Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([CH2:8][O:9][CH2:10][CH2:11][NH2:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:21][C@@H:22]1[C@H:26]([O:27]C(=O)C2C=CC=CC=2)[C@@H:25]([CH2:36][O:37]C(=O)C2C=CC=CC=2)[O:24][C@H:23]1[N:46]1[CH:54]=[N:53][C:52]2[C:47]1=[N:48][C:49]([Cl:56])=[N:50][C:51]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:56][C:49]1[N:50]=[C:51]([NH:12][CH2:11][CH2:10][O:9][CH2:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:52]2[N:53]=[CH:54][N:46]([C:47]=2[N:48]=1)[C@@H:23]1[O:24][C@H:25]([CH2:36][OH:37])[C@@H:26]([OH:27])[C@H:22]1[OH:21]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: NCCOCc1ccccc1
Agent: Cl
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NCCOCc4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 38.7 %

Procedure:
The title compound was prepared by reacting 2-(phenylmethoxy)ethylamine hydrochloride (0.51 g, 2.7 mmol) with 9-(2,3,5-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.43 g, 2.25 mmol), followed by debenzoylation of the purified product using methanolic ammonia to provide the title 2-chloro- N-[2-(phenylmethoxy)ethyl]adenosine (0.38 g, 44%)(after column chromatography) as a solid, mp 115°-124° C., 1H NMR (DMSO-d6)δ 3.50-3.58 (1H, m, H-5'a), 3.60-3.70 (4H, m, H-5'b, --CH2 -- and --CH--), 3.95 (1H, q, H-4'), 4.04-4.16 (2H, m, H-3' and --CH--), 4.52 (1H, br s, H-2' and --CH2 --), 5.07 (1H, t, 5'-0H), 5.21, 5.50 (2H, 2d, 2'- and 3'-OH), 5.84 (1H, d, H-1'), 7.22-7.36 (5H, m, Ar--H), 8.25-8.40 (2H, m, H-8 and N--H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[F:14])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[S:28][C:27]([CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])=[C:26]([O:38][CH3:39])[CH:25]=1>C(#N)C>[Si:31]([O:30][CH2:29][C:27]1[S:28][C:24]([CH2:23][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])=[C:8]([F:14])[CH:9]=2)=[CH:25][C:26]=1[O:38][CH3:39])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33]
Reactant: COc1cc(CBr)sc1CO[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)CCc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCc1ccc(OCc2cc(OC)c(CO[Si](C)(C)C(C)(C)C)s2)cc1F
Yield: 21.6 %

Procedure:
To a solution of 3-(2-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (1.03 g, 4.8 mmol) in acetonitrile (15 mL) is added potassium carbonate (2.31 g, 16.8 mmol) and (5-bromomethyl-3-methoxy-thiophen-2-ylmethoxy)-tert-butyl-dimethyl-silane (1.7 g, 4.8 mmol) at room temperature and the reaction mixture is refluxed for 3 hours. The reaction mixture is concentrated, diluted with water, and extracted with EtOAc (2×30 mL). The combined extracts are washed with water (15 mL) and saturated brine (15 mL), dried over Na2SO4, filtered, and concentrated. The crude material is purified by silica gel chromatography eluting with hexane:ethyl acetate (9.6:0.4) to give the title compound (0.5 g, 21%). 1H NMR (400 MHz, DMSO d6) δ 7.51 (s, 1H), 7.26-7.2 (t, J=8.4 Hz, 1H), 6.92-6.89 (d, J=12 Hz, 1H), 6.83-6.81 (d, J=7.6 Hz, 2H), 4.92 (s, 2H), 4.82 (s, 2H), 4.10-4.05 (q, J=6.4 Hz, 2H), 3.82 (s, 3H), 2.86-2.82 (t, J=16 Hz, 2H), 2.61-2.55 (m, 2H), 1.21-1.17 (t, J=6.8 Hz, 3H), 0.89 (s, 9H), 0.13 (s, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([O-])(=O)C.[NH4+].[N+:17]([CH3:20])([O-:19])=[O:18]>>[N+:17]([CH:20]=[CH:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)([O-:19])=[O:18]
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=[N+]([O-])C=Cc1ccc2[nH]ccc2c1
Temperature: 110 °C

