Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1.Cl[CH2:33][C:34]1[CH:43]=[C:42]([O:44][CH3:45])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]=1[O:46][CH3:47]>>[CH3:47][O:46][C:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:42]([O:44][CH3:45])=[CH:43][C:34]=1[CH2:33][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1
Reactant: COc1cc(CCl)c(OC)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccccc3)cc2)C(O)C1
Product: COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOc3ccccc3)cc2)c(OC)c2ccccc12

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(3-phenoxy-propoxy)-phenyl]-piperidine-1-carboxylate [Example 123 (j)] with 2-chloromethyl-1,4-dimethoxy-naphthalene there was obtained tert-butyl (3RS,4RS)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-4-[4-(3-phenoxy-propoxy)-phenyl]-piperidine-1-carboxylate as a viscous, yellow oil; MS: 628 (M+H)+.
Reaction SMILES: [Na].C[C:3]([CH3:13])([CH2:6][CH2:7][C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[C:4]#N.O1CCCC1.[Cl-].[NH4+]>C(O)C>[CH3:13][C:3]1([CH3:4])[CH2:6][CH2:7][C:8]([CH3:11])([CH3:12])[CH:9]1[NH2:10]
Reactant: CC(C)(C#N)CCC(C)(C)C#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)C1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A flask was charged with 35 g. (0.61 mole) of 40% sodium dispersion in mineral oil. The oil was removed by washing with ethyl ether and decantation. The sodium was then mixed with 400 ml. of ether and a mixture of 32.8 g. (0.20 mole) 2,2,5,5-tetramethyladiponitrile, prepared by the method of Coffman et al., J. Am. Chem. Soc., 80, 2868 (1957), and 400 ml. of tetrahydrofuran was added slowly. The resulting mixture was stirred at room temperature for 4 hours, the excess sodium decomposed by dropwise addition of saturated aqueous ammonium chloride, the crganic layer washed with water, dried (Na2SO4) and evaporated to afford 25.1 g. of crude 2,2,5,5-tetramethylcyclopentylimine. The imine was dissolved in 75 ml. of ethanol and added dropwise to a flask containing 23.3 g. (1 mole) sodium shot. An additional 75 ml. ethanol was added and the mixture heated at reflux until the remaining sodium metal was consumed. The reaction mixture was diluted with water, acidified to pH 1 with concentrated hydrochloric acid, the aqueous phase washed with ether then made strongly basic by addition of sodium hydroxide. The organic layer was extracted with ether, washed with brine, dried (Na2SO4) and evaporated to dryness. The residue was distilled in vacuo to afford 6.6 g. (23%) of the desired amine, B.P. 60°-61° C. (20 mm.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.Cl.[CH3:29][N:30]1[CH:34]=[C:33]([NH2:35])[C:32]([CH3:36])=[N:31]1.FC(F)(F)C(O)=O>CCCCO>[Cl:27][C:5]1[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[CH2:11][CH2:10]2)=[N:7][C:2]([NH:35][C:33]2[C:32]([CH3:36])=[N:31][N:30]([CH3:29])[CH:34]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Cl)ncc3Cl)CC2)CC1
Reactant: Cc1nn(C)cc1N
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: Cc1nn(C)cc1Nc1ncc(Cl)c(NC2CCC3(CCNCC3)CC2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
To a solution of tert-butyl 9-((2,5-dichloropyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (504.1 mg, 1.214 mmol) and 1,3-dimethyl-1H-pyrazol-4-amine hydrochloride (381.0 mg, 2.581 mmol) in n-BuOH (10 mL) was added trifluoroacetic acid (678.1 mg, 5.947 mmol). The mixture was stirred at 100° C. overnight, then quenched with water (30 mL), and adjusted to pH=9 with solid NaHCO3, and then extracted with DCM (200 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the title compound as brown oil (271 mg, 45.57%).
Reaction SMILES: C([O:5][C:6]([C@H:8]([N:10]1[C:15](=[O:16])[C@@H:14]([N:17]=[N+:18]=[N-:19])[C@@H:13]([OH:20])[CH2:12][O:11]1)[CH3:9])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:6]([C@H:8]([N:10]1[C:15](=[O:16])[C@@H:14]([N:17]=[N+:18]=[N-:19])[C@@H:13]([OH:20])[CH2:12][O:11]1)[CH3:9])([OH:7])=[O:5]
Reactant: C[C@H](C(=O)OC(C)(C)C)N1OC[C@H](O)[C@H](N=[N+]=[N-])C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](C(=O)O)N1OC[C@H](O)[C@H](N=[N+]=[N-])C1=O
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
To a cooled (0˜−5° C.) stirred solution of the tert-butyl ester 11 (0.469 g, 1.64 mmol) in CH2Cl2 (8 ml), a precooled (ca. 0° C.) trifluoroacetic acid (6.5 mL) was added portionwise. The reaction mixture was kept for 1.5 hours at room temperature and was evaporated in vacuo to dryness. Traces of trifluoroacetic acid were removed by repeated addition and evaporation of dry ether (3×15 mL). After drying in vacuo, 0.373 g (99%) of the product 12 was obtained as a yellowish semisolid. 1H NMR (400 MHz) in CDCl3 (J, Hz): δ 1.58 (3H, d, 3J=7.4, α-MeCH), 4.10-4.06 (1H, m, 5-H), 4.13 (1H, dd, 2J=−11.7, 3J=4.1 , 6-HA), 4.31 (1H, dd, 2J=−11.7, 3J=5.9, 6-HB), 4.43 (1H, d, 3J=7.4, 4-H), H), 5.12 (1H, q, 3J=7.4, α-CH), 6.51 (2H, br. s, OH, COOH). 13C (100 MHz) in CD3CN: δ 13.51, 54.74, 65.75, 71.38, 78.21, 167.55, 170.91. IR (film), cm−1: 3456, 2959, 2125, 1746, 1654, 1284. MS (CI, isobutane), m/Z: 231 (M++1). The compound was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([CH2:21][O:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].[Na+].[CH3:44]I>C1COCC1.O>[CH2:1]([S:17][CH2:18][CH:19]([CH2:21][O:22][C:23]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:20][CH3:44])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
A solution of 6.0 grams (0.01 mole) (±)-1-S-hexadecyl-3-O-tritylthioglycerol in 250 milliliters of THF was added to a slurry of 0.4 grams (0.014 mole) 80% NaH (oil dispersion) in 50 milliliters of THF and the reaction mixture stirred at room temperature for one hour. Then 1.4 gram (0.13 mole) of CH3I was added and the reaction allowed to proceed at room temperature for 24 hours. The reaction mixture was then diluted with 300 milliliters of distilled water and extracted twice with 200 milliliter portions of ether. The nonaqueous extracts were combined, dried over anhydrous sodium sulfate, filtered and removed in vacuo to provide 6.0 grams of crude product as an oil. 1H-NMR (CDCl3): delta, 0.7-1.7[m, 31H, (CH2)14CH3 ], 2.3-2.8(m, 4H, CH2 --S--CH2), 3.25(m, 5H, CH3O, CH--CH2 --O), 3.6-4.0(m, 1H, CH), 7.6-7.0[m, 15H, C(C6H5)3 ].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1)=O)[CH3:2].[CH:18]1([O:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[CH2:1]([O:3][C:4](=[O:17])/[C:5](=[N:24]/[O:23][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)/[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: NOC1CCCC1
Solvent: CCO
Product: CCOC(=O)/C(=N/OC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 20.8 %

