Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.C(OCC)(=O)C.Cl>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCc2cccs2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: c1csc(CCCN2CCNCC2)c1
Yield: 93.6 %

Procedure:
1.94 g (6.25 mmol) of tert-butyl 4-[3-(2-thienyl) propyl]-1-piperazinecarboxylate was dissolved in 20 ml of methanol, and 15 ml of a 4N hydrogen chloride-ethyl acetate solution was added. After completion of the reaction, the mixture was evaporated. The residue was adjusted to pH 11 with a 2N aqueous sodium hydroxide, then the objective product was extracted with chloroform and dried over anhydrous magnesium sulfate. The solvent was evaporated, to give 1.23 g (5.85 mmol, 93.6%) of the title compound as ayellow oil, as acrude product. 1H-NMR (400 MHz, CDCl3) δ 1.84-1.92 (m, 2H), 2.35-2.48 (m, 6H), 2.83-2.93 (m, 6H), 6.77-6.80 (m, 1H), 6.91 (dd, J 3.2 Hz, 5.2 Hz, 1H), 7.11 (dd, J=1.2 Hz, 5.2 Hz, 1H)
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].[C:24]1([CH3:35])[CH:29]=[CH:28][C:27]([O:30]CC(O)=O)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[S:11]([N:8]1[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][O:30][C:27]2[CH:28]=[CH:29][C:24]([CH3:35])=[CH:25][CH:26]=2)[CH2:6][CH2:7]1)(=[O:13])=[O:12]
Reactant: Cc1ccc(OCC(=O)O)cc1
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(OCC(=O)N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)cc1
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a stirred solution of 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 4, 0.2 g, 0.64 mmol) and 2-(p-tolyloxy)acetic acid (106 mg, 0.64 mmol) in dry DCM (20 mL), DIPEA (495 mg, 3.86 mmol) followed by HATU (486 mg, 1.27 mmol) was added at room temperature and stirred overnight. The mixture was then diluted with DCM and washed with water (2×10 mL) & brine (2×10 mL). The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound (0.21 g, 77.5%) as an off-white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14](C)[CH:13]=2)[CH2:8]1>CO.C(Cl)Cl.[Pd]>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:8]1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC1CCCN1C1CCN(c2ccc(N)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-methyl-1′-(3-methyl-4-nitro-phenyl)-[1,3′]bipyrrolidinyl (Intermediate (iii) obtained above, 2.23 g, 7.7 mmol) in MeOH was de-aerated and nitrogen was introduced. To this solution was added Pd—C (10%). This mixture was stirred under H2 atmosphere at r.t. for 8 h. TLC (10% MeOH in DCM) and LC/MS showed the reaction was complete. The mixture was passed through a Celite pad, rinsed with methanol. The filtrate was concentrated to dryness, and further dried under high vacuum to yield a reddish brown liquid after drying under high vacuum to obtain the title compound as a gummy black liquid, 1.73 g (86%). This material was used in the next step without further purification and storage. MS: 260 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:12][C:13]2[CH:18]=[N:17][CH:16]=[C:15]([Cl:19])[N:14]=2)[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>ClCCl>[Cl:19][C:15]1[N:14]=[C:13]([NH:12][CH:8]([C:4]2[CH:3]=[C:2]([NH:1][C:27](=[O:29])[CH3:28])[CH:7]=[CH:6][CH:5]=2)[CH2:9][CH2:10][CH3:11])[CH:18]=[N:17][CH:16]=1
Reactant: CC(=O)Cl
Reactant: CCCC(Nc1cncc(Cl)n1)c1cccc(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(Nc1cncc(Cl)n1)c1cccc(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.9 %

