Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[O:21]1[C:25]2([CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][NH2:33])[CH2:27][CH2:26]2)[O:24][CH2:23][CH2:22]1>>[O:21]1[C:25]2([CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][NH:33][C:2]3[N:3]=[C:4]([NH2:20])[C:5]4[N:6]=[CH:7][N:8]([C:18]=4[N:19]=3)[C@@H:9]3[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]3[OH:11])[CH2:27][CH2:26]2)[O:24][CH2:23][CH2:22]1
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NCCC1CCC2(CC1)OCCO2
Product: Nc1nc(NCCC2CCC3(CC2)OCCO3)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 4 h

Procedure:
A mixture of 2-chloroadenosine (0.3 g) and 1,4-dioxaspiro[4.5]decane-8-ethanamine (1.0 g) is heated under nitrogen at 140° for 6 hours. It is evaporated to dryness at reduced pressure, the residue is dissolved in ethanol, the solution is treated with propylene oxide (2 ml) and stirred 4 hours. The precipitate is collected, washed with ethanol and dried in vacuo to give 2-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethylamino]adenosine, [alpha]D25 =-27.3° (MeOH), m.p. 133°-137°.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.Br[C:17]1[C:18]([NH2:24])=[N:19][CH:20]=[C:21]([Br:23])[N:22]=1.CCN(CC)CC>CS(C)=O>[NH2:24][C:18]1[C:17]([NH:1][CH2:2][C@H:3]2[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2)=[N:22][C:21]([Br:23])=[CH:20][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CN)C1
Reactant: Nc1ncc(Br)nc1Br
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCO[C@H](CNc2nc(Br)cnc2N)C1
Temperature: 150 °C
Reaction time: 9 h
Yield: 69.9 %

Procedure:
(R)-tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (26 g, 124.83 mmol) was dissolved in DMSO (300 ml), and 3,5-dibromopyrazine-2-amine (37.8 g, 149.79 mmol) and Et3N (20.9 ml, 149.79 mmol) were added, followed by stirring at 150° C. for 9 hours. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:1), to give (R)-tert-butyl 2-(((3-amino-6-bromopyrazine-2-yl)amino)methyl)morpholine-4-carboxylate (33.9 g, 70%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH:32]2[CH2:36][C:35]3[CH:37]=[C:38]([C:41]4[O:45][C:44]([Si](C(C)C)(C(C)C)C(C)C)=[N:43][CH:42]=4)[CH:39]=[CH:40][C:34]=3[O:33]2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH:32]2[CH2:36][C:35]3[CH:37]=[C:38]([C:41]4[O:45][CH:44]=[N:43][CH:42]=4)[CH:39]=[CH:40][C:34]=3[O:33]2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)[Si](c1ncc(-c2ccc3c(c2)CC(C2CCN(C(=O)OC(C)(C)C)CC2)O3)o1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4cnco4)ccc3O2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Tetrabutylammonium fluoride solution (1 M in tetrahydrofuran; 1.00 mL) is added to an ice cooled solution of 4-[5-(2-triisopropylsilanyl-oxazol-5-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (190 mg) in tetrahydrofuran (5 mL) and the resulting mixture is stirred for 1 h. The ice bath is removed and the reaction mixture is stirred for an additional hour at room temperature. Ethyl acetate and water are added; the organic phase is separated, dried over MgSO4, and concentrated in vacuo. The residue is recrystallised from diisopropylether. LC (method 6): tR=1.32 min; Mass spectrum (ESI+): m/z=371 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][N:19]=[N+]=[N-])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1>[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: [N-]=[N+]=NCC1Cc2cccc(-c3c(F)cccc3F)c2O1
Agent: [Pd]
Product: NCC1Cc2cccc(-c3c(F)cccc3F)c2O1
Yield: 90 %

