Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:27])[C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[C:22]([C:24]([OH:26])=O)[N:23]=[C:17]3[CH:16]=2)=[O:13])=[O:6])[CH2:4][CH2:3][CH2:2]1.[F:28][C:29]([F:34])([F:33])[CH2:30][CH2:31][NH2:32].C(N(C(C)C)C(C)C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:27])[C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[C:22]([C:24]([NH:32][CH2:31][CH2:30][C:29]([F:34])([F:33])[F:28])=[O:26])[N:23]=[C:17]3[CH:16]=2)=[O:13])=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(C(=O)O)nc2c1
Reactant: NCCC(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(C(=O)NCCC(F)(F)F)nc2c1
Reaction time: 10 h
Yield: 17.6 %

Procedure:
A mixture of 7-(4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamido)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (140 mg, 0.379 mmole), 3,3,3-trifluoropropan-1-amine (214 mg, 1.9 mmole), N-ethyldiisopropylamine (265 ul, 1.52 mmole) and 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 569 ul, 0.948 mmole) in tetrahydrofurane (7 ml) is stirred for 10 h at roomtemperature. The reaction mixture is poured on sat. aqueous sodium bicarbonate solution (60 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layer is washed once with water, once with brine, dried with magnesium sulfate and the solvent is removed in vacuo. Purification of the residue by chromatography on a 12 g silica cartridge (eluent dichloromethane+2% methanol) affords 7-(4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamido)-N-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (31 mg, 17.6%) as a white foam. MS: m/z=465.3 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[C:33]([CH3:38])=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)=[O:25])(C)(C)C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH:15][C:22](=[O:21])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[C:33]([CH3:38])=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1N
Reactant: Cc1ncccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: Cc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(F)ccc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-4-fluoro-phenyl)-carbamic acid tert-butyl ester (Example J2) (170 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K5) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (308 mg).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1>C(O)(=O)C.Cl.[Pt]=O>[F:1][C:2]([F:10])([F:9])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1
Reactant: FC(F)(F)c1ccccn1
Agent: O=[Pt]
Agent: Cl
Solvent: CC(=O)O
Product: FC(F)(F)C1CCCCN1
Reaction time: 72 h

Procedure:
A mixture of 2-(trifluoromethyl)pyridine (0.38 g, 2.60 mmol) and platinum oxide (0.04 g, 0.18 mmol) in acetic acid (15 mL) and concentrated hydrochloric acid (2 mL) was hydrogenated in a Parr apparatus at 40 psi for 3 d. Filtration through celite and concentration of the filtrate provided 2-(trifluoromethyl)piperidine as hydrochloride salt which was used without further purification. 1H NMR (400 MHz, methanol-d4): 4.18 (m, 1H), 3.50 (m, 1H), 3.15 (m, 1H), 2.16 (m, 1H), 1.99 (m, 2H), 1.71 (m, 3H).
Reaction SMILES: Cl.COC(=O)[C@H]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])CC1C=CC(NC(OC(C)(C)C)=O)=C(C)C=1CO.Cl.[CH3:37][O:38][C:39](=[O:58])[C@@H:40]([CH2:46][C:47]1[C:48]([CH2:56][Cl:57])=[C:49]2[C:53](=[CH:54][CH:55]=1)[NH:52][N:51]=[CH:50]2)CC(OC)=O>>[ClH:57].[CH3:37][O:38][C:39](=[O:58])[C@H:40]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:46][C:47]1[C:48]([CH2:56][Cl:57])=[C:49]2[C:53](=[CH:54][CH:55]=1)[NH:52][N:51]=[CH:50]2
Reactant: COC(=O)C[C@H](Cc1ccc2[nH]ncc2c1CCl)C(=O)OC
Reactant: COC(=O)[C@@H](Cc1ccc(NC(=O)OC(C)(C)C)c(C)c1CO)NC(=O)OCc1ccccc1
Agent: Cl
Product: COC(=O)[C@@H](Cc1ccc2[nH]ncc2c1CCl)NC(=O)OCc1ccccc1
Yield: 99 %