Procedure:
A mixture of the product from step (a) (7.5 g), ammonium acetate (1.5 g) and nitromethane (77 ml) was heated at 110° C. for 2 hours, then cooled and evaporated in vacuo. The residue was triturated with water to give the desired product as a yellow solid which was filtered off and dried (9.2 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:7]=[CH:6][C:5]2[CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=[CH:11][C:4]=2[O:3]1.O.NN.O>C(O)C.[Pt]>[NH2:12][C:9]1[CH:10]=[CH:11][C:4]2[O:3][C:2]([CH3:1])([CH3:15])[CH:7]=[CH:6][C:5]=2[CH:8]=1
Reactant: CC1(C)C=Cc2cc([N+](=O)[O-])ccc2O1
Agent: [Pt]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC1(C)C=Cc2cc(N)ccc2O1
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
Ten grams (10 g, 48.7 mmol) of 2,2-dimethyl 6-nitro 2H-1-benzopyran (3) was dissolved in 60.0 g of ethanol under heating. After cooling to 35° C., 0.6 g of 2% Pt—C (50% water-containing product) was added thereto, and 5.85 g (117.0 mmol) of hydrazine monohydrate (98% product) was added dropwise (dropwise adding was continued for 30 minutes) while controlling internal temperature to 40° C. or less. After completion of dropwise adding, reaction was carried out at a temperature of 40 to 45° C. for 6 hours. The resulting solution was cooled to room temperature, and then 10.0 g of water was added thereto and the resulting solution was filtered through celite. The celite was washed with 20.0 g of 80% water-containing ethanol, and the washing together with the filtrate were subjected to solvent-distillation. The residue was extracted with 40.0 g of toluene and 20.0 g of water. After separating into phases, the aqueous phase was extracted with 20.0 g toluene again. The toluene phases were combined, washed with 20.0 g of water and then subjected to solvent-distillation to obtain a crude product of intended product (4).
Reaction SMILES: [CH2:1]=C1CN(C(OC(C)(C)C)=O)C1.[CH2:13]1[C:18]2([O:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:17][CH2:16][C:15](=O)[CH2:14]1>>[CH2:1]=[C:15]1[CH2:16][CH2:17][C:18]2([O:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:13][CH2:14]1
Reactant: C=C1CN(C(=O)OC(C)(C)C)C1
Reactant: O=C1CCC2(CC1)OCCCO2
Product: C=C1CCC2(CC1)OCCCO2

Procedure:
The title compound was prepared following the methodology described for Compound 28a replacing 1-Boc-3-azetidinone with 7,11-dioxaspiro[5.5]undecan-3-one. After the usual work-up procedure, the residue was purified by means of automated flash chromatography (SP01®TM-Biotage; Et2O) to give the title compound as a pale-yellow oil. Yield: 96.3%.
Reaction SMILES: C1(C([S:9][CH2:10][CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=O)C=CC=CC=1.[OH-].[Na+]>C1COCC1.O>[SH:9][CH2:10][CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]
Reactant: CCOC(CSC(=O)c1ccccc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(CS)OCC

