Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>CCCCCCC.CCOC(C)=O>[Cl:20][CH2:21][CH2:22][CH2:23][N:7]1[C:6]2[CH:12]=[C:2]([CH3:1])[CH:3]=[C:4]([CH3:13])[C:5]=2[O:10][CH2:9][C:8]1=[O:11]
Reactant: Cc1cc(C)c2c(c1)NC(=O)CO2
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1cc(C)c2c(c1)N(CCCCl)C(=O)CO2
Yield: 39.4 %

Procedure:
6,8-Dimethyl-4H-benzo[1,4]oxazin-3-one (81MF2237a) (1.70 g, 9.60 mmol), Cs2CO3 (4.69 g, 14.4 mmol) and 3-chloro-1-iodopropane (2.15 g, 10.6 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (81MF2237b) (0.96 g, 39%). 1H NMR (CDCl3) δ 6.72-6.69 (m, 2H), 4.56 (s, 2H), 4.07 (t, 2H), 3.62 (t, J=6.4 Hz, 2H), 2.30 (s, 3H), 2.20 (s, 3H), 2.19-2.12 (m, 2H); 13C NMR (CDCl3) δ 164.9, 141.5, 131.9, 128.0, 126.7, 126.4, 113.1, 67.8, 42.5, 39.0, 30.3, 21.2, 15.5.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[OH:11])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:15]>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[O:11][CH3:15])=[CH:4][CH:3]=1
Reactant: OC1CCc2ccc(Br)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CCc2ccc(Br)cc21
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of 6-bromoindanol (0.51 g, 2.4 mmol) in anhydrous tetrahydrofuran (10 mL), was added sodium hydride (0.097 g, 3.84 mmol) over a period of five minutes at room temperature. The reaction mixture was stirred at room temperature for fifteen minutes and iodomethane (0.22 mL, 3.6 mmol) was added. After thirty minutes at room temperature, the reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The ethyl acetate layer was washed with brine (20 mL), dried over sodium sulfate and concentrated to yield the title compound (0.485 g, 89%). 1H NMR (CDCl3) : □ 7.5 (s, 1H), 7.3 (d, 1H), 7.0 (d, 1H), 4.7 (m, 1H), 3.3 (s, 3H), 3.0 (m, 1H), 2.7 (m, 1H), 2.3 (m, 1H), 2.0 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=1)[CH2:12][O:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=1)[CH2:12][O:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: Clc1cncc(OCc2cccc(OCc3ccccc3)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(COc2cccc(COc3cncc(N4CCNCC4)n3)c2)cc1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from the product obtained in step 1 above (1.62 g, 4.96 mmol), piperazine (1.28 g, 14.9 mmol) and K2CO3 (0.70 g, 5.1 mmol). The yield of the title compound was 1.16 g (62%) and was obtained as an oil. HRMS m/z calcd for C22H24N4O2 (M)+ 376.1899, found 376.1890. Anal. (C22H24N4O2) C, H, N.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:35])[C@@H:11]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:34])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([OH:33])[CH:27]=2)=[CH:20][C:21]=1[CH3:22])=[O:16])[CH2:12][NH2:13].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[S:77]1[CH:81]=[CH:80][CH:79]=[C:78]1[C:82](O)=[O:83]>CN(C=O)C.CCOC(C)=O>[CH3:8][O:9][C:10](=[O:35])[C@@H:11]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:34])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([OH:33])[CH:27]=2)=[CH:20][C:21]=1[CH3:22])=[O:16])[CH2:12][NH:13][C:82]([C:78]1[S:77][CH:81]=[CH:80][CH:79]=1)=[O:83]
Reactant: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2ccc(F)c(O)c2)cc1C
Reactant: O=C(O)c1cccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2ccc(F)c(O)c2)cc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 3.7 %

Procedure:
To a solution of (S)-3-Amino-2-{[5-(4-fluoro-3-hydroxy-benzylcarbamoyl)-3-methyl-thiophene-2-carbonyl]-amino}-propionic acid methyl ester trifluoro-acetic acid salt (0.73 mmol) in anhydrous DMF (15 mL) was added triethylamine (0.31 mL, 2.19 mmol), HBTU (0.33 g, 0.88 mmol), HOBt (0.12 g, 0.88 mmol), and 2-Thiophenecarboxylic acid (0.098 g, 0.77 mmol). The mixture was stirred at room temperature 15 h, treated with EtOAc (50 mL), washed with brine, dried over sodium sulfate, filtered and evaporated. The solid residue was purified by column (30-100% EtOAc in hexane). Material off the column was determined to be the mixed ester. It was refluxed in MeOH (20 ml) containing a catalytic amount of pTsOH for 15 h, purified by column (60-75% EtOAc in hexane). to give 0.014 g (4%) colorless oil. MS m/e 519.9 (M+H+).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)[CH3:9].[Br:19]([O-])(=O)=O.[K+]>O>[Br:19][C:11]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=1[CH:8]([CH2:7][F:6])[CH3:9]
Reactant: CC(CF)c1ccc([N+](=O)[O-])cc1
Reactant: [O-][Br+2]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CC(CF)c1ccc([N+](=O)[O-])cc1Br