Procedure:
(4-Methylsulfonyl-phenyl)-oxo-acetic acid ethyl ester (218 mg, 0.85 mmol) was stirred in ethanol (1.7 mL) and warmed in a 70° C. oil bath. O-Cyclopentyl-hydroxylamine (prepared as in Example 1, 146 mg, 1.06 mmol) was added. After 2 h, the reaction mixture was allowed to cool and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 □m; 30% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded (E)-cyclopentyloxyimino-(4-methanesulfonyl-phenyl)-acetic acid ethyl ester (60 mg, 21%) as a clear, colorless film containing an unidentified impurity: LC-MS (ESI) m/e calcd for C16H21NO5S [M+] 339.11, found 340 [M+H+].
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Cl)[CH:15]=2)=[C:10]([CH3:22])[CH:9]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]([C:37]2[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=2)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:26][CH:25]=1>CN(C=O)C.CCOC(C)=O>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][C@@H:30]([C:27]1[CH:26]=[CH:25][C:24]([O:23][CH2:20][C:16]2[CH:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][C:10]=3[CH3:22])[CH:19]=[CH:18][CH:17]=2)=[CH:29][CH:28]=1)[C:37]1[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=1)[CH3:36]
Reactant: CCOC(=O)C[C@@H](c1ccc(O)cc1)c1nccn1C
Reactant: Cc1cc(Cl)ccc1-c1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](c1ccc(OCc2cccc(-c3ccc(Cl)cc3C)c2)cc1)c1nccn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
Cs2CO3 (72 mg, 0.22 mmol) and compound 9.9 (53 mg, 0.21 mmol) were added successively to a solution of (S)-ethyl 3-(4-hydroxyphenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoate (9.6) (55 mg, 0.2 mmol) in dry DMF (3 mL). The reaction mixture was stirred at room temperature overnight, diluted with EtOAc (60 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was flash chromatographed on silica gel (0-5% MeOH in DCM) to afford (S)-ethyl 3-(4-[3-(4-chloro-2-methylphenyl)benzyloxy]phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoate (9.10) as a colorless oil (97 mg). LC-MS ESI (pos.) m/e: 489 (M+H).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=[CH:8][N:7]=1)=[O:5].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28]>C1COCC1>[C:12]1([C:10]2[N:9]=[CH:8][N:7]=[C:6]([C:4]([C:23]3[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:5])[CH:11]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CON(C)C(=O)c1cc(-c2ccccc2)ncn1
Reactant: COc1cc([Mg]Br)cc(OC)c1OC
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2cc(-c3ccccc3)ncn2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
To a solution of 38b (0.243 g, 1 mmoL) in 5 mL THF was added a THF solution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 5.6 mL, 1.4 mmol) at 0° C. The mixture was allowed to stir for 30 min and quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 1b (52.3%). NMR (CDCl3) δ 9.40 (d, 1H, J=1.5 Hz), 8.29 (d, 1H, J=1.5 Hz), 8.22-8.18, 7.57-7.54 (m, 5H), 7.46 (s, 2H), 3.96 (s, 3H), 3.91 (s, 6H); MS (ESI) adz 351.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH3:27])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([N:28]2[CH2:29][CH2:30][N:31]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:18]=[C:17]5[C:12]([CH:13]=[CH:14][CH:15]=[N:16]5)=[CH:11][CH:10]=4)[CH:3]=3)[CH2:32][CH2:33]2)[CH3:27])=[CH:22][CH:21]=1
Reactant: Clc1cc(Nc2ccc3cccnc3c2)ncn1
Reactant: C[C@@H](c1ccc(F)cc1)N1CCNCC1
Product: C[C@@H](c1ccc(F)cc1)N1CCN(c2cc(Nc3ccc4cccnc4c3)ncn2)CC1

