Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2Br)[N:11]2[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:29])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[C:36]2[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=2)[N:11]2[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:29])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N1CCn2c(Cc3ccc(Cl)cc3Br)nc(=O)c(OCc3ccccc3)c2C1=O
Reactant: OB(O)c1ccncc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)N1CCn2c(Cc3ccc(Cl)cc3-c3ccncc3)nc(=O)c(OCc3ccccc3)c2C1=O
Temperature: 80 °C
Yield: 51 %

Procedure:
In a sealed tube was placed a stirred solution of 9-benzyloxy-6-(2-bromo-4-chlorobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (380) (100 mg, 0.194 mmol) in dioxane (4 mL). Pyridine 4-boronic acid (23.822 mg, 0.194 mmol), and a 1N solution of potassium carbonate [(80.349 mg, 0.581 mmol) in 0.82 mL water] were added at room temperature and the reaction mixture was purged for 30 min with argon. Pd(triphenyl phosphine)4 (22.395 mg, 0.019 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (15.911 mg, 0.039 mmol) were added to the reaction under argon. The reaction mixture was further degassed for another 10 min and thereafter heated at 80° C. for 4 h (monitored by LC-MS). The reaction mixture was filtered through a pad of celite and the filtrate was diluted with water (5 mL) and extracted with ethyl acetate (2×20 mL). The combined extracts were dried and concentrated. The resulting crude product was purified by column (using amine bound silica gel) to get 9-benzyloxy-6-(4-chloro-2-pyridin-4-yl-benzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (387) (51 mg, 51.1%) as an off-white solid.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:18])=[C:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=2)[CH:5]([C:19]([OH:21])=[O:20])[CH2:4][CH2:3]1.O.NN.[OH-].[K+]>C(O)COCCOCCO>[CH:12]1([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][C:8]=2[Cl:18])[CH:5]([C:19]([OH:21])=[O:20])[CH2:4][CH2:3][CH2:2]3)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=C1CCC(C(=O)O)c2cc(Cl)c(C3CCCCC3)cc21
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: O=C(O)C1CCCc2cc(C3CCCCC3)c(Cl)cc21
Temperature: 195 °C
Yield: 78.6 %

Procedure:
A mixture of 6 g of 4-oxo-6-cyclohexyl-7-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, 4 g of hydrazine hydrate, 6.4 g of potassium hydroxide and 40 ml of triethyleneglycol is heated for 2 hours at 130°-140°C. Then, while distilling off a mixture of hydrazine and water, the temperature is raised to 195°C and the batch is stirred until nitrogen is no longer being given off, then diluted with 50 ml of water, acidified with concentrated hydrochloric acid and the mixture is extracted with ethyl acetate and the ethyl acetate is evaporated. The resulting crude product is recrystallized from toluene, to yield 4.5 g of 6-cyclohexyl-7-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid melting at 119°-120°, of the formula ##SPC10##
Reaction SMILES: FC1C=C2C(C=CC(=O)N2)=CC=1.[H-].[Na+].CS(OCCN1CCC(NC(OC(C)(C)C)=O)CC1)(=O)=O.[C:36]([O:40][C:41](=[O:64])[NH:42][CH:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][N:51]2[C:60]3[C:55](=[CH:56][CH:57]=[C:58]([F:62])[C:59]=3F)[CH:54]=[CH:53][C:52]2=[O:63])[CH2:45][CH2:44]1)([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:40][C:41](=[O:64])[NH:42][CH:43]1[CH2:44][CH2:45][N:46]([CH2:49][CH2:50][N:51]2[C:60]3[C:55](=[CH:56][CH:57]=[C:58]([F:62])[CH:59]=3)[CH:54]=[CH:53][C:52]2=[O:63])[CH2:47][CH2:48]1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(F)c(F)c32)CC1
Agent: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: O=c1ccc2ccc(F)cc2[nH]1
Agent: [H-]
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(F)cc32)CC1

Procedure:
7-Fluoroquinolin-2(1H)-one (Intermediate 29) (500 mg, 3.06 mmol) was deprotonated with sodium hydride (135 mg, 60% in oil, 3.37 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (3.7 mmol) as described for Intermediate 20. Colorless solid, 570 mg (48%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[Br:9]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][Br:9])=[N:6][CH:7]=1
Reactant: Cc1ccc(Br)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(Br)cn1

