Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Br-:15].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[Br:15][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][C:11]=1[CH3:14])[N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][CH2:7]2
Reactant: Cc1ccc2c(c1)N(C(C)C)CCC2
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: Cc1cc2c(cc1Br)CCCN2C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.8 %

Procedure:
To a cooled solution of 7-methyl quinoline (5.00 g, 35 mmol) and nickel (II) chloride hexahydrate (1.40 g, 6 mmol) in methanol (130 mL) was added sodium borohydride (5.50 g, 140 mmol) portionwise. The reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 3 hours. Hydrochloric acid (2N, 200 mL) was added to the black residue and the mixture stirred at room temperature until disappearance of the black precipitate. The acidic solution was neutralized with concentrated ammonium hydroxide and extracted with ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, filtered and evaporated to give 5.28 g of 7-methyl-1,2,3,4-tetrahydro-quinoline (100%), used without further purification. A mixture of 7-methyl-1,2,3,4-tetrahydro-quinoline (1.20 g, 8.2 mmol), potassium carbonate (2.3 g, 16.4 mmol) and isopropyl iodide (3.3 mL, 32.8 mmol) in N,N-dimethylformamide (10 mL) was heated at 60° C. with stirring for 24 hours. The solution was cooled to room temperature and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give 1.28 g (82%) of 1-isopropyl-7-methyl-1,2,3,4-tetrahydro-quinoline. To a solution of 1-isopropyl-7-methyl-1,2,3,4-tetrahydro-quinoline (1.04 g, 5.5 mmol) in dichloromethane was added tetrabutylammonium tribromide (2.65 g, 5.5 mmol) and the solution stirred at room temperature for 5 hours. The solution was washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed and silica gel (ethyl acetate/hexane, 1:9) to give 1.00 g of 6-bromo-1-isopropyl-7-methyl-1,2,3,4-tetrahydro-quinoline (67%).
Reaction SMILES: [C:1]([C:4]1[CH:32]=[CH:31][C:7]2[NH:8][C:9](=[O:30])[C@H:10]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:11]([C@@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH3:15])[C:12](=[O:13])[C:6]=2[CH:5]=1)(=O)[CH3:2].Cl.[NH2:34][OH:35].C(N(CC)CC)C.C(Cl)Cl.CO>CCO>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C@H:10]2[C:9](=[O:30])[NH:8][C:7]3[CH:31]=[CH:32][C:4]([C:1](=[N:34][OH:35])[CH3:2])=[CH:5][C:6]=3[C:12](=[O:13])[N:11]2[C@@H:14]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[CH3:15])=[CH:24][CH:25]=1
Reactant: CC(=O)c1ccc2c(c1)C(=O)N([C@H](C)c1ccc(Cl)cc1)[C@@H](c1ccc(Cl)cc1)C(=O)N2
Reactant: NO
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=NO)c1ccc2c(c1)C(=O)N([C@H](C)c1ccc(Cl)cc1)[C@@H](c1ccc(Cl)cc1)C(=O)N2
Yield: 4.5 %

