Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]O)=[CH:18][CH:17]=1.S(Cl)([Cl:26])=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][Cl:26])=[CH:18][CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CO)cc1
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl alcohol (6.8 g) in chloroform (100 ml) was added thionyl chloride (3.1 g), and the mixture was stirred for one hour at room temperature. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and then water, followed by drying (MgSO4). The solvent was distilled off to leave 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl chloride (6.5 g, 90%) as colorless needles, m.p.93°-94° C.
Reaction SMILES: [C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH:40](=O)[CH2:41][CH2:42][CH2:43][C:44]#[CH:45]>ClCCl>[C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:45][CH2:44][CH2:43][CH2:42][C:41]#[CH:40])[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: C#CCCCC=O
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C#CCCCCN1CC[C@@H](C(C(N)=O)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a stirred solution of (S)-3-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (64.4 g, 0.23 mol); sodium triacetoxyborohydride (50.9 g, 0.24 mol) and acetic acid (13 mL, 0.23 mol) in dichloromethane (511 mL) at room temperature, was added a solution of hex-5-yn-1-al (26.14 g, 0.27 mol) in dichloromethane (256 mL). The reaction mixture stirred at room temperature overnight (ca. 8 hours) and then the reaction mixture was quenched by addition of concentrated hydrochloric acid (30 mL) and stirring was continued for 1 hour at room temperature. The mixture was then diluted with water (750 mL) and made basic to pH 5 using 10 N sodium hydroxide (18 mL). The layers were separated and the organic layer was washed with 1 N sodium hydroxide (200 mL). The organic layer was dried over magnesium sulfate (10 g); filtered and then concentrated in vacuo to afford 67.6 g of the title intermediate as a yellow gummy solid (83% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=1)[CH2:5]2.[CH3:26][N:27]([CH3:31])[CH2:28][C:29]#[CH:30]>C(NC(C)C)(C)C.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.[Cu]I>[CH3:26][N:27]([CH3:31])[CH2:28][C:29]#[C:30][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:15][CH:14]=1)[CH2:5]2
Reactant: O=C1c2ccc(Br)cc2CN1Cc1ccc(Oc2ccccc2)cc1
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: CN(C)CC#Cc1ccc2c(c1)CN(Cc1ccc(Oc3ccccc3)cc1)C2=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
A mixture of 5-bromo-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.100 g, 0.25 mmol), PdCl2(PPh3)2 (0.009 g, 0.013 mmol), and CuI (0.0025 g, 0.013 mmol) in diisopropylamine (4 mL) was treated with dimethyl-2-propynyl-amine (0.032 mL, 0.3 mmol). The reaction mixture was stirred at 100° C. for 2 h. After the complete consumption of bromo-isoindolone (monitored using GC-MS), the reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (20 mL). The solids were removed by filtration and the filtrate was concentrated. Silica gel column chromatography of the resulting material using combinations of chloroform-methanol (typically 10:1 CHCl3-MeOH) afforded 5-(3-dimethylamino-prop-1-ynyl)-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.061 g, 62%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.36 (s, 6H), 3.47 (s, 2H), 4.25 (s, 2H), 4.76 (s, 2H), 6.94-7.54 (m, 1H), 7.80 (d, 1H). GC-MS: 396 (M)+, 353 (M−43)+.
Reaction SMILES: CC([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH2:26])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:10][CH2:9]1)=[O:7])(C)C.N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([NH:26][CH2:25][C@@H:23]1[O:22][C:21](=[O:27])[N:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([OH:5])=[O:7])[CH2:13][CH2:12]3)=[C:15]([F:28])[CH:16]=2)[CH2:24]1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (S)-(-)-4-[4-[5-(aminomethyl)-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step 8, 9.45 g) in dry methylene chloride (96 mL) under N2 is treated with pyridine (5.82 mL) and acetic anhydride (3.40 mL), and the resulting mixture is stirred at ambient temperature for four hours, diluted with methylene chloride (25 mL), washed with water (25 mL), saturated aqueous sodium bicarbonate (25 mL) and saline (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which is then chromatographed on silica gel (230-400 mesh, 350 g), eluting with a gradient of methanol/chloroform (2.5/97.5-7.5/92.5). Pooling and concentration of those fractions with an Rf =0.51 by TLC (methanol/chloroform, 10/90) gives the title compound, mp 144-146° C.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)=[CH:6][CH:5]=1.[F:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]=[CH:31][CH:30]=[C:29]2[NH:36]N>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:36]([C:29]4[C:28]5[C:33](=[CH:34][CH:35]=[C:26]([F:25])[CH:27]=5)[N:32]=[CH:31][CH:30]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: NNc1ccnc2ccc(F)cc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)F)cc2)nc1-c1ccnn1-c1ccnc2ccc(F)cc12

