Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:12])=[CH:3][C:4](=[O:11])[CH2:5][S:6]([NH:9][CH3:10])(=[O:8])=[O:7].CI.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]([CH3:12])=[CH:3][C:4](=[O:11])[CH2:5][S:6]([N:9]([CH3:15])[CH3:10])(=[O:7])=[O:8]
Reactant: CNS(=O)(=O)CC(=O)C=C(C)N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(N)=CC(=O)CS(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 3.8 g of 4-amino-N-methyl-2-oxo-3-pentenesulfonamide and 1.9 ml of methyl iodide in 50 ml of dimethylformamide was treated with 6 g of finely ground dry potassium carbonate and the mixture was thereupon stirred intensively at room temperature under argon for 6 hours. The organic salts were then filtered off, rinsed with methylene chloride and the filtrate was concentrated to dryness under reduced pressure. The residue was partitioned between water and methylene chloride, the organic phase was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The solid product was recrystallized from isopropanol, whereby there were obtained 2.5 g of 4-amino-N,N-dimethyl-2-oxo-3-pentenesulfonamide in the form of colorless crystals, m.p. 137°-140°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:9])=[C:6]([CH:8]=1)[NH2:7].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[C:19]=[O:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:9])=[C:6]([NH:7][C:19]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([F:10])([F:21])[F:22])=[O:20])[CH:8]=1
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: Nc1cc(Cl)ccc1O
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(Cl)ccc1O)Nc1ccccc1C(F)(F)F
Reaction time: 8 h

Procedure:
5-Chloro-2-hydroxyaniline (1 g) was suspended in toluene (50 ml) and treated with 2-trifluoromethylphenylisocyanate (1.2 ml). The reaction was stirred overnight and then filtered. The filter-cake was slurried and filtered twice with 15 ml toluene and washed once more with petrol. Drying at 55° C. gave 1-(5-Chloro-2-hydroxy-phenyl)-3-(2-trifluoromethyl-phenyl)-urea (2.06 g). Mp.=183-184° C. 1-(2-Hydroxy-6-methoxy-pyridin-3-yl)-3-(3-trifluoromethyl-phenyl)-urea (Compound 4):
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10]=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[C:1]([NH:8][CH2:9][CH:10]([OH:11])[CH:12]=[CH2:13])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)CNC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a suspension of dried, powdered 4 A molecular sieves (18 g) and PDC (45 mg, 120 mmol) in 150 mL CH2Cl2 was added a solution of 2-(BOC-amino)ethanol (4.83 g, 30 mmol) in CH2Cl2. The mixture was allowed to stir at ambient temperature for 1.5 hour, then diluted with ether (200 mL) and filtered through a silica gel pad, rinsing throughly with ether. The filtrate was concentrated to afford a clear pale yellow oil (3.46 g, 72%). The aldehyde was used immediately for the next reaction without purification. To a cooled solution of the freshly prepared BOC-Glycinal (410 mg, 2.6 mmol) in 8 mL THF was slowly added 1.0M vinyl magnesium bromide in THF (18 mL) via syringe. The reaction mixture was allowed to stir for 1 hour with warming to -10° C. The reaction was quenched with saturated aqueous ammonium chloride (20 mL) and was extracted with chloroform (×4). The extracts were dried and concentrated. The crude oil was purified by flash chromatography on silica gel, eluting with EtOAc/hexane (1/5~1/1, v/v) to give the title compound as a clear pale yellow oil (380 mg, 78% yield). MS(DCI) m/e 205(M+NH4)+. 1H NMR(CDCl3, 300 MHZ) δ1.45 (s, 9H), 2.54 (br s, 1H), 3.10 (dt, 1H), 3.30-3.43 (m, 1H), 4.24 (br s, 1H), 4.92 (br s, 1 H), 5.21 (d, 1H), 5.35 (d, 1H), 5.86 (ddd, 1H). Anal calc for C9H17NO3 : C, 57.72; H, 9.17; N, 7.48. Found: C, 57.85; H, 9.19; N, 7.42.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH2:27][CH2:28][CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:20][CH2:21][C:22]([O:24][CH2:25]C)=[O:23])(=[O:13])=[O:12])=[CH:7][CH:6]=1.C(O)(=O)C>CO>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH2:27][CH2:28][CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])(=[O:12])=[O:13])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Reaction time: 40 h

