Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:13]=[CH:12][C:11]2[CH2:14][CH2:15][CH2:16][N:9]3[C:10]=2[C:2]=1[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=13.[N+:17]([O-])([O-:19])=[O:18].[K+]>S(=O)(=O)(O)O>[N+:17]([C:13]1[CH:1]=[C:2]2[C:10]3=[C:11]([CH2:14][CH2:15][CH2:16][N:9]3[C:8]3[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2=3)[CH:12]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])[O-]
Reactant: c1cc2c3c(c1)c1c(n3CCC2)CCCC1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2c3c(c1)c1c(n3CCC2)CCCC1

Procedure:
Following the procedure of Example 1, step 2, 5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazole (1.7 g, 8.0 mmol) and potassium nitrate (0.80 g, 8.0 mmol) in concentrated sulfuric acid (20 mL) provided 2-nitro-5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazole. MS (ES) m/z 257.1.
Reaction SMILES: [N:1]([CH:4]1[C:29](=[O:30])[N:6]2[C:7]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])=[C:8]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH2:9][S:10][C@:5]12[O:31][CH3:32])=[N+]=[N-].CCN(CC)CC>C(Cl)(Cl)Cl>[NH2:1][C@@H:4]1[C:29](=[O:30])[N:6]2[C:7]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])=[C:8]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH2:9][S:10][C@:5]12[O:31][CH3:32]
Reactant: CO[C@]12SCC(COC(C)=O)=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2N=[N+]=[N-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CO[C@]12SCC(COC(C)=O)=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)[C@H]2N
Reaction time: 0.17 h
Yield: 103.7 %

Procedure:
A solution of p-nitrobenzyl 7-azido-6-methoxy-3-acetoxymethyl-ceph-3-em-4-carboxylate (249 mg., 0.54 mMol) in CHCl3 (5 ml.) is cooled in an ice-bath and treated with Et3N (150 μl, 1.08 mMol). H2S is bubbled through the cold solution for 2-3 mins., followed by N2 for 10 mins. The resulting solution is diluted with cold CH2Cl2 (5 ml.), washed with cold dilute HCl to pH 6, cold H2O (3x) and brine, dried with MgSO4, filtered, and evaporated in vacuo to provide a mixture (245 mg.) of p-nitrobenzyl 7β-amino-6α-methoxy-3-acetoxymethyl-ceph-3-em-4-carboxylate and the corresponding 7α-amino-derivative as a yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Fc1ccncc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccncc5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-fluoro-pyridine following a procedure analogous to that described for Intermediate 12. LC (method 2): tR=0.93 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=2)=[O:10])[CH3:7])[CH2:3]1.[N+:39]([C:42]1[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[CH:44][CH:43]=1)([O-:41])=[O:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(Cl)Cl>[F:29][C:25]1[CH:24]=[C:23]2[C:28]([C:20]([C:17]3[N:18]=[C:19]4[C:11]([C:9]([NH:8][CH:6]([C@H:4]5[CH2:3][C@H:2]([O:1][C:46](=[O:47])[C:45]6[CH:44]=[CH:43][C:42]([N+:39]([O-:41])=[O:40])=[CH:50][CH:49]=6)[CH2:5]5)[CH3:7])=[O:10])=[CH:12][N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[C:14]4=[N:15][CH:16]=3)=[N:21][N:22]2[CH3:30])=[CH:27][CH:26]=1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](O)C1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(cis-3-hydroxy-cyclobutyl)-ethyl]-amide (200 mg, 0.37 mmol) in THF (4 mL) was added 4-nitrobenzoic acid (124 mg, 0.74 mmol) and triphenylphosphine (204 mg, 0.78 mmol). Then the reaction mixture was cooled to 0° C. and diethyl azodicarboxylate (123 μL, 0.78 mmol) was added dropwise. The reaction was stirred at room temperature overnight then diluted with CH2Cl2 (25 mL) and washed with 1.0 M aqueous NaOH. The aqueous phase was back-extracted with CH2Cl2 then the combined organics were dried over MgSO4 and concentrated. The residue was absorbed onto SiO2 and purified via chromatography with 20% to 80% EtOAc/hexanes to provide 250 mg (98%) of 4-nitrobenzoic acid trans-3-(1-{[2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-cyclobutyl ester as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]([N:15]([CH3:17])[CH3:16])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[K].[F:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][CH:42]=[C:41]2[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][C:52](O)=[O:53]>CO>[CH3:16][N:15]([CH3:17])[C:6]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:52](=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][C:41]2[C:40]3[C:44](=[CH:45][CH:46]=[C:38]([F:37])[CH:39]=3)[NH:43][CH:42]=2)[CH2:8][CH2:7]1
Reactant: O=C(O)CCCCCc1c[nH]c2ccc(F)cc12
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Agent: [K]
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)CCCCCc2c[nH]c3ccc(F)cc23)CC1
Reaction time: 72 h