Procedure:
To 80 ml of concentrated sulfuric acid, 80 ml of water and 18.3 g (0.1 Mol) of 4(fluoromethyl-ethyl)-nitrobenzene are added portionwise with stirring 18.3 g (0.11 Mol) potassium bromate at such a rate that the temperature does not exceed 35°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]=[C:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)[CH3:2].[H][H]>[Pd].CO>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C=C1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1CCOCC1
Yield: 91.3 %

Procedure:
A mixture of (tetrahydro-pyran-4-ylidene)-acetic acid ethyl ester (27 g, 159 mmol) and 10% palladium on activated carbon (3 g) in methanol (300 mL) was stirred at 25° C. under 30 psi of hydrogen for 20 h. The catalyst was filtered off, washed with ethyl acetate and concentrated in vacuo to afford (tetrahydro-pyran-4-yl)-acetic acid ethyl ester (25 g, 91%) as a colorless oil which was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:33][CH3:34])[C@@:4]1([CH3:32])[C@H:9]([OH:10])[C@@H:8]([N:11]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:12][C:13]2[NH:14][CH:15]=[CH:16][N:17]=2)[C:7]2[CH:25]=[C:26]([N+:29]([O-])=O)[CH:27]=[CH:28][C:6]=2[O:5]1>CO.[Pd]>[NH2:29][C:26]1[CH:27]=[CH:28][C:6]2[O:5][C@:4]([CH:3]([O:33][CH3:34])[O:2][CH3:1])([CH3:32])[C@H:9]([OH:10])[C@@H:8]([N:11]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[CH2:12][C:13]3[NH:14][CH:15]=[CH:16][N:17]=3)[C:7]=2[CH:25]=1
Reactant: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2ncc[nH]2)c2ccc(Cl)cc2)[C@H]1O
Agent: [Pd]
Solvent: CO
Product: COC(OC)[C@]1(C)Oc2ccc(N)cc2[C@H](N(Cc2ncc[nH]2)c2ccc(Cl)cc2)[C@H]1O
Reaction time: 12 h
Yield: 74.9 %

Procedure:
To the solution of the nitro compound (521 mg, 1.07 mmol) prepared from example 3 in methanol (3 mL) was added 10% Pd/C. The mixture was hydrogenated at room temperature under 3 atmosphere pressure of H2 for 12 hours, and filtered through a pad of Celite. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (5% methanol in dichloromethane) to afford the title compound (368 mg, 75%).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[NH:8][C:7]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:14])[C:6]=2[N:5]=1)[CH3:3].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.[NH4+].[Cl-]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:5]2[C:6]3[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][C:7]=3[N:8]=[C:4]2[CH:2]([CH3:1])[CH3:3])=[CH:18][CH:17]=1
Reactant: CC(C)c1nc2c([nH]1)CCCCC2=O
Reactant: Clc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(=O)CCCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.5 %

Procedure:
Tetrabutylammonium bromide (1.7 g) was added to a stirred mixture of Intermediate 2 (2 g) and 4-chlorobenzyl bromide (2.4 g) in sodium hydroxide 20% aq. (14.2 mL) and Toluene (7 mL). The RM was stirred at room temp under nitrogen atm for 3 hours. An excess of sat NH4Cl aq. solution was added and the mixture was extracted with EtOAc (3×30 ml). The organics were combined, dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica using a cyclohexane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (1.5 g). LC/MS MH+ 317, Rt 1.91 min (5 minute run).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1>>[CH3:8][C:7]1[CH:9]=[CH:10][C:4]([S:1]([O:19][CH2:18][CH:15]2[CH2:16][CH2:17][N:12]([S:1]([C:4]3[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=3)(=[O:3])=[O:2])[CH2:13][CH2:14]2)(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCNCC1
Product: Cc1ccc(S(=O)(=O)OCC2CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1

