Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[CH3:19][N:20]([CH3:36])[CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]3[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:29]=3[N:30]=2)[CH2:22]1>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]([NH:35][C:33]2[CH:32]=[CH:31][C:29]3[N:30]=[C:26]([N:23]4[CH2:24][CH2:25][CH:21]([N:20]([CH3:36])[CH3:19])[CH2:22]4)[S:27][C:28]=3[CH:34]=2)=[O:9])[CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C1CCN(c2nc3ccc(NC(=O)C=Cc4cccc(Cl)c4)cc3s2)C1
Yield: 49.2 %

Procedure:
Combine 3-chlorocinnamic acid (0.104 g, 0.572 mmol), CH2Cl2 (13 mL), and DMF (3 drops) with stirring. Add oxalyl chloride (0.17 mL, 1.91 mmol) and stir the mixture for 2.5 h at room temperature. Concentrate the mixture in vacuo, add hexane (approximately 10 mL), re-concentrate in vacuo, and add CH2Cl2 (4.0 mL). Transfer the mixture to a 40 mL reaction vial and add a mixture of 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (0.100 g, 0.381 mmol) (Example 1, step 3) in CH2Cl2 (5.0 mL). Shake the reaction vial for 1 h at room temperature. Dilute the reaction mixture with CH2Cl2 (25 mL), wash with 1.0 M NaOH (aqueous) (4×25 mL), dry over sodium sulfate, filter, and concentrate in vacuo. Purify the residue using silica gel chromatography (12 g column, 10-20% MeOH(CH2Cl2) to afford the title compound as a yellow solid (80 mg, 49%). mass spectrum (m/e): 427.2 [M+1], 425.2 [M−1]. 1H NMR (400 MHz, CDCl3 (spiked with CD3OD)): δ 8.28 (s, 1H), 7.61 (d, 1H, J=15.6 Hz), 7.47-7.43 (m, 2H), 7.32 (d, 1H, J=7.2 Hz), 7.30-7.23 (m, 2H), 7.19 (dd, 1H, J=8.8, 2.0 Hz), 6.57 (d, 1H, J=15.6 Hz), 3.78 (t, 1H, J=8.8 Hz), 3.68 (t, 1H, J=10.0 Hz), 3.50 (m, 1H), 3.36 (t, 1H, J=9.2 Hz), 2.88 (m, 1H), 2.29 (s, 6H), 2.23 (m, 1H), 1.97 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C([Sn](CCCC)(CCCC)[C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)CCC>>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Product: COC(=O)c1cc(-c2cccnc2)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 86.8 %

Procedure:
In the same manner as described in Example 139, 505 mg (1.0 mmol) of the product of Example 89 and 515 mg (1.4 mmol) of 3-(tributylstannyl)pyridine provided 437 mg (87%) of the desired product as a pale yellow solid. Electrospray Mass Spec 504 (M+H).
Reaction SMILES: CC(C)([O-])C.[K+].N[CH:8]=[CH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12].CO[CH:18](OC)[CH2:19][C:20]#[N:21].Cl>C(COC)OC>[F:12][C:11]([F:14])([F:13])[C:10](=[O:15])[CH:9]=[CH:8][CH:18]=[CH:19][C:20]#[N:21]
Reactant: NC=CC(=O)C(F)(F)F
Reactant: COC(CC#N)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: COCCOC
Product: N#CC=CC=CC(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
In a three-necked flask, 61.6 g (0.55 mol) of potassium tert-butoxide were introduced into 250 ml of dimethoxyethane under N2 and the solution was cooled to 0° C. 4-Amino-1,1,1-trifluoro-3-buten-2-one, 69.5 g (0.5 mol), was added dropwise at this temperature in the course of 30 min and then 60.3 g (0.525 mol) of 3,3-dimethoxypropionitrile were added dropwise. The mixture was then stirred at 30° C. for 3-4 h. The reaction mixture was added to ice and acidified to pH 3-4 using HCl. The precipitate was filtered off and washed with water.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29]([C:2]2[N:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[CH2:22][CH2:21][CH2:20][C@@H:19]4[CH3:23])[CH:13]=3)[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: C[C@H]1CCCN1c1cccc(Nc2nc(Cl)nc3scnc23)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2nc(Nc3cccc(N4CCC[C@@H]4C)c3)c3ncsc3n2)cn1
Reaction time: 0.15 h
Yield: 24.7 %