Procedure:
A mixture of the diastereoisomers of (4-aminomethyl-1-phenylcyclohexyl)dimethylamine (347 mg, 1.49 mmol.) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (620 mg, 2.2 mmol.) was added to a solution of the potassium salt of 6-(5-fluoro-1H-indol-3-yl)hexanoic acid (430 mg, 1.49 mmol.) in abs. methanol (30 ml), and stirring was carried out for 3 d at RT. For working up, the mixture was concentrated, water (10 ml) and 2M HCl (15 ml) were added to the residue, and washing was carried out with ether (25 ml). The diethyl ether phase was separated off. The aqueous phase and oily drops contained therein were adjusted to pH 11 with 5M NaOH and extracted with EE (4×15 ml). The combined EE extracts were washed with 1M NaOH (2×2 ml), dried, filtered and concentrated. The residue was a diastereoisomeric mixture of the bases of the target product, which was separated by flash chromatography on silica gel (75 g) and purified (eluant: 1500 ml of methanol/EE 1:1). 192 mg of the non-polar diastereoisomer of 6-(5-fluoro-1H-indol-3-yl)hexanoic acid (4-dimethylamino-4-phenylcyclohexylmethyl)amide were obtained (m.p. 52–54° C.).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[N+:50]([C:53]1[CH:54]=[N:55][NH:56][CH:57]=1)([O-:52])=[O:51]>C1COCC1>[N+:50]([C:53]1[CH:54]=[N:55][N:56]([CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH:57]=1)([O-:52])=[O:51]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.7 %

Procedure:
1-Boc-4-hydroxy piperidine (2.6 g, 0.0132 mol), triphenylphosphine (4.1 g, 0.015 mol) and di-tert-butyl azodicarboxylate (3.9 g, 0.0172 mol) are added in portions to a solution of 4-nitro-1H-pyrazole (1.5 g, 0.0132 mol) in THF (40 ml) at 10-15° C. The reaction mixture is stirred at room temperature for 48 h. The mixture is evaporated in a rotary evaporator, and the crude material is chromatographed, giving 2.1 g of a white solid;
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[N:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>>[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[N:13]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(-c2ncccn2)cc1
Reactant: COC(=O)CCCCCCN
Agent: Cl
Product: COC(=O)CCCCCCNCc1ccc(-c2ncccn2)cc1

Procedure:
The title compound of Step A was prepared from 7-amino-heptanoic acid methyl ester hydrochloride, of Preparation 1, and 4-pyrimidin-2-yl-benzaldehyde, of Preparation 21, using the method described in Example 1, Step A. 1H NMR (400 MHz, CDCl3) δ 8.78 (d, 2H), 8.37 (d, 2H), 7.42 (d, 2H), 7.16 (t, 1H), 3.85 (s, 2H), 3.64 (s, 3H), 2.62 (t, 2H), 2.28 (t, 2H), 1.55 (m, 4H), 1.32 (m, 4H); MS 328 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]2[C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])=[O:5])C.O.[OH-].[Li+].Cl>O1CCOCC1.O>[F:23][C:17]1[CH:18]=[C:19]([I:22])[CH:20]=[CH:21][C:16]=1[NH:15][C:14]1[N:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:8]2=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc2ccncn2c1Nc1ccc(I)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc2ccncn2c1Nc1ccc(I)cc1F
Temperature: 60 °C

