Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:29]=[CH:28][C:21]([CH2:22][C@@H:23]([C:25]([OH:27])=[O:26])[NH2:24])=[CH:20][CH:19]=1>>[C:25]([C@@H:23]([NH:24][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:22][C:21]1[CH:28]=[CH:29][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)([OH:27])=[O:26]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: COc1ccc(C[C@H](N)C(=O)O)cc1
Product: COc1ccc(C[C@H](Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)cc1
Yield: 60 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 4-methoxy-L-phenylalanine to provide the title compound in 60% yield as yellow needles (recrystallization from EtOH).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])[CH2:6][CH2:7][C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[N:12]([CH2:20][C:21]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]=[C:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:22]=2)[CH:11]=1)=[O:9].Cl>O1CCCC1.CO.O>[Cl:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]=[C:23]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:22]=1)[CH:11]=[C:10]2[C:8](=[O:9])[CH2:7][CH2:6][C:5]([OH:39])=[O:4]
Reactant: COC(=O)CCC(=O)c1cn(Cc2cc(-c3ccccc3)nc(-c3ccccc3)c2)c2ccc(Cl)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CCC(=O)c1cn(Cc2cc(-c3ccccc3)nc(-c3ccccc3)c2)c2ccc(Cl)cc12
Temperature: 25 °C
Yield: 97 %

Procedure:
2N Sodium hydroxide solution (1.45 mL, 2.9 mmol) was added dropwise to a stirred solution of methyl-4-[5-chloro-1-(2,6-diphenyl-pyridin-4-ylmethyl)-1H-indol-3-yl]-4-oxobutyrate (254 mg, 0.5 mmol) in tetrahydrofuran (10 mL) and methanol (2 mL). The clear reaction mixture was stirred at room temperature until the reaction was complete (TLC control), and then diluted with water (10 mL), and acidified to pH 3 with 2N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (2×20 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 5-10% methanol in methylene chloride as eluent, afforded the title compound as a white solid (240 mg, 98%): Rf: 0.45 (10% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 12.09 (1H, s, COOH), 8.80 (1H, s, ArH), 8.15 (1H, d, J=2 Hz, ArH), 8.09 (4H, m, ArH), 7.83 (2H, s, ArH), 7.69 (1H, d, J=8 Hz, ArH), 7.46 (6H, m, ArH), 7.24 (1H, dd, J=8, 2 Hz, ArH), 5.66 (2H, s, CH2N), 3.17 (2H, t, J=7 Hz, CH2CO), 2.59 (2H, t, J=7 Hz, CH2CO); ESI-LCMS e/z calculated for C30H23ClN2O3 494.976, found 495 [M+H (35Cl)]+, 497 [M+H (37Cl)]+, 517 [M+Na (35Cl)]+, 519 [M+Na (37Cl)]+.
Reaction SMILES: [CH3:1][N:2]1[C:11]([CH2:12][C:13](O)=[O:14])=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][C:6]([CH3:23])=[C:7]([CH3:22])[CH:8]=2)[C:3]1=[O:24].[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([NH:32][C:13](=[O:14])[CH2:12][C:11]1[N:2]([CH3:1])[C:3](=[O:24])[C:4]2[C:9]([C:10]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:8][C:7]([CH3:22])=[C:6]([CH3:23])[CH:5]=2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc2c(-c3ccccc3)c(CC(=O)O)n(C)c(=O)c2cc1C
Product: Cc1cc2c(-c3ccccc3)c(CC(=O)NCc3ccccc3)n(C)c(=O)c2cc1C

Procedure:
1,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolineacetic acid (Reference Example 56) and benzylamine were reacted (amidation) and treated in substantially the same manner as in Example 101 to yield the title compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9]3[C:15](=O)[N:14]([CH3:17])[C:13]4[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=4[O:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[N:8][C:9]3[C:10]=2[O:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[N:14]([CH3:17])[C:15]=3[N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)[CH:7]=1
Reactant: CN1C(=O)c2[nH]c3cc(Cl)ccc3c2Oc2ccccc21
Reactant: CN1CCNCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CN1CCN(C2=C3N=c4cc(Cl)ccc4=C3Oc3ccccc3N2C)CC1