Procedure:
A mixture of (S)-5-chloro-N-(3-(2-methylpyrrolidin-1-yl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine (200 mg, 0.58 mmol), 6-methoxypyridin-3-ylboronic acid (134 mg, 0.87 mmol), Pd2(dba)3 (34 mg, 0.058 mmol), X-Phos (0.58 mg, 0.12 mmol) and sodium carbonate (185 mg, 1.74 mmol) in 1,4-dioxane:water (5 mL:5 mL) was heated to reflux for 16 hours. Then water was added, mixture extracted with ethyl acetate, organics combined washed with brine dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The crude product was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 20% acetonitrile/80% water (0.1% TFA V/V) initially, and then proceed to 45% acetonitrile/55% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give (S)-5-(6-methoxypyridin-3-yl)-N-(3-(2-methylpyrrolidin-1-yl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine (60 mg, 24.8%) as yellow solid. 1H NMR (300 MHz, CD3OD): δ 9.19 (s, 1H), 9.08 (s, 1H), 8.63 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 7.33 (s, 1H), 7.23-7.12 (m, 2H), 6.88 (d, 1H, J=8.7 Hz), 6.42 (d, 1H, J=6.9 Hz), 3.96 (s, 3H), 3.51-3.46 (m, 1H), 3.30-3.24 (m, 2H), 2.17-2.03 (m, 3H), 1.80-1.75 (m, 1H), 1.22 (d, 3H, J=6.3 Hz). LC-MS: 419 [M+H]+, tR=2.04 min. HPLC: 100% at 214 nm, 100% at 254 nm, tR=6.299 min.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH3:13].[ClH:14].[O:15]1[CH2:20][CH2:19][NH:18][C:17]2[N:21]=[CH:22][C:23]([CH:25]=[CH:26][C:27]([OH:29])=O)=[CH:24][C:16]1=2.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC.Cl>CN(C=O)C.C(Cl)Cl.CCOCC.O>[ClH:14].[O:15]1[CH2:20][CH2:19][NH:18][C:17]2[N:21]=[CH:22][C:23](/[CH:25]=[CH:26]/[C:27]([N:2]([CH3:1])[CH2:3][C:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[O:6][C:5]=3[CH3:13])=[O:29])=[CH:24][C:16]1=2
Reactant: CNCc1c(C)oc2ccccc12
Reactant: O=C(O)C=Cc1cnc2c(c1)OCCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc2ccccc2c1CN(C)C(=O)/C=C/c1cnc2c(c1)OCCN2
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of methyl-(2-methyl-benzofuran-3-ylmethyl)-amine (159 mg, 0.91 mmol) in DMF (5 mL) were added in sequential order 3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-acrylic acid hydrochloride (171 mg, 0.83 mmol), 1-hydroxybenzotriazole (127 mg, 0.91 mmol), diisopropylethylamine (289 uL, 1.06 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (182 mg, 0.91 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and treated with water under rapid stirring. The resulting precipitate was collected by filtration, dried and triturated with diethyl ether to yield a pale yellow solid. The solid was re-solvated in methylene chloride (5 mL) and a solution of 2M HCl in ether (2 mL) was added to precipitate an orange solid. The precipitated solid was collected by filtration, dried and triturated with diethyl ether to yield the title compound (118 mg, 39%) as a mixture of amide rotamers. 1H NMR (400 MHz, DMSO-d6) δ 8.76 (1s, 1H), 7.93-7.97 (m, 1H), 7.47-7.59 (m, 3H), 7.12-7.27 (m, 3H), 4.73-4.94 (m, 2H), 4.27 (m, 2H), 3.59 (m, 5H), 3.04 (s, 3H), 2.52 (s, 3H); MS (ESI) m/e 364 (C21H21N3O3+H)+.
Reaction SMILES: [C:1]([C@H:4]1[CH2:7][C@@H:6]([NH:8]C(=O)OCC2C=CC=CC=2)[C:5]1([CH3:20])[CH3:19])(=[O:3])[NH2:2]>[Pd].CO>[NH2:8][C@@H:6]1[CH2:7][C@H:4]([C:1]([NH2:2])=[O:3])[C:5]1([CH3:20])[CH3:19]
Reactant: CC1(C)[C@@H](C(N)=O)C[C@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC1(C)[C@H](N)C[C@@H]1C(N)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 120.6 %