Procedure:
To a solution of 7-(2-fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid ethyl ester (230 mg, 0.54 mmol) in a mixture of dioxane (2 mL) and water (1 mL) was added lithium hydroxide monohydrate (45 mg, 1.08 mmol). The reaction was heated at 60° C. for 1 hour. Aqueous hydrochloric acid (1M) was added dropwise until pH˜5 causing a precipitate to form. The reaction mixture was filtered and the solid residue washed with ethyl acetate (5 mL) to yield the title compound as an off white solid (67 mg, 31%). LCMS (Method B): RT=3.22 min, M+H+=398.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.Br[C:11]([CH3:23])([CH3:22])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>C(#N)C>[F:1][C:2]1([F:8])[CH2:7][CH2:6][N:5]([C:11]([CH3:23])([CH3:22])[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:4][CH2:3]1
Reactant: CC(C)(Br)C(=O)OCc1ccccc1
Reactant: FC1(F)CCNCC1
Agent: Cl
Solvent: CC#N
Product: CC(C)(C(=O)OCc1ccccc1)N1CCC(F)(F)CC1
Temperature: 85 °C
Yield: 11.3 %

Procedure:
A stirred mixture of 4,4-difluoropiperidine/HCl (158 mg), benzyl 2-bromo-2-methylpropanoate (257 mg) and TEA (0.279 mL) in acetonitrile (1.5 mL) in a capped vial was heated at 85° C. overnight. The reaction mixture was evaporated to dryness and the residue was dissolved in ether, washed with satd. NaHCO3, water, brine and dried (MgSO4). The crude product was purified by silica gel FCC (0-1% MeOH in DCM) to afford benzyl 2-(4,4-difluoropiperidin-1-yl)-2-methylpropanoate as a viscous oil (33.7 mg). 1H NMR (400 MHz, CDCl3) δ ppm 7.31-7.46 (5H, m), 5.18 (2H, s), 2.66 (4H, t, J=5.40 Hz), 1.86-2.08 (4H, m), 1.36 (6H, s). Benzyl 2-(4,4-difluoropiperidin-1-yl)-2-methylpropanoate was debenzylated by hydrogenation (10% Pd/C, EtOAc) to afford Cap P-16 as a beige solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.00 (4H, br. s.), 2.18-2.43 (4H, m), 1.45 (6H, s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:11]([C@@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])[CH2:16][CH2:15]1)(=[O:13])[CH3:12]>C1COCC1.O>[OH:13][C:11]([C@@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])[CH2:16][CH2:15]1)([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH3:12]
Reactant: CCCCOC(=O)[C@H]1CC[C@@H](C(C)=O)CC1
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCOC(=O)[C@H]1CC[C@@H](C(C)(O)c2nccs2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of thiazole (800 mg, 9.40 mmol) in THF (94 mL) was cooled to −78° C. nBuLi (2.5 M in THF, 3759 μl, 9.40 mmol) was added and the solution was stirred for 30 minutes at −78° C. Butyl cis-4-acetylcyclohexanecarboxylate (2552 mg, 11.28 mmol) in THF (5 mL) was added in one portion and the solution was stirred for one hour at −78° C. The reaction was diluted with water and then warmed to room temperature. The mixture was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5-30% ethyl acetate/hexanes) to afford cis-butyl 4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexanecarboxylate. MS ESI calc'd. for C16H25NO3S [M+H+] 312. found 312.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([CH3:38])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([CH3:25])=[N:21][O:22][C:23]=2[CH3:24])=[C:15]([C:26]#[C:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[CH:34]=[N:33][CH:32]=[CH:31]3)[N:14]=1)=[O:11])C)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][C:20]1[C:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[CH:9]([NH:7][CH3:6])[CH3:38])=[N:14][C:15]=2[C:26]#[C:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[CH:34]=[N:33][CH:32]=[CH:31]3)=[C:23]([CH3:24])[O:22][N:21]=1
Reactant: Cc1noc(C)c1-c1ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc1C#Cc1ccc2cnccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(C)C(=O)Nc1ccc(-c2c(C)noc2C)c(C#Cc2ccc3cnccc3c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl-N-[1-[[5-(3,5-dimethyl-1,2-oxazol-4-yl)-6-(2-isoquinolin-6-yl-ethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]-N-methylcarbamate E2a (191 mg, 0.36 mmol) and DCM:TFA (9:1, 10 ml) is stirred at RT for 2 h. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 101 mg (65%). HPLC-MS: M+H=426; tR=1.30 min (*Method—1).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:43]=[CH:42][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)=[CH:20][C:19]=3[N:33]([CH3:41])C(=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1>FC(F)(F)C(O)=O>[CH3:41][N:33]1[C:19]2[CH:20]=[C:21]([O:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[CH:22]=[CH:23][C:18]=2[N:17]=[C:15]1[CH2:14][O:13][C:12]1[CH:42]=[CH:43][C:9]([CH2:8][CH:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[O:7])=[CH:10][CH:11]=1
Reactant: COc1ccc(Oc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc1
Yield: 72.3 %

