Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[CH:11](NC(C)C)(C)C.[Li].C1CCCCC1.CI.[NH4+].[Cl-]>>[Br:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][C:6]=1[CH3:11]
Reactant: Brc1csc2ccccc12
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCCCC1
Product: Cc1sc2ccccc2c1Br
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
1.06 g of 3-Bromo-benzo[b]thiophene (5.0 mmol) is dissolved in 10 ml of dry tetrahedrofuran and cooled to −78° C. and 3.67 ml of lithium diisopropylamine 1.5M in cyclohexane (5.5 mmol) is added slowly and stirred at −78° C. for 15 min. 0.35 ml of Methyl iodide (5.6 mmol) is added and the reaction mixture is stirred at room temperature for 1 h, sat. NH4Cl is added, and the mixture is extracted with CH2Cl2, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt=10:1) to give the title compound. 835 mg (74%). 1H-NMR (CDCl3): 7.76 (t, 2H, J=7.7 Hz), 7.46 (t, 1H, J=7.7 Hz), 7.37 (t, 1H, J=7.7 Hz), 2.60 (s, 3H)
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:16]=[C:9]2[N:10]=[C:11]([CH3:15])[CH:12]=[C:13](Cl)[N:8]2[N:7]=1)(=O)C.NC(N)=[S:19]>C(O)C>[OH:4][CH2:5][C:6]1[N:16]=[C:9]2[N:10]=[C:11]([CH3:15])[CH:12]=[C:13]([SH:19])[N:8]2[N:7]=1
Reactant: NC(N)=S
Reactant: CC(=O)OCc1nc2nc(C)cc(Cl)n2n1
Solvent: CCO
Product: Cc1cc(S)n2nc(CO)nc2n1
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
In 400 ml of ethanol was dissolved 23.7 g of 2-acetoxymethyl-7-chloro-5-methyl-s-triazolo[1,5-a]pyrimidine, and 19 g of thiourea was added thereto and the mixture was stirred for 30 minutes under reflux. The reaction mixture was ice-cooled and the precipitated crystals were collected by filtration, washed with ethanol and dried. After the obtained crystals were dissolved in a 10% potassium hydroxide aqueous solution and stirred for 30 minutes, pH was adjusted to 2 with addition of a 2N hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and dried to obtain 15.3 g of the title compound.
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.C([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1C=O)(OC(C)(C)C)=O.S([O-])([O-])(=O)=[O:45].[Na+].[Na+].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[NH2:4][C@:5]1([C:22]([OH:23])=[O:45])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH2:40][CH:41]2[CH2:39][CH2:38][CH2:37][NH:36]2)[CH2:6]1
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C=O
Reactant: O=S(=O)([O-])[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: N[C@@]1(C(=O)O)CN(CC2CCCN2)C[C@@H]1CCCB(O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) and N-BOC-piperidine-2-carboxaldehyde (0.15 g, 0.75 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and glacial acetic acid (30 mg, 0.5 mmol), stirred at room temperature for 3 h, then cooled to room temperature and treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and stirred for 18 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and brine (20 mL each), dried (MgSO4), and concentrated in vacuo. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(pyrrolidin-2-ylmethyl)pyrrolidine-3-carboxylic acid (144 mg, 70%) as a white foam. NMR (D2O) δ 3.85-4.05 (m, 3 H), 3.60-3.80 (m, 3 H), 3.40 (m, 1 H), 3.30 (m, 2 H), 2.55-2.70 (m, 1 H), 2.20-2.35 (m, 1 H), 1.85-2.10 (m, 2 H), 1.75 (m, 1 H), 1.60 (m, 1 H), 1.15-1.40 (m, 3 H), 0.63-0.73 (m, 2 H). MS (m+1): 300.1; MS (m−H2O+1): 282.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]2[C:14]=1[C:13](=[O:15])[CH:12]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]1.[BrH:17].[Br:18]Br>C(O)(=O)C>[Br:17][C:3]1[C:2]([OH:1])=[C:14]2[C:6]([CH:7]3[C:12]([Br:18])([C:13]2=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]3)=[C:5]([CH3:16])[CH:4]=1
Reactant: Cc1ccc(O)c2c1C1CCCCC1C2=O
Reactant: Br
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc(Br)c(O)c2c1C1CCCCC1(Br)C2=O
Temperature: 0 °C