Procedure:
A solution of 7-Acetyl-3-(S)-(4-chloro-phenyl)-4-[1-(R)-(4-chloro-phenyl)-ethyl]-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (50 mg, 0.11 mmol), hydroxylamine hydrochloride salt (22 mg, 0.33 mmol), triethylamine (0.074 mL, 0.55 mmol) in EtOH (0.5 mL) was heated to 80° C. After 2 h reaction solution was applied to a prep tlc plate (Analtech Silica Gel GF, 20×20 cm, 2000 microns) and developed using methylene chloride/MeOH 10:1. Desired bands were scraped off, extracted with MeOH, filtered and concentrated to give the title compound (2.4 mg). 1H NMR (400 MHz, DMSO-d6) δ 7.82–7.83 (m, 1H), 7.47–7.51 (m, 3H), 7.32 (s, 3H), 7.26–7.30 (m, 2H), 6.80–6.84 (m, 2H), 6.66–6.70 (d, J=8.4 Hz, 2H), 6.52–6.55 (d, J=8.6 Hz, 2H), 6.36–6.42 (m, 2H), 5.17 (s, 1H), 1.67–1.71 (d, J=7.3 Hz, 3H). Mass spectrum (LCMS, ESI pos.): Calcd for C25H21Cl2N3O3: 481.1; found 482.1 (M+H).
Reaction SMILES: O[CH:2]([C:38]1[CH:39]=[N:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=1)[C:3]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH2:16][O:17]C3CCCCO3)[C:9](=[O:24])[N:8]([CH3:25])[C:7]=2[N:6]=[CH:5][C:4]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]([F:37])([F:36])[F:35])[CH:28]=1.O[Li].O>C(O)=O.[Zn]>[OH:17][CH2:16][CH2:15][CH2:14][N:10]1[C:11](=[O:13])[C:12]2[C:3]([CH2:2][C:38]3[CH:39]=[N:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=3)=[C:4]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]([F:35])([F:36])[F:37])[CH:28]=3)[CH:5]=[N:6][C:7]=2[N:8]([CH3:25])[C:9]1=[O:24]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(C(F)(F)F)nc3)c(Oc3cccc(OC(F)(F)F)c3)cnc21
Agent: [Li]O
Agent: [Zn]
Solvent: O
Solvent: O=CO
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(C(F)(F)F)nc3)c(Oc3cccc(OC(F)(F)F)c3)cnc21
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 29.2 %

Procedure:
To a solution of 5-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-6-(3-(trifluoromethoxy)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (40 mg, 0.06 mmol) in HCOOH (2 mL) was added Zn dust (19.5 mg, 0.3 mmol). The reaction was heated at 100° C. for 1 h then cooled to RT and filtered. The filtrate was concentrated and dried to a residue which was dissolved in water (1 ml) and THF (1 mL). Next LiOH.H2O (25 mg, 0.6 mmol) was added and the reaction was stirred at RT for 10 min then extracted with EA (3×5 mL). The combined organic layers were dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethoxy)phenoxy)-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (10 mg, 29.4% yield) as clear oil. 1H NMR (CDCl3) δ: 8.65 (s, 1H), 8.40 (s, 1H), 7.78 (d, J=6.8 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.36 (t, J=8.3 Hz, 1H), 7.01 (d, J=8.3 Hz, 1H), 6.81 (dd, J=8.3, 2.2 Hz, 1H), 6.75 (s, 1H), 4.82 (s, 2H), 4.23 (t, J=6.2 Hz, 2H), 3.57 (t, J=5.5 Hz, 2H), 2.93 (s, 1H), 2.00-1.87 (m, 2H). LCMS: MH+ 571 and TR=3.069 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([Si:13](Cl)([CH3:15])[CH3:14])([CH3:12])([CH3:11])[CH3:10].N1C=CN=C1>CN(C)C=O>[Si:13]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:15])[CH3:14]
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
A mixture of 1400 g (8.1 mol) of 3-bromophenol, 1218 g (8.1 mol) of tert-butylchlorodimethylsilane and 1376 g (20.2 mol) of imidazole in 1600 mL of N,N-dimethylformamide was stirred at room temperature under nitrogen for 18 hours. The reaction mixture was poured into pH 8 aqueous buffer solution and extracted with diethyl ether. The ether extracts were washed with water and brine, dried over sodium sulfate, and the solvent was evaporated under vacuum to give 2314 g of crude 3-bromophenyl tert-butyldimethylsilyl ether as an orange oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[O:43]1[CH2:48][CH2:47][CH2:46][O:45][CH:44]1[CH2:49][CH2:50][Mg]Br.Cl>O1CCCC1>[O:43]1[CH2:48][CH2:47][CH2:46][O:45][CH:44]1[CH2:49][CH2:50][CH:36]([OH:37])[CH2:35][O:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([N:18]2[C:17](=[O:42])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)[CH2:29][CH2:30]1
Reactant: Br[Mg]CCC1OCCCO1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ncnn12
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)CCC3OCCCO3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-[(trans-4-{6-[(2′-Cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (1.5 g) was dissolved in tetrahydrofuran (15 mL), 2-(1,3-dioxan-2-yl)ethylmagnesium bromide (15 mL, 0.5M tetrahydrofuran solution) was added dropwise, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was dissolved in tetrahydrofuran (5 mL) and methanol (10 mL), and sodium tetrahydroborate (0.16 g) was added at 0° C. The reaction mixture was stirred at 0° C. for 2 hr and then at room temperature for 18 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, the solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.71 g, 44%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:15])[C:9]=3[C:8]([C:16]3[NH:20][C:19]4[CH:21]=[C:22]([N+:25]([O-])=O)[CH:23]=[CH:24][C:18]=4[N:17]=3)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:28][C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>CS(C)=O>[NH2:15][C:14]1[C:9]2[C:8]([C:16]3[NH:20][C:19]4[CH:21]=[C:22]([NH:25][S:35]([C:31]5[CH:32]=[CH:33][CH:34]=[C:29]([F:28])[CH:30]=5)(=[O:37])=[O:36])[CH:23]=[CH:24][C:18]=4[N:17]=3)=[CH:7][N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: Nc1ncnc2c1c(-c1nc3ccc([N+](=O)[O-])cc3[nH]1)cn2C1CCCC1
Solvent: CS(C)=O
Product: Nc1ncnc2c1c(-c1nc3ccc(NS(=O)(=O)c4cccc(F)c4)cc3[nH]1)cn2C1CCCC1

