Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[C:27]([O:32]C)(=[O:31])[C@@H:28]([CH3:30])[OH:29].N(OCCC(C)C)=O.[Li+].[OH-]>O.CO>[O:23]=[C:14]1[N:13]([CH2:24][CH2:25][CH3:26])[C:12]2[N:11]=[C:10]([C:5]34[CH2:6][CH2:7][C:2]([O:29][C@H:28]([CH3:30])[C:27]([OH:32])=[O:31])([CH2:9][CH2:8]3)[CH2:3][CH2:4]4)[NH:18][C:17]=2[C:16](=[O:19])[N:15]1[CH2:20][CH2:21][CH3:22]
Reactant: COC(=O)[C@@H](C)O
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(N)(CC3)CC4)nc2n(CCC)c1=O
Agent: CC(C)CCON=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C34CCC(O[C@H](C)C(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 60 °C
Yield: 20 %

Procedure:
8-(4-Amino-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (Example 20) (0.100 g. 0.279 mmol) was combined with 1.5 ml of (R)-methyl lactate and 0.075 ml of isoamyl nitrite. The mixture was heated to 60° C. for 2 h and cooled to rt. The reaction mixture was conc'd in vacuo and the residue was stirred with 8 ml of a 50% MeOH solution and 0.050 g LiOH overnight. The reaction mixture was conc'd in vacuo, taken up in 8 ml of water, the pH of the solution was adjusted to 10 and the mixture extracted twice with 6-ml portions of CH2Cl2. The water layer was acidified with conc'd HCl and the resultant precipitate collected by suction filtration to give 0.024 g (20% yield). (MH+=433.08)
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4[CH2:27][CH2:26][CH2:25]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[C:30]1([CH2:36][C:37]([N:39]=[C:40]=[O:41])=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O.CCCCCC.C(OCC)C>[C:30]1([CH2:36][C:37]([NH:39][C:40](=[O:41])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]4[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]5[CH2:27][CH2:26][CH2:25]5)[CH2:18][CH2:17]4)=[O:15])[CH:8]=3)=[CH:28][CH:29]=2)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCN(CCN4CCC4)CC3)c2)cc1
Reactant: O=C=NC(=O)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCN(CCN4CCC4)CC3)c2)cc1
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of 4-[2-(azetidin-1-yl) ethyl]piperazine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (36.3 mg) in N,N-dimethylformamide (1 ml) was added a solution of 0.25 M 2-phenylacetyl isocyanate in hexane (1.1 ml) under a nitrogen atmosphere, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml), brine (50 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated to give a residue, which was then suspended in diethyl ether (3.0 ml) and hexane (1.5 ml). The solid was filtered off and dried under aeration to provide the titled compound (28.6 mg, 56.0%) as white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:14][CH2:15][CH2:16]Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:9]#[N:10])[CH2:16][CH2:15][CH2:14]2)[CH:5]=[N:6][CH:7]=1
Reactant: N#CCc1cncc(Br)c1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(c2cncc(Br)c2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5-bromo-pyridin-3-yl)-acetonitrile (Stage 220.1.3, 1.37 mmol) in dry DMF (10 ml) was added 55% sodium hydride in oil (1.507 mmol). After 30 min stirring at rt was added 1-bromo-3-chloropropane (1.507 mmol). The RM was stirred for 1 h at rt then was added 55% sodium hydride in oil (1.507 mmol). The RM was stirred for 1 h at it then quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine (2×), dried over Na2SO4, filtered and evaporated. The residue was taken in DMA and purified by preparative HPLC. The fractions containing product were basified with NaHCO3, concentrated and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as a red oil. (HPLC: tR 2.86 min (Method A); M+H=237, 239 MS-ES)
Reaction SMILES: [C-:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.[Fe+2:28].[C:29]([O-:32])(=[S:31])[CH3:30].[K+]>>[C:29]([S:31][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)(=[O:32])[CH3:30].[CH-:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.[Fe+2:28]
Reactant: CC([O-])=S
Reactant: BrCCCCCCCCCCCCCCCC[c-]1cccc1
Agent: [Fe+2]
Agent: [K+]
Agent: c1cc[cH-]c1
Product: CC(=O)SCCCCCCCCCCCCCCCC[c-]1cccc1
Yield: 89.7 %