Procedure:
(6-Chloropyrimidin-4-yl)-quinolin-7-yl-amine, Example 4(c), (59 mg, 0.23 mmol) was reacted with 1-[(1S)-1-(4-fluorophenyl)ethyl]piperazine (57 mg, 0.27 mmol, prepared from (1S)-1-(4-fluorophenyl)ethylamine (SynQuest) according steps (a) and (b) of Example 4) under the conditions of Example 4(d) to give the title compound. M.p.: 206-207° C. MS (ESI, pos. ion.) m/z: 429 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:16](=[O:17])O[CH:14]3O)=[CH:5][CH:4]=1.[C:22]1([NH:28][NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:16](=[O:17])[N:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:29]=[CH:14]3)=[CH:7][CH:8]=1
Reactant: NNc1ccccc1
Reactant: COc1ccc(/C=C/c2ccc3c(c2)C(O)OC3=O)cc1
Product: COc1ccc(/C=C/c2ccc3c(=O)n(-c4ccccc4)ncc3c2)cc1

Procedure:
Following the procedure of Example 18 above trans-5-[2-(4-methoxyphenyl)ethenyl]-3-hydroxyphthalide (15 g) and phenyl hydrazine (10 ml) were reacted to give the 2-phenyl-1(2H)-phthalazinone derivative (9.8 g), mp 198°-199° C.
Reaction SMILES: ClCl.C(Cl)(Cl)(Cl)Cl.[CH3:8][O:9][C:10]([C:12]1[CH:13]([O:17][CH3:18])[CH2:14][S:15][CH:16]=1)=[O:11]>C(Cl)(Cl)(Cl)Cl>[CH3:8][O:9][C:10]([C:12]1[C:13]([O:17][CH3:18])=[CH:14][S:15][CH:16]=1)=[O:11]
Reactant: COC(=O)C1=CSCC1OC
Agent: ClCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cscc1OC
Reaction time: 1 h
Yield: 93 %