Procedure:
4.50 Grams of 8-hydroxy-5-methyl-1,2,3,4,4a,9a-hexahydro-9-fluorenone was dissolved in 50 ml of acetic acid and to the solution were gradually added dropwise 0.2 ml of hydrobromic acid and 1.3 ml of bromine, followed by refluxing under heating for 1 hour. The reaction mixture was poured into ice water and extracted with chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in this order and then dried with magnesium sulfate. The solvent was distilled off and the residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:10) and then recyrstallized from ethanol to obtain 3.86 g of 7,9a-dibromo-8-hydroxy-5-methyl-1,2,3,4,4a,9a-hexahydro-9-fluorenone.
Reaction SMILES: CN1[CH2:7][N:6]([CH3:8])[CH2:5][N:4]([CH3:9])C1.Cl[Si](C)(C)C.[CH3:15][N:16]1[C:28]2[CH2:27][CH2:26][CH2:25][C:24](=[O:29])[C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2.[CH3:30]C1NC=CN=1>C(#N)C.C1(C)C=CC=CC=1>[CH3:15][N:16]1[C:28]2[CH2:27][CH2:26][CH:25]([CH2:8][N:6]3[CH:7]=[CH:9][N:4]=[C:5]3[CH3:30])[C:24](=[O:29])[C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2
Reactant: Cc1ncc[nH]1
Reactant: Cn1c2c(c3ccccc31)C(=O)CCC2
Reactant: CN1CN(C)CN(C)C1
Agent: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: Cc1ccccc1
Product: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Reaction time: 0.17 h
Yield: 54 %

Procedure:
To the solution 19.5 g of 1,3,5-trimethylhexahydro-1,3,5-triazine in 20 ml of actonitrile and 150 ml of toluene, was slowly added 19 ml of chlorotrimethylsilane, which was then stirred for 10 min. 10 g of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one and 8.2 g of 2-methyl imidazole was subsequently added to the reaction mixture, which was then stirred under reflux. After completion of reaction, the reaction mixture was evaporated, and then 200 ml of water was added to the resulting residue, which was then stirred for 2 hours at room temperature. The resulting solid was filtered and washed with water to give 7.95 g of light yellow title compound (yield 54%).
Reaction SMILES: [P:1]([C:5]([NH:7][NH2:8])=[O:6])([OH:4])([OH:3])=[O:2].N(CCO)[CH2:10][CH2:11][OH:12]>O>[NH4+:7].[CH2:11]([OH:12])[CH3:10].[CH2:11]([OH:12])[CH3:10].[P:1]([C:5]([NH:7][NH2:8])=[O:6])([OH:4])([OH:3])=[O:2]
Reactant: OCCNCCO
Agent: NNC(=O)P(=O)(O)O
Solvent: O
Product: CCO
Product: [NH4+]

Procedure:
4.4 parts by weight of phosphonoformic acid hydrazide are run in 20 parts by volume of water and neutralised by a 2 molar solution of diethanol amine in water. The resulting solution is evaporated, the evaporation residue is triturated with a mixture of ethanol and methanol (90 parts by volume plus 10 parts by volume) and the crystals are isolated 11 parts by weight of diethanol ammonium salt of phosphonoformic acid hydrazide are obtained (yield 100%).
Reaction SMILES: [N:1]1([C:7]([NH:9][C:10]2[CH:31]=[CH:30][C:13]([O:14][CH2:15][C:16]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:17]=3[O:18][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:12][C:11]=2[F:32])=[S:8])[CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.Cl[C:34](OC(Cl)(Cl)Cl)=[O:35].C(N(CC)CC)C>O1CCOCC1>[N:1]12[CH:7]([N:9]=[C:10]3[CH:31]=[CH:30][C:13]([O:14][CH2:15][C:16]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:17]=4[O:18][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:12][CH:11]3[F:32])[S:8][C:34](=[O:35])[N:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2
Reactant: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc(NC(=S)N2CCCCN2)c(F)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)C(C)Oc1cc(C)ccc1COC1=CC(F)C(=NC2SC(=O)N3CCCCN23)C=C1
Yield: 31.4 %

