Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:71]/[O:72][C:73]([C:86]2[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=2)([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)/[C:27]([NH:29][CH:30]2[C:69](=[O:70])[N:32]3[C:33]([C:57]([O:59][CH2:60][C:61]4[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=4)=[O:58])=[C:34]([CH:37]=P(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:92]([O:99][CH2:100][CH:101]=O)([C:95]([CH3:98])([CH3:97])[CH3:96])([CH3:94])[CH3:93]>ClCCl.CCCCCC.C(OCC)(=O)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:71]/[O:72][C:73]([C:80]2[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=2)([C:74]2[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=2)[C:86]2[CH:87]=[CH:88][CH:89]=[CH:90][CH:91]=2)/[C:27]([NH:29][CH:30]2[C:69](=[O:70])[N:32]3[C:33]([C:57]([O:59][CH2:60][C:61]4[CH:62]=[CH:63][C:64]([O:67][CH3:68])=[CH:65][CH:66]=4)=[O:58])=[C:34](/[CH:37]=[CH:101]\[CH2:100][O:99][Si:92]([C:95]([CH3:96])([CH3:97])[CH3:98])([CH3:93])[CH3:94])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: COc1ccc(COC(=O)C2=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@@H]3C(NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C(/C=C\CO[Si](C)(C)C(C)(C)C)CS[C@@H]3C(NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 60 %

Procedure:
A solution of 4-methoxyphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(triphenylphosphoranylidene)methyl-3-cephem-4-carboxylate (9.07 g; 7.27 mmol) and t-butyldimethylsilyloxyacetaldehyde (1.8 g; 10.34 mmol) in dichloromethane (100 ml) was stirred at room temperature for 16 hours. After the solvent was distilled off under reduced pressure, the residue was purified by chromatography on a silica gel column (n-hexane:ethyl acetate=2.5:1) whereby the title compound (4.99 g; 4.36 mmol; 60.0%) was obtained.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([OH:10])=O.[CH2:11]([C@H:18]1[CH2:22][NH:21][C@H:20]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[O:24])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:22][N:21]([C:8](=[O:10])[CH2:7][C:3]2[S:2][CH:6]=[CH:5][CH:4]=2)[C@H:20]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:28][CH:27]=2)=[O:24])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)Cc1cccs1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)Cc1cccs1
Yield: 39.8 %

Procedure:
Proceeding as in Example 1, but substituting 2-(thien-2-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 117, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(thien-2-yl)acetyl)pyrrolidine-2-carboxamide (12.3 mg, 39.8%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.34 (s, 1H), 7.55-7.60 (m, 2H), 7.37-7.39 (m, 2H), 7.28-7.32 (m, 2H), 7.17-7.23 (m, 5H), 6.94-7.03 (m, 6H), 4.48-4.51 (m, 1H), 3.90 (d, 2H), 3.75-3.80 (m 1H), 3.56 (m, 1H), 2.63-2.73 (m, 3H), 1.88-1.97 (m, 2H). MS (EI) for C30H27FN2O3S. found 515.6 (MH+).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[O:3][C:2]=1[C:10]1[C:11]([NH2:27])=[N:12][CH:13]=[C:14]([C:16]2[CH:17]=NN(C3CCNCC3)[CH:20]=2)[CH:15]=1.[CH3:28][O:29][C:30]1C=C(B2OC(C)(C)C(C)(C)O2)C=[CH:32][C:31]=1[OH:45]>>[NH2:27][C:11]1[N:12]=[CH:13][C:14]([C:16]2[CH:20]=[CH:32][C:31]([OH:45])=[C:30]([O:29][CH3:28])[CH:17]=2)=[CH:15][C:10]=1[C:2]1[O:3][C:4]2[C:9]([N:1]=1)=[CH:8][CH:7]=[CH:6][N:5]=2
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cccnc2o1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: COc1cc(-c2cnc(N)c(-c3nc4cccnc4o3)c2)ccc1O
Yield: 101.6 %

