Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][O:13]2)[CH:3]=1.[C:22]([C:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26])([OH:24])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.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>[CH:12]1([CH2:11][NH:10][C:4]2[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:30]3[CH:29]=[C:28]([C:25]([CH3:27])([CH3:26])[C:22]([OH:24])=[O:23])[CH:33]=[CH:32][CH:31]=3)[CH:3]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][O:13]1
Reactant: COc1nc(Cl)cc(NCC2OCCc3ccccc32)n1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(NCC2OCCc3ccccc32)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 85 °C
Yield: 94.8 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-isochroman-1-ylmethyl-amine (141 mg, 0.46 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl-boronic acid (125 mg, 0.6 mmol), and Cs2CO3 (0.37 g, 1.15 mmol) in ethylene glycol dimethyl ether (8 mL) and water (2 mL) is degassed by bubbling with Ar gas for 5 minutes, and treated with tetrakis(triphenylphosphine)palladium(0) (27 mg, 0.023 mmol) at room temperature. The mixture is heated at 85° C. for 3 h. The mixture is diluted with H2O (20 mL), and extracted with EtOAc (20 mL). The aqueous layer is separated, acidified to pH 2.5 with 1M HCl solution, and extracted with EtOAc (2×30 mL). The extracts are dried (MgSO4), filtered through a short pad of SiO2 to afford 2-(3-{6-[(isochroman-1-ylmethyl)-amino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid (189 mg, Example 91). LCMS: RT=2.03 minutes; MS: 434 (M+H); 1H NMR (300 MHz, CDCl3) □9.8 (1H, s), 8.02 (1H, s), 7.82 (1H, d, J=6 Hz), 7.5-7.1 (6H, m), 6.43 (1H, s) 5(1H), 4 (3H, s), 3.85-3.75 (1H, m), 3.65-3.55 (1H, m), 3.04-2.95 (1H, m), 2.75 (1H), 1.8 (6H, s). IC50=23 nM
Reaction SMILES: C(P(CCCC)CCCC)CCC.CN(C(/N=N/C(N(C)C)=O)=O)C.[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[OH:35].[CH2:36]([O:38][C:39](=[O:52])[CH2:40][CH:41]1[C:50]2[C:45](=[CH:46][C:47](O)=[CH:48][CH:49]=2)[CH2:44][CH2:43][CH2:42]1)[CH3:37]>C1C=CC=CC=1>[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[O:35][C:47]1[CH:46]=[C:45]2[C:50](=[CH:49][CH:48]=1)[CH:41]([CH2:40][C:39]([O:38][CH2:36][CH3:37])=[O:52])[CH2:42][CH2:43][CH2:44]2
Reactant: OC1Cc2ccccc2C1
Reactant: CCOC(=O)CC1CCCc2cc(O)ccc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Solvent: c1ccccc1
Product: CCOC(=O)CC1CCCc2cc(OC3Cc4ccccc4C3)ccc21

Procedure:
Tributyl phosphine (137 mg, 0.68 mmol) and TMAD (122 mg, 0.68 mmol) were added successively to a dry benzene (10 mL) solution of 2-indanol (92 mg, 0.68 mmol) and ethyl 2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetate 52.5 (160 mg, 0.68 mmol) with stirring under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 days. The product was isolated by silica gel column chromatography after filtration and evaporation of the solvent in vacuo. (R/S)-Ethyl 2-(6-(2,3-dihydro-1H-inden-2-yloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)acetate (52) was obtained as a colorless oil (85 mg, 35%). LC-MS ESI (pos.) m/e: 351 (M+H).