Procedure:
The product was obtained starting from 1-(4-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-9) and (6-fluoro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=450.1 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:19][C:20]#[C:21][CH2:22][CH3:23])[C:12](=[O:13])[CH:11]=[CH:10][CH:9]1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:7])(C)(C)C.[BH4-].[Na+].C(O)(=O)C>CO>[CH3:18][O:17][C:15]([CH2:14][CH:9]1[CH2:10][CH2:11][CH:12]([OH:13])[C:8]1([C:6]([O:5][CH3:1])=[O:7])[CH2:19][C:20]#[C:21][CH2:22][CH3:23])=[O:16]
Reactant: CCC#CCC1(C(=O)OC(C)(C)C)C(=O)C=CC1CC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCC#CCC1(C(=O)OC)C(O)CCC1CC(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 5 q quantity of 5-methoxycarbonyl-4-methoxycarbonylmethyl-5-(2-pentynyl)-2-cyclopentenone (compound (2-a)) and 1.35 g of sodium borohydride are dissolved in 200 ml of methanol, and the solution is refluxed in a nitrogen atmosphere for one hour. The reaction mixture is cooled to room temperature, and about 30 ml of acetic acid is added to the mixture. The resulting mixture is stirred for 30 minutes and thereafter concentrated in a vacuum. The residue is dissolved in a mixture of benzene and ethyl acetate, and the solution is purified with a silica gel column. After removing the solvent from the product, the product is distilled in a vacuum, affording 3-methoxycarbonylmethyl-2-methoxycarbonyl-2-(2-pentynyl)-cyclopentanol (compound (1-a), R1 =R2 +CH3) in a yield of 92.5%, b.p. 70-75° C./0.005 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[N:10]([CH2:18][CH2:19][CH3:20])[C:9]=1[CH3:21].[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:30])[C:26]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:18][CH2:19][CH3:20])[C:9]([CH3:21])=[C:8]2[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])([CH3:28])[CH3:27])[CH3:23]
Reactant: CCCn1c(C)c(-c2ccccc2Cl)c2cc(O)ccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCn1c(C)c(-c2ccccc2Cl)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
Following a procedure analogous to that of Example 10, the above compound was prepared from 3-(2-chloro-phenyl)-2-methyl-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][O:10][C@H:9]1[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:16]1)(C)(C)C.[ClH:30]>O1CCOCC1>[ClH:30].[ClH:30].[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C@@H:17]2[CH2:18][CH2:19][CH2:20][N:15]([CH2:14][C@H:9]3[C@H:8]([NH2:7])[CH2:13][CH2:12][CH2:11][O:10]3)[CH2:16]2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCO[C@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1CCCO[C@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1
Reaction time: 1 h

Procedure:
To {(2S,3R)-2-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-yl}-carbamic acid tert-butyl ester (33 mg, 0.0813 mmol) was added 4 M hydrogen chloride in dioxane (7 mL). After stirring for one hour, the solution was concentrated in vacuo to give (2S,3R)-2-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-ylamine dihydrochloride as a pale yellow residue (30.8 mg, 100%). This residue was dissolved in ethyl acetate and poured into 1N sodium hydroxide (20 mL). The layers were separated, and the resulting aqueous layer was washed with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated in vacuo to yield (2S,3R)-2-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-ylamine (24.9 mg, 100%) as a pale yellow oil. MS (APCI), m+/z: (M+H)+=307.4.
Reaction SMILES: Br[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=1.C1(B2OC(C)(C)[C:22](C)(C)[O:21]2)CC1.C([O-])([O-])=O.[K+].[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.CO>[CH3:22][O:21][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: O=[N+]([O-])c1cnc(Br)c(-c2ccccc2)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: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ncc([N+](=O)[O-])cc1-c1ccccc1
Temperature: 100 °C
Yield: 60.3 %