Procedure:
In the same way as described in example 1, 3-chloro-7-methyl-7H-indolo[3,2-b][1,5]benzoxazepine-6(5H)-one, phosphorous pentachloride and N-methyl piperazine were reacted. The solid product was recrystallized from ethanol for analysis, mp. 187°-8°.
Reaction SMILES: CO.[O:3]=[CH:4][CH:5]=[C:6]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7]1.[BH4-].[Na+]>C(O)(=O)C>[OH:3][CH2:4][CH:5]=[C:6]1[CH2:7][CH2:8][CH:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH2:11]1
Reactant: COC(=O)C1CCC(=CC=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C1CCC(=CCO)CC1
Temperature: 3 °C
Yield: 68.7 %

Procedure:
A solution was prepared from 77 ml of methanol and 13.0 g of methyl 4-(oxoethylidene)cyclohexanecarboxylate and cooled to 3° C. with an ice-water bath. With vigorous stirring, 3.1 g of sodium borohydride was added in portions over 30 minutes. The reaction was allowed to stir for an additional hour at 3° C. before glacial acetic acid (1 ml) was added to quench the reaction and the methanol was removed under reduced pressure. The residue was taken up in 200 ml of dichloromethane and partitioned with 400 ml of water. The organic layer was separated and washed with 200 ml of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting oil was purified on the Prep LC (30% ethyl acetate/hexane, 250 ml/min., 2 min./cm, 2 columns, Rt =13 min.) to give 11.5 g of fairly pure product. Bulb-to-bulb distillation on the Kugelrohr at 150°-160° C./0.8 mm yielded 9.03 g (69%) of methyl 4-(2-hydroxyethylidene)cyclohexanecarboxylate. 1H NMR (CDCl3 60 MHz) δ 5.40 (t, 1 H); 4.10 (d, 2 H); 3.70 (s, 3 H); 2.9-1.3 (10 H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][CH:12]([C:19]([O:21]CC)=O)[CH2:13][C:14]([O:16]CC)=O.[CH2:24]([NH2:28])[CH2:25][CH2:26][CH3:27]>>[CH2:24]([NH:28][C:14]([CH2:13][CH:12]([C:19]([NH:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:21])[CH2:11][S:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[O:16])[CH2:25][CH2:26][CH3:27]
Reactant: CCOC(=O)CC(CSc1nc2ccccc2s1)C(=O)OCC
Reactant: CCCCN
Product: CCCCNC(=O)CC(CSc1nc2ccccc2s1)C(=O)NCCCC
Temperature: 90 °C

Procedure:
18.0 parts of diethyl 3-(benzothiazol-2-ylthio)-propane-1,2-dicarboxylate and 30.0 parts of n-butylamine are stirred for 3 hours at 90° C. Volatile material are removed by heating at 90° C. under a vacuum of 0.1 mm to give N,N'-dibutyl 3-(benzothiazol-2-ylthio)-1,2-propane dicarboxylic acid diamide as a viscous liquid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH:12]([C:14]1[N:18]2[N:19]=[C:20]([C:23](=[O:25])[CH3:24])[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)C.N1C=CN2C=1C=CC=N2>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:14]1[N:18]2[N:19]=[C:20]([C:23](=[O:25])[CH3:24])[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1
Reactant: CC(=O)c1ccc2ncc(C(C)c3cc4cnn(C)c4cc3F)n2n1
Agent: c1cnn2ccnc2c1
Product: CC(=O)c1ccc2ncc(Cc3cc4cnn(C)c4cc3F)n2n1

Procedure:
The title compound was prepared as a white solid in analogy to the synthesis of compound 39.4 from 6-(1-ethoxyvinyl)-3-(6-fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine. LCMS (method B): [MH]+=324, tR=2.41 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16](=[O:25])[NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][O:15][C:16](=[O:25])[NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1COC(=O)NCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4COC(=O)NCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using benzyl-carbamic acid 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl.F[CH2:3][C:4]([C:8]1[O:12][N:11]=[C:10]([NH:13][C:14](=[O:38])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:26][N:25]=3)=[CH:18][CH:17]=2)[CH:9]=1)([CH3:7])[CH2:5]F.[O:39]1[CH2:42]C(=O)[CH2:40]1>CC(C)=O>[C:4]([C:8]1[O:12][N:11]=[C:10]([NH:13][C:14](=[O:38])[NH:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:32][CH2:33][N:34]([CH:35]5[CH2:42][O:39][CH2:40]5)[CH2:36]4)=[CH:26][N:25]=3)=[CH:20][CH:21]=2)[CH:9]=1)([CH3:3])([CH3:7])[CH3:5]
Reactant: O=C1COC1
Reactant: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Agent: Cl
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCN(C5COC5)C4)cn3)cc2)no1
Yield: 73 %

