Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[C:3]1B1OC(C)(C)C(C)(C)O1.[CH2:20]([CH:22]([C:25]1[C:26]2[N:27]([C:32](I)=[C:33]([CH3:35])[N:34]=2)[N:28]=[C:29]([CH3:31])[CH:30]=1)[CH2:23][CH3:24])[CH3:21].C([O-])([O-])=O.[Na+].[Na+].COCCOC.O>C(Cl)Cl.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.CCO>[CH2:20]([CH:22]([C:25]1[C:26]2[N:27]([C:32]([C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[CH:4]=3)=[C:33]([CH3:35])[N:34]=2)[N:28]=[C:29]([CH3:31])[CH:30]=1)[CH2:23][CH3:24])[CH3:21]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cn1c(B2OC(C)(C)C(C)(C)O2)cc2cccnc21
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: ClCCl
Solvent: CCO
Product: CCC(CC)c1cc(C)nn2c(-c3cc4cccnc4n3C)c(C)nc12
Yield: 39.3 %

Procedure:
A solution of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine 1-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (example Rupp-30) (0.23 g, 0.89 mmol), 2M Na2CO3 (0.72 mL, 1.45 mmol), and 7:3:2 DME:Water: EtOH (5 mL) is degassed with nitrogen for 15 minutes. Pd(PPh3)4 (0.051 g, 0.044 mmol) is added and the solution is heated at a reflux for three days. The solution is diluted with CH2Cl2 (50 mL), washed with 10% Na2CO3 (30 mL), water (30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated. The material is purified by ISCO (15%-30% EtOAc gradient) to furnish the title compound (0.12 g, 0.35 mmol, 48%). 1H NMR (CDCl3), δ 0.90 (t, J=7.5 Hz, 6H), 1.78-1.95 (m, 4H), 2.50 (s, 3H), 2.53 (s, 3H), 3.32-3.40 (m, 1H), 3.74 (s, 3H), 6.64 (s, 1H), 6.72 (s, 1H), 7.11 (dd, J=8.3, 4.8 Hz, 1H), 7.96 (dd, J=8.3, 1.3 Hz, 1H), 8.40 (dd, J=4.8, 1.3 Hz, 1H) ppm. LC/MS (m/z): calcd. for C21H25N5 (M+H)+: 348.3. found: 348.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([NH:33][C@H:34]([C:40]([NH2:42])=[O:41])[CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])(OC(C)(C)C)=O.[ClH:43].O1CCOCC1.C(OCC)C>ClCCl>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[ClH:43].[ClH:43].[NH2:33][C@H:34]([C:40]([NH2:42])=[O:41])[CH2:35][CH2:36][CH2:37][CH2:38][NH2:39]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(N)=O
Agent: COc1ccc(/C=C(/C#N)c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCCC[C@H](N)C(N)=O

Procedure:
(E)-3-(3-Amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-enenitrile-Boc-L-lysineamide (1,1000 mg, 1.64 mmols) were dissolved in 10 ml of dichloromethane, and 5 ml of a solution of 4-M hydrochloric acid and dioxane were added thereto. The mixture was reacted at 60° C. for 3 hours. One-hundred milliliters of diethyl ether were added thereto, and the mixture was filtered. The resulting powder was purified through medium-pressure liquid chromatography (ODS, mixture of water and acetonitrile at a ratio by volume of from 95:5 to 85:15), and was dissolved in a small amount of methanol (10 ml). A mixture of acetonitrile and ethyl acetate was added thereto, and the precipitate obtained was collected by filtration to produce 300 mg (0.554 mmols) of the final product in a yield of 34%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1.Cl.O>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9]3[NH:23][C:20]4[C:21]([C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=1)=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=4
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CCc1c-2[nH]c2ccc(OC)cc12
Yield: 74 %

