Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH2:19](O)C>[Pd]>[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:2][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:19]
Reactant: CC(=Cc1ccccn1)c1ccccc1[N+](=O)[O-]
Reactant: CCO
Agent: [Pd]
Product: CC(Cc1ccccc1N)c1ccccn1

Procedure:
2-(β-Methyl-2-nitrostyryl)pyridine (24.0 g., 0.1 mole) is hydrogenated on a Parr apparatus in 200 ml. of ethanol with 3 g. of 10% Pd/C as catalyst. The catalyst is filtered and the filtrate evaporated, providing 2-[2-(2-aminophenyl)-1-methylethyl]pyridine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[CH3:11][N:12]([CH3:39])[C:13]1[CH:14]=[C:15]([CH:36]=[CH:37][CH:38]=1)[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:35])=[C:23]([NH:25][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[CH:24]=1)=[O:17].C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[CH3:39][N:12]([CH3:11])[C:13]1[CH:14]=[C:15]([CH:36]=[CH:37][CH:38]=1)[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:35])=[C:23]([NH:25][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[CH:29][CH:28]=2)[CH:24]=1)=[O:17]
Reactant: ClCCCN1CCOCC1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc(OCCCN2CCOCC2)cc1
Temperature: 60 °C
Yield: 78.5 %

Procedure:
4-(3-Chloropropyl)morpholine (0.1 g) was added to a stirred mixture of N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]4-hydroxybenzamide (0.195 g), potassium carbonate (0.21 g) and DMA (5 ml). The mixture was then heated to 60° C. for 36 hours. The mixture was poured into water (150 ml) and the resultant solid was collected, washed with water and with diethyl ether. The product was dried under vacuum. There was thus obtained the title compound (0.203 g) as a colourless solid; NMR Spectrum: (DMSOd6) 1.88 (m, 2H), 2.18 (s, 3H), 2.36 (t, 4H), 2.41 (t, 2H), 2.96 (s, 6H), 3.58 (t, 4H), 4.08 (d, 2H), 6.9 (m, 1H), 7.01 (d, 2H), 7.19 (m, 3H), 7.26 (t, 1H), 7.58 (d, 1H), 7.78 (s, 1H), 7.98 (d, 2H), 9.72 (s, 1H), 10.08 (s, 1H); Mass Spectrum: M+H+517.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:18]3[C:13](=[C:14]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:15]=[CH:16][C:17]=3[O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[C:11]([C:43](OC)=[O:44])[C:10]=2[C:47]([O:49]C)=[O:48])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>O.CO.C1COCC1>[C:1]1([CH2:7][O:8][C:9]2[C:10]3[C:47](=[O:48])[O:49][C:43](=[O:44])[C:11]=3[C:12]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[C:13]3[C:18]=2[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:16][CH:15]=[C:14]3[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(C(=O)OC)c(OCc2ccccc2)c2c(OCc3ccccc3)ccc(OCc3ccccc3)c2c1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C1OC(=O)c2c1c(OCc1ccccc1)c1c(OCc3ccccc3)ccc(OCc3ccccc3)c1c2OCc1ccccc1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
12.50 g of dimethyl 1,4,5,8-tetrakis(phenylmethoxy)-2,3-napthalene dicarboxylate prepared in Step 2A-c above was refluxed with 12.0 g of KOH in 24 mL of water, 300 mL of methanol and 100 mL of THF for 1 hour. The solvent was removed, and the residue acidified with 1N HCl. The solid was then collected by filtration and was refluxed in 55 mL of acetic anhydride for 30 minutes. After cooling to room temperature, a mixed solvent of 1:1 v/v diethyl ether and petroleum ether was added. The yellow crystalline solid was collected by filtration to yield 8.94 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[S:14])[NH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:16][CH:17]=O>C(O)(C)(C)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]2[S:14][CH:16]=[CH:17][N:13]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=CCCl
Reactant: NC(=S)CCc1ccc([N+](=O)[O-])cc1
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1ccc(CCc2nccs2)cc1
Yield: 27.8 %

Procedure:
A mixture of 3-(4-nitrophenyl)propanethioamide (1.0 g), chloroacetaldehyde (40% aqueous solution, 2.83 g) and tert-butanol (20 mL) was heated under reflux for 2 hrs. The reaction mixture was concentrated, and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-[2-(4-nitrophenyl)ethyl]-1,3-thiazole as pale-yellow crystals (0.31 g, yield 28%) from a fraction eluted with hexane-ethyl acetate (3:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 92-93° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N+:13]([O-])=[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]2=[N:10]1.C1(C)C=CC=CC=1.CNC.[H][H]>[C].[Pd].O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]2=[N:10]1
Reactant: [H][H]
Reactant: Cc1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1
Agent: [Pd]
Agent: CNC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Yield: 89 %

