Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.O>C(O)C>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:14][CH2:13][CH2:12][CH2:11][N:8]2[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:20][C:19]3[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=3)[CH2:10][CH2:9]2)=[CH:18][CH:17]=1
Reactant: NCCCN1CCN(CCCN)CC1
Reactant: O=Cc1ccc(F)cc1
Solvent: O
Solvent: CCO
Product: Fc1ccc(CNCCCN2CCN(CCCNCc3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.51 mL, 2.5 mmol) and 4-fluorobenzaldehyde (0.59 mL, 5.5 mmol) in absolute ethanol (20 mL), 3 Å molecular sieves are added. After stirring the mixture at room temperature for 5 h, NaBH (0.47 g, 12.5 mmol) was added portionwise and the mixture was stirred for 12 h at room temperature. The reaction was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL). Combined organic layers were extracted with HCl 1M. The combined aqueous layers were neutralized with NaOH 1M and extracted with CH2Cl2. Combined organic layers were dried over MgSO4. Crude compound is purified thick-layer chromatography (acetone/NH4OH:90/10).
Reaction SMILES: C([O-])(=[O:3])C.[Cs+].Cl[CH2:7][C:8]1[NH:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][C:12]3[CH2:21][CH2:20][CH2:19][C:13]=3[CH:14]=2)[N:9]=1>CN(C=O)C>[OH:3][CH2:7][C:8]1[NH:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][C:12]3[CH2:21][CH2:20][CH2:19][C:13]=3[CH:14]=2)[N:9]=1
Reactant: CC(=O)[O-]
Reactant: O=c1[nH]c(CCl)nc2cc3c(cc12)CCC3
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(CO)nc2cc3c(cc12)CCC3
Temperature: 40 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A solution of caesium acetate (14.4 g, 75.2 mmol) in dry DMF (40 ml) was heated to 60° C. under argon for 30 min. The mixture was cooled to 40° C. and a suspension of 2chloromethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (L. Skelton, V. Bavetsias, A. Jaclinan, WO 00/050417-A1; 2.2 g, 9.4 mmol) in dry DA (60 ml) was added via a cannula. The mixture was heated to 80° C. under argon for 16 h. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was suspended in water (50 ml) and MeOH (20 ml). The pH was adjusted to 12.5 with 1M sodium hydroxide solution and the brown suspension was stirred for 2 h at room temperature. The insoluble brown solid was removed by filtration and the resulting solution was acidified to pH 5 with 1M hydrochloric acid. The precipitate was collected by filtration, washed with acidified water and dried in vacuo over P2O5 to yield the product as a pale yellow solid (1.17 g, 58%); m.p. 205-210° C.; 1H NMR (DMSO-d6) δ 2.07 (quin, J=7.4 Hz, 2H, 7-H), 2.98 (q, J=6.95 Hz, 4H, 6-H and 8-H), 4.38 (s, 2H, 2-CH2), 7.46 (s, 1H, 9-H), 7.92 (s, 1H, 5-H); MS (FAB-m/z): Found 217 [(M+H)+, 100%]; RRMS: measured 217.0977; calculated for C12H13N2O2 (M+H)+: 217.0977.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]#[CH:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:16][O:11][C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][C:14]#[CH:15]
Reactant: O=C([O-])[O-]
Reactant: C#CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: C#CC[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Reaction time: 3 h

Procedure:
The commercially available compound, 2-(R)-tert-butoxycarbonylaminopent-4-ynoic acid (0.321 g, 1.50 mmol) was dissolved in anhydrous DMF (5 mL). To the solution was added cesium carbonate (0.54 g, 1.65 mmol) in one portion. The mixture was stirred at room temperature for 45 min before methyl iodide (0.20 mL, 3.00 mmol) was added, and further stirred for three hours. The reaction was quenched with water (10 mL). The organics was extracted with dichloromethane (2×30 mL), washed with water (3×50 mL), and dried over anhydrous sodium sulfate. The solvent was completely removed under vacuum. The residue was further dried under high vacuum over night and used in the next reaction without further purification. The product 220 was obtained as a colorless viscous oil (0.326 g, 95% yield). 1H NMR (300 MHz, CDCl3): δ 1.48 (s, 9H), 2.08 (t, J=2.6 Hz, 1H), 2.75 (t, J=6.3 Hz, 2H), 3.78 (s, 3H), 4.46 (m, 1H), 5.32 (br s, 5H).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH3:8])=[CH2:7])=[CH:4][CH:3]=1.[Mg].Cl[C:13]([O:15][CH3:16])=[O:14]>C1COCC1>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([C:13]([O:15][CH3:16])=[O:14])=[CH:3][CH:4]=1)([CH3:8])=[CH2:7]
Reactant: C=C(C)c1ccc(Cl)cc1
Reactant: COC(=O)Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: C=C(C)c1ccc(C(=O)OC)cc1

