Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[N:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[CH:5]=[CH:6][CH:7]=1.[F:16][C:17]1[CH:35]=[CH:34][C:20]2[C:21]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]3)=[N:22][O:23][C:19]=2[CH:18]=1.[NH4+].[Cl-]>O1CCCC1.CCOCC.BrC(Br)C>[F:16][C:17]1[CH:35]=[CH:34][C:20]2[C:21]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:28][CH2:29][C:30]([C:3]4[N:4]([CH2:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[F:15])[CH:5]=[CH:6][CH:7]=4)([OH:33])[CH2:31][CH2:32]3)=[N:22][O:23][C:19]=2[CH:18]=1
Reactant: O=C1CCN(CCCc2noc3cc(F)ccc23)CC1
Reactant: Fc1ccccc1Cn1cccc1Br
Agent: CC(Br)Br
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(c2cccn2Cc2ccccc2F)CCN(CCCc2noc3cc(F)ccc23)CC1
Yield: 72.3 %

Procedure:
To a suspension of magnesium turnings (1.0 g, 0.04 mole) in 25 ml tetrahydrofuran (THF) and 10 ml ether, was added a few drops of a solution of 2-bromo-1-(2-fluorobenzyl)pyrrole (10 g, 0.04 mole) in 30 ml THF. The reaction was initiated with a few drops of dibromoethane and heat, and reflux was maintained by the addition of the bromo compound. After stirring at reflux for 30 minutes, the mixture was cooled; then a solution of 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-piperidone (5.2 g, 0.019 mole) in 50 ml THF was added. After stirring at ambient temperature for one hour, the mixture was poured into an NH4Cl solution, then extracted with ether. The ether layer was washed with water, then dried over anhydrous MgSO4. After evaporation of the solvent, the resultant oil (13 g), was purified by HPLC using ethyl acetate with 0.5% Diethylamine as the eluent to give 6.2 g of 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-[1-(2-fluorobenzyl)pyrrol-2-yl]-4-piperidinol, m.p. 100°-4° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:10]([NH:12][C@H:13]2[CH2:21][CH2:20][CH2:19][C@H:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[C@@H:17]([O:30][CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C@H:16]([CH3:38])[O:15][C:14]2=[O:39])=[O:11])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-].[CH2:48]([O:50][CH2:51][C:52]([O:54][CH2:55]Cl)=[O:53])[CH3:49]>CC(C)=O>[CH2:48]([O:50][CH2:51][C:52]([O:54][CH2:55][O:1][C:2]1[C:3]([C:10](=[O:11])[NH:12][C@H:13]2[CH2:21][CH2:20][CH2:19][C@H:18]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)[C@@H:17]([O:30][CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C@H:16]([CH3:38])[O:15][C:14]2=[O:39])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9])=[O:53])[CH3:49]
Reactant: CCOCC(=O)OCCl
Reactant: COc1ccnc(C(=O)N[C@H]2CCC[C@H](Cc3ccc(C)cc3)[C@@H](OCCCC(F)(F)F)[C@H](C)OC2=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOCC(=O)OCOc1c(OC)ccnc1C(=O)N[C@H]1CCC[C@H](Cc2ccc(C)cc2)[C@@H](OCCCC(F)(F)F)[C@H](C)OC1=O
Temperature: 40 °C
Reaction time: 17 h
Yield: 55.3 %

Procedure:
To a 25 mL screw top vial were added 3-hydroxy-4-methoxy-N-((3S,7R,8R,9S)-9-methyl-7-(4-methylbenzyl)-2-oxo-8-(4,4,4-trifluorobutoxyl)oxonan-3-yl)picolinamide (87.9 mg, 0.159 mmol), Na2CO3 (33.8 mg, 0.319 mmol), NaI (6.3 mg, 0.264 mmol), anhydrous acetone (2 mL), and chloromethyl 2-ethoxyacetate (40.8 mg, 1.68 mmol), and the resulting mixture was warmed to 40° C. and stirred for 17 h. The reaction was cooled to room temperature, concentrated under a stream of nitrogen, and purified by column chromatography on SiO2 (2→40% acetone/hexanes) to provide the title compound as a colorless oil (58.8 mg, 52%): 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J=8.1 Hz, 1H), 8.25 (d, J=5.4 Hz, 1H), 7.09 (d, J=7.9 Hz, 2H), 7.03 (d, J=8.0 Hz, 2H), 6.93 (d, J=5.4 Hz, 1H), 5.80 (s, 2H), 4.89 (dq, J=9.1, 6.4 Hz, 1H), 4.55 (dt, J=10.9, 7.4 Hz, 1H), 4.08 (s, 2H), 3.88 (s, 3H), 3.80 (dt, J=8.9, 6.1 Hz, 1H), 3.64-3.54 (m, 3H), 3.17 (t, J=9.0 Hz, 1H), 2.96 (dd, J=13.3, 3.4 Hz, 1H), 2.40-2.13 (m, 7H), 1.92-1.76 (m, 3H), 1.65-1.37 (m, 6H), 1.30-1.14 (m, 4H), 0.93-0.80 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 172.62, 169.97, 162.83, 160.09, 145.73, 143.81, 142.18, 137.20, 135.41, 129.02, 128.58, 131.42-122.86 (m), 109.65, 89.44, 84.20, 74.83, 71.60, 67.71, 67.10, 56.15, 51.69, 45.80, 36.42, 33.56, 30.73 (q, J=29.0 Hz), 26.62, 23.01 (q, J=3.1 Hz), 20.93, 18.75, 18.05, 14.94; 19F NMR (376 MHz, CDCl3) δ −66.35, ESIMS: m/z 669 ([M+H]+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:13]1=[O:30])(C)(C)C.[ClH:32]>C(O)C>[ClH:32].[O:30]=[C:13]1[C:14]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:16](=[O:17])[N:12]1[CH2:11][CH2:10][CH2:9][CH2:8][NH2:7]
Reactant: CC(C)(C)OC(=O)NCCCCN1C(=O)C(c2ccccc2)=C(c2ccccc2)C1=O
Agent: Cl
Solvent: CCO
Product: NCCCCN1C(=O)C(c2ccccc2)=C(c2ccccc2)C1=O

Procedure:
8.2 g (<18 mmol) N-[4-(2,5-dioxo-3,4-diphenyl-2,5-dihydropyr-rol-1-yl)-butyl]-carbamic acid tert-butylester are dissolved in 80 ml ethanol and heated under reflux for two hours after addition of 4.5 ml (54 mmol) concentrated hydrochloric acid. The cooled solution is concentrated under vacuum and the residue is dried under high vacuum. The accumulated crude product is further processed without further purification: Yield 6.3 g of a yellow solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH2:12]([CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[C:13]#[CH:14]>>[CH2:12]([CH:15]1[CH2:20][CH2:19][N:18]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:17][CH2:16]1)[C:13]#[CH:14]
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)OCc1ccccc1
Product: C#CCC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
Benzyl chloroformate (6.9 g, 40.4 mmol) was added to a solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (1.65 g, 13.4 mmol) according to general procedure 1. Yield=0.700 g, 37%. m/z MH+=258.02. HPLC rt=10.2 min.
Reaction SMILES: [C@H:1]1([C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:4][C@H:3]([C:5]([O:7]CC2C=CC=CC=2)=[O:6])[CH2:2]1>CO.[C].[Pd]>[C@H:1]1([C:15]([OH:17])=[O:16])[CH2:4][C@H:3]([C:5]([OH:7])=[O:6])[CH2:2]1
Reactant: O=C(OCc1ccccc1)[C@H]1C[C@H](C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@H]1C[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of dibenzyl trans-cyclobutane-1,3-dicarboxylate (100 mg, 0.31 mmol) and 10% palladium-carbon (10 mg, 0.09 mmol, 50%, wet) in MeOH (2.0 mL) was stirred at room temperature for 5 hr under hydrogen atmosphere (1 atm). The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give crude trans-cyclobutane-1,3-dicarboxylic acid as a colorless oil.