Procedure:
A solution of t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-methoxyphenoxy)phenyl}-N-methylcarbamate (3.28 g) in trifluoroacetic acid (50 ml) was stirred at 65° C. for 8 hours and allowed to stand at ambient temperature for 1 night. The reaction mixture was concentrated and to the residue was added water and neutralized with aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate and then evaporated. On addition of ether/ethyl acetate=1/1 to the residue crystals were formed and isolated by filtration to give the title compound (1.91 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:6][C:7]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10].Cl>C1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:9]([C:8]1[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:7]=1[Cl:6])=[O:10]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: c1ccsc1
Agent: Cl
Solvent: c1ccccc1
Product: O=C(c1cccs1)c1ccc(F)cc1Cl
Reaction time: 3 h

Procedure:
To a stirred mixture of 25.25 parts of thiophene, 58.1 parts of 2-chloro-4-fluorobenzoyl chloride and 200 parts of anhydrous benzene are added dropwise 78.16 parts of stannic chloride (fuming) at room temperature (slightly exothermic reaction: the temperature is kept for 3 hours at 25° C). The reaction mixture is poured onto a mixture of crushed ice and concentrated hydrochloric acid solution. The while is stirred for a few minutes and the layers are separated. The organic layer is diluted with 80 parts of toluene, washed successively with 200 parts of sodium hydroxide solution 5% and with 200 parts of water, dried and evaporated. The residue is distilled, yielding 2-chloro-4-fluorophenyl 2-thienyl ketone; bp. 129°-130° C at 0.5 mm pressure.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3].CO[CH2:15][N:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:17][Si](C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:22]([N:16]1[CH2:15][CH2:3][CH:2]([C:1]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH2:17]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=CC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.9 %

Procedure:
A solution of 10.0 g (61.6 mmol) of benzyl acrylate and 19 mL (74.2 mmol) of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine in 75 mL of CH2Cl2 at 0° C. was treated with 0.5 mL (6.5 mmol) of TFA while maintaining the internal temperature at less than 3° C. The reaction was warmed to rt and stirred for 2.5 h. The reaction mixture was washed with 250 mL of 1N NaHCO3 and 250 mL of sat'd NaCl. The organic layer was dried over Na2SO4 and concentrated. The residue was purified on a 40L Biotage column using 19:1 v/v hexane/acetone as the eluant to afford 18 g (99%) of the title compound as a light yellow oil: RF: 0.28 (9:1 v/v hexane/acetone); 1H-NMR (500 MHz) δ 2.15-2.20 (m, 2H), 2.60 (m, 1H), 2.73-2.77 (m, 2H), 3.02 (m, 1H), 3.13 (m, 1H), 3.66-3.73 (m, 2H), 5.17 (s, 2H), 7.28-7.42 (m, 5H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29](O)=[O:30])[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.CCCP(=O)=O.[O:45]1[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][CH2:53][NH2:54])[CH2:47][CH2:46]1>CN(C1C=CN=CC=1)C.ClCCCl>[CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29]([NH:54][CH2:53][CH2:52][CH2:51][N:48]5[CH2:49][CH2:50][O:45][CH2:46][CH2:47]5)=[O:30])[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: NCCCN1CCOCC1
Reactant: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cncc4C(=O)O)C3)c2)c1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cncc4C(=O)NCCCN4CCOCC4)C3)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.3 %

