Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:22]([O:24][CH3:25])=[O:23])([CH3:21])[NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5].[H-].[Na+].[CH3:28]N(C)C=O.IC>O>[CH3:28][N:3]([C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)=[O:5])[C:2]([CH3:1])([C:22]([O:24][CH3:25])=[O:23])[CH3:21]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC(=O)C(C)(C)N(C)C(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
As shown in Reaction Scheme 11, a mixture of methyl 2-methyl-N-[(4′-nitrobiphenyl-4-yl)carbonyl]alaninate (1.32 g, 3.9 mmol), sodium hydride (117 mg, 4.6 mmol), and N,N-dimethylformamide (15 mL) was stirred for 2 h at rt. Iodomethane (0.48 mL, 7.7 mmol) was added, and the reaction mixture was stirred overnight at rt. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (2×10 mL). The combined extracts were evaporated to dryness, and crude product was purified by flash chromatography (Biotage®, 4:1 hexanes/EtOAc) to yield methyl N,2-dimethyl-N-[(4′-nitrobiphenyl-4-yl)carbonyl]alaninate as an off-white solid (1.29 g, 94%). 1H NMR (400 MHz, DMSO-d6) δ 1.47 (s, 6H), 2.93 (s, 3H), 3.58 (s, 3H), 7.52 (d, 2H), 7.84 (d, 2H), 7.98 (d, 2H), 8.30 (d, 2H); LC-MS m/z 356.9 (MH+), retention time 2.98 minutes.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:14]([O:16]CC)=[O:15])[CH:6]=[C:7]([CH:13]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].O.O.[OH-].[Li+]>C(O)C>[CH2:11]([O:10][C:8]([C:7]1[CH:6]=[C:5]([CH:4]=[C:3]([CH2:2][OH:1])[CH:13]=1)[C:14]([OH:16])=[O:15])=[O:9])[CH3:12]
Reactant: CCOC(=O)c1cc(CO)cc(C(=O)OCC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(CO)cc(C(=O)O)c1

Procedure:
A mixture of diethyl 1,3,5-benzenetricarboxylate (5.2 g) and borane methylsulfide complex (6.1 g) is stirred in THF (150 mL) at 20–25 degrees C. overnight. The mixture is then treated with methanol, concentrated to dryness, and chouromatographed (silica gel) to give diethyl 5-(hydroxymethyl)isophthalate. Diethyl 5-(hydroxymethyl)isophthalate (3.4 g) is hydroyzed in ethanol and water with lithium hydroxide monohydrate (0.57 g) at 20–25 degrees C. for 3.5 hours at which time the solvents are removed under reduced pressure. Water (100 mL) is added and the mixture is acidified to pH=4 with concentrated hydrochloric acid. The mixture is extracted with ethyl acetate and dried over magnesium sulfate, filtered, and concentrated to give 3-(ethoxycarbonyl)-5-(hydroxymethyl)benzoic acid, high resolution MS MH+=225.0769. 3-(Ethoxycarbonyl)-5-(hydroxymethyl)benzoic acid (2.3 g), EDC (3.0 g), 1-HOBT (2.1 g), diisopropylethylamine (2.7 mL), dipropyl amine (2.8 mL), and DMF (50 mL) are stirred at 20–25 degrees C. overnight. The mixture is then partitioned between ethyl acetate, water, and saline. The organic phase is separated and dried over magnesium sulfate, filtered, and concentrated. Chromatography (silica gel) gives ethyl 3-[(dipropylamino)carbonyl]-5-(hydroxymethyl)benzoate, NMR (CDCl3) δ 0.77, 1.0, 1.4, 1.6, 1.7, 3.2, 3.5, 4.4, 4.8, 7.6, 8.0 and 8.1.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]([CH2:13][C:14](OCC)=[O:15])(=O)[CH2:10][CH3:11].FC(F)(F)C(O)=O.S(=O)(=O)(O)O>>[CH2:10]([C:9]1[C:8]2[C:1](=[CH:3][C:4]([OH:5])=[CH:6][CH:7]=2)[O:2][C:14](=[O:15])[CH:13]=1)[CH3:11]
Reactant: CCOC(=O)CC(=O)CC
Reactant: Oc1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(=O)oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.4 %

