Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][CH:33]=1)[CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]2[CH:21]([CH2:24][C:25]([O:27]C)=[O:26])[CH2:22][O:23][C:19]=2[CH:18]=1.CO.[OH-].[Na+].Cl>O.O1CCCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][CH:33]=1)[CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]2[CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][O:23][C:19]=2[CH:18]=1
Reactant: COC(=O)CC1COc2cc(OCc3cccc(-c4c(C)ccc5ccccc45)c3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc2ccccc2c1-c1cccc(COc2ccc3c(c2)OCC3CC(=O)O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.1 %

Procedure:
To a solution of methyl (6-{[3-(2-methyl-1-naphthyl)benzyl]oxy}-2,3-dihydro-1-benzofuran-3-yl)acetate (0.801 g, 1.90 mmol) in a mixed solvent of methanol (6 mL) and tetrahydrofuran (6 mL) was added 2 M aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at room temperature for 20 hr. Water was added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane-ethyl acetate), and recrystallized from ethyl acetate-hexane to give the title compound (0.444 g, yield 55%) as colorless needle crystals.
Reaction SMILES: [F-:1].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:34])[C:22]([CH3:33])([CH3:32])[CH2:23]OS(C(F)(F)F)(=O)=O>C1COCC1>[CH3:19][O:20][C:21](=[O:34])[C:22]([CH3:33])([CH3:32])[CH2:23][F:1]
Reactant: [F-]
Reactant: COC(=O)C(C)(C)COS(=O)(=O)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)CF
Temperature: 0 °C
Reaction time: 6 h

Procedure:
27 mL of a 1 M solution of tetrabutylammonium fluoride in THF are added slowly and under ice cooling to a solution of 7.25 g (27.4 mmol) 2,2-dimethyl-3-trifluoromethanesulfonyloxy-propionic acid methyl ester in 150 mL of THF. The resulting solution is stirred 6 h at 0° C. and then 10 h at RT. The solvent is evaporated carefully and the residue partitioned between DCM and brine. The organic phase is washed with brine, dried with sodium sulfate and evaporated carefully. The brown oil is distilled in a Kugelrohr-oven (oven temperature 120 to 150° C.) to give the title compound as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:18]=3)[S:13][C:6]=12.[BH4-].[Na+]>CCO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:29][C:27]1[CH:26]=[CH:25][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[N:15]=[CH:16][N:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:18]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:28]=1
Reactant: CCOC(=O)Cn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of thienopyridine 374 (0.25 g, 0.56 mmol) and nickel chloride hexahydrate (0.26 g, 1.1 mmol) in absolute EtOH (50 mL) was added sodium borohydride (0.085 g, 2.2 mmol) in small portions. The resulting mixture was stirred at r.t. for 1 h, then filtered through celite, run through a short plug of silica, eluting with 1:1 ethyl acetate/ethanol, and concentrated, affording title compound 375 (0.21 g, 91% yield). LRMS (M+H): 413.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([C:33]1[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:34]=1[O:41][CH3:42])[CH:12]([C:23]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[O:21][CH3:22].O>ClCCl>[CH3:40][O:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([O:41][CH3:42])[C:33]=1[C:11]([C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[C:12]([C:23]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[C:13]1[C:14]([O:21][CH3:22])=[CH:15][CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1cccc(OC)c1C(c1c(OC)cccc1OC)C(c1c(OC)cccc1OC)c1c(OC)cccc1OC
Solvent: ClCCl
Solvent: O
Product: COc1cccc(OC)c1C(=C(c1c(OC)cccc1OC)c1c(OC)cccc1OC)c1c(OC)cccc1OC
Reaction time: 18 h

Procedure:
To a solution of commercial triphenylmethylhexafluorophosphate (0.69 g, 1.8 mmol) in dichloromethane at room temperature was added a rotational isomer of 1,1,2,2-tetrakis(2′,6′-dimethoxyphenyl)ethane (0.90 g, 1.5 mmol). After stirring for 18 hours, water (10 mL) was added and the resulting mixture was extracted with dichloromethane and dried over anhydrous magnesium sulfate. Filtration and removal of the solvent gave tetrakis(2,6-dimethoxyphenyl)ethylene after washing with diethyl ether. {Note: Only one of the rotational isomers gives (5) upon treatment with trityl cation.}
Reaction SMILES: C=C(O[C@H:7]1[C@H:12]([OH:13])[CH:11]=[CH:10][C:9]([C:14]([OH:16])=[O:15])=[CH:8]1)C(O)=O.C1([CH2:23][C:24](=[O:28])[C:25]([O-:27])=[O:26])C=CC=CC=1>>[CH:11]1[CH:12]([OH:13])[CH:7]=[CH:8][C:9]([C:14]([OH:16])=[O:15])([CH2:23][C:24]([C:25]([OH:27])=[O:26])=[O:28])[CH:10]=1
Reactant: O=C([O-])C(=O)Cc1ccccc1
Reactant: C=C(O[C@@H]1C=C(C(=O)O)C=C[C@H]1O)C(=O)O
Product: O=C(O)C(=O)CC1(C(=O)O)C=CC(O)C=C1