Procedure:
Using the procedure described in the starting material portion of Example 41, 5-bromo-3-oxazolo[5,4-b]pyridin-2-yl-pyridin-2-amine (1 g, Example 9 starting material) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (902 mg) were reacted to afford 4-(6-amino-5-oxazolo[5,4-b]pyridin-2-yl-3-pyridyl)-2-methoxy-phenol (940 mg) as a solid. NMR Spectrum: (DMSOd6) 3.89 (s, 3H), 6.87 (d, 1H), 7.11 (dd, 1H), 7.25 (d, 1H), 7.53 (dd, 1H), 7.74 (bs, 2H), 8.29 (dd, 1H), 8.39 (dd, 1H), 8.44 (d, 1H), 8.57 (d, 1H), 9.11 (bs, 1H); Mass spectrum: M+H+ 335.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N+:2]=[N-:3].N([CH2:25][CH2:26]N)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:26]=[CH:25][C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1)=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Yield: 97.5 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.383 g, 1.43 mmol) the acid chloride was reacted with 2-azidoethanamine (0.124 g, 1.43 mmol) and triethylamine (0.290 g, 2.87 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-4-nonylbenzamide (0.441 g, 97% yield). 1H NMR (300 MHz, CDCl3) δ 7.72 (d, 2H), δ 7.26 (t, 1H), δ 7.18 (d, 2H), δ 3.57 (q, 2H), δ 3.45 (t, 2H), δ 2.60 (t, 2H), δ 1.58 (m, 2H), δ 1.27 (m, 12H), δ 0.86 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.5, 147.3, 131.7, 128.8, 127.4, 50.9, 39.7, 36.1, 32.1, 31.5, 29.8, 29.7, 29.6, 29.5, 22.9, 14.4 ppm; HRMS (ESI) calcd for C18H28N4O (M+) 316.2263. found 316.2268.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[C:6]([CH:24]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])=[CH:7][C:8]([N:11]([S:20]([CH3:23])(=[O:22])=[O:21])[NH:12]C(OC(C)(C)C)=O)=[N:9][CH:10]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>CCCCCC>[Cl:4][C:5]1[C:6]([CH:24]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)(=[O:34])=[O:35])[C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])=[CH:7][C:8]([N:11]([S:20]([CH3:23])(=[O:22])=[O:21])[NH2:12])=[N:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)NN(c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1)S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: CS(=O)(=O)N(N)c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 21 h
Yield: 64.9 %

Procedure:
To a methylene chloride (5 ml) solution of t-butyl N′-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]-N′-methylsulfonylhydrazine carboxylate (167 mg, 0.268 mmol) was added trifluoroacetic acid (2.5 ml). The resulting mixture was stirred at room temperature for 21 hours, followed by concentration under reduced pressure. To the residue thus obtained was added a saturated aqueous solution of sodium bicarbonate. The resulting mixture was extracted with methylene chloride. The organic layer obtained by separation was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate (=2:1) eluate was concentrated under reduced pressure to afford the title compound (91 mg, 0.174 mmol, 65%) as a white solid. The resulting solid was washed with ether and collected by filtration to give the title compound (60 mg) as a white powder.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].C(=O)(O)O.[NH2:10][C:11]([NH2:13])=[NH:12].C(=O)=O>O>[C:1]([O-:5])(=[O:4])[CH2:2][OH:3].[NH2:12][C:11]([NH2:13])=[NH2+:10]
Reactant: N=C(N)N
Reactant: O=C(O)CO
Agent: O=C(O)O
Agent: O=C=O
Solvent: O
Product: NC(N)=[NH2+]
Product: O=C([O-])CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Glycolic acid (3.0 g, 39.45 mmol) was dissolved in 15 ml of distilled water. Guanidine carbonate (3.55 g, 19.72 mmol) was added in portions at room temperature (carbon dioxide gas was evolved) and the reaction was stirred at room temperature for 4 hours. The water was removed in vacuo with heating to approximately 90° C. The product was isolated as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][CH2:13][O:14][C:7]3=[CH:6][C:5]=2[C:4](=O)[C:3]1=[O:16].O.NN>O1CCOCC1.C(OCC)(=O)C>[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][CH2:13][O:14][C:7]3=[CH:6][C:5]=2[CH2:4][C:3]1=[O:16]
Reactant: CN1C(=O)C(=O)c2cc3c(cc21)OCCO3
Agent: NN
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CN1C(=O)Cc2cc3c(cc21)OCCO3
Temperature: 25 °C
Yield: 87.5 %