Procedure:
2-(R)-Benzyloxycarbonylamino-3-(4-tert-butoxycarbonylamino-2-hydroxymethyl-3-methyl-phenyl)-propionic acid methyl ester hydrochloride was reacted in a manner analogous to the preparation of 2-(S)-(4-chloromethyl-1H-indazol-5-ylmethyl)-succinic acid dimethyl ester hydrochloride. Title compound was obtained as an orange solid in 99% yield. 1H NMR (300 MHz, CD3OD): δ=8.43 (s, 1H), 7.50 (d, J=8.8, 1H), 7.38 (d, J=8.4, 1H), 7.24 (m, 5H), 5.06 (d, J=11.0, 1H), 4.98 (d, J=4.8, 2H), 4.56 (dd, J1=5.7, J2=9.3, 1H), 3.71 (s, 3H), 3.42 (dd, J1=5.5, J2=14.3, 1H), 3.17 (dd, J1-9.3, J2=14.1, 1H). MS m/e (M+H)+=402.0.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[ClH:18].[CH2:19]([NH:26][C:27]1[C:36]([CH2:37][Cl:38])=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:39][CH3:40])[CH:33]=2)[N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:38].[ClH:18].[CH2:19]([NH:26][C:27]1[C:36]([CH2:37][C:6]2[C:7]3[C:12](=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=3)[C:3]([CH2:1][CH3:2])=[N:4][C:5]=2[OH:17])=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:39][CH3:40])[CH:33]=2)[N:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: COc1ccc2nc(NCc3ccccc3)c(CCl)cc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NCc2ccccc2)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 9 %

Procedure:
To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (70 mg, 0.30 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added N-benzyl-3-(chloromethyl)-6-methoxyquinolin-2-amine hydrochloride SLA 41008 (105 mg, 0.30 mmol) followed by a 2 N aq. LiOH (0.30 mL, 0.60 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) provided, after evaporation, 17.3 mg of 4-((2-(benzylamino)-6-methoxyquinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.28 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((2-(benzylamino)-6-methoxyquinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 44 as a yellow solid (16 mg, 9% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]=[C:16]([NH:20][NH2:21])[C:15]=3[CH2:22][CH2:23][CH3:24])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:25](OC(=O)C)(=O)[CH3:26].C([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]4[C:25]([CH3:26])=[N:21][N:20]=[C:16]4[C:15]=3[CH2:22][CH2:23][CH3:24])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1c(Cn2ccnc2-c2ncccc2F)ncnc1NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2c(C)nnc12
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A suspension of 131 (620 mg, 0.7 mmol) and acetic anhydride (2 mL) is stirred at 110° C. for one hour. NaHCO3 (aq.) (10 mL) and dichloromethane (10 mL) are added. The organic layer is separated and the aqueous layer is extracted with dichloromethane (2×10 mL). The combined organic layers are dried (NaSO4) and solvent removed. The crude product is separated by PTLC (5% methanol in dichloromethane) to yield 186; LC-MS, M+1 352.18; 1H-NMR (CDCl3) δ: 8.59 (s, 1H), 8.42 (d, 1H), 7.54 (t, 1H), 7.23–7.35 (m, 2H), 7.21 (s, 1H), 5.77 (s, 2H), 2.98 (t, 2H), 2.78 (s, 3H), 1.62–1.74 (m, 2H), 0.97 (t, 3H).
Reaction SMILES: [ClH:1].[C:2](=[NH:7])([O:4]CC)[CH3:3].[NH2:8][CH2:9][C:10]([NH:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])=[O:11]>C(O)C>[ClH:1].[CH3:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=1[NH:12][C:10]([CH2:9][NH:8][C:9](=[N:8][CH2:3][C:2](=[O:7])[NH:4][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])[CH3:10])=[O:11]
Reactant: Cc1cccc(C)c1NC(=O)CN
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Product: CC(=NCC(=O)Nc1c(C)cccc1C)NCC(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4.85 Grams (0.039 mole) of ethyl acetimidate hydrochloride and 7.0 g of 2-amino-2',6'-dimethylacetanilide were dissolved in 75 ml of anhydrous ethanol and stirred at room temperature for two days. The solid which formed was collected on a filter, recrystallized from ethanol, and dried overnight under vacuum at 60° C. M.P. 240°-241° C.
Reaction SMILES: C[N:2](C)[C:3](=[N:5][C:6](=O)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([O:15][CH3:16])=[N:9][C:8]=1[CH3:17])[CH3:4].O.[NH2:21]N>C(O)(=O)C>[CH2:13]([C:11]1[C:10]([O:15][CH3:16])=[N:9][C:8]([CH3:17])=[C:7]([C:6]2[N:5]=[C:3]([CH3:4])[NH:2][N:21]=2)[CH:12]=1)[CH3:14]
Reactant: CCc1cc(C(=O)N=C(C)N(C)C)c(C)nc1OC
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(-c2n[nH]c(C)n2)c(C)nc1OC
Temperature: 90 °C
Reaction time: 12 h
Yield: 79.7 %

