Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(CCCN=C=NCC)C.C(N(CC)CC)C.[CH:31]1([CH2:34][N:35]2[C:43]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[N:42][C:41]3[C:36]2=[N:37][C:38]([C:56]2[CH:57]=[N:58][C:59]([NH2:62])=[N:60][CH:61]=2)=[N:39][C:40]=3[N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[CH2:33][CH2:32]1.[N:63]1([CH2:68][C:69](O)=[O:70])[CH:67]=[CH:66][N:65]=[CH:64]1>ClCCl.CO.CN(C)C=O>[CH:31]1([CH2:34][N:35]2[C:43]([N:44]3[CH2:49][CH2:48][N:47]([C:69](=[O:70])[CH2:68][N:63]4[CH:67]=[CH:66][N:65]=[CH:64]4)[CH2:46][CH2:45]3)=[N:42][C:41]3[C:36]2=[N:37][C:38]([C:56]2[CH:61]=[N:60][C:59]([NH2:62])=[N:58][CH:57]=2)=[N:39][C:40]=3[N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[CH2:32][CH2:33]1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCNCC4)n(CC4CC4)c3n2)cn1
Reactant: O=C(O)Cn1ccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCN(C(=O)Cn5ccnc5)CC4)n(CC4CC4)c3n2)cn1
Reaction time: 17.5 h
Yield: 79.3 %

Procedure:
1-Hydroxybenzotriazole monohydrate (38.2 mg, 0.25 mmol), 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (71.8 mg, 0.37 mmol), and triethylamine (52.2 μl, 0.37 mmol) were added to an N,N-dimethylformamide suspension (3.0 ml) of 5-[9-(cyclopropylmethyl)-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl]pyrimidin-2-amine (109.0 mg, 0.25 mmol) and imidazol-1-ylacetic acid (37.8 mg, 0.30 mmol) at room temperature. The resulting mixture was stirred for 17.5 hours and the reaction mixture was poured into dichloromethane-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (dichloromethane:methanol=6:1) to give the title compound (108.0 mg, 79%) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:11])[CH:7]=[N:8]2)=[C:4]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1>>[CH:13]1([NH:12][C:4]2[N:3]=[C:2]([N:21]3[C:20]([CH3:19])=[CH:24][C:23]([CH3:25])=[N:22]3)[N:10]=[C:9]3[C:5]=2[N:6]([CH3:11])[CH:7]=[N:8]3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cn1cnc2nc(Cl)nc(NC3CCCCC3)c21
Reactant: Cc1cc(C)[nH]n1
Product: Cc1cc(C)n(-c2nc(NC3CCCCC3)c3c(ncn3C)n2)n1

Procedure:
Was prepared according to Example 6 from (2-chloro-7-methyl-7H-purin-6-yl)cyclohexyl-amine and 3,5-dimethylpyrazole.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:13]([O:15]CC)=[O:14])=[CH:6][CH:5]=1.Cl>C1COCC1.CO.O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(C)(CCc1ccc(Br)cc1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(CCc1ccc(Br)cc1)(C(=O)O)S(C)(=O)=O
Temperature: 0 °C
Yield: 32.3 %

