Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([O:15][CH3:16])=[C:6]([C:11]([Cl:14])=[CH:12][CH:13]=1)[C:7]([NH:9][OH:10])=[O:8].Br[CH2:18][C:19]([OH:21])=[O:20].Cl>O.C(O)C>[Cl:3][C:4]1[C:5]([O:15][CH3:16])=[C:6]([C:11]([Cl:14])=[CH:12][CH:13]=1)[C:7]([NH:9][O:10][CH2:18][C:19]([OH:21])=[O:20])=[O:8]
Reactant: COc1c(Cl)ccc(Cl)c1C(=O)NO
Reactant: O=C(O)CBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1c(Cl)ccc(Cl)c1C(=O)NOCC(=O)O
Temperature: 25 °C

Procedure:
To a solution of 86.34 g. of sodium hydroxide in 1.2 W of water was added 900 ml. of 95% ethanol and 240 g. of 3,6-dichloro-2-methoxybenzohydroxamic acid. To aid dissolution, an additional 300 ml. 95% ethanol and 60 ml. H2O were added. A solution of 153.12 g. bromoacetic acid in 120 ml. of 95% ethanol was then added to the reaction mixture over 0.5 hours, followed by 60 ml. of water. The mixture was then heated to reflux for 3 hours, cooled to ambient temperature, and 150 ml. 20% HCl added. The reaction mixture was then extracted twice with ethyl acetate. The ethyl acetate solutions were combined, washed with brine, and dried over MgSO4 overnight, then filtered and solvent evaporated in vacuo. The residue was crystallized from chloroform to yield [(3,6dichloro-2methoxybenzoyl)aminooxy]acetic acid as a white solid in two crops (m.p. 145°-154° C.).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([F:12])[C:5]=1[F:13].[Li+].[BH4-]>C1COCC1.CCOC(C)=O>[F:13][C:5]1[C:6]([F:12])=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=1[CH2:3][OH:2]
Reactant: COC(=O)c1cc(OC)cc(F)c1F
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(F)c(F)c(CO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,3-difluoro-5-methoxy-benzoic acid methyl ester (925 mg, 4.58 mmol) in THF (25 mL), cooled to 0° C., was added a solution of LiBH4 (199 mg, 9.15 mmol) in THF (5 mL). The reaction mixture was stirred at RT for overnight. An additional aliquot of LiBH4 (4 equiv) was added and stirring was continued at RT for 6 h, and subsequently at 60° C. overnight. The mixture was diluted with EtOAc, the organics were washed with 1N aqueous NaOH solution (50 mL), dried (Phase separator) and evaporated in vacuo to afford the title compound as a white solid. TLC Rf (c-hexane/EtOAc 1:1)=0.57; MS (LC/MS): 198.0 [M+Na]+; tR (HPLC conditions c): 3.74 min.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([NH:16][C:17](=O)[CH3:18])=[C:5]([N:7]2[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]2[CH2:13][CH2:14][CH3:15])[N:6]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>P(Cl)(Cl)(Cl)=O>[CH3:1][C:2]1[S:3][C:4]2[N:16]=[C:17]([CH3:18])[C:11]3[N:7]([C:8]([CH2:13][CH2:14][CH3:15])=[N:9][C:10]=3[CH3:12])[C:5]=2[N:6]=1
Reactant: CCCc1nc(C)cn1-c1nc(C)sc1NC(C)=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1nc(C)c2c(C)nc3sc(C)nc3n12
Temperature: 130 °C
Yield: 7.7 %