Procedure:
A solution of 130.15 g of sodium methoxide in 2.4 l methanol is added at room temperature to a solution of 5469 g of ethyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoate in 52.3 l of methanol. The mixture is stirred for 40 h under nitrogen. Glacial acetic acid (145.5 g) is added and the reaction mixture is evaporated to dryness at 60° and 3 mm Hg (=4.00 mbar). The residue is dissolved in 40 l of ethyl acetate, the solution is washed with dilute sodium bicarbonate solution and then with 5% sodium bisulfite, dried over sodium sulfate, treated with charcoal and evaporated to dryness to yield crude methyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoate (compound of example 4a).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[O:19][C:18]([C:20]([O-:22])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na+].[CH3:24][C:25]([NH2:28])([CH3:27])[CH3:26].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[C:25]([NH:28][C:20]([C:18]1[O:19][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10]2)=[CH:16][CH:17]=1)=[O:22])([CH3:27])([CH3:26])[CH3:24]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)[O-])o2)CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)o1
Reaction time: 2 h
Yield: 47.9 %

Procedure:
To a solution of sodium 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)furan-2-carboxylate (4.558 g, 13.72 mmol), 2-methylpropan-2-amine (1.003 g, 13.72 mmol, 1.441 mL) and triethylamine (4.16 g, 41.1 mmol, 5.72 mL) in dichloromethane was added 1-propanephosphonic acid cyclic anhydride (17.46 g, 27.4 mmol, 16.33 mL, 50% solution in ethyl acetate). The reaction was stirred for 2 hours then concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with sodium bicarbonate, water and brine. The organic phase was concentrated under reduced pressure to give the title compound (2.4 g). MS (ESI) m/z 366.3 [M+H]+
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12]Br.[C-:14]#[N:15].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][C:14]#[N:15]
Reactant: BrCc1ccc2ccccc2c1Br
Reactant: [C-]#N
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: N#CCc1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 99 parts of 1-bromo-2-(bromomethyl)naphthalene, 103 parts of potassium cyanide and 1 part of benzyl triethylammonium chloride in 150 parts by volume of methylene chloride and 30 parts by volume of water is stirred at room temperature for about 72 hours. The mixture is then diluted with additional quantities of methylene chloride and water, the organic layer separated, dried over calcium sulfate, and concentrated to give α-(1-bromo-2-naphthyl)acetonitrile, as a solid.
Reaction SMILES: N(C(OCC1C=CC=CC=1)=O)[C@H](C(O[C:11]([CH3:14])([CH3:13])[CH3:12])=O)CCC(=O)O.[Li+].[BH4-].[NH:27]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:28]([C:34]([O:36]C(C)(C)C)=O)[CH2:29][CH2:30][C:31](=[O:33])[OH:32]>>[C:11]([O:32][C:31](=[O:33])[CH2:30][CH2:29][CH:28]([CH2:34][OH:36])[NH:27][C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)[C@H](CCC(=O)O)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)CCC(CO)NC(=O)OC(C)(C)C

Procedure:
Cbz-Glu-OtBu 51 is converted to 52 via the methyl ester followed by LiBH4 reduction according to the procedure of Y. Hamada, M. Shibata, T. Sugiura, S. Kato and T. Shioiri, J. Org. Chem.52:1242, 1987 used for the conversion of t-Boc-Glu-OtBu to the corresponding alcohol.
Reaction SMILES: [C:1]([CH:3]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)#[N:2].N.[H][H].[ClH:22]>[Ni].C(OCC)(=O)C.CO>[ClH:22].[NH2:2][CH2:1][CH:3]([C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: COc1ccc(C(C#N)C2(O)CCCCC2)cc1
Agent: [Ni]
Agent: Cl
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(C(CN)C2(O)CCCCC2)cc1

