Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22]([OH:24])=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].CN(C)P(=O)(N(C)C)N(C)C.Br[CH2:38][CH:39]=[CH2:40]>O>[C:1]1([NH:7][C:8]2([C:22]([O:24][CH2:40][CH:39]=[CH2:38])=[O:23])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCBr
Reactant: O=C(O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Agent: [Na]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCOC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
A mixture of 10.4 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylic acid, sodium salt and 75 parts of hexamethylphosphoric triamide is stirred and heated to 110° C. for a while. After cooling to 20° C., 3.63 parts of 3-bromo-1-propene are added dropwise. Upon completion, stirring is continued for 20 hours at room temperature. The reaction mixture is poured onto 150 parts of water and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from hexane, yielding 2-propenyl 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylate; mp. 57.2° C.
Reaction SMILES: [CH:1]1([CH:6]=[CH:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCN2C(=NCCC2)CC1.[C:21]([O:27][CH2:28][N:29]1[C:33]2[N:34]=[CH:35][N:36]=[C:37]([C:38]3[CH:39]=[N:40][NH:41][CH:42]=3)[C:32]=2[CH:31]=[CH:30]1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>C(#N)C>[C:21]([O:27][CH2:28][N:29]1[C:33]2[N:34]=[CH:35][N:36]=[C:37]([C:38]3[CH:39]=[N:40][N:41]([CH:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:7][C:8]#[N:9])[CH:42]=3)[C:32]=2[CH:31]=[CH:30]1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: N#CC=CC1CCCC1
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(C(CC#N)C4CCCC4)c3)ncnc21
Temperature: 55 °C
Yield: 30.9 %

Procedure:
Method A. 3-Cyclopentylacrylonitrile (8, 14.6 g, 0.12 mol, 1.20 equiv) and DBU (18.2 mL, 0.12 mol, 1.2 equiv) was added to a suspension of 4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7yl]methyl pivalate (19, 30.0 g, 0.1 mol) in acetonitrile (45 mL) at room temperature. The resulting reaction mixture was heated to 50-60° C. for 17 hours (a clear solution developed midway through heating) then to room temperature for 8 hours. When LCMS analysis showed the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in 2 L of ethyl acetate. The resulting solution was washed with water (3×200 mL), dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure to give the crude product (20) as a thick oil. The crude product was then purified by flash chromatography (SiO2, 0-50% EtOAc/hexanes gradient elution) to afford racemic (4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 13.0 g, 42.14 g theoretical, 30.8% yield) as a white solid. For 20: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.84 (s, 1H), 8.78 (s, 1H), 8.39 (s, 1H), 7.74 (d, 1H, J=3.7 Hz,), 7.11 (d, 1H, J=3.8 Hz), 6.23 (s, 2H), 4.53 (ddd, 1H, J=9.9, 9.6, 4.2 Hz), 3.26 (dd, 1H, J=17.4, 9.9 Hz), 3.19 (dd, 1H, J=17.2, 4.3 Hz), 2.41 (m, 1H), 1.87-1.13 (m, 8H), 1.07 (s, 9H); C23H28N6O2 (MW, 420.51), LCMS (EI) m/e 421.4 (M++H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](I)[CH:9]=1)(=[O:3])[CH3:2].[CH3:27][O:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:34]2[C:29]([O:28][CH3:27])=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COc1ncccc1B(O)O
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(I)c1
Product: COc1ncccc1-c1cccc(O[C@@H]2SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c1
Yield: 66 %

Procedure:
By carrying out the operation analogously to example 3, starting from 3-iodophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation I, and 2-methoxy-3-pyridineboronic acid, the expected product is obtained in the form of a white powder with a yield of 66%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[S:10](Cl)(=[O:12])=[O:11].[OH-].[NH4+:15]>CC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[S:10]([NH2:15])(=[O:12])=[O:11]
Reactant: [NH4+]
Reactant: COCCc1ccsc1S(=O)(=O)Cl
Agent: [OH-]
Solvent: CC(C)=O
Product: COCCc1ccsc1S(N)(=O)=O
Reaction time: 8 h

