Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[CH:6][N:7](C)C)C.[NH:16]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1)N.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)C>[N:10]1([C:5]2[C:4](=[O:15])[N:16]([C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=3)[NH:7][CH:6]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnc1
Reactant: Cc1ccnc(NN)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: Cc1ccnc(-n2[nH]cc(-n3ccnc3)c2=O)c1

Procedure:
200 mg (1.0 mmol) of the compound from Example 42A and 118 mg (1.0 mmol) of the compound from Example 1A are dissolved in 2 ml ethanol and 44 mg (0.2 mmol) camphor-10-sulfonic acid are added. The mixture is heated under reflux for 16 h and then concentrated and the residue is purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid in the water).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:11].[H-].[Na+].[Br:14][CH2:15][CH2:16][CH2:17]Br>C1COCC1.[Cl-].[Na+].O>[Br:14][CH2:15][CH2:16][CH2:17][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:2]([CH3:1])[C:3]1=[O:11]
Reactant: Cn1c(=O)[nH]c2ccccc21
Reactant: BrCCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCBr)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.6 %

Procedure:
Add portion wise 3-methyl-1,3-dihydro-benzoimidazol-2-one (400 mg, 27.0 mmol) to a suspension of sodium hydride (1.296 g, 32.4 mmol of 60% dispersion in oil) in anhydrous THF (200 mL) under nitrogen over 15 min, then continue to stir for 30 min. Add 1,3-dibromopropane (11.0 mL, 108 mmol) and stir overnight. Then heat at reflux for 3 days. Cool the suspension to room temperature, pour into brine (400 mL), extract with diethyl ether (300 mL), dry over MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 1:1 gradient over 40 min) to give the title compound as a colourless oil (2.15 g, 30%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][O:14][CH3:15])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:16]([CH2:20][C:21](Cl)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][O:14][CH3:15])[CH2:7][CH2:8][N:9]([C:21](=[O:22])[CH2:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(CCOC)CCN(C(=O)CC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.9 %

Procedure:
To a solution of 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.646 g) under an argon atmosphere were added triethylamine (0.668 g, 0.92 ml) and tert-butyl acetyl chloride (0.44 g, 0.45 ml) under ice cooling. The reaction mixture was stirred at RT for 3 h. It was then partitioned between methylene chloride and aqueous 1M HCl, the layers were separated and the aqueous layer washed with 2M aqueous KHCO3 and dried over Na2SO4. The solvent was evaporated off, the residue purified by flash chromatography (AcOEt/heptane, gradient from 0 to 50%) to give 1-(3,3-Dimethyl-butyryl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, (0.46 g) as a light yellow solid. MS (ESI): 314 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6]2[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:23])[C@@H:20]([CH3:22])[NH2:21])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:24][C:2]1([CH3:1])[C:6]2[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[C:19](=[O:23])[C@@H:20]([CH3:22])[NH:21][C:33]4=[O:35])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: C[C@@H](N)C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)CO3)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1NC(=O)N(c2ccc(Oc3cccc4c3C(C)(C)CO4)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 140.1 %

Procedure:
To a solution of N1-{4-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]phenyl}-D-alaninamide (Intermediate 57, 66 mg) in dichloromethane (20 ml, SCRC) was added triethylamine (0.085 ml, 0.607 mmol, SCRC). Triphosgene (24.00 mg, 0.081 mmol, SCRC) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 0.5 hours. The mixture was quenched with water (20 ml) and it was extracted with dichloromethane (3 times 50 ml, SCRC). The combined organic layers were dried, evaporated and purified by column chromatography on silica gel with EtAc/PE (1/30) as eluents to afford the title compound as a white solid (40 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:7]2=[O:16].[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](F)=[CH:27][CH:26]=1)(=[O:24])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:17]([N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:2]=2[O:1][C:28]2[CH:29]=[CH:30][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:26][CH:27]=2)[C:7]1=[O:16])[CH:18]([CH3:20])[CH3:19]
Reactant: COC(=O)c1cc(O)c2c(c1)C(=O)N(CC(C)C)CC2
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)C(=O)N(CC(C)C)CC2
Temperature: 100 °C

