Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH2:14][CH2:15][CH2:16][OH:17])=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)N>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([O:13][CH2:14][CH2:15][CH2:16][OH:17])[C:3]=23)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: CN(C)C=Nc1[nH]nc(OCCCO)c1C#N
Product: OCCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 52.1 %

Procedure:
The procedure described in Example 1 was repeated using N′-[4-cyano-3-(3-hydroxypropoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (150 mg, 0.63 mmol) and 3-chloro-4-(pyridin-2-ylmethoxy)aniline (148 mg, 0.63 mmol) to give the title compound as a white solid (140 mg, 52%); NMR Spectrum: 1.94-1.98 (m, 2H), 3.59-3.62 (m, 2H), 4.39 (t, 2H), 4.62 (br s, 1H), 5.29 (s, 2H), 7.23 (d, 1H), 7.35-7.38 (m, 1H), 7.54-7.59 (m, 2H), 7.86-7.91 (m, 2H), 8.28 (s, 1H), 8.43 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 427 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([O:12][C:13](=[O:17])[C:14]#[C:15][CH3:16])[CH3:11].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:10]([O:12][C:13](=[O:17])/[CH:14]=[C:15](/[O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[F:1])\[CH3:16])[CH3:11]
Reactant: CC#CC(=O)OCC
Reactant: Cc1cccc(O)c1F
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(C)c1F
Yield: 22.3 %

Procedure:
To a stirred mixture of 2-fluoro-3-methyl-phenol (20.0 g, 0.158 mol) and ethyl-2-butynoate (33.6 g, 0.300 mol) in tetrahydrofuran (100 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (25.4 g, 0.167 mol) slowly. After addition was complete the mixture was stirred at reflux overnight. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated and residue purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 330 g, 0% to 15% ethyl acetate/hexanes) which afforded (E)-3-(2-fluoro-3-methyl-phenoxy)-but-2-enoic acid ethyl ester (8.40 g, 23%) as a clear oil.
Reaction SMILES: [C:1]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH2:16]([O:23][C:24]1[CH:29]=[C:28](F)[CH:27]=[C:26]([F:31])[C:25]=1[N+:32]([O-:34])=[O:33])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([O:23][C:24]1[C:25]([N+:32]([O-:34])=[O:33])=[C:26]([F:31])[CH:27]=[C:28]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1cc(F)c([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 19.7 %

Procedure:
To a solution of tert-butyl ethyl malonate (10.0 g, 51.0 mmol) in DMF (200 ml) was added sodium hydride (60% in oil, 2.04 g, 51.0 mmol) at 0° C. under stirring. The reaction mixture was stirred at the same temperature for 30 minutes. A solution of 2-benzyloxy-4,6-difluoronitrobenzene (9.02 g, 34.0 mmol) in DMF (60 ml) was added dropwise to the reaction mixture at 0° C. The reaction mixture was then stirred at 80° C. for 18 hours. After cooling to room temperature, the reaction mixture was poured in ice-1N HCl to neutralize therewith, followed by extraction with ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, then distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from with ethyl acetate/hexane (1/5) eluate fractions, tert-butyl ethyl 5-benzyloxy-3-fluoro-4-nitrophenylmalonate (2.91 g, 17%) was obtained as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[N:7]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([C:28](O)=[O:29])[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:31])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.Cl.[CH3:63][O:64][NH:65][CH3:66].CN1CCOCC1.Cl>O1CCCC1>[C:1]([O:5][C:6](=[O:43])[N:7]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([C:28](=[O:29])[N:65]([O:64][CH3:63])[CH3:66])[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:31])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)O)c2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Reactant: CNOC
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cc(C(=O)N(C)OC)c2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 107.2 %

Procedure:
To 10 mL of a tetrahydrofuran solution containing 600 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-5-carboxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 420 mg of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 108 mg of O,N-dimethylhydroxylamine hydrochloride and 112 mg of N-methylmorpholine were added, and stirred at room temperature for 22 hours. Hydrochloric acid was added to the reaction mixture to make acidic, the organic layer was separated, washed sequentially with water, aqueous saturated sodium hydrogen carbonate solution and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate], to give 0.69 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-5-((methoxy)(methyl)carbamoyl)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].Cl.Cl.[NH2:25][C@H:26]1[CH2:30][NH:29][CH2:28][C@@H:27]1[OH:31]>>[NH2:25][C@@H:26]1[C@@H:27]([OH:31])[CH2:28][N:29]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[Br:1])[CH2:30]1
Reactant: N[C@H]1CNC[C@@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(F)c(Br)c1
Agent: Cl
Product: N[C@H]1CN(c2ccc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2Br)C[C@@H]1O