Procedure:
To a stirred solution of N-[1-(3-aminophenyl)butyl]-6-chloropyrazin-2-amine (0.10 g, 0.36 mmol) and triethylamine (100 μl, 0.72 mmol) in dichloromethane (3 mL) cooled to 0° C. was added acetyl chloride (31 μL, 0.43 mmol). The resulting mixture was stirred at room temperature for 18 h. then diluted with dichloromethane (10 mL) and washed with H2O (10 mL) and brine (10 mL). The organic phase was collected, dried and concentrated and the residue purified by flash chromatography eluting with ethyl acetate-hexane (1:1) to give pure product (94 mg, 82%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([CH2:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[CH:19]4)=[N:13][N:14]=2)[N:11]=1)=[CH2:5])C.Cl.C([O-])(O)=O.[Na+]>CO>[N:22]1[C:23]2[C:18](=[CH:17][C:16]([CH2:15][C:12]3[N:10]4[N:11]=[C:6]([C:4](=[O:3])[CH3:5])[CH:7]=[CH:8][C:9]4=[N:14][N:13]=3)=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: C=C(OCC)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Yield: 51.3 %

Procedure:
To a solution of 6-((6-(1-ethoxyvinyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline in MeOH (30 mL) was added excess 3N HCl solution. The solution was stirred at rt overnight and neutralized with saturated NaHCO3 solution. Organic solvent was evaporated and the residue was extracted with EtOAc three times. Organic layers were combined, washed with brine and dried over Na2SO4. Solvent was evaporated and the crude was purified by column chromatography (DCM:MeOH=95:5) to give the title compound as yellow solid (51.3%). LCMS (method B): [MH]+=304.1, tR=1.708 min.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:35])[CH2:5][C@@H:6]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Br[CH2:37][N:38]1[C:42](=[O:43])[N:41]([CH3:44])[N:40]([CH3:45])[C:39]1=[O:46]>CN(C)C=O>[CH3:3][CH:4]([CH3:35])[CH2:5][C@@H:6]([C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[C:7]([CH2:37][N:38]1[C:42](=[O:43])[N:41]([CH3:44])[N:40]([CH3:45])[C:39]1=[O:46])([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: Cn1c(=O)n(CBr)c(=O)n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(Cn1c(=O)n(C)n(C)c1=O)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.5 %

Procedure:
0.284 g of 60% sodium hydride was added to a stirred ice-cold solution of 3.01 g of 1,2-dibenzyl 1-tert.butyl 4-methyl-1,1,2(R)-pentanetricarboxylate in 50 ml of dry dimethylformamide under a nitrogen atmosphere. The mixture was stirred for 30 minutes at 0° and for an additional 1.5 hours at ambient temperature, and again cooled to 0° before the addition of 1.6 g of 4-bromomethyl-1,2-dimethylurazole. The mixture was allowed to return to ambient temperature and was stirred for 3 hours. The volatiles were evaporated under high vacuum and the residue was dissolved in ethyl acetate and washed with 5% aqueous citric acid solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography on silica gel using hexane/ether (1:1) followed by ether for the elution. There were obtained 2.464 g of 1,2-dibenzyl 1 -tert.butyl 4-methyl-l-[(1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl) methyl]-1,1,2(R)-pentanetricarboxylate in the form of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:30])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH2:16][CH2:15]2)[C:5]2[N:10]=[C:9](S(C)=O)[S:8][C:6]=2[N:7]=1.[F:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1>O1CCOCC1>[NH2:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:15][CH2:16][N:17]([C:20](=[O:30])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH2:18][CH2:19]2)[C:5]2[N:10]=[C:9]([NH:36][C:35]3[CH:37]=[CH:38][C:32]([F:31])=[CH:33][CH:34]=3)[S:8][C:6]=2[N:7]=1
Reactant: Nc1ccc(F)cc1
Reactant: CS(=O)c1nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc2s1
Solvent: C1COCCO1
Product: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(Nc3ccc(F)cc3)sc2n1
Yield: 87.6 %