Procedure:
16-Ferrocenylhexadecyl bromide 26 (1.1 g, 2.3 mmol) was treated with potassium thioacetate (0.4 g, 3.5 mmol) for 20 h following the same procedure described for 27 to afford yellow crystals (1.0 g, 93%): mp 55-57° C.; 1H NMR δ 1.25 (s, 22H), 1.51 (m, 2H), 2.30 (m, 2H), 2.32 (s, 3H), 2.86 (m, 2H), 4.04 (s, 2H), 4.05 (s, 2H), 4.09 (s, 5H); 13C NMR δ 29.5, 29.8, 30.2, 30.3, 30.3, 31.8, 67.7, 68.8, 69.2, 90.0, 197.5; FAB-MS obsd 484.2518, calcd exact mass 484.2514; Anal. Calcd for C28H44FeOS: C, 69.40; H, 9.15. Found: C, 69.45; H, 9.07.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:18][CH2:19][C@@H:20]([C:22]1[CH:23]=[CH:24][C:25]([OH:33])=[C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:27]=1)[OH:21]>>[OH:21][C@H:20]([C:22]1[CH:23]=[CH:24][C:25]([OH:33])=[C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:27]=1)[CH2:19][NH:18][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C(O)Cc1ccc(N2CCC(=O)CC2)cc1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(CC(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from [4-(4-oxo-piperidin-1-yl)-phenyl]-acetic acid (which was obtained in Example 149) and N-[5-(2-amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 179 as a pale yellowish solid; mp>140° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.25–1.40 (m, 2 H), 1.75–1.95 (m, 2 H), 2.50–3.60 (m, 7 H), 2.88 (s, 3 H), 3.16 (s, 2 H), 4.47 (dd, J=8.0, 4.1 Hz, 1 H), 6.78 (d, J=8.2 Hz, 1 H), 6.84 (d, J=8.3 Hz, 2 H), 6.95 (dd, J=8.2, 1.7 Hz, 1 H), 7.05 (d, J=8.3 Hz, 2 H), 7.16 (d, J=1.7 Hz, 1 H); MS (ES) m/z: 464.1 (MH+); HRMS Calcd. for C22H28N3O6S(M−H)−: 462.1704. Found: 462.1696.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.CS(C)=O.C1([O:15][C:16](=O)[NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[C:34]4[C:29](=[CH:30][C:31]([O:37][CH2:38][C@H:39]5[CH2:41][O:40]5)=[C:32]([C:35]#[N:36])[CH:33]=4)[N:28]=[CH:27][CH:26]=3)=[CH:20][C:19]=2[F:42])C=CC=CC=1.O>C(OCC)(=O)C>[F:42][C:19]1[CH:20]=[C:21]([O:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:38][C@H:39]4[CH2:41][O:40]4)=[C:32]([C:35]#[N:36])[CH:33]=3)[N:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23][C:18]=1[NH:17][C:16]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:15]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Oc4ccccc4)c(F)c3)ccnc2cc1OC[C@H]1CO1
Reactant: NC1CC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc2c(Oc3ccc(NC(=O)NC4CC4)c(F)c3)ccnc2cc1OC[C@H]1CO1
Reaction time: 0.17 h

Procedure:
Cyclopropylamine (0.04 ml) was added to dimethylsulfoxide (3 ml), and then [2-fluoro-4-([6-cyano-7-([(2R)-oxiran-2-yl]methoxy)-4-quinolyl]oxy)phenyl]carbamic acid phenyl ester (212 mg) was dissolved therein and the solution was stirred for 10 minutes. Water and ethyl acetate were added to the reaction solution, and the precipitated crystals were filtered out to obtain the title compound (150 mg).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[NH:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:17][CH2:18]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:29]1[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[N:31]=[C:30]1[N:38]1[CH2:39][CH2:40][O:41][CH2:42][CH2:43]1)=[N:3][C:4]=2[N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: c1ccc2[nH]c(N3CCOCC3)nc2c1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(N4CCOCC4)nc4ccccc43)nc21

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 4-(1H-benzo[d]imidazol-2-yl)morpholine were reacted to give 238. LCMS m/z: 576.4 (MH+)
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C@H:17]3[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[ClH:30].O1CCOCC1>C(O)C>[ClH:30].[ClH:30].[NH:19]1[CH2:20][CH2:21][CH2:22][C@H:17]([NH:16][C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[CH:9]3)[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2ccc3c(cnn3C3CCCCO3)c2)C1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: c1cc2[nH]ncc2cc1N[C@H]1CCCNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A 1 L round bottom flask was charged with (3S)-tert-butyl 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-ylamino)piperidine-1-carboxylate (32.4 g, 0.0809 mol, 1.00 eq) and EtOH (500 mL). To the ethanol solution was added 4N HCl in dioxane (40.0 mL 0.160 mol, 2.0 eq), and the solution was stirred at room temperature for 2 h, giving an inhomogeneous dark brown solution. The solution was then heated to 75° C. with a mechanical stirrer and maintained at that temperature for 2 h, after which it was cooled to room temperature. A large amount of fine white solid was observed to form and was collected by filtration, and the filter cake was washed with isopropyl acetate (500 mL). The solid was dried in a vacuum oven at 45° C. for 3 days to give the title compound as an off-white powder (18.1 g, 77%).
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[Cl-:9].[CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][P+:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Cl-]