Procedure:
A mixture of methyl 5-hydroxy-2-isobutyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (250 mg, 0.90 mmol), 4-fluorophenyl methyl sulfone (236 mg, 1.35 mmol), Cs2CO3 (441 mg, 1.35 mmol) and Cul (100 mg, 1 mmol) in DMF (20 mL) was heated to 100° C. for 4 hours. The solvent was removed under reduced pressure. The residue was poured into water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layers was washed with brine (20 mL×2), dried over Na2SO4 and concentrated. The product was purified via column chromatography on silica gel eluted with 10-30% EtOAc in hexanes to afford the ether (312 mg, 78%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.97 (d, J=6.78 Hz, 6 H) 1.94-2.16 (m, 1 H) 2.94 (t, J=6.59 Hz, 2 H) 3.04-3.16 (m, 3 H) 3.41 (d, J=7.54 Hz, 2 H) 3.55 (t, J=6.59 Hz, 2 H) 3.87-4.01 (m, 3 H) 7.00-7.11 (m, 2 H) 7.80 (d, J=1.70 Hz, 1 H) 7.88-8.00 (m, 2 H) 8.66 (d, J=1.51 Hz, 1 H); MS (ESI, pos): 432.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]([CH2:21][CH2:22][OH:23])[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]([CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(c1cccc(F)c1)c1ccc2c(c1)OCCC2CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1CCOc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Reaction time: 2 h

Procedure:
A solution of 2-[7-(3-Fluoro-benzenesulfonyl)-chroman-4-yl]-ethanol (1.35 g, 4.01 mmol) in CH2Cl2 (40 ml) was cooled to 0° C. Et3N (4.06 g, 40.2 mmol) was added at 0° C. followed by methanesulfonylchloride (0.91 g, 8.00 mmol). The reaction mixture was stirred in an ice bath for 2 hours, then diluted with CH2Cl2, washed with brine, dried with MgSO4, filtered and concentrated to give AN oil residue. The residue was purified with flash chromatography to give methanesulfonic acid 2-[7-(3-fluoro-benzenesulfonyl)-chroman-4-yl]-ethyl ester as a clear oil: 1.35 g; MS: 415.2 (M+H)+, 829.2 (2M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2F)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([CH2:29][N:30]2[CH2:34][C@H:33]([OH:35])[CH2:32][C:31]2=[O:36])[CH:26]=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:19])[CH3:18])[CH:12]=[CH:11][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([CH2:29][N:30]3[CH2:34][C@H:33]([OH:35])[CH2:32][C:31]3=[O:36])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: O=C1C[C@@H](O)CN1Cc1cccc(Br)n1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CN4C[C@H](O)CC4=O)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.16 g, 0.54 mmol) and (4R)-1-[(6-bromopyridin-2-yl)methyl]-4-hydroxypyrrolidin-2-one (0.14 g, 0.53 mmol) as the starting materials.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C-:12]#[N:13].[Na+].[OH-].[Na+]>C(#N)C.O>[C:12]([CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:13]
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: [C-]#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: N#CCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 26.4 %

Procedure:
A solution of 4-bromomethyl-benzoic acid (4.0 g, 18.6 mmol) in acetonitrile (186 mL) was treated with a solution of sodium cyanide (1.0 g, 20.4 mmol) and sodium hydroxide (0.74 g, 18.6 mmol) in water (24 mL). The reaction mixture was heated at reflux for 2 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The resulting solution was washed with chloroform (1×50 mL). The aqueous layer was acidified to pH=3 with a 1N aqueous hydrochloric acid solution. The aqueous layer was extracted with a solution of chloroform/methanol (9:1, 3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 4-cyanomethyl-benzoic acid (0.79 g, 26.3%) as a white solid: mp 193–195° C.; EI-HRMS m/e calcd for C9H7NO2 (M+) 161.0476, found 161.0483.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1Br.CC1(C)COB([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=2)OC1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:3]([OH:12])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1[C:20]1[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1sc(Br)c(Br)c1O
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1sc(-c2ccnn2C)c(Br)c1O
Reaction time: 12 h
Yield: 14.9 %

