Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:31][C:11]3[C:12](=[O:30])[N:13]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[N:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C=O.[C:34](O)(=O)C>C(Cl)Cl.CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:31][C:11]3[C:12](=[O:30])[N:13]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]5[CH2:25][CH2:26][N:27]([CH3:34])[CH2:28][CH2:29]5)[N:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1c2sc(-c3ccc(Cl)cc3)cc2cnn1Cc1cccc(OC2CCNCC2)n1
Reactant: CC(=O)O
Agent: C=O
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(Oc2cccc(Cn3ncc4cc(-c5ccc(Cl)cc5)sc4c3=O)n2)CC1
Reaction time: 2 h

Procedure:
To a solution of 2-(4-chlorophenyl)-6-{[6-(piperidin-4-yloxy)pyridin-2-yl]methyl}thieno[2,3-d]pyridazin-7(6H)-one (0.16 g, 0.34 mmol) in DCM/MeOH (1:1, 10 mL) was added (polystyrylmethyl)trimethylammonium cyanoborohydride (0.25 g, 1.03 mmol), 36% aq. formaldehyde (0.05 mL, 0.69 mmol) and acetic acid (one drop). After 3 hours of stirring one additional amount of (polystyrylmethyl)trimethylammonium cyanoborohydride, formaldehyde and acetic acid added to the reaction mixture and stirred for two hours. The reaction mixture was filtrated, concentrated in vacuo and purified by flash chromatography using a gradient with EtOAc:MeOH:TEA (1:0.1:0.05) in n-heptane, which gave the product. Yield: 0.084 g (52%). 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.57-7.64 (m, 2H), 7.30-7.49 (m, 4H), 6.71 (d, 1H, J=7.31 Hz), 6.52 (d, 1H, J=8.16 Hz), 5.47 (s, 2H), 4.69-4.79 (m, 1H), 2.49-2.58 (m, 2H), 2.13 (s, 3H), 1.87-1.99 (m, 2H), 1.75-1.84 (m, 2H), 1.58-1.69 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 163.0, 157.4, 153.5, 152.3, 140.3, 139.3, 136.4, 136.0, 133.1, 131.3, 129.8, 128.1, 113.8, 110.1, 70.5, 55.6, 53.3, 46.4, 31.0 MS (ESI+) 467.08 (M+1H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Br:19][CH:20]([CH2:24][CH2:25][Br:26])[C:21](Cl)=[O:22]>O1CCCC1.Cl>[Br:19][CH:20]([CH2:24][CH2:25][Br:26])[C:21]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][N:3]=1)=[O:22]
Reactant: Nc1cc(C(F)(F)F)ccn1
Reactant: O=C(Cl)C(Br)CCBr
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)ccn1)C(Br)CCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A solution of 2-amino-4-trifluoromethylpyridine (5.00 g) and triethylamine (3.43 g) in dry tetrahydrofuran (50 ml) was added dropwise, over ten minutes, to a stirred solution of 2,4-dibromobutanoyl chloride (9.51 g) in dry tetrahydrofuran (50 ml), whilst maintaining the temperature below 5° C. The mixture was allowed to stir overnight at room temperature, diluted with hydrochloric acid (1M) and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using hexane-ethyl acetate (5:1) as eluant, to give the title compound (10.09 g, yellow gum) sufficiently pure for use in Step 2 below. Rechromatographed material had NMR (CDCl3): δ 2.57(1H,m); 2.74(1H,m); 3.62(2H,m); 4.71(1H,dd); 7.33(1H,dd); 8.49(3H,d+s); 8.84(1H,bs). MS: M+ 388.
Reaction SMILES: C[Si](C)(C)[O:3][C:4](=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:20]OC(F)(F)F>ClC(F)(F)F>[F:20][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3]
Reactant: FOC(F)(F)F
Reactant: C[Si](C)(C)OC(=Cc1ccccc1)c1ccccc1
Agent: FC(F)(F)Cl
Product: O=C(c1ccccc1)C(F)c1ccccc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
A solution of 18.8 g (0.07 mol) of the aforesaid α-trimethylsiloxystilbene in 200 ml of chlorotrifluoromethane was cooled to -70° C. and 7.3 g (0.07 mol) of trifluoromethyl hypofluorite were passed into the solution over a 3 hour period. The reaction mixture then was warmed to room temperature and evaporated to dryness under reduced pressure to give a white solid. Recrystallization from heptane gave 10.81 g (72% yield) of α-fluoro-α-phenylacetophenone as colorless crystals: mp 50°-51° C.; 19F NMR (CDCl3) δ-176.5 ppm (d, J=49 Hz); 1H NMR (CDCl3) δ 6.52 ppm (d, J=49 Hz, 1H), 7.2-8.2 ppm (m, 10H). Anal. Calcd. for C14H11FO: C, 78.49; H, 5.18; F, 8.87; Found: C, 78.52; H, 5.13; F, 8.65.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]([NH2:15])=[CH:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1.[CH:16]1([C:19](=O)[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1.C1C=CC=CC=1>CC(O)=O>[CH:16]1([C:19]2[CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:13]3[CH:12]=[N:11][N:10]([CH2:9][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[C:14]=3[N:15]=2)[CH2:17][CH2:18]1
Reactant: COc1ccc(Cn2nccc2N)cc1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C2CC2)nc2c1cnn2Cc1ccc(OC)cc1
Temperature: 63 °C
Yield: 71 %

