Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([F:14])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([Cl:15])[CH:5]=1)(=O)[NH2:2].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1>[Cl:15][C:6]1[CH:5]=[C:4]([C:1]#[N:2])[CH:13]=[C:12]([F:14])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1c(F)cc(C(N)=O)cc1Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1c(F)cc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a suspension of methyl 4-carbamoyl-2-chloro-6-fluorobenzoate (2.527 g, 10.9 mmoles) in 1,4-dioxane (25 mL) at room temperature was added pyridine (38.2 mmoles, 3.02 g), followed by trifluoroacetic anhydride (5.04 g, 24.0 mmoles). The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (100 mL), extracted with EtOAc (3×100 mL). The combined organics were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-15% EtOAc/hexane) to afford methyl 2-chloro-4-cyano-6-fluorobenzoate as a white solid (1.953 g, yield: 84%). 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=1.1 Hz 1H), 7.37 (dd, J=8.0, 1.2 Hz, 1H), 4.00 (s, 3H). LCMS (APCI+) 214.0 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][N:22]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:24]4[CH:25]=[CH:26][C:21]([NH2:20])=[N:22][CH:23]=4)[N:3]=[CH:4]3)[N:12]=2)=[CH:14][CH:15]=1
Reactant: Clc1ccc(-c2ccnc(-n3cnc(Br)c3)n2)cc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cn(-c3nccc(-c4ccc(Cl)cc4)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(4-chloro-phenyl)pyrimidine (example E.15) (0.27 g, 0.8 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.18 g, 0.8 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.083 g, 30%). MS (ISP) 349.3 [(M+H)+]; mp 188-190° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH3:26][C@H:27]([NH2:36])[C@H:28]([OH:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(O)(=O)C.C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[CH2:23][NH:36][C@@H:27]([CH3:26])[C@H:28]([OH:35])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@@H](C)[C@H](O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
(2′-Formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.094 g, 0.27 mmol), (1R,2S)-(−)-norephedrine (0.054 g, 0.35 mmol), and sodium triacetoxyborohydride (0.113 g, 0.53 mmol) were combined in dichloroethane (1 mL). Acetic acid (1 drop) was added, and the reaction was stirred at room temperature for 40 minutes. Analytical tlc showed that only starting material was present, so the reaction was heated to 50° C. and stirred overnight. Analytical LCMS showed that some starting material was still present, so additional (1R,2S)-(−)-norephedrine (0.057 g, 0.38 mmol), and sodium triacetoxyborohydride (0.115 g, 0.53 mmol) were added, and the reaction was stirred for 3.5 hours at 50° C. After cooling to room temperature, the mixture was diluted with CH2Cl2 and saturated aqueous NaHCO3, and the aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[C:4]([CH3:14])([CH3:13])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[CH3:16][C:17]1[C:18]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)=[N:19][CH:20]=[C:21]([CH3:23])[CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:16][C:17]1[C:18]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([C:2]3[C:3](=[O:15])[C:4]([CH3:14])([CH3:13])[O:5][C:6]=3[C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)=[CH:28][CH:27]=2)=[N:19][CH:20]=[C:21]([CH3:23])[CH:22]=1
Reactant: CC1(C)OC(c2ccncc2)=C(Br)C1=O
Reactant: Cc1cnc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cnc(COc2ccc(C3=C(c4ccncc4)OC(C)(C)C3=O)cc2)c(C)c1
Yield: 23.9 %

Procedure:
A mixture of 4-bromo-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (0.28 g, 1.04 mmol), 3,5-dimethyl-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyridine (0.32 g, 0.94 mmol), and Cs2CO3 (1.3 g, 4.0 mmol) in toluene (10 mL) and water (3 mL) was degassed, Pd(dppf)Cl2 (0.14 g, 0.16 mmol) was added under an inert atmosphere and again degassed. Then the reaction was refluxed for 2 h and was filtered through a pad of Celite®. The filtrate was diluted with EtOAc (50 mL), washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (90 mg, 24%) as an oil. 1H NMR (500 MHz, d6-DMSO): δ 8.72 (d, J=7.5 Hz, 2 H), 8.24 (d, J=7.8 Hz, 1 H), 7.50 (d, J=8.6 Hz, 3 H), 7.23 (d, J=7.4 Hz, 2 H), 7.08 (d, J=7.5 Hz, 2 H), 5.18 (s, 2 H), 2.35 (s, 3H), 2.25 (s,3H), 1.52 (s, 6 H). MS: [M+H]: m/z=401.1. HPLC: 95.2% (RT-1.78 min), Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:4].[CH3:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:3](=[O:4])[CH2:2][NH:1][C:29]([NH:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[CH:23]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1ccccc1F
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2F)c1
Yield: 47.6 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with tert-butyl 2-[2-amino-N-(2-fluorophenyl)acetamido]acetate (2.5 g) and 3-methylphenyl isocyanate (1.2 g), and after recrystallisation in diisopropyl ether, tert-butyl 2-{N-(2-fluorophenyl)-2-[3-(3-methylphenyl)ureido]-acetamido}acetate (1.75 g), m.p. 148° C., is obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[CH2:10][CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:14]=3[N:13]=[N:12]2)[CH:8]([OH:34])[CH:7]1[OH:35])=[O:5])[CH3:2].[NH2:36][CH2:37][C:38]1[CH:43]=[CH:42]C=CN=1>>[OH:35][CH:7]1[CH:8]([OH:34])[CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:14]=3[N:13]=[N:12]2)[CH2:10][CH:6]1[C:4]([NH:3][CH2:1][C:2]1[CH:42]=[CH:43][CH:38]=[CH:37][N:36]=1)=[O:5]
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCC)C(O)C3O)c2n1
Reactant: NCc1ccccn1
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCc4ccccn4)C(O)C3O)c2n1