Procedure:
To a solution of 6-methyl-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione (3.00 g, 13.7 mmol) in 1,4-dioxane (25 mL) was added hydrazine monohydrate (25 mL). The reaction mixture was stirred at reflux for 4 h, allowed to cool to ambient temperature, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was recrystallized from ethyl acetate/hexanes to afford 6-methyl-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one (2.46 g, 87%): 1H NMR (300 MHz, CDCl3) δ 6.75 (s, 1H), 6.49 (s, 1H), 4.19-4.12 (m, 4H), 3.36 (s, 2H), 3.00 (s, 3H); MS (ES+) m/z 206.2 (M+1).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]([CH3:16])[N:4]=1)=O.[C:17]([N:36]1[CH:40]=[CH:39][N:38]=[C:37]1[NH2:41])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C1(C)C=CC=CC=1>[CH3:16][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=2)[C:3]([CH2:1][NH:41][C:37]2[N:36]([C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:40]=[CH:39][N:38]=2)=[N:4]1
Reactant: COC(=O)c1ccc2c(C=O)nn(C)c2c1
Reactant: Nc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc2c(CNc3nccn3C(c3ccccc3)(c3ccccc3)c3ccccc3)nn(C)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product of Step A (204 mg, 1 mmol) is dissolved in toluene (10 mL) with N-trityl-2-aminoimidazole (357 mg, 1.1 mmol) and heated to reflux with a Dean-Stark trap. Four aliquots of toluene (3 mL each) are removed via distillation at 1.5 hour intervals, being replaced by dry toluene each time, and then the solution is left to reflux for 18 hours. The reaction is cooled to room temperature and sodium triacetoxyborohydride (1 gram, 5 mmol) is added in one portion. The reaction is stirred at room temperature for 24 hours, poured into water, and the layers separated. The aqueous layer is extracted with ethyl acetate and the combined organic layers are washed with saturated bicarbonate, water, and brine, dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[C:18]1([CH2:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:25](=[O:26])[CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][CH2:5]2
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Brc1ccc2c(c1)CCN2
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.4 %