Procedure:
In a round bottom flask under a nitrogen atmosphere N-(1-dimethylaminoethylidene)-5-ethyl-6-methoxy-2-methyl-nicotinamide (synthesized on 0.567 mmol scale) prepared in accordance with the procedures of Step 1, Example 19 is treated with glacial acetic acid (1 mL), followed by hydrazine hydrate (36 μL, 0.742 mmol). The resulting mixture is stirred at 90° C. for 12 hr. The reaction mixture is evaporated and the residue is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (49:1). Fractions containing the product are combined, evaporated and re-purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (99:1). Fractions containing the product are combined and the solvent evaporated to give 3-ethyl-2-methoxy-6-methyl-5-(5-methyl-1H-1,2,4-triazol-3-yl)pyridine (105 mg, 80% yield, 2 steps) as a orange-red. MS: m/e=233 (M+H); 1H NMR (CDCl3, δ, ppm): 9.8-11.6 (1H, br.s), 7.81 (1H, s), 3.97 (3H, s), 2.69 (3H, s), 2.59 (2H, q), 2.52 (3H, s), 1.19 (3H, t).
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:22])=[O:21])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:33][O:34][C:35](=[O:38])[CH2:36]Br.CCCCCC>CN(C=O)C.CCOC(C)=O>[CH3:33][O:34][C:35](=[O:38])[CH2:36][N:19]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:21])=[O:22])[C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([CH2:9][C:8]1[CH:29]=[CH:30][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=1)[CH:11]=[CH:12]2
Reactant: COC(=O)CBr
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(NS(=O)(=O)c4ccccc4)ccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)CN(c1ccc2c(ccn2Cc2ccc(C(C)(C)C)cc2)c1)S(=O)(=O)c1ccccc1
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To N-[1-(4-tert-butyl-benzyl)-1H-indol-5-yl]-benzenesulfonamide (0.20 g, 0.48 mmol) in DMF (5 ml) at room temperature under a nitrogen atmosphere was added sodium hydride (60% dispersion in mineral oil, 0.03 g, 0.72 mmol) in one portion. The resulting brown mixture was stirred 10 minutes upon which bromo-acetic acid methyl ester was added (0.19 g, 0.96 mmol). After 90 minutes total reaction time, the reaction was quenched with water (2 ml). The brown solution was partitioned between EtOAc (15 ml) and H2O (10 ml) and the layers were separated. The aqueous layer was extracted with EtOAc (5 ml). All organics were combined, extracted with brine (3×10 ml), dried with MgSO4, filtered and concentrated in vacuo to afford a brown powder. Gradient SiO2 chromatography (Hexane:EtOAc) afforded {benzenesulfonyl-[1-(4-tert-butyl-benzyl)-1H-indol-5-yl]-amino}-acetic acid methyl ester as a pale red powder (0.18 g, 72% yield): MS (ESI) m/z 533.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[OH:8].[H-].[Na+].Br[CH2:14][CH:15]1[CH2:17][CH2:16]1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[C:7](=[O:8])[C:6]([O:9][CH3:10])=[CH:5][N:4]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[N:3]=1
Reactant: COc1cnnc(Cl)c1O
Reactant: BrCC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cn(CC2CC2)nc(Cl)c1=O
Reaction time: 0.5 h

Procedure:
3-Chloro-5-methoxypyridazin-4-ol (0.20 g) was dissolved in DMF (3.1 mL), NaH (0.0595 g, 60%, in oil) and tetrabutylammoniumiodide (0.0916 g) were added at 0° C., and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added (bromomethyl)cyclopropane (0.138 mL) at 0° C., and the mixture was stirred at 0° C. for 2.5 hr, at room temperature for 1 day and at 40° C. for 20 hr. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate/hexane→methanol/ethyl acetate) to give the title compound (0.136 g).
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][O:31][CH3:32])([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[CH3:32][O:31][CH2:30][C:10]1[CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])[CH:13]=[CH:14][C:9]=1[O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1COC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1OC(C)(C)C(=O)O
Temperature: 55 °C
Yield: 64.8 %

