Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1
Reactant: OCc1cc(-c2cccc(F)c2)c(Cl)cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc(-c2cccc(F)c2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (5-chloro-4-(3-fluorophenyl)pyridin-2-yl)methanol (0.138 g, 0.58 mmol) in dichloromethane (5 mL) at room temperature was added manganese dioxide (0.49 g, 5.6 mmol). The reaction mixture was stirred at room temperature for 3 d, filtered, and concentrated. Purification by flash column chromatography on silica gel (10% to 20% EtOAc in hexanes) gave 5-chloro-4-(3-fluorophenyl)picolinaldehyde.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:9]=[C:8]([C:19]([O:21]C)=[O:20])[C:7]=2[C:6]([CH3:23])=[N:5]1)([CH3:3])[CH3:2].C(N1C2C=C(C3C=C4C=CNC4=NC=3)C=C(C(OC)=O)C=2C=N1)(C)C.O[Li].O>C1COCC1.O>[CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:9]=[C:8]([C:19]([OH:21])=[O:20])[C:7]=2[C:6]([CH3:23])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(-c2cccnc2)cc2c1c(C)nn2C(C)C
Agent: COC(=O)c1cc(-c2cnc3[nH]ccc3c2)cc2c1cnn2C(C)C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(C(C)C)c2cc(-c3cccnc3)cc(C(=O)O)c12
Temperature: 80 °C

Procedure:
To a stirred solution of methyl 1-isopropyl-3-methyl-6-(pyridin-3-yl)-1H-indazole-4-carboxylate, 1 (0.5 g, 1.618 mmol) in a mixture of THF and H2O (30 mL) was added LiOH.H2O (0.2 g, 4.85 mmol) and the mixture was refluxed at 80° C. for 8 h. THF was distilled off and the aqueous layer was adjusted to pH˜5 with 10% HCl at 0° C. and the precipitated solid was collected by filtration and dried to afford 1-isopropyl-3-methyl-6-(pyridin-3-yl)-1H-indazole-4-carboxylic acid as an off-white solid (0.51 g). LCMS (ES+) m/z: 296.7.
Reaction SMILES: [CH:1]1[C:9]2[C:4]3=[C:5]([CH2:10][CH2:11][N:3]3[C:2]=1C(O)=O)[CH:6]=[CH:7][CH:8]=2.C(OCC)(=O)C>N1C2C(=CC=CC=2)C=CC=1.[Cr]([O-])([O-])=O.[Cu+2]>[CH2:1]1[C:9]2[C:4]3=[C:5]([CH:10]=[CH:11][N:3]3[CH2:2]1)[CH:6]=[CH:7][CH:8]=2
Reactant: O=C(O)c1cc2cccc3c2n1CC3
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: c1cc2c3c(c1)ccn3CC2
Temperature: 200 °C
Yield: 61.1 %