Procedure:
A mixture of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-methylsulfinyl-thiazolo[5,4-d]pyrimidine (47 mg, 0.1 mmol) and 4-fluoroaniline (95 μl, 1 mmol) in dioxane (5 ml) was heated under reflux for 12 hours. The reaction mixture was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/80), yielding the pure title compound (45 mg, 88%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]2[C@H:29]([CH3:30])[C@H:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:27][C:26]2=[O:37])[CH:7]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:46][CH3:47]>CC#N>[CH2:1]([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:46][CH3:47])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]2[C@H:29]([CH3:30])[C@H:28]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[O:27][C:26]2=[O:37])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(O)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(OCC)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To {4-hydroxy-3-[2-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid ethyl ester (0.060 g, 0.12 mmol) in MeCN (2 mL) was added cesium carbonate (0.086 g, 0.26 mmol) and iodoethane (0.02 mL, 0.26 mmol), and the reaction was stirred at room temperature overnight. After work-up with EtOAc and 10% aqueous HCl, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:3]=1.[CH2:30]([NH2:34])[CH2:31][CH2:32][NH2:33]>>[O:28]=[S:20]1(=[O:29])[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[CH2:23][N:17]([C:4]2[CH:3]=[C:2]([NH:33][CH2:32][CH2:31][CH2:30][NH2:34])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:10]=3)[N:5]=2)[CH2:18][CH2:19]1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Reactant: NCCCN
Product: NCCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(OC(F)(F)F)cc12

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 481, 1H NMR (400 MHz, CD3OD) δ ppm 8.16-8.15 (d, J=2.4 Hz, 1 H), 8.09-8.07 (dd, J=5.2, 8.0 Hz, 1 H), 7.94-7.92 (d, J=10 Hz, 1 H), 7.90-7.88 (d, J=8 Hz, 1 H), 7.72-7.70 (m, 2 H), 7.58-7.55 (m, 1 H), 6.03 (s, 1 H), 5.34 (s, 2 H), 4.55 (s, 2 H), 3.75 (s, 2 H), 3.62-3.59 (t, J=6.8 Hz, 2 H), 3.14-3.10 (t, J=8.0 Hz, 2 H), 2.15-2.11 (m, 2 H).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([NH:12][NH2:13])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].[CH3:25][N:26]=[C:27]=S.C(O)C>CN(C=O)C>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]2[C:25]([NH:26][CH3:27])=[N:13][NH:12][C:8]=2[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)cc(NN)n(Cc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: CN=C=S
Solvent: CN(C)C=O
Solvent: CCO
Product: CCCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccc([N+](=O)[O-])cc2)c1=O
Yield: 32 %

Procedure:
A solution of 3-butyl-6-hydrazino-1-(4-nitrobenzyl)uracil (1.7 g, 5 mM) and methyl isothiocyanate (0.7 ml, 10 mM) in DMF (20 ml) was stirred at 120° C. for 20 hours. To the solution was added ethanol (20 ml) and the mixture was cooled to give crystalline product. Recrystallization from DMF/ethanol gave pale yellow crystals (0.61 g, 32%), m.p. 277°-279° C.
Reaction SMILES: [CH3:1][CH:2]([C:8](=O)[CH2:9][C:10](=O)[CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:14][NH2:15]>C1COCC1.O>[CH3:11][C:10]1[CH:9]=[C:8]([CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[NH:15][N:14]=1
Reactant: CCOC(=O)C(C)C(=O)CC(C)=O
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1cc(C)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.4 %

Procedure:
To a solution of 18.6 g (100. mmol) of ethyl 2-methyl-3,5-dioxohexanoate from step A in 200 mL of THF and 50 mL of water was added 3.45 mL (110 mmol) of anhydrous hydrazine. The biphasic reaction mixture was stirred at ambient temperature overnight then evaporated to dryness in vacuo. The crude yellow residue was dissolved in an ethyl acetate and water mixture and flushed through a 50 g silica gel plug. The filtrate was then evaporated to dryness in vacuo and the residue purified by silica gel chromatography eluting with a 0-100% ethyl acetate in hexanes gradient to afford the title compound as a yellow oil (1.89 g, 10%). 1H NMR (CDCl3, 500 MHz) δ 7.26 (s, 1H), 5.98 (s, 1H), 4.20-4.12 (m, 2H), 3.81 (q, J=7.3 Hz, 1H), 2.28 (s, 3H), 1.51 (d, J=7.3 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H). LC-MS: m/z (ES) 183 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].CN(C)P(N(C)C)(N(C)C)=O>O>[C:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)([O:28][CH3:29])=[O:27]
Reactant: COC(=O)CCCCCCCCCCCCCCCBr
Reactant: N#Cc1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C#N)cc1