Procedure:
Methyl 4,5-dibromo-3-hydroxy-2-thiophenecarboxylate (500 mg, 1.59 mmol), 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (339 mg, 1.75 mmol), Pd(PPh3)4 (92 mg, 79.4 μmol) and K2CO3 (876 mg, 6.35 mmol) in dioxane (6.6 mL) and H2O (1.3 mL) were combined in a sealed tube. After 12 h at 80° C., the reaction contents were partitioned between H2O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 0.5% MeOH in DCM) affording the title compound (75 mg, 15%) as a brown residue: LCMS (ES) m/z=318 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([Li])[CH2:7][CH2:8][CH3:9]>CCCCCC>[C:3]1([C:4]2([CH:5]=[O:1])[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:2]=1
Reactant: [Li]CCCC
Reactant: C1CCOC1
Solvent: CCCCCC
Product: O=CC1(c2ccccc2)CCCC1
Temperature: -78 °C

Procedure:
In starting the procedure, to a 250 ml (3-necked, round bottom) flask equipped with a nitrogen inlet tube, a rubber septum and a magnetic stirrer is added 100 ml tetrahydrofuran solution of 5.64 g (0.04 mole) of 2, benzyl-4,4,6-tetramethyl- 4,5-dihydro-1,3-oxazine. The mixture is cooled to -78° C and 0.044 mole of normal butyllithium disssolved in hexane is slowly added.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1C1C=CC=CC=1O)([CH3:4])([CH3:3])[CH3:2].[P:22]([O:37]C1C=CC=CC=1)([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C[O-].[Na+]>>[P:22]([O:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([O:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[O:37][C:6]1[CH:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=1[C:1]([CH3:3])([CH3:2])[CH3:4]
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: CC(C)(C)c1ccc(-c2ccccc2O)c(C(C)(C)C)c1
Agent: C[O-]
Agent: [Na+]
Product: CC(C)(C)c1ccc(OP(Oc2ccccc2)Oc2ccccc2)c(C(C)(C)C)c1

Procedure:
Bis (tetrahydroabietyl)-2,4 di-tert-butyl phenyl phosphite was prepared by first reacting 206 g (1 mol) of 2,4 di-tert-butylphenyl phenol with 310 g (1 mol) of triphenyl phosphite catalyzed with 2 g of sodium methylate (or phenate) to obtain a nominal 2,4 di-tert-butylphenyl diphenyl phosphite. Phenol was distilled through a 20 cm Raschig ring packed column to 150° C. and 30 mm. The reaction terminates at 190° C. at 4 mm after distilling the calculated 1 mol of phenol. The product mixture contained approximately 85% of the desired 2,4,di-tert-butylphenyl diphenylphosphite. The remainder was identified as being predominantly a mixture of bis (2,4 -di-tert-butylphenyl) phenyl phosphite and unreacted triphenyl phosphite.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][N:23]([C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])[CH:24]=1.C(O)(=O)C>C(O)C>[CH:15]1([C@:10]2([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]4[CH:21]=[N:22][N:23]([C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])[CH:24]=4)[N:7]=3)[C:9]2=[O:18])[CH2:17][CH2:16]1
Reactant: N#C[C@@]1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O
Reactant: CC(C)(CO)n1cc(N)cn1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(CO)n1cc(Nc2nccc(N3CC[C@@](C#N)(C4CC4)C3=O)n2)cn1
Yield: 41.3 %

Procedure:
A solution of (3S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (11.5 g) obtained in Step E of Example 103, 2-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-1-ol (7.1 g) obtained in Step H of Example 103 and acetic acid (2.6 mL) in ethanol (200 mL) was stirred in a sealed tube reactor at 150° C. for 1 hr, and the solvent was evaporated under reduced pressure. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (diisopropyl ether/ethyl acetate) to give the title compound (6.9 g).
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1Br)(C)(C)C.[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>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.[Cu]I.C(#N)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:17])=[C:10]([C:25]#[C:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1ccccc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl(2-bromo-4-chlorophenoxy)acetate (350 mg; 1.09 mmol) and phenylacetylene (Aldrich; 122 mg; 1.20 mmol) in degassed, anhydrous ACN (2.80 mL) was treated with dichlorobis(triphenylphosphine)palladium(II) (38 mg; 0.05 mmol), copper(I) iodide (10 mg; 0.05 mmol) and triethylamine (0.45 mL; 3.26 mmol). The reaction mixture was heated at 50° C. under stirring for 16 hours. The solvent was evaporated, the residue dissolved in DCM (4 mL) and TFA (1 mL) was added. After stirring for 45 minutes, the solvents were removed under vacuum and the crude product purified by preparative HPLC. The title compound was obtained as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[F:22].FC(F)(F)C(O)=O>ClCCl>[F:22][C:3]1[CH:4]=[C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)[CH:20]=[CH:21][C:2]=1[NH2:1]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(N)c(F)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(CC2CCNCC2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 118.4 %

