Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:25]([O-:27])=[O:26])[C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:70][N:71](C)CCN(C)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].[C-]#N.[Zn+2].[C-]#N>[C:70]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:25]([O-:27])=[O:26])[C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]1)#[N:71]
Reactant: O=C(N[C@H]1CCCN(c2c(Br)cncc2[N+](=O)[O-])C1)OCc1ccccc1
Reactant: CN(C)CCN(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cncc([N+](=O)[O-])c1N1CCC[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 140 °C
Yield: 225.7 %

Procedure:
A mixture of benzyl [(3S)-1-(3-bromo-5-nitropyridin-4-yl)piperidin-3-yl]carbamate (0.082 g, 0.19 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.0097 g, 0.0094 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.0109 g, 0.0188 mmol), zinc cyanide (0.066 g, 0.56 mmol), N,N,N′,N′-tetramethylethylenediamine (0.0114 mL, 0.0755 mmol) in DMF (1.40 mL) was in a vial was deoxygenated. The vial was purged with nitrogen several times, then sealed. The reaction mixture was heated in the sealed vial at 140° C. under microwave irradiation for 10 min. After cooling to ambient temperature, the crude reaction mixture was filtered through a pad of diatomaceous earth and the inorganics were washed thoroughly with EtOAc. The filtrate was diluted EtOAc (40 mL) and water (3 mL). The layers were separated and the organic layer was washed with water (3×3 mL). The combined aqueous phases were extracted with EtOAc (3 mL). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the sub-title compound (0.065 g). The crude product was used without further purification in the subsequent reaction. LCMS (ESI) calc. for C19H20N5O4 [M+H]+: m/z=382.1. found 382.0.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1C=C[C:7]([C:8](O)=O)=[CH:6][CH:5]=1.CCCC([O:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1Br)=[O:23])CC.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:3]([O:2][C:27]1[CH:26]=[CH:25][C:24]([C:22](=[O:23])[CH2:21][OH:20])=[CH:29][CH:28]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCC(CC)OCC(=O)c1ccccc1Br
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCOc1ccc(C(=O)CO)cc1
Temperature: 60 °C
Reaction time: 10 h
Yield: 45 %

Procedure:
To a solution of terephthalic acid monomethyl ester (1.0 g, 5.6 mmol) and 4-hexyloxy-2′-bromoacetophenone (synthesized by following (2.0 g, 6.7 mmol) in DMF (10 mL) was added K2CO3 (0.77 g, 5.6 mmol) and heated at 60° C. After 10 h, the reaction mixture was cooled to room temperature and poured into water. The product was extracted using EtOAc, washed with brine, dried and concentrated. The crude residue was purified by combiflash to afford 1.0 g (45%) product. 1H NMR (500 MHz, CDCl3): δ 0.94 (t, 3H, J=7.0 Hz), 1.36-1.39 (m, 4H), 1.48-1.58 (m, 2H), 1.81-1.85 (m, 2H), 3.99 (s, 3H), 4.07 (t, 2H, J=6.5 Hz), 5.58 (s, 2H), 6.99 (d, 2H, J=9.0 Hz), 7.92 (d, 2H, J=9.0 Hz), 8.16 (d, 2H, J=9.0), 8.122 (d, 2H, J=9.0 Hz).
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].C(Cl)(=O)C([Cl:16])=O>ClCCl>[CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([Cl:16])=[O:4]
Reactant: CC(C)(C(=O)O)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C(=O)Cl)c1ccccc1

Procedure:
A solution of 2-Methyl-2-phenylpropionic acid (10 mmol, 1.0 eq.) and oxalyl chloride (40 mmol, 4.0 eq.) in dichloromethane (30 mL) was stirred at room temperature for 18 h. The mixture was concentrated in vacuo to afford the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].Br[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br>>[CH3:25][O:24][C:11]1[CH:12]=[C:13]([C:20]([F:21])([F:22])[F:23])[CH:14]=[C:15]([C:16]([F:19])([F:18])[F:17])[C:10]=1[C:9]([NH:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]1[N:1]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26]
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: BrCCCCCBr
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N1CCCCC1