Procedure:
N-(2-methyl-4-(4-methyl-2-propyl-1H-imidazol-1-yl)thiazol-5-yl)acetamide (60 mg, 0.2 mmol) was suspended in phosphorus oxychloride (5 mL) and P2O5 (280 mg, 2 mmol) was added quickly. The resulting mixture was heated at 130° C. in a sealed tube overnight. After POCl3 was evaporated, the residue was quenched with ice water very carefully. The mixture was neutralized with saturated Na2CO3 solution and extracted with ethyl acetate (3×30 mL). The organic layer was dried over Na2SO4, concentrated and purified by prep-HPLC to give 4 mg of the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH:28]2[O:33][CH2:32][CH2:31][NH:30][CH2:29]2)[CH2:23][CH2:22]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:30]4[CH2:31][CH2:32][O:33][CH:28]([CH2:27][N:24]5[CH2:23][CH2:22][O:21][CH2:26][CH2:25]5)[CH2:29]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1COC(CN2CCOCC2)CN1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCOC(CN4CCOCC4)C3)c(F)cc2c1=O

Procedure:
By the use of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(morpholinomethyl)morpholine, the reaction is similarly carried out as Example 11 to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-[2-(morpholinomethyl)morpholino]-4-oxoquinoline-3-carboxylic acid, melting at 171°-172° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[CH:7]=[CH:6]1.C([O-])([O-])=O.[K+].[K+].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CC#N>[N:23]1([CH2:2][CH2:3][CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=3)[CH:7]=[CH:6]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc2ccn(CCCCl)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2ccn(CCCN3CCOCC3)c2c1
Yield: 100.1 %

Procedure:
A solution of compound 148 (2.35 g, 9.845 mmol) in dry CH3CN (40 mL) was treated with K2CO3 (13.6 g, 98.458 mmol), KI (16.3 g, 98.458 mmol) and morpholine (8.58 mL, 98.458 mmol) at room temperature. The resulting mixture was refluxed for overnight (15 h). The reaction was brought to room temperature and the solvent was evaporated. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The combined ethyl acetate layer was washed with water (25 mL), brine (20 mL) and dried (Na2SO4). The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (EtOAC: 2M NH3 in methanol/CH2Cl2, 1:1) to obtain compound 149 (2.85 g, quantitative) as a syrup. 1H-NMR (CDCl3) δ 1.97-2.06 (m, 2H), 2.23 (t, 2H, J=6.3 Hz), 2.38 (brs, 4H), 3.75 (t, 4H, J=4.5 Hz), 4.33 (t, 2H, J=6.6 Hz), 6.59 (d, 1H, J=3.0 Hz), 7.39 (d, 1H, J=3.0 Hz), 7.64 (d, 1H, J=8.7 Hz), 8.00 (dd, 1H, J=1.8, 8.7 Hz), 8.42 (brs, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][C:14](=[O:25])[N:15]([CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:16]=3)[S:10][C:3]=12.[F:26][C:27]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=1[OH:36].C([O-])([O-])=O.[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1>[F:26][C:27]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=1[O:36][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][C:14](=[O:25])[N:15]([CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:16]=3)[S:10][C:3]=12
Reactant: O=c1ncc(-c2cc3nccc(Cl)c3s2)cn1CCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1ncc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1CCN1CCOCC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 25.8 %

Procedure:
To a solution of the pyridone 414 (236 mg, 0.63 mmol) in Ph2O (1.3 mL) was added 2-fluoro-4-nitrophenol (197 mg, 1.26 mmol) and K2CO3 (173 mg, 1.26 mmol). The mixture was stirred at 100° C. for 1 h, then at 180° C. for 2 h, cooled and evaporated under reduced pressure. The residue was purified by flash chromatography with a gradient of methanol (2-10%) in dichloromethane to give title compound 415 (81 mg, 26% yield). MS (m/z): 498.0 (M+H). 1H NMR (DMSO-d6) δ (ppm): 9.16 (d, J=3.3 Hz, 1H), 8.66 (d, J=3.3 Hz, 1H), 8.60 (d, J=5.3 Hz, 1H), 8.47 (dd, J=10, 2.5 Hz, 1H), 8.19 (d, J=8.8 Hz, 1H), 8.02 (s, 1H), 7.69 (t, J=8.6 Hz, 1H), 6.98 (d, J=5.3 Hz, 1H), 4.02 (t, J=5.5 Hz, 2H), 3.58-3.43 (m, 4H), 2.59 (t, J=5.5 Hz, 2H), 2.50-2.41 (m, 4H).
Reaction SMILES: [CH:1]([CH:3]([CH:14]([CH3:16])[CH3:15])[CH2:4][C:5]1[CH:9]([C:10]([CH3:12])=[CH2:11])[CH2:8][CH2:7][C:6]=1[CH3:13])=[O:2].[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>[N+](C)([O-])=O>[O:2]1[CH:1]2[CH2:11][CH:10]([CH3:12])[C:9]31[C:5]([CH2:4][CH:3]2[CH:14]([CH3:16])[CH3:15])=[C:6]([CH3:13])[CH2:7][CH2:8]3
Reactant: C=C(C)C1CCC(C)=C1CC(C=O)C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Product: CC1=C2CC(C(C)C)C3CC(C)C2(CC1)O3
Yield: 78.8 %