Procedure:
Six grams of crude 3-(2-methoxyethyl)thiophene-2-sulfonyl chloride was dissolved in 25 mL of acetone and added dropwise with stirring at ambient temperature to 25 mL of concentrated aqueous ammonium hydroxide. The reaction mixture was allowed to stand overnight and the acetone removed by evaporation. The aqueous residue was extracted with three 100 mL portions of methylene chloride which were combined, dried over magnesium sulfate, filtered and evaporated to yield a residue which was a mixture of an oil and a solid. The sulfonamide was isolated by passing the residue through a 30 cm high by 80 mm diameter column of silica gel using 1:1 ethyl acetate mixed hexanes solvent system and taking 100 mL fractions. The desired product came off in fractions 4 to 12. After evaporation of the solvent 1.84 grams was obtained, m.p. 64°-73°. Analysis by mass spectroscopy showed a molecular weight of 221 AMU in agreement for the desired sulfonamide.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])=[N:5][O:6][C:7]=1[CH3:8].C[O:18][C:19](=[O:32])[CH2:20][O:21][C:22]1[CH:30]=[CH:29][C:28]([SH:31])=[C:27]2[C:23]=1[CH2:24][CH2:25][CH2:26]2>>[Cl:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[C:9]=1[C:4]1[C:3]([CH2:2][S:31][C:28]2[CH:29]=[CH:30][C:22]([O:21][CH2:20][C:19]([OH:32])=[O:18])=[C:23]3[C:27]=2[CH2:26][CH2:25][CH2:24]3)=[C:7]([CH3:8])[O:6][N:5]=1
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1CBr
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1CSc1ccc(OCC(=O)O)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using commercially available 4-bromomethyl-3-(2,6-dichloro-phenyl)-5-methyl-isoxazole and 12C. MS m/z 478 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]=[C:9]([C:11]3[N:15]([CH3:16])[C:14]([SH:17])=[N:13][C:12]=3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[CH2:25]([N:27]([CH2:30]CCl)[CH2:28]C)[CH3:26].[OH-].[Na+]>>[CH3:28][N:27]([CH3:30])[CH2:25][CH2:26][S:17][C:14]1[N:15]([CH3:16])[C:11]([C:9]2[S:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[N:10]=2)=[C:12]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:13]=1
Reactant: Cn1c(S)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(C)CCSc1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C
Temperature: 60 °C

Procedure:
A mixture of 5-(7-amino[1,3]thiazolo[5,4-d]pyrimidin-2-yl)-1-methyl-4-phenyl-1H-imidazole-2-thiol (Intermediate 47) (10 mg), N,N-diethyl-2-chloroethylamine hydrochloride (9 mg) and 2M NaOH (1 mL) was heated at 60° C. for 6 hours. After which the reaction mixture was cooled to ambient temperature and the title compound isolated by filtration as a yellow solid (6 mg, 50%);
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:24]=[CH:23][C:12]3[C@:13]4([CH3:22])[C@@H:18]([CH2:19][CH2:20][C:11]=3[CH:10]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]4)=[CH:5][CH:4]=1)#[N:2].[CH2:25](O)CCC.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:25][N:17]1[C@H:18]2[C@@:13]([CH3:22])([C:12]3[CH:23]=[CH:24][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[CH:10][C:11]=3[CH2:20][CH2:19]2)[CH2:14][CH2:15][C:16]1=[O:21]
Reactant: CCCCO
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccc(C#N)cc3)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(C#N)cc4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(4-cyanophenyl)-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (24 mg, 0.08 mmol), 0.20 mL of n-butanol, and potassium t-butoxide (26 mg, 0.24 mmol). Methyl iodide (0.014 mL, 0.24 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography ethyl acetate eluent) to give 20 mg (80%) of the title compound as a white solid. mp 148°-150°. FDMS: m/e=330.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][O:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Reactant: OCCc1ccc(F)cc1
Product: O=C(O)CNC(=O)c1ccc(OCCc2ccc(F)cc2)cc1
Yield: 76.6 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (249 mg, 0.991 mmol) prepared in Example 1 (1a) and 2-(4-fluorophenyl)ethanol (150 μL, 1.20 mmol) to give 241 mg of the title compound (yield: 91%).
Reaction SMILES: CO.[Cl:3][C:4]1[C:9]([O:10]C(OC)=O)=[CH:8][C:7]([N:15]2[C:23](=[O:24])[C:18]3=[CH:19][CH2:20][CH2:21][CH2:22][N:17]3[C:16]2=[O:25])=[C:6]([F:26])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(OCC)C>[Cl:3][C:4]1[C:9]([OH:10])=[CH:8][C:7]([N:15]2[C:23](=[O:24])[C:18]3=[CH:19][CH2:20][CH2:21][CH2:22][N:17]3[C:16]2=[O:25])=[C:6]([F:26])[CH:5]=1
Reactant: COC(=O)Oc1cc(N2C(=O)C3=CCCCN3C2=O)c(F)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: O=C1C2=CCCCN2C(=O)N1c1cc(O)c(Cl)cc1F
Yield: 35.6 %