Procedure:
One assay commonly used to measure chorismate mutase activity is based on the spectrophotometric estimation of phenylpyruvate obtained by acid conversion of the reaction product of prephenate. Metzenberg and Mitchell (1954) Arch Biochem and Biophys 243:374. In this assay, phenylpyruvate is estimated by the absorbance of either the enol-tautomer in alkaline solution (E=17,500 M−1 cm−1 at 320 nm in 1 M NaOH) or the enol-borate complex in either a concentrated solution of sodium borate and arsenate or phosphate (E=9292 M−1 cm−1 at 300 nm). Alternatively, the disappearance of chorismate may be assayed spectrophotometrically. Nishioka and Woodin (1972) Anal Biochem 45:617. The details of these assays and their advantages and disadvantages are described in Gilchrist and Connelly (1987) Methods in Enzymology 142:450-463.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:17][CH:16]=3)=[C:12]([CH3:26])[C:11]3[C:10]([OH:27])=[CH:9][CH:8]=[C:7]([F:28])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:35][O:36][C:37](=[O:41])[C@H:38](Cl)[CH3:39]>O>[CH3:35][O:36][C:37](=[O:41])[C@@H:38]([O:27][C:10]1[CH:9]=[CH:8][C:7]([F:28])=[C:6]2[C:11]=1[C:12]([CH3:26])=[C:13]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=1)[C:4]([CH:1]1[CH2:2][CH2:3]1)=[N:5]2)[CH3:39]
Reactant: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C2CC2)nc2c(F)ccc(O)c12
Reactant: COC(=O)[C@@H](C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)[C@H](C)Oc1ccc(F)c2nc(C3CC3)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Temperature: 0 °C
Yield: 41.9 %

Procedure:
A mixture of 2-cyclopropyl-8-fluoro-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-ol (0.064 g), (N-dimethylformamide (0.86 mL), potassium carbonate (0.071 g) and (R)-2-chloropropionic acid methyl ester (0.032 g) was stirred at 40° C. for 3 days. The mixture was cooled to 0° C., diluted with water (40 mL) and extracted with ethyl acetate (3×10 mL). The combined extracts were washed saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (0:1 to 4:6 by volume) gave title compound as a colourless oil (0.033 g).
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31][CH:32](P(=O)(OCC)OCC)[C:33]3=[O:35])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(O)C>O1CCCC1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31]/[C:32](=[CH:8]\[C:7]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:5]([O:4][CH3:3])[CH:6]=4)/[C:33]3=[O:35])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3ccc(Cl)cc3)N2C1=O
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(/C=C2\CC[C@H]3CC[C@@H](c4ccc(Cl)cc4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 78.9 %

Procedure:
Lithium hydroxide (355 mg) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (875 mg) and diethyl [(3S,8aR)-3-(4-chlorophenyl)-5-oxooctahydroindolizin-6-yl]phosphonate (2.5 g) in tetrahydrofuran (8 mL)-ethanol (30 mL), and the reaction solution was stirred under shading at room temperature for five hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 1.43 g of the title compound as a colorless solid. The property values of the compound are as follows.
Reaction SMILES: [N:1]#CBr.C([O-])([O-])=O.[K+].[K+].[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19][N:18]=2)[CH2:13][CH2:12]1>C(Cl)(Cl)Cl>[C:10]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19][N:18]=2)[CH2:13][CH2:12]1)#[N:1]
Reactant: CN1CCC(c2nsc3ccccc23)CC1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC(c2nsc3ccccc23)CC1
Yield: 108.8 %

