Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C@@H:12]([CH3:13])[C:11](=O)[NH:10][C@H:9]([CH3:15])[C:8]2=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:8][C@H:9]([CH3:15])[NH:10][CH2:11][C@H:12]2[CH3:13])=[CH:4][CH:3]=1
Reactant: C[C@H]1NC(=O)[C@H](C)N(Cc2ccc(F)cc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CN[C@@H](C)CN1Cc1ccc(F)cc1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
To a solution of (3R,6S)-1-(4-fluoro-benzyl)-3,6-dimethyl-piperazine-2,5-dione (22 g, 87.9 mmol) in dry tetrahydrofuran (160 mL) at 0° C. was added a solution of lithium aluminum hydride (1M in tetrahydrofuran, 373 mL, 373 mmol) dropwise over 40 minutes. The reaction mixture was then refluxed for 4 hours, cooled to ambient temperature and slowly quenched with water. The resulting mixture was filtered through a pad of celite and the filter cake was washed with ethyl acetate. The filtrate was then concentrated, diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (17.7 g).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:23][O:24][C:25](=[O:39])[C@@H:26]1[CH2:30][C@@H:29]([NH2:31])[CH2:28][N:27]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].Cl.[CH3:41][N:42]([CH3:47])[CH2:43][C:44](O)=[O:45]>ClCCl.C(N(CC)CC)C>[CH3:23][O:24][C:25](=[O:39])[C@@H:26]1[CH2:30][C@@H:29]([NH:31][C:44](=[O:45])[CH2:43][N:42]([CH3:47])[CH3:41])[CH2:28][N:27]1[C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33]
Reactant: CN(C)CC(=O)O
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](NC(=O)CN(C)C)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 74.2 %

Procedure:
Triethylamine (362 μL), 1-hydroxybenzotriazole (160 mg), and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (249 mg) were added to a mixture of N-tert-butoxycarbonyl-trans-4-amino-L-proline methyl ester(Compound D101 (M), 264 mg) and N,N-dimethylglycine hydrochloride (181 mg) in dichloromethane (10 mL) at 0° C. After stirring at 0° C. for 30 min and at room temperature for 18 hr, the solvent was removed in vacuo. The residue was diluted with saturated sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform then chloroform:methanol=50:1 to 30:1, v/v) to afford the title compound (264 mg) as a pale yellow oil. The compound appears as a mixture of rotamers: 1H NMR (400 MHz, CDCl3) δ 1.42 and 1.46 (each s, total 9H), 2.28 (s, 6H), 2.13-2.40 (m, 2H), 2.94 (s, 2H), 3.22-3.43 (m, 1H), 3.74 (s, 3H), 3.75-3.88 (m, 1H), 4.28-4.48 (m, 1H), and 4.50-4.62 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[CH:9]=2)=[O:5])[CH3:2].P(Cl)(Cl)(Cl)=O.O.[OH-].[Na+].CN([CH:27]=[O:28])C>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:27]=[O:28])=[CH:12][CH:11]=[C:10]([Cl:15])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1C=O
Temperature: 60 °C

Procedure:
To a stirred solution of 2.36 g (0.011 mol) of 6-chloro-1H-indole-2-carboxylic acid ethyl ester in DMF (20 ml) was added phosphorus oxychloride (1.08 ml, 0.012 mol) at RT. The solution was heated at 60° C. for 2 hours, then cooled to RT, and poured into water. The ph was adjusted to 7 by careful addition of aq. NaOH 2N. The resulting brown precipitate was collected by filtration and dried over night in a vacuum oven (50° C.). The title compound was obtained as light brown solid, 2.05 g (77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12](=[O:17])[CH2:13][S:14]([CH3:16])=[O:15])=[C:6]([CH:11]=1)[N:7]([CH3:10])[CH:8]=O>[OH-].[Na+]>[F:1][C:2]1[CH:11]=[C:6]2[C:5]([C:12](=[O:17])[C:13]([S:14]([CH3:16])=[O:15])=[CH:8][N:7]2[CH3:10])=[CH:4][CH:3]=1
Reactant: CN(C=O)c1cc(F)ccc1C(=O)CS(C)=O
Agent: [Na+]
Agent: [OH-]
Product: Cn1cc(S(C)=O)c(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5'-fluoro-N-methyl-2'-methylsulphinylacetylformanilide (1.99 g), prepared in a similar manner to that described in Example 8, and aqueous sodium hydroxide solution (1M; 50 ml) was stirred for 2 hours at ambient temperature and then filtered. The solid was washed with water (2×10 ml) and then toluene (2×10 ml). The solid was dried at 50° in vacuo to give 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone, m.p.228.5°-230° (1.55 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[CH3:15][CH:16]([CH3:44])[CH2:17][CH2:18][N:19]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42]O)=[CH:38][CH:37]=1)[C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[N:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:15][CH:16]([CH3:44])[CH2:17][CH2:18][N:19]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([CH2:42][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[CH2:10][CH:9]3[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=2)=[CH:40][CH:41]=1)[C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=2)[N:24]=1
Reactant: CC(C)CCN(Cc1ccc(CO)cc1)c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Reactant: COC(=O)C1CC1c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)C1CC1c1ccc(OCc2ccc(CN(CCC(C)C)c3nc(-c4ccc(C(F)(F)F)cc4)cs3)cc2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 46.2 %

Procedure:
A solution of methyl 2-(4-hydroxyphenyl)cyclopropanecarboxylate (0.152 g, 0.790 mmol), {4-[((3-methylbutyl){4-[4-(trifluoromethyl)phenyl]-1,3- thiazol-2-yl}amino)methyl]phenyl}methanol (0.312 g, 0.718 mmol) and tributylphosphine (0.291 g, 1.44 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.363 g, 1.44 mmol) was added, and the mixture was stirred at room temperature for 60 hr. Hexane (15 mL) was added to the reaction mixture, and the precipitated insoluble material was filtrated. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-30:70) to give the title compound (0.202 g, yield 42%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[NH:27][C:26]3=[O:34])[CH2:21][CH2:20]2)=[O:18])=[C:9]1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:39][CH2:40][N:41]([CH3:43])[CH3:42]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]([CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])[C:26]3=[O:34])[CH2:21][CH2:20]2)=[O:18])=[C:9]1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)c2ccccc2n1Cc1ccccc1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N2CCC(n3c(=O)n(CCN(C)C)c4ccccc43)CC2)c2ccccc2n1Cc1ccccc1
Reaction time: 0.33 h
Yield: 52.1 %

Procedure:
To a stirred solution of 20 mg (0.043 mmol) of 1-[1-(1-benzyl-2-methyl-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one (the preparation of which is described hereinafter) in DMF (3 ml) at RT, was added 2.0 mg (0.051 mmol) of NaH (60% in oil). The mixture was stirred 20 min. and then 5.6 mg (0.051 mmol) of (2-chloro-ethyl)-dimethyl-amine in 1 ml of DMF was added. The mixture was stirred an additional 5 hours at 50° C. and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Flash chromatography (CH2Cl2/MeOH 8/2) afforded 12 mg (50%) of 1-[1-(1-benzyl-2-methyl-1H-indole-3-carbonyl)-piperidin-4-yl]-3-(2-dimethylamino-ethyl)-1,3-dihydro-benzoimidazol-2-one as a viscous oil. ES-MS m/e (%): 536.2 (M+H+).
Reaction SMILES: [Sn](Cl)Cl.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([CH:14]2[CH2:16][CH2:15]2)=[C:9]([N+:11]([O-])=O)[CH:10]=1>C(O)C.O>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([CH:14]2[CH2:16][CH2:15]2)=[C:9]([CH:10]=1)[NH2:11]
Reactant: O=[N+]([O-])c1cc(Br)ccc1C1CC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(Br)ccc1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tin(II)chloride (16.0 g, 0.10 mol) is added in one portion to a solution of crude 5-bromo-2-cyclopropylnitrobenzene (8.68 g) in ethanol (190 ml) and water (1.9 ml). The reaction mixture is stirred at room temperature overnight, followed by addition of further tin(II)chloride (28 g, 0.175 mol) and additional stirring overnight. After concentration in vacuo ice is added, and the solution is basified with 2M aqueous sodium hydroxide. After extraction with ethyl acetate (×2) the organic phase is washed again with 2M aqueous sodium hydroxide, then also distilled water and brine. After drying over magnesium sulfate the solution is concentrated in vacuo to give a brown oil which is purified by flash column chromatography on silica gel (9:1 isohexane/ethyl acetate eluant) to afford 5-bromo-2-cyclopropylaniline as a brown oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][NH:6][CH3:7].Br[C:9]1[S:10][CH:11]=[CH:12][N:13]=1.O>C(Cl)(Cl)Cl>[CH3:1][N:2]([C:9]1[S:10][CH:11]=[CH:12][N:13]=1)[CH2:3][CH2:4][CH2:5][NH:6][CH3:7]
Reactant: CNCCCNC
Reactant: Brc1nccs1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CNCCCN(C)c1nccs1
Temperature: 120 °C
Yield: 60 %

Procedure:
2.45 g (24.0 mmol) N,N3-dimethylpropane-1,3-diamine was added to 0.36 ml (4.0 mmol) 2-bromothiazole and heated to 120° C. for 1 h. After cooling to RT, dilution with water and chloroform took place. The phases were separated and the aqueous phase was extracted with chloroform. The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. Column chromatography (SiO2, DCE/MeOH/25% aq. NH3-soln 4:4:1) was carried out on the residue, yielding 440 mg (2.4 mmol, 59%) N1,N3-dimethyl-N1-(thiazol-2-yl)propane-1,3-diamine.
Reaction SMILES: O[Li].O.O.[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][CH2:10][C:9]2([C:17]([O:19]C)=[O:18])[OH:16]>C1COCC1>[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][CH2:10][C:9]2([C:17]([OH:19])=[O:18])[OH:16]
Reactant: COC(=O)C1(O)CCOc2ccc(Cl)cc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(O)CCOc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
LiOH.H2O (0.19 g; 4.6 mmol) and water (4 mL) were added to a solution of 6-chloro-4-hydroxychroman-4-yl-carboxylic acid, methyl ester (0.56 g, 2.3 mmol; from step (i) above) in THF (6 mL). The reaction mixture was stirred at room temperature for 3 h, THF was evaporated and the water solution was washed with methylene chloride. The reaction mixture was acidified with HCl (2M) and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and evaporated, yielding a slowly crystallizing oil. Yield: 490 mg (93%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([CH3:9])([CH3:8])[C:6]#[N:7].[C-:10]#[N:11]>>[CH3:8][C:5]([CH3:9])([CH2:4][CH2:3][CH2:2][C:10]#[N:11])[C:6]#[N:7]
Reactant: [C-]#N
Reactant: CC(C)(C#N)CCCCl
Product: CC(C)(C#N)CCCC#N

Procedure:
treating said 5-chloro-2,2-dimethylpentanenitrile with a cyanide-delivering reagent in the presence of a phase-transfer catalyst to form 2,2-dimethyladiponitrile;
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[OH-].[Na+].[CH2:11](Cl)Cl>CS(C)=O>[CH2:11]1[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: Oc1ccccc1O
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: c1ccc2c(c1)OCO2
Yield: 80 %

Procedure:
A solution of 110 g. of catechol, 160 g. of 50 percent aqueous sodium hydroxide, and 100 ml. of DMSO was stirred and heated to 95°-100° C. for 15 minutes. The temperature of the solution was maintained in the same range while the solution was added over a period of 30 minutes to a refluxing solution of 100 ml. of methylene dichloride in 400 ml. of DMSO. After the addition, the temperature of the refluxing reaction mixture reached 120° C., and was maintained at this level for 2.5 hours. Following the same isolation procedures as indicated in (A) above, 99.7 g. (80 percent) of methylenedioxybenzene was isolated.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:18][CH2:19][C:20]#[N:21])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][O:10]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[F:27][C:25]([F:26])([F:28])[C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([C:2]([F:30])([F:29])[F:1])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:18][CH2:19][CH2:20][NH2:21])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][O:10]1
Reactant: N#CCCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCc2ccccc21
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NCCCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCc2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(1-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-1,3-dihydroisobenzofuran-1-yl)propanenitrile (190 mg, 0.44 mmol) and nickel(II) chloride hexahydrate (158 mg, 0.66 mmol) in methanol (4 mL) at 0° C. was added sodium borohydride (117 mg, 3.1 mmol) in several portions over 30 minutes. The ice bath was removed and stirring continued for 1 h. Very clean and mostly complete conversion to product (by LC/MS) was observed. The reaction was cooled to 0° C. and treated with concentrated hydrochloric acid (85 μL). After 5 min, celite was added, and the mixture was filtered. The solution was made basic by addition of solid sodium bicarbonate, and filtered again. The organics were concentrated to give the crude amine which was purified by column chromatography (10% MeOH/DCM-->10:90:0.5 MeOH/DCM/Me3N in EtOH) to give 114 mg (59%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz) δ 7.73 (s, 1H), 7.63 (s, 2H), 7.05-7.40 (m, 4H), 5.11 (s, 2H), 4.61 (qAB, JAB=13.1 Hz, 2H), 3.66 (s, 2H), 2.64 (m, 2H), 1.70-2.10 (m, 4H), 1.50 (m, 1H), 1.20 (m, 1H); 13C-NMR (CDCl3, 126 MHz) δ 141.42, 141.39, 140.1, 131.7 (q, J=33.6 Hz), 128.1, 127.5, 127.1, 123.4 (q, J=273 Hz), 121.6, 121.4, 121.1, 90.3, 76.8, 72.9, 72.0, 42.3, 34.1, 27.3. Mass spec.: 434.25 (MH)+. Accurate mass spec.: m/z 434.1542 [MH]+, Δ=1.3 ppm.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[C:15]2[C:6]([C:7](=[O:24])[C:8]3[CH:9]=[CH:10][C:11]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:12][C:13]=3[C:14]2=[O:17])=[CH:5][CH:4]=1)#[N:2].[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[NH4+]>>[NH:25]1[C:1]([C:3]2[CH:16]=[C:15]3[C:6]([C:7](=[O:24])[C:8]4[CH:9]=[CH:10][C:11]([N:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]5)=[CH:12][C:13]=4[C:14]3=[O:17])=[CH:5][CH:4]=2)=[N:2][N:27]=[N:26]1
Reactant: N#Cc1ccc2c(c1)C(=O)c1cc(N3CCCCC3)ccc1C2=O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: O=C1c2ccc(-c3nnn[nH]3)cc2C(=O)c2cc(N3CCCCC3)ccc21
Yield: 70.4 %

Procedure:
The above nitrile (1 g) was treated with sodium azide (0.66 g) and ammonium chloride (0.57 g) as in the preceding example to give 1-[7(1H-tetrazol-5-yl)-anthraquinon-2-yl] piperidine (0.8 g), m.p. 297-8°C, after crystallisation from dimethylformamide/acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)N2CCNCC2)=[CH:4][CH:3]=1.C1(C(C2C=CC=CC=2)CC(O)=[O:30])C=CC=CC=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:30])=[CH:4][CH:3]=1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: OC(c1ccccc1)c1ccc(Cl)cc1
Yield: 78 %

Procedure:
To a solution of 1-[(4-chloro-phenyl)-phenyl-methyl]-piperazine (0.59 g, 2.08 mmol) in dry CH2Cl2 (40 ml) was added 3,3-diphenylpropanoic acid (0.472 g, 2.08 mmol) under nitrogen. To the reaction was added EDC (0.797 g, 4.16 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temp. over night. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (30 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using hexane: ethyl acetate (3:1) to give desired product in 78% yield.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8][CH3:9])C.[C:26]1([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[O:33][C:34]([CH3:50])=[C:35]([CH2:37][CH2:38]OS(C3C=CC(C)=CC=3)(=O)=O)[N:36]=2)[CH:27]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[C:26]1([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[O:33][C:34]([CH3:50])=[C:35]([CH2:37][CH2:38][O:24][C:21]3[CH:22]=[CH:23][C:18]([CH2:17][C:5]([O:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)([CH2:6][CH2:7][CH2:8][CH3:9])[C:4]([OH:3])=[O:25])=[CH:19][CH:20]=3)[N:36]=2)[CH:27]=1
Reactant: CCCCC(Cc1ccc(O)cc1)(Oc1ccccc1)C(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CCCCC(Cc1ccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1)(Oc1ccccc1)C(=O)O

Procedure:
A mixture of 2-(4-hydroxybenzyl)-2-phenoxyhexanoic acid ethyl ester (0.030 mmol) (see Ex 61, Part C), toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 2, Part F) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 2-{4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-hexanoic acid. 1H NMR (400 MHz, CDCl3) δ 8.12 (t, 1H, J=1.56 Hz), 7.86 (d, 1H, J=7.82 Hz), 7.58–7.54 (m, 3H), 7.42–7.35 (m, 3H), 7.30–7.18 (m, 3H), 6.97 (t, 1H, J=7.23 Hz), 6.93–6.87 (m, 4H), 6.68 (d, 2H, J=8.60 Hz), 4.11 (t, 2H, J=6.65 Hz), 3.21 (s, 2H), 2.89 (t, 2H, J=6.65 Hz), 2.29 (s, 3H), 2.02–1.89 (m, 2H), 1.33–1.09 (m, 4H), 0.71 (t, 3H, J=7.04 Hz); MS (ES+) calcd for C37H38NO5: Found m/e 576.3 (M+1, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]([OH:18])[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: Cc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(Cc1ccccn1)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
50 ml of a solution of 5.58 g of 2-picoline in tetrahydrofuran was cooled to -65° C., followed by the dropwise addition thereto of 26.4 ml of a 2.5M solution of n-butyllithium in hexane. The obtained mixture was stirred at a bulk temperature of -50° to -30° C. for 30 minutes, followed by the dropwise addition thereto of 50 ml of a tetrahydrofuran solution of 8.85 g of 3-chlorobenzaldehyde at -50° C. The temperature of the obtained mixture was raised to 0° C. The resulting mixture was cooled, treated with an aqueous solution of ammonium chloride, and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated (yield: 13.5 g). This concentrate was used in the subsequent step without purification.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[OH:26].Br[CH2:29][CH2:30][CH3:31]>>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[O:26][CH2:29][CH2:30][CH3:31]
Reactant: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Reactant: CCCBr
Product: CCCOc1cc(-c2nc(CNC(=O)c3ncccc3C)co2)ccc1OC(F)F

Procedure:
Using the compound obtained in Example 97 and 1-bromopropane, white powdery N-[2-(4-difluoromethoxy-3-propoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained following the procedure of Example 3.
Reaction SMILES: [ClH:1].[N:2]1(C2C=CC(CC3CCNCC3)=CC=2)[CH:6]=N[N:4]=[N:3]1.[N+:20]([C:23]1[CH:41]=[CH:40][CH:39]=[CH:38][C:24]=1[CH2:25][CH:26]1[CH2:31][CH2:30][N:29](C(=O)C(F)(F)F)[CH2:28][CH2:27]1)([O-])=O>>[ClH:1].[N:20]1([C:23]2[CH:41]=[CH:40][CH:39]=[CH:38][C:24]=2[CH2:25][CH:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]2)[CH:6]=[N:2][N:3]=[N:4]1
Reactant: O=C(N1CCC(Cc2ccccc2[N+](=O)[O-])CC1)C(F)(F)F
Reactant: c1cc(-n2cnnn2)ccc1CC1CCNCC1
Agent: Cl
Product: c1ccc(-n2cnnn2)c(CC2CCNCC2)c1

Procedure:
By a similar manner to the production of 4-[4-(1H-tetrazol-1-yl)benzyl]piperidine hydrochloride (Reference Example 95), the titled compound was synthesized by using 4-(2-nitrobenzyl)-1-(trifluoroacetyl)piperidine as a starting compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]3[CH:18]=[C:19]([NH:23]C(=O)OC(C)(C)C)[CH:20]=[N:21][CH:22]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]([F:31])=[CH:4][N:3]=1.CO.[ClH:34]>O1CCOCC1>[ClH:1].[ClH:34].[NH2:23][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][C:11]2[CH:10]=[C:9]([NH:8][C:6]3[C:5]([F:31])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:14]=[CH:13][CH:12]=2)[CH:22]=[N:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cccc(Nc3nc(Cl)ncc3F)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cncc(CCc2cccc(Nc3nc(Cl)ncc3F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Into a reaction flask were added tert-butyl [5-(2-{3-[(2-chloro-5-fluoropyrimidin-4-yl)amino]phenyl}ethyl)pyridin-3-yl]carbamate (48 mg, 0.11 mmol), methanol (0.50 mL) and 4.0 M of hydrogen chloride in 1,4-dioxane (0.50 mL). The reaction mixture was stirred at rt for 2 h and then concentrated under vacuum to give the desired product as an off-white powder (35 mg, 97%). LCMS for C17H16ClFN5 (M+H)+: m/z=344.0.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:29][CH2:30][CH3:31])[N:14]([CH2:15][CH2:16][C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH:18]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:32]>CO>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]2[CH:18]=[C:17]([CH2:16][CH2:15][N:14]3[C:10]4[C:9]5[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=5[N:3]=[C:2]([NH2:32])[C:11]=4[N:12]=[C:13]3[CH2:29][CH2:30][CH3:31])[O:21][N:20]=2)=[CH:23][CH:24]=1
Reactant: N
Reactant: CCCc1nc2c(Cl)nc3ccccc3c2n1CCc1cc(-c2ccc(F)cc2)no1
Solvent: CO
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCc1cc(-c2ccc(F)cc2)no1
Temperature: 150 °C

Procedure:
A mixture of 4-chloro-1-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}-2-propyl-1H-imidazo[4,5-c]quinoline (1.22 g, 2.81 mmol) and 7 N ammonia in methanol (100 mL) was sealed in a pressure vessel and heated at 150° C. for 12 hours and allowed to cool to room temperature. The volatiles were removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluting with 10% to 15% CMA in chloroform). The product was then triturated sequentially with toluene and hexane/diethyl ether to provide 0.312 g of 1-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 208.0-209.0° C.