Procedure:
To a mixture of 7-(3-{[(3-isopropylphenyl)amino]carbonyl}phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carboxylic acid (25 mg, 0.06 mmol), triethylamine (0.017 mL, 0.12 mmol), and catalytic DMAP in 1.1 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.043 mL, 0.072 mmol). After 5 min at rt, 3-morpholinopropylamine (0.011 mL, 0.072 mmol) was added and the reaction stirred at rt for 1.5 hours. The reaction was partitioned between EtOAc and brine/aqueous NaHCO3 solution, the EtOAc layer washed with brine/aqueous NaHCO3 solution, dried with anhydrous Na2SO4 and rotary evaporated. This material was chromatographed eluting with CHCl3/MeOH to give the title compound as an off-white solid (17 mg, 54%). 1H NMR (CDCl3) δ: 8.50 (s, 1H), 8.48 (s, 1H), 7.83-7.92 (m, 2H), 7.54 (d, J=4.7 Hz, 2H), 7.46 (d, J=8.2 Hz, 1H), 7.34-7.41 (m, 1H), 7.20-7.33 (m, 2H), 7.13 (d, J=7.9 Hz, 1H), 7.03 (d, J=7.3 Hz, 1H), 4.50 (s, 2H), 3.52-3.63 (m, 8H), 3.23 (t, J=5.7 Hz, 2H), 2.87-2.98 (m, 1H), 2.56 (t, J=6.0 Hz, 2H), 2.47 (br. s., 4H), 1.75-1.85 (m, 2H), 1.27 (d, J=7.0 Hz, 6H)
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([CH2:15][C:16]([OH:18])=O)[CH:14]=2)[S:3]1.[F:21][C:22]([F:31])([F:30])[C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O>[F:21][C:22]([F:30])([F:31])[C:23]1[CH:24]=[CH:25][C:26]([NH:27][C:16](=[O:18])[CH2:15][C:13]2[CH:14]=[C:9]([CH:8]=[C:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])[CH:10]=[CH:11][C:12]=2[O:19][CH3:20])=[CH:28][CH:29]=1
Reactant: COc1ccc(C=C2SC(=O)NC2=O)cc1CC(=O)O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C=C2SC(=O)NC2=O)cc1CC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 72.1 %

Procedure:
2-[5-[(2,4-Dioxothiazolidin-5-ylidene)methyl]-2-methoxyphenyl]-acetic acid (440 mg, 1.50 mmol), 4-(trifluoromethyl)aniline (242 μL, 1.50 mmol), triethylamine (210 μL, 1.51 mmol) and dehydrated N,N-dimethylformamide (5 mL) were mixed, and, under an atmosphere of argon, diethyl cyanophosphate (228 μL, 1.50 mmol) was added under cooling with ice and stirring. After stirring for 1 hour at room temperature, the mixture was allowed to stand for 3 days. The reaction mixture was poured into ice water and the precipitated crystals were collected by filtration. The crystals were washed with ethyl acetate, and then dried to obtain 472 mg (72%) of the title compound as yellow crystals.
Reaction SMILES: C(OC(N1C[CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=O)(C)(C)C.[CH3:31][O:32][C:33]1[CH:39]=CC(N)=C[CH:34]=1>>[CH3:31][O:32][C:33]1[CH:39]=[CH:9][C:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])=[CH:11][CH:34]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: COc1ccc(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 4-methoxyaniline instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 365 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, br. s.) 10.14 (1H, s) 9.73 (1H, s) 8.00 (1H, d, J=5.42 Hz) 7.85 (1H, d, J=5.42 Hz) 7.44-7.55 (3H, m) 7.29 (1H, dd, J=3.20, 2.71 Hz) 6.89 (2H, d, J=8.98 Hz) 6.80 (1H, d, J=5.47 Hz) 6.42 (1H, dd, J=3.47, 1.90 Hz) 3.72 (3H, s)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([C@@H:18]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:19]3[CH:20]=[C:21]([C:25](=[NH:28])[NH:26][OH:27])[CH:22]=[CH:23][CH:24]=3)[CH2:15]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:36](OCC)(OCC)OCC>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:15][N:16]([C@@H:18]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:19]3[CH:20]=[C:21]([C:25]4[N:28]=[CH:36][O:27][N:26]=4)[CH:22]=[CH:23][CH:24]=3)[CH2:17]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(F)[C@H](c1cc(F)cc(Br)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C(=N)NO)c2)C1
Solvent: Cc1ccccc1C
Product: CC(C)(F)[C@H](c1cc(F)cc(Br)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(-c3ncon3)c2)C1
Temperature: 127.5 °C
Reaction time: 4 h

Procedure:
A mixture of 70 mg (0.125 mmol) of 3-[(S)-{3-[(1S)-1-(3-bromo-5-fluoro phenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}(4-chlorophenyl)methyl]-N-hydroxybenzenecarboximidamide, 1.5 mL of triethyl orthoformate, and 2 mL of xylene was stirred for 4 h at 125-130° C. Then it was concentrated, and the residue was purified by silica gel chromatography with hexanes/acetone to afford the title compound as a white solid; Mass Spectrum: m/e=572 (M+1, 35Cl), 574 (M+1, 37Cl).