Reaction SMILES: Br[C:2]#[C:3][C:4]1[N:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]=1[CH2:17][O:18][CH3:19])=[C:13]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:12]=[CH:11][CH:10]=3.O1CCCC1.C([Li])(C)(C)C.O>CCCCC>[CH2:21]([O:20][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[C:15]1[C:16]([CH2:17][O:18][CH3:19])=[C:4]([C:3]#[CH:2])[N:5]=[CH:6][C:7]=1[NH:8]2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COCc1c(C#CBr)ncc2[nH]c3cccc(OCc4ccccc4)c3c12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: O
Product: C#Cc1ncc2[nH]c3cccc(OCc4ccccc4)c3c2c1COC
Temperature: -78 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A solution of 0.164 g of 1-bromo-2-(5-benzyloxy-4-methoxymethyl-beta-carbolin-3-yl)acetylene in 5 ml of abs. tetrahydrofuran is cooled under N2 atmosphere to -78° C. and mixed with 0.46 ml of a 1.4 molar solution of tertbutyllithium in pentane. After 1 hour stirring at -78° C. the reaction mixture is heated to room temperature and stirred for 1.5 hours more. Then it is carefully decomposed with water and extracted with dichloromethane. The organic phases are combined, dried and the solvent evaporated. The residue is chromatographed over silica gel with acetone/hexane=1+1 as eluant. 0.056 g of 5-benzyloxy-3-ethinyl-4-methoxymethyl-beta-carboline with a melting point of 207°-209° is obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[CH2:13][OH:14].[ClH:15]>O>[Cl:15][C:6]1[CH:7]=[CH:8][C:9]([O:14][CH3:13])=[CH:10][C:5]=1[S:2]([CH3:1])(=[O:4])=[O:3].[Cl:15][C:6]1[C:7]([O:14][CH3:13])=[CH:8][CH:9]=[CH:10][C:5]=1[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: Cl
Reactant: CCO
Reactant: CS(=O)(=O)c1ccc(O)cc1
Solvent: O
Product: COc1ccc(Cl)c(S(C)(=O)=O)c1
Product: COc1cccc(S(C)(=O)=O)c1Cl

Procedure:
4-Methanesulfonylphenol (2.0 g, 11.6 mmol) mixed with 21:14 mL of EtOH:conc HCl was cooled to 0° C., then KClO3 (0.708 g, 5.81 mmol) dissolved in 17 mL of water was added slowly. After reaction overnight, the mixture was extracted with EtOAc and the extracts were concentrated in vacuum. The resulting residue was purified by reverse-phase HPLC to give both 1-chloro-2-methanesulfonyl-4-methoxy-benzene and 2-chloro-1-methanesulfonyl-3-methoxy-benzene. MS (DCI) m/z 224 (M+NH4)+.
Reaction SMILES: Cl.[NH2:2][OH:3].[Br:4][C:5]1[N:6]=[CH:7][C:8]([NH:11][C:12](=[O:33])[CH:13]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[C:24]([Cl:32])[CH:23]=2)[CH2:14][CH:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)=[N:9][CH:10]=1>CO.N1C=CC=CC=1>[Br:4][C:5]1[N:6]=[CH:7][C:8]([NH:11][C:12](=[O:33])[CH:13]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[C:24]([Cl:32])[CH:23]=2)[CH2:14][CH:15]2[CH2:20][CH2:19][C:18](=[N:2][OH:3])[CH2:17][CH2:16]2)=[N:9][CH:10]=1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)CC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=NO)CC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A solution of hydroxylamine hydrochloride (13 mg, 0.18 mmol) in methanol (0.5 mL) and pyridine (0.5 mL) was treated with N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 59, 62 mg, 0.12 mmol). The reaction mixture was heated under reflux for 2 h, cooled to 25° C., and concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water (1×5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 3/7 hexanes/ethyl acetate eluted to 8/2 hexanes/ethyl acetate) afforded the N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-hydroxyimino-cyclohexyl)-propionamide (51 mg, 80%) as a white foam: EI-HRMS m/e calcd for C20H22BrClN4O4S (M+H)+ 529.0307, found 529.0308.