Procedure:
The title compound was prepared by treatment of 5-(6-Amino-1H-benzoimidazol-2-yl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (1E, 20 mg in 1.0 mL NMP) with 1.2 equiv. of 3-fluoro-benzenesulfonyl chloride (14.3 mg) at 80° C. for 2.5 h. LCMS was used to confirm product formation and the resulting reaction mixture was diluted with 1.0 mL DMSO and purified via preparative HPLC to furnish the desired product (M/Z 491.2, retention time 2.3 min. with analytical HPLC method 2).
Reaction SMILES: [ClH:1].C([O:4][C:5](=O)[CH2:6][CH2:7][CH2:8][C:9]1([CH2:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]1=[O:24])C.B.CO>C1COCC1>[ClH:1].[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1([CH2:25][C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]1=[O:24]
Reactant: CCOC(=O)CCCC1(Cc2ccncc2)C(=O)N(c2ccccc2)c2ccccc21
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C1N(c2ccccc2)c2ccccc2C1(CCCCO)Cc1ccncc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of 2,3-Dihydro-2-oxo-1-phenyl-3-(4-pyridinylmethyl)-1H-indole-3-butanoic acid ethyl ester hydrochloride (10.0 g, 22.2 mmol) in 50 ml dry THF was treated with excess 1M BH3 -THF and stirred at room temperature for 3 days. The excess borane was decomposed with MeOH, and the mixture was concentrated in vacuo. The residue was digested with 100 ml 1N HCl for 3 hours at 80° C. , and the solution was concentrated. The residue was partitioned between 200 ml EtOAc and 100 ml 5% NaHCO3. The organic phase was washed with water and brine, dried over MgSO4, filtered, treated with 44 ml 1N HCl-Et2O, evaporated in vacuo. The residue was suspended in hot CH3CN and left standing overnight. The resulting crystals were collected by filtration, washed with Et2O, and dried to give the product in 30% (2.72 g) yield; mp 196°-197° C.; IR(nujol): OH @3356 cm-1 ; C=O @1709 cm -1 ; NMR(CDCl3TMS): δ1.13, 1.24 (2m, 2H, CH2 --C--CO), 2.51 (m, 2H, CH2 --CO), 2.1-3.0 (m, 2H, CH2 --C--C--CO), [3.40 (d, 1H, J=12.4 Hz), 3.54 (d, 1H, J=12.5 Hz), CH2 -Pyr], 3.48 (t, 2H, OCH2), [6.5 (m, 1H), 7.2 (m, 2H), 7.4 (m, 6H), Phe+1,2-Phe], [6.99 (d, 2H), 8.49 (d, 2H), 4-Pyr]; mass spec m/e 373(M+1); Anal calcd for C24H24N2O2HCl, MW 408.93: C, 70.49; H, 6.16; N, 6.85. Found: C, 70.44; H, 6.00; N, 6.67.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[C:16]([NH:30][CH2:31][CH2:32][CH3:33])=[N:17][C:18]([NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[N:19][CH:20]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:4].Cl.[CH3:36][N:37]([CH3:44])[CH2:38]/[CH:39]=[CH:40]/[C:41](O)=[O:42].Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C.C(OCC)(=O)C>[CH3:36][N:37]([CH3:44])[CH2:38]/[CH:39]=[CH:40]/[C:41]([NH:1][C@@H:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[C:16]([NH:30][CH2:31][CH2:32][CH3:33])=[N:17][C:18]([NH:21][CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)=[N:19][CH:20]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:4])=[O:42]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)NC(=O)/C=C/CN(C)C)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
To a solution of (S)—N-(3-(2-aminopropanamido)phenyl)-4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxamide (A6, 21 mg), 4-dimethylaminocrotonic acid hydrochloride (16 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (38 mg) in N,N-dimethylformamide (2 mL), triethylamine (40 μL) was added at room temperature, and the mixture was stirred at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then saturated aqueous sodium hydrogencarbonate and ethyl acetate were added to the mixture. The organic layer was separated, washed with water, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 95% chloroform/5% methanol) to obtain (S,E)-N-(3-(2-(4-(dimethylamino)-2-butenamido)propanamido)phenyl)-4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxamide (1-2, 11 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH:51]2[CH2:55][CH2:54][O:53][CH2:52]2)(=O)=O)=CC=1>>[CH3:39][O:38][CH2:37][CH2:36][CH2:35][N:31]1[C:30]2[CH:40]=[C:26]([CH2:25][O:24][CH:9]3[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH:51]5[CH2:55][CH2:54][O:53][CH2:52]5)=[CH:3][CH:4]=4)[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[O:15])[CH2:10]3)[CH:27]=[CH:28][C:29]=2[O:34][CH2:33][CH2:32]1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21
Reactant: Cc1ccc(S(=O)(=O)OC2CCOC2)cc1
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC4CCOC4)cc3)cc21