Procedure:
By the method of Example 1, Step D, of U.S. Pat. No. 4,906,281, 1.50 g (0.00325 mole) of methyl 2-[2-[4-(perhydropyridazin-1-ylthiocarbonylamino)-3-fluorophenoxymethyl]-5-methylphenoxy]propionate and 0.36 g (0.09017 mole) of trichloromethyl chloroformate were reacted in the presence of 0.36 g (0.0035 mole) of triethylamine in 35 mL of dioxane, yielding 0.50 g of methyl 2-[2-[4-(8-thia-1,6-diazabicyclo[4.3.0]nonane-7-on-9-ylimino)-3-fluorophenoxymethyl]-5-methylphenoxy]propionate as a syrup. The NMR and IR spectra were consistent with the proposed structure. NMR: 1.60 (d, 3H, JHH =8.0 Hz); 1.78-1.96 (m, 4H); 2.30 (s, 3H); 3.64-3.80 (m, 4H); 3.70 (s, 3H); 4.80 (q, 1H, JHH =8.0 Hz); 5.10 (dd, 2H); 6.58-7.30 (m, 6H) .
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:22]3[O:23][C:24]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:25][C:26](=[O:28])[CH:27]=3)[CH2:11][C:10]=2[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[CH:9]=[C:10]2[C:19]([S:18][C:17]3[C:16]([C:22]4[O:23][C:24]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[CH:25][C:26](=[O:28])[CH:27]=4)=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)Cc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc2c(c1)Cc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [5-(6-Morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-2-yl]-carbamic acid tert-butyl ester (19)(1.08 g, 2.19 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (2 ml) and left under stirring at room temperature overnight. The solvent was dried in vacuo revealing a viscous dark brown liquid. Saturated sodium bicarbonate solution (20 ml) was added to the residue, which was left to stir for 20 mins. The brown precipitate was filtered, washing with water and left to dry in the vacuum oven overnight (0.77 g, 90%). 1HNMR (300 MHz, DMSO-d6): δH=3.40 (4H, t), 3.70 (4H, t), 3.77 (2H, s), 5.23 (2H, bs), 5.50 (1H, d), 6.17 (1H, d), 6.44 (1H, dd), 6.65 (1H, d), 7.09 (1H, d), 7.35 (1H, t), 7.47–7.59 (2H, m); m/z (LC-MS, ESP), RT=3.51 minutes, (M++1)=392.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25](Cl)=[O:26])=[CH:24][C:19]=2[CH2:18][CH2:17]1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:25]([C:23]4[CH:22]=[CH:21][C:20]5[O:16][CH2:17][CH2:18][C:19]=5[CH:24]=4)=[O:26])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: O=C(Cl)c1ccc2c(c1)CCO2
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1ccc2c(c1)CCO2

Procedure:
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 2,3-dihydro-1-benzofuran-5-carbonyl chloride (68 mg; 0.37 mmol; 1.5 eq.) as a white solid (25.7 mg, 29%). HPLC, Rt: 3.14 min. (purity 78.8%). LC/MS, M+(ESI): 347.4, M−(ESI): 345.3.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:19])[CH:8]=2)[N:3]=1.O.[NH2:21][NH2:22]>>[Cl:19][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:21][NH2:22])[CH:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: NN
Reactant: Clc1ccc2nc(Cl)cc(-c3ccccc3Cl)c2c1
Solvent: O
Product: NNc1cc(-c2ccccc2Cl)c2cc(Cl)ccc2n1