Reaction SMILES: [CH2:1]([OH:10])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>NCCCN>[CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[CH:9]
Reactant: CCCCCCC#CCO
Agent: NCCCN
Product: C#CCCCCCCCO
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 67 %

Procedure:
In a round-bottom flask equipped with a stir bar and under an atmosphere of argon was added KH (4.46 g, 111 mmol). The flask was cooled to 0° C. and 1,3-diaminopropane (50 mL) was added slowly via syringe. The solution was stirred for 45 min. Then 2-nonyn-1-ol, dissolved in of 1,3-diaminopropane (30 mL), was added dropwise via syringe to the stirring solution. The reaction was stirred for an additional 30 min at 0° C. before warming to room temperature overnight. The reaction was again cooled to 0° C. before quenching with water. The compound was extracted with Et2O, washed with HCL, water, and brine, dried with MgSO4, and concentrated. This produced 4.94 g of dark orange oil which was purified by flash column chromatography on silica gel (2.5% Et2O in hexane to 50% Et2O in hexane) to give 3.21 g of clear oil (67%): IR (near) ν 3409, 2931, 2242 cm−1, 1H—NMR δ 3.59 (t, 2H, J=7.0 Hz), 2.14 (td, 2H, J=3.0 Hz, 7.0 Hz), 2.10 (s, 1H), 1.91 (t, 1H, J=3.0 Hz), 1.50 (bm, 4H), 1.30 (bm, 6H); 13C—NMR δ 84.6, 68.1, 62.8, 32.6, 28.8, 28.6, 28.3, 25.6, 18.3; MS m/z 147.10 (M++Li). Anal. Calcd for C9H16O: C, 77.09; H, 11.46. Found: C, 77.00; H, 11.46.
Reaction SMILES: C(C1C=CC=CC=1)(=O)C.Cl.C1(CCC2C=C(C(=NO)C)C=CC=2)C=CC=CC=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36]/[C:37](/[C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:41]=2)=[N:38]/[OH:39])[CH2:32][CH2:31]1>>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][CH2:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH:41]=2)=[N:38][OH:39])[CH2:32][CH2:31]1
Reactant: CN1CCN(C/C(=N/O)c2cccc(CCc3ccccc3)c2)CC1
Agent: CC(=NO)c1cccc(CCc2ccccc2)c1
Agent: Cl
Solvent: CC(=O)c1ccccc1
Product: CN1CCN(CC(=NO)c2cccc(CCc3ccccc3)c2)CC1

Procedure:
A Grignard compound synthesized from 1.0 g of magnesium and 10.0 g of 3-(2-phenylethyl)-bromobenzene in 30 ml of tetrahydrofuran was dropped at -60° C. under stirring for 3 min into 7.6 g of anhydrous acetic acid dissolved in 20 ml of tetrahydrofuran in a nitrogen atmosphere and stirred for further one hour. Then, the reaction solution was poured into a mixture of ice and an aqueous saturated solution of ammonium chloride and extracted with toluene. After separating the solution, it was washed with an aqueous 2N-solution of sodium hydroxide and saturated saline solution successively, dried over anhydrous sodium sulfate and then concentrated to solid. The residue was purified by silica gel column chromatography, using benzene/n-hexane (1:1) as an elute, to obtain 7.9 g of 1-(3-(2-phenylethyl)-phenyl)ethanone as an oily product. Then, by using 5.0 g of the thus obtained acetophenone compound, 3.8 g of (Z)-2-(4-methylpiperazin-1-yl)-1-(3-(2-phenylethyl)-phenyl-ethanone oxime hydrochloride with the melting point of from 185° to 188° C. (decomposition) and 0.5 g of (E)-2-(4-methylpiperazin-1-yl)-1-(3-(2-phenylethyl)-phenyl)-ethanone oxime with the melting point from 133° to 134° C. were obtained in the same manner as in Example 33.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1.[C:32]1([C@@H:38]([CH2:42][CH3:43])[C:39](O)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:30][C:29]1[C:24]([CH2:23][N:12]([CH2:11][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:39](=[O:40])[CH:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:42][CH3:43])=[CH:8][C:7]=2[CH2:9][OH:10])[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: Cc1cnc(CN(Cc2ccc(CN)cc2CO)C2CCCc3cccnc32)c(C)c1