Procedure:
24.1 g (0.1 mol) of 2-(2'-hydroxy-5'-methylphenyl)benzotriazole-N-oxide, 0.125 g of 5% palladium carbon, 150 ml of a solvent mixture comprising toluene and water (ratio by volume, 4:1) and 7 g of 50% dimethylamine were charged into a 500-ml four neck flask. After the air in the flask had been replaced by nitrogen, the resultant mixture was agitated at room temperature. Hydrogen was then supplemented to allow for the amount of hydrogen absorbed by the mixture, which was then subjected to reaction until no more hydrogen was absorbed by it. After the reaction had been completed, the catalyst was filtered off, and part of the filtrate was subjected to quantitative analysis using gas chromatography (GC). The results revealed a yield of 89% of 2-(2'-hydroxy-5'-methylphenyl)benzotriazole. The solvent was then distilled off from the filtrate, and the residual solid was crystallized using ethanol and then washed with ethanol to obtain 18 g of 2-(2'-hydroxy-5'-methylphenyl) benzotriazole (yield, 80%; melting point, 128° to 130° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[C:30]2[O:31][CH2:32][O:33][C:29]=2[C:28]([C:34]#[C:35][CH2:36][NH:37][C:38](=[O:42])[N:39]([CH3:41])[CH3:40])=[CH:27][C:26]=1[Cl:43].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:43][C:26]1[CH:27]=[C:28]([C:34]#[C:35][CH2:36][NH:37][C:38](=[O:42])[N:39]([CH3:40])[CH3:41])[C:29]2[O:33][CH2:32][O:31][C:30]=2[C:25]=1[NH:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CN(C)C(=O)NCC#Cc1cc(Cl)c(N)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cc(C#CCNC(=O)N(C)C)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Yield: 72.1 %

Procedure:
This was prepared by the method described in example 4 using 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (200 mg, 0.59 mmol), N′-[3-(7-amino-6-chloro-1,3-benzodioxol-4-yl)prop-2-yn-1-yl]-N,N-dimethylurea (193 mg, 0.65 mmol) and a solution of sodium bis(trimethylsilyl)amide (1.0M in THF, 1.24 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using 10% methanol in dichloromethane as eluent. There was thus obtained the title compound (254 mg, 72%) as a pale brown solid; NMR Spectrum:(DMSOd6) 1.96 (quintet, 2H), 2.39 (m, 4H), 2.45 (t, 2H), 3.81 (s, 6H), 3.60 (m, 4H), 3.94 (s, 3H), 4.10 (d, 2H), 4.20 (t, 2H), 6.15 (s, 2H), 6.84 (t, 1H), 7.08 (s, 1H), 7.20 (s, 1H), 7.82 (s, 1H), 8.34 (s, 1H), 9.50 (s, 1H); Mass Spectrum: M+H+ 597/599.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCOC(C)=O.CCCCCC>C(Cl)Cl.O=[Mn]=O>[CH3:1][C:2]1[C:3]([CH:9]=[O:10])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CO)c(C)c1
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1cnc(C=O)c(C)c1

Procedure:
To a solution of (3,5-dimethyl-pyridin-2-yl)-methanol (2.12 g, 15.45 mmol) (Weidmann, K. et al. J. Med. Chem. 1992, 35, 438-450) in CH2Cl2 (50 mL) was added MnO2 (9.41 g, 108.18 mmol) and the reaction mixture was refluxed overnight. Then it was cooled and the mixture was filtered through a layer of celite. The filtrate was concentrated to afford a brown/yellow oil. Purification by flash column chromatography on silica get using 30% EtOAc/hexane afforded 3,5-dimethyl-pyridine-2-carbaldehyde as a yellow oil (960 mg, 31% over 3 steps). 1H NMR (CDCl3) δ 2.39 (s, 3H), 2.62 (s, 3H), 7.41 (s, 1H), 8.47 (s, 1H), 10.15 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH3:11])([CH2:5][CH2:6][C:7]#[N:8])[CH:3]=O.[NH3:12].[H][H]>>[CH3:1][C:2]1([CH2:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][NH:8][CH2:3]1.[CH3:1][C:2]([CH2:9][CH2:10][CH3:11])([CH2:5][CH2:6][CH2:7][NH2:8])[CH2:3][NH2:12]
Reactant: [H][H]
Reactant: CCCC(C)(C=O)CCC#N
Reactant: N
Product: CCCC(C)(CN)CCCN
Product: CCCC1(C)CCCNC1

Procedure:
Example 1 was repeated using 2-methyl-2-propyl-4-cyanobutanal as the starting material. 33.5 g per hour of 2-methyl-2-propyl-4-cyanobutanal (purity 88.9%, 29.8 g, 0.195 mol) and 1400 ml (840 g, 49.4 mol) per hour of liquid ammonia were pumped at 250 bar and 60° C. through the imination reactor. The product stream was subsequently passed through the hydrogenation reactor from bottom to top at 250 bar and 120° C. while simultaneously passing 100 l(S.T.P.)/h (4.5 mol) of hydrogen through the reactor. The product stream was decompressed to atmospheric pressure and NH3 was removed by distillation. The product from 37.5 hours was separated by fractional distillation on a 30 cm packed column (3 mm glass rings), giving 277.0 g of 3-methyl-3-propylpiperidine (b.p.=46° C./2 mmHg) and 842.1 g of 2-methyl-2-propylpentane-1,5-diamine (b.p.=78°- 81° C./2 mmHg). The diamine yield was 72.9% of theory.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[N:20]([CH:21]=3)[N:19]=[CH:18][N:17]=[C:16]4O)[CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:25]>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:25][C:16]1[C:15]2=[CH:14][C:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH:12]=3)=[CH:21][N:20]2[N:19]=[CH:18][N:17]=1
Reactant: Oc1ncnn2cc(-c3ccnc(N4CCOCC4)c3)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Clc1ncnn2cc(-c3ccnc(N4CCOCC4)c3)cc12
Temperature: 100 °C

Procedure:
To a suspension of 6-(2-morpholinopyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (110 mg, 0.37 mmol) in toluene (100 mL) were added one drop of DMF and POCl3 (30 mL). The flask was sealed and heated at 100° C. for 3 d. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was then dissolved in DCM, neutralized with saturated aq. NaHCO3 solution and the organic layer was separated. The aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product, which was used directly in the next step. MS(ESI) m/z 316.2/318.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([CH:15](C#N)[C:16]2[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[C:19]#[N:20])[C:12]([CH2:27][CH3:28])=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CN(C=[O:43])C>>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([C:15]([C:16]2[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[C:19]#[N:20])=[O:43])[C:12]([CH2:27][CH3:28])=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(OCc2ccccc2)nc(OCc2ccccc2)nc1C(C#N)c1cc(C)cc(C#N)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCc1c(OCc2ccccc2)nc(OCc2ccccc2)nc1C(=O)c1cc(C)cc(C#N)c1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred solution of 3-[(2,6-Bis-benzyloxy-5-ethyl-pyrimidin-4-yl)-cyano-methyl]-5-methyl-benzonitrile (40) (10 g, 21.1 mmol) in anhydrous DMF (80 ml) in a water bath under an atmosphere of nitrogen, was portionwise added 60% sodium hydride (869 mg, 21.7 mmol). After 30 min, oxygen gas was bubbled into the reaction mixture for 5 hr. The mixture was neutralized with aqueous saturated ammonium chloride solution. The crude product was extracted with ether and recrystallized from dichloromethane-hexane to afford 8 g (80%) of a white solid; m.p. 123-124° C.; 1H NMR (200 MHz, CDCl3) δ: 1.09 (3H, t, J=7.4 Hz), 2.43 (3H, s), 2.50 (2H, q, J=7.4 Hz), 5.35 (2H, s), 5.50 (2H, s), 7.27-7.46 (10H, m), 7.67 (1H, s), 7.87 (1H, s), 7.92 (1H, s); m/z (EI): 463 (M+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:9]=[CH:8][C:7]=1[NH:21][C:22](=[O:30])[C:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25].O>N1C=CC=CC=1>[C:1]([NH:5][C:6]1[CH:11]=[C:10]([S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])[CH:9]=[CH:8][C:7]=1[NH:21][C:22](=[O:30])[C:23]([OH:29])([CH3:28])[C:24]([F:27])([F:25])[F:26])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1N)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(S(=O)(=O)c2ccccc2)ccc1NC(=O)C(C)(O)C(F)(F)F
Temperature: 25 °C

Procedure:
Acetyl chloride (0.018 ml) was added to an ice-cooled solution of N-[2-amino-4-(phenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 184) (0.097 g) in pyridine (1 ml) and the solution was allowed to warm up to ambient temperature over 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic extracts were combined, washed with brine and dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 10-40% ethyl acetate/hexane to give the title compound (0.89 g) as a solid. Mp 205-207° C.; NMR: 1.5 (s, 3H), 2.1 (s, 3H), 7.57-7.75 (m, 4H), 7.8-7.9 (m, 2H), 7.9-8.05 (m, 3H), 9.8 (brs, 1H), 10.1 (brs, 1H); MS (ESP−): 429.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CO>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([N:6]=[CH:14][N:15]([CH3:17])[CH3:16])=[O:5]
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1cc(F)ccc1Br
Solvent: CO
Product: CN(C)C=NC(=O)c1cc(F)ccc1Br
Temperature: 120 °C
Yield: 72 %

Procedure:
A mixture of 2-bromo-5-fluorobenzamide (9.50 g, 43.57 mmol) and N,N-dimethylformamide dimethyl acetal (20 ml) was heated under argon at 120° C. for 1.5 h. The methanol formed during the reaction was collected through a reflux condenser. The reaction mixture was allowed to cool and the excess N,N-dimethylformamide dimethyl acetal was removed under reduced pressure. The residual oil was crystallized from a mixture of ether (75 ml) and hexane (50 ml) to give 8.55 g (72% yield) of the title material as white crystals. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.21 (3H, s, CH3), 3.24 (3H, s, CH3), 7.0 (1H, m, aromatic), 7.58 (1H, dd, J=5.0 Hz and J=8.5 Hz, aromatic), 7.64 (1H, dd, J=3.0 Hz and J=9.1 Hz, aromatic), 8.64 (1H, s, CH).
Reaction SMILES: [NH2:1][C:2]([CH3:7])=[CH:3][C:4](=O)[CH3:5].CO[C:10]1(OC)[CH2:14][CH2:13][CH2:12][N:11]1[CH3:15].C(O[Na])(C)(C)C.CC(O)(C)C>C1(C)C=CC=CC=1>[CH3:15][N:11]1[C:10]2=[N:1][C:2]([CH3:7])=[CH:3][C:4]([CH3:5])=[C:14]2[CH2:13][CH2:12]1
Reactant: CC(=O)C=C(C)N
Reactant: COC1(OC)CCCN1C
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: Cc1cc(C)c2c(n1)N(C)CC2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution containing 1.20 g (12.1 mmol) of 4-amino-3-penten-2-one in 8 mL of toluene was added 3.00 g (20.7 mmol) of 2,2-Dimethoxy-1-methylpyrrolidine. The reaction mixture was heated at reflux and stirred for 2 h, cooled to 90° C., and then treated with 2.38 g (24.8 mmol) of t-BuONa and 2 mL of t-BuOH. The reaction mixture was stirred at 90° C. for another 16 h. The cooled reaction mixture was quenched by the addition of 10 mL of sat aq. NH4Cl. The mixture was extracted with three 30-mL portions of EtOAc. The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under diminished pressure. The residue was purified via flash chromatography on a silica gel column (42×2.5 cm). Step gradient elution with 1:4→1:1 ethyl acetate-hexanes as eluent gave 1,4,6-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine as a brown oil: yield 0.62 g (32%); silica gel TLC Rf 0.15 (1:4 ethyl acetate-hexanes); 1H NMR (CDCl3) 1.91 (s, 3H), 2.20 (s, 3H), 2.65 (t, 2H, J=8.4 Hz), 2.76 (s, 3H), 3.23 (t, 2H, J=8.4 Hz), 5.98 (s, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.S(Cl)([Cl:12])=O.[CH3:14]O>>[ClH:12].[NH2:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH3:14])=[O:8])[CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: N[C@H]1CC[C@@H](C(=O)O)C1
Product: COC(=O)[C@@H]1CC[C@H](N)C1
Product: Cl
Temperature: 0 °C

Procedure:
A suspension of (1R,3S)-3-aminocyclopentanecarboxylic acid (500 mg, 3.8 mmol) in methanol (10 mL) was stirred at 0° C. and thionyl chloride (1.40 mL, 19.3 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. The resulting clear solution was evaporated, azeotroped with methanol (2×5 mL), air-dried and the title compound obtained as a white powder (680 mg).
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][C:2]1[C:11]([NH:12][C:13]([N:35]2[CH2:34][CH2:33][N:32]([C:26]3[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=3)[CH2:37][CH2:36]2)=[O:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: Cc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc4ccccc4nc3C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Phenyl N-(2-methylquinolin-3-yl)carbamate(140 mg, 0.5 mmol) and 1-(3,5-dimethoxyphenyl)piperazine(112 mg, 0.5 mmol) were dissolved in tetrahydrofuran and DBU(117 mg, 0.75 mmol) was added and then the mixture was stirred at room temperature for 2 hrs. The above solution was concentrated under the reduced pressure to remove tetrahydrofuran and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:20][CH2:19][N:18]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:17][CH2:16][C:4]=2[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][O:14][CH3:15])[CH2:9][CH2:8][CH2:7]2.[F:27][C:28]([F:33])([F:32])C([O-])=O.[Na+].CN1CCCC1=O.O>[Cu](I)I.C(OCC)(=O)C>[F:25][C:22]([F:24])([F:23])[C:21]([N:18]1[CH2:19][CH2:20][C:3]2[C:2]([C:28]([F:33])([F:32])[F:27])=[C:11]3[C:6]([CH2:7][CH2:8][CH2:9][N:10]3[CH2:12][CH2:13][O:14][CH3:15])=[CH:5][C:4]=2[CH2:16][CH2:17]1)=[O:26]
Reactant: O=C([O-])C(F)(F)F
Reactant: COCCN1CCCc2cc3c(c(Br)c21)CCN(C(=O)C(F)(F)F)CC3
Agent: I[Cu]I
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COCCN1CCCc2cc3c(c(C(F)(F)F)c21)CCN(C(=O)C(F)(F)F)CC3
Temperature: 170 °C
Reaction time: 18 h
Yield: 20.5 %

Procedure:
1.1946 g of 1-[11-bromo-1-(2-methoxyethyl)-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-yl]-2,2,2-trifluoroethanone, 2.2395 g of sodium trifluoroacetate, and 1.568 g of copper iodide were added to 24 ml of N-methylpyrrolidone under an argon atmosphere, followed by stirring at 170° C. for 18 hours. To the reaction mixture were added water and ethyl acetate, and filtered through celite was performed. The filtrate was subjected to liquid separation, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: Hex-AcOEt) to obtain 239 mg of 2,2,2-trifluoro-1-[1-(2-methoxyethyl)-11-(trifluoromethyl)-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-yl]ethanone as a pale yellow solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:33](Cl)([CH3:36])(=[O:35])=[O:34].N1C=CC=CC=1>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 90.3 %

Procedure:
A solution of Example 39H (2.76 g, 5.80 mmol), mesyl chloride (1.79 mL, 23.2 mmol), and pyridine (3.75 mL, 46.4 mmol) in acetone (80 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (2.71 g, 90%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.43 m, 1 H) 0.74 m, 7 H) 1.34 (m, 1 H) 1.57 m, 3 H) 2.15 m, 2 H) 3.08 m, 3 H) 7.56 m, 3 H) 7.75 m, 3 H) 8.16 m, 1 H) 10.26 m, 1 H) 13.76 m, 1 H).
Reaction SMILES: [OH-].[Na+:2].[CH2:3]([C:5]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:32]([OH:42])=[CH:31][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([CH2:28][CH2:29][CH3:30])=[C:14]([NH:18][C:19](=[O:27])[CH2:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])[CH:15]=[CH:16][CH:17]=1)[CH3:4].O>C1COCC1>[CH2:3]([C:5]1[CH:34]=[C:33]([C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)[C:32]([OH:42])=[CH:31][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([CH2:28][CH2:29][CH3:30])=[C:14]([NH:18][C:19](=[O:27])[CH2:20][C:21]([CH3:26])([CH3:25])[C:22]([O-:24])=[O:23])[CH:15]=[CH:16][CH:17]=1)[CH3:4].[Na+:2]
Reactant: CCCc1c(NC(=O)CC(C)(C)C(=O)O)cccc1OCCCOc1cc(O)c(-c2ccc(F)cc2)cc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(NC(=O)CC(C)(C)C(=O)[O-])cccc1OCCCOc1cc(O)c(-c2ccc(F)cc2)cc1CC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
Add 1 N sodium hydroxide (404 mL) dropwise to a solution of 4-[[3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxy-phenoxy]propoxy]-2-propyl-phenyl]amino]-2,2-dimethyl-4-oxo-butanoic acid (223 g, 404 mmol) in THF (1115 mL) and stir at ambient temperature for 15 min. Reduce the volume in vacuo and add water (1300 mL). Remove additional solvent using a membrane pump, to avoid heating the solution, to obtain a final volume of 1250 mL. Lyophilize the remaining solution in batches to yield the title compound (230 g, 99%) as an off-white solid. ES/MS m/z 552 (M+1, free base).