Procedure:
10.0 g (57 mmol) of 6-methoxy-1-tetralone in 125 ml of ethanol is added in drops within 35 minutes to a boiling solution of 10.0 g (57 mmol) of p-methoxyphenylhydrazine-hydrochloride and 5.0 ml of concentrated hydrochloric acid in 180 ml of ethanol. Then, it is refluxed for 5 hours. After 370 ml of hot water is added, it is allowed to cool. The almost colorless reaction product is suctioned off and recrystallized from ethanol. Yield 74%, melting point 189-191° C.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.C1CCN2C(=NCCC2)CC1.[Cl:24][C:25]1[C:30]2[CH:31]=[C:32]([CH2:34][CH3:35])[O:33][C:29]=2[C:28]([NH:36][C:37](OC2C=CC=CC=2)=[O:38])=[C:27]([F:46])[CH:26]=1.Cl>CN(C)C=O>[Cl:24][C:25]1[C:30]2[CH:31]=[C:32]([CH2:34][CH3:35])[O:33][C:29]=2[C:28]([N:36]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:37]2=[O:38])=[C:27]([F:46])[CH:26]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CCc1cc2c(Cl)cc(F)c(NC(=O)Oc3ccccc3)c2o1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2o1
Temperature: 60 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
80 ml of N,N-dimethylformamide was added to 5.8 g (32 mmol) of ethyl 3-amino-4,4,4-trifluorocrotonate and 6.6 g (43 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene, and 9.6 g (29 mmol) of 4-chloro-2-ethyl-6-fluoro-7-phenoxycarbonylaminobenzofuran was gradually added thereto at room temperature. After stirring at 60° C. for 8 hours, the reaction solution was poured into a 10% hydrochloric acid aqueous solution and acidified, and then extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 4.8 g (yield: 44%) of the desired product as white crystals. Melting point: 154-155° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Br:21])[CH:17]=3)[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:11]=2[CH2:10][CH2:9]1)(C)(C)C>Cl.O1CCOCC1>[Br:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[C:11]1[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:20][C:19]2=1
Reactant: CC(C)(C)OC(=O)NC1CCc2c(c3cc(Br)ccc3n2Cc2cccc(F)c2)C1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCc2c(c3cc(Br)ccc3n2Cc2cccc(F)c2)C1
Reaction time: 0.17 h
Yield: 109.7 %

Procedure:
To remove the —BOC protecting group, dissolve [6-bromo-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-carbamic acid tert-butyl ester (6.0 mg, 12.7 mmol) in 4N HCl in dioxane (100 mL). Stir for 10 min and then add more dioxane (50 mL) to aid in stirring the thick white solid. Collect the solid and wash with diethyl ether to give 5.2 g (99%) 6-bromo-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylamine as the HCl salt. MS (ES): m/z 356, 358 (M+1); HPLC: Rt=1.84 min, (96%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11]3[C:20]([C:21]4[CH:26]=[C:25](S(C)=O)[N:24]=[C:23]([CH3:30])[N:22]=4)=[N:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH3:31]>O1CCOCC1>[NH2:31][C:25]1[N:24]=[C:23]([CH3:30])[N:22]=[C:21]([C:20]2[C:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[N:2][NH:1]4)=[N:12][C:13]3[C:18]([N:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:26]=1
Reactant: Cc1nc(-c2nc3ccccc3nc2Nc2cccc3[nH]ncc23)cc(S(C)=O)n1
Reactant: N
Solvent: C1COCCO1
Product: Cc1nc(N)cc(-c2nc3ccccc3nc2Nc2cccc3[nH]ncc23)n1
Temperature: 100 °C
Yield: 31.3 %

Procedure:
A glass microwave reaction vessel was charged with N-(1H-indazol-4-yl)-3-(2-methyl-6-(methylsulfinyl)pyrimidin-4-yl)quinoxalin-2-amine (36 mg, 0.087 mmol) in dioxane (2 mL), ammonia was bubbled in for 5 minutes. The reaction mixture was stirred and heated at 100° C. for 4 h. More NH3 was bubbled in and the mixture was heated for an additional 2 h. The mixture was cooled to room temperature and concentrated in vacuo. Prep TLC purification (5% MeOH in DCM as developed reagent) gave 3-(6-amino-2-methylpyrimidin-4-yl)-N-(1H-indazol-4-yl)quinoxalin-2-amine (10 mg, 0.027 mmol, 31.3% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 13.22 (s, 2H); 8.52 (d, J=7.07 Hz, 1H); 8.31 (s, 1H); 7.95 (d, J=8.09 Hz, 1H); 7.82 (d, J=9.10 Hz, 1H); 7.72-7.80 (m, 1H); 7.64 (s, 1H); 7.55-7.62 (m, 1H); 7.34-7.46 (m, 2H); 7.26 (d, J=9.10 Hz, 1H); 2.70 (s, 3H). m/z (ESI, +ve ion) 369 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C@@H:11]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][N:12]1C(OC(C)(C)C)=O)(=[O:10])[NH2:9]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:16][C:14]1([F:17])[CH2:13][NH:12][C@H:11]([C:8]([NH2:9])=[O:10])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)[C@@H]1CC(F)(F)CN1
Reaction time: 1 h