Procedure:
Lithium hydroxide (3.29 g, 78.5 mmol) was added to a stirred solution of (+/−)-ethyl 4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoate (9.50 g, 78.5 mmol) in THF:MeOH:water (2:2:1, 225 mL) at 0° C. The reaction was warmed to room temperature as the ice bath expired. After 18 hours the reaction was acidified to pH 4 with 1N HCl (aq) and extracted with ethyl acetate (2×). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo to give a white solid (8.5 g, 97%). LCMS m/z 333.1 (M−1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (s, 3H) 1.95-2.05 (m, 1H) 2.30-2.48 (m, 2H) 2.67-2.79 (m, 1H) 3.10 (s, 3H) 3.26 (br. s., 1H) 7.17-7.24 (m, 2H) 7.43-7.52 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]12[CH2:28][CH2:27][C:22]3([O:26][CH2:25][CH2:24][O:23]3)[CH2:21][CH:9]1[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[C:17]([CH:19]=[O:20])[N:16]=[CH:15][C:14]=12.[F:29][C:30]1[CH:35]=[CH:34][C:33]([Mg]Br)=[CH:32][CH:31]=1.[NH4+].[Cl-].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1>[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH:19]([C:17]2[N:16]=[CH:15][C:14]3[C@:8]4([CH2:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH2:28][CH2:27][C:22]5([O:26][CH2:25][CH2:24][O:23]5)[CH2:21][C@H:9]4[CH2:10][CH2:11][CH2:12][C:13]=3[CH:18]=2)[OH:20])=[CH:32][CH:31]=1
Reactant: O=Cc1cc2c(cn1)C1(Cc3ccccn3)CCC3(CC1CCC2)OCCO3
Reactant: Fc1ccc([Mg]Br)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)c1cc2c(cn1)[C@]1(Cc3ccccn3)CCC3(C[C@H]1CCC2)OCCO3

Procedure:
Rac-(7aR,11aS)-11a-(Pyridin-2-ylmethyl)-5,6,7,7a,8,10,11,11a-octahydro spiro[benzo[6,7]cyclohepta[1,2-c]pyridine-9,2′-[1,3]dioxolane]-3-carbaldehyde (146, R2=Pyridin-2-ylmethyl) (0.400 g, 1.06 mmol) and THF (10 mL) were added to a round bottom flask and stirred. (4-Fluorophenyl)magnesium bromide (2M in diethyl ether) (0.95 mL, 1.90 mmol) was added and the mixture was stirred at rt for about 1 h. Sat. aq. NH4Cl was added and the product was extracted with EtOAc (15 mL), dried over MgSO4 and concentrated in vacuo. The residue was taken into DCM (6 mL) and stirred at rt. Dess-Martin periodinane (0.556 g, 1.31 mmol) was added and mixture was stirred at rt for about 2 h. Sat. aq. NaHCO3 (5 mL) and sat. aq. Na2S2O3 (5 mL) were added and the resulting mixture was extracted with EtOAc (15 mL), dried over Na2SO4 and concentrated in vacuo.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH:7]([O:18][Si](C)(C)C)[CH2:8][P:9]([CH2:14][CH2:15][CH2:16][CH3:17])(=[O:13])[O:10]CC)C(=O)C2=CC=CC=C12.[ClH:29]>>[ClH:29].[NH2:5][CH2:6][CH:7]([OH:18])[CH2:8][P:9]([CH2:14][CH2:15][CH2:16][CH3:17])(=[O:10])[OH:13]
Reactant: CCCCP(=O)(CC(CN1C(=O)c2ccccc2C1=O)O[Si](C)(C)C)OCC
Agent: Cl
Product: CCCCP(=O)(O)CC(O)CN
Temperature: 25 °C