Procedure:
Resorcinol (1.21 g, 11.0 mmol) was dissolved in hot ethyl propionylacetate (1.52 g, 10.0 mmol). To this stirred mixture at ice-water temperature was added dropwise a mixture of trifluoroacetic acid (1.70 mL, 22.0 mmol) and concentrated sulphuric acid (2.2 mL, 22.0 mmol) at such a rate that the reaction temperature was kept below 10° C. (about 30 min). The reaction mixture was then allowed to warm to room temperature and thereupon stirred for an additional 3 h before being quenched cautiously with ice-water. After stirring the suspension that formed for 1 h, the bright yellow precipitate was collected by suction filtration, washed exhaustively with water and then re-dissolved into acetone. The resulting solution was heated with activated charcoal, filtered and evaporated to give a light orange residue which was dried azeotropically with isopropyl alcohol. The crude product that obtained was purified by recrystallisation from acetone/hexane (2:3) to give 3 as creamy crystals (806 mg, 4.24 mmol, 42%); mp 175–178° C. [Lit. [68] 177° C. (ethanol)]; δH (400 MHz, DMSO-d6) 1.22 (3H, t, J=7.3 Hz, CH3), 2.77 (2H, q, J=7.3 Hz, CH2), 6.09 (1H, s, C3-H), 6.71 (1H, d, JC6-H, C8-H=2.4 Hz, C8-H), 6.80 (1H, dd, JC8-H, C6-H=2.4 Hz and JC6-H, C6-H=8.4 Hz, C6-H), 7.64 (1H, d, JC6-H, C5-H=8.8 Hz, C5-H) and 10.53 (1H, s, exchanged with D2O, OH); MS (FAB+) m/z (rel. intensity) 190.8[100, (M+H)+]; MS (FAB−) m/z (rel. intensity) 342.8[60, (M−H+NBA)−], 188.8[100, (M−H)−]. Found: C, 69.4; H, 5.35; C11H10O3 requires C, 69.43; H, 5.30%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[ClH:8].[ClH:8].[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: C1CNCCN1
Product: COc1ccc(CN2CCNCC2)cc1
Product: Cl
Yield: 75 %

Procedure:
A mixture of 4-methoxybenzylchlorine and piperazine was treated according to the general preparation 1 to obtain N-(4-methoxybenzyl) piperazine dihydrochloride, yield 75%, mp. 250-252° C. The N1-(4-methoxybenzyl)-N4-phenacyl piperazine dihydrochloride (0.5 g, 1.23 mmol) could be preparated according to the general preparation 2, and then reduced according to the general preparation 3 to obtain 0.38 g of the title compound, yield 77.55%, mp 244-246° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:5][NH:6][CH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:8]1=[O:14].CCN(C(C)C)C(C)C.[Cl:29][C:30]1[S:34][C:33]([S:35](Cl)(=[O:37])=[O:36])=[CH:32][CH:31]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:5][N:6]([CH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:8]1=[O:14])[S:35]([C:33]1[S:34][C:30]([Cl:29])=[CH:31][CH:32]=1)(=[O:37])=[O:36]
Reactant: COc1ccc(CNC2CCCCNC2=O)cc1F
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)s2)cc1F
Reaction time: 8 h

