Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:7][CH2:8][CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:11].Cl.[CH2:13]([N:20]([CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C>O.C(N(CC)CC)C.CN(C=O)C>[ClH:11].[ClH:11].[CH2:13]([N:20]([CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:9][CH2:8][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:26][CH2:25]1)[CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCOc1ccccc1
Reactant: CN(CCC1CCNCC1)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCC1CCN(CCOc2ccccc2)CC1)Cc1ccccc1

Procedure:
2-Bromoethyl phenyl ether (4.94 g) was added to a mixture of 4-[2-(N-benzyl-N-methylamino)ethyl]piperidine dihydrochloride (7.5 g), DMF (50 ml) and triethylamine (13.7 ml) The mixture was heated on a steam bath for 18 hours and then poured into water (300 ml) and acidified with 2M hydrochloric acid. The mixture was washed with ether then basified with 2M sodium hydroxide solution and extracted with dichloromethane to give a gum. The gum was dissolved in petroleum ether b.p. 60°-80° C., treated with charcoal and hot filtered. The filtrate was evaporated and the residual oil was dissolved in ether, acidified with ethereal hydrogen chloride, and filtered. The solid obtained was washed with ether and recrystallised from absolute ethanol to give 4-[2-(N-benzyl-N-methylamino)ethyl]-1-(2-phenoxyethyl)piperidine dihydrochloride, m.p. 276°-278° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]#[N:25])[N:21]=[C:20]([Cl:26])[N:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[NH2:28][OH:29]>CO.CCOC(C)=O>[NH2:25]/[C:24](=[N:28]\[OH:29])/[C:22]1[N:21]=[C:20]([Cl:26])[N:19]=[C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[CH2:13][CH2:14]2)[CH:23]=1
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C#N)nc(Cl)n3)CC2)c(Cl)c1Cl
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(/C(N)=N/O)nc(Cl)n3)CC2)c(Cl)c1Cl
Temperature: 80 °C
Yield: 33 %

Procedure:
3,4-Dichloro-N-[1-(2-chloro-6-cyanopyrimidin-4-yl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Example 199, 150 mg, 0.36 mmol), hydroxylamine hydrochloride (25 mg, 0.36 mmol) and TEA (0.05 ml, 0.36 mmol) were combined in MeOH (5 ml), and the reaction was heated at 80° C. for 2 h. The reaction was diluted with EtOAc and washed with water. The aqueous portion was extracted with EtOAc, and the combined organic portions were dried (sodium sulfate), filtered and concentrated to give a pale yellow solid. The crude material was purified by preparatory HPLC, using a gradient of 35-75% acetonitrile/water (0.1% TFA) to give 53 mg of the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]([C:23]1[C:28]([C:29]2[O:33][N:32]=[C:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)[CH:30]=2)=[CH:27][C:26]([C:41]2[CH:46]=[CH:45][C:44]([S:47]([CH:50]([CH3:52])[CH3:51])(=[O:49])=[O:48])=[CH:43][N:42]=2)=[CH:25][N:24]=1)C(=O)OC(C)(C)C)=O)(C)(C)C>C(Cl)Cl>[CH:50]([S:47]([C:44]1[CH:45]=[CH:46][C:41]([C:26]2[CH:27]=[C:28]([C:29]3[O:33][N:32]=[C:31]([C:34]4[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=4)[CH:30]=3)[C:23]([NH2:15])=[N:24][CH:25]=2)=[N:42][CH:43]=1)(=[O:48])=[O:49])([CH3:52])[CH3:51]
Reactant: Cc1ccc(-c2cc(-c3cc(-c4ccc(S(=O)(=O)C(C)C)cn4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2cc(-c3cc(-c4ccc(S(=O)(=O)C(C)C)cn4)cnc3N)on2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.2 %