Procedure:
N-(4-(3-(5-tert-Butylisoxazol-3-yl)ureido)phenyl)-5-(1-(oxetan-3-yl)pyrrolidin-3-yloxy)picolinamide (77 mg, 73%) was prepared as a white powder using a procedure analogous to that described in Example 20, substituting N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-5-(pyrrolidin-3-yloxy)picolinamide hydrochloride from Step 2 of Example 25 for N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride, and oxetan-3-one for acetone used in Example 20. LC-MS (ESI) m/z 521 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]1[CH2:8][C@@H:7](O)[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(CC)CC)C.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[C@H:4]1[CH2:8][C@@H:7]([S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105 %

Procedure:
A solution of 20 g (71.6 mmol) of N-Cbz-cis-4-hydroxy-D-proline methyl ester, 15 mL (107 mmol) of triethylamine and 0.4 g (3.3 mmol) of 4-dimethylaminopyridine in 200 mL of CHCl3 was treated with 15.1 g (79.2 mmol) of p-toluenesulfonyl chloride in portions. The reaction was stirred at room temperature for 18 hours and was washed successively with 100 mL of H2O, 100 mL of 1N aqueous citric acid, and 100 mL of H2O. The organic fraction was dried over Na2SO4 and evaporated in vacuo to give 31.4 g of an oil which was purified by flash chromatography (SiO2 ; 50 percent EtOAc in hexanes) to afford 18.2 g (42 mmol; 59 percent) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1.S(=O)(=O)(O)O.[H][H]>CO.[Pd]>[NH2:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH2:1])=[O:18])=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: NCc1ccc(C(=O)Nc2ccccc2N)cc1
Yield: 96.2 %

Procedure:
To a solution of N-(2-aminophenyl)-4-cyanobenzamide (237 mg, 1 mmol) in methanol (40 ml) was added sulfuric acid (196 mg, 1 mmol) and 5% palladium on charcoal (0.20 g). The mixture was stirred under an atmosphere of hydrogen at room temperature until hydrogen uptake ceased. The mixture was filtered through celite, and the filtrate was neutralized with 1 N NaOH solution in methanol (2 ml). The resulting mixture was filtered, and the filtrate was evaporated under vacuum to give the title compound (232 mg, 96% yield) as a grey solid. LC-MS (m/z) 242 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:20])=[C:12]2[C:3]=1[C:4](=[O:27])[C:5]1[CH:6]=[C:7]3[C:25](=[O:26])[O:24][C:22](=[O:23])[C:8]3=[CH:9][C:10]=1[C:11]2=[O:21].[CH2:28]([OH:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].S(=O)(=O)(O)O.O>CO>[CH2:28]([O:36][C:22]([C:8]1[C:7]([C:25]([O:24][CH2:18][CH2:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:10][CH3:9])=[O:26])=[CH:6][C:5]2[C:4](=[O:27])[C:3]3[C:12](=[C:13]([OH:20])[C:14]4[C:19]([C:2]=3[OH:1])=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:11](=[O:21])[C:10]=2[CH:9]=1)=[O:23])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: O=c1oc(=O)c2cc3c(=O)c4c(O)c5ccccc5c(O)c4c(=O)c3cc12
Reactant: CCCCCCCCO
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: CCCCCCCCOC(=O)c1cc2c(cc1C(=O)OCCCCCCCC)C(=O)c1c(c(O)c3ccccc3c1O)C2=O
Reaction time: 18 h
Yield: 164.6 %