Procedure:
Reaction of tosyl chloride and piperidin-4-yl-methanol as described in Preparation 1 gave the desired compound, (1-tosylpiperidin-4-yl)methyl 4-methylbenzenesulfonate, which was used without further purification.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:20]=2)[CH:15]=[C:14]1[C:27](OCC)=[O:28])[CH3:12])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(O)C>[CH3:12][CH:11]1[N:13]2[C:21]3[CH:20]=[C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:17][C:16]=3[CH:15]=[C:14]2[C:27](=[O:28])[NH:8][CH2:9][CH2:10]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)CCNC(=O)OC(C)(C)C)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2cc3n(c2c1)C(C)CCNC3=O
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a solution of diethyl 1-{4-[(tert-butoxycarbonyl)amino]butan-2-yl}-1H-indole-2,6-dicarboxylate (1.04 g, 1.8 mmol) in CH2Cl2 (4 mL) is added TFA (4 mL). The reaction mixture is stirred for 1 h and the solvent is removed under vacuum. To a solution of the residue in ethanol (10 mL) is added triethylamine (0.75 mL, 5.4 mmol) and K2CO3 (742 mg, 5.4 mmol). The reaction mixture is refluxed for 3 h. Then the solvent is evaporated, the residue is partitioned between EtOAc and water. The organic layer is then separated, dried (MgSO4) and concentrated to afford crude compound which is purified by flash column chromatography to afford the title compound (300 mg, 59% for two steps).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1F.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=1[Cl:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)Cc1ccc(Cl)c(F)c1
Reactant: OCc1ccccc1
Product: O=C(O)Cc1ccc(Cl)c(OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 185, Step 1, using the following starting materials: 4-chloro-3-fluorophenylacetic acid and benzyl alcohol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([F:10])[CH:3]=1.[C-:11]#[N:12].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[C:4]([F:10])[CH:3]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(Br)cc1F
Temperature: 40 °C
Yield: 87.4 %

Procedure:
To a solution of 4-bromo-1-(bromomethyl)-2-fluorobenzene (5.0 g, 18.7 mmol) in DMF (80 mL) and H2O (8 mL) was added KCN (1.21 g, 18.7 mmol). The mixture was heated to 40° C. for 3 hours before it was cooled down to room temperature. The reaction was diluted with H2O (40 mL) and extracted with Et2O (3×100 mL). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed and the residue was purified by flash column chromatography (0-15% EtOAc in hexanes) to give the product (3.5 g, 87% yield). 1H NMR (300 MHz, CDCl3) δ: 3.72 (s, 2H), 7.26-7.35 (m, 3H).
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([OH:31])[C:23]=3[CH2:32][CH2:33][CH3:34])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1.[OH-].[Li+]>CO>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([S:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:35])=[O:2])=[CH:5][CH:6]=3)(=[O:13])=[O:12])=[CH:15][CH:16]=2)=[C:23]([CH2:32][CH2:33][CH3:34])[C:24]=1[OH:31])(=[O:30])[CH3:29]
Reactant: CCCc1c(OCc2ccc(S(=O)(=O)Nc3ccc(C(=O)OC)cc3)cc2)ccc(C(C)=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCc2ccc(S(=O)(=O)Nc3ccc(C(=O)O)cc3)cc2)ccc(C(C)=O)c1O
Reaction time: 24 h
Yield: 76.5 %