Procedure:
The preceding thiobenzoyl derivative (V) (17.2 g) was dissolved in 100 ml THF followed by the addition of 6 g NaOH in 20 ml H2O. The mixture was refluxed under N2 for 15 h, then cooled and diluted with water (200 ml) and the product extracted with ether (3×200 ml). The extract was dried, the solvent removed in vacuo and the residue distilled in vacuo to yield 7.1 g of pure (VI), b.p. 60-62°/18 mm. It was characterized by 1H NMR δ(ppm in CDCl3):
Reaction SMILES: I[Si](C)(C)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[N:18]3[C:19](=[O:24])[CH2:20][CH2:21][CH2:22][CH2:23][C@@H:17]3[CH2:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.CN(C)CCN(C)C.[I:33]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C@@H:13]2[N:18]3[C:19](=[O:24])[CH:20]([I:33])[CH2:21][CH2:22][CH2:23][C@@H:17]3[CH2:16][CH2:15][CH2:14]2)=[CH:11][CH:12]=1
Reactant: II
Reactant: O=C1CCCC[C@@H]2CCC[C@H](c3ccc(F)cc3)N12
Agent: CN(C)CCN(C)C
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1C(I)CCC[C@@H]2CCC[C@H](c3ccc(F)cc3)N12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
Iodotrimethylsilane (0.11 mL) was added to a solution of (4R*,10aR*)-4-(4-fluorophenyl)octahydropyrido[1,2-a]azepin-6-one (140 mg) and N,N,N′,N′tetramethylethylenediamine (0.28 mL) in methylene chloride (15 mL) at 0° C., and the reaction solution was stirred at 0° C. for 30 minutes. Iodine (204 mg) was added to the reaction solution, which was then stirred at 0° C. for one hour. Ethyl acetate and a saturated sodium thiosulfate solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 208 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=1.Cl>C1COCC1.O>[CH2:16]([O:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[O:2])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCOc1cccc(OCCCCC(OC)OC)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCOc1cccc(OCCCCC=O)c1
Temperature: 50 °C
Yield: 107.8 %

Procedure:
A solution of 1-(5,5-dimethoxypentyloxy)-3-(hexyloxy)benzene (127 mg, 0.39 mmol) and 2 M aq HCl (0.47 mL, 0.94 mmol) in THF (4.5 mL), H2O (0.28 mL) was stirred at rt overnight. Later, the reaction was heated at 50° C. for 5 h. After cooling to rt the reaction mixture was diluted with H2O, extracted with Et2O (3×), washed (aq NaHCO3, brine), dried (Na2SO4) and concentrated under reduced pressure to yield 5-(3-(hexyloxy)phenoxy)pentanal as a colorless oil (117 mg). The material was used in the following step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 9.80 (s, 1 H), 7.16 (t, J=8.08 Hz, 1 H), 6.43-6.53 (m, 3 H), 3.89-4.01 (m, 4 H), 2.50-2.57 (m, 2 H), 1.14-1.92 (m, 12 H), 0.92 (t, J=6.69 Hz, 3 H). MS ESI [M+H]+, calcd for [C17H26O3+H]+: 279.2 found m/z 279.2 (95) and 301.1 ([M+Na]+, 100).
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C:7]3([C:17]2=[O:20])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]3)=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)#[N:22]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:20]=[C:17]1[C:7]2([CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8]2)[CH2:6][C:5]2[C:18]1=[CH:19][C:2]([C:27]1[CH:28]=[C:23]([CH:24]=[CH:25][CH:26]=1)[C:21]#[N:22])=[CH:3][CH:4]=2
Reactant: O=C1c2cc(Br)ccc2CC12CCc1ccccc1C2
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(CCc4ccccc4C2)C3)c1
Yield: 20 %

Procedure:
6-Bromo-3′,4′-dihydro-1′H-spiro[indene-2,2′-naphthalen]-1(3H)-one (163 mg, 0.5 mmol), 3-cyanophenylboronic acid (147 g, 1 mmol) in [1,4]-dioxane (12 mL), Cs2CO3 (2 N, 3.2 mL), then Pd(PPh3)2Cl2 (5 mg, 0.01 mmol) was added under Ar2, the mixture was refluxed for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by TLC to give 3-(1-oxo-1,3,3′,4′-tetrahydro-1′H-spiro[indene-2,2′-naphthalene]-6-yl)benzonitrile (35 mg, 6%).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH:5]=[CH2:6].[CH2:8]([NH2:11])[CH:9]=[CH2:10]>>[CH2:8]([NH:11][CH2:2][CH:3]([OH:7])[CH2:4][CH:5]=[CH2:6])[CH:9]=[CH2:10]
Reactant: C=CCN
Reactant: C=CCC(O)CCl
Product: C=CCNCC(O)CC=C
Temperature: 90 °C
Reaction time: 16 h
Yield: 58.4 %