Reaction SMILES: [C-:1]#[N:2].[K+].[N:4]([CH:7]([CH2:12][CH2:13]I)[C:8]([O:10][CH3:11])=[O:9])=[N+:5]=[N-:6].O>CS(C)=O>[N:4]([CH:7]([CH2:12][CH2:13][C:1]#[N:2])[C:8]([O:10][CH3:11])=[O:9])=[N+:5]=[N-:6]
Reactant: COC(=O)C(CCI)N=[N+]=[N-]
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(CCC#N)N=[N+]=[N-]
Temperature: 10 °C
Reaction time: 0.75 h
Yield: 79.3 %

Procedure:
To a cold (10°) suspension of potassium cyanide (1.5 g, 23 mmol) in dry DMSO (25 ml) was added methyl 2-azido-4-iodobutyrate (4.0 g, 15 mmol) and the mixture stirred at 10° C. for 10 min and at room temperature for 45 min. The reaction mixture was poured into cold water (200 ml) and the solution was extracted with chloroform (4×80 ml). The chloroform extract was washed with water (4×50 ml), dried and evaporated to give a syrup (2.0 g) which on tlc (silica, 10% ether-benzene) showed a major spot of Rf 0.4 and some impurities (Rf 0, 0.67, and 1.0). The product was purified by chromatography on a silica column (20 cm×2.9 cm 1-D) using 10% ether in benzene as eluent to give 1.1 g (44%) of title compound as a syrup; ir (neat) νmax : 2100, 1745 cm-1 ; 1Hmr (CDCl3) δ:2.17 (m, 2H, --CH2 --), 2.5 (m, 2H, CH2CN), 3.83 (s, 3H, OCH3) and 4.13 ppm (q, J=9, 6 Hz, 1H, CHN3). Anal. calcl for C6H8N4O2 : C 42.84, H 4.89, N 33.31; found: C 42.76, H 4.72, N 33.16.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][C:13]1[CH:14]=[C:15]([C:19]2([CH3:26])[NH:24][C:23](=O)[CH2:22][O:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][C:13]1[CH:14]=[C:15]([C:19]2([CH3:26])[NH:24][C:23](=[S:36])[CH2:22][O:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(c2cccc(Nc3cccc4cc(Cl)cnc34)c2)COCC(=O)N1
Solvent: C1CCOC1
Product: CC1(c2cccc(Nc3cccc4cc(Cl)cnc34)c2)COCC(=S)N1
Yield: 71 %

Procedure:
A solution of (RS)-5-[3-(3-chloro-quinolin-8-ylamino)-phenyl]-5-methyl-morpholin-3-one (368 mg, 1.1 mmol) in tetrahydrofuran was treated with Lawesson's reagent (500 mg, 1.2 mmol) at room temperature during 3 hours. The progress of the reaction was checked by LC-MS. For the workup, the reaction mixture was evaporated at reduced pressure. The residue was partitioned between water (5 ml) and ethyl acetate (5 ml), then the organic layer separated, dried over sodium sulphate and evaporated. The crude product was purified by flash chromatography on silica gel using a gradient of cyclohexane/ethyl acetate as the eluent yielding 300 mg (71%) of (RS)-5-[3-(3-chloro-quinolin-8-ylamino)-phenyl]-5-methyl-morpholine-3-thione; (calculated) C20H18ClN3OS [383.90]; (found) [M+H]+=384.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:54]([O:58][C:59]([NH:61][C:62]1[S:63][CH:64]=[C:65](/[C:67](=[N:71]/[O:72][C:73]([C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])([CH3:75])[CH3:74])/[C:68](O)=[O:69])[N:66]=1)=[O:60])([CH3:57])([CH3:56])[CH3:55].CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O.Cl>ClCCl.O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH:25][C:68](=[O:69])/[C:67](/[C:65]4[N:66]=[C:62]([NH:61][C:59]([O:58][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:60])[S:63][CH:64]=4)=[N:71]\[O:72][C:73]([C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])([CH3:74])[CH3:75])[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SC(Sc3c[nH]nn3)C(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SC(Sc4c[nH]nn4)C(c4ccccc4)(c4ccccc4)c4ccccc4)CS[C@H]23)cs1
Temperature: -30 °C
Reaction time: 0.83 h
Yield: 69.2 %

Procedure:
To a solution of 7β-amino-3-(trityl-1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (800 mg: 1.06 mMol.) and (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-(1-t-butoxycarbonyl-1-methylethoxyimino)acetic acid (479 mg: 1.12 mMol.) in dichloromethane (8 ml) cooling at -30° C. are added N-methylmorpholine (0.27 ml) (2.46 mMol.) and phenyl dichlorophosphate (0.19 ml: 1.27 mMol.), and the mixture is stirred at -30° C. for 50 minutes. The reaction mixture is mixed with 10% hydrochloric acid (1 ml), diluted with water, and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (toluene: ethyl acetate=10:1 to 5:1) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-(1-t-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-(trityl-1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (855 mg) as yellow foam. Yield: 69%.