Procedure:
The title compound, white solid, MS: m/e=453.2 [(M+H)+], was prepared in accordance with the general method of example 10 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and 1,5-dibromopentane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([O:18]C)=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].C1COCC1>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2c1cccc(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)CCC2c1cccc(Br)c1

Procedure:
The title compound was synthesized from methyl 4-(3-bromophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.315 g, 0.98 mmol) and lithium hydroxide (0.415 g, 9.9 mmol), according to General Procedure 7. A 1:1 mixture of THF and methanol (8 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford the title compound. 0.119 g (40% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.16 (ddt, J=12.67, 8.50, 6.30, 6.30 Hz, 1H), 2.67-2.93 (m, 3H), 4.13 (t, J=7.20 Hz, 1H), 6.54 (s, 1H), 7.11-7.17 (m, 2H), 7.26-7.32 (m, 2H); LCMS (ESI+) 328.0 (M+Na); HPLC (UV=93.7%), (ELSD=99.9%).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:33]1[C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[CH:33]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:39]=2[C:40]2[C:45]1=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: BrC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN(C2c3ccccc3-c3ccccc32)[C@H](Cc2ccccc2)C1)C(F)(F)F
Yield: 47.4 %

Procedure:
200 mg (0.467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 25a with 138 mg (0.561 mmol) of 9-bromofluorene and 155 mg (1.12 mmol) of potassium carbonate in 2.5 ml of acetone. The title compound (131 mg, 47%) is obtained as oil. TLC:toluene/ethyl acetate (1:1) Rf =0.43; FD-MS:M+ =591.
Reaction SMILES: C(O[C:4]([CH2:6][N:7]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:8]([CH2:13]O)[C:9]([O:11][CH3:12])=[O:10])=[O:5])C.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]1[C:4](=[O:5])[CH2:6][N:7]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:8]([C:9]([O:11][CH3:12])=[O:10])[CH2:13]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)CN(C(CO)C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Reactant: NCc1ccccc1
Product: COC(=O)C1CN(Cc2ccccc2)C(=O)CN1S(=O)(=O)c1ccc(OC)cc1

Procedure:
A title compound was prepared by the same method as in Example 4, except that the compound of Example 3 and benzylamine were used.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:14](=[O:15])[C@@H:13]2[CH2:16][C@H:9]1[CH2:10][CH2:11][C@@H:12]2[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C@H:13]([CH2:14][OH:15])[CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
A solution of (1R,2S,5R)-2-benzyloxycarbonylamino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (10.21 g, 27.3 mmol) in tetrahydrofuran (200 mL) was treated with water (40 mL) and then with sodium borohydride (5.16 g, 136 mmol). The mixture was stirred at room temperature for 2 h, then was treated with saturated aqueous sodium bicarbonate and stirred until the bubbling subsided. The mixture was extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated under vacuum. The residue was recrystallized from ethyl acetate-hexane to provide (1R,3R,4S)-(4-benzyloxycarbonylamino-3-hydroxymethylcyclohexyl)carbamic acid tert-butyl ester as a white solid (6.8 g); additional product (2.1 g) was obtained by flash column chromatography of the residue from concentration of the mother liquors, eluting with 40%, then 50% ethyl acetate-hexane. MS found: (M+H)+=379.28.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(N(CC)CC)C.CN(C=O)C.Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27]>C1COCC1>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH3:27]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNc1cc(F)c(F)cc1[N+](=O)[O-]
Yield: 20.1 %