Procedure:
Preparation of the Grignard compound of 4-chloro-α-methylstyrene by means of Rieke magnesium in THF under reflux and subsequent reaction with 0.95 equivalents of methyl chloroformate at RT. Aqueous working up, extraction with ethyl acetate and column chromatography using cyclohexane/ethyl acetate 85:15 affords methyl 4-isopropenylbenzoate as colorless crystals.
Reaction SMILES: [CH:1]1[C:17]2=[C:18]3[C:8]([C:9]([C:11]4[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=4)=[O:10])=[CH:7][CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.O.[Cl:20]([O-])(=O)=O.[K+].Cl>C(O)(=O)C>[Cl:20][C:3]1[CH:2]=[CH:1][C:17]2[C:16]3[C:11]([C:9](=[O:10])[C:8]4[C:18]=2[C:4]=1[CH:5]=[CH:6][CH:7]=4)=[CH:12][CH:13]=[CH:14][CH:15]=3
Reactant: [O-][Cl+2]([O-])[O-]
Reactant: O=C1c2ccccc2-c2cccc3cccc1c23
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2-c2ccc(Cl)c3cccc1c23
Reaction time: 2 h

Procedure:
A 10g amount of benzanthrone was dissolved in a solvent mixture of 100g acetic acid and 100 g of water. 6 g of potassium chlorate was added to the solution and the mixture was heated and stirred at 90°-95° C for 2 hours. 12 g of conc. hydrochloric acid was added dropwise to the mixture during 1 hour and 20 minutes. After the addition, the mixture was stirred for 1 hour to complete the reaction. The reaction mixture was cooled, filtered, washed with water and dried. The product was recrystallized from chlorobenzene to obtain 3-chlorobenzanthrone having a melting point of 179°-190° C (orange needle crystals).
Reaction SMILES: [CH:1]([N:4]1[C:18]2[C:19]3[C:6]([CH2:7][C@@H:8]4[C@@H:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:12][C@@H:11]([C:20]([OH:22])=[O:21])[CH2:10][NH:9]4)=[CH:5]1)([CH3:3])[CH3:2].[CH:23]1(O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:1]([N:4]1[C:18]2[C:19]3[C:6]([CH2:7][C@@H:8]4[C@@H:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:12][C@@H:11]([C:20]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:21])[CH2:10][NH:9]4)=[CH:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@@H](C(=O)O)CN[C@@H]1C2
Reactant: OC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@@H](C(=O)OC3CCCCC3)CN[C@@H]1C2

Procedure:
Following the procedure of Example 1, 1.5 g of 1-isopropylergoline-8β-carboxylic acid were esterified with 15 g of cyclohexanol in the presence of 1.5 g of p-toluenesulfonic acid to yield 1-isopropyl-8β-(cyclohexyloxycarbonyl)ergoline. The product, 1.91 g of an oil, was converted to the maleate salt in a 6:1 ether/ethyl acetate solvent mixture. The salt was isolated by evaporation and then recrystallized from ether/methanol; yield=0.93 g of cyclohexyl 1-isopropyl-8β-(cyclohexyloxycarbonyl)ergoline maleate (96.77% pure by HPLC); molecular ion at 380; [α]25D =-40.64° .
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[NH:19][CH:18]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2].[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[CH2:1]([NH:3][C:4]([CH:6]1[N:19]([C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([F:25])=[CH:27][CH:28]=2)[CH:18]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCNC(=O)C1Cc2c([nH]c3ccccc23)C(C(=O)OCC)=CN1
Product: CCNC(=O)C1Cc2c([nH]c3ccccc23)C(C(=O)OCC)=CN1C(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using ethyl 2-ethylcarbamoyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and 4-fluorobenzoyl chloride; 1H-NMR (CDCl3): δ 10.21 (1H, br s), 8.27 (1H, s), 7.71-7.79 (3H, m), 7.53 (1H, m), 7.36 (1H, d), 7.20 (1H, m), 7.11 (2H, m), 6.11 (1H, d), 5.32 (1H, t), 4.21 (2H, m), 3.87 (1H, dd), 3.20 (1H, dd), 2.86-3.06 (2H, m), 1.18(3H, t), 0.57 (3H, t); MS (ES): 450 (MH+).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:9](=[O:18])[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.[CH3:19][C:20]([CH3:58])([CH3:57])[CH2:21][N:22]1[CH2:35][C:27]2[C:28]3[CH:29]=[N:30][NH:31][C:32]=3[CH:33]=[CH:34][C:26]=2[CH2:25][C@H:24]([CH2:36][C:37](=[O:55])N2CCC(N3CC4C(=CC=CC=4)NC3=O)CC2)[C:23]1=[O:56]>>[CH2:21]([N:22]1[C:23](=[O:56])[C@H:24]([CH2:36][C:37](=[O:55])[N:2]2[CH2:3][CH2:4][CH:5]([C:8]3[C:9](=[O:18])[NH:10][C:11]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:6][CH2:7]2)[CH2:25][C:26]2[CH:34]=[CH:33][C:32]3[NH:31][N:30]=[CH:29][C:28]=3[C:27]=2[CH2:35]1)[C:20]([CH3:58])([CH3:57])[CH3:19]
Reactant: CC(C)(C)CN1Cc2c(ccc3[nH]ncc23)C[C@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Agent: Cl
Product: CC(C)(C)CN1Cc2c(ccc3[nH]ncc23)C[C@@H](CC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C1=O
Yield: 31 %