Procedure:
15 Parts by volume of a Cl2 /CCl4 solution (7.1 parts of chlorine in 100 parts of CCl4) are added in the course of 10 minutes to a solution, cooled to 0° C., of 1.74 parts of 3-methoxy-dihydrothiophene-4-carboxylic acid methyl ester in 15 parts by volume of CCl4. The mixture is kept at 0° C. for one hour. The end product is isolated from the reaction mixture by the method described in Example 1c. 1.6 parts (93% of theory) of 3-methoxythiophene-4-carboxylic acid methyl ester of melting point 66°-67° C. are obtained.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][N:4]=1)=O.OS(O)(=O)=O.[CH:18]([O:23][CH3:24])([O:21][CH3:22])OC>CO>[CH3:24][O:23][CH:18]([O:21][CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][N:4]=1
Reactant: COC(OC)OC
Reactant: COC(=O)c1ccc(C=O)nc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc(C(OC)OC)nc1
Yield: 75 %

Procedure:
To a solution of methyl 2-formylpyridine-5-carboxylate (2.00 g, 12.1 mmol) in methanol (20 ml) and trimethyl orthoformate (5 ml) was added H2SO4 (conc., 1.5 ml). After refluxing overnight, the reaction was cooled and concentrated to a thick slurry and then poured into saturated NaHCO3 (50 ml). The latter was extracted with ether (3×30 ml) and the combined organic layers dried (MgSO4) and concentrated to afford title product (1.91 g, 75%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[CH2:22][O:21][C:20](=[O:24])[NH:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:23]3[CH2:22][O:21][C:20](=[O:24])[N:19]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2COC(=O)N3)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2COC(=O)N3Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.9 %

Procedure:
To a solution of 4-(2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (43 m g, 0.13 mmol) in 2 ml anhydrous dimethylformanide was added sodium hydride (8 mg of a 60% suspension in mineral oil, 0.2 mmol) portion-wise at 0° C. The solution was stirred with a magnetic stirrer at 0° C. for 20 minutes, at which time the initial off-gassing ended. Benzyl bromide (0.02 ml, 0.17 mmol) was added in one portion and the reaction mixture was stirred at 0° C. for an hour. The solution was allowed to warm to room temperature and the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic fractions were washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by prep TLC to give 33 mg of 4-(1-benzyl-2-oxo-1,4-dihydro-2H-benzo[d] [1,3]oxazin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester as a white solid (60%). MS: 424 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[NH2:28][C:29]1[N:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][CH:30]=1>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=[C:2]([C:33]3[N:34]=[C:29]([NH2:28])[CH:30]=[CH:31][CH:32]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: CC1(C)OB(c2cccc(N)n2)OC1(C)C
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cccc(N)n4)nc3s2)CC1

Procedure:
2-Chloro-4-morpholino-6-((4-N-methylsulfonylpiperazin-1-yl)methyl)thieno[2,3-d]pyrimidine (0.44 mM) and 6-aminopyridine-2-boronic acid pinacol ester were coupled using General Procedure A to give 297 (TFA salt) after reverse-phase HPLC purification. MS (Q1) 491 (M+)
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([N:6]3[C:11]([CH2:12][O:13]2)=[N:10][NH:9][C:8](=[O:16])[C@H:7]3[CH3:17])=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[CH:15]=[C:14]2[C:5]([N:6]3[C:11]([CH2:12][O:13]2)=[N:10][NH:9][C:8](=[O:16])[C@H:7]3[CH3:17])=[CH:4][CH:3]=1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(Br)ccc3N21
Reactant: OB(O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)ccc3N21
Temperature: 90 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
A mixture of (R)-7-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #10, Step E, 5.0 g, 16.88 mmol), (2-fluorophenyl)boronic acid (3.54 g, 25.32 mmol), K2CO3 (4.67 g, 33.78 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (2.76 g, 3.37 mmol) in dioxane (60 mL) and water (10 mL) was stirred at 90° C. for 2 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluting with 10-50% EtOAc in petroleum ether) to give (R)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (2.5 g, 46%) as a red solid. 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.51 (m, 1H), 7.43-7.13 (m, 6H), 4.83 (q, J=6.4 Hz, 1H), 4.69-4.60 (d, J=13.2 Hz, 2H), 1.33 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@H:30]1[CH2:35][CH2:34][C@H:33]([CH:36]=O)[CH2:32][CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29].CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:31][CH2:32]1
Reactant: BrC(Br)(Br)Br
Reactant: CCCCC[C@H]1CC[C@H](C=O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](C=C(Br)Br)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 77.4 %