Procedure:
In the manner given in Preparation 4, 2,6-dichloro-4-(o-chlorophenyl)quinoline was heated with hydrazine hydrate to give 6-chloro-2-hydrazino-4-(o-chlorophenyl)quinoline.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.O1CCCC1.Cl[CH2:16][C:17]1[CH:36]=[CH:35][C:20]([O:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:19][CH:18]=1>O>[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:35][CH:36]=2)[N:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: Cc1cc(C)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)n(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
Sodium hydride (60%, oily, 880 mg) was added to a mixture of 3,5-dimethylpyrazole (2.11 g) and tetrahydrofuran (50 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. After 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (6.28 g) was added to the reaction mixture, the mixture was refluxed for 24 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and 3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazole (5.49 g, yield: 74%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 86–87° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:17]([C:18](=[O:20])[CH3:19])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH:26]=O.COC1C=CC(NC2C(C=CC(C3C=C(OC)C(OC)=C(OC)C=3)=O)=CC=CN=2)=CC=1.Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:17]([C:18](=[O:20])[CH:19]=[CH:26][C:25]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:23]([O:22][CH3:21])[CH:24]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2ncccc2C(C)=O)cc1OC
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: COc1ccc(Nc2ncccc2C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(Nc2ncccc2C(=O)C=Cc2cc(OC)c(OC)c(OC)c2)cc1OC
Reaction time: 0.08 h
Yield: 90.8 %

Procedure:
To a solution of 1-(2-(3,4-dimethoxyphenylamino)pyridin-3-yl)ethanone (100 mg, 0.367 mmol) in methanol (5 mL) was added 2N Ba(OH)2 solution (2 ml) and stirred for 5 minutes. Then added 3,4,5-trimethoxybenzaldehyde (71.93 mg, 0.0.367 mmol) and the reaction mixture was stirred at a temperature of 30° C. for 6h and the reaction was monitored by TLC. After 8h the reaction mixture is acidified with 2N HCl. The resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The precipitate was recrystallized using ethanol to obtain pure (7c) (150 mg, 90% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](O)=[O:27])=[O:17].C(N(CC)CC)C.ClC(OCC)=O.[NH2:45][OH:46]>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:45][OH:46])=[O:27])=[O:17]
Reactant: O=C(O)CCCCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Reactant: NO
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCCCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
8-(3-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)octanoic acid (424 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (224 mg, 51%) as a brown solid. LC-MS (m/z) 440 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[C:11]1[S:12][CH:13]=[CH:14][N:15]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1
Reactant: Brc1nccs1
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Oc2nccs2)cc1
Temperature: 160 °C
Yield: 72.7 %

Procedure:
A mixture of 4-methoxyphenol (5.50 g, 44.3 mmol, 1.1 eq.), 2-bromothiazole (6.64 g, 40.0 mmol, 1.0 eq.), and K2CO3 (6.60 g, 47.8 mmol, 1.2 eq.) in dimethyl sulfoxide (40 mL) was heated to 160° C. for 5 hours. The reaction mixture was poured into water and extracted with ether. The ether layer washed with 10% NaOH, then brine, dried over MgSO4, filtered and concentrated. The residue was purified on silica gel eluting with ethyl acetate:hexane (0-20%) to give the title compound (6.03 g, 73%),
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[CH:12]1([CH2:15][OH:16])[CH2:14][CH2:13]1.[CH3:17][C:18]([CH3:21])([O-])C.[K+].O>C1COCC1>[CH:12]1([CH2:15][O:16][C:2]2[N:7]=[N:6][C:5]([C:8]([O:10][CH2:11][CH:21]3[CH2:18][CH2:17]3)=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: OCC1CC1
Reactant: COC(=O)c1ccc(Cl)nn1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCC1CC1)c1ccc(OCC2CC2)nn1
Temperature: 0 °C