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 1 using 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluorobenzamide (Stage 76.2) and (3S,4S)-4-aminopyrrolidin-3-ol dihydrochloride (Stage 76.3) to give the title product as a beige solid. HPLC (Condition 7) tR=6.08 min, UPLC-MS (Condition 3) tR=0.82 min, m/z=476.1/478.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1CCCC1.C1(=O)C2C(=CC=CC=2)CCC1>CO>[CH:14](=[C:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: O=C1CCCc2ccccc21
Solvent: C1CCNC1
Solvent: CO
Product: COc1ccc2c(c1)CCC(=Cc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 63.3 %

Procedure:
To a stirred solution of 6-methoxy-1-tetralone (227 mmole, 40 gm) and benzaldehyde (272 mmole, 27.5 mL) in 450 mL of methanol was added pyrrolidine (272 mmole, 23.6 mL). The mixture was stirred at room temperature for about 4 days until TLC indicated that no starting tetralone was present. The mixture was concentrated in vacuo, then dissolved in EtOAc, washed with four portions of 10% HCl, two portions of saturated NaHCO3 solution, and one portion of brine. The solvent was removed in vacuo and the crude oil was triturated with diethyl ether to afford 38 g of the title compound of this Preparation 1A, mp 100-102° C. Analysis calculated for C18H16O2 : 264.1146. Found: 264.1149.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(#N)C.Cl.[NH:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25]([CH:27]2[C:40]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:34][C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:26])[CH2:20][CH2:19]1>O>[CH2:8]([N:18]1[CH2:19][CH2:20][CH:21]([NH:24][C:25]([CH:27]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=3[O:34][C:35]3[C:40]2=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:26])[CH2:22][CH2:23]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=C(NC1CCNCC1)C1c2ccccc2Oc2ccccc21
Reactant: CCCCCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCCCN1CCC(NC(=O)C2c3ccccc3Oc3ccccc32)CC1
Temperature: 25 °C

Procedure:
60 mg of potassium carbonate and 25 ml of iodohexane were successively added to 5.0 ml of acetonitrile suspension having 50 mg of N-(piperidin-4-yl)xanthene-9-carboxamide hydrochloride, followed by reflux under heating for 4 hours. After cooled to room temperature, water was added to the reaction solution, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was purified by preparative thin layer chromatography (Kieselgel™60F254, Art5744 produced by Merck Co.: chloroform/methanol=10/1), and 35 mg of the title compound as a white solid was obtained.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].C1(C)C=CC=CC=1.C1OCCOCCOCCOCCOC1.Cl[CH2:53][CH2:54][CH2:55][CH:56]1[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1>C(OCC)C>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][CH2:53][CH2:54][CH2:55][CH:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]2)[N:10]=[CH:9]1
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: ClCCCC1CCCCC1
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: c1nc(CCCOCCCC2CCCCC2)c[nH]1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
5 mmol of sodium 3-[1-(triphenylmethyl)imidazol-4-yl]propoxide in 10 ml of toluene containing 0.5 mmol of 15-Crown-5 and 5 mmol of (3-chloropropyl)cyclohexane are mixed and the mixture is stirred for 24 h at 75° C. The suspension is concentrated under vacuum, the product obtained is dissolved in diethyl ether, the solution is filtered and the residue washed with petroleum ether (40°-60° C.). The filtrate obtained is concentrated and maintained for 1 h at the boiling point in a 2N aqueous/alcohol (ethanol/water) hydrochloric acid solution. The ethanol is removed under a low vacuum and the precipitate is filtered under vacuum. The solution is basified, extracted with dichloromethane and the organic phase is concentrated. The title compound obtained is recrystallized in the hydrogenmaleate form from ethanol/ diethyl ether.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:29](=O)[C:28]3[C:27]([C:31](OC)=[O:32])=[CH:26][CH:25]=[CH:24][C:23]=3[NH:22][CH:21]2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:16][CH:15]=1)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:42][NH2:43]>CO>[CH3:12][N:11]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[C:29]3=[N:42][NH:43][C:31](=[O:32])[C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([C:28]=43)[NH:22][CH:21]2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:18][CH:19]=1)[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccc(CN(C)C(=O)OCc3ccccc3)cc1)C(c1ccccc1)N2
Solvent: CO
Solvent: O
Product: CN(Cc1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 24 h
Yield: 16 %

Procedure:
A mixture of methyl 3-(4-(((benzyloxycarbonyl)(methyl)amino)methyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (220 mg, 0.94 mmol) in hydrazine monohydrate (50 mL) and methanol (5 mL) was stirred at 40° C. for 24 hr. The mixture was cooled to room temperature and filtered to give the crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to give benzyl methyl(4-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzyl)carbamate (80 mg, yield 16%). LC-MS (ESI) m/z: 517(M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](=[O:22])[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[CH3:23][NH2:24].O>CN(C)C=O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH:13]2[CH2:12][C:11](=[O:22])[CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:24]2[CH3:23])=[CH:15][CH:16]=1
Reactant: COc1ccc(C=CC(=O)C=Cc2ccc(OC)cc2)cc1
Reactant: CN
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2CC(=O)CC(c3ccc(OC)cc3)N2C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.9 %

