dried with magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography with a gradient of 0% to 10% methanol in ethyl acetate with 5% triethylamine, giving N-[3,5-bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4-ylmethyl)oxy]pyridin-2-yl}piperazine-1-carboxamide (14 mg). 1H NMR (DMSO-d6) δ 9.24 (s, 1H), 8.60 (d, 2H), 8.22 (s, 2H), 7.84 (d, 1H), 7.58 (s, 1H), 7.46 (d, 2H), 7.33 (d, 1H), 6.92 (dd, 1H), 5.23 (s, 2H), 3.62-3.68 (m, 4H) 3.37-3.41 (m, 4H) ppm.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.[C:19]([O-:22])(=[O:21])[CH3:20].[K+].[CH2:24]([O:26][C:27](=[O:38])[C:28]1[CH:33]=[C:32]([CH2:34][Br:35])[CH:31]=[C:30]([CH2:36]Br)[CH:29]=1)[CH3:25]>C(#N)C>[C:19]([O:22][CH2:36][C:30]1[CH:29]=[C:28]([CH:33]=[C:32]([CH2:34][Br:35])[CH:31]=1)[C:27]([O:26][CH2:24][CH3:25])=[O:38])(=[O:21])[CH3:20]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1cc(CBr)cc(CBr)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(CBr)cc(COC(C)=O)c1
Reaction time: 8 h

Procedure:
To a stirred solution of 18-crown-6 (0.103 g) in acetonitrile (15 ml) was added potassium acetate (0.38 g). After 30 minutes 3,5-bis[bromomethyl]benzoic acid ethyl ester (2.61 g) was added and the mixture was stirred overnight. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated and the residue purified by chromatography eluting with 10% ethyl acetate in isohexane. Yield 0.97 g.