Procedure:
A solution of 12 g. of 4-aminobenzonitrile and 15 g. of methyl 16-bromohexadecanoate in 200 ml. of hexamethylphosphoramide is heated at 120° for 22 hours, allowed to cool, and diluted with water. The mixture is chilled and the precipitate which forms is collected, dried, and recrystallized from etherhexane to yield 4-(15-carbomethoxypentadecylamino)benzonitrile as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([Br:9])[C:7]=1[CH3:8].I[CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH:12]([CH3:14])[CH3:13])[CH:5]=[C:6]([Br:9])[C:7]=1[CH3:8]
Reactant: CC(C)I
Reactant: Cc1c(Br)cc(O)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Br)cc(OC(C)C)cc1Br
Temperature: 80 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
A mixture of 3,5-dibromo-4-methyl-phenol (11.2 g, 42.1 mmol), 2-iodopropane (8.50 mL, 85.0 mmol), potassium carbonate (17.5 g, 126 mmol), and anhydrous DMF (100 mL) was stirred at 80° C. for 3 hours. After cooling to room temperature, the reaction mixture was partitioned between ether (300 mL) and water (300 mL). The organic phase was separated, washed with brine (2×300 mL), dried over sodium sulfate, and concentrated under vacuum to give 1,3-dibromo-5-isopropoxy-2-methyl-benzene (Cpd A, 12.8 g, 99% yield) as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.[NH2:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:21]([O:20][C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:10]([C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)=[O:12])=[CH:26][CH:25]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)c2ccc3cc[nH]c3c2)cc1
Temperature: 60 °C
Reaction time: 72 h
Yield: 30.2 %

Procedure:
A solution of 1H-indole-6-carboxylic acid (1.00 g, 6.20 mmol), tert-butyl 4-aminobenzoate (1.20 g, 6.20 mmol), 4-methylmorpholine (3.14 g, 31.0 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (3.53 g, 9.31 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 min, then 4-(dimethylamino)pyridine (758 mg, 6.20 mmol) was added, and the solution was stirred at 60° C. for 3 days. After cooling, the reaction mixture was partitioned between water, heptane, and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) followed by trituration in dichloromethane yielded 4-[(1H-indole-6-carbonyl)-amino]-benzoic acid tert-butyl ester (629 mg, 30%). White solid, MS (ISP): m/e 337.2 (M+H).
Reaction SMILES: ClC1C=C2C(CCN)=C([Si](CC)(CC)CC)NC2=[N:6]C=1.[F:21][C:22]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:23]=1[CH2:24][C:25]1[O:29][N:28]=[C:27]([C:30](O)=[O:31])[CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:21][C:22]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:23]=1[CH2:24][C:25]1[O:29][N:28]=[C:27]([C:30]([NH2:6])=[O:31])[CH:26]=1
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Cc2cc(F)ccc2F)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanamine (0.128 g; 0.413 mmol), 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid intermediate 74 (0.104 g; 0.434 mmol), HATU (N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate) (0.165 g: 0.434 mmol) and N,N-diisopropylethylamine (0.108 mL; 0.619 mmol) in DMF (3 mL) was stirred overnight at room temperature and concentrated under reduced pressure. The crude material was dissolved in dichloromethane and the organic layer was washed with water and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent: 1 to 10% of ethyl acetate in dichloromethane) to give 0.108 g (49%) of N-(2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2, 3-1)]pyridin-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a solid.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[O:3].[Br:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O:20][CH3:21].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[OH:3][C:2]([C:16]1[CH:17]=[CH:18][C:19]2[C:14](=[CH:13][CH:12]=[C:11]([O:20][CH3:21])[C:10]=2[Br:9])[CH:15]=1)([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: COc1ccc2ccccc2c1Br
Reactant: CCOC(=O)C(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(C)(O)c1ccc2c(Br)c(OC)ccc2c1
Temperature: 5 °C
Yield: 11 %