Procedure:
To a stirred mixture of CNBr (5.9 g, 0.056 mole), K2CO3 (8.6 g) and CHCl3 (80 ml) was added dropwise 3-(1-methyl-4-piperidinyl)-1,2-benzisothiazole (11.0 g, 0.051 mole) in CHCl3 (30 ml). The mixture was stirred and refluxed for 4 hours and thereafter cooled and filtered. The filtrate was concentrated in vacuo to a solid. The solid was triturated with hexane and collected to yield 13.5 g of the desired compound. Recrystallization from MeOH--H2O (twice) yielded 4.5 g (36%) of the benzisothiazole, m.p. 118°-120°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:19]([CH:20]3[CH2:23][N:22]([C:24]([C:26]4[NH:30][C:29]5[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=5[N:27]=4)=[O:25])[CH2:21]3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35]>CO>[ClH:35].[NH:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[C:24]([N:22]1[CH2:21][CH:20]([C:19]2[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)=[N:15][CH:16]=[CH:17][N:18]=2)[CH2:23]1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nccnc2C2CN(C(=O)c3nc4ccccc4[nH]3)C2)CC1
Agent: Cl
Solvent: CO
Product: O=C(c1nc2ccccc2[nH]1)N1CC(c2nccnc2C2=CCNCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To 4-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (217 mg, 0.47 mmol) was added 4 M HCl in MeOH (100 mL). The solution was stirred at RT for 2 h. The solvent was removed under reduced pressure to give (1H-benzoimidazol-2-yl)-{3-[3-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone hydrochloride (187 mg, 0.47 mmol, yield 100%). ESI-MS (M+1): 361 calc. for C20H20N6O 360.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CCN=C=NCCCN(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:42][C:43]([F:53])([F:52])[CH2:44][N:45]1[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]1.CN1CCOCC1>CC(N(C)C)=O.O>[F:53][C:43]([F:42])([F:52])[CH2:44][N:45]1[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]1.[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:51][CH:48]3[CH2:49][CH2:50][N:45]([CH2:44][C:43]([F:53])([F:42])[F:52])[CH2:46][CH2:47]3)=[O:16])=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2cccc(F)c2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CCN(CC(F)(F)F)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(NC1CCN(CC(F)(F)F)CC1)c1ccc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 152.2 %

Procedure:
1-(2,2,2-Trifluoroethyl)piperidin-4-amine was synthesized as in steps a-c of Example 1. To a 250 mL round bottom flask containing 6-(3-fluorophenyl)pyridine-3-carboxylic acid (see Example 3, Step A)(2.01 g, 9.25 mmol ) in DMA (35 mL) was added EDAC/EDC*HCl(1.95 g, 10.2 mmol), HOBt (1.38 g, 10.2 mmol), 1-(2,2,2-trifluoroethyl)piperidin-4-amine (1.85 g, 10.2 mmol) and NMM (2.23 mL, 20.4). After stirring at room temperature for 2 hours the reaction mixture was diluted with water (100 mL) and the resulting solid filtered and dried to give the desired product (2.96 g). LCMS (ES+) 4.55 min (TIC, 90%; 1H NMR purity >95%); 1H NMR (400 MHz, DMSO-d6) □ ppm 1.60 (dq, J=11.84, 3.48 Hz, 2 H) 1.81 (d, J=10.62 Hz, 2H) 2.44 (t, J=11.16 Hz, 2H) 2.50 (br. s., 2H) 2.94 (d, J=11.53 Hz, 2H) 3.74-3.87 (m, 1H) 7.32 (dt, J=8.37, 2.29 Hz, 1H) 7.57 (q, 1H) 7.96 (d, J=10.43 Hz, 1H) 8.01 (d, J=7.69 Hz, 1H) 8.14 (d, J=8.24 Hz, 1H) 8.28 (dd, J=8.24, 2.20 Hz, 1H) 8.49 (d, J=7.50 Hz, 1H) 9.07 (d, J=1.83 Hz, 1H); MS(ES+) 382 (M+1); HRMS (TOF, ES+) calculated for C19H19F4N3O+H+: 382.1542; observed 382.1548.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:5]=2[N:6]=1.[CH3:15][N:16]([CH3:25])[C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18].COC(O)C.Cl>C(O)(C)C>[ClH:1].[CH3:15][N:16]([CH3:25])[C:17]([N:19]1[CH2:20][CH2:21][N:22]([C:2]2[NH:3][C:4]3[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:5]=3[N:6]=2)[CH2:23][CH2:24]1)=[O:18]
Reactant: COc1cc2nc(Cl)[nH]c2cc1OC
Reactant: CN(C)C(=O)N1CCNCC1
Agent: COC(C)O
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2nc(N3CCN(C(=O)N(C)C)CC3)[nH]c2cc1OC