Procedure:
A mixture of 1-{[4-(methyloxy)phenyl]methyl}-1H-pyrazol-5-amine (3 g, 14.76 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (2.72 g, 14.76 mmol) and benzene (50 mL) were heated at 63° C. for 16 h. The solvent was removed under reduced pressure. The crude residue was purified via silica gel chromatography (eluent: 0 to 25% EtOAc:Hex) to afford 2.56 g of the desired cyclized product and 1.71 g of the uncyclized adduct. The uncyclized adduct was dissolved in 25 mL of AcOH and heated to reflux for 16 hours. The solvent was removed under reduced pressure and the residue purified via silica gel chromatography (eluent: 0 to 25% EtOAc:Hex) to afford an additional 1.15 g of the desired cyclized product (combined yield=71%). LCMS E-S (M+H)=352.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07-1.13 (m, 4H) 1.38 (t, J=7.07 Hz, 3H) 2.39 (s, 1H) 3.67 (s, 3H) 4.41 (q, J=7.07 Hz, 2H) 5.51 (s, 2H) 6.84 (d, J=8.84 Hz, 2H) 7.21 (d, J=8.59 Hz, 2H) 7.64 (s, 1H) 8.23 (s, 1H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[CH3:14][C@@H:15]1[CH2:17][O:16]1.O>O1CCCC1.CCOCC>[Cl:3][C:4]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:14][C@H:15]([OH:16])[CH3:17]
Reactant: C[C@@H]1CO1
Reactant: Fc1ccc2[nH]ccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H](O)Cn1ccc2c(Cl)c(F)ccc21
Reaction time: 1 h
Yield: 74.5 %

Procedure:
A suspension of 0.11 g of sodium hydride dispersion in 15 ml of tetrahydrofuran was treated with 0.5 g of 4-chloro-5-fluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 0.4 ml of (R)-methyloxirane the reaction mixture was stirred at room temperature for 48 hours and subsequently treated with water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 30 g of silica gel with toluene-ethyl acetate (33:1). There was obtained 0.5 g (74.5%) of (R)-1-(4-chloro-5-fluoro-indol-1-yl)-propan-2-ol as a yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:7]=[C:8]([C:14]#[N:15])[C:9]([C:12]#[N:13])=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.Br[CH:17]([CH2:25][CH3:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[CH:1]1([CH2:4][N:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[C:8]([C:14]#[N:15])[CH:7]=2)[CH:17]([CH2:25][CH3:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(NCC2CC2)cc1C#N
Reactant: CCC(Br)C(=O)OC(C)(C)C
Product: CCC(C(=O)OC(C)(C)C)N(CC1CC1)c1ccc(C#N)c(C#N)c1

Procedure:
Synthesized in a manner similar to example 1B using 4-[(cyclopropylmethyl)amino]-1,2-benzenedicarbonitrile and tert-butyl 2-bromobutanoate: MS (ES) m/z 340 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[CH:7][CH:8]=1.[H-].[Na+].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20](Br)[CH:21]=1)[C:17]#[N:18]>CN(C=O)C.C(OCC)(=O)C>[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:21]=1)[C:17]#[N:18]
Reactant: N#Cc1cc(Br)cc(Br)c1
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(Br)cc(C#N)c2)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 51 %

