Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[N:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[C:6]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:5]=1)=[C:2]=[O:3].[Br:22][C:23]1[CH:30]=[CH:29][C:26]([NH:27][CH3:28])=[CH:25][CH:24]=1>O1CCOCC1>[F:15][C:12]([F:13])([F:14])[CH2:11][O:10][C:8]1[CH:7]=[C:6]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:5]=[C:4]([NH:1][C:2](=[O:3])[N:27]([CH3:28])[C:26]2[CH:29]=[CH:30][C:23]([Br:22])=[CH:24][CH:25]=2)[N:9]=1
Reactant: O=C=Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Reactant: CNc1ccc(Br)cc1
Solvent: C1COCCO1
Product: CN(C(=O)Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
2-Isocyanato-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine (750 mg, 2.4 mmol) was dissolved in anhydrous dioxane (15 mL). To this solution was added 4-bromo-N-methylaniline (440 mg, 2.36 mmol) and the resulting solution was stirred under an N2 atmosphere at room temperature. After ca. 12 h an LCMS analysis of the reaction indicated mostly desired product (91%). The reaction was partitioned between EtOAc and water, the organics separated and the aqueous layer extracted with EtOAc (3×50 mL). Organic extracts were combined, washed with water (2×) and once with brine. The organic layer was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give a yellow oil. The oil was partially purified by column chromatography (silica, hexane/EtOAc) and then recrystallized (EtOAc/cyclohexane) to afford 41 as a white solid (346 mg, 29% yield): m.p. 110-111° C. Anal Calcd for C16H13BrF6N4O3: C, 38.19; H, 2.60; N, 11.13. Found: C, 38.42; H, 2.66; N, 11.20. 1H NMR (300 MHz, CDCl3) δ 9.42 (s, 1H), 7.55 (d, 2H, J=4.5 Hz), 7.26 (d, 2H, J=4.5 Hz), 6.14 (s, 1H), 4.99 (q, 4H, J=4.4 Hz), 3.28 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:5]2=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[C:27]([O:31][C:32](=[O:50])[N:33]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)[C:34]1[S:35][C:36]([CH:40]=[O:41])=[C:37](Cl)[N:38]=1)([CH3:30])([CH3:29])[CH3:28]>O1CCCC1>[C:27]([O:31][C:32](=[O:50])[N:33]([C:34]1[S:35][C:36]([CH:40]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:9]=2)[OH:41])=[CH:37][N:38]=1)[CH2:42][C:43]1[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(Cl)cnc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1)c1nc(Cl)c(C=O)s1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2cnc(N(Cc3ccc(F)cc3)C(=O)OC(C)(C)C)s2)c2cc(Cl)cnc21
Temperature: 0 °C
Yield: 29.5 %

Procedure:
To a solution of 5-chloro-3-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (626, 300 mg, 0.69 mmol) in tetrahydrofuran (10 mL) at −20° C. was added dropwise iso-propyl-magnesium chloride (2M in tetrahydrofuran, 0.44 mL, 0.88 mmol). The reaction mixture was allowed to warm to 0° C. over 10 minutes and then cooled to −40° C. To this reaction mixture was added a solution of (4-fluoro-benzyl)-(4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester (625, 211 mg, 0.63 mmol) in tetrahydrofuran (5 mL). The reaction mixture was allowed to warm to 0° C. over 30 minutes and then quenched with brine (50 mL). The mixture was transferred to a separatory funnel and the layers were separated. The organic layer was dried over sodium sulfate and evaporated in vacuo to give the crude material which was purified by silica gel column chromatography (0-30% ethyl acetate/heptane) to provide the desired compound as a foam (120 mg, 30%), consistent with structure by 1H-NMR.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:3]1.O[N:30]=[C:31]([NH2:33])[CH3:32]>>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:19][CH:20]=3)[CH2:12][CH:11]([C:26]3[O:28][N:33]=[C:31]([CH3:32])[N:30]=3)[CH2:10]2)=[O:8])[CH2:3]1
Reactant: CC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)C2)C1
Product: Cc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(O)C3)C2)n1