Procedure:
Tert-butyl 4-(4-amino-3-fluorobenzyl)piperidine-1-carboxylate (6.49 mmol, 2 g) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (3 mL) was added and the reaction mixture stirred at room temperature for 30 minutes. The reaction mixture was purified by SCX chromatography to give the intermediate 2-fluoro-4-(piperidin-4-ylmethyl)aniline (1.6 g) as a colourless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([CH2:10]Cl)[C:4]=1[OH:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1>[Cl-].[Zn+2].[Cl-]>[Cl:13][C:14]1[CH:15]=[C:16]([N+:21]([O-:23])=[O:22])[C:17]([OH:20])=[C:18]([CH:19]=1)[CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([CH2:10][C:18]2[CH:19]=[C:14]([Cl:13])[CH:15]=[C:16]([N+:21]([O-:23])=[O:22])[C:17]=2[OH:20])[C:4]=1[OH:12]
Reactant: Oc1c(CCl)cc(Cl)cc1CCl
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Agent: [Cl-]
Agent: [Zn+2]
Product: O=[N+]([O-])c1cc(Cl)cc(Cc2cc(Cl)cc(Cc3cc(Cl)cc([N+](=O)[O-])c3O)c2O)c1O
Reaction time: 1 h
Yield: 18.8 %

Procedure:
Zinc chloride (2 g) was added in small portions over 75 min to a melt of 2,6-bis(chloromethyl)-4-chlorophenol (1.2 g) and 4-chloro-2-nitrophenol (3 g) at a temperature of 120°. The mixture was stirred at this temperature for approximately 1 hr. The black product was extracted several times with acetone and the extract filtered to remove black inorganic material. The acetone was removed by distillation under reduced pressure and the residue chromatographed on silica gel. Elution with hexane containing 3% ethyl acetate gave unreacted 4-chloro-2-nitrophenol and elution with hexane containing 20% ethyl acetate gave the title compound (0.5 g) which was recrystallised from aqueous ethanol; m.p. 200°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[NH:12][C:13]1[N:18]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=[CH:15][N:14]=1.[H][H]>C(O)C.[Ni]>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[C:4]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=[CH:15][N:14]=2)[CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(CO)c(Nc2nccc(-c3cccnc3)n2)c1
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(CO)c(Nc2nccc(-c3cccnc3)n2)c1

Procedure:
A solution of N-(2-hydroxymethyl-5-nitro-phenyl)-4-(3-pyridinyl)-2-pyrimidinamine (0.23 g, 0.71 mmol) in ethanol (230 mL) is hydrogenated at atmospheric pressure over Raney nickel (0.2 g) at 25° C.. The calculated amount of hydrogen is taken up in 13 h. The mixture is then filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent 25% aqueous ammonia-ethanol-dichloromethane (1:9:90), to give the title compound as a yellow crystalline solid, m.p. 213-215° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:10])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1Cl.Cl.[NH2:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:10][C:3]1[N:4]=[C:5]([CH3:9])[N:6]=[C:7]([NH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:2]=1[NH2:1]
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Reactant: NC1CCOCC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)c(N)c(NC2CCOCC2)n1
Temperature: 100 °C
Yield: 94.5 %