Procedure:
Title compound was prepared from 3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride in a manner analogous to the preparation of 9-(2,2-Dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Material was obtained as white solid in 31% yield. MS m/e (M+H)+=540.2. 1H NMR (500 MHz, DMSO-D6): δ=11.76 (s, 1H), 8.22 (s, 1H), 7.70 (d, J=8.85, 1H), 7.62 (s, 1H), 7.43 (t, J=7.48, 1H), 7.37 (d, J=8.55, 1H), 7.28 (d, J=8.24, 1H), 7.15 (t, J=7.32, 1H) 7.11 (d, J=8.55, 1H), 5.38 (d, J=17.09, 1H), 4.62 (d, J=16.79, 1H), 4.55 (d, J=11.29, 1H), 4.13 (s, 1H), 3.88 (s, 1H), 3.58 (s, 2H), 3.16 (m, 2H), 3.07 (m, 3H), 2.88 (t, J=14.34, 1H), 2.64 (m, 1H), 2.36 (m, 1H), 1.92 (d, J=10.38, 1H), 1.84 (d, J=11.29, 1H), 1.57 (m, 1H), 1.40 (m, 1H), 0.73 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:17])=[C:5]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7].C1OCCOCCOCCOCCOCCOC1.[C-:36]#[N:37].[K+]>C(#N)C>[Cl:17][C:4]1[C:3]([CH2:2][C:36]#[N:37])=[C:12]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(S(C)(=O)=O)c(CC#N)c1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.4 %

Procedure:
5.0 g of methyl 3-bromomethyl-2-chloro-4-methanesulfonylbenzoate was added to a solution of 0.4 g of 18-crown-6 and 1.9 g of potassium cyanide in 50 ml of acetonitrile. The mixture was stirred for 72 hours at room temperature. After filtering off the solid, water was added to the filtrate, and the mixture was extracted with chloroform. After washing the extract with water and drying it, the solvent was distilled off to obtain a crude product. The crude product was purified by short silica gel column chlomatography (eluent: chloroform) to obtain 4.1 g of the desired product. Melting point: 151°-155° C.
Reaction SMILES: [C:1](=[NH:26])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)=[C:8]([F:25])[CH:7]=1)[NH2:2].[CH2:27](/[C:29](=[CH:35]/O)/[C:30](OCC)=[O:31])[CH3:28].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:9]2[C:10]([F:12])=[CH:11][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:35]=[C:29]([CH2:27][CH3:28])[C:30](=[O:31])[N:26]=3)=[CH:7][C:8]=2[F:25])=[CH:15][C:16]=1[C:21]([F:22])([F:24])[F:23]
Reactant: N=C(N)OCCc1cc(F)c(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Reactant: CCOC(=O)/C(=C\O)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1c[nH]c(OCCc2cc(F)c(Oc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)nc1=O
Temperature: 110 °C
Yield: 27.5 %

Procedure:
A mixture of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3,5-difluorophenyl)ethyl imidocarbamate (250 mg, 0.459 mmol), ethyl (2Z)-2-ethyl-3-hydroxy-2-propenoate (132 mg, 0.918 mmol) and K2CO3 (127 mg, 0.918 mmol) in DMF (3 mL) was heated with a microwave condition at 110° C. for 1.5 h. Purification via MDAP afforded the title compound (60 mg, 27.5% yield). LCMS: rt=3.83 min, [M+H+]=475
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9])(=O)=O.[C:15]1([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:28]1([CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:22]2[CH2:23][CH2:24][N:25]([CH2:6][CH2:7][N:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9])[CH2:26][CH2:27]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CCOC(=O)N(C)CCOS(C)(=O)=O
Product: CCOC(=O)N(C)CCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 64.2 %