Procedure:
200 mg (0.50 mmol) of the compound from Example 112A and 55 mg (0.75 mmol) of N′-hydroxyethanimidamide were reacted according to the General Method 2. Yield: 15 mg (6% of theory).
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH2:9][C:10]3([O:16][C:7]=2[C:6]([O:17][CH3:18])=[CH:5][CH:4]=1)[CH:14]([OH:15])[CH2:13][O:12][CH2:11]3)#[N:2].[H-].[Na+].[CH3:21]I>CN(C)C=O>[C:1]([C:3]1[C:8]2[CH2:9][C:10]3([O:16][C:7]=2[C:6]([O:17][CH3:18])=[CH:5][CH:4]=1)[CH:14]([O:15][CH3:21])[CH2:13][O:12][CH2:11]3)#[N:2]
Reactant: CI
Reactant: COc1ccc(C#N)c2c1OC1(COCC1O)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C#N)c2c1OC1(COCC1OC)C2
Temperature: 40 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
2.0 g (8.0 mmol) of 2,3-dihydro-4-cyano-4′-hydroxy-7-methoxybenzofuran-2-spiro-3′-tetrahydrofuran (A11) in 15 ml of dimethylformamide are added dropwise under a nitrogen atmosphere to a solution of 270 mg (8.8 mmol) of 80% strength sodium hydride in 10 ml of dimethylformamide and the mixture is heated at 40° C. for 1 h. 700 μl (10.6 mmol) of methyl iodide, dissolved in 5 ml of dimethylformamide, are then added dropwise at RT. The mixture is stirred at RT for 2 h, concentrated, and the residue is crystallized from 50 ml of water. 1.97 g of the title compound of m.p. 151-156° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=2[C:19]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:20])=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:15])=[CH:12][C:11]=2[C:19]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:20])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2cccnc2)c1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1cccnc1)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of crude 4-{[(4-fluorophenyl)methyl]oxy}-3-[(3-pyridinylamino)carbonyl]benzoic acid (may be prepared as described in Description 111; 62 mg, 0.17 mmol) in N,N-dimethylformamide (DMF) (5 ml) was added morpholine (0.03 ml, 0.34 mmol), EDC (38.9 mg, 0.20 mmol), HOBT (41.5 mg, 0.27 mmol) and N-ethylmorpholine (0.04 ml, 0.34 mmol). The mixture was stirred at room temperature overnight. The mixture was evaporated and the residue was purified by MDAP.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]2[C@@H:5]([C@H:6]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@:4]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:3]1[CH2:30][S:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH3:39])[CH:33]=1.C(N(CC)CC)C.[C:47](Cl)(=[O:49])[CH3:48]>ClCCl>[C:47]([NH:1][C@H:2]1[C@@H:7]2[C@@H:5]([C@H:6]2[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[C@:4]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[C@@H:3]1[CH2:30][S:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH3:39])[CH:33]=1)(=[O:49])[CH3:48]
Reactant: Cc1cc(SC[C@@H]2[C@@H](N)[C@H]3[C@H](C(=O)OC(C)(C)C)[C@H]3[C@]2(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1F
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H]1[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@](NC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)[C@@H]1CSc1ccc(F)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.1 %

Procedure:
Di-tert-butyl (1S,2R,3R,4S,5R,6S)-4-amino-2-(tert-butoxycarbonylamino)-3-[(4-fluoro-3-methyl-phenyl)sulfanylmethyl]bicyclo[3.1.0]hexane-2,6-dicarboxylate (0.15 g, 264.67 μmol) is dissolved in dichloromethane (10 mL). To this mixture is added triethylamine (55.34 μL, 397.01 μmol) and acetyl chloride (28.25 μL, 397.01 μmol). The mixture is stirred at ambient temperature for 10 minutes. The solvent is removed under reduced pressure to give a residue. The residue is purified by flash chromatography (10% to 100% ethyl acetate/hexanes) to give the title compound (100 mg, 164.27 μmol, 62.06% yield); 1H NMR (CD3Cl) δ 1.44 (t, 27H), 1.95 (s, 3H), 2.16 (m, 1H), 2.22 (s, 3H), 2.60 (dd, 1H), 2.78 (bs, 1H), 3.10 (dd, 1H), 4.59 (m, 1H), 5.50 (d, 1H), 6.92 (t, 1H), 7.06 (m, 1H), 7.11 (d, 1H).
Reaction SMILES: [CH2:1]1[CH2:7][S:4](=[O:6])(=O)[O:3][CH2:2]1.[CH3:8][C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1>CCOCC.C(OCC)(=O)C>[S:4](=[CH:7][CH2:1][CH2:2][N:13]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:8])[CH2:14]1)(=[O:6])=[O:3]
Reactant: Cc1cnccn1
Reactant: O=S1(=O)CCCO1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC1=NC=CN(CCC=S(=O)=O)C1