Procedure:
A mixture of benzyl ((1R,3S)-3-carbamoyl-2,2-dimethylcyclobutyl)carbamate (193 mg, 0.70 mmol) and palladium on activated carbon (10% Pd, 30 mg) in MeOH (5 mL) was stirred at 25° C. under hydrogen atmosphere for 5 h. The reaction mixture was filtered through celite and the filtrate was concentrated to afford the crude title compound (120 mg, crude). MS (ESI) m/z 143.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:7]1[C:11](=O)[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=O)CCCC#C.C=O.C[NH:21]C.O.NN>>[CH3:1][N:7]([CH3:11])[CH2:8][C:9]#[C:16][CH2:15][CH2:14][CH2:13][CH2:10][NH2:21]
Reactant: C#CCCCCN1C(=O)c2ccccc2C1=O
Reactant: CNC
Agent: C=O
Agent: NN
Solvent: O
Product: CN(C)CC#CCCCCN

Procedure:
In a manner similar to Description 1 (iii) and (iv) reaction of N-5-hexynylphthalimide, paraformaldehyde and dimethylamine, followed by treatment with hydrazine hydrate gave the title compound b.p. 110°-20° C. (0.3 mm Hg).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(O)(=O)C>C(O)C.[Pt]=O>[OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4]
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Agent: O=[Pt]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)[C@@H](O)CC1CCCCC1
Yield: 95.2 %

Procedure:
α(S)-Hydroxybenzene propanoic acid (4.99 g, 30 mmol) was hydrogenated at 4 bar in ethanol (175 ml) and acetic acid (10 ml) using platinum oxide (0.5 g) as catalyst. After filtration, evaporation of the solvent gave the sub-title acid (4.92 g).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([NH:17]C(=O)OC(C)(C)C)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].Cl>C(O)C.C(OCC)C>[CH2:1]([C:4]1[N:5]([NH2:17])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCCc1nc2cnc3ccccc3c2n1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
A solution of tert-butyl (2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)carbamate (7.23 g, 22.2 mmol) in 40 mL of ethanol was treated with HCl (37 mL, 111 mmol, 3 M in ethanol) and heated to reflux. After 1 h, the reaction mixture was cooled to ambient temperature, diluted with 80 mL of diethyl ether, and cooled in an ice water bath. The HCl salt of the product was collected by vacuum filtration and rinsed with diethyl ether until the filtrate ran clear. The dried HCl salt was dissolved in 75 mL of water and treated with 50% NaOH solution until the pH of the water was 12–13. The free base of the product precipitated out and was triturated in the basic water for 30 min while being cooled in an ice water bath. The solid was collected by vacuum filtration and dried under vacuum to give 4.64 g of 2-propyl-1H-imidazo[4,5-c]quinolin-1-amine as a tan granular solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:13]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:10][C:4]=2[S:3]1.[CH3:24][NH:25][CH3:26]>>[CH3:24][N:25]([CH3:26])[C:21]([C:20]1[C:13]2[C:12]([NH:11][C:9]3[CH:8]=[CH:7][C:5]4[NH:6][C:2](=[O:1])[S:3][C:4]=4[CH:10]=3)=[N:17][CH:16]=[N:15][C:14]=2[NH:18][CH:19]=1)=[O:22]
Reactant: O=C(O)c1c[nH]c2ncnc(Nc3ccc4[nH]c(=O)sc4c3)c12
Reactant: CNC
Product: CN(C)C(=O)c1c[nH]c2ncnc(Nc3ccc4[nH]c(=O)sc4c3)c12