Reactant: CC[C@@H](C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(C(=O)NCc1ccc(CN(Cc2ncc(C)cc2C)C2CCCc3cccnc32)c(CO)c1)c1ccccc1
Yield: 41 %

Procedure:
Using General Procedure G: To a solution of (5-aminomethyl-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol (0.12 g, 0.26 mmol) dissolved in CH2Cl2 (10 mL) was added (R)-2-phenylbutyric acid (60 μl, 0.39 mmol), EDCI (0.08 g, 0.39 mmol), HOBT (0.05 g, 0.39 mmol), and DIPEA (67 μl, 0.39 mmol). Purification via column chromatography on silica gel (CH2Cl2:MeOH, 97:3, v/v) afforded the product as a colorless oil (0.06 g, 36%). 1H NMR (CDCl3) δ 0.88 (m, 3H), 1.51 (m, 1H), 1.86 (m, 1H), 2.05 (m, 1H), 2.11 (m, 3H), 2.14 (s, 3H), 2.24 (s, 3H), 2.79 (m, 2H), 3.20 (m, 1H), 3.70 (m, 4H), 4.09 (m, 2H), 4.33 (m, 3H), 5.69 (s, 1H), 6.95 (m, 2H), 7.13 (m, 2H), 7.22 (m, 7H), 8.15 (s, 1H), 8.35 (s, 1H); ES-MS m/z 564 (M+H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[C:7]([N:16]([CH3:23])[CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:8]([CH3:15])=[C:9]([CH:14]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:2]1.C=O.[C:26](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:15][C:8]1[C:7]([N:16]([CH3:23])[CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:6][C:5]([CH:3]2[CH2:2][N:1]([CH3:26])[CH2:4]2)=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: CC(=O)O
Reactant: COC(=O)c1cc(C2CNC2)cc(N(C)C2CCOCC2)c1C
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1cc(C2CN(C)C2)cc(N(C)C2CCOCC2)c1C
Reaction time: 4 h
Yield: 88.2 %

Procedure:
To a stirred solution of methyl 5-(azetidin-3-yl)-2-methyl-3-[methyl(oxan-4-yl)amino]benzoate (320 mg, 1.01 mmol) in DCE (10 ml) under a nitrogen atmosphere was added paraformaldehyde (151 mg, 5.03 mmol) followed by acetic acid (0.115 ml, 2.01 mmol) and the reaction was left to stir for 5 min before the addition of sodium triacetoxyborohydride (852 mg, 4.02 mmol). The reaction was stirred for 16 h at room temperature after which time additional paraformaldehyde (21 mg) and sodium triacetoxyborohydride (98 mg) was added and the reaction was stirred for a further 4 h whereupon distilled water (20 ml) was added and solid NaHCO3 was added until the aqueous phase was pH7. The phases were separated, the aqueous phase was washed with DCM (3×20 ml), the combined organic phases were then washed with brine (50 ml), dried using MgSO4, filtered and evaporated to afford the title compound as an oil (296 mg, 89%). LC-MS 100%, m/z=333.1, 1H NMR (500 MHz, Chloroform-d) δ 7.42 (d, J=1.4 Hz, 1H), 7.09 (s, 1H), 3.96 (d, J=11.2 Hz, 2H), 3.92-3.82 (m, 5H), 3.74 (d, J=7.2 Hz, 1H), 3.30 (dt, J=22.2, 15.0 Hz, 4H), 3.00-2.89 (m, 1H), 2.62 (s, 3H), 2.49-2.39 (m, 6H), 1.75-1.59 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:30][C:31]1[N:36]=[C:35](Cl)[CH:34]=[C:33]([O:38][CH3:39])[N:32]=1.CO>O1CCOCC1>[CH3:39][O:38][C:33]1[CH:34]=[C:35]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[NH:11][C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=4)=[N:14][N:13]=3)=[CH:16][CH:17]=2)[N:36]=[C:31]([NH2:30])[N:32]=1
Reactant: COc1cc(Cl)nc(N)n1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(Oc2ccc(-c3nnc(Nc4cccc(C(F)(F)F)c4)[nH]3)cc2)nc(N)n1
Yield: 40.5 %

Procedure:
4-(5-{[3-(trifluromethyl)phenyl]amino}-4H-1,2,4-triazol-3-yl)phenol (100 mg, 0.31 mmol) was dissolved in 3 mL of anhydrous dioxane in 2-5 mL microwave vial (Personal Chemistry). Solid Cs2CO3 (101.7 mg, 0.31 mmol) was added, followed by 2-amino-4-chloro-6-methoxypyrimidine (55.0 mg, 0.34 mmol). The vial was capped and microwaved at 200° C. for 15 min. Then ca. 3 mL of MeOH was added to dissolve the formed suspension. The resulting reddish-brown solution was transferred into a round-bottom flask and solvent was removed in vacuo. The residue was re-dissolved in 3 mL of DMF, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetontrile/water system with 0.01% of TFA. The fractions, containing the product, were collected and partitioned between EtOAc and saturated aqueous NaHCO3. Ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title compound as an off-white solid (55.6 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]([C:19]2([C:22]3[CH:30]=[CH:29][C:25]4[O:26][CH2:27][O:28][C:24]=4[CH:23]=3)[CH2:21][CH2:20]2)=[O:18])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8]2.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>CN(C=O)C>[C:38]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]([C:19]2([C:22]3[CH:30]=[CH:29][C:25]4[O:26][CH2:27][O:28][C:24]=4[CH:23]=3)[CH2:20][CH2:21]2)=[O:18])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8]2)(=[O:40])[CH3:39]
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc(CN)c2[nH]1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NCc1cc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc2cc(C(C)(C)C)[nH]c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-(7-(Aminomethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (20 mg, 0.049 mmol) was dissolved in DMF (0.5 mL) containing triethylamine (20.6 μL, 0.147 mmol) and a magnetic stir bar. Acetyl chloride (4.2 μL, 0.054 mmol) was then added to the reaction mixture. The reaction mixture was allowed to stir for 16 h at room temperature. The crude product was purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield N-(7-(acetamidomethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 447.2, found 448.3 (M+1)+. Retention time of 1.76 minutes.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][O:37][C:36]([CH3:41])([CH3:40])[CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][O:37][C:36]([CH3:41])([CH3:40])[CH2:35]5)[CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CC1(C)CN(C2CNC2)CCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOC(C)(C)C4)C3)n(C)c2n1
Reaction time: 40 h

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (112 mg, 0.29 mmol), 4-azetidin-3-yl-2,2-dimethylmorpholine (58 mg, 0.34 mmol) and 4 Å powdered molecular sieves (200 mg) in DCE (5 mL) was stirred at room temperature for 4 h before the addition of sodium triacetoxyborohydride (121 mg, 0.57 mmol). The reaction mixture was stirred for 40 h then filtered through celite, washing with DCM. The organic phase was washed with brine (x 1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 331 as a yellow solid (121 mg, 76%). LCMS (Method G): RT 6.85 min [M+H]+ 546.3. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.97 (m, 1 H); 7.77-7.73 (m, 1 H); 7.29-7.22 (m, 2 H); 4.35 (m, 4 H); 3.91-3.82 (m, 9 H); 3.73 (m, 2 H); 3.57 (t, J=6.6 Hz, 2 H); 3.35 (q, J=7.5 Hz, 2 H); 3.10 (t, J=6.6 Hz, 2 H); 2.98 (p, J=6.6 Hz, 1 H); 2.24 (m, 2 H); 2.04 (s, 2 H); 1.44 (t, J=7.5 Hz, 3 H) and 1.25 (s, 6 H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@H:9]2[C:11]([O:13]C)=[O:12])=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@@H]1c1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CC1c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of ester from step 2 in THF-MeOH (4:1, 0.5M) was added LiOH (3 eq, 2M) and the mixture was stirred at 50° C. for 1 h. The organic solvent was evaporated, the aqueous layer was acidified with HCl 1N and the acid extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried and evaporated to afford 2-(4-bromophenyl)cyclopropanecarboxylic acid. Optically active intermediates were obtained by separation on chiral column (Chiral Pak AD) using hexane:EtOH (90:10 with 0.2% TFA)
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[CH3:10][S:11]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)(=[O:13])=[O:12].C(=O)([O-])[O-].[Na+].[Na+].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.O>[CH3:7][C:5]1[O:6][C:2]([C:17]2[CH:18]=[CH:19][C:14]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:15][CH:16]=2)=[CH:3][C:4]=1[CH:8]=[O:9]
Reactant: Cc1oc(Br)cc1C=O
Reactant: CS(=O)(=O)c1ccc(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: COCCOC
Product: Cc1oc(-c2ccc(S(C)(=O)=O)cc2)cc1C=O
Reaction time: 8 h
Yield: 62 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.5 g), 4-(methanesulfonyl)phenylboronic acid (2.0 g), tetrakis(triphenylphosphine)palladium(0) (0.5 g), 2N aqueous sodium carbonate solution (10 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 100% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.3 g, 64%) as a yellow crystal.
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:40][CH2:39][C:15]3([O:19][N:18]=[C:17]([C:20]4[C:21]([NH:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[C:22]5[C:28](C)=[N:27][N:26]([CH2:30][CH3:31])[C:23]5=[N:24][CH:25]=4)[CH2:16]3)[CH2:14][CH2:13]2)(=O)=O)=CC=1.[N-:41]=[N+:42]=[N-:43].[Na+].O>CN(C)C=O>[N:41]([CH:12]1[CH2:40][CH2:39][C:15]2([O:19][N:18]=[C:17]([C:20]3[CH:25]=[N:24][C:23]4[N:26]([CH2:30][CH3:31])[N:27]=[CH:28][C:22]=4[C:21]=3[NH:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:16]2)[CH2:14][CH2:13]1)=[N+:42]=[N-:43]
Reactant: CCn1nc(C)c2c(NC3CCCCC3)c(C3=NOC4(CCC(OS(=O)(=O)c5ccc(C)cc5)CC4)C3)cnc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCC(N=[N+]=[N-])CC4)C3)cnc21
Temperature: 65 °C
Reaction time: 8 h

Procedure:
3-[4-(Cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl 4-methylbenzenesulfonate (0.00090 mole) (example 39) is taken in dimethylformamide. Sodium azide (0.0027 mole) is added. The reaction mixture is stirred at 60-70° C. overnight. It is cooled and water is added and extraction is done with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure to give crude compound, which is purified by column chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4]([O:11][CH3:12])[CH:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][S:21]([CH3:20])(=[O:23])=[O:22])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(F)ccc1CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1cc(F)ccc1CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a solution of 5.1 g (29.97 mmol) of 2-(4-Fluoro-2-methoxy-phenyl)-ethanol in 30 ml of anhydrous dichloromethane was added at 0° C. 6.26 ml (44.95 mmol) of triethylamine and 3.5 ml (44.95 mmol) of methanesulfonyl chloride. The resulting mixture was stirred at 0° C. for 1 h. The mixture was then diluted with water and dichloromethane and extracted with dichloromethane. Organic layer was dried and evaporated to give 7 g(100%) of methanesulfonic acid 2-(4-fluoro-2-methoxy-phenyl)-ethyl ester.