Procedure:
A 5 liter autoclave is charged with 180 g of 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol, 2400 ml of methanol, 600 ml of aqueous ammonia (25% by volume) and 135 g of Raney nickel (pretreated as given under 1a)) and the mixture is subjected to hydrogenation at 27 to 30° C. and 120 psi pressure of hydrogen for 9 to 10 hours. The reaction mixture is filtered through 100 g of the celite and the catalyst bed is washed with 700 ml of methanol. The filtrate is concentrated to get 167.1 g of the crude product as an oily residue. 1.1 g of the crude product is dissolved in 2 ml of dry ethyl acetate and about 2 ml of isopropanolic HCl are added (the pH of the solution is about 2). The solvent is removed at high vacuum to give 1.14 g of 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride.
Reaction SMILES: C(N1C[C@H](C)NC[C@H]1C)C=C.N1C2C=CC=CC=2N=N1.[F:21][C:22]1[CH:23]=[C:24]([N:28]([CH3:39])[C:29](=[O:38])[C:30]2[CH:35]=[CH:34][CH:33]=[C:32](C=O)[CH:31]=2)[CH:25]=[CH:26][CH:27]=1>C1(C)C=CC=CC=1>[F:21][C:22]1[CH:23]=[C:24]([N:28]([CH3:39])[C:29](=[O:38])[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CN(C(=O)c1cccc(C=O)c1)c1cccc(F)c1
Agent: C=CCN1C[C@H](C)NC[C@H]1C
Agent: c1ccc2[nH]nnc2c1
Solvent: Cc1ccccc1
Product: CN(C(=O)c1ccccc1)c1cccc(F)c1

Procedure:
Crude 3-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(1H-benzotriazol-1-yl)methyl)-N-(3-fluorophenyl)-N-methylbenzamide was prepared from (2R,5S)-1-allyl-2,5-dimethylpiperazine (1.89 g), benzotriazole (1.39 g), and N-(3-fluorophenyl)-3-formyl-N-methylbenzamide (3.0 g) in toluene as described in Example 16. Method B.
Reaction SMILES: C([O:3][C:4](=O)/[C:5](/[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:15][CH:14]=1)=[CH:6]/[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)C.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>>[CH:7]1(/[CH:6]=[C:5](\[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:15][CH:14]=2)/[CH2:4][OH:3])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCOC(=O)/C(=C/C1CCCCC1)c1ccc(S(=O)(=O)C(C)C)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC(C)S(=O)(=O)c1ccc(/C(=C\C2CCCCC2)CO)cc1
Yield: 603.2 %

Procedure:
Following the method of example 54e, reaction of (E)-3-cyclohexyl-2-[4-(propane-2-sulfonyl)-phenyl]-acrylic acid ethyl ester (930 mg, 2.55 mmol) and DIBAL in toluene (1 M, 6.38 ml, 6.38 mmol) gives the title compound as an oil (4.96 g). MS (m/e): 323 (M+H).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1)[C:10]([NH2:12])=O.[C:21]([O-])([O-])=[O:22].[Na+].[Na+]>CN(C=O)C>[CH:21]([C:17]1[N:16]([C:15]2[CH:14]=[CH:13][C:9]([C:10]#[N:12])=[CH:8][C:7]=2[CH3:6])[CH:20]=[CH:19][CH:18]=1)=[O:22]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(N)=O)ccc1-n1cccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C#N)ccc1-n1cccc1C=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68 %

Procedure:
POCl3 (65 g, 427 mmol) was added to DMF (34 mL) at 0° C. for 30 min. After addition, the mixture was stirred at room temperature for 1.5 h, and then cooled to 0° C. A solution of 3-methyl-4-(1H-pyrrol-1-yl)benzamide (6A) (42.7 g, 213.5 mmol) in DMF (150 mL) was added at 0° C. and the resultant mixture was stirred at room temperature for 20 min, and then heated to 80° C. for 1 h. The solution was cooled to room temperature and then sat. Na2CO3 was added at 0° C. until pH=8. The mixture was extracted with ethyl acetate three times. The combined organic layers were washed with sat. NaHCO3 and brine, dried over Na2SO4, concentrated and purified by silica gel column chromatography (PE:EA=10:1) to afford 4-(2-formyl-1H-pyrrol-1-yl)-3-methylbenzonitrile as a yellow solid (30.5 g, yield 68%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[C:10]([C:20]#[N:21])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])=O.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:11]1[C:10]([C:20]#[N:21])=[C:9]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[S:8][C:7]=1[C:5]1[NH:4][CH2:3][CH2:2][N:1]=1
Reactant: N#Cc1c(N2CCOCC2)sc(C(=O)NCCN)c1-c1ccc(Cl)cc1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1c(N2CCOCC2)sc(C2=NCCN2)c1-c1ccc(Cl)cc1Cl
Temperature: 120 °C
Reaction time: 0.42 h
Yield: 95.7 %