Procedure:
64.6 mg (178 μmol) 4-[(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (prepared according to example 3) were transformed in analogy to example 4 using N-methylmethanamine to give after working up and purification 32.6 mg (49%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:41][C:42](=[O:51])[O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:8]([C:12]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[N:21]3[CH2:26][C@H:25]([CH3:27])[C@H:24]([N:28]4[CH:32]=[CH:31][N:30]=[N:29]4)[C@H:23]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:22]3)=[O:13])=[N:9]2)=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCO[CH2:62][CH2:61]1.CC1(C)C(C)(C)OB(C=C)O1>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl.O>[C:37]([O:36][C:34]([NH:33][C@H:23]1[C@@H:24]([N:28]2[CH:32]=[CH:31][N:30]=[N:29]2)[C@@H:25]([CH3:27])[CH2:26][N:21]([C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[NH:14][C:12]([C:8]2[C:7]([NH:41][C:42](=[O:51])[O:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)=[CH:6][C:5]3[C:10](=[CH:11][C:2]([CH:61]=[CH2:62])=[CH:3][CH:4]=3)[N:9]=2)=[O:13])[CH2:22]1)=[O:35])([CH3:38])([CH3:39])[CH3:40]
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Reactant: C1COCCO1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: C=CB1OC(C)(C)C(C)(C)O1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Product: C=Cc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnccc3N3C[C@H](C)[C@H](n4ccnn4)[C@H](NC(=O)OC(C)(C)C)C3)nc2c1
Temperature: 90 °C
Yield: 37 %

Procedure:
A pressure tube charged with benzyl {7-bromo-2-[({4-[(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]quinolin-3-yl}carbamate (15 mg, 0.020 mmol), K3PO4 (8.4 mg, 0.04 mmol), 1,4-dioxane (0.26 mL), water (0.042 mL) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (5.5 mg, 0.036 mmol). The reaction mixture was purged with nitrogen for 5 min., then dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (1.6 mg, 0.002 mmol) was added. The pressure tube was sealed and the reaction mixture was heated at 90° C. for 30 min. then allowed to cool. The crude mixture was filtered and purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a light yellow powder (5.2 mg, 37%). LCMS calc. for C38H42N9O5 (M+H)+: m/z=704.3. Found: 704.3.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[CH:18]=[C:19]([CH2:24][CH2:25][OH:26])[CH:20]=[CH:21][C:22]=1[F:23].Cl.C1C[O:31][CH2:30]C1>C(OCC)(=O)C.CN(C=O)C>[F:23][C:22]1[C:17]([F:16])=[CH:18][C:19]([CH2:24][CH2:25][OH:26])=[CH:20][C:21]=1[CH:30]=[O:31]
Reactant: C1CCOC1
Reactant: OCCc1ccc(F)c(F)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1cc(CCO)cc(F)c1F
Temperature: -70 °C
Reaction time: 6 h

Procedure:
2,2,6,6-Tetramethylpiperidine (6.15 mL) was added to a solution of n-butyllithium in hexanes (1.6M, 22.8 mL) at −70° C. A solution of 2-(3,4-difluorophenyl)ethanol (example 32, step a) (1.92 g) in THF (25 mL) was added dropwise. THF (25 mL) was added and the mixture stirred at −70° C. for 6 h. DMF (4.7 mL) was then added and the mixture stirred for 1 h at −70° C. The mixture was then allowed to warm to RT and stirred for 70 h. Aqueous HCl solution (2M, 10 mL) was added followed by ethyl acetate (20 mL) and the layers separated. The aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic solutions were washed with brine (20 mL), dried over magnesium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 4:1 to 2:1 isohexane:diethyl ether gradient. The fractions containing product were combined and evaporated in vacuo to give the subtitled compound as a yellow oil. Yield 1.9 g.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[N+](N[C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[S:25][C:26]([CH2:29][N:30]([CH3:32])[CH3:31])=[CH:27][CH:28]=2)=[CH:18][N:17]=1)([O-])=O>C(O)C>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[S:25][C:26]([CH2:29][N:30]([CH3:31])[CH3:32])=[CH:27][CH:28]=2)=[CH:18][N:17]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CN(C)Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)s1
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2ccc(CN(C)C)s2)c(=O)[nH]1