Procedure:
By using 2.00 g of 2,4,5-trifluoronitrobenzene, 3.43 g of triethylamine, 25 ml of DMF, 25 ml of THF and 1.58 g of glycine ethyl ester hydrochloride, 0.59 g (20%) of N-(4,5-difluoro-2-nitrophenyl)glycine ethyl ester was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:35]([CH3:44])([CH3:43])[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].O>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:35]([CH3:44])([CH3:43])[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl N-[(benzyloxy)carbonyl]-L-tyrosinate (1.00 g) in N,N-dimethylformamide (10.0 mL) were added potassium carbonate (2.71 g) and tert-butyl 2-bromo-2-methylpropanoate (2.01 mL), followed by stirring at 90° C. overnight. To the reaction suspension was added water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl N-[(benzyloxy)carbonyl]-O-(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)-L-tyrosinate (1.21 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([OH:23])=[N:12][C:13]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:14][C:15]=1[Cl:16].C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15]([Cl:16])=[N:14][C:13]([CH:17]2[CH2:18][CH2:19][N:20]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:21][CH2:22]2)=[N:12][C:11]=1[OH:23]
Reactant: Oc1nc(C2CCNCC2)nc(Cl)c1-c1nc2ccccc2s1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(c2nc(O)c(-c3nc4ccccc4s3)c(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.3 %

Procedure:
Into a mixture of 5-(1,3-benzothiazol-2-yl)-6-chloro-2-(piperidin-4-yl)pyrimidin-4-ol (50 g, 144.16 mmol, 1.00 equiv) and triethylamine (36.5 g, 361.39 mmol, 2.51 equiv) in dichloromethane (300 ml) was added benzyl chloroformate (29.5 g, 172.93 mmol, 1.20 equiv) dropwise. The resulting solution was stirred overnight at room temperature. Upon concentrated under vacuum, the residue was purified by flash chromatography on a silica gel column eluting with petroleum ether/ethyl acetate (2:1) to give 3 g of benzyl 4-[5-(1,3-benzothiazol-2-yl)-4-chloro-6-hydroxypyrimidin-2-yl]piperidine-1-carboxylate as yellow solid. MS m/z [M+H]+ (ESI): 481.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](Cl)=O)=[CH:5][CH:4]=1.[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[S:16][C:15]([NH2:17])=[N:14][N:13]=2)=[CH:5][CH:4]=1
Reactant: NNC(N)=S
Reactant: COc1ccc(CC(=O)Cl)cc1
Product: COc1ccc(Cc2nnc(N)s2)cc1
Temperature: 60 °C

Procedure:
A mixture of 2-(4-methoxyphenyl)acetyl chloride (88a, 3.05 g, 16.5 mmol), and thiosemicarbazide (1.37 g, 15.0 mmol) were heated to 60° C. for 3.0 hours. The reaction mixture was then cooled to room temperature, quenched with water and extracted with ethyl acetate. The organic layer was washed with brine and 50% NaOH(aq), dried over. MgSO4(s), and concentrated under reduced pressure to give 5-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (88b).
Reaction SMILES: [CH2:1]([O:8][NH:9][CH2:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19](O)=[O:20]>C(OC(=O)C)(=O)C>[CH:19]([N:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=[O:13])=[O:20]
Reactant: CC(C)CC(CNOCc1ccccc1)C(=O)O
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Product: CC(C)CC(CN(C=O)OCc1ccccc1)C(=O)O
Yield: 100 %

