Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=2[O:20][CH3:21])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:21][O:20][C:13]1[C:14]([O:18][CH3:19])=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[CH:9]=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:11]=1
Reactant: COc1cccc(-c2cc3ncccc3c(Cl)n2)c1OC
Reactant: C1COCCN1
Product: COc1cccc(-c2cc3ncccc3c(N3CCOCC3)n2)c1OC

Procedure:
A solution of 5-chloro-7-(2,3-dimethoxy-phenyl)-[1,6]naphthyridine 3 (50 mg, 0.17 mmol, 1 eq) in morpholine (1.02 mL, 11.7 mmol, 68 eq) was heated up at 100° C. for 5 h under Ar(g). Once cooled down, the solution was subsequently partitioned and extracted with CH2Cl2 (3×5 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (1:2) to furnish the product, A, as a pale yellow solid (48 mg, 81%).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([CH:20]=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:16]=2)[CH2:11]1)=O)(C)(C)C.[ClH:27]>C(O)C>[ClH:27].[NH2:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([CH:20]=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:16]=2)[CH2:11]1
Reactant: CCOC(=O)C=Cc1ccc2c(c1)CC(CNC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C=Cc1ccc2c(c1)CC(CN)CC2

Procedure:
A solution of the compound obtained in step d) above (0.7 g, 0.002 mol) in absolute ethanol (40 ml) is allowed to react at room temperature for 4 hours with a solution of hydrogen chloride saturated ethanol (10 ml).
Reaction SMILES: [C:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:4]=1[NH:19][C:20](=O)[CH3:21])#[N:2].P(=O)(O)(O)[OH:24]>>[CH3:21][C:20]1[NH:2][C:1](=[O:24])[C:3]2[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]([C:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[CH3:18])[C:4]=2[N:19]=1
Reactant: CC(=O)Nc1c(C#N)c(C)c(C)n1-c1c(C)cc(C)cc1C
Reactant: O=P(O)(O)O
Product: Cc1cc(C)c(-n2c(C)c(C)c3c(=O)[nH]c(C)nc32)c(C)c1
Temperature: 130 °C

Procedure:
A mixture of the compound of step B(157.600 g, 0.53 mol) and 100 ml of 85% phosphoric acid was heated for 0.5 hours in an oil bath at a temperature of 130° C. All the starting material was consumed and the desired product formed. The mixture was cooled, poured into 1200 ml of ice-water, and stirred. Precipitate formed and was filtered. The solid was washed with water, dried overnight to give 113.220 g of the title compound as brick-pink solid. 1H NMR (CDCl3) δ 1.85(s, 6H), 1.87(s, 3H), 2.34(s, 3H), 2.41(s, 3H), 2.44(s, 3H), 7.00(s, 2H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.CN(C)C=O>[C:26]1([NH:25][C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1ccc(Br)cc1)Nc1ccccc1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A mixture of 4-bromophenyl acetic acid (5.0 g, 23.3 mmol), and oxalyl chloride (3.25 g, 25.6 mmol) in dichloromethane (100 mL), was stirred at ambient temperature, treated with 3 drops of N,N-dimethylformamide, then stirred for 2.5 hours. The solvents were removed under reduced pressure then the residue was dissolved in dichloromethane (100 mL) and triethylamine (5.9 g, 58.3 mmol). Aniline (2.4 g, 25.6 mmol) was added and the mixture was stirred an additional 1 hour. The solution was washed with 1N aqueous hydrochloric acid (2×50 mL), saturated sodium bicarbonate (100 mL), brine (50 mL), then dried over magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to give N1-phenyl-2-(4-bromophenyl)acetamide (4.62 g, 68%) [RP-HPLC (Hypersil HS C18, 5 m, 100 A, 250×4.6 mm; 25%-00% acetonitrile over 10 min, 1 mL/min) tr 10.85 min.] which was used without further purification. A mixture of N1-phenyl-2-(4-bromophenyl)acetamide (4.62 g, 15.9 mmol), diboron pinacol ester (4.45 g, 17.5 mmol), potassium acetate (4.68 g, 47.8 mmol) and [ 1.1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1: 1) (0.39 g, 0.5 mmol) in N,N-dimethylformamide (90 mL) was heated at 100° C. under an atmosphere of nitrogen for 18 hours then cooled to ambient temperature. The solvent was removed under reduced pressure and the residue was triturated with dichloromethane (100 mL). The insoluble material was removed by filtration through a pad of celite and then the filtrate was concentrated under reduced pressure and purified by flash chromatography on silica gel using dichloromethane/ethyl acetate (95:5) as an eluent to provide N1-phenyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide (4.82 g, 89%):1H NMR (DMSO-d6, 400 MHz) 10.15(s, 1H), 7.64(d, 2H), 2.59(d, 2H), 7.36(d, 2H), 7.29(t, 2H), 7.03 (t, 1H), 3.67(s, 2H), 1.29(s, 12H); RP-HPLC (Hypersil HS C18, 5 m, 100 A, 250×4.6 mm; 5%-50% acetonitrile over 25 min, 1 mL/min) tr 11.7 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:25][CH2:26][CH:27]=[CH2:28])=[C:8]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[CH:9]=1)([O-])=O>C(O)(=O)C.[Zn]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:25][CH2:26][CH:27]=[CH2:28])=[C:8]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[CH:9]=1
Reactant: C=CCOc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccccc3)ccc2o1
Agent: [Zn]
Solvent: CC(=O)O
Product: C=CCOc1ccc(N)cc1-c1nc2cc(-c3ccccc3)ccc2o1
Yield: 172.2 %