Procedure:
p-Isopropylbenzylchoride (168.5 g, 1 mol.) and triphenylphosphine (275 g, 1.05 mol.) were refluxed overnight in acetonitrile (600 ml). Approximately 300 ml of acetonitrile were removed in vacuo and 500 ml ether was added. The salt was allowed to crystallize and the salt was filtered off and washed with ether. Yield of the first crop of crystals was 388 g (90%) of desired salt. Some additional salt could be recovered from the mother liquors.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.C([N:20](CC)CC)C.C(Cl)(=O)OCC.N>O.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([NH2:20])=[O:17])=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)CCc1conc1-c1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)CCc1conc1-c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a mixture of 3-[3-(4-chlorophenyl)-4-isoxazolyl]propionic acid (1.28 g), triethylamine (1.1 ml) and tetrahydrofuran (100 ml) was added ethyl chlorocarbonate (0.6 ml) at −30° C. and the mixture was stirred at −20° C. for 1 hr. To the obtained mixture was added aqueous ammonia (15 ml) and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated to give 3-[3-(4-chlorophenyl)-4-isoxazolyl]propionamide (0.91 g, yield 71%) as colorless crystals. The crystals were recrystallized from acetone-hexane. melting point: 158–159° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.[CH:8]([C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)=[O:9].C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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.CCOC(C)=O>[CH3:7][C:4]1[S:3][C:2]([C:13]2[CH:14]=[CH:15][C:10]([CH:8]=[O:9])=[CH:11][CH:12]=2)=[N:6][N:5]=1
Reactant: Cc1nnc(Br)s1
Reactant: O=Cc1ccc(B(O)O)cc1
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: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nnc(-c2ccc(C=O)cc2)s1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.8 %

Procedure:
To a solution of 2-bromo-5-methyl-1,3,4-thiadiazole (2.0 g, 11.17 mmol) in dioxane (40 ml) was added 4-formylbenzeneboronic acid (3.35 g, 22.34 mmol) and 2M Na2CO3 (23 ml). This mixture was degassed with a stream of argon for 2 min. Tetrakis(triphenylphosphine)palladium (0.636 g, 0.55 mmol) was added and this mixture was heated at reflux overnight under argon. After cooling to room temperature, H2O (30 ml) and EtOAc (50 ml) were added and stirred for 5 min. The organic layer was separated and washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (10 to 20% EtOAc/hexanes) gave 4-(5-methyl-1,3,4-thiadiazol-2-yl)benzaldehyde as a pale yellow liquid (1.16 g, 51% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Reactant: CCNCC
Product: CCN(CC)CCCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
According to the method in example 23, Methanesulfonic acid 4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester and Diethylamine were converted to yield {4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-diethyl-amine, MS: 373 (MH+, 1Cl).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH3:59])=[C:53]([F:60])[C:52]=3[F:61])[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH2:62][OH:63])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH3:59])=[C:53]([F:60])[C:52]=3[F:61])[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH:62]=[O:63])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](C=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
Oxalyl chloride (0.37 mL, 4.37 mmol) was dissolved in 20 mL dichloromethane and cooled to −78° C., followed by dropwise addition of a solution (10 mL) of dimethyl sulfoxide (0.5 mL, 7.05 mmol) in dichloromethane and a solution (20 mL) of [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 3i (2.5 g, 3.36 mmol) in dichloromethane in turn. The reaction mixture was stirred for 30 minutes at −78° C. Triethylamine (2.33 mL, 16.8 mmol) was added before the reaction mixture was warmed and stirred for 16 hours at room temperature. Thereafter, the reaction mixture was partitioned after 15 mL 1 M hydrochloric acid were added. The organic extract was washed with saturated sodium chloride solution (20 mL×2) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 3j (2.4 g, yellow grease), yield: 96.0%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:16]Br)=[CH:11][C:10]=1[CH2:26][OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:42])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][NH2:41])[CH:34]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:42])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][NH:41][CH2:16][C@@H:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([CH2:26][OH:27])[CH:11]=2)[O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:34]=1)[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(CO)c1
Reactant: CCOC(=O)Cc1cccc(CCN)c1
Product: CCOC(=O)Cc1cccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c(CO)c2)c1

Procedure:
Prepared according to the procedure used for preparation 22 using [2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]methanol (Preparation 23) and ethyl[3-(2-aminoethyl)phenyl]acetate (Preparation 58) to give the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]([CH2:11][CH3:12])[S:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>CCCCO>[CH2:11]([CH:10]1[C:3]2[C:2]([N:23]3[CH2:22][CH2:21][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:25][CH2:24]3)=[N:7][CH:6]=[N:5][C:4]=2[CH2:8][S:9]1)[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCC1SCc2ncnc(Cl)c21
Solvent: CCCCO
Product: CCC1SCc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Yield: 43.7 %