Procedure:
To a solution of 5-bromoindoline (13.86 g) and triethylamine (8.50 g) in dichloromethane (100 mL) was added dropwise phenylacetyl chloride (11.9 g) at 5° C. and the mixture was stirred at ambient temperature for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to give 5-bromo-1-(phenylacetyl)indoline (16.01 g) as a white powder.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]([F:26])([F:25])[C:5]([F:24])([F:23])[O:6][C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[O:9][C:10]([F:18])([F:17])[CH2:11][O:12][CH2:13][CH2:14][CH2:15]Cl.BrCCCCl.FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)CO.[CH2:58]([C:66]1[CH:67]=[N:68][C:69]([C:72]2[CH:77]=[CH:76][C:75]([OH:78])=[CH:74][CH:73]=2)=[N:70][CH:71]=1)[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65]>>[CH2:58]([C:66]1[CH:71]=[N:70][C:69]([C:72]2[CH:77]=[CH:76][C:75]([O:78][CH2:15][CH2:14][CH2:13][O:12][CH2:11][C:10]([O:9][C:8]([F:19])([F:20])[C:7]([F:21])([F:22])[O:6][C:5]([F:23])([F:24])[C:4]([F:25])([F:26])[O:3][C:2]([F:28])([F:27])[F:1])([F:18])[F:17])=[CH:74][CH:73]=2)=[N:68][CH:67]=1)[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)COCCCCl
Agent: ClCCCBr
Agent: OCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F
Product: CCCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 3-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)1-chloropropane (18.3 g, 38.5 mmol; prepared from 1-bromo-3-chloropropane (107 g, 0.7 mol) and 2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethanol (125 g, 0.31 mol) essentially as in Example 2) with 5-octyl-2-(4-hydroxyphenyl)pyrimidine (10 g, 35 mmol). The crude product was further purified by Kugelrohr distillation (b.p. 200-210° C. at 0.4 torr; yield of 10.0 g).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]2[N:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=2)=[O:10])[CH2:3][CH2:2]1.[N:18]1([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH:1]1([CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]2[N:12]=[N:13][C:14]([N:21]3[CH2:22][CH2:23][N:18]([C:24](=[O:25])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:35])([F:33])[F:34])[CH2:19][CH2:20]3)=[CH:15][CH:16]=2)=[O:10])[CH2:3][CH2:2]1
Reactant: O=C(NCCCCC1CC1)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: O=C(NCCCCC1CC1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (4-cyclopropylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (3-cyclobutylpropyl)amide to react with piperazin-1-yl-(2-trifluoromethyl-phenyl)methanone, the title compound was obtained as a white powder (21% yield). 1H NMR (300 MHz, CDCl3) δ 8.03, 7.86, 7.72, 7.58, 7.34, 6.98, 4.05, 3.89-3.62, 3.48-3.31, 1.64-1.41, 1.20, 0.60, 0.39-0.30, −0.04. 13C NMR (75 MHz, CDCl3) δ 167.6, 162.9, 160.0, 145.4, 134.3, 132.4, 129.5, 127.2, 126.9, 126.7, 125.4, 121.8, 112.6, 46.4, 44.6, 44.4, 41.2, 39.5, 34.4, 29.4, 27.0, 10.7, 4.4. MS (ES+) m/z 476.1 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18]([C@@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[O:19])[O:14][N:13]=1)([CH3:11])[CH2:3][O:4]C1CCCCO1.CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(#N)C>O>[OH:4][CH2:3][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18]([C@@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[O:19])[O:14][N:13]=1)([CH3:11])[CH3:1]
Reactant: CC(C)(COC1CCCCO1)c1cc(NC(=O)[C@@H]2CCCN2c2ccc(Cl)cc2)on1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CC#N
Product: CC(C)(CO)c1cc(NC(=O)[C@@H]2CCCN2c2ccc(Cl)cc2)on1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of (S)-1-(4-Chloro-phenyl)-pyrrolidine-2-carboxylic acid {3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl}-amide (130 mg, 0.29 mmol) in the mixture of methanol in water (10:1, 3 mL) is added p-toluenesulfonic acid monohydrate (10 mg, 0.053 mmol) and acetonitrile (1 mL). The reaction mixture is stirred at room temperature for 18 hours. After this time, the reaction mixture is concentrated in vacuo. Purification by flash chromatography on silica gel using ethyl acetate/hexanes provides the title compound, ESI m/z 364 [M+H+].
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:14][S:15]([NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NS(C)(=O)=O)C1
Reaction time: 2 h