Procedure:
A methanol (40 mL) solution of 2-(4-chloro-2-fluoro-5-methoxycarbonyloxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (3.13 g, 8.8 mmol) and potassium carbonate (1.22 g, 8.8 mmol) was stirred at 50°-60° C. for 8 hours. Diethyl ether (20 mL) and 1N hydrochloric acid (30 mL) were added to the resulting mixture, and the organic layer was separated and then the aqueous layer was extracted with diethyl ether (20 mL×2 times). The organic layer combined was washed with a saturated sodium chloride solution (30 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane=1/1) to obtain a white solid of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.93 g, yield:5.8%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH:31]1[CH2:34][CH:33]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH2:32]1.C(N(CC)CC)C>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:31]3[CH2:34][CH:33]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH2:32]3)=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: C1CN(C2CNC2)CCO1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CC(N3CCOCC3)C2)no1
Yield: 105.9 %

Procedure:
A solution of ethyl 5-{(1R)-1 -[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (1.00 g, 2.54 mmol) in ethanol (10 ml) was treated with 4-(3-azetidinyl)morpholine dihydrochloride (2.72 g, 12.6 mmol) and triethylamine (2.56 g, 25 mmol) and the resulting mixture was heated under reflux under a nitrogen atmosphere for 24 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed sequentially with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (97:3) gradually changing to dichloromethane:methanol (95:5) to afford the title compound as a colourless oil (1.32 g).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[OH:12][CH2:13][CH2:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([CH2:26][CH2:27][CH2:28][S:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:22][C:23]=2[OH:25])[N:18]([CH3:34])[CH:17]([CH3:35])[CH2:16]1.C(Cl)(Cl)Cl>C(O)(=O)C>[OH:12][CH2:13][CH2:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([CH2:26][CH2:27][CH2:28][S:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[O:9])=[CH:22][C:23]=2[OH:25])[N:18]([CH3:34])[CH:17]([CH3:35])[CH2:16]1
Reactant: CCCCSCCCc1cc(O)c2c(c1)N(C)C(C)CC2CCO
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCCCS(=O)CCCc1cc(O)c2c(c1)N(C)C(C)CC2CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Equimolar amounts of m-chloroperbenzoic acid and dl-4-(2-hydroxyethyl)-5-hydroxy-1,2-dimethyl-7-(4-thiaoctyl)-1,2,3,4-tetrahydroquinoline are added to a mixture of chloroform and acetic acid (2:1 v/v) and the mixture stirred at room temperature for one hour. The mixture is washed with water, the organic phase dried (MgSO4) and evaporated to dryness at reduced pressure to afford the title compound.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[S:14]1[C:18](B(O)O)=[CH:17][C:16]2[CH:22]=[CH:23][CH:24]=[CH:25][C:15]1=2.C(=O)([O-])[O-].[Na+].[Na+].O>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>[S:14]1[C:18]([C:2]2[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=2)[CH:7]=[O:8])=[CH:17][C:16]2[CH:22]=[CH:23][CH:24]=[CH:25][C:15]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: COc1cc(OC)c(C=O)cc1Br
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: COCCOC
Solvent: O
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.6 %