Procedure:
A 4.69 g (27 mmol) sample of 5-bromo-2-picoline from step 1 was dissolved in 250 mL of carbon tetrachloride, treated with 4.85 g (27 mmol) of N-bromosuccinimide (NBS) and 400 mg (2.4 mmol) of azobisisobutyronitrile (AIBN), and stirred at reflux for 3 h. Filtration and concentration in vacuo provided crude 5-bromo-2-bromomethylpyridine which was 64% monobrominated by NMR; no purification was attempted: NMR (CDCl3) δ4.50 (s, 2H), 7.34 (d, J=8 Hz, 1H), 7.82 (dd, J=8 and 2 Hz, 1H), 8.63 (d, J=2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[N:12]=O>[NH4+]=S>[NH2:12][C:3]1[C:4](=[O:11])[N:5]([CH3:10])[C:6]([S:8][CH3:9])=[N:7][C:2]=1[NH2:1]
Reactant: CSc1nc(N)c(N=O)c(=O)n1C
Product: CSc1nc(N)c(N)c(=O)n1C

Procedure:
To 4.0 g (0.02 mole) of 6-amino-3-methyl-2-methylthio-5-nitroso-pyrimidine-4-one (44) was added 40 mL of 20% aqueous ammonium sulfide solution. The mixture was heated under reflux for 30 min. After cooling the precipitate was collected, washed with a little ethanol and dried in a desiccator to give 45 as 2.72 g (75% yield) of colorless crystals (m.p. 211°-212° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([OH:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18]Br>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[O:9][CH2:18][CH2:17][O:8][C:5]2=[N:6][CH:7]=1
Reactant: BrCCBr
Reactant: Oc1cc(Br)cnc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cnc2c(c1)OCCO2
Temperature: 100 °C

Procedure:
To a suspension of 5-Bromo-pyridine-2,3-diol (10.0 g, 52.63 mmol, commercially available, CAS 34206-49-0) in DMF (150 mL) was added K2CO3 (21.78 g, 158 mmol) and 1,2-dibromo ethane (11.87 g, 63.2 mmol). The reaction mixture was heated to 100° C. for 5 h. The reaction mixture was cooled to rt and poured into ice cold water EtOAc was added and the phases were separated and the aq layer was extracted with more ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4 and concentrated under vacuo to get the crude compound. The crude compound was purified by silica gel chromatography (eluent 10% ethyl acetate in petrol ether). Yield of 6-Bromo-[1,3]dioxolo[4,5-b]pyridine 2.2 g (18%) pure by 1H NMR (400 MHz, DMSO) δ 7.85 (d, 1H, J=2 Hz), 7.59 (d, 1H, J=2 Hz), 4.41 (m, 2H), 4.27 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][CH2:23][Cl:24]>CN(C)C=O>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][N:8]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: ClCCCCBr
Reactant: O=C(Nc1cccnc1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)N(CCCCCl)c1cccnc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.1 %

Procedure:
To a stirred solution of 21.6 parts of 4-fluoro-N-(3-pyridinyl) benzamide in 235 parts of N,N-dimethylformamide were added portionwise 5.76 parts of a sodium hydride dispersion 50% at <25° C. under nitrogen atmosphere. After stirring for 1.5 hours at room temperature, the mixture was cooled to 0° C. and 27.8 parts of 1-bromo-4-chlorobutane were added. The reaction mixture was stirred for 3 hours at 60° C. After cooling, the whole was poured into 1000 parts of ice water and the product was extracted twice with methylbenzene. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 7.4 parts (24.1%) of N-(4-chlorobutyl)-4-fluoro-N-(3-pyridinyl)benzamide as a residue (int. 67).
Reaction SMILES: C(OC(NCCCCC#CCOC1C=CC=CC=1S([N:26]1[CH2:31][CH2:30][S:29][C:28]([CH3:33])([CH3:32])[CH:27]1[C:34]([O-:36])=[O:35])(=O)=O)=O)(C)(C)C.[I-].[Li+]>>[CH3:32][C:28]1([CH3:33])[S:29][CH2:30][CH2:31][NH:26][CH:27]1[C:34]([OH:36])=[O:35]
Reactant: CC(C)(C)OC(=O)NCCCCC#CCOc1ccccc1S(=O)(=O)N1CCSC(C)(C)C1C(=O)[O-]
Agent: [I-]
Agent: [Li+]
Product: CC1(C)SCCNC1C(=O)O