Procedure:
Ethyl pyruvate (1,64 g, 14,1 mmol) in dichloromethane (5 mL), was added to a mixture of 1-bromo-2-methoxynaphthalene (2,23 g, 9,41 mmol) and aluminium chloride (1,88 g, 14,1 mmol) in dichloromethane (20 mL) at 5° C. over 30 minutes. The mixture was stirred at 5° C. for a further 1,5 hours and poured on to ice. Ethyl 2-hydroxy-2-(5-bromo-6-methoxynaphth-2-yl)propionate was formed in 11% yield. 1HNMR δ (CDCl3) 1.24 (3H,t), 1.85 (3H,s), 4.00 (3H,s), 4.26 (2H,q), 7.2-8.2 (5H2 m).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])[NH2:6].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:11]1(=[O:20])[N:10]([C:9]2[CH:8]=[CH:7][C:5]([NH:6][C:21](=[O:23])[CH3:22])=[CH:4][C:3]=2[CH3:2])[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]12
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(N)ccc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(N2C(=O)c3ccccc3C2=O)c(C)c1

Procedure:
The product aniline of Example 31 was acetylated at room temperature using 8.2 ml (86.6 mmole) of acetic anhydride in 100 ml of pyridine. After one day the mixture was concentrated in vacuo to a syrup which afforded a solid upon trituration with water. The solid was collected, washed with water, and dried under vacuum at 40°, giving 4.8 g (16.3 mmole) of 2-phthalimido-5-acetamidotoluene. The intermediate compound was heated at reflux in 100 ml of ethanol containing 3.2 ml (65.2 mmole) of hydrazine hydrate. After 45 minutes the mixture was filtered and the filtrate was concentrated to dryness. The crude amine was used in subsequent reactions without further purification.
Reaction SMILES: [Mg].[CH:2](Cl)([CH3:4])[CH3:3].[CH3:6][C:7]([CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:8][CH:9]=[O:10]>CCOCC>[CH3:3][CH:2]([CH:9]([OH:10])[CH:8]=[C:7]([CH3:6])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH3:4]
Reactant: CC(C)Cl
Reactant: CC(=CC=O)CC(C)C
Agent: [Mg]
Solvent: CCOCC
Product: CC(=CC(O)C(C)C)CC(C)C
Temperature: 0 °C
Yield: 72.6 %

Procedure:
26.4 g (1.1 gram atom) of magnesium shavings and 100 ml of anhydrous ether are added to a round flask which is provided with a stirrer, condenser, thermometer and dropping funnel. There is now slowly added thereto a solution of 90.2 g (1.15 mol) of isopropyl chloride in 150 ml of ether. After completion of the addition, the mixture is held at reflux temperature for a further 1 hour. There are now added thereto at a temperature of 10° C. 126.2 g (1 mol) of 3,5-dimethyl-2-hexenal dissolved in 250 ml of anhydrous ether. The mixture is held at reflux temperature for 3 hours, then cooled down to 0° C. and decomposed by the addition of 370 ml of 10% ice-cold hydrochloric acid. The ethereal solution is washed neutral with water and dried, and the solvent is evaporated. There are thus obtained 168 g of crude material, fractional distillation of which yields 123.7 g (72.6%) of 2,5,7-trimethyl-4-octen-3-ol of boiling point 78°-79° C./5 mmHg; nD20 =1.4526.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].C([Li])(C)(C)C.CCCCC.[B:20](OC)([O:23]C)[O:21]C>O1CCCC1>[CH3:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[B:20]([OH:23])[OH:21]
Reactant: COB(OC)OC
Reactant: Cc1cccc(C)c1Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1cccc(C)c1B(O)O

Procedure:
Following General Procedure A and using 1-bromo-2,6-dimethyl-benzene (Aldrich, 5 g, 27 mmol), 50 mL of anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane (32 mL, 54 mmol) and trimethyl borate (6.05 mL, 54 mmol), the title compound was obtained after recrystallization from ethyl acetate-hexane mixture (0.7 g, 10%).