Procedure:
TFA (1 mL, 12.98 mmol) was added to a stirred solution of tert-butyl N-tert-butoxycarbonyl-N-[5-(5-isopropylsulfonyl-2-pyridyl)-3-[3-(p-tolyl)isoxazol-5-yl]-2-pyridyl]carbamate (90 mg, 0.1418 mmol) in DCM (5 mL) and the reaction stirred at ambient temperature for 16 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The residue was redissolved in MeCN/water and passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a pale yellow solid (26 mg, 39% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.22 (d, J=6.8 Hz, 6H), 2.40 (s, 3H), 3.56 (sept, 1H), 7.05 (s, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.61 (s, 1H), 7.88 (d, J=8.1 Hz, 2H), 8.24-8.31 (m, 2H), 8.74 (d, J=2.2 Hz, 1H), 8.99 (d, 1H) and 9.02 (d, 1H) ppm; MS (ES+) 435.1.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[F:13][C:14]([F:22])([F:21])[C:15]1([C:18](O)=[O:19])[CH2:17][CH2:16]1.CCCP(=O)=O>CN(C=O)C>[CH3:5][O:4][N:3]([CH3:2])[C:18]([C:15]1([C:14]([F:22])([F:21])[F:13])[CH2:17][CH2:16]1)=[O:19]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: CNOC
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of N,O-dimethyl hydroxylamine hydrochloride (0.48 g, 4.87 mmol, Aldrich) in DMF (15 mL, Aldrich) was added triethylamine (0.68 mL, 4.87 mmol, Aldrich). After completed addition the reaction was stirred at RT for 5 min. 1-trifluoromethylcyclopropane-1-carboxylic acid (0.5 g, 3.24 mmol, Alfa Aesar, A Johnson Matthey Company) was added and the reaction was stirred at room temperature for 1 min. The reaction was cooled to 0° C. and propylphosphonic anhydride solution (50 wt. % in DMF; 3.10 mL, 4.87 mmol, Acros Organics) was added dropwise. The resulting mixture was stirred at room temperature for 5 days. The reaction was quenched with saturated NaHCO3 and stirred at RT for 5 min. The reaction was extracted with diethyl ether (2×40 mL) and the combined organic extracts were washed with saturated ammonium chloride, water, dried over MgSO4, and concentrated to give 229 mg of the title compound as a light yellow liquid. MS (ESI, positive ion) m/z: 198.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][C:3]=1[F:10].CN(CCN(CCN(C)C)C)C.[Li]CCCC.[Br:28][C:29]1[N:30]=[C:31]([CH:53]=[O:54])[N:32]([C:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=1>C1COCC1>[Br:28][C:29]1[N:30]=[C:31]([CH:53]([C:4]2[CH:5]=[C:6]([CH2:8][CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=2[F:10])[OH:54])[N:32]([C:34]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:33]=1
Reactant: O=Cc1nc(Br)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCc1ccc(F)c(Cl)c1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(Cl)c(F)c(C(O)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: -40 °C
Yield: 85857.7 %

Procedure:
To a solution of Intermediate 221.1 (100 mg, 0.631 mmol) and PMDTA (0.15 mL) in 5 mL THF at −70° C., was added BuLi (1.4 M in hexanes, 0.473 mL, 0.662 mmol). The mixture was stirred with warming to −40° C. over 30 min, recooled to −70° C., then a solution of Intermediate 175.1 (263 mg, 0.631 mmol) in 2 mL THF was added. The mixture was slowly warmed to −20° C. over 1 h. The reaction was quenched with sat. NH4Cl, then was diluted with EtOAc. The organic phase was washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient) to afford 312 g of Intermediate 221.2 as a colorless solid. LCMS (50 to 100% B, 4 min gradient, A=95% H2O/5% CH3CN/0.1% TFA, B=5% H2O/95% CH3CN/0.1% TFA) RT=5.45 min, 575.28 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:2][CH2:3][N:4]2[C:8](=[O:9])[C:7]3=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]3[C:5]2=[O:14])[CH2:18][CH2:17]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: CN1CCNCC1
Product: CN1CCN(CCN2C(=O)c3ccccc3C2=O)CC1

Procedure:
The title compound was synthesized by using N-(2-bromoethyl)phthalimide and 1-methylpiperazine according to the same process as in Preparation Example 2.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH3:16])[CH2:5][CH2:6][CH2:7][C@H:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13].[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-]>CCOCC>[CH3:16][C@H:4]([CH2:5][CH2:6][CH2:7][C@H:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][OH:2]
Reactant: COC(=O)[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CO
Reaction time: 2 h
Yield: 100 %