Reaction SMILES: C[N:2](C)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:17]=3[C@H:16]3[C@H:11]([CH2:12][CH2:13][N:14]([CH3:25])[CH2:15]3)[N:10]=2)=[CH:5][CH:4]=1>C(O)=O>[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:17]=3[C@H:16]3[C@H:11]([CH2:12][CH2:13][N:14]([CH3:25])[CH2:15]3)[N:10]=2)=[CH:5][CH:4]=1.[CH2:21]=[O:23]
Reactant: COc1ccc2c(c1)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(N(C)C)cc1
Solvent: O=CO
Product: C=O
Product: COc1ccc2c(c1)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(N)cc1

Procedure:
The cis-6-(4-dimethylaminophenyl)-9-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine, required as starting material, is obtained in accordance with Leuckart-Wallach from cis-6-(4-aminophenyl)-9-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]-naphthyridine by reductive dimethylation with formaldehyde and formic acid. The resulting crude product is used as such for the next reaction.
Reaction SMILES: [C:1]([O:18][CH2:19][C:20](=[CH2:33])[CH2:21][O:22][C:23](=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Br:31])(=[O:17])[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].[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[Br-:31].[C:1]([O:18][CH2:19][C:20](=[CH2:33])[CH2:21][O:22][C:23](=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N+:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:17])[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: C=C(COC(=O)CCCCCCCBr)COC(=O)CCCCCCCCCCCCCCC
Reactant: c1ccncc1
Product: C=C(COC(=O)CCCCCCCCCCCCCCC)COC(=O)CCCCCCC[n+]1ccccc1
Product: [Br-]
Temperature: 100 °C

Procedure:
1-Hexadecanoyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane (from Preparation 30) (0.80 g) was dissolved in dry pyridine (20 ml) and heated to 100° C. for 8 hours. Excess pyridine was removed in vacuo.
Reaction SMILES: [CH3:1][N:2]1[C:19]2[CH:18]=[C:17]3[O:20][CH2:21][CH2:22][O:23][C:16]3=[CH:15][C:14]=2[C:4]2([C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]2=[O:13])[C:3]1=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1>CN(C)C=O.O.C(OCC)(=O)C>[CH3:1][N:2]1[C:19]2[CH:18]=[C:17]3[O:20][CH2:21][CH2:22][O:23][C:16]3=[CH:15][C:14]=2[C:4]2([C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[C:5]2=[O:13])[C:3]1=[O:24]
Reactant: BrCc1ccccn1
Reactant: CN1C(=O)C2(C(=O)Nc3ccccc32)c2cc3c(cc21)OCCO3
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C2(C(=O)N(Cc3ccccn3)c3ccccc32)c2cc3c(cc21)OCCO3
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