Procedure:
The solution of 2.4 g of ethyl 3-phthalimido-2-trimethylsilyloxy-propyl(n-butyl)phosphinate in 50 ml of concentrated aqueous hydrochloric acid is heated to reflux for 20 hours. After this time the suspension is cooled to room temperature and filtered.The filtrate is evaporated to dryness and the resulting semi-solid is co-evaporated with water (5×50 ml) and absolute ethanol (5×100ml) and the white solid dried in high vacuum overnight. Crystallisation from absolute ethanol affords 3-amino-2-hydroxy-propyl(n-butyl)phosphinic acid hydrochloride, m.p. 158°-160°.
Reaction SMILES: C([N:8]1[C:12]2[C:13]([C:17]([NH:19][C:20]3[CH:51]=[CH:50][C:23]([C:24]([N:26]([CH3:49])[C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=4[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]4)=[O:41])=[O:25])=[CH:22][C:21]=3[O:52][CH3:53])=[O:18])=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:54][O:55][CH3:56])C1C=CC=CC=1.C(O)=O>CO>[CH3:53][O:52][C:21]1[CH:22]=[C:23]([CH:50]=[CH:51][C:20]=1[NH:19][C:17]([C:13]1[C:12]2[N:8]=[C:9]([CH2:54][O:55][CH3:56])[NH:10][C:11]=2[CH:16]=[CH:15][CH:14]=1)=[O:18])[C:24]([N:26]([CH3:49])[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]1)=[O:41])=[O:25]
Reactant: COCc1nc2cccc(C(=O)Nc3ccc(C(=O)N(C)c4ccc(C)cc4OCCCCCC(=O)N4CCN(C)CC4)cc3OC)c2n1Cc1ccccc1
Solvent: CO
Solvent: O=CO
Product: COCc1nc2c(C(=O)Nc3ccc(C(=O)N(C)c4ccc(C)cc4OCCCCCC(=O)N4CCN(C)CC4)cc3OC)cccc2[nH]1
Yield: 27.2 %

Procedure:
A mixture of 4-(3-benzyl-2-methoxymethyl-3 H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]-phenyl]benzamide (200 mg) and 5% formic acid in methanol solution (10 ml) was refluxed for 24 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in chloroform. The solution was washed with saturated aqueous sodium bicarbonate solution and the organic layer was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by preparative thin-layer chromatography (chloroform-methanol=10:1) to give 3-methoxy-4-(2-methoxymethyl-1 H-benzimidazol-4-yl)carbonylamino-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (48 mg) as a powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:8](OCC)(OCC)[O:9][CH2:10][CH3:11]>Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:1]=[CH:8][O:9][CH2:10][CH3:11])[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cccnc1
Agent: Cl
Product: CCOC=Nc1cccnc1

Procedure:
A solution of 3-aminopyridine (20.0 g, 0.21 m) in excess triethyl orthoformate (100 ml) and ethanolic hydrogen chloride (0.3 ml) was heated under reflux for 72 hours. Ethanol and excess triethyl orthoformate were then removed by distillation over a period of 5 hours. Solid potassium carbonate (100 mg) was added to the residue, and the last traces of triethyl orthoformate were removed in vacuo. The residue was then distilled under reduced pressure to yield the desired imido ester, ethyl N-(3-pyridyl)-formimidate, as a colourless liquid, (b.p. 62°/0.5 mm) (24 g, 75%), n.m.r. (CDCl3): δ=1.4 (t, --CH2CH3), 4.32 (q, --CH2CH3), 7.73 (s, --N=CH--O).
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Na+].[Na+].[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([O:18][CH:19]([F:21])[F:20])[CH:17]=1)[S:14][CH2:13][CH2:12][C@:11]2([OH:24])CO>O.[Pt]>[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([O:18][CH:19]([F:20])[F:21])[CH:17]=1)[S:14][CH2:13][CH2:12][C@@:11]2([C:1]([OH:2])=[O:4])[OH:24]
Reactant: O=C([O-])[O-]
Reactant: OC[C@@]1(O)CCSc2c(OC(F)F)cc(Cl)cc21
Agent: [Pt]
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@]1(O)CCSc2c(OC(F)F)cc(Cl)cc21
Temperature: 95 °C
Reaction time: 30 h
Yield: 74.9 %

