Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([N:19]3[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]3)[CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:6]=[CH:7][CH:8]=1.[OH:28]O>CO.O.Cl>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([N:19]3[CH2:20][CH2:21][CH:22]([C:25]([OH:27])=[O:26])[CH2:23][CH2:24]3)[CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:6]=[CH:7][CH:8]=1)=[O:28]
Reactant: OO
Reactant: CSc1cccc(-c2nc(N3CCC(C(=O)O)CC3)cc3cccnc23)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: CS(=O)c1cccc(-c2nc(N3CCC(C(=O)O)CC3)cc3cccnc23)c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
Example 41 (1-[8-(3-Methylsulfanyl-phenyl)-[1,7]naphthyridin-6-yl]-piperidine-4-carboxylic acid) (30 mg, 0.07 mmol) is dissolved in methanol (200 μl), and hydrogen peroxide (11.1 μl) is added at room temperature. After 3 hours a further amount of hydrogen peroxide (15 μl) is added and the reaction mixture stirred at 45° C. overnight. The mixture is then cooled to room temperature, diluted with water and acidified with 7 M HCl (1 drop). The reaction mixture is extracted into ethyl acetate, which is washed with water and brine. The organic layer is then dried over magnesium sulfate and concentrated to give the product as an amorphous solid. MS (ES+) 396.1308
Reaction SMILES: C1(C(=[N:14][CH:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:16]#[N:17])C2C=CC=CC=2)C=CC=CC=1.[ClH:26].O>C1COCC1>[ClH:26].[NH2:14][CH:15]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[C:16]#[N:17]
Reactant: N#CC(Cc1ccc(F)cc1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: N#CC(N)Cc1ccc(F)cc1
Reaction time: 3 h
Yield: 93 %

Procedure:
To a solution of 2-(diphenylmethyleneamino)-3-(4-fluorophenyl)propanenitrile, intermediate 1 (1.65 g, 5.02 mmol, 1.0 equiv) in THF (20.1 mL) was added HCl (5.53 mL of a 1 M aqueous solution, 5.53 mmol, 1.1 equiv). After stirring 3 h, the reaction was poured into water and washed with ether (×3). The aqueous layer was neutralized by the addition of 10 M NaOH and extracted with CH2Cl2 (×3). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo to provide the title compound (0.77 g, 93% yield) as a colorless oil. For convenience, the amine could be converted into the hydrochloride salt by dissolution in ether, treating with 2 M HCl in ether, and filtering the resulting white solid: 1H NMR (400 MHz, CDCl3) δ ppm 7.24-7.29 (m, 2H), 7.01-7.08 (m, 2H), 3.85-3.96 (m, 1H), 2.92-3.07 (m, 2H), 1.60 (d, J=7.55 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:42]C(OC(C)(C)C)=O)[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][C:25]([O:27][CH2:28][CH:29]3[C:41]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:35]4[C:30]3=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.Cl>CCOC(C)=O>[ClH:1].[NH2:42][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25]([O:27][CH2:28][CH:29]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=3[C:36]3[C:41]2=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:26])[CH2:14][CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2NC(=O)OCC2c3ccccc3-c3ccccc32)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 16 (Step b) from N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(fluoren-9-ylmethoxy)carbonylamino]-phenyl}piperidyl)-2-oxoethyl](tert-butoxy)carboxamide (Step c) (6.8 g, 10 mmol) and satd anhydrous HCl in EtOAc (50 mL). The title compound was obtained as a white solid (6.1 g). MS (ESI, pos. ion) m/z: 580 (M+1); MS (ESI, neg. ion) m/z: 578 (M−1). Calc'd for C35H35Cl2N3O3: 579.23.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH2:18][OH:19])=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([NH2:24])=[O:23]>>[OH:19][CH2:18][C@@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[C:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:24][C:22](=[O:23])[C:21]([CH3:26])([CH3:25])[CH3:20])=[CH:3][CH:4]=2)[N:9]=[C:8]([CH3:12])[CH:7]=1
Reactant: CC(C)(C)C(N)=O
Reactant: Cc1cc(N2CCC[C@H]2CO)c2ccc(I)cc2n1
Product: Cc1cc(N2CCC[C@H]2CO)c2ccc(NC(=O)C(C)(C)C)cc2n1