Procedure:
rac-3-(3-Fluoro-4-methoxy-benzylamino)-azepan-2-one (213 mg, 0.80 mmol) was dissolved in CH2Cl2 (7.7 ml) and treated with DMAP (30 mg, 0.24 mmol), Hünig's base (0.30 ml, 1.76 mmol) and ⅛ of the cooled (0° C.) reaction mixture was reacted with 5-chloro-thiophene-2-sulfonyl chloride (48 mg, 0.22 mmol) and shaken overnight in a parallel reaction block. Solvent was removed under reduced pressure and the residue dissolved in aqueous acetonitrile solution and purified using high throughput preparative RP(C18) chromatography: lyophilisate 13 mg;
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][S:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]1[CH3:14].[C:15]1([CH3:26])[CH:20]=[CH:19][C:18]([S:21]([O:24]C)(=[O:23])=[O:22])=[CH:17][CH:16]=1>CC(C)=O>[C:15]1([CH3:26])[CH:16]=[CH:17][C:18]([S:21]([O-:24])(=[O:22])=[O:23])=[CH:19][CH:20]=1.[CH3:14][N+:4]1([CH3:15])[CH:3]([CH2:2][OH:1])[CH2:7][S:6][CH:5]1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CN1C(CO)CSC1c1ccccc1
Solvent: CC(C)=O
Product: C[N+]1(C)C(CO)CSC1c1ccccc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 184.1 %

Procedure:
In 10 ml of acetone, 1.00 g of 4-hydroxymethyl-3-methyl-2-phenylthiazolidine and 0.89 g of methyl p-toluenesulfonate were heated under reflux for 52 hours. The mixture was then placed under reduced pressure to distill off the solvent, and ether was added to the residue. Insolubles were washed with ether and dried under reduced pressure to give 1.74 g of the desired compound.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[N:29]([CH3:30])[C:28]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:21]([CH2:31][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:20](=[O:40])[C:19]=3[C:18]=2[O:41][CH3:42])=[O:16])[CH2:10][CH2:9]1)=[O:7])(=O)C.[OH-].[Na+].C(O)C.Cl>C1COCC1.O>[OH:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[N:29]([CH3:30])[C:28]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:21]([CH2:31][C:32](=[O:39])[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:20](=[O:40])[C:19]=3[C:18]=2[O:41][CH3:42])=[O:16])[CH2:10][CH2:9]1)=[O:7]
Reactant: COc1c(C(=O)NC2CCN(C(=O)COC(C)=O)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1c(C(=O)NC2CCN(C(=O)CO)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Yield: 51.2 %

Procedure:
A mixed solution of the compound of Example 123 (125 mg, 0.218 mmol) and 8N aqueous sodium hydroxide solution (1 mL) in THF (2 mL)-ethanol (7 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, acidified with 6N hydrochloric acid (1.5 mL), and extracted twice with ethyl acetate. The extract was combined, washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate), and the obtained solid was recrystallized from ethyl acetate-THF to give the title compound (59.2 mg, 51%) as white crystals.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][C:23]=3[F:32])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:33][N:34](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:35].F[P-](F)(F)(F)(F)F.CNC>CN(C=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29](=[O:30])[N:34]([CH3:35])[CH3:33])=[CH:24][C:23]=3[F:32])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1c(Oc2ccc(CC(=O)O)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1c(Oc2ccc(CC(=O)N(C)C)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
A mixture of 4-[6-(4-carboxymethyl-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (150 mg, 0.335 mmol) and HATU (178 mg, 0.469 mmol) in DMF (4 mL) was stirred for 30 minutes at room temperature. Then, dimethylamine (235 μL, 0.47 mmol) was added and the reaction was stirred for 24 hours at room temperature. The reaction was quenched with water and the product extracted in ethyl acetate. The organic layer was concentrated in vacuo and purified by HPLC to provide Compound C150 as a white solid (40 mg, 25%). 1H NMR (DMSO-d6, 400 MHz) δ 1.21 (d, 6H), 1.62-1.72 (m, 2H), 1.92-2.01 (m, 2H), 2.16 (s, 3H), 2.87 (s, 3H), 3.06 (s, 3H), 3.32-3.41 (m, 2H), 3.61-3.69 (m, 2H), 3.75 (s, 2H), 4.08 (h, 1H), 5.33 (h, 1H), 7.08 (d, 1H), 7.23-7.33 (m, 2H), 8.27 (s, 1H). Exact mass calculated for C24H31FN4O5 474.53, found 475.5 (MH+).
Reaction SMILES: Br[CH:2]1CC2C(=CC=C(C3C=CC=C(Cl)C=3)C=2)C1=O.C(N)(=S)C.Br.[Cl:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:43]=[CH:42][C:41]3[C:36]4([OH:44])[N:37]=[C:38]([CH3:40])[S:39][CH:35]4[CH2:34][C:33]=3[CH:32]=2)[CH:28]=[CH:29][CH:30]=1>CC(C)=O>[Cl:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:43]=[CH:42][C:41]3[C:36]4[N:37]=[C:38]([CH3:40])[S:39][C:35]=4[CH2:34][C:33]=3[CH:32]=2)[CH:28]=[CH:29][CH:30]=1.[Cl:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:43]=[CH:42][C:41]3[C:36]4([O:44][CH3:2])[N:37]=[C:38]([CH3:40])[S:39][CH:35]4[CH2:34][C:33]=3[CH:32]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: CC1=NC2(O)c3ccc(-c4cccc(Cl)c4)cc3CC2S1
Reactant: O=C1c2ccc(-c3cccc(Cl)c3)cc2CC1Br
Agent: Br
Agent: CC(N)=S
Solvent: CC(C)=O
Product: COC12N=C(C)SC1Cc1cc(-c3cccc(Cl)c3)ccc12
Product: Cc1nc2c(s1)Cc1cc(-c3cccc(Cl)c3)ccc1-2
Temperature: 0 °C
Reaction time: 5 h