Procedure:
To a solution of 4-chloro-5-ethyl-5,7-dihydrothieno[3,4-d]pyrimidine (0.3 g, 1.5 mmol) in n-BuOH (30 mL) was added 1-Boc-piperazine (0.8 g, 4.3 mmol), and the mixture was refluxed for 30 hours. The solvent was removed and the residue was purified by silica gel chromatography, eluting with Hexane/ethyl acetate (4:1-1:1) to give tert-butyl 4-(5-ethyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (0.23 g, 44%). 1H NMR (CDCl3, 400 MHz) δ 8.54 (s, 1H), 4.61 (d, J=8.8 Hz, 1H), 4.10 (m, 2H), 3.80-3.60 (m, 8H), 2.02 (m, 1H), 1.60 (m, 1H), 1.49 (s, 9H), 0.95 (m, 3H). MS (APCI+) [M+H]+ 351.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2[C:15](=[O:17])[NH:14][CH:13]=[CH:12]3)=[CH:3][CH:2]=1.Br/[CH:19]=[CH:20]/[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.O.CC(=O)OCC>CN(C=O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2[C:15](=[O:17])[N:14](/[CH:19]=[CH:20]/[C:21]2[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=2)[CH:13]=[CH:12]3)=[CH:3][CH:2]=1
Reactant: O=c1[nH]ccc2cccc(-c3ccncc3)c12
Reactant: Br/C=C/c1ccc2ccccc2n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1c2c(-c3ccncc3)cccc2ccn1/C=C/c1ccc2ccccc2n1
Temperature: 115 °C
Reaction time: 10 h
Yield: 40 %

Procedure:
8-(Pyridin-4-yl)isoquinolin-1(2H)-one (40 mg, 0.180 mmol) and (E)-2-(2-bromovinyl)quinoline (50.6 mg, 0.216 mmol) were dissolved in 2 mL of DMF under argon. The reaction mixture was stirred for 10 h at 115° C. Then, water and EA were added. The organic phase was washed with water and brine, dried (MgSO4) and concentrated. The crude product was purified by chromatography (CombiFlash, normal phase, gradient elution, using 3-5% DCM in methanol) to yield the title compound as yellow solid (27 mg, 40.0%). LCMS: 376.1; Rt=1.497.
Reaction SMILES: [CH:1]([NH2:3])=O.[CH3:4][C:5]1([CH3:12])[C:8](=O)[C:7](C)([CH3:10])[S:6]1.O.O.O.O.O.O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[NH2:3][CH:1]1[C:7]([CH3:10])([CH3:8])[S:6][C:5]1([CH3:12])[CH3:4]
Reactant: NC=O
Reactant: CC1(C)SC(C)(C)C1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC1(C)SC(C)(C)C1N
Temperature: 170 °C
Yield: 59.6 %

Procedure:
Formamide (8.0 g, 178 mmol), 2,2,4,4-tetramethyl-3-oxothietane (1.0 g, 6.933 mmol) and aluminum chloride hexahydrate (100 mg) were placed in a Teflon lined Parr bomb and heated at 170° C. for 18 hours. The reaction was then cooled and taken up in water (20 ml). The aqueous solution was extracted with methylene chloride (3×20 ml), the extracts combined and concentrated under reduced pressure. The residue was refluxed with 1N HCl (20 ml) for 4 hours, the reaction cooled and washed with methylene chloride (2×20 ml). It was then brought to pH 14 by addition of 6N sodium hydroxide and extracted with the methylene chloride (3×20 ml). The combined extracts were dried (Na2SO4) and concentrated to give 0.600 g (60%) of title product, verified by its 1H-NMR spectrum.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13](O)=[CH:14][CH:15]=1.CI.C[CH2:20][O:21]CC.C(=O)([O-])[O-].[K+].[K+]>O.CC(C)=O>[CH2:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[O:21][CH3:20])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: CCOCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCc1ccccc1OC

Procedure:
Nonyl anisole was prepared from nonylphenol, available from Jefferson Chemicals, and methyl iodide under typical Williamson ether synthesis conditions. Nonylphenol (1.0 mole), methyl iodide (1.2 moles), potassium carbonate (1.25 moles) and acetone were placed in a round bottom flask and heated to reflux. After refluxing overnight, the reaction mixture was poured into water and extracted with ether. The ether extract was washed with saturated sodium chloride solution, dried and evaporated to an oil which was then purified by vacuum distillation. The product was analyzed as nonyl anisole by IR and NMR spectroscopy.