Procedure:
A mixture of 1-chloropent-4-en-2-ol (23.40 g, 194.06 mmol, 1.00 Eq) and prop-2-en-1-amine (33.00 g, 578.03 mmol, 2.98 Eq) was stirred at 90° C. for 16 hr. The mixture was cooled to 25° C. and concentrated in reduced pressure at 60° C. The residue was poured into ice-water (w/w=1/1) (150 mL) and stirred for 20 min. The aqueous phase was extracted with EA. The combined organic phase was washed with saturated brine (200 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (DCM:MeOH=30/1 to 10/1) to afford 1-(allylamino)pent-4-en-2-ol (16.00 g, 113.31 mmol, 58.39% yield) as yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].[F:38][C:39]([F:45])([F:44])[CH2:40][C:41](O)=[O:42]>>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C@H:9]([CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:41](=[O:42])[CH2:40][C:39]([F:45])([F:44])[F:38])[CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)=[O:4])(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: O=C(O)CC(F)(F)F
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Product: CC(C)CN([C@H](CO)CCCNC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)CC(F)(F)F)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (see example 8) as described in general procedure E using 3,3,3-trifluoropropionic acid. The final product was obtained in 76% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.O.[C:12]([OH:16])(=[O:15])[CH:13]=O>C(=O)([O-])[O-].[K+].[K+]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])/[CH:9]=[CH:13]/[C:12]([OH:16])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=CC(=O)O
Reactant: CC(=O)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)/C=C/C(=O)c1cccc(Cl)c1
Temperature: 130 °C
Yield: 39.2 %

Procedure:
A stirred mixture of 3'-Chloroacetophenone (15 mL, 97 mmol) and glyoxylic acid monohydrate (9 g, 97 mmol) was heated at 130° C. under reduced pressure (1,5 mmHg), over 8 hours. During this time the reduced pressure was maintained in order to remove the water formed during the reaction. After cooling, the crude reaction product was taken up in aqueous 10% potassium carbonate solution (100 mL) and the resulting solution was washed with diethyl ether (3×30 mL), the alkaline aqueous layer was cooled at 0° C. and then cautiously acidified with 6N HCl. The resulting suspension was extracted with ethyl acetate (3×50 mL), the collected organic extracts were washed with brine and dried (Na2SO4). Concentration of the solvent in vacuo afforded a yellow solid (8 g) which was chromatographed (SiO2 ;CH2Cl2 /MeOH 98:2) to provide the pure acid (6 g, 30%), lightly yellow solid melting at 158-59° C. (diisopropyl ether).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.[Br:8][CH:9]([CH3:17])[C:10](=O)[CH2:11][C:12](OC)=[O:13].[OH-].[Na+]>C(Cl)Cl>[Br:8][CH:9]([C:10]1[N:7]=[C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]2[C:12](=[O:13])[CH:11]=1)[CH3:17]
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: Cc1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1csc2nc(C(C)Br)cc(=O)n12
Temperature: 110 °C
Reaction time: 5 h
Yield: 42.4 %