Procedure:
9.54 mL of trifluoroacetic acid was added to a solution of (S)-tert-butyl 2-carbamoyl-4,4-difluoropyrrolidine-1-carboxylate (1.25 g, 5 mmol) in 10 mL of dichloromethane. The solution was stirred for 1 hour before evaporation. The residue was washed with ether to yield white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([CH2:10][NH2:11])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]([CH2:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][N:24]=1)[CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=1.CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([CH2:10][NH:11][S:39]([CH3:38])(=[O:41])=[O:40])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]([CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=1)[CH2:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(CN)ccc1CN(Cc1ncccc1C)Cc1ncccc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(CNS(C)(=O)=O)ccc1CN(Cc1ncccc1C)Cc1ncccc1C

Procedure:
To a solution of 5-aminomethyl-2-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-benzoic acid methyl ester (0.382 g, 0.944 mmol) and Et3N (0.191 g, 1.89 mmol) in dry THF (20 mL) was added MsCl (0.162 g, 1.42 mmol) at room temperature. After the addition the mixture was stirred at room temperature for 2 h saturated aqueous NaHCO3 (20 mL) was added. THF was then removed, and the aqueous residue was extracted with CH2Cl2 (3×20 mL). The extracts were combined and dried over MgSO4. After filtration the solvent was removed to afford 2-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-5-(methanesulfonylamino-methyl)-benzoic acid methyl ester as a pale yellow foam (0.460, 100%).
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[CH2:6]1[CH2:10]O[CH2:8][CH2:7]1>>[CH3:1][Si:2]([CH3:4])([CH3:8])[C:3]1[CH:7]=[C:6]([CH3:10])[C:8]([Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:7][C:6]=1[CH3:10]
Reactant: C1CCOC1
Reactant: C[Si](C)(C)Cl
Product: Cc1cc([Si](C)(C)C)c(C)cc1[Si](C)(C)C
Yield: 61 %

Procedure:
10.52 g of 2,5-dibromo-p-xylene (40 mmol) was reacted with 2.08 of magnesium turnings (88 mmol) in 40 ml of anhydrous THF for 4 hours with refluxing (initiated by iodine) to give the 2,5-bisbromomagnesium-p-xylene Grignard reagent. To this solution, cooled in an ice bath, was added a solution of 11.2 ml trimethylsilyl chloride (88 mmol) in 40 ml of anhydrous THF. The mixture was refluxed for 24 hours and then cooled in an ice bath. After it was quenched with saturated ammonium chloride aqueous solution, THF was evaporated and the residue was extracted with hexane (30 ml×2). The combined organic layers were washed with water, brine and then dried over anhydrous magnesium sulfate. After the solution was evaporated under a reduced pressure, the residue was recrystallized in ethanol to afford white plate crystals 6.1 g, (yield 61%). M.p. 56.0-57.5° C. MS: 250. 1H NMR (300 MHz, CDCl3, ppm) δ 0.31 (18H, s, —Si(CH3)3), 2.42 (6H, s), 7.24 (2H, s). Anal. Calcd for C14H26Si2: C, 67.12; H, 10.46. Found: C, 66.94; H, 10.23.
Reaction SMILES: C([NH:5][S:6]([CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])(=[O:8])=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O>[S:6]([CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])(=[O:7])(=[O:8])[NH2:5]
Reactant: CC(C)(C)NS(=O)(=O)CC(=O)Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)CC(=O)Nc1ccccc1
Yield: 96.4 %

Procedure:
The solution of compound 2-(N-tert-butylsulfamoyl)-N-phenylacetamide (2.5 g, 9.2 mmol.) in 40 mL of TFA was stirred at room temperature overnight. TLC analysis showed the reaction complete. Excess TFA was removed in vacuo. The value of pH was adjusted to 7-8 with NaHCO3. The mixture was extracted with EtOAc (30 mL×3). The combined organic layer was over Na2SO4, concentrated to afford compound 2-(sulfamoyl)-N-phenylacetamide (1.9 g, 96%), which was used directly without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].C1(C2CC(O)C3C(=CC=C(O)C=3)[O:34]2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15][CH:14]3[OH:34])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)C(O)CC(c2ccccc2)O3)nc1