Procedure:
2(R),6(R),10-trimethylundecanoic acid methyl ester (172 mg., [α]D25 -11.30°) and lithium aluminum hydride (170 mg.) in absolute ether (20 ml.) were refluxed with stirring for 21/2 hours. The reaction mixture was cooled in an ice-bath and excess of hydride was destroyed by carefully adding water followed by 30 ml. of 1 N aqueous H2SO4. The aqueous phase was extracted with ether (3 × 40 ml.) and the combined ether extract was washed with water (3 × 30 ml.) and dried (MgSO4). The crude product (155 mg.) was purified by evaporative distillation to give 152 mg. (100% yield) of 2(R),6(R),10-trimethylundecan-1-ol as a colorless liquid, b.p. 100°-102° C./0.08 mm Hg.; [α]D25 +6.09° C. (c 2.0366, hexane).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:17]#[N:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][CH3:10].[N+](C1C=CC([O:28][C:29]([N:31]2[CH:35]([C:36]3[CH:41]=[C:40]([F:42])[C:39]([F:43])=[C:38]([F:44])[CH:37]=3)[CH2:34][O:33][C:32]2=[O:45])=O)=CC=1)([O-])=O>C1COCC1>[C:17]([C:8]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9][CH2:10][CH:5]([NH:4][CH2:3][CH2:2][NH:1][C:29]([N:31]2[CH:35]([C:36]3[CH:41]=[C:40]([F:42])[C:39]([F:43])=[C:38]([F:44])[CH:37]=3)[CH2:34][O:33][C:32]2=[O:45])=[O:28])[CH2:6][CH2:7]1)#[N:18]
Reactant: CCC(C#N)(CCCNCCN)c1ccccc1
Reactant: O=C1OCC(c2cc(F)c(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: N#CC1(c2ccccc2)CCC(NCCNC(=O)N2C(=O)OCC2c2cc(F)c(F)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[(2-amino-ethyl)-amino]-4-cyano-4-phenylhexane (25 mg, 0.103 mmol) in 10 mL of THF, 4-(3,4,5-trifluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester (30 mg, 0.079 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by MeOH:EtOAc=1:9 (Rf =0.60, MeOH:EtOAc=1:3) to obtain the title compound. The compound was dissolved in CH2Cl2 (3 mL) and was treated with 1N HCl in ether (1 mL). The solvent was removed in vacuo to give the corresponding hydrochloride salt as a pale yellow solid. M. P. 130-134° C.; [α]D =+43.5, (c=0.25, MeOH); Anal. Calcd. For C25H26N4O3F3Cl 1.10 C3H6O: C, 57.92; H, 5.60; N, 8.55. Found: C, 58.33; H, 5.90; N, 8.52.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:3]1=[O:24].[C:25]([O:29][C:30]([NH:32][C@H:33]([CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([CH2:47][CH2:48][F:49])[CH:39]=1)[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[F:49][CH2:48][CH2:47][N:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38]([CH2:37][C@@H:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])[C:34](=[O:35])[NH:1][CH:2]2[CH2:11][C:10]3[C:5](=[C:6]([N:12]4[CH2:16][CH2:15][CH2:14][C:13]4=[O:17])[CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[C:3]2=[O:24])=[CH:39]1
Reactant: NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cn(CCF)c2ccccc12)C(=O)O
Product: CC(C)(C)OC(=O)N[C@H](Cc1cn(CCF)c2ccccc12)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Yield: 107.7 %

Procedure:
The procedure of Example 14(a) was repeated, except that (−)-3-amino-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-3,4-dihydroquinolin-2(1H)-one (350 mg) and (R)-2-(tert-butoxycarbonylamino)-3-[1-(2-fluoroethyl)-1H-indol-3-yl]propanoic acid (431 mg) synthesized in Referential Example 1(c) were used, whereby the title compound (744 mg) was yielded.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:32]4[S:33][CH:34]=[CH:35][CH:36]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(Nc3ncnc4ccc(-c5cccs5)cc34)cc2)cc1
Yield: 59.8 %

Procedure:
The (4-benzyloxy-phenyl)-(6-bromoquinazolin-4-yl)-amine (200 mg, 0.49 mmol), 2-(tributylstannyl)thiophene (200 mg, 0.53 mmol) and bis(triphenylphosphine)palladium(II) chloride (catalytic) were dissolved in dioxan (3 ml) and heated at reflux under nitrogen for 4 hr. The cooled reaction mixture was absorbed onto silica and purified by flash column chromatography (silica gel, eluting with an ethyl acetate/iso-hexane gradient). The resulting solid was triturated with iso-hexane/ethyl acetate to give the product (120 mg, 60%) as a pale yellow solid; δH [2H6]-DMSO 9.88 (1H, b, NH), 8.76 (1H, s, 5-H), 8.49 (1H, s, 2-H), 8.12 (1H, d, 7-H), 7.82-7.60 (5H, m, thiophene-3-H, thiophene-5-H, 8-H, 2′-H, 6′-H), 7.52-7.30 (5H, m, 5×Ph-H), 7.23 (1H, t, thiophene-4H), 7.18 (2H, d, 3′-H, 5′-H), 5.11 (2H, s, CH2); m/z 410 (M+1)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:18][C:19](C)([O-])[CH3:20].[K+].C(Br)C=C>C(O)(C)(C)C>[CH3:1][O:2][CH:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:20][CH:19]=[CH2:18]
Reactant: CC(C)(C)[O-]
Reactant: COC(C(=O)c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C=CCBr
Product: C=CCc1ccccc1C(=O)C(OC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.6 %