Procedure:
In analogy to example 47, on reaction of (S)-[1-(7-iodo-2-methyl-quinolin-4-yl)-pyrrolidin-2-yl]-methanol with trimethylacetamide there was obtained (S)-N-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yl]-2,2-dimethyl-propionamide as amorphous white yellow solid. ISP mass spectrum, m/e: 342.3 (M+1 calculated for C20H27N3O2: 342).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([Sn](C)(C)C)=[N:14][N:13]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:10]3=[CH:11][N:12]=2)[CH:2]=1.Br[C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1.[Li+].[Cl-]>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:35][C:32]1[CH:33]=[CH:34][C:29]([C:15]2[C:9]3[C:10](=[CH:11][N:12]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)[N:13]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:14]=2)=[N:30][CH:31]=1
Reactant: Cc1ccc(Br)nc1
Reactant: C[Si](C)(C)CCOCn1nc([Sn](C)(C)C)c2cc(-c3cccnc3)ncc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nn(COCC[Si](C)(C)C)c3cnc(-c4cccnc4)cc23)nc1
Temperature: 120 °C
Yield: 54 %

Procedure:
To a mixture of 5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(trimethylstannyl)-1H-pyrazolo[3,4-c]pyridine (250 mg, 0.51 mmol) and 2-bromo-5-methylpyridine (87 mg, 0.51 mmol) in DMF 10 mL, was added TEA (10 mL), LiCl (64 mg, 1.53 mmol), CuI (97 mg, 0.51 mmol), and Pd(PPh3)4 (294 mg, 0.25 mmol). The reaction mixture was heated at 120° C. under microwave irradiation for 1 h, and the reaction was monitored by LCMS. Upon completion of the reaction, the mixture was extracted with 100 mL EtOAc, washed with 50 mL brine, and dried. The solvent was distilled off and the crude material was purified via flash chromatography, eluting with 33% to 66% ethyl acetate in heptane to afford 3-(5-methylpyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine as an clear oil (115 mg, 54%). ESI MS m/z=417.2 (M+1).
Reaction SMILES: [F:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[CH:3]=[O:4].[BH4-].[Na+].[NH4+].[Cl-]>C(Cl)Cl.C(O)C>[F:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[CH2:3][OH:4]
Reactant: O=C[C@H](F)c1cccc(Br)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Product: OC[C@H](F)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (R)-2-fluoro-2-(3-bromophenyl)acetaldehyde in CH2Cl2 and ethanol is treated with NaBH4 (189 mg, 5 mmol), stirred for 30 min, cooled to 0° C., treated with saturated NH4Cl, warmed to room temperature, stirred vigorously for 1 h at room temperature and diluted with CH2Cl2. The phases are separated. The aqueous phase is extracted with CH2Cl2. The organic phase and the extracts are combined, washed with NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by column chromatography (5% EtOAc and hexane as eluant)to give (R)-2-fluro-2-(3-bromophenyl)-1-ethanol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][C:12]=3[F:19])=[N:10][C:5]2=[CH:4][CH:3]=1.Cl.[NH:21]1[CH2:24][CH:23]([C:25]([O:27][CH3:28])=[O:26])[CH2:22]1.C(N(C(C)C)C(C)C)C.C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCl.CO>[Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH2:15][N:21]4[CH2:24][CH:23]([C:25]([O:27][CH3:28])=[O:26])[CH2:22]4)=[CH:13][C:12]=3[F:19])=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)C1CNC1
Reactant: O=Cc1ccc(-c2nc3ccc(Cl)nc3s2)c(F)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(Cl)nc4s3)c(F)c2)C1
Reaction time: 0.08 h

Procedure:
A mixture of 4-(5-chlorothiazolo[5,4-b]pyridine-2-yl)-3-fluorobenzaldehyde (2.08 g, 7.11 mmol), methyl azetidine-3-carboxylate hydrochloride (1.62 g, 10.7 mmol), N-ethyl-N-isopropylpropan-2-amine (1.86 mL, 10.7 mmol) in dichloromethane (40.00 mL) and methanol (30.00 mL) was stirred for 5 min. Then acetic acid (1.64 mL, 28.4 mmol) was added and the mixture was allowed to stir for 90 min at 50° C. Sodium cyanoborohydride (0.223 g, 3.55 mmol) was added. After 15 min, the solvent removed, and the mixture concentrated onto silica gel. Purification by silica gel chromatography, 120 g column, 30-40% EtOAc/hex followed by 50-60% (3% TEA in EtOAc/hex) gave methyl 1-((4-(5-chlorothiazolo[5,4-b]pyridine-2-yl)-3-fluorophenyl)methyl)azetidine-3-carboxylate. MS (ESI) m/z: calculated: 391.1; Observed: 392.0 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].[CH:16]([N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1)([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH:22]3[CH2:23][CH2:24][N:19]([CH:16]([CH3:18])[CH3:17])[CH2:20][CH2:21]3)=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(O)ccc2o1
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)ccc2o1
Reaction time: 3 h
Yield: 56.4 %

Procedure:
The above prepared 5-hydroxy-benzofuran-2-carboxylic acid ethyl ester (1.50 g, 7.27 mmol) was dissolved in 36 mL of THF and treated successively at 10° C. with 1-isopropyl-piperidin-4-ol (1.46 g, 1.4 eq.), triphenylphosphine (2.67 g, 1.4 eq.) and DIAD (2.00 mL, 1.4 eq.), and the mixture then kept at ambient temperature for another 3 h. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, NEt3/AcOEt=2/98), yielded finally 1.36 g of the title compound as light yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:42]([O:49][C:50]1[CH:77]=[CH:76][C:75](O)=[CH:74][C:51]=1[C:52]([NH:54][C:55]1[CH:67]=[C:66]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH:65]=[CH:64][C:56]=1[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[O:53])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O1CCCC1>[CH2:42]([O:49][C:50]1[CH:77]=[CH:76][C:75]([O:1][CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][CH2:6][CH2:5]2)=[CH:74][C:51]=1[C:52]([NH:54][C:55]1[CH:67]=[C:66]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH:65]=[CH:64][C:56]=1[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[O:53])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: OCCN1CCCC1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(O)ccc1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
1-(2-Hydroxyethyl)pyrrolidine (0.016 mL), triphenylphosphine (0.038 g), and diisopropyl azodicarboxylate (0.029 mL) were added to a tetrahydrofuran (1.2 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-hydroxybenzamido)-4-phenylbenzoate (0.060 g), followed by stirring at room temperature for 25 minutes. To the reaction mixture, 1-(2-hydroxyethyl)pyrrolidine (0.016 mL), triphenylphosphine (0.038 g), and diisopropyl azodicarboxylate (0.029 mL) were added, followed by stirring at room temperature for 20 minutes. To the reaction mixture, 1-(2-hydroxyethyl)pyrrolidine (0.016 mL), triphenylphosphine (0.038 g), and diisopropyl azodicarboxylate (0.029 mL) were added, followed by stirring at room temperature for 30 minutes. To the reaction mixture, 1-(2-hydroxyethyl)pyrrolidine (0.016 mL), triphenylphosphine (0.038 g), and diisopropyl azodicarboxylate (0.029 mL) were added, followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: 80-0% hexane/ethyl acetate] to obtain 0.071 g of tert-butyl 2-(2-(benzyloxy)-5-(2-(pyrrolidin-1-yl)ethoxy)benzamido)-4-phenylbenzoate.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cnc2ccc(OC)nc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2ccc(OC)nc2c1Cl

Procedure:
A mixture of ethyl 4-hydroxy-6-methoxy-1,5-naphthyridine-3-carboxylate (2.48 g) and phosphorus oxychloride (25 ml) was stirred and heated at 50°-55° C. for 30 minutes. The mixture was worked up as described in Example B1 to give ethyl 4-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate, m.p. 98°-100° C.
Reaction SMILES: Cl.C(O)(=O)C.[Br:6][C:7]1[C:8]([F:37])=[C:9]([F:36])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25]C(C)(C)C)[N:18]=1)[CH:14]=[C:13]([C:30]([O:32]CC)=[O:31])[C:12]2=[O:35]>O>[NH2:25][C:19]1[N:18]=[C:17]([N:15]2[C:16]3[C:11](=[CH:10][C:9]([F:36])=[C:8]([F:37])[C:7]=3[Br:6])[C:12](=[O:35])[C:13]([C:30]([OH:32])=[O:31])=[CH:14]2)[C:22]([F:23])=[CH:21][C:20]=1[F:24]
Reactant: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(Br)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)c(F)cc1F
Reaction time: 5 h
Yield: 95.2 %

Procedure:
To a mixed solution of 3.5 ml of 4N hydrochloric acid and 3.5 ml of acetic acid was added 1.38 g of ethyl 8-bromo-1-[6-(t-butylamino)-3,5-difluoropyridin-2-yl]-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 5 hours. After adding 5 ml of distilled water, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 1.10 g of the title compound as a colorless powder.
Reaction SMILES: O[C:2]1[C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[CH:3]=1.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>>[C:17]([C:2]1[C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[CH:3]=1)(=[O:20])[CH2:18][CH3:19]
Reactant: CCCCCCCCC1(C)SC(=O)C=C1O
Reactant: CCC(=O)Cl
Product: CCCCCCCCC1(C)SC(=O)C=C1C(=O)CC
Yield: 48.1 %

Procedure:
From 32 (40 mg, 0.17 mmol) and propionyl chloride (20 μL, 0.22 mmol) following general procedure K was obtained 64 (23.1 mg, 47%) after flash chromatography (15% EtOAc/Hexanes). 1H NMR (300 MHz, CDCl3) δ 0.85 (t, J=7 Hz, 3H), 1.12-1.25 (m, 13H), 1.42-1.49 (m, 2H), 1.64 (s, 3H), 1.78-1.84 (m, 2H), 2.57 (q, J=7.5 Hz, 2H), 6.39 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 8.71, 14.0, 22.6, 25.1, 25.9, 27.9, 29.1, 29.3, 29.5, 31.8, 38.6, 60.4, 113.8, 169.1, 177.0, 179.9. IR (NaCl) 2928, 1787, 1688 cm−1; Analysis Calculated for C16H26O3S: C, 64.4; H, 8.78; Found: C, 64.3; H, 8.89.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:12]2[CH2:17][C@@H:16]([C:18]3[O:22][NH:21][C:20](=[O:23])[CH:19]=3)[CH2:15][CH2:14][N:13]2C(OC)=O)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Br>>[F:1][C:2]1[CH:3]=[C:4]([C@H:12]2[CH2:17][C@@H:16]([C:18]3[O:22][NH:21][C:20](=[O:23])[CH:19]=3)[CH2:15][CH2:14][NH:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)c(F)c1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](c3ccc(C(F)(F)F)c(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.4 %

Procedure:
(2R,4S)-Methyl 2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (319 mg, 0.82 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 6.5 mL, 36.97 mmol) and stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-piperidin-4-yl)isoxazol-3(2H)-one (150 mg, 55%). 1H NMR (600 MHz, dmso) δ 1.33 (q, 1H), 1.45 (dq, 1H), 1.84-1.90 (m, 1H), 1.99-2.05 (m, 1H), 2.72 (dt, 1H), 2.83-2.91 (m, 1H), 3.07-3.14 (m, 1H), 3.72-3.79 (m, 1H), 5.73 (s, 1H), 7.41 (d, 1H), 7.48 (d, 1H), 7.70 (t, 1H). HRMS Calculated for [C15H14F4N2O2+H]+: 331.1070. Found: 331.1058.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:9].[NH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1.C(N(C(C)C)CC)(C)C.O>CCCCO.CN(C1C=CN=CC=1)C>[C:20]([O:19][C:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@@H:11]([NH:10][C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=2[O-:9])[CH2:12]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: Cc1ccc[n+]([O-])c1Cl
Agent: CN(C)c1ccncc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc[n+]([O-])c1N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Yield: 25 %

Procedure:
To a solution of the compound from Step 1 2-chloro-3-methylpyridine 1-oxide (14.5 g, 101 mmol) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (24.27 g, 121.2 mmol) in n-BuOH (120 mL) were added diisopropylethyl amine (14.35 g, 111 mmol) and DMAP (1.22 g, 9.99 mmol) slowly at 0° C. The resulting mixture was heated at 100° C. for 36 h. The reaction was cooled, and water was added. The mixture was then extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel chromatography eluting with a gradient of petroleum ether:EtOAc (80:20 to 50:50) to afford the title compound (7.9 g, 25%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][NH:10][CH:11]([CH3:13])[CH3:12])[C:5]2[C:14](I)=[N:15][N:16]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:4]=2[CH:3]=1.CC([O-])(C)C.[Na+].C1COCC1>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:16]([C:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:15]=[C:14]3[C:5]2=[C:6]([CH2:8][CH2:9][N:10]3[CH:11]([CH3:12])[CH3:13])[N:7]=1
Reactant: CC(C)NCCc1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)N1CCc2nc(Cl)cc3c2c1nn3C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 55 °C

Procedure:
N-(2-(6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)ethyl)propan-2-amine (554 mg, 0.913 mmol) and RuPhos pre-catalyst (66.5 mg, 0.091 mmol) were charged in a 2 dram vial, evacuated and backfilled with nitrogen and taken in toluene (4 mL) before the addition of a solution of 2M NaOtBu in THF (1.15 mL, 2.3 mmol). The reaction mixture was heated at 55° C. for 1 hour before it was diluted with EtOAc and washed with water, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-50% EtOAc-hexanes) gave 7-chloro-3-isopropyl-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridine. MS ESI calc'd. for C30H27ClN4 [M+H]+ 480. found 480.
Reaction SMILES: O[CH:2]=[C:3]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:31])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=3)[CH2:14][CH2:13]2)[O:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=O.[NH2:33][NH2:34]>C(O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([N:15]2[CH2:14][CH2:13][C:12]3([C:3]4[CH:2]=[N:34][NH:33][C:4]=4[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=4[O:11]3)[CH2:17][CH2:16]2)=[O:31])=[CH:20][C:21]=1[C:27]([F:28])([F:29])[F:30]
Reactant: NN
Reactant: COc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2C(=O)C3=CO)cc1C(F)(F)F
Solvent: CCO
Product: COc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2[nH]ncc23)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(hydroxymethylene)-1′-[4-methoxy-3-(trifluoromethyl)-benzoyl]spiro[chromane-2,4′-piperidine]-4-one (54 mg, 0.12 mmol) and hydrazine (3.8 μL, 0.12 mmol) in ethanol (1.7 mL) was allowed to stir for 1 h at 25° C., then for 2.5 h at 50° C. The mixture was cooled and then concentrated in vacuo. The residue was taken up in DMF and was purified by reverse phase HPLC to give (4-methoxy-3-(trifluoromethyl)phenyl)(1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone. ESI-MS m/z talc. 443.2, found 444.1 (M+1)+; Retention time: 2.40 minutes (4 min run). 1H NMR (400 MHz, CDCl3) δ 9.15-8.90 (m, 1H), 7.73 (s, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.58 (s, 1H), 7.52 (d, J=7.7 Hz, 1H), 7.33-7.18 (m, 1H), 7.04 (dd, J=18.8, 8.3 Hz, 2H), 6.91 (t, J=7.5 Hz, 1H), 6.05-5.60 (m, 1H), 4.50-4.05 (m, 2H), 4.08-3.55 (m, 3H), 3.97 (s, 3H), 2.50-2.32 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]2[NH:15][CH:16]=[CH:17][C:18](=[O:20])[N:19]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[O:29])=[CH:24][N:23]=1.[OH-].[Na+]>Cl>[CH3:1][O:2][C:3]1[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]2[NH:15][CH:16]=[C:17]([CH:28]([C:25]3[CH:24]=[N:23][C:22]([CH3:21])=[CH:27][CH:26]=3)[OH:29])[C:18](=[O:20])[N:19]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(C=O)cn1
Reactant: COc1cccnc1CCCCNc1nc(=O)cc[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cccnc1CCCCNc1nc(=O)c(C(O)c2ccc(C)nc2)c[nH]1
Yield: 31.9 %

Procedure:
2-[[4-(3-Methoxy-2-pyridyl)butyl]amino]-4-(1H)-pyrimidinone (1.42 g, 0.005 mol) was dissolved in concentrated hydrochloric acid (10 ml) and 2-methyl-5-formylpyridine (1.35 g, 0.012 mol) was added. The solution was stirred at reflux temperature for 24 hours, cooled, basified with 10N sodium hydroxide to pH 8.5 and the product left to separate as an oil. The aqueous mother liquor was decanted and the oil subjected to medium pressure liquid chromatography (Kieselgel 60, 230-400 mesh) with methanolic ammonia: dichloromethane (10:90) as eluent. The relevant fractions were combined and evaporated under reduced pressure to afford the title compound (0.63 g). Crystallisation from aqueous methanol afforded the title product as a white crystalline solid, m.p. 82° C.; δ(CDCl3) 1.6 (4H, m), 2.5 (3H, s) 2.75 (2H, m), 3.3 (2H, m), 3.8 (3H, s), 5.7 (1H, s), 7.1 (3H, m), 7.4 (1H, s), 7.65 (1H dd), 7.9 (1H, dd), 8.5 (1H, m) ppm.
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10][CH2:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:18]([O-])=[O:19].[Na+]>Cl.O>[N:1]1([CH2:7][CH:8]2[N:13]([N:18]=[O:19])[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10][CH2:9]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: c1ccc2c(c1)NC(CN1CCOCC1)CO2
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1c2ccccc2OCC1CN1CCOCC1

Procedure:
Similarly 17.4 g (0.074 mole) of (+)-3-(4-morpholinylmethyl)-3,4-dihydro-2H-1,4-benzoxazine in 300 ml of 2N aqueous hydrochloric acid was treated with 5.6 g (0.081 mole) of sodium nitrite in 60 ml of water at 0° C. to produce (+)-3-(4-morpholinylmethyl)-4-nitroso-3,4-dihydro-2H-1,4-benzoxazine, which was used as such in the next synthetic step without further purification or characterization.