Procedure:
The methyl ester of methyl (3 S}[4 {[({7-[(tert-butoxycarbonyl)amino]-2-heptynyl}oxy)phenyl]sulfonyl}-2,2-dimethyl-3-thiomorpholine carboxylate was converted into the analogous carboxylic acid using lithium iodide according to the procedure of Example 250 to provide (3 S)-4-{[4-{7-[(tert-butoxycarbonyl)amino]-2-heptynyl)oxy)phenyl]sulfonyl}-2,2- dimethyl-3-thiomorpholine carboxylic acid as a white solid Electrospray Mass Spec: 541.2(M+H)+
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[O-]CC.[Na+].I[CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16].[Cl-].[NH4+]>CS(C)=O>[CH3:14][Si:15]([CH3:18])([CH3:17])[CH2:16][CH:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC#N
Reactant: C[Si](C)(C)CI
Agent: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C#N)C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
A solution of ethyl cyanoacetate (5.34 g, 47.3 mmol) in dimethyl sulfoxide (DMSO, 20 ml) was added portionwise with sodium ethoxide (3.21 g, 47.2 mmol), and the mixture was stirred at room temperature for 4 hours with occasionally cooling the mixture on ice when temperature elevation was observed. The reaction mixture was put on an ice bath, and added dropwise with a solution of iodomethyltrimethylsilane (7.78 g, 36.4 mmol) in DMSO (5 ml), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was added with saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography [hexane/ethyl acetate (49:1)] to obtain ethyl 3-(trimethylsilyl)-2-cyanopropionate (6.06 g, 65%) mentioned in the title as colorless oil.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:29])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:30][CH2:31][CH2:32]Br.[OH-].[K+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>>[Br:30][CH2:31][CH2:32][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C:18]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]3[CH2:9][CH2:10][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:6][CH2:7]3)[CH:12]=2)=[O:29])=[CH:21][C:22]=1[O:27][CH3:28]
Reactant: BrCCBr
Reactant: COc1cc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)ccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [K+]
Agent: [OH-]
Product: COc1cc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)ccc1OCCBr
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide (the compound of Example 20) (1.5 g), 1,2-dibromethane (15 ml), 40% aqueous potassium hydroxide solution (5 ml) and 40% aqueous tetrabutylammonium hydroxide solution (0.5 ml) is stirred at 50° C. for 18 hours. The reaction solution is washed with water, and the organic layer is dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (1.6 g).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[CH2:20]([NH2:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:26][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CCCCCCN
Solvent: CN(C)C=O
Product: CCCCCCNC1=C(c2ccccc2)S(=O)(=O)N(CCCC)C1=O
Yield: 49.9 %

Procedure:
A solution of 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.110 g, 0.33 mmol) and hexylamine (0.100 g, 0.984 mmol) in DMF (0.5 mL) was heated in a microwave reactor at 140° C. for 25 mins. The residue was purified by preparative HPLC (Ace C8 column, 0.1M NH4OAc/MeCN, gradient) to give the title compound (0.060 g, 47%); 1H-NMR (400 MHz, CD3CN): δ 7.49-7.53 (m, 5H), 5.85 (bs, 1H), 3.66 8 (t, 2H), 2.85 (dd, 2H), 1.71-1.80 (m, 2H), 1.37-1.48 (m, 2H), 1.13-1.34 (m, 4H), 0.94-1.09 (m, 7H), 0.82 (t, 3H); Mass Spectrum: M+H 365.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:9](Cl)([N:10]=1)[N:8]=[CH:7][N:6]=2.[CH3:12][C:13]1[NH:17][N:16]=[C:15]([NH2:18])[CH:14]=1>C(O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:9]([NH:18][C:15]3[CH:14]=[C:13]([CH3:12])[NH:17][N:16]=3)([N:10]=1)[N:8]=[CH:7][N:6]=2
Reactant: Cc1cc(N)n[nH]1
Reactant: ClC1=NC2(Cl)N=CN=C2C=N1
Solvent: CCO
Product: Cc1cc(NC23N=CN=C2C=NC(Cl)=N3)n[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.6 %

Procedure:
To a suspension of 2,4-dichloro-purine (2.0 g, 10.6 mmol) in anhydrous ethanol (10 mL) was added 5-methyl-1H-pyrazol-3-yl amine (2.05 g, 21.2 mmol). The resulting mixture was stirred at room temperature for 48 h. The resulting precipitate was collected by filtration, washed with ethanol, and dried under vacuum to afford 1.524 g (58% yield) of (2-chloro-purin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[N:25]4[CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=[C:24]4[C:23](Cl)=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:35]1[CH2:40][CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH2:37][CH2:36]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[N:25]4[CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=[C:24]4[C:23]([C:38]4[CH2:39][CH2:40][O:35][CH2:36][CH:37]=4)=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CCOC(=O)c1cn2c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)cnc(Cl)c2n1
Product: CCOC(=O)c1cn2c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)cnc(C3=CCOCC3)c2n1
Yield: 44 %