Procedure:
Treatment of (±)-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (3.5 g, 13.35 mmol) with p-toluenesulfonyl chloride (3.05 g, 16.01 mol) generally according to the procedure described for Intermediate 10 gave 3.5 g (64%) of (±)-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of (±)-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (3.0 g, 7.20 mmol) with sodium azide (1.87 g, 28.8 mmol) generally according to the procedure described for Intermediate 98 gave (±)-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide. Treatment of the azide with palladium on carbon (0.20 g, 10 wt. %) generally according to the procedure described for Example 1 provided 1.69 g (90%) of (±)-1-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 219-222° C.; Anal. calcd. for C15H13F2NOHCl: C, 60.51; H, 4.74; N, 4.7. Found: C, 60.34; H, 4.87; N, 4.58.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[Br:17]N1C(=O)CCC1=O>C(#N)C>[Br:17][C:10]1[N:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nccn1CCCCOC
Solvent: CC#N
Product: CCOC(=O)c1nc(Br)cn1CCCCOC
Temperature: 60 °C
Reaction time: 14 h
Yield: 23.5 %

Procedure:
Ethyl 1-(4-methoxybutyl)-1H-imidazole-2-carboxylate (2.18 g) was dissolved in acetonitrile (30 ml), N-bromosuccinimide (1.71 g) was added and the mixture was stirred at 60° C. for 14 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-70:30) was concentrated under reduced pressure to give the object product (689 mg).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1.[CH3:19][C:20]([NH2:27])([C:22]1[N:26]=[CH:25][O:24][N:23]=1)[CH3:21]>>[CH3:19][C:20]([NH:27][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]([F:18])([F:17])[F:16])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:22]1[N:26]=[CH:25][O:24][N:23]=1)[CH3:21]
Reactant: CC(C)(N)c1ncon1
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CC2)n1
Product: CC(C)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1)c1ncon1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113 d) and 1-methyl-1-[1,2,4]oxadiazol-3-yl ethylamine (CAN 1153757-41-5) as starting materials, MS (EI): m/e=371.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH:28](=[O:30])[CH3:29].P([O-])(O)(O)=O.[K+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([CH:28]([OH:30])[CH3:29])=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccccc2)on1
Reactant: CC=O
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)c1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.8 g) was dissolved in tetrahydrofuran (16 ml), and butyllithium (1.6M hexane solution, 3.7 ml) was added dropwise thereto at -70° C. under a nitrogen atmosphere, and the mixture was stirred for 10 minutes. After acetaldehyde (0.22 ml) was added dropwise to the reaction mixture, the resulting mixture was stirred for 10 minutes and the temperature of the mixture was raised to 0° C. The mixture was then poured into ice-cold water and the pH of the mixture was adjusted to a value of 6 with an aqueous potassium dihydrogenphosphate solution. After the reaction mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous NaCl solution, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=2/1) to obtain the title compound (0.90 g, 98%) as a colorless oil.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:26])=[C:8](C(O)=O)[NH:9][C:10]=1[CH:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=2)[NH:14][C:13]1=[O:22])([OH:3])=[O:2].[OH-].[K+].O.Cl>C(O)CO>[CH3:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:22])[C:12]2=[CH:11][C:10]1[NH:9][CH:8]=[C:7]([CH3:26])[C:6]=1[CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: Cc1ccc2c(c1)C(=Cc1[nH]c(C(=O)O)c(C)c1CCC(=O)O)C(=O)N2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cc1ccc2c(c1)C(=Cc1[nH]cc(C)c1CCC(=O)O)C(=O)N2
Temperature: 90 °C
Reaction time: 2 h
Yield: 29.5 %

Procedure:
4-(2-carboxyethyl)-3-methyl-5-(5-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid (496 mg) suspended in ethylene glycol (2 mL) was held in a sealed tube in a pre-heated oil bath at 200° C. for 2 hours. The reaction mixture was cooled to 90° C. and potassium hydroxide (157 mg) was added. It was then stirred at 90° C. for 30 minutes. The reaction mixture was cooled, poured into water, and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 128 mg (29%) of 3-[2-(5-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrol-3-yl]-propionic acid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH:15]([CH3:18])[CH2:16]I)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH:15]([CH3:18])[CH2:16][N:24]2[CH2:25][CH2:26][CH2:27][CH:22]([CH2:21][O:20][CH3:19])[CH2:23]2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CI)Cc1cccc(Oc2ccccc2)c1
Reactant: COCc1cccnc1
Product: COCC1CCCN(CC(C)Cc2cccc(Oc3ccccc3)c2)C1
Temperature: 25 °C
Yield: 19.9 %