Procedure:
The subtitle compound was prepared according to the method of example 39, step a) using the product of example 1, step c) and 2-(aminomethyl)pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.C(N(C(C)C)C(C)C)C.[NH2:42][CH:43]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=1)[CH2:44][OH:45]>ClCCl.CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:19])[NH:42][CH:43]([CH2:44][OH:45])[CH2:46][C:47]3[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=3)=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NC(CO)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC(CO)Cc4ccc(Cl)cc4)cc3)c(Cl)cc21
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.100 g, 0.2654 mmol) in dichloromethane (1.5 ml) and DMF (1 drop) was added oxalyl dichloride (0.02778 ml, 0.3185 mmol), and the reaction was stirred for 30 minutes. N-ethyl-N-isopropylpropan-2-amine (0.1112 ml, 0.6370 mmol) and 2-amino-3-(4-chlorophenyl)propan-1-ol (0.06405 g, 0.3450 mmol) were added, and the reaction was stirred for 16 hours. The reaction was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified on a Biotage SP1 system eluting with 25-100% EtOAc in hexanes to yield 111 mg of the title compound (76.82% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([NH:19][CH2:20][C:21]#[N:22])=[CH:17][CH:16]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([NH:6][C:7]([N:19]([CH2:20][C:21]#[N:22])[C:18]1[CH:17]=[CH:16][C:15]([Cl:14])=[CH:24][CH:23]=1)=[O:8])=[O:5]
Reactant: N#CCNc1ccc(Cl)cc1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: c1ccccc1
Product: N#CCN(C(=O)NC(=O)c1c(Cl)cccc1Cl)c1ccc(Cl)cc1
Reaction time: 12 h
Yield: 80 %

Procedure:
16.0 g of 2,6-dichlorobenzoylisocyanate are added in small portions to a solution of 11.66 g of p-chloroanilino-acetonitrile in 100 ml of dry benzene with moderate cooling. After some time a substance crystallizes out, which after about 12 hours is drawn off and washed with benzene. After drying the weight is 25.25 g. i.e. 93.7% the melting point being 185° C with spontaneous decomposition on the Kofler heating bench. Thin-layer chromatography (solvent either ethylacetate or chloroform) shows that the substance is pure, however, if desired, it may be recrystallized from 250 ml of benzene with a yield of 80%.
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:20]N1C(=O)CCC1=O>ClCCl>[C:1]([NH:8][C:9]1[S:10][C:11]([Cl:20])=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)Nc1sccc1-c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1sc(Cl)cc1-c1ccccc1
Temperature: 25 °C
Yield: 66.6 %

Procedure:
To 2-(N-Boc-amino)-3-phenyl-thiophene (89 mg, 0.32 mmol) in dichloromethane (4 ml) at 0° C. was slowly added N-chlorosuccinimide (48 mg, 0.36 mmol), and the mixture allowed warm to ambient temperature for 16 hr. The mixture was diluted with dichloromethane, washed with water, and the organic phase concentrated in vacuo. Flash chromatography on silica gel (ethyl acetate/hexanes) yielded 2-(N-Boc-amino)-5-chloro-3-phenyl-thiophene (66 mg, 66%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31].C(OC(N1CCC2N(CCCCC(OC)=O)N=C(C3C=CC(Cl)=CC=3)C=2CC1)=O)(C)(C)C>>[CH3:33][O:32][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][N:13]1[C:12]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1
Reactant: COC(=O)CCCCCl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: COC(=O)CCCCn1nc(-c2ccc(Cl)cc2)c2c1CCN(C(=O)OC(C)(C)C)CC2
Product: COC(=O)CCCCn1nc2c(c1-c1ccc(Cl)cc1)CCNCC2