Procedure:
Sodium carbonate (0.72 g, 6.7 mmol) and 5% Pt/C (1.50 g, 75% weight of reactant) were added to a solution of (R)-6-chloro-8-difluoromethoxy-4-hydroxy-4-hydroxymethylthiochromane (2.0 g, 6.7 mmol; from step (v) above) in H2O (180 mL). The mixture was vigorously stirred at ca. 95° C. for 20-40 h with air being directly bubbled into the reaction mixture. The reaction was cooled to room temperature and filtered through a pad of Celite with saturated Na2CO3 solution (ca. 100 mL). The resulting liquid was slowly acidified with 2 N HCl (ca. 200 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (75 mL), dried (Na2SO4), filtered, and concentrated in vacuo to afford 1.56 g (ca. 75%) of the sub-title compound as a brown oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[CH3:15])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([N:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(c1ccccc1-c1ccc(Cl)cc1)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(c1ccccc1-c1ccc(Cl)cc1)N1CCNCC1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of EXAMPLE 175B (650 mg) in dichloromethane (6 mL) was added trifluoroacetic acid (6 mL) at 0° C. The reaction mixture was stirred at 0° C. for 50 minutes and concentrated. The concentrate was dissolved in dichloromethane, washed with aqueous NaHCO3 and the organic layer was dried over Na2SO4, and concentrated.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])=[C:24]([CH3:37])[CH:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:31]([C:30]3[CH:29]=[C:28]([C:25]4[CH:26]=[CH:27][C:22]([F:21])=[CH:23][C:24]=4[CH3:37])[CH:36]=[CH:35][CH:34]=3)=[O:32])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: Cc1cc(F)ccc1-c1cccc(C(=O)O)c1
Reactant: CSc1nccc(Oc2ccc(N)c3ccccc23)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1nccc(Oc2ccc(NC(=O)c3cccc(-c4ccc(F)cc4C)c3)c3ccccc23)n1
Yield: 13.5 %

Procedure:
4-(2-Methylsulfanylpyrimidin-4-yloxy)-naphthalen-1-ylamine (320 mg, 1 mmol), 3-(4-fluoro-2-methylphenyl)benzoic acid (230 mg, 1.0 mmol), HBTU (569 mg, 1.5 mmol) and diisopropylethylamine (0.53 ml, 3.0 mmol) are stirred at room temperature in anhydrous dimethylformamide (5 ml) for 1 day. The mixture is then poured into ethyl acetate (100 ml) and washed with water (100 ml). The organic layer is then dried over anhydrous sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluted with 20-30-40% ethyl acetate in hexanes to give product as a pink solid recrystalized from ethyl acetate/hexanes to give 4′-fluoro-2′-methyl-biphenyl-3-carboxylic acid[4-(2-methylsulfanylpyrimidin-4-yloxy)-naphthalen-1-yl]-amide as pink crystals (67 mg). 1H NMR 400 MHz (CDCl3) 8.30(d, 1H, J=6 Hz), 8.14(s, 1H), 8.0(d, 1H, J=8 Hz), 7.86-7.92(m, 4H), 7.44-7.56(m, 4H), 7.28(d, 1H, J=8.4), 7.18(m, 1H), 6.9-6.97(m, 2H), 6.46(d, 1H, J=5.6 Hz), 2.23(d, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].[O:26]1[CH2:30][CH2:29][CH:28]([C:31](O)=O)[CH2:27]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.C([O-])(O)=O.[Na+]>CN(C=O)C>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:31]([CH:28]5[CH2:29][CH2:30][O:26][CH2:27]5)[N:24]([CH3:25])[C:3]=4[CH:4]=3)[C:9](=[O:23])[CH:10]=2)=[CH:21][CH:20]=1
Reactant: O=C(O)C1CCOC1
Reactant: CNc1cc(-n2ccc(OCc3ccc(F)cc3)cc2=O)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(C2CCOC2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (56.1 mg), tetrahydro-3-furoic acid (0.016 ml), HATU (66.0 mg) and N,N-diisopropylethylamine (0.087 ml) in DMF (1.50 ml) was stirred at room temperature for 1 h. The mixture was poured into saturated NaHCO3 solution and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in AcOH (1.50 ml), and the mixture was stirred at 80° C. for 1 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/EtOAc). The solid was washed with EtOAc/hexane to give the title compound (34.3 mg) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C:3]=1N.Cl.[OH2:18]>>[Cl:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:2]([CH3:1])[C:3]=1[OH:18]
Reactant: O
Reactant: Cc1cccc(Oc2cccc(Cl)c2)c1N
Agent: Cl
Product: Cc1cccc(Oc2cccc(Cl)c2)c1O