To a stirred solution of 6-methyl-2,3-dihydrospiro[1,4-dioxino[2,3-f]indole-8,3′-indole]-2′,7(1′H,6H)-dione (0.07 g, 0.21 mmol) in N,N-dimethylformamide (5 mL) was added cesium carbonate (0.20 g, 0.61 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, 2-(bromomethyl)pyridine hydrobromide (0.08 g, 0.31 mmol) was added and the mixture was stirred at ambient temperature for 18 h. The mixture was diluted with water and ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography and eluted with ethyl acetate/hexanes (3/2) to afford 6-methyl-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[1,4-dioxino[2,3-f]indole-8,3′-indole]-2′,7(1H,6H)-dione (0.02 g, 26%): mp 87-89° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.64-8.63 (m, 1H), 7.71-7.62 (m, 2H), 7.26-7.17 (m, 2H), 6.96-6.47 (m, 3H), 6.47 (s, 1H), 6.46 (s, 1H), 5.33 (s, 2H), 4.24-4.06 (m, 4H), 3.22 (s, 3H); MS (ES+) m/z 414.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]2=[O:14])=[CH:4][CH:3]=1.[OH:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>O1CCOCC1.CCOC(C)=O.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>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:24]3[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][CH2:18][OH:17])=[CH:22][CH:23]=3)[CH:10]=[CH:9][C:8]2=[O:14])=[CH:4][CH:3]=1
Reactant: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1
Reactant: OCCCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=c1ccc(-c2ccc(CCCO)cc2)cn1Cc1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 66.7 %

Procedure:
According to Scheme 3 Method A: To a solution of 1-(4-chlorobenzyl)-5-bromopyridin-2(1H)-one (1 eq, 0.33 mmol, 0.10 g) in dioxane/saturated aqueous NaHCO3 (1:1, 6 mL) was added Pd(PPh3)4 (0.15 eq, 0.05 mmol, 58 mg) and 4-(3-hydroxypropyl)phenylboronic acid (1.5 eq, 0.50 mmol, 90.0 mg). The reaction was then stirred at 90° C. for 4.5 hours. The reaction was allowed to cool and diluted with AcOEt. The reaction washed with saturated NH4Cl solution, brine and the organic phase extracted (×3). The combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 15 g SiO2) using pure AcOEt as the eluent to afford 1-(4-chlorobenzyl)-5-(4-(3-hydroxypropyl)phenyl)pyridin-2(1H)-one (0.22 mmol, 78 mg, 66%) as a white solid. M.p.: 165° C.; Rf=0.05 (CH2Cl2/AcOEt 80/20); LC (XTerra RP18, 3.5 μm, 3.0×50 mm Column): RT=3.78 min; MS m/z (CI) [MH]+=354, 356; 1H NMR (300 MHz, DMSO-d6) δ 1.64-1.77 (m, 2H), 2.61 (t, J=7.3 Hz, 2H), 3.32-3.46 (m, 2H), 4.48 (t, J=5.1 Hz, 1H), 5.15 (s, 2H), 6.52 (d, J=9.5 Hz, 1H), 7.24 (d, J=8.1 Hz, 2H), 7.35-7.44 (4H), 7.47 (d, J=8.1 Hz, 2H), 7.83 (dd, J=2.6 Hz, 9.5 Hz, 1H), 8.23 (d, J=2.6 Hz, 1H).