Procedure:
16.0 g of 1,3-propane sultone was dissolved in 200 ml of 1:1 ether/ethyl acetate and 15.1 g of 2-methylpyrazine added. It was then stored and the solvent allowed to evaporate.
Reaction SMILES: Cl.Cl.[N:3]1([C:10]2[CH:11]=[C:12]([CH:20]([CH3:22])[CH3:21])[CH:13]=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[CH2:24][C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:28][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[CH:20]([C:12]1[CH:13]=[C:14]2[C:19](=[C:10]([N:3]3[CH2:9][CH2:8][CH2:7][N:6]([CH2:24][C:25]4[N:26]=[C:27]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)[S:28][CH:29]=4)[CH2:5][CH2:4]3)[CH:11]=1)[N:18]=[CH:17][CH:16]=[CH:15]2)([CH3:22])[CH3:21]
Reactant: CC(C)c1cc(N2CCCNCC2)c2ncccc2c1
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1cc(N2CCCN(Cc3csc(-c4ccccc4)n3)CC2)c2ncccc2c1
Temperature: 60 °C
Yield: 49.7 %

Procedure:
A mixture of 8-[1,4]-diazepan-1-yl-6-isopropyl-quinoline dihydrochloride (0.34 g, 1 mmol, 1 equiv), 4-chloromethyl-2-phenyl-thiazole (0.21 g, 1 equiv) and Cs2CO3 (1.63 g, 5 equiv) in 5 mL of DMF was heated to 60° C. for 3 hours and then cooled to room temperature. EtOAc (˜70 mL) was added and the mixture washed with saturated aqueous NaHCO3 (70 mL) and brine (70 mL), dried over magnesium sulfate and concentrated. The residue was purified by silica gel flash column chromatography using 5% to 40% EtOAc in hexanes. Silica gel chromatography was repeated using 5% to 10% MeOH in EtOAc to afford the title compound (0.22 g, 50%) as light tan solid. 1H NMR (400 MHz, d6-CD3OD) δ 8.66 (dd, 1H, J=1.8 and 4 Hz), 8.07 (dd. 1H, J=1.5 and 8.4 Hz), 7.91 (m, 1H), 7.90 (d, 1H, J=2.2 Hz), 7.41 (m, 3H), 7.36 (s, 1H), 7.31 (dd, 1H, J=4.0 and 8.0 Hz), 7.16 (d, 1H, J=1.6 Hz), 7.04 (d, 1H, J=1.6 Hz), 3.90 (s, 2H), 3.71 (m, 2H), 3.59 (t, 2H, J=5.6 Hz), 3.11 (m, 2H), 2.92 (m, 3H), 2.10 (m, 2H), 1.31 (d, 6H, J=7.2 Hz). MS (ES) m/z 443.2 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12.[CH2:12]([NH2:16])[CH:13]([CH3:15])[CH3:14]>O.C(O)C>[CH3:8][C:6]1[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]2=[C:2]([NH:16][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:7]=1
Reactant: Cc1cc(Cl)c2[nH]ncc2n1
Reactant: CC(C)CN
Solvent: O
Solvent: CCO
Product: Cc1cc(NCC(C)C)c2[nH]ncc2n1
Yield: 40.8 %

Procedure:
A mixture of 7-chloro-5-methyl-1H-pyrazolo[4,3-b]pyridine (1.0 g, 0.006 mole) and isobutylamine (58 g) in water (100 ml) and ethanol (50 ml) was heated under reflux for 10 days. The reaction mixture was cooled and evaporated to dryness. The oily residue was basified to pH8-9 with 10% sodium carbonate solution. The residue was extracted with ethyl acetate (3×100 ml), dried (Na2SO4) and evaporated to dryness to give a yellow oil. This was purified by column chromatography on alumina, and eluted with chloroform/methanol to give the desired compound as a white solid (500 mg). m.p. 162°-164° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[N:19]([CH3:28])[C:20](=[O:27])[N:21]([CH3:26])[C:22](=[O:25])[C:23]=1[CH3:24]>>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[N:19]([CH3:28])[C:20](=[O:27])[N:21]([CH3:26])[C:22](=[O:25])[C:23]=1[CH3:24])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1c(NCCCCN)n(C)c(=O)n(C)c1=O
Reactant: c1ccc(OCC2CO2)cc1
Product: Cc1c(NCCCCNCC(O)COc2ccccc2)n(C)c(=O)n(C)c1=O
Reaction time: 48 h