Procedure:
Ex-3A: A sample of 5-bromo-2,4-dimethoxybenzaldehyde (4.9 g, 20.0 mmol) was dissolved in ethylene glycol dimethyl ether (50 mL). Tetrakis(triphenylphosphine)palladium(0) (2.32 g, 2 mmol) was added, and the mixture was stirred at room temperature under nitrogen for 5 min. Benzo[b]thiophene-2-boronic acid (4.27 g, 24 mmol) and sodium carbonate solution (2 M, 20 mL) were added. The mixture was stirred at reflux under nitrogen for 24 hours. Upon cooling to room temperature, the mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. Silica gel chromatography (hexane/ethyl acetate 2:1 then 1:1) gave 4.75 g (83%) of the desired 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde. 1H NMR (CDCl3) δ 10.36 (s, 1H), 8.20 (s, 1H), 7.83–7.78 (m, 2H), 7.68 (s, 1H), 7.36–7.27 (m, 2H), 6.54 (s, 1H), 4.06 (s, 3H), 4.00 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[C:12]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])[N:13]2[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20].[P:30]([O-:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33]>C(Cl)(Cl)(Cl)Cl>[P:30]([O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:12]1[N:13]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:14]2[C:10]([N:11]=1)=[C:9]([Cl:8])[N:17]=[CH:16][N:15]=2)([O:34][CH2:35][CH3:36])([O:31][CH2:32][CH3:33])=[O:37]
Reactant: CCOP([O-])OCC
Reactant: CC(C)(C)Cn1c(-c2ccccc2O)nc2c(Cl)ncnc21
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)Oc1ccccc1-c1nc2c(Cl)ncnc2n1CC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (1.1 mmol) was added slowly to an ice-cooled solution of 6-chloro-N9-neopentyl-8-(2-hydroxyphenyl)purine (1 mmol) and diethyl phosphite (1 mmol) in carbontetrachloride. The reaction was stirred at room temperature overnight. Triethylamine hydrochloride was precipitated as a white solid mass. Extraction and chromatography gave diethyl 2-(6-Chloro-N9-neopentylpurin-8-yl)phenyl phosphate.
Reaction SMILES: Cl.[NH2:2]O.[OH-].[K+].COCCOCCOC.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24](=[N:27][OH:28])[C:25]#[N:26]>O>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]1[C:25]([NH2:2])=[N:26][O:28][N:27]=1
Reactant: N#CC(=NO)c1nc2ccccc2[nH]1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOCCOC
Product: Nc1nonc1-c1nc2ccccc2[nH]1
Temperature: 170 °C
Yield: 48.6 %

Procedure:
To an ice-cooled stirred solution of 13.2 g of hydroxylamine hydrochloride (190 mmol, 3 eq) in 20 ml of water, 15.3 g of potassium hydroxide (27.2 mmol, 4.3 eq) are slowly added. Then 60 ml of diglyme (diethylene glycol dimethyl ether) and 11.8 g of (1H-benzoimidazol-2-yl)-hydroxyimino-acetonitrile (63.4 mmol, 1 eq) are added. The ice-bath is removed and the reaction mixture is heated to reflux for 8 h (bath temperature 170° C.). After cooling to room temperature, the reaction mixture is filtered and the residue is washed with water to give the first crop of the desired product (6.2 g). The filtrate is treated with 150 ml of water. The resulting suspension is filtered and washed with water to provide a second product crop (2.17 g). Both crops are combined and used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:9]=2[CH:10]=1.[NH2:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].[BH4-].[Na+].O>CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([CH2:17][NH:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH:3]=1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: O=Cc1cc(F)cc2c1cnn2C1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(CCNCc1cc(F)cc2c1cnn2C1CCCCO1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.9 %