Procedure:
tert-Butyl(3S)-3-aminopyrrolidine-1-carboxylate (0.09 mL, 0.5 mmol) was combined with methanesulfonyl chloride (0.050 mL, 0.64 mmol) and triethylamine (0.22 mL, 1.6 mmol) in methylene chloride (2 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, and concentrated. The residue was purified on silica gel (eluting with 0-10% methanol in dichloromethane) to give tert-butyl(3S)-3-[(methylsulfonyl)amino]pyrrolidine-1-carboxylate, LCMS [M+Na]+: m/z=287.1. The latter was treated with 4.57 M hydrogen chloride in 1,4-dioxane (1 mL, 4 mmol) at room temperature for 1 hour. The mixture was concentrated to give the desired product, which was used directly in the next step. LCMS calculated for C5H13N2O2S (M+H)+: m/z=165.1; Found: 165.1.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:29])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=1)[C:11]([CH3:28])([CH3:27])[CH2:10]2)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:29][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:16]=1)[C:11]([CH3:28])([CH3:27])[CH2:10]2
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(N3CCOCC3)c1)C(C)(C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(Cl)cc(C(=O)O)c2NC1c1cccc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.8 %

Procedure:
To a stirred mixture solution of 6-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (400 mg, 1.0 mmol) in methanol (15.0 mL) and tetrahydrofuran (15.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 6-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (360 mg, 90%) as a light yellow solid: LC/MS m/e calcd for C22H25ClN2O3 (M+H)+: 401.91, observed: 401.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1Cl.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:3]2[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2c(Cl)cccc2[N+](=O)[O-])CC1
Yield: 70.2 %

Procedure:
To a stirred solution of 1,2-dichloro-3-nitrobenzene (0.96 g, 5.0 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.93 g, 5.0 mmol) in acetonitrile (5 mL) was added of K2CO3 (1.38 g, 10 mmol). The mixture was heated at reflux for 48 h. The solvent was removed under reduced pressure. The crude material was partitoned between EtOAc (100 mL) and H2O (20 mL). The organic layer was washed with H2O (2×20 mL), dried over Na2SO4 and concentrated. Column chromatography (silica, 10-20% EtOAc/hexanes) provided 4-(2-chloro-6-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.2 g, 70%). TLC (silica, 20% EtOAc/hexanes): Rf=0.45. MS (electrospray): exact mass calculated for C15H20CIN3O4, 341.1; m/z found, 364.1 [M+Na]30 . 1H NMR (400 MHz, CDCl3) 7.56 (dd, J=8.2, 1.4 Hz, 1H), 7.50 (dd, J=8.2, 1.4 Hz, 1H), 7.13 (t, J=8.2 Hz, 1H), 3.38-3.56 (m, 4H), 3.06 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: COCCOC.[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:21]([O:28][C:29]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[CH:48][C:30]=1[C:31]([NH:33][C:34]1[CH:46]=[C:45](Br)[CH:44]=[CH:43][C:35]=1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.O>[CH2:21]([O:28][C:29]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:53][CH2:54][O:55][CH2:56][CH2:57]2)=[CH:48][C:30]=1[C:31]([NH:33][C:34]1[CH:46]=[C:45]([C:8]2[O:7][CH:11]=[CH:10][CH:9]=2)[CH:44]=[CH:43][C:35]=1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1cc(N2CCOCC2)ccc1OCc1ccccc1
Reactant: OB(O)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccco2)cc1NC(=O)c1cc(N2CCOCC2)ccc1OCc1ccccc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
Ethylene glycol dimethyl ether (2.0 mL), water (0.60 mL), furan-2-boronic acid (0.047 g), sodium carbonate (0.093 g), and bis(triphenylphosphine)palladium(II) dichloride (4.9 mg) were added to tert-butyl 2-(2-(benzyloxy)-5-(morpholin-4-yl)benzamido)-4-bromobenzoate (0.20 g), followed by stirring at 75° C. for 2 hours. The reaction mixture was cooled to room temperature, and bis(triphenylphosphine)palladium(II) dichloride (4.9 mg) was added thereto, followed by stirring at 75° C. for 2 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 85-70% hexane/ethyl acetate] to obtain 0.14 g of tert-butyl 2-(2-(benzyloxy)-5-(morpholin-4-yl)benzamido)-4-(furan-2-yl)benzoate as a light yellow solid.