Procedure:
A mixture of 0.23 g of 2-(N-ethoxycarbonyl-N-methylamino)ethyl methanesulfonate (prepared as described in Preparation 34') and 0.26 g of 4-diphenylmethylpiperazine was stirred at 80° C. for 5 hours. At the end of this time, the mixture was purified by column chromatography through silica gel, using a 20:1 by volume mixture of ethyl acetate and ethanol as the eluent, to give 0.25 g (yield 64%) of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccc(F)cc1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3ccc(F)cc3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(4-fluoro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:16]1([C:3]2[C:2]([N:31]3[CH2:32][CH2:33][N:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[CH2:29][CH2:30]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccccn4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 106.5 %

Procedure:
A solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (50 mg, 0.15 mmol, 1.00 equiv), 1-(pyridin-2-yl)piperazine (50 mg, 0.31 mmol, 2.00 equiv), and DIEA (100 mg, 0.78 mmol, 3.00 equiv) in DMF (10 mL) was placed in a 20-mL sealed tube under an inert atmosphere and stirred overnight at 100° C. in an oil bath and then concentrated under vacuum. Purification via silica gel column (ethyl acetate/petroleum ether (1:10)) yielded 68 mg (crude) of methyl 2-phenyl-3-(4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid
Reaction SMILES: [CH2:1]([O:4][NH:5][C@@H:6]1[C:11]([CH3:12])=[CH:10][C@@H:9]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[NH:8][CH2:7]1)[CH:2]=[CH2:3].C(N(CC)C(C)C)(C)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C>[CH2:1]([O:4][N:5]1[C:32](=[O:34])[N:8]2[CH2:7][C@H:6]1[C:11]([CH3:12])=[CH:10][C@H:9]2[CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[CH:2]=[CH2:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCON[C@H]1CN[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 228.5 %

Procedure:
To a solution of O-allyl-N-((3R,6S)-6-((tert-butyldimethylsilyloxy)methyl)-4-methyl-1,2,3,6-tetrahydropyridin-3-yl)hydroxylamine (Intermediate 12, 2 g, 6.40 mmol) and N,N-diisopropylethylamine (4.46 mL, 25.60 mmol) in acetonitrile (555 mL) at 0° C. was added triphosgene (0.760 g, 2.56 mmol) as a solution in acetonitrile (45 mL). The triphosgene solution was added via syringe pump at a rate of 0.1 mL/min. Once addition was complete the reaction was stirred at room temperature overnight. The reaction mixture was concentrated to dryness, diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The aqueous washes were found to contain some product and were extracted twice with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered and combined with previous extracts. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the desired product (1.980 g, 91%) as a light orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)O)=[CH:5][CH:4]=1.C([SiH](CC)CC)C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(O)c2ccc(-c3ccccc3)o2)cc1
Agent: CC[SiH](CC)CC
Product: COc1ccc(Cc2ccc(-c3ccccc3)o2)cc1
Yield: 98.8 %

Procedure:
The title compound (940 mg, 99%) was prepared from the product of step 2 (1.0 g, 3.6 mmol) and triethylsilane (2.3 g, 21.4 mmol) using the procedure of Example 159, step 3.
Reaction SMILES: [Si](OCC[C:11]1[CH:27]=[N:26][C:14]2[S:15][C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[N:18]([CH2:19][O:20][CH3:21])[C:13]=2[N:12]=1)(C(C)(C)C)(C)C.[O:28]1CC[CH2:30][CH2:29]1>>[CH3:21][O:20][CH2:19][N:18]1[C:17]2[CH:22]=[C:23]([CH2:30][CH2:29][OH:28])[CH:24]=[CH:25][C:16]=2[S:15][C:14]2[N:26]=[CH:27][CH:11]=[N:12][C:13]1=2
Reactant: C1CCOC1
Reactant: COCN1c2ccccc2Sc2ncc(CCO[Si](C)(C)C(C)(C)C)nc21
Product: COCN1c2cc(CCO)ccc2Sc2nccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
463 mg of 8-[(2-(tert-butyldimethylsilyloxy)ethyl]-10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine was dissolved in 5 ml of tetrahydrofuran. After adding 1.3 ml of n-tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran), the resulting mixture was stirred at room temperature for 1 hour and then at 4° C. for additional 13 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 281 mg of the title compound as a pale orange solid.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([NH2:28])=[O:27])=[C:24]([CH:29]([OH:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[N:23]=[C:22]2[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.Cl>>[CH2:35]([C:22]1[N:21]([CH2:20][C:17]2[CH:18]=[CH:19][C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:6]([OH:7])=[O:5])=[CH:15][CH:16]=2)[C:25]([C:26]([NH2:28])=[O:27])=[C:24]([CH:29]([OH:34])[C:30]([CH3:32])([CH3:33])[CH3:31])[N:23]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CCCCc1nc(C(O)C(C)(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Product: CCCCc1nc(C(O)C(C)(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Following a procedure similar to that described in Example 52(c), but using 326 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxy-2,2-dimethylpropyl)imidazole-5-carboxamide [prepared as described in step (e) above], 228 mg of the hydrochloride of the title compound were obtained as a powdery solid, melting at 150°-154° C. (with softening).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH3:9])[C:5](F)=[CH:4][N:3]=1.O.[NH2:13][NH2:14]>C(O)CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:8]([CH3:9])=[N:14][NH:13][C:5]2=[CH:4][N:3]=1
Reactant: NN
Reactant: CC(=O)c1cc(Br)ncc1F
Solvent: O
Solvent: OCCO
Product: Cc1n[nH]c2cnc(Br)cc12
Temperature: 165 °C
Reaction time: 0.17 h
Yield: 73.1 %