Procedure:
1.89 g (5.2 mmoles) of 6,11-dihydroxy-naphthacene-5,12-dione-2,3-dicarboxylic acid anhydride (product of example 9), 6.77 g (52 mmoles) of 1-octanol, and 0.2 g (2.08 mmoles) of 96% sulfuric acid are refluxed for 3 h with azeotropic removal of the reaction water. The mixture is kept at 25° for 18 h, then stirred with methanol and filtered. The precipitate is washed with water and dried in vacuo to give 2.58 g (81%) of red crystals, m.p. 95-96°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH3:34])[CH:9]([CH3:22])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]#[N:21])[CH:19]=1)[NH:16][CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3.C(=O)([O-])[O-].[K+].[K+].Br[CH2:68][C:69]([O:71][CH2:72][CH3:73])=[O:70]>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]([CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH3:34])[CH:9]([CH3:22])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]#[N:21])[CH:19]=1)[N:16]([CH2:68][C:69]([O:71][CH2:72][CH3:73])=[O:70])[CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc(C#N)c2c(c1)CCN2
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CN1CCc2cc(CC(C)N(CCOc3ccccc3OCC)C(=O)OC(C)(C)C)cc(C#N)c21
Yield: 34.9 %

Procedure:
To a solution of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carbonitrile (300 mg) and cis-dicyclohexano-18-crown-6 (24 mg) in dry tetrahydrofuran (4 ml) were added potassium carbonate (107 mg) and ethyl bromoacetate (129 mg), and the mixture was reacted in a sealed tube at 100° C. for 24 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of hexane and ethyl acetate (1/2) as eluent to give 124 mg of ethyl [5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]-7-cyanoindolin-1-yl]acetate as an oil.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][Si](CC)(CC)CC)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[F-].C([N+](CC)(CC)CC)C>C(#N)C>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:18][CH:17]=1)#[CH:20]
Reactant: CC[Si](C#Cc1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1)(CC)CC
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: CC#N
Product: C#Cc1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-((triethylsilyl)ethynyl)phenyl)ethyl)-1,3-oxazinan-2-one (184 mg, 0.375 mmol) in acetonitrile (5 mL) was added tetraethylammonium fluoride (112 mg, 2 equiv). The mixture was stirred for 3 h at rt and LC-MS showed the reaction was complete. The mixture was concentrated and purified by chromatography on a 12 g silica cartridge, eluted with a 70-100% EtOAc in hexanes gradient, to afford to afford (S)-3-((S)-1-(4-ethynylphenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (128 mg, 91%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH3:22][O:23]C1C=C2C(CCC2N)=CC=1>>[CH2:1]([C:3]1[C:4]([NH:11][CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:22])[CH:19]=3)[CH2:14][CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: COc1ccc2c(c1)C(N)CC2
Product: CCc1cnc(CC)c(NC2CCc3ccc(OC)cc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 6-methoxyindan-1-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.31, 1.87, 2.59, 2.67, 2.75, 2.87, 2.95, 3.79, 4.55, 5.75, 6.83, 7.19, 7.70; HRMS (FAB) calcd for C18H23N3O+H 298.1919, found 298.1909. Anal. Calcd for C18H23N3O: C, 72.70; H, 7.80; N, 14.13. Found: C, 72.19; H, 7.76; N, 13.84.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:14])(=[O:13])[CH2:5][CH2:4][CH:3]1[C:15]([O:17]C)=O.[NH2:19][C:20]1[CH:24]=[C:23]([CH3:25])[O:22][N:21]=1.C1(C)C=CC=CC=1>CCOCC>[OH:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:13])(=[O:14])[CH2:5][CH2:4][C:3]=1[C:15]([NH:19][C:20]1[CH:24]=[C:23]([CH3:25])[O:22][N:21]=1)=[O:17]
Reactant: Cc1cc(N)no1
Reactant: COC(=O)C1CCS(=O)(=O)c2ccccc2C1=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1cc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)CC2)no1
Yield: 53.8 %

Procedure:
A mixture of 17 g (0.05 mol) of crude methyl 2,3,4,5-tetrahydro-5-oxo-1-benzothiepin-4-carboxylate 1,1-dioxide, 6.0 g (0.061 mol) of 3-amino-5-methylisoxazole, and 350 ml of toluene was refluxed for 24 hours in a Soxhlet apparatus the thimble of which contained 20 g of Linde type 4A molecular sieve. The mixture was diluted with 500 ml of ether and the resulting precipitate (10 g) was collected and recrystallized from 400 ml of tetrahydrofuran to give 9.0 g of product mp 226°-228°. Recrystallization gave an analytical sample mp 227°-229°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[N:15][C:14]([NH2:17])=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH:2]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](I)[CH:20]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:17][C:14]2[N:15]=[CH:16][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ncc(-c2cccnc2)c2cccnc12
Reactant: Clc1cccc(I)c1
Product: Clc1cccc(Nc2ncc(-c3cccnc3)c3cccnc23)c1

