Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:18]=[CH:17][N:16]([S:19]([C:22]4[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[C:13]3=[N:14][CH:15]=2)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:45][C:46]([F:50])([F:49])[CH2:47]I.C([O-])(O)=O.[Na+].[ClH:56]>C1COCC1.C(OC(C)C)(=O)C.CCOC(C)=O>[ClH:56].[F:45][C:46]([F:50])([F:49])[CH2:47][CH:9]([C:10]1[N:11]=[C:12]2[CH:18]=[CH:17][N:16]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:20])=[O:21])[C:13]2=[N:14][CH:15]=1)[NH2:8]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CN=C(c4ccccc4)c4ccccc4)cnc32)cc1
Reactant: FC(F)(F)CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C(N)CC(F)(F)F)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
To a solution of N-(diphenylmethylene)-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine (0.722 g, 1.55 mmol) in THF (3 mL) at about −78° C. was added NaHMDS (0.5 M in THF, 1.55 mL, 1.55 mmol). After about 30 min, 1,1,1-trifluoro-2-iodoethane (1.51 mL, 15.5 mmol) was added to the reaction mixture. After about 4 h, the reaction mixture was allowed to warm to rt slowly over night. After about 15 h, EtOAc (30 mL) and saturated aqueous NaHCO3 (30 mL) were added. The organic layer was separated, concd in vacuo and purified by chromatography on silica gel eluting with EtOAc/heptane (20-50%) to provide the crude alkylated imine. The imine was dissolved in isopropyl acetate (30 mL) and concd HCl (0.50 mL) was added. The reaction mixture was spun on a rotory evaporator for 1 h prior to partial concentration to approx 10 mL. Additional isopropyl acetate (30 mL) was added and the solvent was partially removed in vacuo until approx. 10 mL remained. Et2O (30 mL) was added and the solution was allowed to age for about 30 min. The resulting solids were collected by filtration and dried in vacuo to provide 3,3,3-trifluoro-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)propan-1-amine hydrochloride (0.150 g, 23%) as a colorless solid. LC/MS (Table 1, Method a) Rt=1.88 min; MS m/z 385 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:45])[C@@H:4]([NH:18][C:19]([C:21]1[C:30]([S:31][CH2:32][CH3:33])=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=3)[CH:27]=2)[N:22]=1)=[O:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.C(Cl)Cl>C(Cl)Cl.CO>[C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([NH:18][C:19]([C:21]2[C:30]([S:31][CH2:32][CH3:33])=[N:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:34][C:35]4[CH:36]=[CH:37][C:38]([C:41]([CH3:42])([CH3:43])[CH3:44])=[CH:39][CH:40]=4)[CH:27]=3)[N:22]=2)=[O:20])[C:3]([OH:45])=[O:2])=[CH:11][CH:10]=1
Reactant: CCSc1nc2cc(Oc3ccc(C(C)(C)C)cc3)ccc2nc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)OC
Solvent: ClCCl
Solvent: CO
Product: CCSc1nc2cc(Oc3ccc(C(C)(C)C)cc3)ccc2nc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Yield: 75.7 %

Procedure:
3-Biphenyl-4-yl-(2S)-{[6-(4-tert-butyl-phenoxy)-3-ethylsulfanyl-quinoxaline-2-carbonyl]-amino}-propionic acid methyl ester (30 mg, 0.048 mmol) was hydrolyzed as described in general procedure C. Column chromatography over silica using DCM and 95:5 DCM-methanol as eluants gave the title compound (22 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:21][CH3:22])[CH:13]([OH:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O)(=O)=O.[C:39]([SiH:43]([CH3:45])[CH3:44])([CH3:42])([CH3:41])[CH3:40].O>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:21][CH3:22])[CH:13]([O:20][Si:43]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:45])[CH3:44])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(O)[C@H](CC)NC(=O)OCc1ccccc1
Reactant: C[SiH](C)C(C)(C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(O[Si](C)(C)C(C)(C)C)[C@H](CC)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of ethyl (4S)-4-{[(benzyloxy)carbonyl]amino}-3-hydroxyhexanoate (63.2 g) and 2,6-lutidine (47.6 mL) in tetrahydrofuran (800 mL) was added tert-butyldimethylsilane trifluoromethanesulfonate (70 mL) under ice-cooling and, after warming to room temperature, and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate-1/0→1/1) to give ethyl (4S)-4-{[(benzyloxy)carbonyl]amino}-3-(tert-butyldimethylsilyloxy)hexanoate as a colorless oil (yield: 64.0 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]([NH2:15])[CH3:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:16]([O:20][C@@H:21]([C@H:23]1[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29]1[CH:34]=[CH:33][N:32]=[C:31](F)[N:30]=1)[CH3:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)C(C)C)C>CS(C)=O.CCOC(C)=O>[C:16]([O:20][C@@H:21]([C@H:23]1[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([NH:15][CH:13]([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:12]=2)[CH3:14])[N:30]=1)[CH3:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(N)c1cc(-c2ccc(Cl)cc2)no1
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1ccnc(F)n1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1cc(-c2ccc(Cl)cc2)no1
Temperature: 120 °C
Yield: 37.6 %