Procedure:
1,5-Bis(4-methoxyphenyl)-1, 4-pentadien-3-one (20e, 0.40 g, 1.4 mmol) was dissolved in dimethyl formamide (10 ml). Methylamine (51, 0.75 ml, 8.7 mmol, 40% in water) was added and the mixture stirred for 24 hr at room temperature. The mixture was poured into water (50 ml) and stirred for 2 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was chromatographed on silica gel with ethyl acetate/hexane to afford a solid that was recrystallized from ethanol to give 0.30 g (68%) of a white solid: mp 141-143° C. [expected mp 129-130° C.]; 1H NMR δ 1.77, (s, 3H), 2.45 (d, 2H, J=14.5 Hz), 2.78 (t, 2H, J=12.9 Hz), 3.33 (d, 2H, J=11.9 Hz), 3.79 (s, 6H), 6.88 (d, 4H, J=8.5 Hz), 7.32 (d, 4H, J=8.5 Hz); 13C NMR: δ 40.6, 50.9, 55.3, 69.5, 114.1, 128.0, 135.3, 158.9, 207.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:26])[CH:9]2[CH2:25][CH2:24][C:12]3([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:28][N:29]1[C:37]([CH3:38])=[C:36]2[C:31]([CH:32]=[C:33]([NH2:39])[CH:34]=[CH:35]2)=[N:30]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:28][N:29]1[C:37]([CH3:38])=[C:36]2[C:31]([CH:32]=[C:33]([NH:39][C:2]3[N:7]=[C:6]([N:8]([CH3:26])[CH:9]4[CH2:10][CH2:11][C:12]5([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]5)[CH2:24][CH2:25]4)[CH:5]=[CH:4][N:3]=3)[CH:34]=[CH:35]2)=[N:30]1
Reactant: CN(c1ccnc(Cl)n1)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Reactant: Cc1c2ccc(N)cc2nn1C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1c2ccc(Nc3nccc(N(C)C4CCC5(CC4)CCN(C(=O)OC(C)(C)C)C5)n3)cc2nn1C
Temperature: 150 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a suspension of tert-butyl 8-((2-chloropyrimidin-4-yl)(methyl)amino)-2-azaspiro[4.5]decane-2-carboxylate (500.0 mg, 1.3 mmol) and 2,3-dimethyl-2H-indazol-6-amine hydrochloride (778.6 mg, 3.9 mmol) in n-BuOH (10 mL) was added DIPEA (1.04 g, 8.0 mmol). The reaction mixture was stirred at 150° C. in a sealed tube overnight, then cooled down to rt, and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the title compound as a yellow solid (657 mg, 100%).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:32][CH:31]2[C:33]([O:35]CC)=[O:34])=[CH:26][CH:25]=1>>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)\[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][O:14][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:32][CH:31]3[C:33]([OH:35])=[O:34])=[CH:26][CH:25]=2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)C1CC1c1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccc(OC)cc1
Product: CO/N=C(\COc1ccc(COc2ccc(C3CC3C(=O)O)cc2)cc1)c1ccc(OC)cc1
Yield: 13.26 %

Procedure:
Compound 46 was synthesized from (1Z)-2-[4-(hydroxymethyl)phenoxy]-1-(4-methoxyphenyl)ethanone O-methyloxime (0.146 g, 0.48 mmol) and ethyl 2-(4-hydroxyphenyl)cyclopropanecarboxylate (0.1 g, 0.4 mmol) by following the procedure described in scheme 18 (0.01 g, yield: 13.26%); Purity: 92.24%.
Reaction SMILES: C(O)CCO.C(C=C)=O.[C:10]1([CH3:20])[CH:15]=CC(S(O)(=O)=O)=C[CH:11]=1.[CH:21]([CH:23]1[O:28]CCC[O:24]1)=[CH2:22]>O>[CH:21]([CH:23]1[O:28][CH2:11][CH:10]([CH3:20])[CH2:15][O:24]1)=[CH2:22]
Reactant: C=CC1OCCCO1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=CC=O
Solvent: O
Solvent: OCCCO
Product: C=CC1OCC(C)CO1
Temperature: 26 °C