Procedure:
A mixture of 2-bromo-5-nitro-3-phenylpyridine (0.72 mmol, 0.2 g), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.86 mmol, 0.16 ml), Pd(PPh3)4 (0.04 mmol, 0.05 g), K2CO3 (2 mmol, 0.28 g) in a toluene/methanol 4:1 mixture (10 ml) was heated at 100° C. for 30 minutes in a microwave, under argon atmosphere. The solvent was evaporated and the crude mixture was extracted between water and ethyl acetate. The solid residue was purified by chromatography over SiO2 eluting with hexane/ethyl acetate mixtures affording 2-methoxy-5-nitro-3-phenylpyridine (0.1 g, yield 55%) of an unexpected product.
Reaction SMILES: C1(C2[O:12][CH2:11][CH:10]([C:13]3([CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH:24]([N:27]([C:35]5[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][N:36]=5)[C:28]([C:30]5[O:31][CH:32]=[CH:33][CH:34]=5)=[O:29])[CH2:23][CH2:22]4)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][O:8]2)C=CC=CC=1.Cl>CO>[OH:12][CH2:11][CH:10]([C:13]1([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([N:27]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][N:36]=3)[C:28]([C:30]3[O:31][CH:32]=[CH:33][CH:34]=3)=[O:29])[CH2:25][CH2:26]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[CH2:9][OH:8]
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(C4COC(c5ccccc5)OC4)CCCCC3)CC2)nc1
Agent: Cl
Solvent: CO
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(C(CO)CO)CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-[1-[2-[1-(2-phenyl-1,3-dioxan-5-yl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide (110 mg) in methanol (5 mL) was added 4N hydrochloric acid (0.5 mL). After stirring the solution at room temperature for 2 hours, it was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue and it was extracted with chloroform. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound. To a solution of the residue in ethyl acetate (10 mL) was added a 4N hydrochloric acid/ethyl acetate solution (0.15 mL), and the solution was stirred at room temperature for 1 hour. The crystals thus separated out were then filtered to give its hydrochloride (60 mg).
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22]C(C3C=CC=CC=3)=O)[CH:16]=2)=[CH:11][CH:10]=1)/[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O:34][CH2:35][CH3:36])(=O)C>>[C:35]([CH2:36][NH:22][CH2:21][C:17]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:8][CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:10][CH:11]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:34])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)/C(C)=C/c1ccc(-c2cccc(CNC(=O)c3ccccc3)c2)cc1
Product: CCOC(=O)C(C)Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1
Reaction time: 2 h

Procedure:
2.2 g (5.3 mmol) of ethyl (E)-2-methyl-3-(3′-{[(1-phenylmethanoyl)amino]methyl}biphenyl-4-yl)acrylate and 100 ml of ethyl acetate are introduced into a three-necked flask. The reaction medium is degassed, 450 mg of palladium-on-charcoal (10%) are added and the mixture is hydrogenated under atmospheric pressure for two hours. The reaction medium is filtered and evaporated, and the residue obtained is purified by chromatography on a column of silica eluded with a mixture of heptane and ethyl acetate (80/20). After evaporation of the solvents, 1.45 g (64%) of ethyl 3-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}-2-methylpropionate are collected in the form of an oil.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.C(O)(C(F)(F)F)=O.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[C:31](=[O:35])[CH:30]=[CH:29]2>C(Cl)Cl>[CH2:10]([N:4]1[CH2:3][CH:29]2[C:28]3[CH:27]=[C:26]([O:25][CH3:24])[CH:34]=[CH:33][C:32]=3[C:31](=[O:35])[CH:30]2[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COc1ccc2c(c1)C=CC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C1CN(Cc3ccccc3)CC1C2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(Methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (17.3 mL, 67.6 mmol) and TFA (3.4 mL) were added to a solution of 5-methoxy-inden-1-one (5.4 g, 33.8 mmol) in CH2Cl2 (165 mL) at 0° C. The reaction was stirred for 3 hours at room temperature and quenched with saturated aqueous NaHCO3 (165 mL). The organic layer was separated, washed with brine (100 mL), dried over MgSO4, and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C19H19NO2+H: 294, observed: 294.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[N:8][C:7]=2[N:6]([CH2:27][CH2:28][CH3:29])[C:5]1=[O:30])[CH2:2][CH3:3].Br[CH2:32][C:33]([OH:35])=[O:34].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[O:30]=[C:5]1[N:6]([CH2:27][CH2:28][CH3:29])[C:7]2[N:8]=[C:9]([C:22]3[CH:26]=[N:25][N:24]([CH2:32][C:33]([OH:35])=[O:34])[CH:23]=3)[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:21])[CH3:19])[C:11]=2[C:12](=[O:13])[N:4]1[CH2:1][CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2c(nc(-c3cn[nH]c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Reactant: O=C(O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC(=O)O)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 80 °C
Yield: 62 %