Procedure:
To a solution of 1-(3-(4-chlorophenyl)isoxazol-5-yl)ethanamine (610 mg, 2.74 mmol) and (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (774 mg, 2.74 mmol) in DMSO (5 ml) was added N-ethyl-N-isopropylpropan-2-amine (2 eq, 0.96 mL, 5.48 mmol) and heated in a microwave at 120° C. for 2 hours. Dilute with EtOAc (50 ml), wash with water (50 ml), brine (50 ml), concentrate in vacuo. Flash column chromatography (silica, 40 g) eluting w/0-25% EtOAc/DCM afforded 500 mg of white solid: 1H NMR (400 MHz, CDCl3) b 8.24 (dd, J=5.8, 1.6 Hz, 1H), 7.80-7.65 (m, 2H), 7.58 (dd, J=5.8, 1.6 Hz, 1H), 7.49-7.37 (m, 2H), 6.48-6.35 (m, 1H), 5.66-5.44 (m, 1H), 4.71 (dddd, J=9.8, 8.5, 4.6, 3.0 Hz, 1H), 4.63 (ddd, J=9.4, 3.1, 2.1 Hz, 1H), 4.50-4.26 (m, 2H), 1.71 (s, 1H), 1.25 (s, 5H), 1.15 (s, 5H), 1.03 (dd, J=22.4, 6.4 Hz, 3H), 5.44-5.13 (m, 1H). HRMS(B) tR=3.36 min; m/z 485.1830
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([CH3:12])[CH:3]=1.[C:13]([CH:15]1[CH2:17][CH2:16]1)#[CH:14]>C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:15]1([C:13]#[C:14][C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:12])[CH:3]=2)[CH2:17][CH2:16]1
Reactant: C#CC1CC1
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Cc1cc(C#CC2CC2)ccc1C(=O)O
Temperature: 80 °C
Yield: 71.5 %