Procedure:
To a solution, cooled to -40°, of 3.3 g of 2-(2-formyl-3-methylbutyl)-3-isopropenyl-1-methyl-1-cyclopentene in 225 ml of nitromethane were added 45 ml of a 0.5-M solution of tin tetrachloride in nitromethane. The reaction mixture became intensely yellow in colour and an initially resulting precipitate dissolved again. The mixture was treated immediately with excess 2-N sodium carbonate solution and extracted with ether. After washing, the ethereal phase was dried in a conventional manner and the solvent was removed. Distillation under a high vacuum yielded 2.6 g of crude 3a,6-epoxy-7-isopropyl-1,4-dimethyl-2,3,3a,4,5,6,7,8-octahydroazulene in the form of a colourless oil which could be separated by chromatography on 40 times the amount of Florisil (magnesium silicate gel) with hexane/ether (19:1) into two pairs of epimers (A and B). Epimer A: b.p.0.01 ca 75°; IR(film): νmax = 1465/40, 1380, 1345, 1245, 1162, 1125, 1108, 1080, 1050, 995, 965, 945, 910, 880 cm-1. The odour is camphorous, woody. Epimer B: b.p.0.01 ca 80° IR(film): νmax = 1465/34, 1380, 1340, 1295, 1245, 1200/1195, 1170, 1145, 1110, 1060, 1030, 1000, 990, 950, 925, 910, 878 cm-1. The odour is camphorous, dull.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][N:15]([CH3:36])[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH3:28])=[CH:21][CH:20]=1.O>O1CCCC1.CCCCCC>[CH3:28][CH2:27]/[C:26](/[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[C:25](/[C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][N:15]([CH3:14])[CH3:36])=[CH:24][CH:23]=1)\[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Ic1ccc(I)cc1
Reactant: CCC(C(=O)c1ccc(OCCN(C)C)cc1)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC/C(=C(\c1ccccc1)c1ccc(OCCN(C)C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 1,4-diiodobenzene (4.21 g, 12.7 mmol) in dry tetrahydrofuran (20 ml) was cooled under nitrogen by a dry ice-acetone bath. n-Butyllithium (8.5 ml of a 1.55M solution in hexane, 12.7 mmol) was added. After 5 minutes, a solution of 1-[4-(2-dimethylaminoethoxy)phenyl]-2-phenyl-1-butanone (2.0 g, 6.4 mmol) was added and the mixture allowed to warm to room temperature. After 15 hours, the mixture was poured into water (60 ml) and extracted with ether (2×50 ml). The ether extracts were concentrated and the residual oil dissolved in ethanol (20 ml). Concentrated hydrochloric acid (10 ml) was added and the mixture heated under reflux for 4 hours, then cooled, and poured into water (100 ml). The solution was basified with aqueous sodium hydroxide (3M) and extracted with ether (100 ml). The ether extract was dried with sodium sulphate, concentrated, and the residue applied to a column of silica (Merck 15111, 80 g). Elution with 1:1 light petroleum (b.p. 40°-60° C.-ether containing an increasing proportion of triethylamine gave after a forerun of tamoxifen which was discarded, at 5% triethylamine, a mixture of 4-iodotamoxifen and its Z isomer:-