Procedure:
A mixture of 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.37 g) and 2-nitroamino-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone (2.32 g) in ethanol was heated under reflux for 48 hrs. The ethanol was evaporated at reduced pressure yielding 2-[2-(5-methyl-4-imidazolyl-methylthio)ethylamino]-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone as a glassy residue which was washed with hot water by decantation. The residue was dissolved in isopropanol and a solution of ethanolic hydrochloric acid (3 ml) was added. Excess of solvent was removed at reduced pressure and trihydrochloride crystallized as a light buff solid (3.11 g). The solid was recrystallized from methanol-ethanol (2.36 g) 185.5°-188.5° C.
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]([S:18](Cl)(=[O:20])=[O:19])=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH:10]([S:18]([NH:8][C:1](=[NH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:20])=[O:19])=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Reactant: N=C(N)c1ccccc1
Product: N=C(NS(=O)(=O)C=Cc1ccccc1)c1ccccc1

Procedure:
Reaction of benzamidine and styrylsulfonyl chloride according to the above procedure provides N-(STYRYLSULFONYL)BENZAMIDINE, m.p. 192.5°-194.5° C. (corr.), crystallized from acetone.
Reaction SMILES: C[C:2]([CH:15]=C)([CH:5](C(C)=C)[CH2:6][CH:7]=[C:8]([CH3:11])[CH:9]=[CH2:10])[CH:3]=[O:4].C(=O)([O-])[O-].[Na+].[Na+].CO.[C:25]1([CH3:32])[C:26](C)=CC=[CH:29][CH:30]=1>>[CH3:11]/[C:8](/[CH2:7][CH2:6]/[CH:5]=[C:2](/[CH:3]=[O:4])\[CH3:15])=[CH:9]\[CH2:10]/[CH:26]=[C:25](/[CH:30]=[CH2:29])\[CH3:32]
Reactant: C=CC(C)=CCC(C(=C)C)C(C)(C=C)C=O
Reactant: Cc1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: C=C/C(C)=C/C/C=C(\C)CC/C=C(\C)C=O

Procedure:
Low boiling solvents may equally provide useful media whenever the reaction is effected at a pressure higher than the atmospheric pressure. For economical reasons xylene is preferred. It will be appreciated that the reaction time may vary within a wide range and depends particularly on the temperature chosen for carrying out the rearrangement. In a typical experiment 2,6-dimethyl-2-vinyl-3-isopropenyl-octa-5,7-dienal in xylene was heated at reflux for 40 min. under nitrogen. Sodium carbonate and methanol were added to the reaction mixture and the reaction mixture was further refluxed for 18 h while stirring. After dilution with pentane and drying over anhydrous sodium sulphate, the mixture was distilled to yield α-sinensal.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12]([NH:21][CH2:22][CH3:23])=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[O:9])=[CH:6][C:5]([Br:24])=[CH:4][N:3]=1.[H-].[Na+]>CN(C=O)C.O>[Br:24][C:5]1[CH:4]=[N:3][C:2]2[N:21]([CH2:22][CH3:23])[C:12]3[N:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:11]=3[NH:10][C:8](=[O:9])[C:7]=2[CH:6]=1
Reactant: CCNc1nc(C(F)(F)F)ccc1NC(=O)c1cc(Br)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1c2nc(C(F)(F)F)ccc2NC(=O)c2cc(Br)cnc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 28.7 %