Procedure:
A mixture of solution of 1,3-dipropyl-8-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (600 mg, 1.38 mmol), bromo acetic acid (289 mg, 2.08 mmol) and K2CO3 (575 mg, 4.16 mmol) in acetone (10 ml) was heated at 80° C. for 3 hrs. The reaction mixture was filtered through celite and washed with acetone. The organic layer was concentrated and the residue obtained was purified by column chromatography to obtain {4-[2,6-dioxo-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]-pyrazol-1-yl}-acetic acid (420 mg, 61%) as white solid.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[C:4]([O:16][CH3:17])[CH:3]=1.C([Li])CCC.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[CH:28]=[O:29].COC1C=C(C(C2C=CC=C(OC)C=2)=CC#N)C=C(OC)C=1>>[C:10]([Si:7]([CH3:9])([CH3:8])[O:6][C:5]1[CH:14]=[CH:15][C:2]([CH:28]([C:27]2[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=[C:25]([O:24][CH3:23])[CH:26]=2)[OH:29])=[CH:3][C:4]=1[O:16][CH3:17])([CH3:13])([CH3:12])[CH3:11]
Reactant: COc1cc(Br)ccc1O[Si](C)(C)C(C)(C)C
Reactant: COc1cc(C=O)cc(OC)c1
Agent: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Agent: [Li]CCCC
Product: COc1cc(OC)cc(C(O)c2ccc(O[Si](C)(C)C(C)(C)C)c(OC)c2)c1

Procedure:
(4-bromo-2-methoxyphenoxy)-tert-butyldimethylsilane (4.37 g, 13.77 mmol), n-butyl lithium (5.51 ml, 13.77 mmol), and 3,5-dimethoxybenzaldehyde (2.08 g, 12.52 mmol) were treated in the same manner as described above for the synthesis of 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crude was purified via flash column chromatography (5% EtOAc in hexane gradient to 20% EtOAc in hexane in about 40 min.) to give [4-(tert-butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-(3,5-dimethoxy-phenyl)-methanol a clear oil (3.94 g, 78%): 1HNMR (CDCl3) 6.89 (s, wide, 1H, Ar), 6.78 (s, wide, 2H, Ar), 6.53 (d, J=2 Hz, 2H, Ar), 6.36 (t, J=2 Hz, 1H, Ar), 5.69 (d, J=3 Hz, 1H, CHOH), 3.77 (s, 3H, OCH3), 3.76 (s, 6H, 2OCH3), 2.19 (d, J=3 Hz, 1H, OH), 0.98 (s, 9H, 3CH3), 0.14 (s, 6H, 2CH3). The product was carried over to the next step.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[C:31]3=[N:32][CH:33]=[CH:34][C:35](B4OC(C)(C)C(C)(C)O4)=[C:30]3[CH:29]=[CH:28]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[CH3:7][C:5]1[O:6][C:2]([C:35]2[CH:34]=[CH:33][N:32]=[C:31]3[N:27]([S:24]([C:21]4[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=4)(=[O:25])=[O:26])[CH:28]=[CH:29][C:30]=23)=[C:3]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:4]=1
Reactant: Cc1nc(-c2ccc([N+](=O)[O-])cc2)c(Br)o1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)ccnc32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4oc(C)nc4-c4ccc([N+](=O)[O-])cc4)ccnc32)cc1