Procedure:
321 mg of 2-bromo-5-(3-chlorophenyl)indan-1-one are dissolved with 83 mg of thioacetamide in 10 ml of dry acetone and stirred at 0° C. for 5 h. The precipitate consisting of 6-(3-chlorophenyl)-2-methyl-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol hydrobromide is filtered off with suction, washed with acetone, dried in vacuo and then dissolved in 20 ml of dry methanol. The solution is left to stand at room temperature for 2 weeks. It is made basic with triethylamine, concentrated and purified on silica gel with ethyl acetate/n-heptane 1/1. 6-(3-Chlorophenyl)-2-methyl-8H-indeno[1,2-d]thiazole is obtained with a melting point of 111-112° C. in addition to 6-(3-chlorophenyl)-3a-methoxy-2-methyl-8,8a-dihydro-3aH-indeno[1,2-d]thiazole with a melting point of 80-82° C.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.S(=O)(=O)(O)[O-].[Na+].[C:25]([BH3-])#N.[Na+].Cl[CH:30](Cl)[CH3:31]>C(O)(=O)C.C(OCC)(=O)C.CC(C)=O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH:30]([CH3:31])[CH3:25])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(Cl)Cl
Reactant: [BH3-]C#N
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCN2)no1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)N1CCCC1C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of acetone and (S)-pyrrolidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (0.2 g; 0.843 mmol) in dichloroethane (3 mL) with several drops of acetic acid and approximately 10 equivalents of sodium bisulfate is stirred for 30 minutes followed by the addition of sodium cyanoborohydride (0.079 g; 1.265 mmol). The mixture is stirred overnight at room temperature. After this time, the mixture is diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution and brine. The organics are dried (Na2SO4), filtered and concentrated in vacuo to afford crude material. Excess starting material is removed using polystryrene bound-isocyante resin (500 mg: 1.51 mmol/g) in dichloromethane (5 mL) for several hours. Crude product is eluted from resin using methylene chloride and tetrahydrofuran. The filtrate is concentrated and final purification done using reverse phase preparative HPLC to afford title compound. ESI m/z 280 [M+H]+
Reaction SMILES: CO[CH2:3]/[C:4](=[CH:6]\[CH2:7][CH2:8][CH:9]([CH2:11][CH:12]=[O:13])[CH3:10])/[CH3:5].[Mg].[CH3:15]I.S(=O)(=O)(O)O.[CH2:22]([O:24]CC)C>>[CH3:22][O:24][C:4]([CH3:3])([CH3:5])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:10])[CH2:11][CH:12]([OH:13])[CH3:15]
Reactant: CCOCC
Reactant: CI
Reactant: COC/C(C)=C\CCC(C)CC=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Product: COC(C)(C)CCCC(C)CC(C)O
Temperature: 0 °C