Reaction SMILES: [CH3:1][C:2]1[N:12]2[C:13]3[C:8]([O:9][CH2:10][CH:11]2[CH2:14][OH:15])=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:1][C:2]1[N:12]2[C:13]3[C:8]([O:9][CH2:10][CH:11]2[CH2:14][O:15][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc2cccc3c2n1C(CO)CO3
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COc3cccc4nc(C)n2c34)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-Methyl-3,4-dihydro-5-oxa-1,2a-diaza-acenaphthylen-3-yl)-methanol (2.0 g, 9.8 mmole) was dissolved in pyridine (35 mL), p-toluenesulfonyl chloride (4.0 g, 20.9 mmole) was added and the resulting mixture was stirred at room temperature overnight. The solvent was removed and the residue partitioned between 400 mL each of methylene chloride and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuum. The crude residue was column chromatographed on silica gel using methylene chloride to elute 2.6 g of the title compound. 1H NMR (DMSO-d6): δ 7.60 (d, 1H); 7.20 (m, 3H); 7.05 (t, 1H); 6.65 (d, 1H); 4.75 (d, 1H); 4.57 (dd, 1H); 4.10 (m, 3H); 2.58 (s, 3H); 2.47 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.Cl.[CH3:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1.CCN(C(C)C)C(C)C>CS(C)=O.O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([N:26]3[CH2:27][CH2:28][CH2:29][C@H:25]3[CH3:24])=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: C[C@@H]1CCCN1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC[C@H]3C)nc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (150 mg, 0.47 mmol) in DMSO (2 mL), was added (R)-2-methylpyrrolidine hydrochloride (61 mg, 0.50 mmol) and DIEA (92 mg, 0.71 mmol). After stirring overnight at 70° C., the reaction mixture was dissolved in water (100 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford a residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford (R)-methyl 2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate as a light yellow solid (95 mg, 55%).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH:15]=CN=[CH:12][C:11]=3[N:10]=[CH:9]2)=[N:6][CH:7]=1.Br[C:18]1C=CC(F)=C[N:19]=1>>[N:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[N:8]1[C:16]2[CH:15]=[N:19][CH:18]=[CH:12][C:11]=2[N:10]=[CH:9]1
Reactant: Fc1ccc(Br)nc1
Reactant: Fc1ccc(-n2cnc3cnccc32)nc1
Product: c1ccc(-n2cnc3ccncc32)nc1