Procedure:
For the sake of comparison, a mixture of 0.5 mole 1,3-propanediol and 0.55 mole acrolein were reacted at 50° C in the presence of 0.3 g. p-toluenesulfonic acid. Layers did not separate until the reaction mixture was cooled to 26° C. The mixture gave 18 g. of an aqueous layer which contained about 40% diol, 21% acrolein, 10% 2-vinyl-1,3-dioxane and 25% water. The acetal layer of 49 g. contained 63% 2-vinyl-1,3-dioxane, 23% acrolein, 8% diol and 5% water, conversion to acetal was about 60% which represents only a negligible increase over equilibrium conversion.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:17])([CH3:16])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32](OC(=O)C(F)(F)F)=[CH:31][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].[CH3:51][C:52]1[CH:57]=[CH:56][N:55]=[C:54]([Sn](CCCC)(CCCC)CCCC)[CH:53]=1>CN(C=O)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>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:16])([CH3:17])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:54]2[CH:53]=[C:52]([CH3:51])[CH:57]=[CH:56][N:55]=2)=[CH:33][CH:34]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(OC(=O)C(F)(F)F)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1ccnc(-c2ccc(C[C@H]3[C@H](C[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)OC(C)(C)N3C(=O)OCc3ccccc3)cc2)c1
Yield: 38.6 %

Procedure:
A solution containing the product from Example 23I (0.183 g, 0.259 mmol) in DMF (2.6 mL) was treated with LiCl (0.110 g, 2.59 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.055 g, 0.078 mmol), and the product from Example 80A (0.495 g, 1.29 mmol), heated at 100° C. for 16 hours, cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-10% ethyl acetate in dichloromethane, to give the title compound (0.065 g, 39% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:11]1[N:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[CH:18][C:13]=2[CH:12]=1)=[O:10].C(N(C(C)C)CC)(C)C.Cl.[NH2:41][CH:42]([CH3:47])[C:43]([CH3:46])([OH:45])[CH3:44]>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:11]1[N:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:14]2[N:15]=[C:16]([NH:41][CH:42]([CH3:47])[C:43]([OH:45])([CH3:46])[CH3:44])[N:17]=[CH:18][C:13]=2[CH:12]=1)=[O:10]
Reactant: CC(N)C(C)(C)O
Reactant: CS(=O)(=O)c1ncc2cc(C(=O)Cc3ccccc3Cl)n(-c3ccc(F)cc3)c2n1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncc2cc(C(=O)Cc3ccccc3Cl)n(-c3ccc(F)cc3)c2n1)C(C)(C)O
Temperature: 120 °C

Procedure:
To a solution of 2-(2-chloro-phenyl)-1-[7-(4-fluorophenyl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-ethanone, 31, (0.036 g, 0.080 mmol) in N-methylpyrrolidinone (2 mL) is added diisopropylethylamine (0.071 mL, 0.410 mmol) and 3-amino-2-methyl-butan-2-ol hydrochloride salt (0.035 g, 0.240 mmol). The mixture is heated to 120° C. for 4 hours. The reaction crude product is then purified by preparative HPLC to afford the desired product as a yellowish solid: 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 7.54 (s, 1H), 7.42-7.38 (m, 1H), 7.32-7.10 (m, 7H), 4.36 (s, 2H), 3.92-3.82 (m, 1H), 1.26 (d, J=9.1 Hz, 6H), 1.20 (d, J=6.8 Hz, 3H); ESI+ MS: m/z (rel intensity) 467.0 (100, M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C>>[F:26][C:27]([F:38])([F:39])[C:28]1[CH:29]=[CH:30][C:31]([CH2:34][C:35]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:36])=[CH:32][CH:33]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)Cc4ccc(C(F)(F)F)cc4)c3)c2c1
Yield: 11.4 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 4-(trifluoromethyl)phenylacetic acid (0.15 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 28 mg (11% yield) of the title compound. 1H NMR (DMSOd6) δ 10.4 (s, 1H), 8.6 (s, 1H), 8.22 (s, 1H), 8.1 (br s, 1H), 7.9 (dd, 1H), 7.8-7.68 (m, 3H), 7.6 (m, 3H), 7.5 (t, 1H), 7.35 (s, 1H), 7.17 (m, 2H), 3.8 (s, 2H); ES-MS (m/z) 439 [M+H]+.
Reaction SMILES: [CH3:1][NH2:2].CS(O[CH2:8][CH2:9][CH:10]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)(=O)=O>C1COCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:10]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:9][CH2:8][NH:2][CH3:1])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NC(CCOS(C)(=O)=O)c1ccc(Cl)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNCCC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 125 °C
Yield: 90 %

Procedure:
Methylamine gas was bubbled into a solution of 3-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propyl methanesulfonate (Intermediate 31) (70 mg, 0.19 mmol) in THF (5 mL) at 22° C. over a period of 5 minutes. The mixture was sealed into a microwave tube. The reaction was heated to 125° C. for 30 minutes in the microwave reactor and cooled to ambient temperature. The mixture was evaporated and the residue was purified by flash silica chromatography, elution gradient 4 to 8% (10:1 MeOH/conc. NH3 (aq)) in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 1-(4-chlorophenyl)-3-(methylamino)propylcarbamate (52 mg, 90%) as a colourless oil.