Procedure:
A mixture of 4,5-dihydro-pyrrolo[3,2,1-hi]indole-2-carboxylic acid (120 mg, 0.64 mmol) and copper chromite (50 mg) in quinoline (5 ml) in a sealed vessel was heated to 200° C. in a microwave for 20 minutes. After cooling to room temperature the mixture was poured into ethyl acetate (100 ml) and washed with 1M hydrochloric acid (3×100 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by preparative thin layer chromatography (SiO2, 20% EtOAc in hexanes) to yield 1,2-dihydro-pyrrolo[3,2,1-hi]indole as a pale yellow crystalline solid (56 mg). 400 MHz 1H NMR (CDCl3) δ: 7.33 (d, J=8.0 Hz, 1H), 7.14 (d, J=2.8 Hz, 1H), 7.04-6.97 (m, 1H), 6.91 (d, J=6.8 Hz, 1H), 6.44 (d, J=2.8 Hz, 1H), 4.51 (t, J=7.2 Hz, 2H), 3.80 (t, J=7.2 Hz, 2H); LCMS: 144 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:28].CC(O)=O.[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([CH2:39][C:38]3[CH:41]=[CH:42][C:35]([F:34])=[CH:36][CH:37]=3)[CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccc(F)cc3)C1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
(±)-(E)-3-[4-Oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester hydrochloride (Intermediate 2, 600 mg, 1.78 mmol) was suspended in DCM (30 ml). TEA (0.248 ml, 1.78 mmol) was added and the pH was adjusted to 5 with AcOH. 4-Fluorobenzaldehyde (265 mg, 2.14 mmol) and NaBH(OAc)3 (566 mg, 2.67 mmol) were added and the resulting mixture was stirred overnight at RT, then washed with 5% NaHCO3, brine and dried over Na2SO4. The crude mixture was purified by column chromatography (eluent: DCM/MeOH 99:1) to give (±)-(E)-3-[1′-(4-fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (660 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]([C:14]#[N:15])[CH2:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]1=2)[CH3:2].[ClH:20]>CCOCC>[ClH:20].[CH:4]([N:3]([CH:9]([CH3:10])[CH3:8])[CH2:1][CH2:2][C:7]1([C:14]#[N:15])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:3]([CH2:1][CH3:2])[C:4]2[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=2[CH2:6]1)([CH3:19])[CH3:5]
Reactant: CCN1c2ccccc2CC(C#N)c2ccccc21
Agent: Cl
Solvent: CCOCC
Product: CCN1c2ccccc2CC(C#N)(CCN(C(C)C)C(C)C)c2ccccc21

Procedure:
A solution of 28 parts of 10-[2-diisopropylamino)ethyl]-5-ethyl-10,11-dihydro-5H-dibenz[b,f]azepine-10-carbonitrile in a minimal amount of anhydrous ether is acidified with a 20% solution of hydrogen chloride in anhydrous ether. The white solid which precipitates is filtered off, dried in vacuo at 60°-70°, and then recrystallized from absolute ethanol to give 10-[2-(diisopropylamino)ethyl]-5-ethyl-10,11-dihydro-5 H-dibenz[b,f]azepine-10-carbonitrile hydrochloride melting at 230°-233°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([CH:10]2[O:16][CH:11]2[C:12](=[N:14]O)[CH3:13])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:13][C:12]1[CH:11]=[C:10]([CH:3]2[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH:7]=[C:2]2[CH3:1])[O:16][N:14]=1
Reactant: CC1=CCCC(C)(C)C1C1OC1C(C)=NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1=CCCC(C)(C)C1c1cc(C)no1

Procedure:
54 g of 4-[2,6,6-trimethyl-cyclohex-2-en-1-yl]-3,4-epoxy-2-butanone-oxime, which can be prepared as indicated above, in 500 ml of benzene were refluxed in the presence of 2 g of p-toluenesulphonic acid for about 4 hours. The water formed in the course of the reaction was removed as it formed by azeotropic distillation.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][S:9]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)=[O:21])=[CH:17][CH:18]=2)[N:13]([C:35]2[N:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:37][N:36]=2)[CH:12]=1)=[O:10].C(=O)([O-])O.[Na+]>ClCCl.O>[CH3:8][S:9]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:21])=[CH:17][CH:18]=2)[N:13]([C:35]2[N:36]=[CH:37][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:39][N:40]=2)[CH:12]=1)=[O:10]
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)c1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)N3CCNCC3)ccc12
Reaction time: 2 h

Procedure:
TFA (0.5 mL) was added to compound 12d) (170 mg, 0.311 mmol) in dichloromethane (5 mL) at room temperature and the solution was stirred for 2 h. The reaction mixture was then diluted with water, adjusted to pH 8 via addition of saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated. The remnant was purified by preparative TLC using a blend of 5% methanol in dichloromethane as eluent. White solid. Yield: 75 mg (51% of theory). Melting range: 193-197° C. HPLC (method 3): Rt=4.02 min. Mass spectroscopy: m/z: [M+H]+=446.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH:10]([C:12]([O:14]CC)=[O:13])[CH2:9][N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:7]1)=[O:5])[CH3:2].Cl>P([O-])([O-])([O-])=O.O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9][N:8]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC(C(=O)OCC)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: CCOC(=O)C1CC(C(=O)O)CN(C(=O)OC(C)(C)C)C1
Yield: 94.3 %

