Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:6][C:7]=1[C:8](OCC)=[O:9])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([C:3]1[S:4][C:5]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:6][C:7]=1[CH:8]=[O:9])[CH3:2]
Reactant: CCOC(=O)c1cc(C2CCOCC2)sc1CC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1sc(C2CCOCC2)cc1C=O
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a solution (20 mL) of ethyl 2-ethyl-5-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxylate (1.35 g) synthesized above in tetrahydrofuran was added 1.5M diisobutylaluminum hydride in toluene solution (15.1 mL) at 0° C., and the mixture was stirred for 1 hr. 1N Hydrochloric acid was added to quench the reaction, the organic solvent was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a colorless oil. To a solution of the obtained oil in methylene chloride (20 mL) was added Dess-Martin reagent (2.47 g), and the mixture was stirred at room temperature for 1.5 hr. Saturated aqueous sodium sulfite solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3, volume ratio) to give the title compound (692 mg, 61%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C@H:10]([OH:24])[C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1.Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([C@H:10]([O:24][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2cccc(Cl)c2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
To a suspension of NaH (7.44 g, 161 mmol) in anhydrous DMF (50 mL) at 0-5° C. was added dropwise a solution of (R)-tert-butyl 3-((R)-(3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (17.45 g, 54 mmol) in anhydrous DMF (100 mL), the reaction mixture was stirred for 1 hr at rt. A solution of ethyl bromoacetate (17.82 g, 11.87 mL, 107 mmol) in anhydrous DMF (100 mL) was added dropwise to the above mixture at 0-5° C. After addition, the reaction mixture was stirred for 2-3 hr at rt. The reaction mixture was poured into saturated aqueous NH4Cl and EtOAc (1000 mL) was added. The organic layer was washed with water (3×200 mL) and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on silica gel chromatography to afford (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate (14 g, 64% yield).
Reaction SMILES: C[N:2](C)[C:3]([CH3:32])=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[C:17]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:16]=[C:15]([O:30][CH3:31])[N:14]=2)[CH:8]=1)=O.O.[NH2:35]N.CCO.CCOC(C)=O>CCCCCCC>[CH3:31][O:30][C:15]1[N:16]=[C:17]([NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[CH:18]=[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:5]3[NH:35][N:2]=[C:3]([CH3:32])[CH:4]=3)[CH:8]=2)[N:14]=1
Reactant: NN
Reactant: COc1ccc(CCNc2cc(-c3cccc(C(=O)C=C(C)N(C)C)c3)nc(OC)n2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COc1ccc(CCNc2cc(-c3cccc(-c4cc(C)n[nH]4)c3)nc(OC)n2)cc1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
In a sealed tube are combined 3-dimethylamino-1-(3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-but-2-en-1-one [147 mg, 0.33 mmol, Intermediate (47) prepared as described in Example 38, Step 1], hydrazine hydrate (200 μL), and EtOH (3 mL). Heated the mixture to 85° C. and stirred for 1.5 hours. The reaction mixture is concentrated to provide an oil which is subjected to flash column chromatography on silica gel eluting with 20 to 60% EtOAc in heptane gradient, to afford {2-methoxy-6-[3-(5-methyl-2H-pyrazol-3-yl)-phenyl]-pyrimidin-4-yl}-[2-(4-methoxy-phenyl)-ethyl]-amine [136 mg, 99%, Example 39]. LCMS: RT=2.79 minutes, MS: 416 (M+H). 1H NMR (300 MHz, CDCl3) δ 8.29 (1H, s), 7.9 (1H, d, J=0.027 Hz), 7.72 (1H, d, J=0.025 Hz), 7.4 (1H, t, J=0.026 Hz), 7.09 (2H, d, J=0.028 Hz), 6.82 (2H, d, J=0.028 Hz), 6.35 (2H, d, J=0.024 Hz), 5.18 (1H, s), 3.98 (3H, s), 3.75 (3H, s), 3.59 (2H, m), 2.83 (2H, t, J=0.023), 2.3 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N+:3]=1[O-:9].S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>>[Br:1][C:2]1[CH:7]=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=[C:4]([Br:8])[N+:3]=1[O-:9]
Reactant: [O-][n+]1c(Br)cccc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Br)[n+]([O-])c(Br)c1
Temperature: 79 °C
Reaction time: 3.5 h

Procedure:
2,6-dibromo pyridine 1-oxide (10 g, 39.5 mmol) was added to 65 mL of concentrated sulfuric acid at room temperature without cooling. Concentrated sulfuric acid (15 ml) and nitric acid (13.3 ml) were mixed and placed in a pressure equalising dropping funnel. The reaction mixture was heated to 79° C. then the nitrating mixture was added in portions over 25 minutes. When the addition was complete the mixture was stirred at 83-85° C. for 3.5 hours. The mixture was cooled to room temperature and slowly poured onto ˜250 g crushed ice. A very pale yellow solid formed which was filtered off and washed with water (100 ml), dried in vacuum oven at 50° C. overnight to give 10.9 g of the title compound.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O-])=[O:6])[CH:3]=1.[CH3:14][NH:15][CH3:16].CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>C1COCC1.CO.O>[CH3:14][N:15]([CH3:16])[C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=1)[C:1]([O:12][CH3:13])=[O:11])=[O:6]
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc(C(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Methyl isophthalate (2.00 g, 11.1 mmol) was dissolved in THF (60 mL), and a 2.0 mol/L solution of dimethylamine (11.1 ml, 22.2 mmol) in methanol, EDC hydrochloride (4.27 g, 22.2 mmol) and 1-hydroxybenzotriazole monohydrate (3.40 g, 22.2 mmol) were added thereto, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:3) to afford methyl 3-(N,N-dimethylcarbamoyl)benzoate (2.30 g, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:29]1[N:33]=[C:32]([NH2:34])[O:31][CH:30]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1CCCCC1.CC(C)=O>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:34][C:32]2[O:31][CH:30]=[CH:29][N:33]=2)=[N:3][CH:4]=1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: Nc1ncco1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: C1COCCO1
Solvent: C1CCCCC1
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3ncco3)ncc2Cl)CC1
Yield: 6 %

Procedure:
A suspension of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.150 g, 0.446 mmol), Cs2CO3 (436 mg, 1.34 mmol) and 2-aminoxazole (75.0 mg, 0.892 mmol) in 1,4-dioxane (3 mL) was sonicated for 10 minutes. Xantphos (10 mg, 18 μmol) and Pd(II) acetate (2.0 mg, 8.9 μmol) were added and the reaction was irradiated in the microwave for 20 minutes at 120° C. The resulting mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-100% EtOAc in cyclohexane then 0-20% MeOH in EtOAc) to give a solid. Acetone (0.5 mL) followed by cyclohexane (25 mL) was added and the mixture was sonicated for 10 minutes. The resulting precipitate was collected by filtration and the filter cake was washed with cyclohexane (25 mL) and dried under high vacuum to give the title compound 11 as a white solid (10 mg, 6%). LCMS-B: rt 4.64 min; m/z 384.0 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[O:8][C:9](=[O:24])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][N:18]=C(OCC)C.[ClH:25]>C1COCC1>[ClH:25].[O:7]=[C:4]1[CH2:5][CH2:6][C:2](=[O:1])[N:3]1[O:8][C:9](=[O:24])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][NH2:18]
Reactant: CCOC(C)=NOCCCCCCCC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: C1CCOC1
Product: NOCCCCCCCC(=O)ON1C(=O)CCC1=O
Reaction time: 4 h

Procedure:
To a solution of 6 (5.8 g, 17 mmol) in THF (30 mL) was added a mixture of HCl and THF (4 mL, 2 mL of c.HCl and 2 mL of THF. The reaction mixture was stirred for 4 h, concentrated to a wet solid and washed with 5% EtOAc/hexane. The product solidified (hygroscopic) under vacuum was used without further purification. 1H NMR (DMSO-d6): δ 1.28-1.37 (6H, m), 1.57-1.65 (4H, m), 2.65 (2H, t, J=7.3), 2.82 (4H, s), 4.02 (2H, t, J=6.3), 11.09 (3H, br s).
Reaction SMILES: O1C[CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].C([Mg]Br)(C)C.Cl>O>[CH3:6][O:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]([OH:11])[CH:3]([CH3:4])[CH3:2]
Reactant: COc1ccccc1C=O
Reactant: C1CCOC1
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: O
Product: COc1ccccc1C(O)C(C)C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
Dry tetrahydrofuran (3 mL) was added to 1.01 g (7.43 mmol) of commercially available 2-methoxybenzaldehyde under nitrogen atmosphere, and the mixture was ice-cooled. To the mixture was added dropwise a 3.8 mL (7.6 mmol) of tetrahydrofuran solution containing 2 mol/L isopropylmagnesium bromide. After completion of dropwise addition, the reaction mixture was stirred in an ice bath for 1 hour. The reaction mixture was poured into water, made acidic with diluted hydrochloric acid, and then, extracted with ether. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 1.00 g (5.56 mmol, Yield: 74.8%) of 1-(2-methoxyphenyl)-2-methyl-1-propanol.
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][C:20]=3[CH3:26])=[C:16]([F:27])[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.[C:28]([Si](C)(C)C)#[CH:29]>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:28]#[CH:29])=[CH:21][C:20]=3[CH3:26])=[C:16]([F:27])[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)NOCC2CC2)cc2[nH]cnc2c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#Cc1ccc(Nc2c(C(=O)NOCC3CC3)cc3[nH]cnc3c2F)c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxyamide 11ccc (0.025 g, 0.052 mmol) is dissolved in 1:1 acetonitrile/triethylamine (0.50 mL). Ethynyltrimethylsilane (0.013 mL, 0.092 mmol), Pd(PPh3)2Cl2 (0.004 g, 0.006 mmol), and CuI (0.002 g, 0.011 mmol) are added consecutively and the reaction mixture is stirred at 60° C. for 1 hour under N2. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is purified by FCC (eluting with 20:1 methylene chloride:methanol) to yield 0.020 g (87%) of the desired product.
Reaction SMILES: [CH2:1]([Cl:10])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].C(=O)C1C=CC=CC=1>>[C:4]1([CH:2]([OH:3])[CH2:1][Cl:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(CCl)c1ccccc1
Solvent: O=Cc1ccccc1
Product: OC(CCl)c1ccccc1
Yield: 103.3 %

Procedure:
The procedure of Example 10 was followed using 0.773 g (5 mmol) of phenacyl chloride in lieu of benzaldehyde, to give 809 mg of 1-phenyl-2-chloroethanol as an oil. Conversion rate: 97.5%; yield 80.4%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.Br[C:38]1[S:39][C:40]2[C:46]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:38]3[S:39][C:40]4[C:46]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:45][CH:44]=[CH:43][C:41]=4[N:42]=3)[CH2:14][C@H:13]2[N:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2N2CCCC2)nc1Cl
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N4CCCC4)C3)sc12
Yield: 53.8 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-pyrrolidin-1-ylpiperidine-1-carboxylate obtained in Example (201d) (21.0 mg, 0.049 mmol), 4 N hydrochloric acid/1,4-dioxane (2 mL), ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (16 mg, 0.054 mmol) and sodium carbonate (52 mg, 0.493 mmol), to obtain 14 mg of the title compound (54%) as a pale yellow oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[N:19]=[C:20]([CH2:27][O:28][CH2:29][CH3:30])[N:21]([CH2:22][C:23]([NH2:26])([CH3:25])[CH3:24])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:38]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[N:19]=[C:20]([CH2:27][O:28][CH2:29][CH3:30])[N:21]([CH2:22][C:23]([NH:26][C:44]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:45])([CH3:24])[CH3:25])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)N
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NC(=O)C1CCCCC1
Reaction time: 8 h
Yield: 84.2 %

Procedure:
2-(8-Benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethylamine (2.19 g, 5.4 mmol), triethylamine (1.5 mL, 10.8 mmol), and dichloromethane (50 mL) were combined. Cyclohexanecarbonyl chloride (0.95 mL, 6.0 mmol) was added and the reaction was stirred overnight. Saturated sodium bicarbonate was added and the layers were separated. The organic fraction was sequentially washed with a second portion of saturated sodium bicarbonate and then brine; dried over sodium sulfate; filtered; and concentrated under reduced pressure to provide an orange foam. The residue was purified by column chromatography on a HORIZON HPFC system. A silica gel cartridge was used eluting with a gradient of 0-20% CMA in chloroform to provide 2.34 g of N-{2-[8-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}cyclohexanecarboxamide as a tan solid.
Reaction SMILES: [CH3:1][C:2]12[CH:9](O)[C:6]([CH3:11])([CH2:7][CH2:8]1)[CH2:5][CH2:4][CH2:3]2.[BrH:12]>>[CH3:1][C:2]12[CH:9]([Br:12])[C:6]([CH3:11])([CH2:7][CH2:8]1)[CH2:5][CH2:4][CH2:3]2
Reactant: Br
Reactant: CC12CCCC(C)(CC1)C2O
Product: CC12CCCC(C)(CC1)C2Br
Yield: 85.1 %

Procedure:
1,5-dimethyl-8-hydroxy bicyclo[3,2,1]octane (13.6 g (0.1 mol)) was boiled with 50 ml 48% hydrogen bromide for 4 hours under stirring in the presence of 1 g AMBERLYST A15 ion-exchange resin. The reaction product was extracted after cooling with pentane. The pentane layer was washed with water and a diluted sodium bicarbonate solution. After drying over anhydrous sodium sulfate and boiling down pentane the residue was subjected to fractional distillation under reduced pressure. 18.5 g 1,5-dimethyl-8-bromobicyclo[3,2,1]octane was obtained in 85.1% yield (b.p. 93° C./10 mm Hg). The product obtained was identical with the compound according to the process described in Example 2a.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=1[C@@H:17]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:18][CH2:19][N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])C1C=CC=CC=1.CO.C1(C)C=CC=CC=1>[Pd].O>[CH:24]([N:20]([CH:21]([CH3:23])[CH3:22])[CH2:19][CH2:18][C@@H:17]([C:10]1[CH:11]=[C:12]([CH2:15][OH:16])[CH:13]=[CH:14][C:9]=1[OH:8])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH3:25]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CO)ccc1OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CO)ccc1O)C(C)C
Reaction time: 2 h

Procedure:
11 L (R)-[4-Benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]-methanol solution formula (H) and Pd/C (10%, 0.18 Kg) and methanol (30 L) was added in SS autoclave cell at 25° C. to 35° C. and the mixture was hydrogenated with 4 kg pressure at 25° C. to 35° C. for 2 hours. The mixture was then filtered and to the filtrate add 4.1 g sodium borohydride portion wise within 15-30 minutes at 25° C. to 35° C. and stir the reaction mass for 30 minutes. Methanol is distilled out under vacuum below 55° C. Further, reaction mass is cooled to 25° C. to 35° C. Toluene (10.0 L) was added followed by addition of RO water (1.50 L). The reaction mass is heated to 50° C. to 55° C. and maintained for 30 minutes. The layers were separated and to the organic layer add toluene (1.6 L) 25° C. to 35° C. The reaction mass is heated to 65° C. to 70° C. and maintain for 30 minutes. Further cooled to 25° C. to 35° C. and stirred for 2 hours and further cooled to 0° C. to 5° C. and stirred for 30 minutes. The reaction mass is washed with toluene (2×0.25 L) to afford the title compound as (R)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxy methyl phenol having impurity X content about 0.03%.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]1[CH2:14][CH2:13][C:12]2([CH2:18][CH2:17][N:16](CC)[CH2:15]2)[CH2:11]1)[C:4]1C=CC=CC=1>CO.[Pd]>[ClH:1].[ClH:1].[CH2:3]([N:10]1[CH2:14][CH2:13][C:12]2([CH2:18][CH2:17][NH:16][CH2:15]2)[CH2:11]1)[CH3:4]
Reactant: CCN1CCC2(CCN(Cc3ccccc3)C2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN1CCC2(CCNC2)C1
Yield: 196.6 %

Procedure:
A solution of 9.5 g (0.03 mole) 2-benzyl-7-ethyl-2,7-diazaspiro[4.4]nonane dihydrochloride in 100 ml methanol was hydrogenated with 1.0 g 20% palladium on carbon catalyst at 4.5×105Pa for 22 hours. After filtration, the solution was concentrated to a syrup and crystallized from acetonitrile to afford 6.7 g of the title compound, mp 168-172° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CCOCCOCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCOCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 83.5 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (300 mg) in N,N-dimethylformamide (2.0 mL) was added cesium carbonate (728 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 1-bromo-2-(2-ethoxyethoxy)ethane (496 mg), and the mixture was stirred at room temperature for 20 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic layer washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column-chromatography (silica gel, eluent:hexane/ethyl acetate=9/1→0/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (440 mg) as a colorless transparent oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2[CH:24]=[CH:25][CH:26]=[N:27]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:27][CH:26]1[CH2:24][CH2:25]1)=[O:9]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1cc(Br)cc(C(=O)O)c1C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C(=O)NC2CC2)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred DMF (0.2 M) solution of 5-bromo-2,3-dimethylbenzoic acid (1 eq.) from the previous step was added HATU (1.3 eq.), cyclopropylamine (1.2 eq.) and Hunig's base (3 eq.). The resulting reaction mixture was stirred at RT for 18 h. The reaction was then quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 7:3 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[BH4-].[Na+]>CO.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-bromo-4-fluorobenzaldehyde (35.0 g, 172.4 mmol) in methanol (400 mL) and tetrahydrofuran (200 mL) was added sodium borohydride (6.5 g, 172.4 mmol) in portions at about 0° C. The mixture was stirred for about 3 h while being allowed to warm to ambient temperature. The solvents were removed under vacuum, the residue was diluted with water (600 mL) and was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure to provide the desired product. MS (DCI-NH3): m/z 204, 206 (M)+.