Procedure:
Methyl 4-Bromo-2-methylbenzoate (1.0 g, 4.4 mmol) was dissolved in triethylamine (5 mL). To the mixture was added copper iodide (43 mg, 5 mol %), followed by PdCl2(PPh3)2 (157 mg, 5 mol %) and ethynylcyclopropane (1.43 ml, 12 mmol). The mixture was heated in a sealed pressure tube at 80° C. for 3 hours. After completion of the reaction, the triethylamine was evaporated and the residue was dissolved in EtOAc and filtered through Celite®. The organic layer was washed with water, brine, and dried (Na2SO4), then filtered and concentrated under vacuum. The residue was purified by column chromatography on sililca gel using EtOAc-hexane (0-100% gradient) as eluent to give the desired product (630 mg). The product was dissolved in 10 mL of MeOH and 10 mL of 2N LiOH and the mixture was refluxed overnight. The MeOH was evaporated and the basic layer was washed with EtOAC, acidified, and re-extracted with EtOAC. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated under vacuum to give the desired product as a beige solid (461 mg). m/z 201 (M+1).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28](=[O:58])[N:29]([CH2:38][C:39]1[CH:40]=[N:41][C:42]([CH3:57])=[C:43]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([C:55]#[N:56])[CH:50]=2)[C:44]=1[CH2:45][OH:46])[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=1)([CH3:26])([CH3:25])[CH3:24].C(=O)(O)[O-].[Na+]>ClCCl>[C:23]([O:27][C:28](=[O:58])[N:29]([CH2:38][C:39]1[CH:40]=[N:41][C:42]([CH3:57])=[C:43]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([C:55]#[N:56])[CH:50]=2)[C:44]=1[CH:45]=[O:46])[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)c(CO)c1OCc1cccc(C#N)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)c(C=O)c1OCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
A mixture of Dess-Martin periodinone (5.0 g, 11.8 mmol) and [5-(3-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-(4-cyano-phenyl)-carbamic acid tert-butyl ester (106) (5.26 g, 10.8 mmol) in dichloromethane (200 mL) was stirred at room temperature for 30 minutes. The reaction mixture was then poured into a solution of saturated aqueous sodium bicarbonate, and the crude product extracted with dichloromethane, dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a crude residue, which was purified by column chromatography on silica gel using a gradient mixture of ethyl acetate:hexane (0:1 to 2:3) as an eluant to give [5-(3-cyano-benzyloxy)-4-formyl-6-methyl-pyridin-3-ylmethyl]-(4-cyano-phenyl)-carbamic acid tert-butyl ester (109) (4.6 g, 88% yield) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[BH3-][C:15]#N.[Na+]>C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:15])[CH2:10][CH2:9]1
Reactant: [BH3-]C#N
Reactant: Brc1ccccc1N1CCNCC1
Agent: C=O
Agent: [Na+]
Product: CN1CCN(c2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.4 %

Procedure:
1-(2-Bromophenyl)piperazine (200 mg) was dissolved in formaldehyde (36.5% in water, 0.603 mL) and the solution was stirred 3 h at RT. NaBH3CN (78.2 mg) was added and the mixture was stirred at RT overnight. NaBH3CN (78.2 mg) was added again and the mixture was stirred at RT for 6 h. The solvents were removed in vacuo and the residue was taken up in EA, washed with sat. NaHCO3, dried (Na2SO4) and evaporated to dryness. The residue was purified by CC (Biotage, SNAP 25 g cartridge, solvent A: Hept; solvent B: EA; gradient in % B: 18 for 4CV, 18 to 100 over 10CV, 100 for 2CV, then MeOH flush for 4CV) to afford 1-(2-bromophenyl)-4-methylpiperazine (111 mg, colorless oil). LC-MS (B): tR=0.57 min; [M+H]+: 255.05.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[OH-].[K+].[CH3:11]O>CS(C)=O>[CH3:11][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[N:4][CH:3]=1
Reactant: CO
Reactant: Cc1ccc(O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc(C)nc1
Temperature: 20 °C
Reaction time: 15 h
Yield: 56 %

Procedure:
150 ml of 3-hydroxy-6-methylpyridine are metered into a solution of 84 g of potassium hydroxide in 400 ml of methanol and 500 ml of dimethyl sulphoxide in the course of one hour. After removal of the methanol on a rotary evaporator, 213 g of methyl iodide, dissolved in 100 ml of dimethyl sulphoxide, are added dropwise, while cooling with ice, and the reaction mixture is stirred at 20° C. for 15 hours and subjected to steam distillation. The distillate is extracted continuously in the extractor with methylene chloride and the extract is concentrated. 85 g (56% of theory) of 5-methoxy-2-methylpyridine are obtained as a colourless oil.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oleyl alcohol, also called cis 9 octadecen-1-ol, (100 g, 0.37M) was dissolved in DCM, dichloromethane and cooled to 0° C. Triethylamine (56.5 g, 78 ml, 0.56M, 1.5 equivalents) was added to the solution at this temperature and the mixture was stirred for one hour. Methanesulphonyl chloride (47 g, 31.8 ml, 1.1 equivalents) was then added to the mixture at this temperature and the mixture was stirred at 0° C. for 30 minutes before being allowed to warm to room temperature. The reaction mixture was washed with ice/water, cold 10% hydrochloric acid, cold solution of sodium bicarbonate, water and brine successively, then dried with sodium sulphate. After filtration, the solvent was removed under vacuum to yield and oil which was chilled overnight to yield a solid with a low melting point (yield 126.5 g, 99%).
Reaction SMILES: C([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=[O:26])[C@@H:22]([NH:28][C:29](=[O:51])[C@H:30]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C@H:20]1[OH:21])(=O)C1C=CC=CC=1>CO.C(N)CCC>[NH2:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=[O:26])[C@@H:22]([NH:28][C:29](=[O:51])[C@H:30]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=2)[NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C@H:20]1[OH:21]
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)O[C@@H]2C(=O)O)cc1
Solvent: CO
Solvent: CCCCN
Product: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@@H]2C(=O)O)cc1
Yield: 78.4 %