Procedure:
The title compound, MS: m/e=333.1 (M+H+), was prepared in accordance with the general method of example 6 step 3 from 5-pyridin-3-yl-[1,7]naphthyridin-8-ylamine and 1-chloro-3-iodobenzene.
Reaction SMILES: N([O-])=O.[Na+].N[C@@H:6]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:7]([OH:9])=[O:8].[Br-:17].[K+].S(=O)(=O)(O)O>O>[Br:17][C@@H:6]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:7]([OH:9])=[O:8]
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Reactant: [Br-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=C(O)[C@@H](Br)CC1CCCCC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 53 %

Procedure:
A solution of sodium nitrite (2.26 g, 32.7 mmol) in water (6 ml) was added drop-wise at 0° C. over 4 hours to a stirred mixture of (s)-α-aminocyclohexanepropionic acid (5 g, 29.2 mmol), potassium bromide (11.40 g, 95.8 mmol) and concentrated sulphuric acid (3.3 ml) in water (35 ml). The mixture was stirred for 5 hours at 0° C. then at ambient temperature for 16 hours. The product was extracted into diethyl ether (4×50 ml) then the combined ethereal layers were washed with saturated aqueous sodium chloride solution (2×50 ml), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by chromatography over silica gel eluting with a gradient of methanol:dichloromethane 1:50→1:20. Appropriate fractions were combined and the solvents removed in vacuo to leave (S)-α-bromocyclohexanepropionic acid as a pale yellow oil (3.64 g, 53%). TLC (single spot, Rf=0.45, 10% methanol in dichloromethane), HPLC-MS (single main peak with Rt=8.85 mins, 234.1/236.1 [M+H]+).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[S:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[CH2:19]([Sn]CCCC)CCC.CI>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:19][O:9][C@@H:8]1[C@H:10]([OH:11])[C@@H:12]([CH2:13][OH:14])[O:15][C@H:7]1[N:6]1[CH:16]=[C:2]([CH3:1])[C:3](=[O:18])[NH:4][C:5]1=[S:17]
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=S)[nH]c1=O
Reactant: CCCC[Sn]CCCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CI
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(C)c(=O)[nH]c1=S
Temperature: 50 °C

Procedure:
To a stirred solution of 5-methyl-2-thiouridine (0.500 g, 1.8 mmol) in DMF (10 ml) is added dibutyltin ox-de 0.500 g, 2.0 mmol), tetrabutyl ammonium iodide (0.738 g, 2 mmol), and methyl iodide (1.022 g, 7.2 mmol). The reaction flask is sealed and heated at 50° C. for 16 hours. The mixture is cooled and another portion of methyl iodide is added (1.022 g, 7.2 mmol) and the reaction heated for an additional 16 hours. At the end of this time, the reaction mixture is cooled to room temperature and diluted with methylene chloride and chromatographed using a methylene chloride/methanol gradient. The appropriate fractions are collected and concentrated to give 2'-O-methyl-5-methyl-2-thiouridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-fluorophenol (4.52 g, 40.29 mmol), 4-fluorobenzaldehyde (5.00 g, 40.29 mmol) and potassium carbonate (6.70 g, 48.35 mmol) in DMAC (40 mL) was refluxed for 12 h and cooled to room temperature. Water was added and the reaction mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated to afford an oil which was chromatographed on silica gel (15% ethyl acetate/hexane) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH2:9]O)=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][CH2:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: OCc1cnc(Cl)cc1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: ClCc1cnc(Cl)cc1Cl

Procedure:
20.2 g. of 2,4-dichloropyridin-5-methanol (0.11 mol.) and 150 ml. of phosphorus oxychloride are refluxed for 19 hours. Then the excess phosphorus oxychloride is removed in vacuo and ice is added to the residue. 5-Chloromethyl-2,4-dichloropyridine is filtered off, washed with water, dried in the desiccator over P2O5 and recrystallized from hexane; yield 17.95 g. (83%), m.p. 55°-56°.