Procedure:
The title compound (0.0042 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.15 g) using methyl 5-chlorovalerate (0.90 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-1-(4-methoxycarbonyl-butyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C19H24ClN3O2, 361.16; found, m/z 362.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.54-7.51 (m, 2H), 7.31-7.29 (m, 2H), 3.95 (t, J=7.0 Hz, 2H), 3.60 (s, 3H), 3.03-3.01 (m, 2H), 2.93-2.91 (m, 4H), 2.56-2.53 (m, 2H), 2.16 (t, J=7.4 Hz, 2H), 1.67-1.62 (m, 2H), 1.41-1.38 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:17][CH2:16][C@H:15]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[CH:20]=[CH:19]2)[CH2:14][CH2:13]1.[Cl-].[NH4+].[CH2:27]1[CH2:31]OC[CH2:28]1>>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:13][CH2:14][C@H:15]([CH:18]2[CH2:23][CH2:22][C:21]([CH2:28][CH2:27][CH3:31])([OH:24])[CH:20]=[CH:19]2)[CH2:16][CH2:17]1
Reactant: C1CCOC1
Reactant: CCOc1ccc([C@H]2CC[C@H](C3C=CC(=O)CC3)CC2)c(F)c1F
Agent: [Cl-]
Agent: [NH4+]
Product: CCCC1(O)C=CC([C@H]2CC[C@H](c3ccc(OCC)c(F)c3F)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 4.97 g of 4-(trans-4-(2,3-difluoro-4-ethyloxyphenyl)cyclohexyl)-2-cyclohex enone (r-15) was dissolved into 60 mL of THF, 18.0 mL of propylmagnesium bromide THF solution (1 M/L) was added dropwise thereto at room temperature, and the resultant mixture was stirred at 50° C. for 30 minutes, and then stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added dropwise under ice-cooling, the resultant mixture was subjected to extraction with ethyl acetate, and then organic layers were combined, the resultant organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. A solvent was evaporated under reduced pressure, and the resultant residue was purified by fractionation on silica gel column chromatography (eluate:heptane:ethyl acetate=6:4), and thus 3.79 g of 4-(trans-4-(2,3-difluoro-4-ethyloxyphenyl)cyclohexyl)-1-propyl-2-cyclohexene-1-ol (compound (r-16)) was obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]([O:10][CH2:11][CH3:12])=[O:9].O.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>CC(C)=O.O>[CH2:11]([O:10][C:8]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[O:9])[CH3:12]
Reactant: NCCCCO
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)NCCCCO
Reaction time: 2 h

Procedure:
In an amount of 25.5 g of 4-aminobutanol was dissolved in 255 ml of a mixed solvent of acetone/water (3:1). Under ice cooling, the mixture was added with 43.5 g of potassium carbonate, added dropwise with 27.6 ml of ethyl chloroformate over 13 minutes, and then stirred for 2 hours. The reaction mixture was added with 100 ml of water, and extracted with 100 ml of ethyl acetate, and then the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain 45.3 g of 4-ethoxycarbonylaminobutanol. Physicochemical Properties of this Compound
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CCN=C=NCCCN(C)C.[C:25](O)([CH3:28])([CH3:27])[CH3:26]>CN(C)C1C=CN=CC=1.ClCCl>[C:25]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92.9 %

Procedure:
4-methyl-3-nitrobenzoic acid (40.0 g, 221 mmol), 4-dimethylaminopyridine (54.5 g, 446 mmol) and WSC (84.4 g, 440 mmol) were dissolved in dichloromethane (450 ml). tert-Butanol (34.4 g, 464 mmol) was added with stirring at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was concentrated under reduced pressure, and diluted with ethyl acetate-hexane=1:1 mixed solvent (500 ml). The organic layer was washed with water, 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (48.7 g, yield 93%) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:17][CH2:18][CH2:19]Cl.C#C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([CH:19]=[CH:18][Cl:17])=[O:5]
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1Cl
Reactant: ClCCCl
Agent: C#C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(C=CCl)c1cc(F)c(Cl)cc1Cl

Procedure:
113.75 g (0.5 mole) of 2,4-dichloro-5-fluorobenzoyl chloride are added dropwise to a suspension of 73 g of anhydrous aluminum chloride and 200 ml of dry 1,2-dichloroethane at 0°-10° C., while cooling with ice and stirring. Acetylene is passed in at 40°-50° C. for 6.5 hours. The reaction mixture is poured onto ice, the organic phase is taken up in methylene chloride and the mixture is subsequently extracted with methylene chloride. After drying with sodium sulphate, the solvent is distilled off in vacuo. 121.7 g of 2-chlorovinyl 2,4-dichloro-5-fluoro-phenyl ketone are obtained as a crude product of melting point 65°-70° C. Distillation under a fine vacuum gives 99.8 g (78.7%) of pure product of boiling point: 124°-128° C./0.1 mbar and melting point 71°-73° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1.[BrH:19].C(O)(=O)C.CS(C)=O.C(OC(C)C)(C)C>C(O)(=O)C>[BrH:19].[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:10][CH:11]=1
Reactant: NCCCCc1ccc(C2=NNC(=O)CC2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Solvent: CS(C)=O
Product: NCCCCc1ccc(-c2ccc(=O)[nH]n2)cc1