Procedure:
A 25 mL round bottomed flask was charged with 2-{2-methoxymethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic acid ethyl ester (0.039 g, 0.087 mmol), ethanol (2 mL), and then aqueous 2N NaOH (0.22 mL, 0.44 mmol). The solution was heated at 55° C. for 1 h. The mixture was concentrated, acidified using 5% H2SO4 (1.5 mL), and partitioned between CH2Cl2 (15 mL) and brine (15 mL). The organic layer was dried (Na2SO4), filtered, and concentrated and to give a white solid (0.024 g, 66%). MS (ES) m/e 426 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[F:30][C:31]1[C:39]([F:40])=[C:38]([F:41])[C:37]([F:42])=[C:36]2[C:32]=1[CH:33]=[CH:34][NH:35]2.C([SiH](CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:33]2[C:32]3[C:36](=[C:37]([F:42])[C:38]([F:41])=[C:39]([F:40])[C:31]=3[F:30])[NH:35][CH:34]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1c(F)c(F)c2[nH]ccc2c1F
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(c2c[nH]c3c(F)c(F)c(F)c(F)c23)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
To a solution of N-benzyloxycarbonyl-4-piperidone (20.2 g, 90.6 mmol) in methylene chloride (600 ml) at 0° C. was added trimethylsilyl trifluoromethanesulfonate (35.1 ml, 181.2 mmol) followed by the slow dropwise addition of a solution of 4,5,6,7-tetrafluoroindole (17.1 g, 90.6 mmol) in methylene chloride (300 ml) over 2.5 h. After 1.5 h, triethylsilane (57.9 ml, 362.4 mmol) was added and the reaction was allowed to warm to RT over 30 min. The reaction mixture was quenched with sat. sodium bicarbonate and the separated organic layer was dried over MgSO4 and concentrated in vacuo. The residue was partitioned between 50% acetonitrile/hexanes (1400 ml) and the separated acetonitrile layer was concentrated in vacuo. The solid residue was recrystallized from absolute EtOH to afford N-benzyloxycarbonyl-4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine (66%) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:35]=[CH:36][CH:37]=1)[CH2:14][N:15]1[CH2:34][CH2:33][C:18]2([O:23][C:22]([CH3:25])([CH3:24])[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]2)[CH2:17][CH2:16]1.C1(C)C=CC=CC=1>C(Cl)Cl>[CH3:24][C:22]1([CH3:25])[CH2:21][NH:20][CH2:19][C:18]2([CH2:33][CH2:34][N:15]([CH2:14][C:13]3[CH:12]=[C:11]([CH2:10][CH2:9][OH:8])[CH:37]=[CH:36][CH:35]=3)[CH2:16][CH2:17]2)[O:23]1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)OC2(CCN(Cc3cccc(CCO)c3)CC2)C1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CNCC2(CCN(Cc3cccc(CCO)c3)CC2)O1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl 9-(3-(2-hydroxyethyl)benzyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (Example 271, step d) (0.78 g) in DCM (20 mL) and the reaction mixture allowed to stand for 30 minutes at 20° C. Toluene (40 mL) was added and the solvents evaporated under reduced pressure, the residue was azeotroped with acetonitrile (×2). The residue was dissolved in water (30 mL) and washed with ethyl acetate, the aqueous layer was basified by addition of solid sodium carbonate and stirred for 30 minutes at 20° C. The aqueous mixture was then extracted with DCM (×6), the combined DCM layers were dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.4 g.
Reaction SMILES: [CH3:1][P:2]([C:6]1[CH:11]=[C:10]([S:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:7]=1[N+:15]([O-])=O)(=[O:5])[O:3][CH3:4]>C(O)(=O)C.[Fe]>[CH3:1][P:2]([C:6]1[CH:11]=[C:10]([S:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:7]=1[NH2:15])(=[O:5])[O:3][CH3:4]
Reactant: CCSc1ccc([N+](=O)[O-])c(P(C)(=O)OC)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: CCSc1ccc(N)c(P(C)(=O)OC)c1

Procedure:
To a solution of methyl P-methyl-2-nitro-5-ethylthiophenylphosphinate (3.6 g) in 5% aqueous acetic acid (40 ml) is added 3.0 g of iron by portions at reflux temperature. After addition is complete, the mixture is heated under reflux for another 2 hours. The reaction mixture is filtered and the filtrate is extracted with methylene chloride (3×). The combined extracts are washed, dried and concentrated to dryness to yield methyl P-methyl-2-amino-5-ethylthiophenylphosphinate.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=O)[CH2:6]1)[CH:2]([CH3:4])[CH3:3].[C:12]([O-:17])(=[O:16])[C:13]([CH3:15])=O.[Na+].Cl.Cl.N1C=CC=CC=1>C(O)(=O)C>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:13]([CH3:15])[C:12]([OH:17])=[O:16])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(=O)C(=O)[O-]
Reactant: CC(C)CC1CCCC(=O)C1
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1