Procedure:
Add lipase (1.7 g, Amano AY30) to a slurry of piperidine-1,3,5-tricarboxylic acid 1-tert-butyl ester 3,5-diethyl ester (5.8 g, 17.6 mmol) in pH 7.2 phosphate buffer (58 mL). Stir 48 H, dilute with water then acidify to pH 2.5 with 1N HCl. Extract 3× with EtOAc. Wash with brine, dried over Na2SO4, filter and concentrate to dryness to give the title compound (5.0 g, 94%) as a mixture of cis isomers as a white solid. MS(IS) 300.2 (M−1); Anal. Calc'd for C14H23NO6.0.5CHCl3: C, 54.91; H, 7.56; N, 4.56. Found: C, 54.90; H, 7.59; N, 4.55.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH:12]=[O:13])[CH:5]=[CH:4]1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.[Cl-].[NH4+]>C1COCC1>[S:21]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH:12]=[O:13])[CH:5]=[CH:4]1)([C:18]1[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3cccc(C=O)c32)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.7 %

Procedure:
To a suspension of sodium hydride (240 mg, 5.9 mmol) in THF (10 mL) was added 1H-indole-7-carbaldehyde (570 mg, 3.9 mmol) at room temperature. After being stirred at room temperature for 20 min, 4-methylbenzene-1-sulfonyl chloride (1.1 g, 5.9 mmol) was added to the mixture. The mixture was stirred at room temperature for 1 hour. The mixture was poured into saturated ammonium chloride aqueous solution, and the aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (4:1 (v/v)) to give 1.0 g (89% yield) of the title compound as a white solid:
Reaction SMILES: [F:1][C:2]([F:18])([CH:7]([O:12]C(=O)C(C)=C)[CH2:8][CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH3:6])=[O:4].[CH2:19](O)C.C1C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[F:1][C:2]([F:18])([CH:7]([OH:12])[CH2:8][CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:19])=[O:4]
Reactant: CCO
Reactant: C=C(C)C(=O)OC(CC(C)C)C(F)(F)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C(F)(F)C(O)CC(C)C
Yield: 123.2 %

Procedure:
To a mixture of 25.0 g of Intermediate 1 (Example 1), 20 g of ethanol and 200 g of benzene was added 0.15 g of p-toluenesulfonic acid monohydrate. With stirring in a nitrogen atmosphere, the mixture was heated for 20 hours while water of reaction was sequentially removed out of the system. After cooling, the reaction mixture was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with ethyl acetate. The ethyl acetate solution was washed, dried, and concentrated, obtaining 24.5 g (yield 85%) of crude ethyl 2,2-difluoro-3-hydroxy-5-methylhexanoate. This crude product had a sufficient purity as an intermediate and was ready for use in the subsequent step.
Reaction SMILES: Cl[C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.[Cu]>[N:17]1([C:2]2[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]3[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: CC1Oc2cc([N+](=O)[O-])c(Cl)cc2NC1=O
Reactant: c1c[nH]cn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1Oc2cc([N+](=O)[O-])c(-n3ccnc3)cc2NC1=O