Procedure:
Compound 90g (1.08 g, 2.10 mmol) was subjected to Suzuki coupling with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane using the method described in Example 87, Step D to obtain compound 90h as a yellow solid (520 mg, 44% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H34N6O5: 535.3 (M+H). found: 535.6.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[OH:24])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Cl[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]=1[O:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH3:43]>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[O:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH3:43])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCOCOc1c(CCl)ccc2ccccc12
Product: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2OCOCCOC)cc1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate [Example 86(b)] with 2-chloromethyl-1-(2-methoxy-ethoxymethoxy)-naphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-[1-(2-methoxy-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate, from which by cleavage of the allyl group by means of bis-(triphenylphosphine)-palladium(II) diacetate analogously to Example 152(e) there was obtained tert-butyl (3RS,4RS)-4-(4-hydroxy-phenyl)-3-[1-(2-methoxy-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate. Subsequent alkylation with 5-bromomethyl-3-thiophen-2-yl-[1,2,4]oxadiazole analogously to Example 44(e) gave tert-butyl (3RS,4RS)-3-[1-(2-methoxy-ethoxymethoxy)-naphthalen-2-ylmethoxy]-4-[4-(3-thiophen-2-yl-[1,2,4]oxadiazol-5-ylmethoxy)-phenyl]-piperidine-1-carboxylate as a colourless, viscous oil; MS: 702 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[F:5][C:6]1[CH:7]=[C:8]([N:18]2[CH2:22][C@H:21]([C:23](Cl)=[O:24])[O:20][C:19]2=[O:26])[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>O1CCCC1.O>[F:5][C:6]1[CH:7]=[C:8]([N:18]2[CH2:22][C@H:21]([C:23]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:24])[O:20][C:19]2=[O:26])[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C=CCN
Reactant: O=C(Cl)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Solvent: O
Solvent: C1CCOC1
Product: C=CCNC(=O)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
To a flame-dried flask under nitrogen is added allylamine (0.60 mL, 8.05 mmol). The flask is cooled in an ice bath, and a solution of (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarbonyl chloride (EXAMPLE 1, Step 2, 0.805 mmol theory) in anhydrous tetrahydrofuran (8.0 mL) is added. The resulting mixture is stirred under nitrogen for 2 h, allowing the cooling bath to slowly expire, and is then diluted with water (10 mL) and extracted with methylene chloride (20 mL). The organic phase is washed with water (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product is chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with a gradient of methanol/methylene chloride (0.5/99.5-2/98). Pooling and concentration of those fractions with an Rf=0.44 by TLC (methanol/chloroform, 5/95) provides the title compound, mp 167-169° C.; MS (ESI+) for C17H20FN3O4 m/z 350 (M+H)+; [α]25D=−44° (c 0.94, DMSO).
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:15]=2)[C:10]([CH:26]=[O:27])=[CH:9]1)(OC(C)(C)C)=O.I[C:29]1[C:37]2[C:32](=[N:33][CH:34]=[N:35][C:36]=2[NH2:38])[N:31]([CH:39]([CH3:41])[CH3:40])[N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:38][C:36]1[N:35]=[CH:34][N:33]=[C:32]2[N:31]([CH:39]([CH3:41])[CH3:40])[N:30]=[C:29]([C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[NH:8][CH:9]=[C:10]4[CH:26]=[O:27])[C:37]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: CC(C)(C)OC(=O)n1cc(C=O)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
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: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2ccc3[nH]cc(C=O)c3c2)c2c(N)ncnc21
Temperature: 80 °C

Procedure:
A solution of N-Boc-3-formyl-5-indoleboronic acid pinacol ester (40 mg, 0.11 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA). The TFA from purification hydrolyzed the Boc to yield BA43. ESI-MS (M+H)+ m/z calcd 321.1, found 321.0.
Reaction SMILES: Cl.N1C=CC=CC=1.[CH2:8]([C:12]1([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:20][C:19]2[C:14](=[C:15]([Cl:24])[C:16]([Cl:23])=[C:17]([O:21]C)[CH:18]=2)[C:13]1=[O:25])[CH2:9][CH2:10][CH3:11]>CCOCC>[CH2:8]([C:12]1([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:20][C:19]2[C:14](=[C:15]([Cl:24])[C:16]([Cl:23])=[C:17]([OH:21])[CH:18]=2)[C:13]1=[O:25])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCC1(C2CCCC2)Cc2cc(OC)c(Cl)c(Cl)c2C1=O
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Temperature: 190 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To pyridine hydrochloride (50 g) fused at 190° C. was added 2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-methoxy-1H-inden-1-one (6.6 g). The reaction mixture was stirred at 190° C. in an inert atmosphere for 11/2 hours then poured onto ice water. The resulting solid was dissolved in ether, washed with water, dried over MgSO4, evaporated at reduced pressure then triturated with hexane (50 ml) to give 5.5 g of 2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-1H-inden-1-one, m.p. 159.5°-160° C.