Procedure:
Dissolve 4-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-benzenesulfonylamino]-benzoic acid methyl ester (1.48 g, 2.98 mmol) in methanol (15 mL) and add 2N aqueous lithium hydroxide solution (9 mL). Stir 24 hours. Concentrate under reduced pressure to remove majority of methanol, add 1N hydrochloric acid to the dark brown solution to afford a white precipitate. Triturate in 1N hydrochloric acid for 1 hour and collect the solid by filtration. Triturate the collected solid in 1:1 ether/hex and filter to collect the title compound as a white solid (1.102 g, 2.28 mmol): 1H NMR (DMSO-d6) δ 0.85 (t, 3H), 1.46 (m, 2H), 2.58 (m, 5H), 5.30 (s, 2H), 6.65 (d, 1H), 7.20 (d, 2H), 7.61 (d, 2H), 7.80 (m, 3H), 7.87 (m, 2H), 10.82 (br s, 1H), 12.72 (br s, 1H), 12.82 (s, 1H); MS (m/z): 482 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@:9]2([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][N:18]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:16])[C:11]([OH:13])=O)=[CH:4][CH:3]=1.C([N:32]1CCOCC1)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@:9]2([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][N:18]2[C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])=[O:16])[C:11](=[O:13])[NH2:32])=[CH:4][CH:3]=1
Reactant: CCN1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@]1(C(=O)O)C[C@@H]1c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@]1(C(N)=O)C[C@@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(1R,2R)-2-(4-Bromophenyl)-1-((S)-1-(tert-butoxycarbonyl)piperidine-2-carboxamido)cyclopropanecarboxylic acid (3 g) was dissolved in DMF (17 mL) and to the solution was added N-ethylmorpholine (1.219 mL) followed by TBTU (3.09 g). The reaction mixture was stirred at RT for 20 min then it was cooled to 0° C. Aqueous ammonia (1.461 mL) was added and the mixture was allowed to reach RT over 1 h. The reaction appeared to have proceeded ˜70%, so it was left to stir for a further 2 h. LCMS showed little change so further TBTU (400 mg) and ammonia (0.3 mL) were added, and the mixture stirred for a further 2 h. The reaction mixture was partitioned between ethyl acetate and diluted brine, and reextracted into ethyl acetate twice more. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (2.75 g) as a pale gum.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1.O.C(=O)(O)[O-].[Na+].[C:31](OC(=O)C)(=[O:33])[CH3:32]>O1CCOCC1>[C:31]([N:7]([CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1)[C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)(=[O:33])[CH3:32]
Reactant: O=C1NC(=O)C(Cc2ccc(OCCNc3ncccn3)cc2)S1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N(CCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ncccn1

Procedure:
A stirred solution of 5-[4-(2-(2-pyrimidinylamino)ethoxy)benzyl]-2,4-thiazolidinedione (800 mg) in acetic anhydride (15 ml) and 1,4-dioxan (5 ml) was boiled under reflux for 3 hours. After cooling, the mixture was added to water (300 ml), neutralized (sodium bicarbonate) and extracted with dichloromethane (3×200 ml). The organic extracts were washed with brine (100 ml), dried (MgSO4), filtered and evaporated to dryness. Chromatography on silica-gel in dichloromethane of the residual oil afforded the title compound (m.p. 137° C.).
Reaction SMILES: [C:1]([C:4]1[C:5](Cl)=[N:6][C:7]([Cl:11])=[N:8][C:9]=1[Cl:10])([OH:3])=[O:2].C(N(CC)CC)C.[CH:20]1[CH:25]=[CH:24][C:23]([CH2:26][SH:27])=[CH:22][CH:21]=1>CN(C)C=O.O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:26]([S:27][C:5]1[C:4]([C:1]([OH:3])=[O:2])=[C:9]([Cl:10])[N:8]=[C:7]([Cl:11])[N:6]=1)[C:23]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: SCc1ccccc1
Reactant: O=C(O)c1c(Cl)nc(Cl)nc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1c(Cl)nc(Cl)nc1SCc1ccccc1
Reaction time: 1 h

Procedure:
To a mixture of 5-carboxy-2,4,6-trichloropyrimidine (prepared in the above (1)) 100 mg, triethylamine 89 mg in dimethylformamide 3 ml is added at room temperature a 1.0M solution of benzylthiol in tetrahydrofuran 0.44 ml, and the mixture is stirred for 1 hour. The reaction mixture is diluted with a 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-benzylthio-5-carboxy-2,6-dichloropyrimidine as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1.[K+].[C:18]([C:20]1[N:21]=[C:22]([C:33]([O-])=[O:34])[N:23](COCC[Si](C)(C)C)[CH:24]=1)#[N:19]>>[C:11]1([C:3]2[CH:4]=[C:5]([CH2:8][CH2:9][OH:10])[CH:6]=[CH:7][C:2]=2[NH:1][C:33]([C:22]2[NH:21][C:20]([C:18]#[N:19])=[CH:24][N:23]=2)=[O:34])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: Nc1ccc(CCO)cc1C1=CCCCC1
Agent: [K+]
Product: N#Cc1cnc(C(=O)Nc2ccc(CCO)cc2C2=CCCCC2)[nH]1