Procedure:
3.50 g 2-chloro 5,6-dimethoxybenzimidazole, 7.50 g N,N-dimethyl 1-piperazine carboxamide [J. Org. Chem. 13 144 (1948)], 20 ml methoxyethanol was reacted as described in Example I. The product was converted to the HCl salt with HCl in isopropyl alcohol. Yield: 5.33 g mp 252°-254° C (85%)
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([S:6]([OH:9])(=[O:8])=[O:7])[C:3]1=[O:10].[C:11]1([CH2:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])O.[Na+:25]>O.O1CCCC1>[C:11]1([CH2:17][C:18]([NH:1][CH:2]2[CH2:5][N:4]([S:6]([O-:9])(=[O:8])=[O:7])[C:3]2=[O:10])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+:25]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC1CN(S(=O)(=O)O)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cc1ccccc1)NC1CN(S(=O)(=O)[O-])C1=O
Yield: 45.6 %

Procedure:
In 1 ml of water is dissolved 50 mg of the above 3-amino 2-oxoazetidine-1-sulfonic acid, followed by addition of a solution of 69 mg phenylacetyl chloride in 1 ml tetrahydrofuran and 101 mg of sodium hydrogen carbonate in alternate portions with ice-cooling and stirring. After stirring at room temperature for 30 minutes, the mixture is adjusted to pH 5.8 with phospheric acid. The tetrahydrofuran is then distilled off under reduced pressure. The water layer is washed with ethyl acetate and purified by XAD-II chromatography, whereby 42 mg of sodium 3-phenylacetamido-2-oxoazetidine-1-sulfonate is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:29])=[CH:4][C:5]2[C:6]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17][C:7]=3[N:8]([CH2:11][C:12](OCC)=[O:13])[C:9]=2[CH:10]=1.[Li+].[BH4-].[OH-].[Na+].CCOC(C)=O>C1COCC1.O>[Cl:1][C:2]1[C:3]([Cl:29])=[CH:4][C:5]2[C:6]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:18][CH2:17][C:7]=3[N:8]([CH2:11][CH2:12][OH:13])[C:9]=2[CH:10]=1
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)c(Cl)cc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCO)c3cc(Cl)c(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 59.4 %

Procedure:
A solution tert-butyl 8,9-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.95 g, 2.15 mmol) in dry THF (10 mL) was cooled to 0° C. Then, LiBH4 (0.14 g, 6.43 mmol) was added and the reaction was allowed to warm slowly to rt. After 17 h, the reaction was diluted with H2O (50 mL) followed by addition of 10% aqueous NaOH (10 mL) and extraction with EtOAc (3×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was first purified by two column chromatographies (Biotage, 40M) with heptane/EtOAc (1:1) and (Biotage, 40S) with heptane/EtOAc (2:1) to give 0.51 g of impure product. Finally, crystallization from Et2O/heptane gave 0.45 g (52%) of pale yellow crystals: mp 130.5-133° C.; IR (diffuse reflectance) 3469, 2976, 2937, 2869, 1676, 1477, 1449, 1415, 1366, 1342, 1240, 1219, 1172, 1164, 853 cm−1; MS (EI) m/z 398 (M+), 400, 398, 342, 341, 270, 268, 86, 84, 57, 51; Anal. Calcd for C19H24Cl2N2O3: C, 57.15; H, 6.06; N, 7.01; found: C, 57.24; H, 6.19; N, 6.95.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([NH:17]C(=O)C)[NH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].OS(O)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([NH2:17])[NH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: CC(=O)Nc1nc(-c2ccc(C(F)(F)F)c(F)c2)c[nH]1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CO
Product: Nc1nc(-c2ccc(C(F)(F)F)c(F)c2)c[nH]1
Temperature: 25 °C