Procedure:
To a suspension of N-(2-aminoethyl)-4-cyano-3-(2,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxamide (2.50 g, 5.90 mmol) in toluene (20 mL) was added phosphoryl chloride (4.70 mL, 50.0 mmol) and the mixture was stirred under microwave irradiation at 120° C. for 25 minutes. The reaction mixture was evaporated and the residue was suspended in methylene chloride and then quenched with ice water. The aqueous layer was basified by addition of KOH, the layers were separated and the aqueous layer was extracted again with methylene chloride. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the crude product (2.3 gr, 77%). LCMS: (FA) ES+ 408. 1H NMR (400 MHz, d6-DMSO) δ: 7.78-7.75 (m, 1H), 7.52-7.49 (m, 2H), 3.79-3.73 (m, 4H), 3.63-3.55 (m, 2H), 3.54-3.48 (m, 4H), 3.20-3.11 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[OH:17][CH:16]([C:13]1[CH:14]=[CH:15][C:10]([C@@H:8]([NH:7][C:6](=[O:18])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:9])=[CH:11][CH:12]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
70 mg of the compound [15-1] was dissolved in 5 mL of tetrahydrofuran and cooled to 0° C. Thereafter, 300 μL of benzylmagnesium chloride (2.0M tetrahydrofuran solution) was added thereto, and the mixture was stirred overnight while gradually heating back to room temperature. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the solution was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and then the resulting residue was purified by preparative thin-layer chromatography, to obtain 11 mg of the tert-butyl {(1S)-1-[4-(1-hydroxy-2-phenylethyl) phenyl]ethyl}carbamate [16-1] (hereinafter, referred to as the compound [16-1]) as a colorless oily product.
Reaction SMILES: CCN(C(C)C)C(C)C.[Li]CCCC.[Cl:15][C:16]1[C:17]2[CH:24]=[CH:23][S:22][C:18]=2[N:19]=[CH:20][N:21]=1.Cl[C:26]([O:28][CH3:29])=[O:27].[Cl-].[NH4+]>C1COCC1>[Cl:15][C:16]1[C:17]2[CH:24]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[S:22][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: COC(=O)Cl
Reactant: Clc1ncnc2sccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2c(Cl)ncnc2s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 9.6 %

Procedure:
A solution of THF (50 mL) and Hünig's base (2.14 mL, 15.2 mmol) were cooled to −78° C. and n-BuLi (2.5 M in hexanes, 5.7 mL, 14.1 mmol) added drop wise. The solution was warmed to 0° C. for 10 minutes, re-cooled to −78° C. and 4-chlorothieno[2,3-d]pyrimidine (2.0 g, 11.7 mmol) added. The anion was stirred for 10 minutes at −78° C., methyl chloroformate (1.0 mL, 12.9 mmol) added drop wise and the reaction maintained at −78° C. for 0.5 hours. The reaction was allowed to warm to ambient temperature. After 1 hour, the mixture was poured into saturated aqueous ammonium chloride (50 mL) and extracted with EtOAc (4×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash-column chromatography (100% DCM) to yield yellow solid (0.256 g, 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]([F:17])([F:16])[F:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[N:11]([CH3:22])[N:10]=1.[N+:23]([O-])([OH:25])=[O:24]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:23]([O-:25])=[O:24])=[CH:4][C:3]=1[C:9]1[C:13]([C:14]([F:16])([F:17])[F:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[N:11]([CH3:22])[N:10]=1
Reactant: Cn1nc(-c2ccc(Cl)cc2Cl)c(C(F)(F)F)c1C(F)(F)F
Reactant: O=[N+]([O-])O
Product: Cn1nc(-c2cc([N+](=O)[O-])c(Cl)cc2Cl)c(C(F)(F)F)c1C(F)(F)F
Temperature: 0 °C

Procedure:
21 g (58 mmol) of 3-(2,4-dichlorophenyl)-1-methyl-4,5-di-(trifluoromethyl)-1H-pyrazole were added, at (-30)° C., to 250 ml of concentrated nitric acid, whereupon the mixture was stirred for 1 hour at (-10)° C. The solution was subsequently stirred into 1.2 l of ice-water. The product was then extracted with dichloromethane. The organic phase was dried over magnesium sulfate and concentrated.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:15]>Cl.[Pd]>[Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][C:7]2=[N:6][C:5]=1[CH3:15]
Reactant: Cc1nc2ccccn2c(=O)c1CCCl
Agent: [Pd]
Agent: Cl
Product: Cc1nc2n(c(=O)c1CCCl)CCCC2
Yield: 88 %