Procedure:
p-Methoxybenzyl alcohol (2.6 mL) was dissolved in anhydrous DMF (50 mL) and NaH (808 mg, 60% dispersion in oil) was added in several portions. After gas evolution ceased, 3,5-dibromobenzonitrile (5.0 g) was added and the reaction mixture was stirred at 70° C. After 2 h additional amount of NaH (147 mg) was added and heating was continued for 6 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 3.1 g of the title compound (51% yield). HRMS calcd for C15H12O2BrN M+ 371.0051, observed 371.0048.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[F:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:13]1[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1ccccc1CBr
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2F)CC1

Procedure:
Prepared from 1-(bromomethyl)-2-fluorobenzene and tert-butyl 1-piperazine-carboxylate using the procedure described in Step A of Intermediate 113. LC/MS: m/z (ES) 295.0 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31](=[O:44])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[CH:33]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31](=[O:44])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[CH:33]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1

Procedure:
The title compound was prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert-butyl ester {CAS-No. [335255-26-0]} (231 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K3) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (313 mg, 44%).
Reaction SMILES: [N:1]1C=CC=C[CH:2]=1.Cl[C:8]1[C:13]([Cl:14])=[C:12]([Cl:15])[CH:11]=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17].Cl>C1(C)C=CC=CC=1>[Cl:14][C:13]1[C:12]([Cl:15])=[CH:11][CH:10]=[C:9]([N+:16]([O-:18])=[O:17])[C:8]=1[C:2]#[N:1]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Cl
Reactant: c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Product: N#Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Reaction time: 0.5 h

Procedure:
Under a nitrogen atomosphere, pyridine (42 ml, 0.52 mol) was spread evenly over a mixture of 2,3,4-trichloronitrobenzene (225 g, 1 mol) and cuprous cyanide (89.6 g, 1 mol). The mixture was heated to 100° and held at this temperature until it became stirrable. Then the stirred mixture was heated to 165° over 1.5 hours, and held at this temperature for 30 minutes. The dark mixture was allowed to cool, then concentrated HCl (500 ml) and toluene (250 ml) were added. The mixture was vigorously stirred for 1.5 hours. The layers were separated and the aqueous phase was extracted with toluene (3 × 250 ml). The combined toluene extracts were washed with concentrated HCl (3 × 250 ml), water (250 ml) and saturated aqueous NaCl (2 × 250 ml). The toluene solution was dried over Na2SO4, filtered and stripped to obtain 185 g (85%) of the title benzonitrole. The product was 87% pure and contained about 7% trichloronitrobenzene. Recrystallization from methanol (2.1 ml/g) gave a product of 99% purity.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4](Br)[CH:3]=1.[C:23]1([S:29]([O-:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na+]>>[F:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(F)cc(Br)cc3c2C1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3c(F)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Yield: 57 %

Procedure:
The product of step B was coupled with sodium benzenesulfinate using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 7:3 hexane/ethyl acetate) provided tert-butyl 6-fluoro-8-phenylsulfonyl-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (141 mg, 57%) as a light-yellow solid: 1H NMR (CDCl3, 300 MHz) δ 7.97-7.94 (m, 2H), 7.88 (br s, 1H), 7.61-7.47 (m, 4H), 4.57 (s, 2H), 3.84 (t, J=5.4 Hz, 2H), 2.89 (br s, 2H), 1.51 (s, 9H).
Reaction SMILES: CN(C)C.[CH2:5]([O:7][C:8](=[O:14])[CH2:9][C:10]([CH2:12]Cl)=O)[CH3:6].Cl>>[CH2:5]([O:7][C:8]([C:9]1[CH2:12][CH:10]=[C:9]([C:8]([O:7][CH2:5][CH3:6])=[O:14])[CH2:12][CH:10]=1)=[O:14])[CH3:6]
Reactant: CCOC(=O)CC(=O)CCl
Agent: CN(C)C
Agent: Cl
Product: CCOC(=O)C1=CCC(C(=O)OCC)=CC1
Temperature: 10 °C