Procedure:
To a stirred solution of Step 1 intermediate (1.1 g, 3.829 mmol) in a mixture of methanol (20 ml) and water (20 ml) was added conc. H2SO4 (2 ml) and the resulting mixture was refluxed for 24 h. The reaction mixture was cooled to room temperature, saturated solution of potassium carbonate was added and extracted with ethyl acetate (2×50 ml). The organic layers were combined and dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using 5% methanol in chloroform to obtain 290 mg of the product as a yellow solid; 1H NMR (300 MHz, DMSO-d6): δ 5.55 (br s, 2H), 7.32 (s, 1H), 7.59-7.67 (m, 3H), 11.30 (br s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][CH2:9][CH3:10])[NH2:6].[C:12](O)(=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.C(OCC)C>[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][CH2:9][CH3:10])[NH:6][C:12](=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16]
Reactant: CCCC[C@H](N)C(=O)OC
Reactant: C=CCCC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: C=CCCC(=O)N[C@@H](CCCC)C(=O)OC
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of L-norleucine methyl ester hydrochloride (0.50 g, 2.75 mmol) and 4-pentenoic acid (0.33 g, 3.30 mmol) in DMF (5 mL) was added EDC (0.79 g, 4.13 mmol) and HOBt (0.56 g, 4.13 mmol). The reaction mixture was stirred at 50° C. for 15 h, cooled and poured onto a mixture of ethyl ether and water. The organic layer was washed with water, dried over NaSO4, filtered and concentrated. The crude product was purified by silica gel chromatography (gradient elution 10% to 90% ethyl acetate in hexanes) to give N-pent-4-enoyl-L-norleucine methyl ester.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[OH:12][C:13]1[N:17]=[C:16]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[S:15][N:14]=1.C(OC(C)C)(C)C>O1CCCC1>[CH3:8][NH:9][C:10]([N:14]1[C:13](=[O:12])[N:17]=[C:16]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[S:15]1)=[O:11]
Reactant: Oc1nsc(SCc2ccc(Cl)cc2)n1
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Product: CNC(=O)n1sc(SCc2ccc(Cl)cc2)nc1=O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
0.2 ml of triethylamine and 6 ml of methyl isocyanate were added to a solution of 12.9 g of 3-hydroxy-5-(p-chlorobenzylthio)-1,2,4-thiadiazole in 100 ml of tetrahydrofuran and after stirring the mixture for 2 hours at 20° C, isopropyl ether was added thereto. The mixture was filtered and the crystals were empasted with isopropyl ether and dried to obtain 15 g of 2-(N-methylcarbamoyl)-5-(p-chlorobenzylthio)-1,2,4-thiadiazole-3-one melting at 140° C.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].O1CCCCC1[N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]3([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24]3)=[CH:20][CH:21]=2)[C:16]([C:30]2[N:35]=[C:34]([O:36][C@H:37]3[CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41][C:38]43[CH2:40][CH2:39]4)[CH:33]=[N:32][CH:31]=2)=[N:15]1>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[CH2:39]1[C:38]2([CH2:41][CH2:42][NH:43][CH2:44][C@@H:37]2[O:36][C:34]2[N:35]=[C:30]([C:16]3[C:17]4[C:22](=[CH:21][CH:20]=[C:19]([C:23]5([C:26]([F:27])([F:28])[F:29])[CH2:25][CH2:24]5)[CH:18]=4)[NH:14][N:15]=3)[CH:31]=[N:32][CH:33]=2)[CH2:40]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(C5(C(F)(F)F)CC5)cc34)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)C1(c2ccc3[nH]nc(-c4cncc(O[C@H]5CNCCC56CC6)n4)c3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
TFA (0.5 mL, 6.49 mmol) was added to a solution of (4R)-tert-butyl 4-((6-(1-(tetrahydro-2H-pyran-2-yl)-5-(1-(trifluoromethyl)cyclopropyl)-1H-indazol-3-yl)pyrazin-2-yl)oxy)-6-azaspiro[2.5]octane-6-carboxylate (25.2 mg, 0.041 mmol) in DCM (0.5 mL) and the resulting solution was stirred at 25° C. for 2 h. The mixture was concentrated in vacuo and the residue was taken up in DMSO (2.0 mL) and purified by rpHPLC (Phenomenex Gemini C18 column (150×30 mm, 10 μm), 35 mL/min, 5-100% CH3CN/H2O+0.1% TFA, 15 min, 254 nm) to provide 3-(6-((4R)-6-azaspiro[2.5]oct-4-yloxy)-2-pyrazinyl)-5-(1-(trifluoromethyl)cyclopropyl)-1H-indazole tris(2,2,2-trifluoroacetate) (12.0 mg, 0.016 mmol, 38% yield) as a yellow foam: 1H NMR (400 MHz, MeOH-d4) δ ppm 9.04 (1 H, s), 8.42-8.46 (1 H, m), 8.31 (1 H, s), 7.60-7.64 (1 H, m), 7.55-7.59 (1 H, m), 5.07 (1 H, s), 3.89 (1 H, d, J=12.7 Hz), 3.57 (1 H, m, J=13.3, 1.0 Hz), 3.47-3.54 (1 H, m), 3.34-3.39 (1 H, m), 2.72 (1 H, td, J=13.9, 4.5 Hz), 1.45-1.49 (2 H, m), 1.22-1.27 (1 H, m), 1.17-1.22 (2 H, m), 0.99 (1 H, dt, J=8.9, 5.6 Hz), 0.77-0.85 (2 H, m), 0.67-0.73 (1 H, m). 19F NMR (377 MHz, MeOH) δ ppm −71.41 (3 F, s), −77.45 (9 F, br. s.). MS (ESI, pos. ion) m/z: 430.1 (M+1).