Procedure:
1.0 g of N-benzyloxy 2(RS)-isobutyl-3-amino-propionic acid in 10 ml of formic acid and 1 ml of acetic anhydride was stirred at room temperature for 2 hours and then evaporated. The residue was taken up in ethyl acetate, washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to yield 1.2 g (100%) of N-formyl-N-benzyloxy 2(RS)-isobutyl-3-aminopropionic acid as a gum. Rf (toluene/acetic acid 4:1) 0.39.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:15])=O>>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:15])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
A mixture of p-nitrobenzoic acid (500 g, 3.0 moles, 1 equiv) and thionyl chloride (600 mL, 8.2 moles, 2.73 equiv) is heated to reflux for approximately 6-7 hours until a clear solution is obtained. Excess of thionyl chloride is removed by distillation followed by co-distillation with toluene (300 mL). The reaction mass is cooled to room temperature, and hexane (1.5 L) is added, forming a precipitate, which is then filtered and dried under vacuum, yielding 4-nitrobenzoyl chloride as a yellow solid (530 g, approximately 100% yield), which is used without any further purification.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:5]([CH3:18])=[C:6]([CH:11]=[CH:12][C:13]=1[S:14]([CH3:17])(=[O:16])=[O:15])[C:7]([O:9][CH3:10])=[O:8].[CH3:19][O:20][CH2:21][CH2:22]Br.[I-].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:19][O:20][CH2:21][CH2:22][O:3][C:4]1[C:5]([CH3:18])=[C:6]([CH:11]=[CH:12][C:13]=1[S:14]([CH3:17])(=[O:16])=[O:15])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COCCBr
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(O)c1C
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1c(S(C)(=O)=O)ccc(C(=O)OC)c1C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a stirred suspension of sodium hydride (60%, 22.0 mg, 5.32 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added methyl 3-hydroxy-2-methyl-4-(methylsulfonyl)benzoate (1 g, 4.09 mmol) under nitrogen atmosphere at room temperature. After stirring for 30 minutes, 2-bromoethyl methyl ether (1.13 g, 8.18 mmol) and potassium iodide in a catalytic amount were added thereto, and the reaction solution was stirred at 60° C. for 12 hours. 200 mL of ethyl acetate was added to the reaction solution, and the solution was washed twice with a saturate brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2) to obtain methyl 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoate as an oil (680 mg).
Reaction SMILES: C12(COC3C(I)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[C:24]12([CH2:34][O:35][C:36]3[C:44]([C@@H:45]4[CH2:47][C@H:46]4[CH2:48][O:49][CH3:50])=[CH:43][C:39]([C:40](O)=[O:41])=[C:38]([F:51])[CH:37]=3)[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2.N1(S(N)(=O)=O)CCC1.[CH3:60][S:61]([NH2:64])(=[O:63])=[O:62]>>[C:24]12([CH2:34][O:35][C:36]3[C:44]([C@@H:45]4[CH2:47][C@H:46]4[CH2:48][O:49][CH3:50])=[CH:43][C:39]([C:40]([NH:64][S:61]([CH3:60])(=[O:63])=[O:62])=[O:41])=[C:38]([F:51])[CH:37]=3)[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2
Reactant: CS(N)(=O)=O
Reactant: COC[C@@H]1C[C@H]1c1cc(C(=O)O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Agent: NS(=O)(=O)N1CCC1
Agent: O=C(O)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: COC[C@@H]1C[C@H]1c1cc(C(=O)NS(C)(=O)=O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2