Procedure:
Powdered zinc (377 mg, 5.8 mmol) was added to a solution of 2-(5-nitro-2-allyloxyphenyl)-5-phenylbenzoxazole (216 mg, 0.58 mmol) in acetic acid (2 ml). After 2 h the reaction mixture was filtered through celite and the filtrate concentrated. The residue was dissolved in ethyl acetate (10 ml) and washed with saturated sodium hydrogen carbonate solution (2×25 ml). The organic layer was dried over sodium sulfate and concentrated to give the subtitle compound (342 mg, 100%). The product was used directly in the next step without purification.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]([F:24])([F:23])[C:8]([F:22])([F:21])[C:9]([F:20])([F:19])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:25][CH:26]([CH2:40][CH3:41])[CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][N:32]=1>>[CH3:25][CH:26]([CH2:40][CH3:41])[CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([O:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:9]([F:19])([F:20])[C:8]([F:21])([F:22])[C:7]([F:23])([F:24])[CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:13][CH:14]=2)=[O:36])=[CH:33][N:32]=1
Reactant: CCC(C)CCCOc1ccc(C(=O)O)cn1
Reactant: CCCCOCC(F)(F)C(F)(F)C(F)(F)COc1ccc(O)cc1
Product: CCCCOCC(F)(F)C(F)(F)C(F)(F)COc1ccc(OC(=O)c2ccc(OCCCC(C)CC)nc2)cc1

Procedure:
4-(5-Butoxy-2,2,3,3,4,4-hexafluoropentoxy)phenyl 6-(4-methylhexyloxy)nicotinate (Compound 7, Table 1) was prepared by esterification of 4-(5-butoxy-2,2,3,3,4,4-hexafluoropentoxy)phenol (prepared essentially as in Example 5) with 6-(4-methylhexyloxy)nicotinic acid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[N:21]=[C:20]([CH:22]4[CH2:27][CH2:26][N:25](S(CC5C=CC=CC=5)(=O)=O)[CH2:24][CH2:23]4)[NH:19][C:18]=3[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:16][C:11]=2[O:10][CH2:9]1.C(N(C(C)C)CC)(C)C>C1COCC1>[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[N:21]=[C:20]([CH:22]4[CH2:27][CH2:26][N:25]([C:1](=[O:3])[CH3:2])[CH2:24][CH2:23]4)[NH:19][C:18]=3[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:16][C:11]=2[O:10][CH2:9]1
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(Cc1ccccc1)N1CCC(c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CCC(c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.6 %