Procedure:
A mixture of 2-methyl-6-(3-chlorophenoxy)aniline (40 g) and conc. hydrochloric acid (36 ml) in water (125 ml) was treated in a similar manner to that of Example 6-(1) to give oily 6-(3-chlorophenoxy)-o-cresol (13.9 g)
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([C:8]1[CH:22]=[CH:21][C:11]([CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)#[N:7].CI>CCCCCC.O1CCCC1>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH:12]([P:13](=[O:20])([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19])[CH3:1])=[CH:21][CH:22]=1)#[N:7]
Reactant: [Li]CCCC
Reactant: CCOP(=O)(Cc1ccc(C#N)cc1)OCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: CCOP(=O)(OCC)C(C)c1ccc(C#N)cc1
Temperature: -40 °C
Reaction time: 0.42 h

Procedure:
18.7 ml of a 1.6M solution of n-butyllithium in n-hexane are added dropwise with stirring at -50° C. to a solution of 7.5 g of diethyl 4-cyanobenzylphosphonate in 60 ml of tetrahydrofuran, the mixture is subsequently stirred at -40° C. for 25 minutes and 4.7 g of methyl iodide in 20 ml of tetrahydrofuran are then added dropwise at -40° C. After stirring overnight at ambient temperature, the mixture is evaporated down, the residue is taken up in ethyl acetate and washed with water, and the organic phase is dried and evaporated down. After purification by column chromatography on Silica gel (petroleum ether/2-propanol=6:1 to 2:1, v/v), 5.7 g of the title compound are obtained as a colourless oil. Rf value: 0.52 (Silica gel, petroleum ether/2-propanol=3:1, v/v).
Reaction SMILES: Cl.[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:4])[CH3:3].[CH3:32][CH:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>>[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:27][CH2:28][N:29]([S:35]([CH:33]([CH3:34])[CH3:32])(=[O:37])=[O:36])[CH2:30][CH2:31]1)=[O:25])([CH3:3])[CH3:4]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3C(C)C)CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)C(C)C)CC2)n3C(C)C)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-isopropyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and 2-propanesulfonyl chloride. Off-white solid. MS (m/z): 519.3 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][CH2:12][CH:13]=[C:14]([CH3:18])[C:15](Cl)=[O:16])(=[O:10])[CH3:9].[CH3:19][C:20]1[CH2:25][CH2:24][CH2:23][C:22]([CH3:27])([CH3:26])[C:21]=1[CH2:28][CH:29]=[C:30]([CH3:33])[C:31]#[CH:32]>[Cu]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.C1COCC1>[C:8]([O:11][CH2:12][CH:13]=[C:14]([CH3:18])[C:15](=[O:16])[C:32]#[C:31][C:30]([CH3:33])=[CH:29][CH2:28][C:21]1[C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][CH2:25][C:20]=1[CH3:19])(=[O:10])[CH3:9]
Reactant: C#CC(C)=CCC1=C(C)CCCC1(C)C
Reactant: CC(=O)OCC=C(C)C(=O)Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCC=C(C)C(=O)C#CC(C)=CCC1=C(C)CCCC1(C)C
Reaction time: 0.08 h