Procedure:
In a 300 mL glass pressure reactor, combine 5-amino-4,6-dichloro-2-methylpyrimidine (20.0 g, 97%, 109.0 mmol), 4-aminotetrahydropyran hydrochloride (21.0 g, 152.6 mmol), di-isopropylethylamine (57.0 mL, 326.9 mmol) and isopropyl alcohol (100 mL). Seal the pressure vessel tightly, start stirring, and adjust the set-point for heat control to 100° C. Stir the mixture at 100° C. for 24 hours. Cool the reactor contents to 60° C., vent the vessel of pressure, and add 4-aminotetrahydropyran hydrochloride (2.25 g, 16.3 mmol). Re-seal the vessel, heat the contents to an internal temperature of 100° C., and stir for an additional 24 hours. Cool the reaction mixture to ambient temperature, vent the reactor of pressure, and transfer the contents to a recovery flask. Concentrate the mixture under reduced pressure to approximately ⅓ of its original volume. Add water (200 mL) and ethyl acetate (200 mL) and transfer the resulting mixture to a separatory funnel Separate the layers, re-extract the aqueous layer with ethyl acetate (100 mL) and combine all organics. Wash with water (2×100 mL) and brine (100 mL), then dry the organic layer over anhydrous sodium sulfate. Concentrate under reduced pressure to afford 6-chloro-2-methyl-N*4*-(tetrahydro-2H-pyran-4-yl)-pyrimidine-4,5-diamine as an off-white solid (25.0 g). MS (m/z): 243/245 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:18])[C:5]2[C:10]([C:11](=[O:15])[C:12]=1[O:13][CH3:14])=[C:9]([C:16]#[N:17])[CH:8]=[CH:7][CH:6]=2.C(O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:1]([O:2][C:3]1[C:4](=[O:18])[C:5]2[C:10]([C:11](=[O:15])[C:12]=1[O:13][CH2:14][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[C:9]([C:16]#[N:17])[CH:8]=[CH:7][CH:6]=2)[C:3]1[CH:4]=[CH:5][CH:10]=[CH:11][CH:12]=1
Reactant: COC1=C(OC)C(=O)c2c(C#N)cccc2C1=O
Reactant: OCc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1cccc2c1C(=O)C(OCc1ccccc1)=C(OCc1ccccc1)C2=O
Reaction time: 0.33 h

Procedure:
14b From Example 9 (972 mg, 4 mmol) is dissolved in tetrahydrofuran (100 ml) containing benzyl alcohol (8 ml) and the tetrahydrofuran (40 ml) is distilled off. The remaining solution is cooled to 15° and sodium hydride (5 mg) with 3 A molecular sieve (2 g) is added. The resulting mixture is stirred at 15°-20° for 20 minutes. The mixture is filtered through a celite bed, the filtrate concentrated to dryness and the residue crystallized from isopropanol giving 1.01 g (64%) of 23 with mp 118°-121°.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]([NH2:10])=[O:9])[CH2:2][CH2:3][CH3:4].[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15]N.N>>[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15][NH:10][C:8](=[O:9])[CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCC(N)=O
Reactant: CN(C)CCCN
Agent: N
Product: CCCCOCCC(=O)NCCCN(C)C

Procedure:
145.2 g (1.0 mole) of 3-n-butoxypropionamide are heated with 107.3 g (1.05 mole) of 3-dimethylaminopropylamine for 8 hours in a temperature range of 150°-170° C. until the evolution of ammonia is complete. In the subsequent distillation in a high vacuum, 204 g (0.89 mole =89% of the theoretical yield) of colorless liquid are obtained having a Bp0.1 of 122° to 124° C.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:19]=O)=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[N+:25](CC)([O-])=O.C([O-])(=O)C.[Na+]>O>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:19]#[N:25])=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc2c(cc1O)N(Cc1ccccc1)CCC2
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cc2c(cc1O)N(Cc1ccccc1)CCC2
Temperature: 115 °C
Yield: 44.5 %

Procedure:
To a solution of 1-benzyl-7-hydroxy-1,2,3,4-tetrahydro-quinoline-6-carbaldehyde (45 mg, 0.17 mmol) from step 3 in acetic acid (0.38 mL, 6.6 mmol) was added nitroethane (0.24 mL, 3.4 mmol) and sodium acetate (270 mg, 3.4 mmol). The reaction mixture was heated at a sealed tube at 115° C. overnight. Added some water and extracted it with ether. Combined organic layer and evaporated under vacuum. It was purified by prep TLC eluting with 10% ethyl acetate-hexane and providing 20 mg (45%) of the title compound. 1H-NMR (CDCl3) δ 7.36-7.21 (m, 3H), 7.18-7.14 (m, 2H), 6.99 (s, 1H), 5.98 (s, 1H), 4.48 (s, 2H), 3.41 (t, J=5.7Hz, 2H), 2.70 (t, J=6.4Hz, 2H), 1.97 (m, 2H).