Procedure:
To a manually stirred polyphosphoric acid (80 g, 800 mmol) in a 1000 mL beaker was added 4-methyl-1,3-thiazol-2-amine (Aldrich, 16 g, 140 mmol), followed by methyl 4-bromo-3-oxopentanoate (34.9 g, 167 mmol). The mixture was heated with stirring at 110° C. for 5 h. After cooling, the dark slurry was transferred into 300 g of ice. The pH of the mixture was adjust to 6-7 with 10% sodium hydroxide. The aqueous layer was discarded and the dark oil layer was diluted with methylene chloride and washed with 1 N NaOH, brine, dried over magnesium sulfate, and evaporated to dryness to yield the desired product (16.2 g, 42.6%). LCMS calculated for C9H10BrN2OS (M+H)+: m/z=273.0. Found: 273.1.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[CH2:9]([C:13]1[S:17][C:16]([CH:18]2[CH2:20][CH:19]2[C:21](Cl)=[O:22])=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12].O>[Na]>[CH2:9]([C:13]1[S:17][C:16]([CH:18]2[CH2:20][CH:19]2[C:21]([N:4]2[CH2:5][CH:6]([CH3:8])[O:7][CH:2]([CH3:1])[CH2:3]2)=[O:22])=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CC1CNCC(C)O1
Reactant: CCCCc1ccc(C2CC2C(=O)Cl)s1
Agent: [Na]
Solvent: O
Product: CCCCc1ccc(C2CC2C(=O)N2CC(C)OC(C)C2)s1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
2,6-Dimethylmorpholine (5.0 g, 0.043 mol) was added dropwise to a solution of 2-(5-n-butylthiophen-2-yl)-cyclopropanecarbonyl chloride (4.85 g, 0.02 mol) in sodium dried ether (40 ml) at 10° C. and after complete addition the solution was stirred at 20° C. for 3 hours. The reaction mixture was poured into water and extracted with diethyl ether (2×100 ml). The ethereal extracts were washed with water, dried over anhydrous sodium sulphate, and the solvent removed to give 2-(5-n-butylthiophen-2-yl)-cyclopropanecarbonyl-2,6-dimethylmorpholine (5.8 g, 90% as a yellow oil. A solution of 2-(5-n-butylthiophen-2-yl)-chclopropanecarbonyl-2,6-dimethylmorpholine (5.8 g, 0.018 mol) in sodium dried ether (30 ml) was added dropwise to a suspension of lithium aluminium hydride (0.8 g, 0.02 mol) in sodium dried ether (20 ml) and the reaction mixture stirred at room temperature for 3 hours. The reaction mixture was poured carefully into water and extracted with diethyl ether. The ethereal extracts were washed with water, dried over anhydrous sodium sulphate, and the solvent removed to give a colourless oil. This oil was purified by column chromatography (silica eluted with ethyl acetate/petroleum ether 2:3) to give the title compound (1.3 g, 24%).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].[Cl:33][CH2:34][C:35]([CH3:38])([OH:37])[CH3:36].C(=O)([O-])[O-].[K+].[K+].Cl>CCO.O.CCOC(C)=O.C(Cl)Cl.CCOCC>[ClH:33].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[CH2:29][CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(C)(O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCCCc1nnc(OC2CCN(CC(C)(C)O)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (Example 14, 0.2 mmol, 97 mg) in EtOH (2 mL) was added 1-chloro-2-methyl-2-propanol (0.4 mmol, 44 μL), and potassium carbonate (0.6 mmol, 83 mg). And the mixture was stirred at 50° C. for 4 hours. It was then diluted with water/EtOAc. The organic layers were combined, dried, and condensed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM+10% MeOH) to give a colorless sticky solid, which was dissolved in DCM (2 mL), 1N HCl in ether (2 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to yield 1-{4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidin-1-yl}-2-methyl-propan-2-ol dihydrochloride (86 mg, 77% yield). LCMS: m/z 483 [M+1]. 1H NMR (400 MHz, CD3OD): δ 7.53 and 7.62 (1H, s), 7.41-7.46 (2H, m), 7.10-7.14 (2H, m), 5.42-5.52 (1H, m), 4.41-4.46 (1H, m), 3.65-3.83 (2H, m), 3.25-3.47 (3H, m), 3.05-3.12 (2H, m), 2.22-2.55 (5H, m), 1.98-2.03 (2H, m), 1.78-1.83 (2H, m), 1.40-1.63 (7H, m), 1.38 (6H, s), 1.22-1.36 (3H, m), 0.81 (3H, t).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:34])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]2[S:25][C:26]3[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:27]=3[N:28]=2)=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:34])[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][NH:23][C:24]2[S:25][C:26]3[CH:32]=[C:31]([O:33][CH2:39][CH2:38][N:37]([CH3:41])[CH3:36])[CH:30]=[CH:29][C:27]=3[N:28]=2)=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCO
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CNc2nc3ccc(O)cc3s2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc2nc(NCc3ccc(C(=O)Nc4ccccc4NC(=O)OC(C)(C)C)cc3)sc2c1
Reaction time: 4 h
Yield: 37.5 %