Procedure:
Following the procedure as described in Example 299 Step 2 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with 4-(adamantan-1-ylmethoxy)-2-fluoro-5-(trans-2-(methoxymethyl)cyclopropyl)benzoic acid and to replace azetidine-1-sulfonamide with methanesulfonamide, the title compound was obtained as a colorless solid (0.0678 g, quant.): 1H NMR (300 MHz, DMSO-d6) δ 11.89 (br s, 1H), 7.18 (d, J=8.3 Hz, 1H), 6.93 (d, J=13.1 Hz, 1H), 3.66 (d, J=9.4 Hz, 1H), 3.61 (d, J=9.5 Hz, 1H), 3.46-3.35 (m, 2H), 3.34 (s, 3H), 3.25 (s, 3H), 2.04-1.89 (m, 4H), 1.78-1.61 (m, 12H), 1.34-1.22 (m, 1H), 1.06-0.97 (m, 1H), 0.90-0.81 (m, 1H); MS (ES−) m/z 464.2 (M−1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][N:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[CH2:26][CH2:27][C:28](O)=[O:29])[CH3:2].C[CH2:32][N:33](C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN>CN(C=O)C.C1COCC1.C([O-])(O)=O.[Na+]>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:16][N:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[CH2:26][CH2:27][C:28]([NH:33][CH3:32])=[O:29])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1CCC(=O)O
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1CCC(=O)NC
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
To a solution of 3-{2-ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionic acid (40 mg 89 μmol) in DMF (5 mL), DIPEA (35 mg, 268 μmol) is added. The mixture is cooled to 0° C. before PyBOP (51 mg, 98 μmol) is added. The mixture is stirred at 0° C. for 15 min before methylamine (58 μL of a 2 M solution in THF) is added. The mixture is stirred at rt for 16 h, diluted with sat. aq. NaHCO3 solution, and extracted twice with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates using heptane:EA 1:4 to give the title compound (35 mg) as a white solid; LC-MS: tR=1.10 min, [M+H]+=421.25; 1H NMR (CDCl3): δ 1.00 (d, J=6.5 Hz, 6H), 1.31 (t, J=7.3 Hz, 3H), 1.89-2.00 (m, 1H), 2.34-2.41 (m, 2H), 2.44 (s, 3H), 2.47 (s, 3H), 2.63 (d, J=7.0 Hz, 2H), 2.76 (q, J=7.8 Hz, 2H), 2.85 (d, J=4.5 Hz, 3H), 3.06-3.13 (m, 2H), 5.38 (s br, 1H), 7.91 (s, 1H), 7.93 (s, 1H), 8.10 (s, 1H), 8.55 (s, 1H).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][C:12]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:14][C:13]1[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([F:20])([F:21])[F:22])[C:12]=1[CH3:11]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Cc1c(N)cccc1C(F)(F)F
Product: Cc1c(Nc2nc3ccccc3[nH]2)cccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 2-methyl-3-(trifluoromethyl)aniline by Procedure A. The product was isolated by filtration and preparative LCMS to give the title compound as the free base (white solid, mp 204-206° C.). MS(ES+) m/z 292 ([M+1]+, 100).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>[NH4+].[OH-]>[CH3:1][N:2]1[CH2:3][CH:4]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[N:10]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reactant: Brc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [NH4+]
Product: CN1CC=C(c2cn(-c3cccnc3)c3ccc([N+](=O)[O-])cc23)CC1
Temperature: 160 °C
Reaction time: 2.5 h

Procedure:
3-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro--1H-indole (4.5 g), 3-bromopyridin (6.0 g), CuBr (4.5 g) and K2CO3 (8.0 g) were heated under stirring at 160° C. for 2.5 h. After cooling the reaction mixture was poured into diluted NH4OH (500 ml) and extracted with ethyl acetate (2×300 ml). The combined organic phases were dried (MgSO4) and the solvent evaporated. The title compound was obtained by recrystallization from acetone. Yield: 3.4 g (58%). M.p. 175°-177° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:24]([N:26]([C:28]([NH2:30])=[O:29])[NH2:27])[CH3:25]>>[CH2:24]([N:26]([C:28]([NH2:30])=[O:29])/[N:27]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22])[CH3:25]
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: CCN(N)C(N)=O
Product: CCN(/N=C(\C)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1)C(N)=O
Yield: 57 %

Procedure:
The title compound was prepared in 57% yield as a white solid in analogy to the synthesis of example 52 from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone and 1-ethylhydrazine-carboxamide. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.61 (s, 1H), 8.89 (d, 1H), 8.36 (d, 1H), 8.03 (s, 1H), 8.00 (d, 1H), 7.83 (d, 1H), 7.53 (m, 1H), 6.61 (d, 2H), 6.22 (s, 2H), 3.80 (q, 2H), 2.42 (s, 3H), 1.07 (t, 3H). LCMS (method B): [MH]+=390, tR=1.98 min.