Procedure:
A suspension of 1-(6-benzoylamino-9H-purin-9-yl)-3-(N-benzyloxycarbonyl-O-methyl-L-tyrosylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (300 mg) prepared in Example 2 in a mixture of methanol (20 ml) and n-butylamine (10 ml) was boiled under reflux for 1 hour. The mixture was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol (7:3). The fractions containing the object compound were combined and the solvent was evaporated to give 1-(6-amino-9H-purin-9-yl)-3-(N-benzyloxycarbonyl-O-methyl-L-tyrosylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (200 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[OH-].[Na+].[CH2:14](Br)[CH2:15][CH2:16][CH3:17].O>C(O)C>[CH2:14]([O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCBr
Reactant: Oc1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCOc1ccc2ccccc2c1
Yield: 84.9 %

Procedure:
In 100 g of ethanol were dissolved 50 g (0.347 mol) of 2-naphthol and 14.6 g (0.364 mol) of sodium hydroxide. Under reflux, 50 g (0.364 mol) of n-butyl bromide was added to the solution, which was refluxed for a further 4 hours. To the reaction solution were added 200 g of water and 4 g of sodium hydroxide. The organic layer thus separated, 75 g, was distilled in vacuo, obtaining 59 g of 2-n-butoxynaphthalene. The distillate (liquid) solidified when allowed to stand at room temperature.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: Cc1cc(C)c(C(=O)O)c(C)c1
Reactant: O=S(Cl)Cl
Product: Cc1cc(C)c(C(=O)Cl)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 328 mg of 2,4,6-trimethylbenzoic acid and 3 mL of thionyl chloride was stirred at room temperature for 2 hours. The volatile components were evaporate in vacuo, the residue was redissolved in 5 mL of CH2Cl2, and the volatile components were again evaporated in vacuo to give 2,4,6trimethylbenzoyl chloride.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([O:21][CH2:22][C:23](=O)[N:24]([CH3:26])[CH3:25])=[CH:16][CH:15]=2)=O)C>O1CCCC1>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][O:21][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH2:10][OH:9])=[CH:20]2
Reactant: CCOC(=O)c1cc2cc(OCC(=O)N(C)C)ccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc2[nH]c(CO)cc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.4 %

Procedure:
Lithium aluminum hydride (1.7 g, 45 mmol) was added to 5-dimethylcarbamoylmethoxy-1H-indole-2-carboxylic acid ethyl ester (1.4 g, 4.8 mmol) in tetrahydrofuran (80 mL). The mixture was stirred at room temperature for 4 hours and cooled to 0° C. It was then quenched with water (1.7 mL), 15% sodium hydroxide (1.7 mL) and water (1.7 mL). The precipitate was filtered off and the filtrate was concentrated to give 0.6 g (54%) of [5-(2-dimethylamino-ethoxy)-1H-indol-2-yl]-methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:32]([O:33][CH3:34])=[CH:31][C:6]2[CH2:7][C:8](=[O:30])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.C=O.[C:37]([BH3-])#N.[Na+]>>[CH3:1][O:2][C:3]1[C:32]([O:33][CH3:34])=[CH:31][C:6]2[CH2:7][C:8](=[O:30])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:37])[CH2:16][CH2:17][CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(NCCCNCCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Product: COc1ccc(NCCCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-3-(3,4-dimethoxyphenylamino)-propylamine, paraformaldehyde and sodium cyanoborohydride analogously to Example 5.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[N:3][CH:2]=1.Br.[CH3:16][C:17]1([CH3:23])[NH:21][C:20]([NH2:22])=[N:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:16][C:17]1([CH3:23])[CH2:18][N:19]2[C:9](=[O:11])[CH:8]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)[N:22]=[C:20]2[NH:21]1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Reactant: CC1(C)CN=C(N)N1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC1(C)Cn2c(nc(-c3ccncn3)cc2=O)N1