Procedure:
The process according to claim 1, wherein 3-isobutyl-cyclohexanone and sodium pyruvate are heated in a HCl and acetic acid solution to give a mixture of condensation products and said condensation products are heated for 4 to 5 hours with pyridine hydrochloride to give p-isobutylhydratropic acid.
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][C@@H:5]([C:7]([OH:9])=[O:8])[NH2:6].Cl.[CH3:15]O>C(Cl)Cl>[I:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][C@@H:5]([C:7]([O:9][CH3:15])=[O:8])[NH2:6]
Reactant: N[C@@H](Cc1ccccc1I)C(=O)O
Reactant: CO
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1ccccc1I
Temperature: 25 °C
Yield: 94 %

Procedure:
To a 500 mL 3-necked flask equipped with a magnetic stirrer and a reflux condenser were added 5.00 g of 2-iodo-L-phenylalanine.HCl and 100 mL of anhydrous MeOH. The mixture was stirred and acidified by bubbling HCl gas through for 3 min. A clear solution resulted which was heated at reflux for 5h. The solution was cooled to RT and concentrated in vacuo to dryness to give a white solid. The material was suspended in 120 mL of CH2Cl2 and washed with 5% aqueous NaHCO3 (4×80 mL). The CH2Cl2 solution was concentrated to a volume of 20 mL, diluted to 60 mL with ethyl ether and treated with 16 mL of 1M ethereal HCl. A white solid precipitated which was collected by vacuum filtration and dried in vacuo to afford 4.90 g (94%) of methyl 2-iodo-L-phenylalaninate.HCl m.p. 194-196° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[C:20](=O)[CH2:19][C:18]([CH3:23])([CH3:22])[CH2:17][C:16]2=O)=[CH:11][CH:10]=1.O.[OH-].[Na+]>C(OCC)C>[CH3:22][C:18]1([CH3:23])[CH2:17][CH2:16][N:15]([C:12]2[CH:13]=[N:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH2:20][CH2:19]1
Reactant: COc1ccc(N2C(=O)CC(C)(C)CC2=O)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC1(C)CCN(c2ccc(O)nc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
Under a nitrogen atmosphere lithium aluminium hydride (1.90 g, 50.0 mmol) was added portionwise to a stirred suspension of 6′-methoxy-4,4-dimethyl-4,5-dihydro-3H-[1,3′]bipyridinyl-2,6-dione (2.85 g, 10.0 mmol) in dry diethyl ether (100 mL). After stirring for 3 hours at room temperature, water (1.90 mL), 15% aqueous sodium hydroxide (1.90 mL) and water (5.70 mL) were added respectively. After stirring for 1 hour at room temperature the salts were removed by filtration and washed three times with diethyl ether. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, dichloromethane followed by ethyl acetate/heptane 25/75) yielding the title compound (1.28 g, 58% yield) as a yellow oil.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])=[CH:7][CH:6]=1)\[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Cl:29][CH2:30][C:31](Cl)=O>CC(C)=O>[Cl:29][CH2:30][C:31]1[O:1][N:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]3[CH2:15][C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:22]3)=[O:13])=[CH:7][CH:6]=2)[N:4]=1
Reactant: N/C(=N\O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(-c2noc(CCl)n2)cc1)N1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 25 mL round-bottomed flask containing (Z)—N-(4-(N′-hydroxycarbamimidoyl)phenyl)isoindoline-2-carboxamide (1.5 g, 5.06 mmol) in acetone (5 ml) was added potassium carbonate (7.00 g, 50.6 mmol) in a single portion. The reaction mixture was cooled to 0° C. and 2-chloroacetyl chloride (3.22 ml, 40.5 mmol) was added slowly. The resulting mixture was warmed to room temperature and stirred for two hours. The solvent was removed and the solid was triturated with water and then filtered with water washes. The dried solid was dissolved in DMF, heated to 100° C. and stirred for two hours. Work-up with water and dichlormethane followed by chromatography provided the title compound.