Procedure:
4.5 g. Phenyl glycidyl ether and 12.0 g. 4-(4-aminobutylamino)-1,3,5-trimethylpyrimidine-2,6(1H,3H)-dione are mixed and left to stand for 48 hours at ambient temperature. The reaction mixture is then separated chromatographically and salt formation is carried out in the manner described in Example 29. There are obtained 2.6 g. (19% of theory) of the desired product in the form of colorless crystals; m.p. 148°-150° C., with bubble formation.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:22][C@H:11]1[CH2:10][C@@H:9]([O:8][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:14][CH2:13][N:12]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1C[C@@H](OS(C)(=O)=O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
Triethylamine (0.49 mL, 3.49 mmol) was added to a 0° C. solution of (rac)-tert-butyl (cis)-4-hydroxy-2-methylpiperidine-1-carboxylate (250 mg, 1.16 mmol) and methanesulfonyl chloride (0.14 mL, 1.74 mmol) in dichloromethane (4.5 mL). The resulting mixture was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (10 mL) and dichloromethane (10 mL) was added. The organic layer was separated and washed with 1M aqueous citric acid (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 20-30% ethyl acetate in hexanes) to afford (rac)-tert-butyl (cis)-2-methyl-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (315 mg, 92%) as a colorless oil that slowly solidified to a white solid upon standing. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.17 (d, J=7.04 Hz, 3H), 1.38 (s, 9H), 1.63-1.76 (m, 1H), 1.85-1.90 (m, 3H), 2.96-3.06 (m, 1H), 3.18 (s, 3H), 3.72-3.78 (m, 1H), 4.16-4.24 (m, 1H), 4.93-4.98 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH2:17]Br.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:17][C:16]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:15]=1[F:14])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)n1cccc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 2,4-difluorobenzyl bromide (1.03 eq.) and sodium hydride (1.3 eq.). ESI (m/z): 309 (M+H)+.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:32](O)[CH2:33][OH:34].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]2([O:34][CH2:33][CH2:32][O:26]2)[CH:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CN(Cc2ccccc2)CCC12OCCO2
Temperature: 25 °C
Yield: 66 %

Procedure:
p-Toluenesulfonic acid monohydrate (1.5 g) was added to a solution (600 ml) of ethyl 1-benzyl-4-oxo-3-piperidinecarboxylate (CAS Registry No. 1454-53-1, 44.7 g) and ethylene glycol (100 ml) in toluene and the resultant mixture was heated under reflux overnight. After cooling the mixture to room temperature, ice water (500 ml) and a saturated aqueous solution (300 ml) of sodium bicarbonate were added thereto followed by extraction with ethyl acetate (400 ml) for three times. The organic phase was washed successively with water (200 ml) twice and brine (300 ml) and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (30.4 g) as a yellow oil (yield: 66%).
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C@@H:26]([NH2:28])[CH3:27]>>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C@@H:26]([NH:28][CH2:16][CH2:15][C:2]1([OH:1])[CH2:3][CH2:4][C:5]2([O:6][CH2:7][C:8]([CH3:11])([CH3:12])[CH2:9][O:10]2)[CH2:13][CH2:14]1)[CH3:27]
Reactant: C[C@H](N)c1ccc(F)cc1F
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Product: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(F)cc1F
Yield: 66 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(2,4-difluoro-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 66% of theory; LC (method 5): tR=0.99 min; Mass spectrum (ESI+): m/z=384 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S(Cl)(Cl)=O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:7]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 87 %

Procedure:
A solution of 14.61 g. (0.079 m.) of 3-fluoro-4-nitrobenzoic acid, 200 ml. of benzene, 10 ml. of thionyl chloride, and 1 ml. of N,N-dimethylformamide was stirred overnight at room temperature under a calcium chloride drying tube. The resulting clear solution was then heated to reflux for one hour, after which time the solution was concentrated to approximately 75% of the original volume by distillation. The mixture was cooled by placing the flask in an ice bath. With additional cooling, 20 g. of aluminum chloride was added in portions through Gooch tubing over a period of about 45 minutes. The resulting dark mixture was stirred and allowed to warm to room temperature overnight. The reaction flask was again cooled in an ice bath as 300 ml. of 1N hydrochloric acid was added dropwise. The mixture was extracted several times with ethyl acetate and the combined extracts were washed with water, a saturated solution of sodium bicarbonate, water, a saturated solution of sodium chloride, and then dried over magnesium sulfate. Filtration and evaporation of the solvent in vacuo provided 16.8 g. (87% yield) of the desired compound as an oil which solidified on scratching. Recrystallization from 95% ethanol afforded yellow needles, m.p. about 77°-79° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:18][O:19][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH:10][C:9]3=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:37][C@H:38]2[CH2:42][CH2:41][CH2:40][O:39]2)(=O)=O)=CC=1>CC(=O)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:18][O:19][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:37][C@H:38]1[CH2:42][CH2:41][CH2:40][O:39]1)[C:9]3=[O:17]
Reactant: O=C1Nc2ccccc2C12COc1cc(Br)ccc12
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc(Br)ccc12
Yield: 101.7 %