Procedure:
Analogously to Method D, 0.065 g of benzyl 4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate and 0.0288 g of tetrahydrofuran-3-yl toluene-4-sulphonate are reacted. The title compound is obtained as an orange oil. Rf=0.22 (2:1 EtOAc-heptane). Rt=5.25.
Reaction SMILES: S([O-])([O-])(=O)=O.[NH2:6][CH2:7][CH2:8][NH:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11].[OH-].[Na+].[CH:20]1([CH2:24][O:25][CH2:26][CH2:27][O:28][C:29]2[CH:39]=[CH:38][C:32]([O:33][CH:34]3[O:37][CH:35]3[CH3:36])=[CH:31][CH:30]=2)[CH2:23][CH2:22][CH2:21]1>C(O)C>[OH:37][CH:35]([CH2:34][O:33][C:32]1[CH:38]=[CH:39][C:29]([O:28][CH2:27][CH2:26][O:25][CH2:24][CH:20]2[CH2:23][CH2:22][CH2:21]2)=[CH:30][CH:31]=1)[CH2:36][NH:6][CH2:7][CH2:8][NH:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11]
Reactant: NCCNC(=O)N1CCOCC1
Reactant: CC1OC1Oc1ccc(OCCOCC2CCC2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NCCNCC(O)COc1ccc(OCCOCC2CCC2)cc1)N1CCOCC1