Procedure:
Intermediate 10 was prepared in a manner analogous to Intermediate 1, substituting 2-bromopyridine for 2-bromo-5-fluoropyridine. MS (ESI): mass calculated for C11H8N4, 196.07; m/z found 197.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=2)[O:10][CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([O:14]C)=[O:13])[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=2)[O:10][CH:11]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:12]([OH:14])=[O:13])[N:3]=1
Reactant: COC(=O)C(Oc1cccc(-c2noc(C)n2)c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(-c2cccc(OC(C(=O)O)c3ccccc3)c2)no1
Temperature: 80 °C

Procedure:
A solution of 1.77 g (5.46 mmol) of methyl [3-(5-methyl[1,2,4]oxadiazol-3-yl)phenoxy]-2-phenylacetate in 15 ml of methanol is treated with 10 ml of 1 N aqueous sodium hydroxide solution and heated at 80° C. for 3 hours. The reaction mixture is concentrated and the residue is treated with 1 N hydrochloric acid. It is extracted with ethyl acetate and the organic phase is evaporated. A colourless solid is obtained; FAB 311
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:16]([OH:18])=O)=[N:5][N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1.CC[N:21]=C=NCCCN(C)C.Cl.[NH4+].[Cl-]>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[C:4]([C:16]([NH2:21])=[O:18])=[N:5][N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cn(COCC[Si](C)(C)C)nc1C(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COc1cn(COCC[Si](C)(C)C)nc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
To a solution of 4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylic acid (compound 280.4, 5 g, 18.4 mmol) in N,N-dimethylformamide (50 mL) were added EDC.HCl (7 g, 36.5 mmol), NH4Cl (1.97 g, 36.8 mmol) and 4-dimethylaminopyridine (8.95 g, 73.3 mmol). The mixture was stirred for 2 h at room temperature, then warmed to 50° C. for 3 h. The reaction mixture was quenched with 30 mL of NH4Cl (sat). The aqueous phase was extracted with 2×100 mL of ethyl acetate. The combined organic layers were washed with 3×100 mL of NH4Cl (sat), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:5) as the eluent to furnish 1.3 g (26%) of the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][NH:9][CH2:10][CH2:11][O:12][CH3:13])[CH:5]=[CH:4][CH:3]=1.[CH2:14]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:15][C:16]#[CH:17]>>[CH3:13][O:12][CH2:11][CH2:10][NH:9][CH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([C:17]#[C:16][CH2:15][CH2:14][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:7]=1
Reactant: COCCNCc1cccc(Br)n1
Reactant: C#CCCN1CCCCC1
Product: COCCNCc1cccc(C#CCCN2CCCCC2)n1
Yield: 13 %

Procedure:
The title compound (13%) was prepared in a manner similar to that described in Example 18, Step D, using (6-bromo-pyridin-2-ylmethyl)-(2-methoxy-ethyl)-amine (0.300 g, 1.23 mmol) and 1-but-3-ynyl-piperidine (0.336 g, 2.45 mmol). MS (ESI): exact mass calcd. for C18H27N3O, 301.44; m/z found, 302.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.56 (t, 7.7, 1H), 7.26 (d, J=7.1, 1H), 7.23 (d, J=7.7, 1H), 3.90 (s, 2H), 3.52-3.45 (m, 2H), 3.34 (s, 3H), 2.80 J=5.2, 2H), 2.70-2.59 (m, 4H), 2.48-2.40 (m, 4H), 1.67-1.54 (m, 5H), 1.46-1.38 (m, 2H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12])[C:5]=1[F:17].[AlH4-].[Li+]>O1CCCC1>[F:17][C:5]1[C:4]([CH2:3][OH:2])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12]
Reactant: CCCS(=O)(=O)Nc1cccc(C(=O)OC)c1F
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1cccc(CO)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid methyl ester (65, 3.80 g, 13.8 mmol) in tetrahydrofuran (133 mL) was added lithium tetrahydroaluminate (1.00 M in tetrahydrofuran, 20.0 mL, 20.0 mmol) under an atmosphere of nitrogen at room temperature. The reaction was stirred at room temperature for 8 hours, followed by addition of 10 g of NaSO4.10H2O. After 12 hours, the reaction was filtered, concentrated and purified with silica gel column chromatography eluting with 5% methanol in methylene chloride to give a white solid (66, 3.0 g, 87.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[S:13])[NH:11][N:10]=[N:9]2)=[C:4]([F:14])[CH:3]=1.Br[CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)C>[CH2:16]([S:13][C:12]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:14])[N:9]=[N:10][N:11]=1)[CH3:17]
Reactant: Fc1cc(Cl)ccc1-n1nn[nH]c1=S
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CCSc1nnnn1-c1ccc(Cl)cc1F
Yield: 81.4 %