Procedure:
To a stirred solution of 6-bromospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (1.3 g, 4.3 mmol) in 2-butanone (40.0 mL) was added cesium carbonate (4.2 g, 12.9 mmol) and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (1.4 g, 5.4 mmol). The reaction was refluxed for 16 h, filtered and concentrated in vacuo to dryness. The residue was purified by flash chromatography with 25% ethyl acetate in hexanes to afford 6-bromo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (1.75 g, 100%) as a colorless solid: MS (ES+) m/z 400.0 (M+1), 402.0 (M+1).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]1[CH:35]=[CH:34][C:12]([O:13][C:14]2[C:22]3[N:21]=[C:20](S(C)(=O)=O)[NH:19][C:18]=3[CH:17]=[C:16]([O:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH:15]=2)=[CH:11][CH:10]=1.[NH:36]1[CH:40]=[N:39][CH:38]=[N:37]1>C(OCC)(=O)C>[F:8][C:9]1[CH:35]=[CH:34][C:12]([O:13][C:14]2[C:22]3[N:21]=[C:20]([N:36]4[CH:40]=[N:39][CH:38]=[N:37]4)[NH:19][C:18]=3[CH:17]=[C:16]([O:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH:15]=2)=[CH:11][CH:10]=1
Reactant: c1nc[nH]n1
Reactant: CS(=O)(=O)c1nc2c(Oc3ccc(F)cc3)cc(Oc3cccnc3)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1ccc(Oc2cc(Oc3cccnc3)cc3[nH]c(-n4cncn4)nc23)cc1
Temperature: 160 °C
Reaction time: 8 h

Procedure:
5.0 mg of sodium hydride was added to a dimethylformamide (0.5 ml) solution of 16 mg of 4-(4-fluoro-phenoxy)-2-methanesulfonyl-6-(pyridin-3-yloxy)-1H-benzimidazole, and then 10.4 mg of [1,2,4]triazole was added to it, and the reaction liquid was stirred overnight at 160° C. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), ethyl acetate) to obtain the entitled compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[C:11]([O:14][C:15](=O)[CH3:16])(=O)[CH3:12]>>[CH2:11]([O:14][CH2:15][C:16]1[NH:10][C:8](=[O:9])[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=1)[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1nccnc1N
Product: CCOCc1nc2nccnc2c(=O)[nH]1

Procedure:
A mixture of 8.3 g (0.060 mole) of 3-amino-2-pyrazinecarboxamide [prepared according to R. C. Ellingson et al., J. Am. Chem. Soc. 1945, 67, 1711], 49.5 g (0.24 mole) of triethyl orthoethoxyacetate [prepared according to S. M. McElvain and P. M. Walters, J. Am. Chem. Soc. 1942, 64, 1963] and 53 ml of acetic anhydride is refluxed under a nitrogen atmosphere for 3 hours. The temperature of this reflux falls with the passage of time from 124° to 96° C. and then remains constant at the latter temperature. After cooling, the precipitate formed is isolated by filtration. It is washed with ether and recrystallized from ethanol. Yld: 5.5 g (44%), m.p. 168°-169° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]([F:12])=[C:10]([Br:13])[CH:9]=[C:8]([Br:14])[C:3]=1[C:4]([O:6]C)=[O:5].C(O)C.[OH-].[Na+]>O>[CH3:1][C:2]1[C:11]([F:12])=[C:10]([Br:13])[CH:9]=[C:8]([Br:14])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(Br)cc(Br)c(F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(F)c(Br)cc(Br)c1C(=O)O
Yield: 84.4 %

Procedure:
To methyl 2-methyl-3-fluoro-4,6-dibromobenzoate (75.5 g) are added ethanol (460 ml) and 10% aqueous solution of sodium hydroxide (460 ml) and the mixture is refluxed for 2 hours. After cooling, the reaction mixture is diluted with water and extracted with diethyl ether. The aqueous layer is made acidic with conc. hydrochloric acid and extracted with diethyl ether. The solvent is concentrated to give 2-methyl-3-fluoro-4,6-dibromobenzoic acid (61 g), m.p. 144°-146° C.