Procedure:
A solution of 28 g. of methoxycitronellal in 50 ml. of ether is slowly added dropwise at -20° C. to -10° C. to a Grignard solution prepared from 5.35 g. of magnesium and 28.4 g. of methyl iodide in 100 ml. of diethyl ether. The mixture is then poured onto 100 ml. of ice-water, acidified with dilute aqueous sulfuric acid and extracted twice with diethyl ether. The extracts are washed with semi-saturated and saturated sodium chloride solution, dried over sodium sulfate and evaporated. By distillation in a high vacuum there is obtained pure 8-methoxy-4,8-dimethyl-2-nonanol of boiling point 103° C./0.8 mmHg; nD20 = 1.4451.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[CH:18]1([C:21]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH:18]1([C:21]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][N:30]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]4[N:9]=[C:10]5[C:5]([CH2:4][CH2:3][C:2](=[O:1])[NH:11]5)=[CH:6][CH:7]=4)[CH2:29][CH2:28]3)[CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19]1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Reactant: c1cc(C2CC2)nc(N2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(C5CC5)n4)CC3)nc2N1
Reaction time: 0.33 h

Procedure:
A mixture of 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.47 g, 2.0 mmol) and 1-(6-cyclopropyl-pyridin-2-yl)-piperazine (0.41 g, 2.0 mmol) in dichloroethane (12 mL) was stirred for 20 min and NaBH(OAc)3 (0.55 g, 2.6 mmol) was added. The reaction was stirred at room temperature for 2.5 h. The reaction was quenched with saturated NaHCO3 and extracted with Et2O. The organic layer was washed with brine, dried over MgSO4 and concentrated. Purification by liquid chromatography (Biotage 12M, eluted with CHCl3) gave the title compound as an oil. The oil was dissolved in Et2O and treated with anhydrous HCl gas to give a precipitate. The mixture was filtered, washed with Et2O and hexanes and dried to give a white solid (121 mg). MS: APCI: M+1: 422.3 (Exact Mass: 421.25).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1O.[CH2:11]([CH:13]1O[CH2:14]1)[Cl:12].[OH-:16].[K+].Cl>C(O)C.O>[Cl:12][CH2:11][CH2:13][CH2:14][C:3]1[CH:4]=[CH:5][C:6]([C:8]#[N:9])=[C:7]2[O:16][C:2]=12
Reactant: N#Cc1ccc(O)c(Cl)c1
Reactant: ClCC1CO1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(CCCCl)c2c1O2
Yield: 42.8 %

Procedure:
While a solution of 2-chloro-4-cyanophenol (50 g) and epichlorohydrin (60.3 g) in ethanol (55 ml) was refluxed, a solution of potassium hydroxide (21.9 g) in ethanol (90 ml) was added dropwise over a period of 40 minutes and the reaction mixture was further refluxed for 100 minutes. After the mixture was cooled, water (50 ml) was added thereto and it was neutralized with 1N hydrochloric acid. After the solvent was distilled off, the residue was extracted with diethyl ether. The extract was dried (over magnesium sulfate) and the diethyl ether was distilled off. The residue was distilled under reduced pressure to give 27 g of 3-chloro-4-(2,3-epoxy)propylbenzonitrile as a colorless oil. After crystallization, the crystals are recrystallized from isopropyl ether-ethyl acetate to give colorless needles. m.p. 71.0°-71.8° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[C:13]([O:18][C@H:19]4[CH2:23][CH2:22][O:21][CH2:20]4)=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:24]([OH:26])=O.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH2:32]>>[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH:32][C:24]([C:3]1[S:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:11][C:12]3[C:13]([O:18][C@H:19]4[CH2:23][CH2:22][O:21][CH2:20]4)=[N:14][CH:15]=[CH:16][CH:17]=3)[C:10]=2[C:2]=1[CH3:1])=[O:26]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3O[C@H]3CCOC3)c12
Reactant: CN(C)CCCN
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3cccnc3O[C@H]3CCOC3)c12