Procedure:
To a solution of 2-chloro-N-{2-(ethylamino)-6-(trifluoromethyl)-3-pyridinyl}-5-bromo-3-pyridinecarboxamide (766 mg, 1.8 mmol) in DMF (18 mL) was added NaH (137 mg, 5.4 mmol). The reaction was stirred at 80° C. After 1 h the reaction was allowed to cool to room temperature, and then was poured in water (20 mL). The resulting mixture was extracted with EtOAc (3×). The combined organic layer was successively washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane:EtOAc, 7:3) to give the desired compound (200 mg, 28% yield) as a yellow solid.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][NH2:7])([CH3:3])[CH3:2].[OH:8][C:9]1[CH:24]=[CH:23][C:12]([C:13](=O)[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]2=O)=[CH:11][CH:10]=1.C(O)(=O)C>O.CCOCC>[OH:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]2[N:7]([CH2:6][CH2:5][NH:4][CH:1]([CH3:3])[CH3:2])[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[CH:14]=2)=[CH:11][CH:10]=1
Reactant: CC(C)NCCN
Reactant: O=C(CC1CCCCC1=O)c1ccc(O)cc1
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: CC(C)NCCn1c(-c2ccc(O)cc2)cc2c1CCCC2
Temperature: 25 °C

Procedure:
A solution of 7.25 g (0.071 mole) of isopropylaminoethylamine, 16.5 g (0.071 mole) of 2-(p-hydroxyphenacyl)cyclohexanone and acetic acid is refluxed under nitrogen for 6 hours, then cooled to ambient temperature, and diluted with water. The aqueous solution is washed with ether, then basified with 10% sodium carbonate and extracted with chloroform. The chloroform solution is washed with saturated sodium chloride solution, treated with charcoal, and dried over magnesium sulfate. The chloroform is removed to give a yellow solid which is recrystallized from acetonitrile to give a yellow-tan solid. The solid is dissolved in ether, the solution is filtered and concentrated to give 2-(p-hydroxyphenyl-1-(2-isopropylaminoethyl)-4,5,6,7-tetrahydroindole as a pale yellow solid, m.p. 149°-150° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:4][C:3]=1[OH:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=1[F:22].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:11][C:3]2[CH:4]=[CH:5][C:6]([CH2:8][CH2:9][OH:10])=[CH:7][C:2]=2[F:1])=[CH:15][C:14]=1[F:22]
Reactant: OCCc1ccc(O)c(F)c1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: OCCc1ccc(Oc2ccc(Cl)c(F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.9 %

Procedure:
To a solution of 2-fluoro-4-(2-hydroxyethyl)phenol (22.41 mmol, 3.5 g) and (4-chloro-3-fluorophenyl)boronic acid (45 mmol, 7.82 g) in dry CH2Cl2 (150 mL) were added copper (II) acetate (4.5 mmol 0.81 g), pyridine (45 mmol, 3.55 g), and 4 A molecular sieves in turn. The mixture was stirred at room temperature under N2 for 72 hours. The reaction mixture was filtered and the filtrate was concentrated to give crude product. The crude product was purified by silica gel chromatography to provide the desired product (1.4 g, 20%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.CC(C)=[O:14]>Cl.C1(NN)C=CC=CC=1.O>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:14])[CH2:1]1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Reactant: CC(C)=O
Agent: Cl
Solvent: NNc1ccccc1
Solvent: O
Product: CC1(C)CC(=O)CC(C)(C)N1
Reaction time: 10 h
Yield: 230 %

Procedure:
80 g of acetonine, 580 g of acetone, 24 g of water and 1.9 g of N-phenylhydrazine hydrochloride were reacted at 50°-55° C. for 3 hours. Then, 50 g of acetonine and 1.3 g of catalyst were added to the reaction solution and reacted for 3 hours. This procedure was repeated twice and the last addition of acetonine and catalyst the reaction was continued for 10 hours at the same temperature and obtained 185.2 g of triacetonamine after stripping and vacuum distillation.