Procedure:
Benzoin methyl ether (50 g) and t-butanol (500 g) were added to a 1 liter, 3neck, round bottom flask equipped with magnetic stirrer, and placed in an oil bath at 80° C. To this mixture, 33.7 g of potassium t-butoxide was added and the solution stirred for 15 minutes. Allyl Bromide (42.3 g) was added dropwise over a 1 hour period and stirring was continued at 85° C. for 2 more hours then cooled to room temperature. After evaporation of t-butanol and filtration of potassium bromide, the product was distilled at 125° C.±2° C. and 0.05 mgHg to yield 49.2 g of allylbenzoin methyl ether which crystallized upon cooling.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:22]=[CH:21][C:8]([CH:9](O)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][N:33]([C:36]([C:38]2[NH:39][C:40]3[C:45]([CH:46]=2)=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:32][CH2:31]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:22]=[CH:21][C:8]([CH:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[CH:12][CH:11]=2)[C:46]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[NH:39][C:38]=2[C:36]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[Cl:23])[CH2:35][CH2:34]2)=[O:37])=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C(O)c2ccc(OCOC)cc2)cc1
Reactant: O=C(c1cc2ccccc2[nH]1)N1CCN(c2ccccc2Cl)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)N3CCN(c4ccccc4Cl)CC3)[nH]c3ccccc23)cc1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
Boron trifluoride-ether complex (0.36 ml, 2.94 mmol) was added dropwise at 0° C. to a solution of 4,4'-bis(methoxymethoxy)benzhydrol (8.96 g, 29.43 mmol) and 1-(2-chlorophenyl)-4-(indol-2-ylcarbonyl)piperazine (10.0 g, 29.43 mmol) in 200 ml of methylene chloride, followed by stirring at 0° C. to room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution for neutralization followed by extraction with chloroform. The resulting organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give a crude product. The obtained crude product was recrystallized from ethanol to, give 15.1 g (yield: 82%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:10]=[C:11]([O:27][CH3:28])[C:12]2[CH2:18][N:17]([C:19](=O)[CH2:20][C:21](=O)[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15][C:13]=2[N:14]=1.N1C=CC=CC=1.[CH3:35][NH:36][NH2:37].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)S2)=CC=1>C1COCC1.[Cl-].[Na+].O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:10]=[C:11]([O:27][CH3:28])[C:12]2[CH2:18][N:17]([C:19]3[N:36]([CH3:35])[N:37]=[C:21]([CH:22]([CH3:23])[CH3:24])[CH:20]=3)[CH2:16][CH2:15][C:13]=2[N:14]=1
Reactant: CNN
Reactant: COc1nc(-c2c(C)cccc2C)nc2c1CN(C(=O)CC(=O)C(C)C)CC2
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1nc(-c2c(C)cccc2C)nc2c1CN(c1cc(C(C)C)nn1C)CC2
Temperature: 125 °C