Procedure:
485 mg of 6-chloro-7-nitro-2-methyl-1,4-benzoxazin-3-one is stirred with 136 mg of imidazole and 332 mg of potassium carbonate in 15 ml of DMF with the addition of copper powder for 6 hours at 180° C. It is diluted with ethyl acetate, extracted with brine, and the organic phase is dried. The crude product is purified by column chromatography with ethyl acetate with the addition of ethanol. 88 mg results.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:15][C:16](=[O:41])[CH:17]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])([CH3:14])([CH3:13])[CH3:12].[CH2:42](I)[CH:43]=[CH2:44]>O1CCCC1>[C:11]([O:15][C:16](=[O:41])[CH:17]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH:18]([CH2:44][CH:43]=[CH2:42])[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])([CH3:13])([CH3:14])[CH3:12]
Reactant: C=CCI
Reactant: COc1ccc(S(=O)(=O)NC(CC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(C(=O)OCc1ccccc1)C(NS(=O)(=O)c1ccc(OC)cc1)C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 1 h

Procedure:
100 ml dry Tetrahydrofuran (THF) are cooled to −78° C. 1M THF-solution of Lithium bis(trimethylsilyl)amide (47.35 ml, 47.35 mmol) are added while the temperature is maintained. 2-(4-Methoxy-benzenesulfonylamino)-succinic acid 4-benzyl ester 1-tert-butyl ester (10.1 g, 22.5 mmol) are dissolved in 45 ml THF and added dropwise to the reaction solution. The reaction mixture is allowed to stir for 1 h and then warmed briefly to −40° C. After re-cooling to −78° C. Allyliodide (3.1 ml, 33.8 mmol) dissolved in 30 ml THF are added drop-wise. The reaction mixture is allowed to warm to −40° C. and is quenched with a NH4Cl-solution. The organic phase is separated dried over MgSO4 and filtered. The solvent is evaporated and the product is purified with a short flash-chromatography column. Hexane/Ethylacetate (9:1): Cal. 489.6 Found. (M)+ 490.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[F:14])[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:14][C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[C:5]1[N:6]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)[S:3][CH:4]=1
Reactant: Fc1ccc(-c2csc(Br)n2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(F)cc3F)cs2)CC1
Yield: 85.8 %

Procedure:
A solution of 2-bromo-4-(2,4-difluorophenyl)-1,3-thiazole (3.23 mg, 11.7 mmol), tert-butyl piperazine-1-carboxylate (4.36 g, 23.4 mmol) and potassium carbonate (1.62 g, 11.7 mmol) in dimethylformamide (40 ml) was stirred at 120° C. for 12 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 3.83 g (85.9%) of the desired product as a solid.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:32][CH:31]([CH2:33][CH2:34][OH:35])[O:30][C:11]2([CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH3:29])[CH:20]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:10]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[ClH:1].[OH:35][CH2:34][CH2:33][CH:31]1[O:30][C:11]2([CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH3:29])[CH:20]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:10][NH:9][CH2:32]1
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(CCO)O3)ccc1OC(C)C
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CO
Product: Cc1cc(C(=O)N2CCC3(CC2)CNCC(CCO)O3)ccc1OC(C)C
Temperature: 75 °C
Yield: 60.5 %