Procedure:
Following the procedure described for Intermediate 6 with 5-bromo-2-methyl-4-(4-nitrophenyl)-1,3-oxazole and [(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine provided the title compound. ESMS [M+H]+: 476.2
Reaction SMILES: [NH2:1][C@H:2]([CH3:9])[CH2:3][CH2:4][NH:5][CH:6]([CH3:8])[CH3:7].FC1C=CC(CNC(C2C(=O)C(O)=C3C(=O)N4[C@H](C)CCN(C(C)C)[C@H]4CN3C=2)=O)=CC=1.C[O:43][C:44]([C:46]1[N:47]([CH2:72][CH:73]=O)[CH:48]=[C:49]([C:61](=[O:71])[NH:62][CH2:63][C:64]2[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=2)[C:50](=[O:60])[C:51]=1[O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=O.C(O)(=O)C>ClCCl>[F:70][C:67]1[CH:66]=[CH:65][C:64]([CH2:63][NH:62][C:61]([C:49]2[C:50](=[O:60])[C:51]([O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[C:46]3[C:44](=[O:43])[N:1]4[C@H:2]([CH3:9])[CH2:3][CH2:4][N:5]([CH:6]([CH3:8])[CH3:7])[C@H:73]4[CH2:72][N:47]3[CH:48]=2)=[O:71])=[CH:69][CH:68]=1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Reactant: CC(C)NCC[C@@H](C)N
Agent: CC(C)N1CC[C@@H](C)N2C(=O)c3c(O)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@H]12
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CC[C@@H](C)N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@H]12
Yield: 56 %

Procedure:
[(3R)-3-Aminobutyl](1-methylethyl)amine. The free diamine was prepared in a similar manlier as described in example Z-29. 1H NMR (400 MHz, CDCl3) δ 1.04 (d, J=6.4 Hz, 6H), 1.06 (d, J=6.4Hz, 3H), 1.41-1.58 (m, 5H), 2.62-2.66 (m, 2H), 2.74-2.80 (m, 1H), 2.92-3.00 (m, 1H). b) (4R,12aR)—N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide. The title compound was made in two steps using a similar process to that described in example Z-2. 16 (40 mg, 0.088 mmol) and [(3R)-3-aminobutyl](1-methylethyl)amine (78 mg, 0.60 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4R,12aR)—N-[(4-fluorophenyl)methyl]-4-methyl-1-(1-methylethyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (26 mg, 56%). This material was hydrogenated in a second step as described in example Z-2 to give (4R,12aR)—N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (21 mg, 90%) as an off-white solid. 1H NMR (4.00 MHz, CDCl3) δ 1.01 (d, J=5.6 Hz, 3H), 1.06 (d, J=6.0 Hz, 3H), 1.31 (d, J=6.8 Hz, 3H), 1.57 (m, 1H), 1.98 (m, 1H), 2.70-2.82 (m, 2H), 3.15 (m, 1H), 4.15-4.19 (m, 1H), 430 (m, 1H), 4.4.8 (s, 1H), 4.54-4.59 (m, 2H), 4.97 (m, 1H), 6.98 (m, 2H), 7.29-7.32 (m, 2H), 8.27 (s, 1H), 10.49 (s, 1H), 12.52 (s, 1H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9]>S(=O)(=O)(O)O>[F:5][C:6]1[CH:13]=[CH:12][C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: O=[N+]([O-])O
Reactant: N#Cc1ccccc1F
Agent: O=S(=O)(O)O
Product: N#Cc1cc([N+](=O)[O-])ccc1F
Temperature: 0 °C
Yield: 93 %

Procedure:
A mixture of 70% nitric acid and concentrated sulfuric acid (1:1, 30 mL) is added dropwise over 30 min to a solution of 2-fluorobenzonitrile (12.11 g, 0.10 mol) in concentrated sulfuric acid (50 mL), stirred under N2 at 0° C. After a further 3 h at 0° C. the yellow solution is poured onto ice (400 g), and the solid is collected by Buchner filtration, rinsed with water (4×50 mL), and dried in vacuo to give 2-fluoro-5-nitrobenzonitrile (15.43 g, 93%) as a pale yellow crystalline solid. 1H NMR (CDCl3) δ8.56 (1H, dd, J=2.8, 5.5 Hz), 8.51 (1H, ddd, J=2.8, 4.4, 9.1 Hz), 7.44 (1H, dd, J=7.8, 9.0 Hz).