Procedure:
To a suspension of compound 129 (1.00 g, 2.04 mmol) in THF (6.8 mL) at room temperature under N2 atmosphere were successively added N,N-dimethylethanolamine (225 μl, 2.24 mmol) and triphenylphosphine (696 mg, 2.65 mmol) followed by diisopropyl azodicarboxylate (550 μL, 2.65 mmol). Heat was evolved and the mixture turned dark red. It was stirred for 4 h, THF was removed in vacuo and the dark residue was partitioned between EtOAc and H2O. Organic phase was collected and extracted with HCl 1N. Acidic extract was separated and neutralized with saturated aqueous NaHCO3 under vigorous stirring. A white precipitate was formed which was collected by filtration to afford the title compound 133 (430 mg, 37% yield). 1H NMR: (acetone-d6) δ (ppm): 7.99 (d, J=8.4 Hz, 2H), 7.70 (dd, J=8.0, 2.2 Hz, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.56 (d, J=1.6 Hz, 1H), 7.33 (d, J=9.0 Hz, 1H), 7.27 (d, J=2.5 Hz, 1H), 7.19 (quint.d, J=7.8, 2.4 Hz, 2H), 6.87 (dd, J=8.8, 2.5 Hz, 1H), 4.80 (s, 2H), 4.08 (t, J=5.9 Hz, 2H), 2.67 (t, J=5.7 Hz, 2H), 2.27 (s, 6H), 1.48 (s, 9H). m/z: 562.5 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(F)cc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)cc1

Procedure:
4-Fluorobenzoic acid, 14.0 g (0.1 mole) is refluxed for 30 minutes in 50 ml of thionyl chloride (SOCl2) and 1 drop of dimethylformamide (DMF). The thionyl chloride is removed under vacuum and azeotroped with 50 ml of benzene to give 4-fluorobenzoyl chloride as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[CH3:18][NH:19][O:20][CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([N:19]([O:20][CH3:21])[CH3:18])=[O:9]
Reactant: CNOC
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cnc(OCC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
A mixture of 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinic acid (2.0 g, 7.8 mmol, Step-1), N,O-dimethylhydroxylamine hydrochloride (0.916 g, 9.39 mmol), HBTU (3.56 g, 9.39 mmol) and triethylamine (5.45 mL, 39.1 mmol) in dichloromethane (39 mL) is stirred at room temperature for 3 hours. The reaction mixture is poured into water (100 mL) and extracted with dichloromethane (200 mL). The organic layer is washed with water (100 mL) and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (4:1) to give 2.2 g (94% yield) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12](=O)[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:14])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[NH2:23]C1C=CC=CC=1O>>[OH:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13](=[O:14])[O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[N:23]=2)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8]
Reactant: Nc1ccccc1O
Reactant: CCCCCCOC(=O)C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Product: O=c1oc2ccccc2nc1-c1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A mixture of 3.93 g of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 1.38 g of 2-aminophenol is melted at 120° while stirring. The melt crystallizes after 5 minutes. After 2 hours it is cooled and recrystallized from methanol. There is obtained 3-(3,4-dihydroxy-5-nitrophenyl)-2H-1,4-benzoxazin-2-one of m.p. 202°-204°.