Procedure:
6-(5-Nitropyridin-2-yloxy)-2-phenylchroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1 (b) starting from 1.5 g of 2-phenylchroman-4,6-diol. The product was passed through a silica gel column using toluene-ethyl acetate (4:1) as an eluant and then crystallised from 2-propanol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.7 Hz), 8.61 (dd, 1H, J 9.1, 2.7 Hz), 7.50-7.36 (m, 5H), 7.25 (d, 1H, J 2.7 Hz), 7.22 (d, 1H, 9.1 Hz), 7.00 (dd, 1H, J 8.7, 2.7 Hz), 6.88 (d, 1H, J 8.7 Hz), 5.65 (d, 1H, J 6.3 Hz), 5.30 (dd, 1H, J 11.9, 1.3 Hz), 4.99 (m, 1H), 2.33 (m, 1H), 1.98 (m, 1H).
Reaction SMILES: O=S(Cl)Cl.[I:5][C:6]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH3:18])=[CH:11][C:7]=1[C:8]([NH2:10])=O.O>CN(C=O)C>[I:5][C:6]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH3:18])=[CH:11][C:7]=1[C:8]#[N:10]
Reactant: CCCOc1ccc(I)c(C(N)=O)c1
Solvent: O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCCOc1ccc(I)c(C#N)c1
Temperature: 115 °C
Reaction time: 1 h

Procedure:
1.67 mL (22.9 mmol) SOCl2 are added to 1.40 g (4.59 mmol) 2-iodo-5-propoxy-benzamide (XXIX.1) in 40 mL DMF. The mixture is stirred at 115° C. for 1 h. After that time, water is added and the mixture is extracted with EtOAc (3×). The combined organic layers are washed with water and brine, dried over sodium sulphate and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, heptane/EtOAc 100/0→60/40).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[NH3:18]>C(O)C>[NH2:18][CH2:3][C@H:2]([OH:1])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@H]2CO2)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CN)CC1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
Tert-butyl 4-[[(2R)-oxiran-2-yl]methyl]piperazine-1-carboxylate 7b (3.55 g, 14.70 mmol) was dissolved in 40 mL of ethanol followed by the addition of 40 mL of aqueous ammonia, stirred for 12 hours. The resulting solution was heated to 50° C. and stirred for another 1 hour, then concentrated under reduced pressure to obtain the crude title compound tert-butyl 4-[(2S)-3-amino-2-hydroxy-propyl]piperazine-1-carboxylate 7c (3.40 g) as a light yellow solid, which was used in the next step without further furification.
Reaction SMILES: [CH:1]([C:4]([C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=1)([CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)[C:5]#[N:6])([CH3:3])[CH3:2]>CO.[Pt]=O>[CH:1]([C:4]([C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=1)([CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])[C:5]#[N:6])([CH3:3])[CH3:2]
Reactant: COc1cc(C(C#N)(CCCNCCCOc2ccccc2[N+](=O)[O-])C(C)C)cc(OC)c1OC
Agent: O=[Pt]
Solvent: CO
Product: COc1cc(C(C#N)(CCCNCCCOc2ccccc2N)C(C)C)cc(OC)c1OC
Yield: 97.2 %

Procedure:
4.78 g of alpha-isopropyl-alpha-[3-[N-[3-(2-nitrophenoxy)propyl]amino]propyl]-3,4,5-trimethoxyphenyl-acetonitrile was hydrogenated in 100 ml of methanol over 50 mg of platinum oxide at atmospheric pressure and room temperature. The catalyst was filtered off and filtrate was evaporated to give 4.36 g of desired compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].Br[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([F:9])[C:7]=1[O:8][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cc(F)c(OCc2ccc3ccccc3c2)c(F)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
Ethyl 3,5-difluoro-4-hydroxybenzenepropanoate (200 mg, 0.87 mmol) was dissolved in DMF (10 mL). 2-(Bromomethyl)naphthalene (212 mg, 0.96 mmol) and potassium carbonate (132 mg, 0.96 mmol) were added thereto, and then the mixture was stirred at 80° C. for 4 hours. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 80:20) to give the title compound (298 mg, yield 93%).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:5][CH2:4]1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CO.[Ni]>[ClH:1].[CH3:14][O:13][C:11]([CH2:10][CH2:9][C@H:6]1[CH2:5][CH2:4][C@H:3]([NH:2][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)=[O:12]
Reactant: COC(=O)CC[C@H]1CC[C@H](N)CC1
Reactant: O=Cc1ccccc1
Agent: [Ni]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CC[C@H]1CC[C@H](NCc2ccccc2)CC1