Procedure:
To a solution of 1-(2-(2,6-dimethylphenyl)-4-methoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylpentane-1,3-dione (5.92 g, 15.52 mmol) in THF (80 mL) was added pyridine (5 mL). the resulting solution was evenly divided into four microwave 20 mL vials. To each microwave via was added, methyl hydrazine (0.312 mL, 5.81 mmol) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson's reagent) (1.88 g, 4.66 mmol). The vials were immediately capped and heated to 125° C. for 10 min via microwave irradiation. The reaction vials were cooled to r.t. and the reaction mixtures were combined and diluted with brine. The mixture was extracted with DCM three times. The combined organic layers were dried over Na2SO4. After filtration and concentration, the resulting residue was purified via silica gel FCC ((1% MeOH in EtOAc):n-heptane=0 to 100%) to provide 2-(2,6-dimethylphenyl)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.15-7.24 (m, 1 H), 7.05-7.12 (m, 2 H), 5.77 (s, 1 H), 4.00-4.04 (m, 2 H), 3.98 (s, 3 H), 3.70 (s, 3 H), 3.28 (t, J=5.8 Hz, 2 H), 3.05 (t, J=5.8 Hz, 2 H), 2.87 (dt, J=13.9, 6.9 Hz, 1 H), 2.12 (s, 6 H), 1.23 (d, J=7.1 Hz, 6 H). MS (ESI+) m/z 392.4 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:19](Br)=[CH:18][C:17]([O:21][C:22](=[O:24])[CH3:23])=[CH:16][C:14]=3[N:15]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC.CC1C=CC(C)=CC=1>C(OCC)C.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[C:22]([O:21][C:17]1[CH:18]=[C:19]([CH:26]=[CH2:27])[C:13]2[O:12][C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]([F:25])[CH:7]=3)=[N:15][C:14]=2[CH:16]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Oc1cc(Br)c2oc(-c3ccc(OC(C)=O)c(F)c3)nc2c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccc(C)cc1
Solvent: CCOCC
Product: C=Cc1cc(OC(C)=O)cc2nc(-c3ccc(OC(C)=O)c(F)c3)oc12
Temperature: 130 °C
Reaction time: 5 h
Yield: 56.9 %

Procedure:
Dichlorobis(tri-o-tolylphosphine)palladium (II) (46 mg, 0.06 mmol) was added into a mixture 4-[5-(acetyloxy)-7-bromo-1,3-benzoxazol-2-yl]-2-fluorophenyl acetate (0.8 g, 1.98 mmol), tributyl(vinyl)tin (0.9 g, 2.8 mmol) and p-xylene (9 mL). The reaction mixture was stirred at 130° C. for 5 h, cooled to room temperature, diluted with ethyl ether (10 mL) and treated with activated carbon. The mixture was filtered through MgSO4 and concentrated. Purification by flash chromatography (hexanes/EtOAc 5/1) gave a white solid (0.4 g, 56% yield, m.p. 154-156° C.); MS m/e 356 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:11])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.[Br:19][CH2:20][CH:21](O)[CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([NH:8][C:9](=[O:10])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19][CH2:20][CH:21]1[CH2:22][O:23][C:15]2([CH2:16][CH2:17][NH:12][CH2:13][CH2:14]2)[O:18]1
Reactant: OCC(O)CBr
Reactant: O=C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)NCc1ccccc1
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: BrCC1COC2(CCNCC2)O1
Temperature: 110 °C

Procedure:
A 5.00 g (21.43 mmol) sample of 4-piperidinone benzyl carbamate, from Step 2 Example 196, 4.69 mL (53.59 mmol) of 3-bromo-1,2-propanediol, and 0.200 g (1.07 mmol) of p-toluenesulfonic acid was added to 100 mL of toluene and the mixture was heated at 110° C. for 24 hours. The reaction solution was poured into 200 mL of 7% sodium bicarbonate solution, washed well, washed with water, dried over anhydrous sodium sulfate and the solvent removed under vacuum to afford 7.79 g of 2-bromomethyl-1,4-dioxa-8-azaspiro[4.5]decane benzyl carbamate, MS (DCl) M/Z 387 (M+NH4), 370 (M+H). NMR (CDCl3): d 1.69 (m, 4H), 3.31 (dd, 1H, J=9.0, 10.5 Hz), 3.44 (dd, 1H, J=6.0, 9.0 Hz), 3.58 (m, 4H), 3.90 (dd, 1H, J=6.0, 9.0 Hz), 4.14 (dd, 1H, J=6.0, 9.0 Hz), 4.37 (m, 1H), 5.13 (s, 2H), 7.34 (m, 5H).
Reaction SMILES: [C:1]1([C@H:11]([N:13]([CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][NH:24][CH2:23]2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>>[C:39]([N:24]1[CH2:25][C@H:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:22]([CH2:21][N:13]([C@@H:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH3:12])[C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH2:23]1)(=[O:41])[CH3:40]
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1

Procedure:
A 309 mg portion of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate was dissolved in 7 ml of acetic anhydride and 14 ml of pyridine and stirred at room temperature for 13Hours. The reaction solution was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-ethyl acetate) to obtain 224 mg of tert-butyl {[(3R,4S)-1-acetyl-4-phenylpyrrolidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate as a colorless amorphous substance. FP: 473.