Procedure:
28 g of 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one obtained in step A) was dissolved in 90 ml of 6N hydrochloric acid, 2.8 g of 10%-palladium was added thereto, and then the mixture was hydrogenated under a hydrogen pressure of 35 psi at room temperature for 8 hours. The reaction mixture was filtered through Cellite and the filtrate was concentrated under a reduced pressure, 200 ml of isopropanol was added to the residue, and then the mixture was stirred. The solid was filtered and dried to obtain 25.1 g of the title compound as a white crystal (yield: 90%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]=[CH:9][NH:8][CH:7]=1.[OH-].[K+].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>O.CCO>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]2[C:7]3[NH:8][CH:9]=[N:10][C:6]=3[CH2:5][CH2:4][NH:3]2)=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: NCCc1c[nH]cn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Brc1ccc(C2NCCc3nc[nH]c32)cc1

Procedure:
Histamine dihydrochloride (3.68 g, 0.02 mole), KOH (3.36 g, 0.06 mole), and 4-bromobenzaldehyde were dissolved in water (250 mL) and 95% EtOH(100 mL). The reaction was heated for 24 h at reflux while being open to the atmosphere. The resulting white precipitate was filtered and dried under vacuum at 40° C. to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([OH:8])[C:4]([CH3:9])=[N:3]1.CN(C=O)C.O1CCOCC1.[H-].[Na+].[Br:23][C:24]1[CH:25]=[C:26]([N+]([O-])=O)[C:27]([C:30]#[N:31])=[N:28][CH:29]=1>O>[Br:23][C:24]1[CH:25]=[C:26]([O:8][C:5]2[C:4]([CH3:9])=[N:3][N:2]([CH3:1])[C:6]=2[CH3:7])[C:27]([C:30]#[N:31])=[N:28][CH:29]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: Cc1nn(C)c(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(C)c(C)c1Oc1cc(Br)cnc1C#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.7 %

Procedure:
A flask was charged with 1,3,5-trimethyl-1H-pyrazol-4-ol (10.46 g, 82.89 mmol), and DMF dioxane (9:1) (700 mL). The reaction mixture was cooled to 0° C. and 60% sodium hydride (3.315 g, 82.89 mmol) was added portionwise. The reaction mixture was stirred for 15 minutes, then 5-bromo-3-nitropicolinonitrile (18 g, 78.95 mmol) was added and the reaction was stirred at ambient temperature for 3 hours. The reaction was poured slowly into 600 mL water and stirred for 10 minutes. The resultant solids were filtered and dried to afford 5-bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinonitrile (23.70 g, 97.74% yield) as very lightly tan (white) solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].Cl.CN.Cl.[CH3:29][N:30](C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:30][CH3:29])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CN(C)CC(=O)O
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(Br)c1)N2
Agent: [Cu]I
Agent: CN
Agent: Cl
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC)c1)N2
Temperature: 120 °C
Reaction time: 16 h
Yield: 112.4 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (970 mg, 2.5 mmol), methylamine hydrochloride (844 mg, 12.5 mmol), copper(I) iodide (285 mg, 1.5 mmol), N,N-dimethylglycine hydrochloride (280 g, 2 mmol) and potassium carbonate (3.455 g, 25 mmol) in dimethyl sulfoxide (15 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 3,3-dimethyl-2-(3-methylamino-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (761 mg, 90%) as a light yellow solid which was used for next step without further purification: LC/MS m/e calcd for C21H26N2O2 (M+H)+: 339.45, observed: 339.2.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[NH2:7]/[C:8](/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1>O.CO>[NH2:7]/[C:8](/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1=[O:2]
Reactant: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N/C(=C1\C(=O)c2ccccc2S1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 2.246 gm (0.0105 mol) of sodium metaperiodate in 10 ml of water was added to a solution of 2.53 gm (0.01 mol) of (E)-2-[(amino)phenylmethylene]-benzo[b]-thiophen-3(2H)-one in 150 ml of methanol, and the mixture was stirred at room temperature for 15 hours. The sodium iodate precipitated thereby was removed by filtration, and the filtrate was diluted with 300 ml of water and extracted exhaustively with dichloromethane. The combined extracts were washed once with water, dried over sodium sulfate and concentrated by evaporation in vacuo. The residue was recrystallized from ethanol/ethyl acetate using activated charcoal, and yielded 2.28 gm (85% of theory) of pale yellow crystals, m.p. 246°-247° C. (decomposition).