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5].[P:19](Cl)(Cl)(=[O:31])[O:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH:7]1([O:6][C:4](=[O:5])[C@@H:3]([N:2]=[P:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][C:22]=2[Cl:1])=[O:31])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: N[C@H](C(=O)OC1CCCCC1)c1ccccc1
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Reactant: Cl
Solvent: ClCCl
Product: O=C(OC1CCCCC1)[C@@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)c1ccccc1
Yield: 78 %

Procedure:
Using the general procedure for synthesizing naphthyl (aminoacid ester) phosphorochloridates, the HCl salt of (S)-cyclohexyl 2-amino-2-phenylacetate (1 g), naphthalen-1-yl phosphorodichloridate (967 mg), TEA (1.03 mL) and DCM (30 mL) were combined to give (2S)-cyclohexyl-2-(chloro(naphthalen-1-yloxy)phosphorylamino)-2-phenylacetate in an 78% yield (1.32 g) as a pale yellow thick oil.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)CCC.Cl[C:20]1[CH:21]=[C:22]2[CH2:30][CH2:29][O:28][C:27](=[O:31])[C:23]2=[C:24]([CH3:26])[N:25]=1.[F-].[K+]>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.C1(C)C=CC=CC=1>[CH3:26][C:24]1[N:25]=[C:20]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[CH:21]=[C:22]2[CH2:30][CH2:29][O:28][C:27](=[O:31])[C:23]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Cc1nc(Cl)cc2c1C(=O)OCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cccs2)cc2c1C(=O)OCC2
Temperature: 100 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
2-(tributylstannyl)thiophene (940 mg, 2.52 mmol) was dropwisely added to a toluene solution of 6-chloro-8-methyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on (250 mg, 1.26 mmol) and Pd(PPh3)4 (146 mg, 0.13 mmol), and then stirred overnight at 100° C. The solution was cooled down to room temperature, added with 15 mL of 0.4M KF solution and then extracted with methylene chloride. The resulting organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. A silica gel column chromatography (33% EtOAC/Hexanes) was performed on the resulting residue and obtained 298 mg (96%) of 8-methyl-6-(thiophene-2-yl)-3,4-dihydro-pyrano[3,4-c]pyridine-1-on in yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH3:12]N(C=O)C.[OH-:17].[Na+]>O>[CH3:12][C:7]1[C:2]([CH:1]=[O:17])=[CH:3][C:4]([O:10][CH3:11])=[C:5]([O:8][CH3:9])[CH:6]=1
Reactant: COc1ccc(C)cc1OC
Reactant: CN(C)C=O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: COc1cc(C)c(C=O)cc1OC
Reaction time: 48 h

Procedure:
Freshly distilled POCL3 (50.6 ml) was added dropwise during 30 min to a stirred mixture of 4 -methylveratrole (65.7 g) and DMF (30 g) freshly distilled after standing two days over CuSO4. Heating overnight on a steam bath under reflux gave a deep brown, viscous solution which when cooled was admixed with 600 ml water. Addition of excess 10% NaOH solution separated out a yellow oil which was extracted with benzene. The combined extracts were washed with water, dried, and evaporated to give a viscous yellow oil. Crystallization from alcohol gave 3.4 g of the aldehyde as a white powder, mp 74°-75°(Lit. 74°). Nmr (δ): 2.58 (s, 3H), 3.90 (s, 3H), 3.95 (s, 3H), 6.68 (s, 1H), 7.30 (s, 1H), 10.20 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@H:7]([O:9][CH2:10][CH3:11])[C@H:6]([NH:12][C:13]2[C:18]([CH2:19][CH3:20])=[N:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:15]([CH2:29][CH3:30])[N:14]=2)[CH2:5]1)(=[O:3])C.[N:31]1(C(Cl)=O)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[N:17]=[C:18]([CH2:19][CH3:20])[C:13]([NH:12][C@H:6]2[C@@H:7]([O:9][CH2:10][CH3:11])[CH2:8][N:4]([C:1]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:3])[CH2:5]2)=[N:14][C:15]=1[CH2:29][CH3:30]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CN(C(=O)N2CCOCC2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting 4-morpholinecarbonyl chloride and making non-critical variations provided the title compound as an oil: 1H NMR (400 MHz, CDCl3) δ) 7.50, 7.34, 7.28, 5.23, 4.69, 4.10, 3.90, 3.80–3.68, 3.58–3.28, 2.70, 2.49, 1.33–1.26, 1.16; IR (liq.) 2970 (s), 2934 (s), 2874 (s), 2353 (w), 1996 (w), 1956 (w), 1642 (s), 1567 (s), 1552 (s), 1500 (s), 1469 (s), 1414 (s,b), 1397 (s), 1118 (s), 1102 (s), cm−1 HRMS (FAB) calcd for C25H33Cl2N5O3+H 522.2039, found 522.2038.