Procedure:
Under nitrogen atmosphere 59.9 mg (0.308 mmol) of copper(I) iodide and 110.3 mg (0.154 mmol) of bis(triphenylphosphine)palladium(II) dichloride [(PPh3)2PdCl2] were added to a 100 ml four-necked flask. At 23° C., 42.0 ml of anhydrous THF was added and the yellow suspension was stirred for 5 min. When 2.15 ml (15.4 mmol) of triethylamine were introduced drop wise via syringe an orange solution was obtained. Within 1 minute 3.10 g (15.4 mmol) of 4-chloro-3-methyl-4-oxobut-2-enyl acetate (compound of formula (Ia)) were added and the solution turned dark orange. Upon drop wise addition of 2.92 g (14.0 mmol) of 1,3,3-trimethyl-2-(3-methylpent-2-en-4-ynyl)cyclohex-1-ene (compound of formula (III))
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:34]3[C:29]([CH3:28])=[N:30][CH:31]=[CH:32][CH:33]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1ncccc1B(O)O
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: Cc1ncccc1-c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 36 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and (2-methylpyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.71 min, m/z=459.0 [M+H]+, m/z=547.2 [M−H]−.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][S:7][C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12)=[N+]=[N-].Cl.[H][H]>C1COCC1.C(O)C.O.[Pd]>[NH2:1][CH2:4][CH2:5][CH2:6][S:7][C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12
Reactant: [N-]=[N+]=NCCCSc1ncn2ccsc12
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: NCCCSc1ncn2ccsc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7-(3-Azidopropyl)thioimidazo[5,1-b]thiazole (1.46 g) was dissolved in 30 ml of THF ethanol and 6 ml of water, and 6.1 ml of a 1 N aqueous hydrochloric acid solution and 1.46 g of 10% Pd-C were added to the solution. The air in the reaction vessel was replaced by hydrogen, and the contents of the reaction vessel were stirred at room temperature for 24 hr. The catalyst was removed by filtration on Celite, and was washed with water. The filtrate was concentrated under the reduced pressure. A 1 N aqueous sodium hydroxide solution (20 ml) was added to the residue, and the mixture was extracted with dichloromethane five times. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation to prepare 1.15 g of 7-(3-aminopropyl)thioimidazo[5,1-b]thiazole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:4][N:3]=1.[CH3:17][C:18]([O:21][C:22]([NH:24][C@@H:25]([CH2:30][C:31]#[CH:32])[C:26]([O:28][CH3:29])=[O:27])=[O:23])([CH3:20])[CH3:19].C(NCC)C>C(OCC)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>[CH3:20][C:18]([O:21][C:22]([NH:24][C@@H:25]([CH2:30][C:31]#[C:32][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:4][N:3]=1)[C:26]([O:28][CH3:29])=[O:27])=[O:23])([CH3:17])[CH3:19]
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Reactant: Fc1ccccc1COc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOCC
Solvent: CCNCC
Product: COC(=O)[C@H](CC#Cc1ccc(OCc2ccccc2F)cn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.4 %

Procedure:
To a solution of 2-bromo-5-{[(2-fluorophenyl)methyl]oxy}pyridine (D82, 0.60 g, 2.13 mmol), methyl (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate (D64, 1.20 g, 5.30 mmol), synthesized with an analogous procedure to the one described hereinabove, and diethylamine (1.10 ml, 10.65 mmol) in diethyl ether (20 ml) were added copper iodide (0.042 g, 0.22 mmol) and PdCl2(PPh3)2 (0.077 g, 0.11 mmol) and the mixture was stirred for three hours at room temperature. The reaction was quenched with a saturated solution of ammonium chloride diluted with water and extracted with diethyl ether. The organic layer was dried (Na2SO4) filtered and evaporated. The residue was purified by chromatography on silica gel using cyclohexane/ethyl acetate (9:1 to 8:2) to afford the title compound as a yellow solid (0.36 g, 40%). Rt (HPLC): 5.64 min; MS: (ES/+) m/z: 429 [MH]+ C23H25FN2O5 requires 428; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.28-8.39 (m, 1H); 7.44-7.53 (m, 1H); 7.32-7.41 (m, 2H); 7.16-7.25 (m, 2H); 7.08-7.16 (m, 1H); 5.37-5.55 (m, 1H); 5.19 (s, 2H); 4.46-4.66 (m, 1H); 3.81 (s, 3H); 2.91-3.07 (m, 2H); 1.47 (s, 9H).