Procedure:
To a solution of [8-benzyl-10-(2-hydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone hydrochloride salt (40 mg, 0.08 mmol) in methanol (750 μL) was added Pd (4 mg, 0.004 mmol) and ammonium formate (25 mg, 0.39 mmol), and the reaction mixture was heated at 75° C. for 1 hour. The reaction mixture was microfiltered and purified by prep LCMS (1-99% ACN/Water, 5 mM HCl modifier) to give [10-(2-hydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone hydrochloride salt (20 mg, 62%). ESI-MS m/z calc. 376.2. found 377.3 (M+1)+; Retention time: 1.01 minutes (3 min run).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH:30]=[N:29][N:28]=[N:27]2)=[C:22]([CH2:24][NH2:25])[CH:23]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH:30]=[N:29][N:28]=[N:27]2)=[C:22]([CH:23]=1)[CH2:24][NH:25][C:14]([C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16]
Reactant: NCc1cc(Cl)ccc1-n1cnnn1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: On1nnc2cccnc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (2S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (299 mg, 1.30 mmol), 1-[5-chloro-2-(1H-tetraazol-1-yl)phenyl]methanamine (293 mg, 1.40 mmol), EDC (376 mg, 1.96 mmol) and HOAt (89 mg, 0.65 mmol) in DMF (7 mL) was stirred at room temperature for 16 h. Water and saturated aqueous K2CO3 were added and the mixture was extracted with EtOAc. The organic layer was washed with brine and the combined aqueous layers were extracted once with CH2Cl2. The combined organic extracts were dried (Na2SO4) and concentrated to a yellow oil. Silica gel chromatography (65% EtOAc-hexanes) afforded the title compound as a light yellow foam. 1H NMR (400 MHz, CDCl3): δ 8.99 (s, 1 H), 7.60 (d, J=1.8 Hz, 1 H), 7.46 (dd, J=1.8, 8.4 Hz, 1 H), 7.29–7.26 (m, 1 H), 6.84 (br m, 1 H), 4.74 (br m, 1 H), 4.29–4.16 (m, 2 H), 4.04 (br m, 1 H), 2.76–2.70 (m, 1 H), 2.24–2.04 (m, 1 H), 1.64–1.32 (br m, 5 H), 1.48 (s, 9 H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][CH2:2][C:3](=[N:14][OH:15])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12]
Reactant: O=C(CCl)c1ccc(F)cc1F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C(CCl)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.8 %

Procedure:
2-Chloro-2′,4′-difluoroacetophenone (3.09 g, 16.2 mmol) was dissolved in ethanol (30 ml). The solution was added under ice-cooling successively with hydroxylamine hydrochloride (1.23 g, 17.7 mmol) and sodium acetate (1.45 g, 17.7 mmol), and the mixture was allowed to warm to room temperature and stirred for 20 hours. The reaction solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and washed with an aqueous sodium bicarbonate solution and then with saturated brine, and dried over magnesium sulfate. Insoluble solids were removed by filtration, and the solvent was evaporated under reduced pressure. The residue was suspended in hexane and dried to obtain the title compound as colorless solid (2.29 g, yield: 69%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)=[CH:8]2)=[O:4].[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[C:13]([Br:34])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)=[CH:8]2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Yield: 57 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(3-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (115 mg, 0.25 mmol) and N-bromosuccinimide (50 mg, 0.28 mmol) in CH2Cl2 (1 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-20% EtOAc/hexanes+1% AcOH) to give 76 mg of the title compound as a yellow solid. MS: (−) m/z 531.17, 533.12 (M-1, 79/81Br).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([O:16]CC)=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1

Procedure:
Ethyl 1-(t-butoxycarbonyl)piperidine-3(S)-carboxylate (35.9 g, 0.099 mol) was dissolved in abs EtOH (70 mL), treated with 0.5N NaOH (418 mL, 0.209 mol), and heated at reflux for 0.75 h. The reaction mixture was cooled and extracted with EtOAc. The aqueous basic layer was cooled with ice, carefully acidified (pH 3) with 3N HCl and extracted with CH2 Cl2 (3×100 mL). The organics were combined, dried (MgSO4), filtered, and concentrated to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:12]4[CH2:13][C:14]5[S:15][CH:16]=[CH:17][C:18]=5[C:11]=4[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:25])([CH3:24])[CH3:26])[N:9]=3)=[CH:4][CH:3]=2)=[CH:31][CH:30]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c2c1-c1ccsc1C2
Temperature: 100 °C
Yield: 35 %

Procedure:
A mixture of the corresponding intermediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pental ene (1.34 g, 3 mmol), 4-Trifluoromethylphenylboronic acid (0.85 g, 4.5 mmol), Na2CO3 (2 M, 7 mL), and Pd(PPh3)2Cl2 (270 mg, 0.2 mmol) in toluene/ethanol (1:1, 18 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 6-(4′-Trifluoromethyl-biphenyl-4-yl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as brown solid in 35% yield.