Procedure:
3-(m-Phenoxyphenyl)-2-methylpropyl iodide (1.0 g) was added to 3-methoxymethylpyridine (1.75 g) at room temperature, and the resultant mixture was stirred at 120° C. for 4 hours, cooled to room temperature and washed with diethyl ether three times. The resultant mixture was admixed with methanol (20 ml) and then with acetic acid (2 ml). To the resulting mixture, 5% palladium-carbon (0.5 g) was added at room temperature under nitrogen stream, and then hydrogenation was carried out under nitrogen stream. After absorption of hydrogen was completed, the catalyst was removed by filtration, and the filtrate was combined with 15% aqueous sodium hydroxide solution (50 ml) and extracted with diethyl ether. The ether layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give N-[3-(m-phenoxyphenyl)-2-methylpropyl]-3-methoxymethylpiperidine (0.2 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([Br:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[O:13][CH3:14].[S:15]1[C:19]([CH:20]=O)=[CH:18][C:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]1=2>>[S:15]1[C:19]([CH2:20][C:2]2[CH:11]=[C:10]([Br:12])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]=2[O:13][CH3:14])=[CH:18][C:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]1=2
Reactant: O=Cc1cc2ccccc2s1
Reactant: COc1c(Br)cc(Br)c2ccccc12
Product: COc1c(Cc2cc3ccccc3s2)cc(Br)c2ccccc12

Procedure:
2,4-Dibromo-1-methoxynaphthalene (see J. Clayden, et al. Org. Lett., 5, (2003) 831) and benzo[b]thiophene-2-carboxaldehyde were treated in a manner similar to Reference Example 1 to give the target compound.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:13]=[C:14]([C:25](O)=[O:26])[C:15]3[C:16]([CH3:24])=[CH:17][N:18]([CH:21]([CH3:23])[CH3:22])[C:19]=3[CH:20]=2)[CH:8]=[CH:9][C:10]=1[F:11])[CH3:3].Cl.[NH2:29][CH2:30][C:31]1[C:32](=[O:39])[NH:33][C:34]([CH3:38])=[CH:35][C:36]=1[CH3:37].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:13]=[C:14]([C:25]([NH:29][CH2:30][C:31]3[C:32](=[O:39])[NH:33][C:34]([CH3:38])=[CH:35][C:36]=3[CH3:37])=[O:26])[C:15]3[C:16]([CH3:24])=[CH:17][N:18]([CH:21]([CH3:22])[CH3:23])[C:19]=3[CH:20]=2)[CH:8]=[CH:9][C:10]=1[F:11])[CH3:3]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1cn(C(C)C)c2cc(-c3ccc(F)c(CN(C)C)c3)cc(C(=O)O)c12
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(F)c(CN(C)C)c3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
To a stirred suspension of 6-{3-[(dimethylamino)methyl]-4-fluorophenyl}-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylic acid (210 mg, 0.570 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone HCl salt (140 mg, 0.742 mmol) and HOAt (100 mg, 0.735 mmol) in DMF (15 mL) was added N-methylmorpholine (82 μl, 0.746 mmol) and EDC free base (110 mg, 0.709 mmol). The reaction was stirred for 4 h at RT and concentrated to near dryness under vacuum. Water was added till the product ppt. out. The suspension was triturated, filtered, rinsed with cold water then dried under vacuum to give the product 6-{3-[(dimethylamino)methyl]-4-fluorophenyl}-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxamide (186 mg, 0.370 mmol, 64.9% yield) as a light tan solid. 1H NMR (400 MHz, DMSO-d6) δ=11.47 (br. s., 1H), 8.15 (t, J=4.9 Hz, 1H), 8.04 (d, J=5.3 Hz, 1H), 7.90-7.86 (m, 1H), 7.39 (t, J=9.2 Hz, 1H), 7.35 (s, 1H), 7.27 (d, J=1.3 Hz, 1H), 5.87 (s, 1H), 4.88 (dt, J=6.6, 13.3 Hz, 1H), 4.36 (d, J=5.1 Hz, 2H), 4.26 (br. s., 2H), 2.69 (s, 6H), 2.24 (s, 3H), 2.17 (s, 3H), 2.11 (s, 3H), 1.44 (d, J=6.6 Hz, 6H). MS(ES)+ m/e 503.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][CH:44]([NH2:46])[CH3:45]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([NH:46][CH:44]([CH3:45])[CH3:43])=[O:22])([CH2:14][CH2:13]1)[CH2:18][CH2:19]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: CC(C)N
Product: CC(C)NC(=O)C12CCC(N(CC(=O)N3C[C@@H](F)C[C@H]3C#N)C(=O)OCc3ccccc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 1-methylethylamine (10.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-1-methylethylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (33.6 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:18]([NH:20][CH:21]1[CH2:23][CH2:22]1)=[O:19])[C:8]2=[O:28].[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH:21]1([NH:20][C:18](=[O:19])[C:17]2[CH:24]=[CH:25][C:26]([CH3:27])=[C:15]([N:9]3[C:8](=[O:28])[C:7]4[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH2:3][CH2:2][NH:1][S:30]([CH3:29])(=[O:32])=[O:31])[CH:6]=4)[N:11]=[CH:10]3)[CH:16]=2)[CH2:22][CH2:23]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OCCN)cc2c1=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OCCNS(C)(=O)=O)cc2c1=O