Procedure:
Prepared analogously to example 10.4 from 5-methyl-4-{2-[(S)-(tetrahydro-furan-3-yl)oxy]-pyridin-3-ylamino}-thieno[2,3-d]pyrimidine-6-carboxylic acid and N1,N1-dimethyl-propane-1,3-diamine.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[CH:16][C:15]=1[C:27]([F:30])([F:29])[F:28].Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([C:27]([F:30])([F:28])[F:29])[CH:16]=2)=[N:22]1)=[O:12])[CH3:9]
Reactant: Cc1cc(Oc2ccc(Cl)c(C(F)(F)F)c2)n[nH]1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)n1nc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
Triethylamine (0.17 g, 1.7 mmol) and ethyl isocyanate (0.12 g, 1.7 mmol) were added to a solution of 3-(4-chloro-3-trifluoromethylphenyloxy)-5-methylpyrazole (0.42 g, 1.5 mmol) in ethyl acetate (5 ml) at 0° C., and the mixture was allowed to have room temperature gradually and stirred for 5 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a yellow viscous substance of N-ethyl-3-(4-chloro-3-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.42 g, yield: 80.1%). 1H-NMR (CDCl3, TMS, ppm): δ 1.22 (t, J=7.2 Hz, 3H), 2.59 (d, J=0.8 Hz, 3H), 3.38 (dq, J=5.9 and 7.2 Hz, 2H), 5.73 (q, J=0.8 Hz, 1H), 6.91 (br s, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.49 (dd, J=2.4 and 8.8 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H).
Reaction SMILES: [CH2:1]([Al:3](CC)[CH2:4][CH3:5])[CH3:2].[CH:8]#[N:9].[C-]#N.C([Al+]CC)C.[C:17]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[C:28](=[O:35])[CH2:29][CH:30]([OH:34])[C:31]=1OC)([O:19][CH3:20])=[O:18].Cl>C1(C)C=CC=CC=1>[C-:8]#[N:9].[CH2:1]([Al+:3][CH2:4][CH3:5])[CH3:2].[C:17]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[C:28](=[O:35])[CH2:29][CH:30]([OH:34])[C:31]=1[C:8]#[N:9])([O:19][CH3:20])=[O:18]
Reactant: C#N
Reactant: COC(=O)CCCCCCC1=C(OC)C(O)CC1=O
Reactant: CC[Al](CC)CC
Agent: CC[Al+]CC
Agent: Cl
Agent: [C-]#N
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCCC1=C(C#N)C(O)CC1=O
Reaction time: 2 h
Yield: 76.7 %

Procedure:
A toluene solution of diethylaluminum cyanide was prepared by reacting 15.7 g of triethylaluminum with 4.1 g of hydrocyanic acid in 300 ml of toluene. Into the obtained toluene solution of diethylaluminium cyanide was added a mixture of 15.4 g of 2-(6'-carbomethoxy-hexyl)-3-methoxy-4-hydroxy-2-cyclopenten-1-one prepared in Step 2 under cooling and the resultant mixture was allowed to stand for 2 hours at room temperature. The reaction mixture was poured into diluted hydrochloric acid under cooling. The organic layer thus formed was separated, and the aqueous layer was extracted with ether. The combined organic layers were washed with aqueous sodium bicarbonate solution and then water and dried over magnesium sulfate. After evaporation of the solvent, the residual oil was purified using chromatography on silica gel to provide 11.6 g of 2-(6'-carbomethoxyhexyl)-3-cyano-4-hydroxy-2-cyclopenten-1-one as an oily material.