Procedure:
A solution of 1.75 g (0.0076 mole) of 1-(4-chloro-2-fluorophenyl)-1,4-dihydro-5H-tetrazol-5-thione, 0.57 ml (0.0076 mole) of bromoethane, and 1.6 g (0.012 mole) of potassium carbonate in 8 ml of acetone was stirred at room temperature for seven hours. The solvent was evaporated from the reaction mixture under reduced pressure leaving a residue. This residue was dissolved in diethyl ether and the organic solution was washed with water. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 1.6 g of (1-(4-chloro-2-fluorophenyl)-1H-tetrazol-5-yl) ethyl sulfide as a solid, m.p. 76°-79° C.
Reaction SMILES: Cl.Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:17]([CH:20]=1)[C:18]#[N:19])[CH2:4][CH2:5][CH3:6].C=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl.O.O.C(Cl)Cl.C(O)(=O)C>[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:37])[CH2:31][CH2:30]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:17]([CH:20]=1)[C:18]#[N:19])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(C#N)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-[3-butyl-6-(piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzonitrile dihydrochloride (19 mg, 0.037 mmol) in dichloromethane (2.0 mL) was added formaldehyde solution in water (37%, 0.2 mL), and 0.1 mL of acetic acid. Then sodium triacetoxyborohydride (200 mg) was added. And the mixture was stirred at room temperature for 10 min then condensed. It was then diluted with water/DCM, neutralized with sat NaHCO3 powder, organic layer was separated washed with water, brine and dried (Na2SO4). The solvent was removed in vacuo and the residue was purified by column chromatography using 5% methanolic solution of ammonia (2.0 M ammonia in methanol) in DCM to get 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzonitrile. This compound was dissolved in DCM (2.0 mL) and 1.0 mL of 4.0 M HCl in dioxane was added. Solvents were evaporated resulting solid was washed with ether and dried to provide the title compound (13 mg, 95%). LCMS: m/z 450 [M+1]. 7.75-7.89 (3H, m), 7.40-7.49 (1H, m), 5.40-5.51 (1H, m), 4.68-4.72 (1H, m), 3.65-3.68 (1H, m), 3.39-3.52 (2H, m), 3.10-3.18 (2H, m), 2.94 (3H, s), 2.54 (1H, d), 2.41 (1H, d), 2.21-2.29 (1H, m), 1.98-2.11 (3H, m), 1.81-1.90 (2H, m), 1.60-1.7 (2H, m), 1.41-1.61 (6H, m), 1.28-1.35 (3H, m), 0.83 (3H, t).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([F:7])[F:6])[CH3:2].I[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[CH:29]=[CH:28][C:27]3[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=3[CH:21]=2)=[O:19])=[CH:13][CH:12]=1>CS(C)=O.[NH4+].[Cl-].[Cu]>[CH3:30][C:26]1([CH3:31])[CH2:25][CH2:24][C:23]([CH3:32])([CH3:33])[C:22]2[CH:21]=[C:20]([C:18]([NH:17][C:14]3[CH:15]=[CH:16][C:11]([C:5]([F:7])([F:6])[C:4]([O:3][CH2:1][CH3:2])=[O:9])=[CH:12][CH:13]=3)=[O:19])[CH:29]=[CH:28][C:27]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Nc3ccc(I)cc3)ccc21
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccc(NC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 58 °C
Reaction time: 18 h
Yield: 74.6 %

Procedure:
Under a nitrogen atmosphere ethylbromodifluoroacetate (0.244 mL, 1.90 mmol) was added to a suspension of 5,6,7,8-tetrahydro-N-(4-iodophenyl)-5,5,8,8-tetramethylnaphthalene-2-carboxamide 22 (826 mg, 1.90 mmol), powder copper (99.999%, 588 mg) in anhydrous DMSO (16.7 mL). The reaction mixture was stirred at 58° C. for 18 h. After cooling, the mixture was poured in aqueous NH4Cl 5% (150 mL). This mixture was extracted with EtOAc (5×150 mL). The organic layer was washed with aqueous NH4Cl 5% (3×100 mL), brine (3×100 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography using as eluent cyclohexane:EtOAc=95:5. Ethyl 2-(4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxamido)phenyl)-2,2-difluoroacetate 23 was obtained (0.61 g, 74.6% yield) as a white solid.