Procedure:
12.0 g of the neutral sulphate of N-2-aminoethyl-4-morpholinecarboxamide and 2.16 g NaOH was refluxed in 100 ml of ethanol for 1 h. Thereafter 10 g of 3-(4-(2-cyclobutylmethoxyethoxy)phenoxy-1,2-epoxypropane in 50 ml of ethanol was added and the mixture refluxed for 20 h, filtered, and evaporated. The residue was dissolved in 175 ml of ethyl acetate and washed twice with water. Thereafter the title compound crystallized from the ethyl acetate phase. The crystals were filtered off and washed with ether. Yield 7.1 g. Melting point 91°-93° C. (base). The structure was determined using NMR-analysis.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:12])[CH3:11])=[CH:2]1.[N:13]([CH2:16][CH2:17][CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([CH3:28])=[CH:25][CH:26]=2)[C:21](=[O:29])[C:20]1=[O:30])=[N+:14]=[N-:15].CNC>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:12])[CH2:11][C:21]2([OH:29])[C:22]3[C:27](=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)[N:19]([CH2:18][CH2:17][CH2:16][N:13]=[N+:14]=[N-:15])[C:20]2=[O:30])=[CH:2]1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2CCCN=[N+]=[N-]
Reactant: CC(=O)c1c[nH]c2ccccc12
Agent: CNC
Solvent: CO
Product: Cc1ccc2c(c1)C(O)(CC(=O)c1c[nH]c3ccccc13)C(=O)N2CCCN=[N+]=[N-]
Temperature: 130 °C

Procedure:
To a clean Biotage microwave vial was added 1-(1H-indol-3-yl)ethanone (0.023 grams, 0.143 mmol, purchased from Fisher Scientific), 1-(3-azidopropyl)-5-methylindoline-2,3-dione (0.02 grams, 0.082 mmol) and 0.27 mL of methanol. After the addition of 9.0 μL of dimethyl amine (40% by weight solution in water, purchased from Fisher Scientific), the vial was sealed and heated in a Biotage Initiator for ten minutes at 130° C. It was then concentrated and purified using a Teledyne ISCO hexanes/ethyl acetate gradient on silica gel. A subsequent purification was done using a preparative thin layer chromatography (ethyl acetate, hexanes (2:1)). Yield 14%. 1H-NMR δ 8.87 (bs, 1H), 8.34 (m, 1H), 7.76 (s, 1H), 7.40 (m, 1H), 7.29 (m, 3H), 7.10 (d, 1H), 6.77 (d, 1H), 5.0 (bs, OH), 3.77 (m, 2H), 3.60 (d, 1H), 3.41 (t, 2H), 3.34 (d, 1H), 2.27 (s, 3H), 1.96 (m, 2H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:13]1[C:17]([NH2:18])=[N:16][N:15]=[N:14]1)[CH2:11][CH3:12]>C(Cl)Cl.CO.CCN(CC)CC>[CH2:10]([N:13]1[C:17]([NH:18][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:16][N:15]=[N:14]1)[CH2:11][CH3:12]
Reactant: O=C(O)c1ccccc1
Reactant: CCCn1nnnc1N
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CCCn1nnnc1NC(=O)c1ccccc1
Yield: 54 %

Procedure:
Employing 0.25 g (2.1 mmol) of benzoic acid and 0.26 g (2.1 mmol) of 1-propyl-1H-tetrazol-5-amine in the procedure described above for Compound F2 and elution with CH2Cl2/MeOH/Et3N (9.8:0.1:0.1) gave the product in 54% yield.
Reaction SMILES: FC1C=CC([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=CC=1.[OH-].[Na+]>C(O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:15]2[CH:14]=[CH:13][C:12]([S:9]([OH:11])(=[O:8])=[O:10])=[CH:17][CH:16]=2)=[CH:20][CH:21]=1
Reactant: O=S(=O)(Oc1ccc(F)cc1)c1ccc(Oc2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=S(=O)(O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.7 %