Procedure:
A solution, cooled to 0° C., of 90.9 g of tetrabromomethane in 100 ml of methylene chloride was treated under argon gasification within 20 minutes with a solution of 143.9 g of triphenylphosphine in 200 ml of methylene chloride. The clear orange solution was stirred at 0° C. for a further 5 minutes and then treated dropwise within 10 minutes at 0° C. with a solution of 25 g of trans-4-pentylcyclohexanecarboxaldehyde (purity about 82%) in 80 ml of methylene chloride. After stirring at 0° C. for 30 minutes, the mixture was poured into 2.5 l of hexane and the precipitate which separated was filtered off. The filtrate was concentrated, digested with 1 l of hexane, filtered and again concentrated. Low-pressure chromatography (0.5 bar) of the residue (52.7 g) on silica gel with hexane gave 35.9 g (77.4%) of trans-1-(2,2-dibromovinyl)-4-pentylcyclohexane as a colourless oil; Rf-value (hexane) 0.58.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[Cl:11][C:12]1[CH:13]=[C:14]([N+:19]([O-])=O)[C:15](I)=[N:16][CH:17]=1>>[NH2:19][C:14]1[C:15]([C:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[O:2][CH3:1])=[O:6])=[N:16][CH:17]=[C:12]([Cl:11])[CH:13]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1I
Reactant: COc1ccccc1C=O
Product: COc1ccccc1C(=O)c1ncc(Cl)cc1N

Procedure:
(3-Amino-5-chloro-pyridin-2-yl)-(2-methoxy-phenyl)-methanone was prepared from 2-methoxybenzaldehyde and 5-chloro-2-iodo-3-nitro-pyridine in three steps according to the General Procedure C. MS m/z: 263.1 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[ClH:14].[H][H]>CO.O.[Pd]>[ClH:14].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CNS(=O)(=O)c1cccc(C#N)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CNS(=O)(=O)c1cccc(CN)c1
Reaction time: 48 h

Procedure:
To a solution of 3-cyano-N-methyl-benzenesulfonamide (4.88 g, 2.49 mmol) in MeOH (160 mL) is added concentrated HCl in water (16 mL) followed by the addition of Palladium on Carbon (10 wt %, 50 wt % water, 1.6 g). With magnetic stirring, the reaction is alternately placed under vacuum and 1 atmosphere of hydrogen (balloon) for three cycles. The reaction is then left under 1 atmosphere of hydrogen with stirring for 2 days. The reaction is filtered through celite and fresh Palladium on Carbon (10 wt %, 50 wt % water, 1.6 g) is added. The reaction is stirred for 24 hours under 1 atmosphere of hydrogen. The reaction is filtered through celite and the filtrate is concentrated in vacuo to provide 3-aminomethyl-N-methyl-benzenesulfonamide hydrochloride, as a solid (99%). MS: 201 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.41 (d, 3H), 4.12 (d, 2H), 7.23-7.57 (m, 2H), 7.70 (d, 1H), 7.81 (d, 1H), 8.49 (broad-s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH:22]=O)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:37][CH2:36][N:35]([CH2:22][CH2:21][CH2:20][C:11]3[CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:12]=3)[CH2:34][CH2:33]2)=[CH:30][CH:31]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccc(OC)cc4)CC3)nn2-c2ccccc2)cc1

Procedure:
81 mg (64%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (75 mg, 0.245 mmol), 1-(4-methoxyphenyl)piperazine (47 mg, 0.245 mmol), DIPEA (0.064 mL, 0.368 mmol) and NaBH(OAc)3 (156 mg, 0.735 mmol).