Procedure:
8.0 g of methyl 3-(trans-4-aminocyclohexyl)propionatehydrochloride, 4.3 g of benzaldehyde and 5.0 ml of triethylamine in 150 ml of methanol are hydrogenated with 1.0 g of Raney nickel at 50° C. under a hydrogen pressure of 50 psi for 4 hours. After cooling, the mixture is suction filtered and the filtrate is evaporated down. The residue is divided between ethyl acetate and water, the aqueous phase is adjusted to pH 8-9 with sodium hydroxide solution and extracted with ethyl acetate. The combined ethyl acetate phases are washed with saturated saline solution, dried and evaporated down. The residue is suspended in diethylether and mixed with methanolic hydrochloric acid. The precipitate is suction filtered, washed with diethylether and dried.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.[C:28]1(=[O:34])[O:33][C:31](=[O:32])[CH2:30][CH2:29]1>C(Cl)Cl>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:15][CH2:16][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([C:28](=[O:34])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:20]3)[CH2:18][CH2:19]1)=[O:13])[CH2:8]2
Reactant: O=C1CCC(=O)O1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNc1ccccc12
Solvent: ClCCl
Product: O=C(O)CCC(=O)N1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
To a solution of N-(2-adamantyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide (20 mg, 0.06 mmol) and succinic anhydride (12 mg, 0.12 mmol) in CH2Cl2 (5 mL) was added TEA. After stirred for 2 h at rt the solvent was removed to give 4-(1′-(2-adamantylcarbamoyl)spiro[indoline-3,4′-piperidine]-1-yl)-4-oxobutanoic acid (20 mg, 74%). LC-MS Method 5 tR=3.6 min, m/z=953.1; 1H NMR (CD3OD) δ=1.69 (d, 2H), 1.75 (d, 2H), 1.80-1.99 (m, 11H), 2.00-2.10 (m, 5H), 2.20 (s, 2H), 2.60-2.70 (m, 2H), 2.80-2.90 (m, 2H), 3.06-3.18 (m, 2H), 3.93 (s, 1H), 4.10-4.19 (m, 2H), 4.20 (s, 2H), 5.90 (d, 1H), 7.10 (m, 1H), 7.19-7.28 (m, 2H), 8.16 (d, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[CH:10][C:9]([B:12]3[O:16]C(C)(C)C(C)(C)[O:13]3)=[CH:8][C:7]=2[CH3:21])[CH2:3][CH2:2]1.I([O-])(=O)(=O)=O.[Na+].C([O-])(=O)C.[NH4+].Cl>CC(C)=O.O>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[CH:10][C:9]([B:12]([OH:16])[OH:13])=[CH:8][C:7]=2[CH3:21])=[O:22])[CH2:2][CH2:3]1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C(=O)NC1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(B(O)O)ccc1C(=O)NC1CC1
Reaction time: 3 h
Yield: 0.1 %

Procedure:
To a solution of N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (20.2 g, 67.13 mol) in acetone (300 mL) at rt was added sodium periodate (43.1 g, 201.40 mot) and ammonium acetate (134.26 mol, 134 mL 1M aqueous solution) and the mixture was stirred for 3 h. More water was added (120 mL), and the mixture was stirred at 40° C. for 2 h more. After addition of 4 N HCl (32 mL), the organic phase was removed in vaccuo and the reminder was extracted with ethyl actate. The organic phase was washed with saturated sodium chloride solution, filtered through a Whatman filter and evaporated. The residue was redissolved in toluene and evaporated (two times) to yield 14.59 g (94.3%) [4-(cyclopropylcarbamoyl)-3-methylphenyl]boronic acid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccccc3)c12
Reactant: c1cn[nH]c1
Product: Cc1csc2nc(-n3cccn3)nc(NCc3ccccc3)c12

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.