Procedure:
To a slurry of 47.43 g (0.131 mol) of 4-(4-fluorophenoxy)benzenesulfonic acid 4-fluorophenyl ester in 475 mL of ethanol was added 13.09 g (0.327 mol, 2.5 equivalents) of sodium hydroxide pellets. This mixture was heated at reflux for three hours and stirred overnight at room temperature. The resulting solids were filtered yielding 37.16 g (98%) of 4-(4-fluorophenoxy)benzenesulfonic acid, sodium salt.
Reaction SMILES: COS([O-])(=O)=O.[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][N+](C)(C)C.[C-:22]#[N:23].[K+]>O>[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][C:22]#[N:23]
Reactant: C[N+](C)(C)Cc1c[nH]c2ccc(Br)cc12
Reactant: [C-]#N
Agent: COS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: N#CCc1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
According to the procedure of C. Huebner et al., J. Am. Chem. Soc., 75, 5887 (1953), (5-bromo-3-indolylmethyl)-trimethylammonium methyl sulfate (41.6 g, 0.11 mol) was added to a solution of potassium cyanide (21.49 g, 0.33 mol) in water (215 mL) and stirred at 60°-70° C. for 1 hour. The reaction was cooled to room temperature, extracted with ether (2×400 mL), washed with saturated NaHCO3, brine, dried (MgSO4), and concentrated under reduced pressure to yield 23.4 g (90%) of product as a white solid.
Reaction SMILES: [P:1]([O:13]C[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C[C@@H]1O)([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2].P(O[CH2:42][C@H:43]1[O:47][C@@H:46]([N:48]2[C:58]3[N:57]=[C:55]([NH2:56])[NH:54][C:52](=O)[C:51]=3[N:50]=[CH:49]2)[CH2:45][C@@H:44]1[OH:59])(OP(OP(O)(O)=O)(O)=O)(=O)O>[Au]>[CH:55]1[N:57]=[C:58]2[N:48]([C@@H:46]3[O:47][C@H:43]([CH2:42][O:12][P:9]([O:8][P:5]([O:4][P:1]([OH:13])([OH:3])=[O:2])([OH:7])=[O:6])([OH:11])=[O:10])[C@@H:44]([OH:59])[CH2:45]3)[CH:49]=[N:50][C:51]2=[C:52]([NH2:54])[N:56]=1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]1
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)n1
Agent: [Au]
Product: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O1

Procedure:
The reaction conditions for the PCR followed a protocol recommended by the enzyme manufacturer (PE Applied Biosystems, Foster City, Calif.). The Banyuls promoter was isolated from Arabidopsis genomic DNA using 30 nanomoles each of primers Ban+1500 and Ban GSP1, 10 micromoles each of dATP, dCTP, dGTP, and TTP, 2.5 units of AmpliTaq Gold in 1×Opti-Prime™ Buffer 3 (Stratagene, La Jolla, Calif.). After an initial incubation at 95° C. for 10 minutes, 30 cycles of PCR were performed with 92° C. for 30 seconds, 56° C. for 30 seconds, and 72° C. for 2 minutes followed by 1 cycle of 72° C. for 7 minutes.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:24]=[N:25][NH:26][CH:27]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:14][N:5]1[C:4]2[CH:3]=[C:2]([C:23]3[CH:24]=[N:25][NH:26][CH:27]=3)[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]1([CH3:13])[CH3:12]
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)C
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1c2cc(-c3cn[nH]c3)sc2C(=O)NC1(C)C
Yield: 45.7 %

Procedure:
A mixture of 6-bromo-1,2,2-trimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (138 mg, 0.50 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (291 mg, 1.50 mmol), sodium carbonate (265 mg, 2.50 mmol), 1,2-dimethoxyethane (5 mL) and water (2.5 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon again. This mixture was refluxed for 18 h. Then, the mixture was poured into saturated aqueous NaHCO3 (100 mL) and EtOAc (100 mL), and the mixture was shaken well. The insoluble materials were filtered off. From the filtrate, the organic layer was collected, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. This residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc, then EtOAc to 90:10 EtOAc/MeOH) to afford a white solid (60 mg). This solid was triturated with EtOAc/hexane and collected by filtration to afford the title compound (50.3 mg, 38%) as a white solid: