Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].[O:3]1[CH2:8][CH2:7][O:6][C:5]2[CH:9]=[C:10]([C:13]([NH:15][C@@H:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:18]([C:29]([O:31]C)=[O:30])[CH2:17]3)=[O:14])[CH:11]=[CH:12][C:4]1=2.Cl>C1COCC1.CO.O>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][C@@H:16]([NH:15][C:13]([C:10]2[CH:11]=[CH:12][C:4]3[O:3][CH2:8][CH2:7][O:6][C:5]=3[CH:9]=2)=[O:14])[CH2:17][C@@H:18]1[C:29]([OH:31])=[O:30])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)[C@H]1C[C@H](NC(=O)c2ccc3c(c2)OCCO3)CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc3c(c2)OCCO3)C[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.1 %

Procedure:
LiOH (1.23 g, 51.4 mmol) was added to a solution of (2R,4R)-1-tert-butyl 2-methyl 4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)piperidine-1,2-dicarboxylate (5.4 g, 12.8 mmol) in THF/MeOH/water (3:2:1) (60 mL) and the resulting solution was stirred at room temperature for 18 hours. 1M HCl solution was added to reaction solution to adjust pH to about 3, extracted with ethyl acetate (2×100 mL). The organic layers were dried over MgSO4 and concentrated to give the acid as a white solid 5.0 g (96%). LC-MS: 407.3; 405.3 (t=2.2 min).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:17])[CH:14]([CH3:16])[CH3:15].[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[NH:27][C@H:28]1[CH2:31][C@H:30]([NH:32][C:33]2[C:38](Cl)=[N:37][CH:36]=[CH:35][N:34]=2)[CH2:29]1>CC(P(C(C)(C)C)C(C)(C)C)(C)C.CC(P(Br)(Br)(C(C)(C)C)C(C)(C)C)(C)C.[Pd].[Pd]>[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[NH:27][C@H:28]1[CH2:31][C@H:30]([NH:32][C:33]2[C:38]([C:14]([CH3:16])([CH3:15])[C:13]#[N:17])=[N:37][CH:36]=[CH:35][N:34]=2)[CH2:29]1
Reactant: CC(C)C#N
Reactant: Clc1nccnc1N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Agent: [Pd]
Agent: CC(C)(C)P(Br)(Br)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CC(C)NC(C)C
Product: CC(C)(C#N)c1nccnc1N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Dibromobis(tri-tert-butylphosphine)dipalladium(I) (0.031 g, 0.040 mmol) was sealed in a microwave vessel under argon. Diisopropylamine (0.200 ml, 1.427 mmol) was added and the mixture cooled in a dry ice bath. A nitrogen needle was added followed by dropwise addition of butyllithium solution (2.5 m in hexanes, 0.500 ml, 1.250 mmol). The mixture was stirred for 5 minutes then isobutyronitrile (0.100 ml, 1.114 mmol) was added. The reaction was removed from the cold bath and allowed to slowly warm to room temperature. A solution of trans-N1-(benzo[d]thiazol-2-yl)-N3-(3-chloropyrazin-2-yl)cyclobutane-1,3-diamine (intermediate 27, 0.150 g, 0.452 mmol) in dry, sparged dioxane (1.5 mL) was added and the nitrogen needle removed. The reaction was heated at 95° C. for 14 hours. The crude was partitioned between water (100 mL), saturated ammonium chloride (10 mL) and ethyl acetate (200 mL). The organic phase was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (dichloromethane to ethyl acetate gradient) gave the desired 2-(3-((trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)amino)pyrazin-2-yl)-2-methylpropanenitrile (0.067 g, 0.184 mmol, 40.7% yield).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[CH3:7]>>[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:1][CH:3]1[O:5][CH2:4]1)[CH3:7]
Reactant: ClCC1CO1
Reactant: CCOc1ccccc1O
Product: CCOc1ccccc1OCC1CO1

Procedure:
In this embodiment of Step 1, illustrated in FIG. 2, Epoxide 1 can be prepared by reacting epichlorohydrin with 2-ethoxyphenol in the presence of a catalytic amount of a phase transfer catalyst without the use of solvents at elevated temperatures in a two-stage process to afford near quantitative yield of 1-(2-ethoxyphenoxy)-2,3-epoxypropane with very few side products. This embodiment of the invention is further illustrated by a non-limiting Example 12. The phase transfer catalyst for this embodiment can be selected from ammonium salts such as benzyltriethylammonium salts, benzyltrimethylammonium salts, tetrabutylammonium salts, etc; phosphonium salts, guanidinium salts, crown ether, polyethylene glycol, polyethylene glycol ether, or polyethylene glycol ester, or other phase transfer catalysts know in the art. The first stage of the process of this embodiment may take place without a solvent in a presence of a large excess of epichlorohydrin. This stage is followed by a de-chlorination stage, before or after removal of excess epichlorohydrin, using a base and a solvent. The reaction produces 1-(2-ethoxyphenoxy)-2,3-epoxypropane in high yield. Example of the bases used herein include but are not limited to NaOH, KOH, LiOH, LiOH/LiCl, K2CO3, Na2CO3, amines such as mono-, di- or tri-substituted amines (such as diethylamine, triethylamine, dibutylamine, tributylamine etc.), DMAP. In one variation of this embodiment of Step 1, the phase transfer catalyst may be used only at the de-chlorination stage of the process. The de-chlorination stage can be carried out in a biphasic system or in a single phase system. For a biphasic system, it can be an organic-aqueous liquid biphasic system, or a liquid-solid biphasic system. Solvents that are useful for the process include but are not limited to non-substituted and substituted aromatic solvents (e.g. toluene, benzene, chlorobenzene, dimethylbenzene, xylene), halo-substituted hydrocarbons (e.g. CH2Cl2, CHCl3), THF, dioxanes, DMF, DMSO, non-substituted and substituted pyridines, ketones, pyrrolidones, ethers, acetonitrile, nitromethane. As mentioned above, this process takes place at the elevated temperature. In one variation of the embodiment, the temperature is above 60° C. In another variation, 2-ethoxyphenol and epichlorohydrin are heated to 60-90° C. for a period of time in the presence of phase transfer catalyst. Excess of epichlorohydrin is removed and the residue is dissolved in a solvent such as toluene or benzene treated with an aqueous base solution, such as NaOH, KOH, LiOH, LiOH/LiCl. In yet another variation of the embodiment, the residue after epichlorohydrin removal can be dissolved in one or more of the said solvent and treated with a base (solid or liquid but not an aqueous solution) and optionally a second phase transfer catalyst, optionally at elevated temperatures.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:5])[CH3:4].Cl[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]>C1C=CC=CC=1>[CH2:10]([O:9][C:7]([NH:1][CH2:2][C@@H:3]([OH:5])[CH3:4])=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](O)CN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccccc1
Product: C[C@H](O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-1-amino-2-propanol (9.76 g, 130 mmol) in anhydrous benzene (60 mL) at 0° C. was added benzyl chloroformate (10.23 g, 60 mmol) in anhydrous benzene (120 mL) slowly, in portions, over a period of 20 min while vigorously stirring under an atmosphere of nitrogen. The mixture was stirred for 1 hour at 0° C., then allowed to warm to room temperature and stirred for a further 2 hours. The mixture was washed with water (2×) and brine (2×) before the organic layer was dried over anhydrous MgSO4. Evaporation of all solvent gave the title product as an oil. 1H NMR (CDCl3) δ1.22 (d, 3H,) 2.40 (bs, 1H), 3.07 (m, 1H), 3.37 (m, 1H) ), 3.94 (m, 1H), 5.16 (s, 2H), 5.27 (m, 1H), 7.38 (m, 5H). MS m/z (electrospray) 232 [M+23]+ (100%), 166 (96).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[Cl:21][C:22]1[N:23]=[N:24][C:25](Cl)=[CH:26][C:27]=1[C:28]([C:30]1[CH:39]=[C:38]([CH3:40])[C:33]2[NH:34][C:35](=[O:37])[O:36][C:32]=2[CH:31]=1)=[O:29].CCN(C(C)C)C(C)C.C(O)=O>CN(C=O)C.O>[Cl:21][C:22]1[N:23]=[N:24][C:25]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)=[CH:26][C:27]=1[C:28]([C:30]1[CH:39]=[C:38]([CH3:40])[C:33]2[NH:34][C:35](=[O:37])[O:36][C:32]=2[CH:31]=1)=[O:29]
Reactant: Cc1cc(C(=O)c2cc(Cl)nnc2Cl)cc2oc(=O)[nH]c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: O
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)c(Cl)nn3)CC1)C(=O)N2

Procedure:
360 mg (1.31 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 480 mg (1.19 mmol) 6-(3.6-dichloro-pyridazine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and 0.300 mL (1.74 mmol) DIPEA were stirred in 3 mL DMF for 4 h at 100° C. Then the reaction mixture was cooled, combined with 0.5 mL formic acid and 15 mL water, the precipitate formed was suction filtered and dried. This was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].[F:30][C:31]([F:54])([F:53])[C:32]1[CH:52]=[CH:51][C:35]([CH2:36][C@H:37]2[CH2:41]OS(=O)(=O)[N:38]2[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:34][CH:33]=1.Cl>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([N:16]([C:17]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:23])[CH2:41][C@@H:37]([NH:38][C:44](=[O:45])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:36][C:35]3[CH:51]=[CH:52][C:32]([C:31]([F:54])([F:53])[F:30])=[CH:33][CH:34]=3)=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(C(F)(F)F)cc2)COS1(=O)=O
Reactant: CC(C)(C)OC(=O)Nc1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 5-(3-fluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-ylcarbamate (0.587 g, 1.72 mmol) and cesium carbonate (1.12 g, 3.45 mmol) were heated to 50° C. in 15 mL THF in a round bottle flask. (S)-tert-Butyl 4-(4-(trifluoromethyl)benzyl)-1,2,3-oxathiazolidine-3-carboxylate-2,2-dioxide (0.855 g, 2.24 mmol) in 10 mL THF was added to the flask dropwise, and the mixture was heated at 50° C. for 30 minutes. The flask was then cooled to 20° C., and 10 mL 1 N HCl was added to the flask. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was combined with 200 mL EtOAc. The organic phase was washed with water, twice with saturated ammonium sulfate, and dried over sodium sulfate. After removing the solvent, the product was obtained as yellow oil. LCMS indicated two major peaks with the same desired product M+1. The product thus obtained was used directly in the next step.
Reaction SMILES: C([NH:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:8][CH2:7]1)(=O)C.Cl>CC(C)=O>[NH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:8][CH2:7]1
Reactant: CC(=O)NCC1CCC(CCC(=O)O)CC1
Agent: Cl
Solvent: CC(C)=O
Product: NCC1CCC(CCC(=O)O)CC1

Procedure:
13 g of 3-[4-(acetylamino-methyl)-cyclohexyl]-propionic acid are added to 200 ml of semi-concentrated aqueous hydrochloric acid and the resulting solution is refluxed overnight. The mixture is combined with acetone, recrystallised and the precipitate is separated off. When the mother liquor is concentrated step by step further fractions of the crystallin product are isolated. The fractions are combined, recrystallised with isopropanol and then dried.
Reaction SMILES: C[Mg]Cl.[CH2:4]([N:11]1[CH2:15][CH:14]=[CH:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:16]([N:23]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:24]=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1([Mg]Br)CCCCC1>O1CCCC1.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.O>[CH2:4]([N:11]1[CH2:15][CH:14]2[CH:13]([CH:24]2[N:23]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C1=CCN(Cc2ccccc2)C1
Reactant: O=CN(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Br[Mg]C1CCCCC1
Agent: C[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CN2CC3C(C2)C3N(Cc2ccccc2)Cc2ccccc2)cc1
Reaction time: 0.17 h
Yield: 69 %

Procedure:
At room temperature, a solution of methylmagnesium chloride (3.4 ml, 3 M in tetrahydrofuran) was added dropwise over a period of 10 min to a mixture of N-benzyl-3-pyrroline (1.48 g) and tetraisopropoxytitanium (2.72 ml, 9.3 mmol) tetrahydrofuran. After the solution had stirred for a further 10 min, a solution of dibenzylformamide (2.1 g) in 5 ml of tetrahydrofuran was added at room temperature over a period of 30 seconds. A solution of cyclohexylmagnesium bromide (5.2 ml, 1.95 M in diethyl ether) was then added dropwise over a period of 2 hours, and the mixture was heated under reflux for another 4 hours. The hot reaction mixture was admixed with water (5 ml) (careful, exothermic reaction), and the resulting precipitate was collected on a filter and washed with 20 ml of diethyl ether. The combined filtrates were concentrated under reduced pressure. Unreacted N-benzyl-3-pyrroline. Dibenzylformamide and unidentified compounds were distilled off from the residue under reduced pressure 1.3×10-4 mbar, bath temperature 150° C.). Further distillation (bath temperature 180-200° C.) gave 3-benzyl-6-(dibenzylamino)-3-azabicyclo[3.1.0]hexane (2.62 g, 90% pure according to 1H NMR, corresponding to a yield of 69%), contaminated by dibenzylformamide, as a slightly yellowish viscous oil.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[F:5][C:6]([F:15])([F:14])[C:7]1[S:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]([CH:12]([C:10]1[N:11]=[C:7]([C:6]([F:5])([F:14])[F:15])[S:8][CH:9]=1)[OH:13])#[CH:2]
Reactant: O=Cc1csc(C(F)(F)F)n1
Reactant: C#C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)c1csc(C(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
11 cm3 of a molar solution of ethynyl magnesium bromide is added to a solution of tetrahydrofuran containing 2 g of 2-(trifluoromethyl) 4-thiazolecarboxaldehyde. The reaction mixture is kept under agitation for 30 minutes at 20°/25° C. then it is poured into an ammonium chloride solution. Extraction is carried out with methylene chloride, the extracts are dried, filtered and brought to dryness. 2.1 g of desired product is obtained.
Reaction SMILES: [Li+].[OH-].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:11]([N:17]2[CH:21]=[N:20][N:19]=[N:18]2)[C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1>C(O)C.O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[C:11]([N:17]2[CH:21]=[N:20][N:19]=[N:18]2)[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Reaction time: 2 h

Procedure:
The saponification was performed by the addition of 1.14 mL of 2.0M LiOH solution to a solution of 0.27 g (0.76 mmole) of ethyl α-[bis(4-fluorophenyl)methylene]-1H-tetrazole-1-acetate in 5 mL of 95% ethanol at room temperature. After two hours, the crude reaction mixture was diluted with water and washed with diethyl ether (20 mL×2). The free acid in the aqueous layer was regenerated by the addition of aqueous HCl then extracted with diethyl ether, dried and evaporated. The crude acid was dried under high vacuum for 48 hours before it was used in the next step.
Reaction SMILES: [Cl-].C[SiH](C)C.[Cl:6][C:7]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([F:16])[C:8]=1[CH2:9]Br.[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=1.O>O1CCCC1.BrC(Br)C.[Zn]>[Cl:17][C:18]1[CH:23]=[C:22]([CH2:9][C:8]2[C:11]([F:16])=[C:12]([CH3:15])[CH:13]=[CH:14][C:7]=2[Cl:6])[N:21]=[CH:20][N:19]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1ccc(Cl)c(CBr)c1F
Agent: CC(Br)Br
Agent: C[SiH](C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Cl)c(Cc2cc(Cl)ncn2)c1F
Reaction time: 0.33 h
Yield: 19.4 %

Procedure:
In 10 ml of tetrahydrofuran was suspended 1.3 g of zinc (powder), to which dibromoethane (2 drops) was added. The mixture was heated under reflux for 5 minutes, to which trimethylsilane chloride was added. The mixture was further heated under reflux for 5 minutes, to which a solution of 2.4 g of 2-chloro-5-methyl-6-fluorobenzyl bromide dissolved in 20 ml of tetrahydrofuran was slowly added with heating under reflux, followed by stirring for 20 minutes. (The solution thus obtained is referred to as solution 0). In 10 ml of tetrahydrofuran were suspended 1.5 g of 4,6-dichloropyrimidine and 0.1 g of dichlorobistriphenylphosphine palladium, to which the above solution L was added, followed by heating under reflux for 3 hours and further stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.53 g of 4-chloro-6-(2-chloro-5-methyl-6-fluorobenzyl)pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:9]=O)=[N:5][CH:6]=[CH:7][N:8]=1.[CH:11]1([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2/[CH:25]=[CH:26]/[CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl.C(O)(=O)C.C(OCC)(=O)C>[CH:11]1([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2/[CH:25]=[CH:26]/[CH:27]2[CH2:32][CH2:31][N:30]([CH2:9][C:4]3[C:3]([O:2][CH3:1])=[N:8][CH:7]=[CH:6][N:5]=3)[CH2:29][CH2:28]2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COc1nccnc1C=O
Reactant: C(=C/C1CCNCC1)\c1ccccc1OCC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1nccnc1CN1CCC(/C=C/c2ccccc2OCC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
After dissolving 131 mg of 3-methoxypyrazine-2-carboxaldehyde and 236 mg of (E)-4-[2-[2-(cyclohexylmethyloxy)phenyl]vinyl]piperidine in 3 ml of 1,2-dichloroethane, 0.07 ml of acetic acid and 276 mg of sodium triacetoxyborohydride were added and the mixture was stirred overnight at room temperature. Aqueous sodium carbonate solution was added to the reaction mixture and extraction was performed with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (255 mg, 77% yield).
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=3)=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+].[C:44]([Cu])#[N:45].[C-]#N.[Na+]>Cl.O>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:13](=[O:14])[N:12]([CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:44]#[N:45])=[CH:3][CH:4]=3)[CH2:9]2)[CH2:24][CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CN1CCN(CCCN(C(=O)Nc2ccc(F)c(Cl)c2)C2CCc3ccc(N)cc3C2)CC1
Reactant: N#C[Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: CN1CCN(CCCN(C(=O)Nc2ccc(F)c(Cl)c2)C2CCc3ccc(C#N)cc3C2)CC1
Temperature: 50 °C
Yield: 23.8 %

Procedure:
To a solution of 1-(7-amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(3-chloro-4-fluoro-phenyl)-1-[3-(4-methyl-piperazin-1-yl)-propyl]-urea (from Preparative Example 27, 0.061 g, 0.13 mmol) in 18% aqueous HCl (0.077 mL) at 0° C. was added, slowly, a solution of NaNO2 (9.4 mg, 0.14 mmol) in H2O (0.091 mL) over 30 min. The mixture was neutralized with Na2CO3 (powder) followed by the addition of a solution of CuCN (0.012 g, 0.13 mmol) and NaCN (14 mg, 0.28 mmol) in H2O (0.091 mL). The mixture was then heated at 50° C. for 30 min. The reaction was concentrated in vacuo and the crude residue was purified on reverse-phase HPLC to give 0.015 g (24%) of 3-(3-chloro-4-fluoro-phenyl)-1-(7-cyano-1,2,3,4-tetrahydro-naphthalen-2-yl)-1-[3-(4-methyl-piperazin-1-yl)-propyl]-urea as a white solid. 1H NMR (300 MHz, CD3OD): □ 7.59 (dd, 1H, J=6.6, 2.7 Hz), 7.50 (s, 1H), 7.46 (dd, 1H, J=8.1, 1.5 Hz), 7.34-7.26 (m, 2H), 7.16 (t, 1H, J=9.0 Hz), 4.31 (m, 1H), 3.55-3.35 (m, 10H), 3.15-3.00 (m, 6H), 2.92 (s, 3H), 2.05 (m, 4H). MS-ESI: 484.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:12][CH:13]2[CH2:15][CH2:14]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC2CC2)cc1Cl
Temperature: 50 °C
Yield: 80.2 %

Procedure:
A solution of 2-chloro-4-hydroxybenzaldehyde (1.00 g, 6.39 mmol), bromomethylcyclopropane (0.93 mL, 9.58 mmol) and potassium carbonate (1.77 g, 12.8 mmol) in DMF (8 mL) was stirred under heating at 50° C. for 1 day. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 3:1) to give the title compound (1.08 g, yield 80%) as an oil.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[C:25]([F:26])=[N:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].[O:27]1[C:31]2([CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)[O:30][CH2:29][CH2:28]1>CCCCCC.O.O1CCCC1>[Cl:16][C:17]1[C:18]2[C:19](=[O:21])[O:20][C:34]3([CH2:35][CH2:36][C:31]4([O:30][CH2:29][CH2:28][O:27]4)[CH2:32][CH2:33]3)[C:22]=2[CH:23]=[N:24][C:25]=1[F:26]
Reactant: O=C(O)c1ccnc(F)c1Cl
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=C1OC2(CCC3(CC2)OCCO3)c2cnc(F)c(Cl)c21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
At −60° C., n-butyllithium (1.50 M hexane solution) (75.9 mL) was dropwise added to tetrahydrofuran (100 mL) solution of 2,2,6,6-tetramethylpiperidine (12.5 g), and stirred at −78° C. for 30 minutes. At −78° C., 3-chloro-2-fluoroisonicotinic acid (5.00 g) was added to the reaction liquid, and stirred at −78° C. for 2 hours. Then, at −78° C., tetrahydrofuran (50 mL) solution of 1,4-dioxaspiro[4.5]decan-8-one (5.78 g) was added to the reaction liquid, and stirred for 30 minutes at −78° C. The reaction liquid was warmed up under cooling with ice, and water and hexane were added thereto in that order. The aqueous layer and the organic layer were separated from each other, then the aqueous layer was made acidic (pH of 1 to 2) with 2 M hydrochloric acid added thereto and the stirred at room temperature for 2 hours. The formed solid was taken out through filtration, washed with water, and dried under reduced pressure to obtain the entitled compound (4.39 g, 49%) as a pale brown solid.