Procedure:
3-[6-(2-Aminoethoxy)-4-oxoquinazolin-3(4H)-yl]-N-cyclopropyl-4-methylbenzamide (0.1 g), methanesulfonyl chloride (0.027 ml), and triethylamine (0.074 ml) were stirred in methylene chloride (2 ml) under an atmosphere of argon for 2 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water (2×), brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting with 10% methanol/ethyl acetate gave the title compound (0.106 g) as a white solid; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 2.15 (s, 3H), 2.85 (m, 1H), 2.96 (s, 3H), 3.41 (m, 2H), 4.19 (t, 2H), 7.30 (t, 1H), 7.54 (m, 2H), 7.60 (s, 1H), 7.75 (d, 1H), 7.84 (s, 1H), 7.91 (d, 1H), 8.20 (s, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 457.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH2:13]Cl.[CH:15]([NH2:17])=[O:16]>O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH2:13][NH:17][CH:15]=[O:16]
Reactant: ClCc1c(Cl)ccc2cc(Cl)cnc12
Reactant: NC=O
Solvent: O
Product: O=CNCc1c(Cl)ccc2cc(Cl)cnc12

Procedure:
24.6 parts of 3,7-dichloro-8-chloromethylquinoline (Example 1) in 300 parts of formamide were refluxed for 5 hours. Water was added and the solid was filtered off with suction and recrystallized from methanol. 23 parts of 3,7-dichloro-8-formylaminomethylquinoline of melting point 110° C. were obtained. The yield corresponds to 94% of theory.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[CH:8]=2)[C:3]=1/[CH:19]=[CH:20]/[C:21]([NH:23][CH3:24])=[O:22]>CCCCCC.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[CH:8]=2)[C:3]=1[CH2:19][CH2:20][C:21]([NH:23][CH3:24])=[O:22]
Reactant: CNC(=O)/C=C/c1c(O)ccc2cc(-c3cccc(O)c3)ccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CNC(=O)CCc1c(O)ccc2cc(-c3cccc(O)c3)ccc12