Procedure:
In a 2.5 liter double casing vessel, equipped with a discharge cock, a mechanical stirrer and thermometer, 1062.7 g of trimethylamine (44.5 percent in water=472.9 g, 100 percent=8 mole) was put up and cooled to 10° C. By means of a dosing pump and a hose submerged in the TMA solution, 272.8 g of 4-chloroacetoacetic acid ethyl ester (96.0 percent=261.9 g, 100 percent=1.59 mole) was added by doses during 3 hours at 10° to 12° C. and the yellowish reaction mixture was concentrated at 40° C. and 25 torr in such manner until the pH value reached 7.6. The excess TMA was subsequently condensed out by means of three cooling traps and was recaptured. After a slight lowering of the pH value with 65 ml of 36% hydrochloric acid to 6 and after the filtering out of the yellowish precipitate obtained (2,5-diethoxycarbonyl-1,4-cyclohexadiene), the reaction solution was hydrogenated in a 2-liter autoclave equipped with a stirring mechanism for 7 hours at 10° C. and 11 atu of pressure with the help of 8.8 g of platinum/activated charcoal catalyst.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].Cl.[NH2:33][CH2:34][CH2:35][SH:36].C(N(CC)CC)C.O>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]/[NH:33][CH2:34][CH2:35][SH:36])/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: NCCS
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@H]1OC(=O)/C(=C\NCCS)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@@]4(C)C3CC[C@@H]4O)[C@]21C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added 32 mg (0.278 mmol) 2-amino-ethanethiol hydrochloride and triethylamine (45 μL, 0.325 mmol). The reaction mixture is stirred at room temperature for 4 h. Water is added and the CH2Cl2 is removed, filtered through a plug of Kimwipe tissue and concentrated in vacuo to give a yellow foam. MS (ESI) m/z 508.5 (M+1).
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C@@H:17]3[O:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1>C(OCC)(=O)C.CO>[ClH:1].[N:2]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C@@H:17]3[O:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(OCCCN3CCCC3)cc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: c1cc([C@H]2CNCCO2)ccc1OCCCN1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Hydrogen chloride in ethyl acetate solution (4N) was added to a solution of tert-butyl (2S)-2-(4-(3-(pyrrolidin-1-yl)propyloxy)phenyl)morpholine-4-carboxylate (1.13 g, 2.89 mmol) in methanol. The mixture was stirred for one hour at room temperature and the solvent was evaporated under reduced pressure to give a white solid, which was recrystallized from ethanol to afford (2S)-2-(4-(3-(pyrrolidin-1-yl)propyloxy)phenyl)morpholine hydrochloride (0.9 g, 86%) as white crystals.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]([C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[F:16])=[N:7][OH:8])[CH:2]=[CH2:3]>C1(C)C(C)=CC=CC=1>[Br:15][C:13]1[CH:12]=[CH:11][C:10]([F:16])=[C:9]([C:6]23[CH2:5][O:4][CH2:1][CH:2]2[CH2:3][O:8][NH:7]3)[CH:14]=1
Reactant: C=CCOCC(=NO)c1cc(Br)ccc1F
Solvent: Cc1ccccc1C
Product: Fc1ccc(Br)cc1C12COCC1CON2
Yield: 70.7 %

Procedure:
A solution of 2-(allyloxy)-1-(5-bromo-2-fluorophenyl)ethanone oxime (120 g, 417 mmol) in xylene (2 L) is heated at 140° C. for 6 h. The reaction is cooled and the solvent is removed under reduced pressure to give a solid. The solid is purified by trituration with 9:1 hexanes/MTBE to give the title compound (85 g, 72%). ES/MS m/e (79Br/81Br) 288, 290 (M+1).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1C.OCC1C(=O)N(CC(C)C)N=C(C2C=CC=CC=2)C=1>>[CH2:15]([N:13]1[C:12](=[O:19])[C:11]([CH2:20][O:21][S:22]([CH3:25])(=[O:23])=[O:24])=[CH:10][C:9]([C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=2)=[N:14]1)[CH:16]([CH3:18])[CH3:17]
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1F
Agent: CC(C)Cn1nc(-c2ccccc2)cc(CO)c1=O
Product: CC(C)Cn1nc(-c2ccccc2)cc(COS(C)(=O)=O)c1=O
Yield: 68.4 %

Procedure:
Following the procedure of Example 1 (9), 4-hydroxymethyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one was reacted to yield the title compound as colorless fine-needles (yield: 68.4%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[BH4-].[Na+].Cl>CO>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][OH:10])=[CH:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)Oc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
With ice cooling, to a solution of 4-isopropoxybenzaldehyde (0.93 g, 5.6 mmol) in methanol (20 mL) was added a solution of sodium tetrahydroborate (0.32 g, 11 mmol) in methanol (10 mL), and the mixture was stirred at room temperature for 4 hours. The mixture was acidified by adding 2 N hydrochloric acid to the reaction solution, and extracted with diethyl ether. The extract was washed with water, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=7:3) to give the title compound (0.76 g, yield 81%) as an oily matter.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([CH3:11])=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.CO.C[CH2:22][O:23][C:24](C)=[O:25]>CS(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].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.[Fe+2]>[CH3:22][O:23][C:24]([C:2]1[C:7]2[S:8][C:9]([CH3:11])=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:25]
Reactant: CCOC(C)=O
Reactant: Cc1cc2cccc(Br)c2s1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2cc(C)sc12
Yield: 82 %