Procedure:
To a solution of methyl 6-chloropyridazine-3-carboxylate (1.24 g) and cyclopropylmethanol (1.16 mL) in THF (20 mL) was added potassium tert-butoxide (1.05 g) at −78° C., and the mixture was stirred at the same temperature, allowed to warm to 0° C., and stirred for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (0.48 g).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:30](OCC)=[O:31])=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].O.[NH2:36][NH2:37]>CO>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:36][NH:37][C:30](=[O:31])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(OC)cc1)C(c1ccc(CN(C)C)cc1)N2
Solvent: O
Solvent: CO
Product: COc1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(CN(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of ethyl 2-(4-((dimethylamino)methyl)phenyl)-3-(4-methoxyphenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (70 mg, 0.15 mmol) and hydrazine monohydrate (1 mL) in methanol (5 mL) was stirred at room temperature for 5 hr. The resulting mixture was evaporated under reduced pressure to a volume of 1 mL and then filtered. The filtrate was concentrated to give the title compound as a white solid (26.5 mg). LC-MS (ESI) m/z: 427 (M+1)+. 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.79 (s, 6H), 3.71 (s, 3H), 4.24 (s, 2H), 4.26 (d, 1H), 4.77 (d, 1H), 6.74 (d, 2H), 6.99 (d, 2H), 7.18-7.21 (m, 1H), 7.35-7.43 (m, 4H), 7.55-7.57 (m, 1H), 7.65 (t, 3H).
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[CH3:18][O:19][CH2:20][CH2:21][NH2:22]>>[CH3:18][O:19][CH2:20][CH2:21][NH:22][C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10]
Reactant: COCCN
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Product: COCCNc1nc(Cc2ccsc2)[nH]c(=O)c1C#N

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 285 mg (3.80 mmol) of 2-methoxyethylamine to give 76 mg (69% of theory) of the title compound.
Reaction SMILES: [CH2:1]([C:7]1[C:8]2[S:17][CH:16]=[C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:9]=2[S:10][C:11]=1C(O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C2C(=CC=CC=2)C=CC=1.C(=O)=O>[Cu].CCCCCC>[CH2:18]([C:15]1[C:9]2[S:10][CH:11]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]=2[S:17][CH:16]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCc1csc2c(CCCCCC)c(C(=O)O)sc12
Agent: [Cu]
Agent: O=C=O
Solvent: CCCCCC
Solvent: c1ccc2ncccc2c1
Product: CCCCCCc1csc2c(CCCCCC)csc12
Temperature: 262 °C
Yield: 68.6 %

Procedure:
A mixture of compound 55 (30 g, 0.085 mol), copper powder (3.76 g) and quinoline (80 mL) is heated at 264-260° C. in a Woods metal bath. When no further bubbles of carbon dioxide gas are detected (about 2 hours), the mixture is allowed to cool to room temperature and hexane (200 mL) is added. This mixture is washed repeatedly with HCl (1-2 M in water) to remove the quinoline. The remaining organic layer is dried over MgSO4 and concentrated by evaporation, leaving a residue, which is purified by column chromatography (SiO2/hexanes) to yield compound 57 (18 g, 68.4%). m.p. 57.5-59.1° C., 1H NMR (CD2Cl2): δ6.97 (s, 2H), 2.70 (t, 4H), 1.73 (m, 4H), 1.37 (m, 12H), 0.88 (t, 6H). 13C NMR: 136.56, 134.96, 109.80, 31.94, 29.31, 29.28, 28.47, 22.96, 14.22.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[N:18]=[CH:17][C:16]=2[C:26](OCC)=[O:27])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1.CCO>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[N:18]=[CH:17][C:16]=2[CH2:26][OH:27])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2ccc(Cl)cc2c1Nc1ccc(Cc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: OCc1cnc2ccc(Cl)cc2c1Nc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a solution of Ethyl 4-(4-benzylphenylamino)-6-chloroquinoline-3-carboxylate (1.1 g, 2.6 mmol) in THF (13 mL) was added lithium aluminum hydride 2 M solution in THF (4.0 mL, 8.0 mmol) in portions over 10 min at 0° C. The dark brown reaction mixture was stirred at room temperature for 30 min and then treated with 3 mL of water. The resulting solution was dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography using a 95:5 v/v CH2Cl2: EtOH as solvent to afford title compound (880 mg, 88% yield) as a yellow solid.