Procedure:
(E)-3-(2-Hydroxy-6-(3-hydroxyphenyl)naphthalene-1-yl)-N-methylacrylamide is stirred over night with Pd(OH)2 in ethanol/THF 2/1 (1.5 ml) under a hydrogen atmosphere at RT. The reaction mixture is filtered, and the solvent is removed in vacuum on a rotary evaporator. The desired product was obtained in quantitative yield.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH:27]=[CH2:28])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].S(C)C.[OH-:32].[Na+].OO>C1COCC1.C(OCC)C>[Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH2:27][CH2:28][OH:32])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:17])([CH3:18])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCOCC
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C)COC1(C)C
Reaction time: 5 h
Yield: 72 %

Procedure:
A solution of (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (26 g, 63 mmol) in THF (200 mL) was cooled in an ice-bath, followed by dropwise addition of 10 M BH3.SMe2 (6.3 mL). After stirring for 5 hr, 10% NaOH solution (32 mL) followed by 30% H2O2 (32 mL) were added carefully. The reaction mixture was stirred at rt for 16 hr. The reaction mixture was diluted with diethyl ether (500 mL) and the aqueous layer was extracted with diethyl ether (3×250 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by column chromatography to afford (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxypentyl)-2,2-dimethyloxazolidine-3-carboxylate (19.6 g, 72%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]([F:25])([F:24])[C:11]([NH:13][C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]2[CH:23]=1)=[O:12]>C(#N)C>[Br:1][C:23]1[N:17]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]2=[N:15][C:14]=1[NH:13][C:11](=[O:12])[C:10]([F:24])([F:9])[F:25]
Reactant: O=C(Nc1cn2cc(F)ccc2n1)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: O=C(Nc1nc2ccc(F)cn2c1Br)C(F)(F)F
Temperature: 25 °C

Procedure:
N-Bromosuccinimide (2.96 g, 0.0166 mol) was added to a solution of 2,2,2-Trifluoro-N-(6-fluoro-imidazo[1,2-a]pyridin-2-yl)-acetamide (compound c, 3.74 g, 0.0151 mol) in acetonitrile (70 mL) and stirred at room temperature. The reaction mixture was stirred at room temperature for 15 minutes. Reaction mixture was concentrated under reduced pressure, crude product taken up in ethyl acetate, washed with water, organic layer collected, dried over Na2SO4, concentrated in vacuo and crude product purified by column chromatography (50% ethyl acetate/hexanes) to give product as an off white solid. Rf 0.47, 50% ethyl acetate/hexanes; MS m/z 327 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][NH:24][C:17]=23)[C:12]([CH3:25])=[CH:11][N:10]=1.[N:26]([CH:29]([CH3:31])[CH3:30])=[C:27]=[O:28]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][N:24]([C:27]([NH:26][CH:29]([CH3:31])[CH3:30])=[O:28])[C:17]=23)[C:12]([CH3:25])=[CH:11][N:10]=1
Reactant: Cc1cnc(-c2cc(F)ccc2F)cc1Nc1ccnc2cn[nH]c12
Reactant: CC(C)N=C=O
Solvent: CC#N
Product: Cc1cnc(-c2cc(F)ccc2F)cc1Nc1ccnc2cnn(C(=O)NC(C)C)c12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
N-(2-(2,5-Difluorophenyl)-5-methylpyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (100 mg, 0.296 mmol) was suspended in acetonitrile (3 mL). 2-Isocyanatopropane (29.1 μl, 0.296 mmol) was added and the reaction was stirred at 70° C. for 2 hours. The mixture was then cooled to give a solid which was collected by filtration to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (6H, d, J=6.57 Hz) 2.38 (3H, s) 4.05-4.19 (1H, m) 7.26-7.45 (3H, m) 7.76 (1H, ddd, J=9.41, 6.13, 3.16 Hz) 7.93 (1H, s) 8.35-8.44 (1H, m) 8.54 (1H, s) 8.60 (1H, s) 8.82 (1H, d, J=8.34 Hz) 11.01 (1H, s). MS [M+H] found 423.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:28][CH2:29][C:30](Cl)=[O:31]>>[Cl:28][CH2:29][C:30]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:31]
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: O=C(Cl)CCl
Product: C[C@H](NC(=O)CCl)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and chloroacetyl chloride (17 mg, 150 μmol). Yield 22 mg (73%).