Procedure:
A mixture containing 2.09 (10.3 mmol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate, 2.0 g (10.3 mmol) of 5,5-dimethyl-4,5-dihydro-1H-imidazol-2-ylamine hydrobromide and 2.85 g (20.6 mmol) of potassium carbonate in 15 ml of methanol were heated at reflux temperature during 18 h.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([NH2:39])[CH:37]=2)[CH2:32][CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:39][C:36]4[CH:37]=[C:38]5[C:33]([CH2:32][CH2:31][CH2:30][N:29]5[S:26]([CH3:25])(=[O:28])=[O:27])=[CH:34][CH:35]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: CS(=O)(=O)N1CCCc2ccc(N)cc21
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc5c(c4)N(S(C)(=O)=O)CCC5)nn23)c1

Procedure:
N-tert-Butyl-3-[2-(1-methanesulfonyl-1,2,3,4-tetrahydro-quinolin-7-ylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzenesulfonamide was prepared from N-tert-butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide and 1-methanesulfonyl-1,2,3,4-tetrahydro-quinolin-7-ylamine in an analogous manner to Example 1052a. Product isolated as a yellow solid (69 mg, 57%). m.p.=187-191° C.; LCMS (m/e) 555 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.50 (s, 1H), 9.04 (s, 1H), 8.51-8.42 (m, 2H), 7.82 (d, 1H, J=7.9 Hz), 7.76-7.65 (m, 3H), 7.62 (s, 1H), 7.20 (d, 1H, J=4.8 Hz), 7.16 (d, 1H, J=8.3 Hz), 6.99 (d, 1H, J=4.8 Hz), 3.73-3.67 (m, 2H), 3.00 (s, 3H), 2.78-2.71 (m, 2H), 1.97-1.87 (m, 2H), 1.11 (s, 9H).
Reaction SMILES: C(O)C.C([O:7][CH:8](OC(=O)C)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:24][C:25](=[O:27])[CH3:26])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)(=O)C.S(=O)(=O)(O)O>O>[C:25]([O:24][C:15]([C:12]1[CH:11]=[CH:10][C:9]([CH:8]=[O:7])=[CH:14][CH:13]=1)([C:16]([F:19])([F:18])[F:17])[C:20]([F:21])([F:23])[F:22])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(OC(C)=O)c1ccc(C(OC(C)=O)(C(F)(F)F)C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CC(=O)OC(c1ccc(C=O)cc1)(C(F)(F)F)C(F)(F)F
Yield: 89.1 %

Procedure:
To 130 ml of ethanol are added 60 g (0.15 mole) of α,α-bis-acetyloxy-4-[1-(acetyloxy)-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]toluene and 13.5 ml of concentrated sulfuric acid in 135 ml of water. The resulting solution is stirred and heated at reflux for thirty minutes. The solution is then cooled and extracted with 1 liter of ether to obtain an ether solution which is washed with water and a saturated sodium bicarbonate solution until the washes were basic. The ether solution is dried with anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to give 42 g of 4-[1-(acetyloxy)-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]benzaldehyde. This compound was not further purified but was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=[O:15])[C:12]([C:16]#[N:17])=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34]>>[NH2:17][C:16]1[C:12]2[C:13](=[N:14][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:10]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[CH:11]=2)[O:15][C:32]=1[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34]
Reactant: O=C(CCl)c1ccccc1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Nc1c(C(=O)c2ccccc2)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the product from Step B (0.300 g; 0.8 mmol) in DMP (8 mL) was treated with cesium carbonate (0.521 g; 1.6 mmol), 2-chloroacetophenone (0.124 g; 0.8 mmol), and stirred at room temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethyl acetate:hexane gradient) afforded the title compound. HPLC/MS: 492.9 (M+1), 494.9 (M+3); Rt=4.58 min.