Procedure:
A mixture of 7-bromo-2-methyl-benzo[b]thiophene (Acheson, R. M.; Cooper, M. W. J. Chem. Soc., Perkin Trans 11980, 1185), (0.88 g, 3.89 mmol), with Pd(OAc)2 (176.4 mg), dppf (637.2 mg), Et3N (3.0 mL) and CH3OH (17 mL) in DMSO (26 mL) is reacted at 80° C./1100 psi of CO for 24 h. The crude reaction mixture is diluted with EtOAc (100 mL), washed with 0.1 M HCl (3×30 mL); dried with Na2SO4; filtered and concentrated. Purification of the crude material by silica gel chromatography to give the title compound (0.66 g, 3.19 mmol, 82%). 1H NMR (CDCl3): δ 2.63 (s, 3H), 4.02 (s, 3H), 7.04 (q, J=0.9 Hz, 1H), 7.38 (t, J=7.9 Hz, 1H), 7.84 (d, J=8.0 Hz, 1H), 8.01 (dd, J=8.0, 1.3 Hz, 1H) ppm. ES-MS (m/z): calcd for C11H10O2S (M+NH4)+: 224.3. found: 224.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C(N(C(C)C)CC)(C)C.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.O>ClCCl>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[O:24])=[CH:21][CH:20]=1
Reactant: NCCCCCCO
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCCCCCO)c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 81.6 %

Procedure:
To a solution of 6-amino-1-hexanol (12.9 g) and diisopropylethylamine (11.9 g) in dry dichloromethane (100 ml) at 5° C. was added 4-chlorobenzoyl chloride (16.1 g) in dry dichloromethane at such a rate to maintain the temperature below 10° C. After stirring for 16 h, the mixture was poured into water and filtered. The solid was washed with water, 2M hydrochloric acid (150 ml), water, dichloromethane and was dried under reduced pressure to give 6-(4-chlorobenzoylamino)hexan-1-ol (19.2 g). 1H-NMR (d6-DMSO) δ 1.25-1.65 (8H, m), 3.24 (2H, q), 3.38 (2H, t), 7.52 (2H, m), 7.84 (2H, m) and 8.54 (1H, bt)
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]1=2.[Br:15][C:16]1[CH:17]=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1.C(O)(=O)C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1.C(Cl)(Cl)Cl.ClCCl.C(OCC)C>[S:6]1[C:10]([C:17]2[C:16]([Br:15])=[CH:21][N:20]=[C:19]([Cl:22])[N:18]=2)=[CH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]1=2
Reactant: Clc1ncc(Br)cn1
Reactant: c1ccc2sccc2c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: Clc1ncc(Br)c(-c2cc3ccccc3s2)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 98.2 %

Procedure:
n-Butyl lithium (20.7 mL, 1.6 M in hexane) is added dropwise to a stirred solution of benzo[b]thiophene (4.12 g, 30.1 mmol) in anhydrous THF (50 mL) at −78° C. under nitrogen. The resultant solution is allowed to stir at −78° C. for 15 minutes. The lithiated benzo[b]thiophene is then added via canula over 20 minutes to a stirred solution of 5-bromo-2-chloro-pyrimidine (5.95 g, 30.1 mmol) in anhydrous THF (100 mL) at −30° C. Upon the completion of the addition, the solution is allowed to stir at −30° C. for an additional 30 minutes then at 0° C. for another 30 minutes. The reaction is quenched with acetic acid (1.99 g, 33.1 mmol), then after 5 minutes, it is treated with a solution of DDQ (7.17 g, 31.6 mmol) in anhydrous THF (150 mL) in portions at 10° C. The mixture is stirred for 20 minutes at 10° C. before it is concentrated to give a dark solid. The solid is then suspended in chloroform (500 mL) and the suspension is sonicated and filtered through a pad of silica. Additional 700 mL chloroform is used to wash the solid. The combined filtrates are concentrated to give a solid. The solid is re-suspended in dichloromethane (20 mL)/diethyl ether (20 mL) and the suspension is sonicated and filtered to give the title compound as a yellowish solid (9.62 g, 98% yield).