Procedure:
To a solution of 6-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbaldehyde (175 mg, 0.71 mmol) in MeOH (7 mL) was added tert-butyl N-(2-aminoethyl)-N-methyl-carbamate (184 mg, 1.06 mmol). The reaction was stirred at RT for 4 h, and then NaBH4 (35.4 mg, 0.92 mmol) was added. The reaction mixture was stirred at RT for 4 h and water was added. MeOH was removed under reduced pressure and the residue was diluted with 1N NaOH solution. The aqueous solution extracted with twice with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to obtain crude tert-butyl (2-(((6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methyl)amino)ethyl)(methyl)carbamate (300 mg, quantitative yield). MS (ESI) m/z: 407.2 [M+1]+.
Reaction SMILES: Br[CH2:2][CH2:3]C.[CH2:5]([O:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1>[CH2:5]([O:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([C:19](=[O:21])[CH2:20][CH2:2][CH3:3])[CH2:15][CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)[C@H]1CC[C@@H](OCc2ccccc2)CC1
Reactant: CCCBr
Solvent: C1CCOC1
Product: CCCC(=O)[C@H]1CC[C@@H](OCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a suspension of Mg (0.51 g, 21.6 mmol, 5.0 eq.) in dry THF (15 mL) under N2 was added 1-bromopropane (0.51 g, 2 mL, 5.0 eq.) dropwise and stirred at room temperature until Mg disappeared, then 1-(cis-4-(benzyloxy)cyclohexyl)ethanone (1.2 g, 4.3 mmol, 1.0 eq.) was added to the reaction mixture in an ice bath. The reaction mixture was warmed to r.t and stirred for 3 h., extracted (EtOAc), washed (brine), dried (Na2SO4), filtered and concentrated. The crude was then purified by silica gel chromatography eluting with EtOAc/Petroleum ether (10:1) to give the title compound (0.6 g, 50%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.34-7.24 (m, 5H), 4.49 (s, 2H), 3.62-3.60 (m, 1H), 2.44-2.40 (m, 2H), 2.34-2.33 (m, 1H), 1.98-1.80 (m, 4H), 1.64-1.46 (m, 6H), 0.89 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH:14]=1
Reactant: Clc1cccc2cc[nH]c12
Reactant: CN1CCC(=O)CC1
Product: CN1CC=C(c2c[nH]c3c(Cl)cccc23)CC1
Yield: 81.1 %

Procedure:
Beginning with 0.50 gm (3.3 mMol) 7-chloro-1H-indole and 0.81 mL (6.6 mMol) 1-methyl-4-piperidone, 0.66 gm (81%) of the title compound were recovered as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1.[CH3:26][O:27][C:28]1[C:29](=O)[C:30](=[O:34])[C:31]=1[O:32]C>CO>[CH3:26][O:27][C:28]1[C:31](=[O:32])[C:30](=[O:34])[C:29]=1[NH:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]=1
Reactant: COc1ccc(C(NCCc2ccccc2)c2cccc(N)c2)cc1
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CO
Product: COc1ccc(C(NCCc2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Yield: 81.2 %

Procedure:
In a similar manner to that described in Example (1c), a solution of 3-[(4-methoxyphenyl)-(2-phenylethylamino)methyl]phenylamine (1.74 g) [prepared as described in step (b) above] in methanol (40 ml) and 3,4-dimethoxy-3-cyclobutene-1,2-dione (776 mg) were reacted, to afford the title compound (1.88 g) as yellow foamy solid.
Reaction SMILES: CC([N:5]([C@@H:9]([C:11]1([OH:22])[CH2:14][N:13](CC2C=CC=CC=2)[CH2:12]1)[CH3:10])[C:6](=[O:8])[O-:7])(C)C.[H][H]>CO.[Pd]>[OH:22][C:11]1([C@H:9]([NH:5][C:6](=[O:8])[O:7][C:11]([CH3:14])([CH3:12])[CH3:9])[CH3:10])[CH2:12][NH:13][CH2:14]1
Reactant: C[C@@H](N(C(=O)[O-])C(C)(C)C)C1(O)CN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H](NC(=O)OC(C)(C)C)C1(O)CNC1
Yield: 211.4 %

Procedure:
To a solution of 1,1-dimethylethyl{(1R)-1-[3-hydroxy-1-(phenylmethyl)azetidin-3-yl]ethyl}carbamate (1.07 g, 3.5 mmol) in methanol was added wet 10% palladium on carbon (50% by mass, 250 mg). The resulting suspension was subjected to 1 atmosphere of hydrogen for 7 h, and an additional 250 mg of catalyst was added over the course of the reaction. The catalyst was then removed by filtration through celite. The filtrate was then concentrated in vacuo to provide 1,1-dimethylethyl [(1R)-1-(3-hydroxyazetidin-3-yl)ethyl]carbamate as a colorless syrup (800 mg, quantitative yield). MS (EI) for C10H20N2O3: 161 (M-tert-butyl+H).