Procedure:
The title compound was prepared by coupling 2-(4-amino-3-cyclohex-1-enyl-phenyl)-ethanol (prepared in the previous step) and 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (prepared in Example 11, step (d)) according to the procedure in Example 42, step (c) followed by SEM deprotection according to the procedure in Example 11, step (g). 1H-NMR (CD3OD, 400 MHz): δ 8.10 (d, J=8.3 Hz, 1H), 8.02 (s, 1H), 7.17 (dd, J=8.3, 1.9 Hz, 1H), 7.08 (d, J=1.9 Hz, 1H), 5.82 (s, 1H), 3.77 (t, J=7.0 Hz, 2H), 2.82 (t, J=7.0 Hz, 2H), 2.31-2.25 (m, 4H), 1.90-1.76 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C19H20N4O2, 337.2 (M+H), found 337.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[Br:13]Br>C(O)(=O)C>[Br:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2[nH]nc(Br)c2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
5-Nitroindazole (10 g, 61.3 mmol) was dissolved in acetic acid (170 mL) and the mixture heated to 80° C. Bromine (3.1 mL, 60.7 mmol) was added slowly and the mixture heated to reflux. After 2 hours, the reaction mixture was allowed to cool to room temperature, and the resulting precipitate filtered off. Additional product was isolated by concentrating the filtrate, partitioning the residue between chloroform and saturated sodium bicarbonate solution, separating and drying the organic phase over sodium sulfate. Concentration gave a solid which was combined with the original precipitate to give the title compound as a yellow solid (11.4 g, 77%). 1H NMR δ 7.74 (1H, d), 8.21 (1H, dd), 8.40 (1H, d), 14.06 (1H, brs); MS (ES−) m/e=240.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[Br-].[CH:13]1([Zn+])[CH2:15][CH2:14]1>C1COCC1.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>[CH:13]1([C:2]2[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=2)[CH2:15][CH2:14]1
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: [Zn+]C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2CC2)cn1
Temperature: 80 °C
Yield: 73.1 %

Procedure:
To a sealed tube were added methyl 5-bromopicolinate (700 mg, 3.24 mmol) in THF (10 ml). The reaction mixture was purged with Ar followed by addition of tetrakis(triphenylphosphine)palladium (187 mg, 0.162 mmol) and finally cyclopropylzinc bromide solution 0.5 m in tetrahydrofuran (7.78 mL, 3.89 mmol). The tube was sealed and heated to 80° C. for 1.5 hrs. Then it was diluted with water, and extracted with EtOAc. The organic layer was washed with brine and concentrated to give crude product. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 25% to 40% to 60% EtOAc in Heptane, to provide methyl 5-cyclopropylpicolinate (420 mg, 2.370 mmol, 73.1% yield) as off-white solid. MS m/z=178.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[CH3:26][NH:27][C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[CH3:26][N:27]([C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1)[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:23])[F:24])[CH:16]=2)(=[O:13])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNc1cccc(C)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N(C)C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (50 mg, 0.12 mmol), methyl-m-tolyl-amine (44 mg, 0.36 mmol), BOP (69 mg, 0.36 mmol), DIEA (130 μL, 0.72 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methyl-m-tolyl-amide: MS m/z: (M+H) 518.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:7]2[CH:8]=[C:9]([C:14]3[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=3)[C:17]#[N:18])[CH:10]=[C:11]([O:12]C)[C:6]=2[NH:5][C:4](=[O:23])[O:3]1.[I-].[Li+]>N1C(C)=CC(C)=CC=1C>[CH3:1][C:2]1([CH3:24])[C:7]2[CH:8]=[C:9]([C:14]3[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=3)[C:17]#[N:18])[CH:10]=[C:11]([OH:12])[C:6]=2[NH:5][C:4](=[O:23])[O:3]1
Reactant: COc1cc(-c2cc(F)cc(C#N)c2)cc2c1NC(=O)OC2(C)C
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: CC1(C)OC(=O)Nc2c(O)cc(-c3cc(F)cc(C#N)c3)cc21

Procedure:
A mixture of 3-(4,4-dimethyl-8-methoxy-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile (0.1 g, 0.31 mmol), Lithium iodide (0.3 g, 2.24 mmol) in 2,4,6-collidine was heated at reflux under nitrogen for 5 hours. The solvent was removed in vacuo and the residue was taken in a mixture of brine (10 mL) and ethyl acetate (30 mL). The organic layer was separated, dried (MgSO4), and evaporated. The resultant residue was purified on a silica gel column chromatography (hexane:ethyl acetate/1:1) to give the title compound as white plates (0.03 mg, 31%): mp 197-198° C.; 1H-NMR (DMSO-d6) δ 10.16 (s, 1H), 9.55 (s, 1H), 8.01 (s, 1H), 7.79-7.87 (m, 2H), 7.20 (s,1H), 7.08 (d, 1H, J=1.0 Hz), 1.65 (s, 6H). MS (ESI) m/z 311 [M−H]−.