Procedure:
In 200 ml of acetic acid was suspended 15.00 g of 6-[4-(4-aminobutyl)phenyl]-4,5-dihydropyridazin-3(2H)-one. To the suspension were added 100 ml of a 25% hydrogen bromide-acetic acid solution and then 5.35 g of dimethylsulfoxide, and the mixture was stirred at room temperature for 4.5 hours. 400 ml of isopropyl ether was added to the reaction mixture, and precipitated crystal was collected by filtration and recrystallized from methanol to obtain 18.94 g of 6-[4-(4-aminobutyl)phenyl]pyridazin-3(2H)-one hydrobromide.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)[CH3:8]>C(O)(C)C.[Pd]>[CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[CH3:8]
Reactant: Cc1cccc(C)c1OCCN(C)CCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CC(C)O
Product: Cc1cccc(C)c1OCCN(C)CCc1ccc(N)cc1
Yield: 100.8 %

Procedure:
A solution containing 0.40 g (1.23 mmol) of N-[2-(2,6-dimethylphenoxy)ethyl]-N-methyl-2-(4-nitrophenyl)ethylamine (Example 2) in 7 ml of isopropanol is added to a suspension of 0.1 g of 10% palladium-on-carbon catalyst in 7 ml of isopropanol. The suspension is hydrogenated under atmospheric pressure. After completion of the reaction, the catalyst is filtered and washed with isopropanol. The filtrate is evaporated to constant weight under reduced pressure to obtain 0.37 g of the oily base (76%), Rf=0.35 (ethyl acetate/methanol=9:1).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[SiH3]Cl.[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].N1C=CN=C1>C1CCCCC1>[Si:1]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Cl:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OCCCCCCCl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [SiH3]Cl
Agent: c1c[nH]cn1
Solvent: C1CCCCC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCCl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 250 ml, three-necked flask was fitted with a large magnetic, egg-shaped stir bar, a thermocouple, reflux condenser, and an argon inlet. This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon. The flask was charged with 15.09 grams (0.100 mole, 1.00 equivalents) of t-butyldimethylsilyl chloride, and 100 grams of cyclohexane. The silyl chloride rapidly dissolved, endothermically. 6-Chloro-1-hexanol, 13.96 grams (0.100 mole, 1.00 equivalent) was then weighed into the flask. After stirring at room temperature for fifteen minutes, the reaction mixture appeared hazy. The stirrer was halted, and a second, immiscible layer was observed in the bottom of the flask. Imidazole, 6.81 grams (0.100 mole, 1.00 equivalent) was then added to the reaction mixture. A fine white precipitate rapidly developed. The reaction mixture was stirred at room temperature, and monitored by GC analysis. An aliquot of the clear supernatant was injected into the GC. After five hours, both starting materials were still present, and the conversion to the desired product was 82.2%. The reaction mixture was stirred overnight at room temperature, under a blanket of argon. The sample after 30 hours indicated all the starting material had been consumed, with the formation of a single, higher boiling component. The reaction mixture was transferred to a small, dry, Chemglass pressure filter. The filtrate was collected in a dry, 500 ml flask. The filter cake was rinsed with additional cyclohexane (2×100 ml). The solvent was removed on the rotary evaporator, with the bath temperature set at 40° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].C([O:13][B:14](OCC)[O:15]CC)C.S(=O)(=O)(O)O>C(OCC)C.O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:14]([OH:15])[OH:13])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: CCOB(OCC)OCC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(B(O)O)cc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
100 ml of a solution of 10 g of p-bromoanisole in anhydrous diethyl ether is added dropwise under reflux to a suspension, under inert gas, of 1.3 g of magnesium turnings in 5 ml of anhydrous diethyl ether, and the mixture is left under reflux for 2 hours. The reaction medium is then poured into a solution of 9.02 ml of triethylborate in 60 ml of anhydrous ether cooled down to −70° C. After agitation for 1 hour at −70° C., then for 1 hour at ambient temperature, the solution is poured into a mixture comprising 11 ml of sulphuric acid and 50 g of ice and water followed by agitation for 1 hour. The organic phase is extracted with 100 ml of an aqueous solution saturated in sodium bicarbonate, the aqueous phases are combined, then reacidified with 6N hydrochloric acid, extracted with ether, dried and evaporated under reduced pressure. 3.9 g of expected product is obtained.