Procedure:
To a 250-mL round-bottomed flask equipped with a reflux condenser was added dry ethylene glycol (30 mL) and 325c (4.3 g, 20 mmol). Then hydrazine hydrate (5.0 mL, 4.8 g, 81.6 mmol) was added dropwise via a syringe. The mixture was heated at 165° C. for 3.5 h. The resulting orange-tan mixture was cooled to room temperature and the contents were poured onto a stirring mixture of 100 mL ice/water (1:1), whereupon precipitation occurred. After stirring for 10 min, the off-white precipitate was collected, which was dried in vacuo to afford 325d as an off-white solid (3.1 g, 74%). MS-ESI: [M+H]+ 211.9.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].N#N.[CH2:9]1[CH2:13][O:12][CH2:11][CH2:10]1>>[CH3:1][CH:2]([CH:11]1[CH2:10][CH2:9][CH2:13][O:12]1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C1CCOC1
Reactant: C=CCCCC
Agent: N#N
Product: CCCCC(C)C1CCCO1
Yield: 96 %

Procedure:
3 g of 1-hexene and 22 g of THF were passed into the reactor tube with a 30 ml/min flow of N2. The reaction mixture was washed with 150 ml of 1:1 v/v water/ether to separate the 1 g. of water soluble THF dimer 2-(1-methyl-pentyl)-tetrahydrofuran which was formed. The organic phase was chromatographed on silica gel. Elution with 5% ether and 5% petroleum ether in cyclohexane to yield material which was shown to be 96% pure title compound by GC. 250 MHz 13C-NMR (CDCl3 ; data for d,l for meso mixture): 13.88 (q, 2C), 14.84 (q, IC), 15.40 (q, IC), 22.73 (t, 2C), 25.65 (t, lC), 25.75 (t, IC), 28.39 (t, lC), 28.74 (t, lC), 29.00 (t, IC), 29.15 (t, IC), 32.54 (t, IC), 33.13 (t, IC), 37.66 (d, 2C), 67.52 (t, 2C), 83.60 (d, 2C).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4].[CH3:11][Si](C=[N+]=[N-])(C)C>CCOCC>[CH3:11][O:4][C:3](=[O:5])[C:2]([CH3:10])([CH3:1])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCCCC(C)(C)C(=O)O
Solvent: CCOCC
Product: CCCCC(C)(C)C(=O)OC
Reaction time: 3 h
Yield: 100.4 %

Procedure:
To a solution of 2,2-Dimethyl-hexanoic acid (10.15 g, 0.07 mol) in ether (150 mL) was added (trimethylsilyl)diazomethane (46 ml, 2M in hexanes, 0.092 mol) drop wise. The mixture was stirred for 3 h, and ether was evaporated without applying reduced pressure. Fractional distillation of the residue provided the title ester 11.12 g (b.p. 90-95° C./1 mmHg). 1H NMR (CDCl3): δ 0.85 (t, J=7.0 Hz, 3H), 1.1-1.2 (m, 2H), 1.13 (s, 6H), 1.21-1.31 (m, 2H), 1.44-1.51 (m, 2H), 3.72 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1
Reactant: Nc1ccccc1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1nc(Nc2ccccc2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-(phenylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, aniline, and triethylamine essentially as described above in Example 1, Scheme A, step b.