Procedure:
Acetic anhydride (0.011 mL, 0.12 mmol) was added to a solution of 2-(5-benzo[1,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-pyridine (0.035 g, 0.10 mmol; prepared as described in Example 11) and diisopropylethylamine (0.021 mL, 0.12 mmol) in anhydrous THF (3 mL). The mixture was stirred at room temperature for 18 hours and was partitioned between ethyl acetate and water. The organic solution was washed with brine, dried over sodium sulfate, filtered, and concentrated. HPLC purification eluting with acetonitrile:water gave 0.010 g (26%) of the title compound as a yellow solid. MS (ESP+) m/z 391.2 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 8.59 (m, 1H), 7.73 (m, 1H), 7.34 (m, 2H), 6.94 (m, 3H), 5.98 (s, 2H), 4.83 (s, 3H), 4.60 (m, 2H), 4.01 (m, 2H), 3.28 (m, 3H), 2.69 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][N:6]1[C:28](=[O:42])[NH:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[CH:32][CH:31]=1)=O.[Li+].[BH4-]>C1COCC1>[F:41][C:38]([F:39])([F:40])[CH2:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:28]([N:6]2[CH2:7][C@@H:8]([O:10][Si:11]([C:24]([CH3:27])([CH3:25])[CH3:26])([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][C@@H:5]2[CH2:3][OH:2])=[O:42])=[CH:35][CH:34]=1
Reactant: COC(=O)[C@H]1C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CN1C(=O)Nc1ccc(OCC(F)(F)F)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](O[C@H]1C[C@H](CO)N(C(=O)Nc2ccc(OCC(F)(F)F)cc2)C1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of (2R,4S)-4-(tert-Butyl-diphenyl-silanyloxy)-1-[4-(2,2,2-trifluoro-ethoxy)-phenylcarbamoyl]-pyrrolidine-2-carboxylic acid methyl ester (5 g, 8.33 mmol) in THF (30 mL) was added LiBH4 (2M in THF, 6.25 mL) at 0° C. and stirred for 2 h. The mixture was quenched with AcOH at 0° C. and diluted with DCM. The organic layer was washed with sat NaHCO3 solution, dried over Na2SO4 and concentrated. The residue was purified through column chromatography over silica (elution with 40% ethyl acetate in hexane) to yield 4.3 g (91%) of the title compound as pale yellow sticky liquid. LC-MS: 573.6 [M+1]+.
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6]([C:9]1[C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][S:11][N:10]=1)(=[O:8])[CH3:7].O.[OH-].[Li+]>CS(C)=O>[C:6]([C:9]1[C:13]([C:14]([OH:16])=[O:15])=[CH:12][S:11][N:10]=1)(=[O:8])[CH3:7]
Reactant: CCOC(=O)c1csnc1C(C)=O
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1nscc1C(=O)O

Procedure:
Following generally the procedure of Example 28, ethyl 3-ethyl-4-isothiazolecarboxylate is reacted with NBS and benzoyl peroxide to give ethyl 3-(1-bromoethyl)-4-isothiazolecarboxylate, which is then reacted with sodium bicarbonate and DMSO and the resulting ethyl 3-acetyl-4-isothiazolecarboxy-late is treated with lithium hydroxide monohydrate to yield 3-acetyl-4-iso-thiazole-carboxylic acid.
Reaction SMILES: O[CH:2]([CH3:6])[C:3](=[O:5])[CH3:4].[C:7]([O:13]CC)(=[O:12])[CH2:8][C:9]([CH3:11])=O.C(O)C>[Cl-].[Zn+2].[Cl-].O>[CH3:11][C:9]1[O:5][C:3]([CH3:4])=[C:2]([CH3:6])[C:8]=1[C:7]([OH:13])=[O:12]
Reactant: CC(=O)C(C)O
Reactant: CCOC(=O)CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CCO
Product: Cc1oc(C)c(C(=O)O)c1C
Yield: 96 %

Procedure:
A mixture of 3-hydroxy-2-butanone (90g.) ethyl acetoacetate (175g.), absolute ethanol (150 ml.) and anhydrous zinc chloride (100g.) was heated under reflux for 24 hours. The cooled solution was poured into water and extracted with benzene. The benzene extract was washed successively with 30% aqueous sodium bisulfite, 5% sodium hydroxide, dilute hydrochloric acid and finally with water. The solvent was removed and the residual ester saponified with aqueous-alcoholic alkali as in example 18 to yield 149 g. or 96% yield of the 2,4,5-trimethyl-3-furoic acid.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][C:7]=2[C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)(=[O:21])[CH3:20].[OH-].[Na+]>CN(C)C=O.O>[N:1]1([C:6]2[CH:13]=[CH:12][C:9](/[CH:10]=[CH:20]/[C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)=[O:21])=[CH:8][C:7]=2[C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: O=Cc1ccc(N2CCCC2)c(-c2cccs2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(C(=O)/C=C/c2ccc(N3CCCC3)c(-c3cccs3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
4-Pyrrolidin-1-yl-3-(thiophen-2-yl)-benzaldehyde (400 mg, 1.55 mmol) from Ex-20B and 4-acetylbenzoic acid (255 mg, 1.55 mmol) were dissolved in dimethylformamide (30 mL). Sodium hydroxide solution (5 N, 1.25 mL) was added in one portion, and the mixture was stirred at room temperature overnight. The reaction was diluted with water (100 mL) and washed with ethyl acetate (100 mL). The aqueous phase was acidified with conc. HCl and extracted with ethyl acetate (2×100 mL). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Silica gel chromatography (100% ethyl acetate) followed by recrystallization from ethanol provided 80 mg (13%) of the title compound as a solid, m.p. 212–214° C. with decomposition. 1H-NMR (300 MHz, CDCl3) δ 8.21 (d, 2H, J=8.4 Hz), 7.06 (d, 2H, J=8.4 Hz), 7.80 (d, 1H, J=15.3 Hz), 7.58 (d, 1H, J=1.9 Hz), 7.52 (dd, 1H, J=8.5 and 1.9 Hz), 7.33 (m, 1H), 7.32 (d, 1H, 15.3 Hz), 7.01–7.06 (m, 2H), 6.82 (d, 1H, 7.9 Hz), 3.12 (m, 4H), 1.84 (m, 4H). MS m/z=403 ([M]+, 100%). HRMS (EI) Calcd. for C24H21NO3S: 403.1242. Found: 403.1251.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:16]([NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=1)(=[O:23])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(O)(=O)C.Cl>CO>[C:16]([NH:20][S:21]([C:24]1[CH:25]=[CH:26][C:27]([CH2:30][NH:15][C:13]2[NH:12][N:11]=[C:10]([NH:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=2)=[CH:28][CH:29]=1)(=[O:22])=[O:23])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(C=O)cc1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)NS(=O)(=O)c1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (100 mg, 410 μmol) in MeOH (5 mL) was added N-tert-butyl-4-formylbenzenesulfonamide (109 mg, 451 μmol) followed by acetic acid (36.7 mg, 35 μl, 611 μmol). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (65.7 mg, 615 μmol) was added and the stirring was continued for 3 days. The reaction mixture was poured into 0.1N HCl solution (25 ml) and was extracted with EtOAc (3×30 ml). The combined organic solution was washed with brine, dried over Na2SO4 and concentrated to give a residue. The crude material was purified by flash chromatography (silica gel, 24 g, 3% to 5% MeOH in DCM) to give an off white solid as desired product (98 mg, 51% yield). MS +m/z: 469 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=1>>[CH2:28]([C:25]1[CH:26]=[CH:27][C:22]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][C:2]([CH3:20])([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)=[CH:23][CH:24]=1)[CH3:29]
Reactant: CCc1ccc(Br)cc1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Product: CCc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)cc1
Yield: 38 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (210 mg, 0.765 mmol) synthesized in Reference example 61 and 1-bromo-4-ethylbenzene (212 mg, 1.15 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 110 mg (yield 38%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[N:4][CH:3]=1>[Pt].C(#N)C.CO>[NH2:12][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:15][CH2:16][C:17]([CH3:18])([OH:19])[CH3:20])=[N:4][CH:3]=[C:2]([Br:1])[CH:11]=2
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(Br)cnc12
Agent: [Pt]
Solvent: CC#N
Solvent: CO
Product: CC(C)(O)CNc1c(N)cnc2cc(Br)cnc12
Yield: 99.6 %

Procedure:
A Parr vessel was charged with 5% platinum on carbon (5.8 g) and a suspension of 1-[(7-bromo-3-nitro[1,5]naphthyridin-4-yl)amino]-2-methylpropan-2-ol (58.00 g) in acetonitrile (800 mL) and methanol (400 mL). The vessel was placed under hydrogen pressure (30 psi, 2.1×105 Pa) for 8 hours. The reaction mixture was filtered through a layer of CELITE filter aid. The filtrate was concentrated under reduced pressure to provide 52.70 g of 1-[(3-amino-7-bromo[1,5]naphthyridin-4-yl)amino]-2-methylpropan-2-ol as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([C:21]3[C:29]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][C:24]=4[NH:23][N:22]=3)=[O:20])[CH2:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[ClH:39]>C(Cl)Cl.CCOCC>[ClH:39].[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([C:21]3[C:29]4[CH2:28][CH2:27][NH:26][CH2:25][C:24]=4[NH:23][N:22]=3)=[O:20])[CH2:15][CH2:14]2)[CH:4]=[C:3]([C:2]([F:1])([F:37])[F:38])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)N3CCC(c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)n[nH]c2C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 3-(4-(3,5-bis(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (51, 75 mg, 0.14 mmol) in CH2Cl2 (1 mL) was added HCl (2N in Et2O, 1 mL). The mixture stirred for 18 h at ambient temperature. The reaction mixture was diluted with Et2O (50 mL) and concentrated to yield (4-(3,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone hydrochloride (52) as a yellow solid (79 mg, >99%): 1H NMR (300 MHz, DMSO-d6) δ 9.37 (br s, 2H), 8.05-7.86 (m, 3H), 4.75-4.44 (m, 2H), 4.39-4.18 (m, 2H), 3.42-3.25 (m, 2H, overlaps with H2O), 3.20-3.03 (m, 2H), 2.95-2.75 (m, 3H), 2.03-1.80 (m, 2H), 1.79-1.62 (m, 2H), missing N—H pyrazole; ESI MS m/z 447 [M+H]+.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C@H:10]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:12]([C:22]([O:24][CH3:25])=[O:23])[CH2:11]1.N1C=CN=C1>CN(C=O)C>[C:4]([Si:1]([CH3:3])([CH3:2])[O:9][C@H:10]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[C@@H:12]([C:22]([O:24][CH3:25])=[O:23])[CH2:11]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 19 h
Yield: 51.1 %

Procedure:
Tert-Butyldimethylsilylchloride (9.36 g) was added to a mixture of O1-tert-butyl O2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (13.83 g) and imidazole (9.61 g) in DMF (100 ml). The reaction was stirred at 20° C. for 19 hours and then evaporated to dryness. The residues were slurried in diethyl ether and filtered. The filtrate was evaporated to dryness and the residues purified by flash chromatography on silica eluting with increasingly polar mixtures of methanol/dichloromethane (0/100-5/95). Fractions containing the desired product were combined and evaporated to dryness to give O1-tert-butyl O2-methyl (2R,4R) 4-(tert-butyl-dimethyl-silyl)oxypyrrolidine-1,2-dicarboxylate (10.35 g) as a colourless oil. NMR Spectrum: (DMSOd6) 0.00 (6H, s); 0.80 (9H, s); 1.32-1.38 (9H, m); 1.84-1.89 (1H, m); 2.30-2.35 (1H, m); 3.06-3.10 (1H, m); 3.49 (1H, q); 3.59 (3H, d); 4.22-4.26 (1H, m); 4.37 (1H, d).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[Br:1][C:2]1[N:3]=[C:4]([CH2:7][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:5][CH:6]=1
Reactant: O=Cc1nc(Br)cs1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Brc1csc(CN2CCOCC2)n1
Reaction time: 12 h
Yield: 76 %

Procedure:
To a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM (4.0 mL) was added morpholine (130 ul, 1.5 mmol) and 3 drops of AcOH. The mixture was stirred for 12 hr and then Na(OAc)3BH (0.335 g, 1.5 mmol) was added. After 6 hr, the mixture was quenched with Sat. NaHCO3 (4.0 mL) and brine (3.0 mL). The organic layer was separated and concentrated to give 200 mg of 4-[(4-bromo-1,3-thiazol-2-yl)methyl]morpholine (76%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH2:13][O:14][CH3:15])[C:7]=2[C:6](=[O:16])[NH:5][C:4]1=[O:17])[CH3:2].Cl[CH2:19][CH2:20][CH:21]([CH3:25])[C:22](=[O:24])[CH3:23]>>[O:24]=[C:22]([CH3:23])[CH:21]([CH3:25])[CH2:20][CH2:19][N:5]1[C:6](=[O:16])[C:7]2[N:8]([CH2:12][CH2:13][O:14][CH3:15])[CH:9]=[N:10][C:11]=2[N:3]([CH2:1][CH3:2])[C:4]1=[O:17]
Reactant: CCn1c(=O)[nH]c(=O)c2c1ncn2CCOC
Reactant: CC(=O)C(C)CCCl
Product: CCn1c(=O)n(CCC(C)C(C)=O)c(=O)c2c1ncn2CCOC

Procedure:
1-(4-Oxo-3-methylpentyl)-3-ethyl-7-(2-methoxyethyl)-xanthine (melting point 83-84° C.) is prepared from 3-ethyl-7-(2-methoxyethyl)xanthine and 1-chloro-3-methylpentan-4-one.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:12])[C:5](Br)=[CH:4][CH:3]=1.[Si:14]([O:21][CH2:22][CH2:23][C:24]1[O:25][CH:26]=[CH:27][C:28]=1B(O)O)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:12])[C:5]([C:28]2[CH:27]=[CH:26][O:25][C:24]=2[CH2:23][CH2:22][O:21][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(N)ccc(Br)c1O
Reactant: CC(C)(C)[Si](C)(C)OCCc1occc1B(O)O
Product: COC(=O)c1c(N)ccc(-c2ccoc2CCO[Si](C)(C)C(C)(C)C)c1O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 26, starting from methyl 6-amino-3-bromo-2-hydroxybenzoate (prepared according to Wang et al, Bioorg Med Chem Lett 2007 17 2817) and 2-[2-(tert-butyldimethylsilanyloxy)-ethyl]-furan-3-yl-boronic acid (Intermediate 33). The material was used without further characterisation.