Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: II.[Cl:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[Cl:12])[CH2:7]Cl.[Cl:13][CH2:14][C:15](Cl)=[O:16].Cl>CN(C)C(=O)C.[Zn].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[Cl:13][CH2:14][C:15](=[O:16])[CH2:7][C:6]1[CH:9]=[CH:10][C:11]([Cl:12])=[C:4]([Cl:3])[CH:5]=1
Reactant: O=C(Cl)CCl
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: II
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=C(CCl)Cc1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
The organozinc species was generated as described by S. Huo (Organic Letters 2003, 5 (4), 423-5). In a flame-dried 25 mL 2-necked round-bottomed flask, under an inert atmosphere, iodine (65 mg, 0.26 mmol) was taken up in 6 mL anhydrous N,N-dimethylacetamide. Zinc dust (0.502 g, 7.67 mmol) was added, and the suspension stirred until the red color of the iodine disappeared. Then, 3,4-dichlorobenzyl chloride (0.71 mL, 1.0 g, 5.1 mmol) was added via syringe, and the mixture heated at 80° C. until the t.l.c. of a hydrolyzed aliquot (5% ethyl acetate in hexanes, visualized by cerium molybdate staining) showed that the starting material had been consumed. The reaction vessel was placed in a water bath to cool it, and Pd(PPh3)4 (0.118 g, 0.102 mmol) was added, followed by dropwise addition, via syringe, of chloroacetyl chloride (0.61 mL, 0.87 g, 7.7 mmol). The brown suspension was allowed to stir overnight at room temperature. To work up the reaction, 12 mL 1 M HCl was added, and the mixture extracted into ethyl acetate (4×12 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and evaporated. The crude product was purified by flash chromatography over silica gel (1-30% ethyl acetate in hexanes), to give material of sufficient purity to be used in the next step (0.545 g, 45% yield): 1H NMR (400 MHz, CDCl3) δ 3.89 (s, 2H) 4.13 (s, 2H) 7.06 (dd, J=8.2, 2.6 Hz, 1H) 7.33 (d, J=2.0 Hz, 1H) 7.42 (d, J=8.3 Hz, 1H).
Reaction SMILES: C(OC(C#CCNCC=CCOC(=O)C)=O)(C)(C)C.[C:20]([O:24][C:25]([N:27]1[CH2:31][CH:30]2[CH:32]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH:33]([NH2:35])[CH2:34][CH:29]2[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[CH2:41]([O:48][C:49]([NH:51][CH2:52][C:53](O)=[O:54])=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[C:20]([O:24][C:25]([N:27]1[CH2:31][CH:30]2[CH:32]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH:33]([NH:35][C:53](=[O:54])[CH2:52][NH:51][C:49]([O:48][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:50])[CH2:34][CH:29]2[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(=O)OCC1C(N)CC2CN(C(=O)OC(C)(C)C)CC21
Agent: CC(=O)OCC=CCNCC#CC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC1C(NC(=O)CNC(=O)OCc2ccccc2)CC2CN(C(=O)OC(C)(C)C)CC21
Temperature: 25 °C

Procedure:
By sequentially following the procedures of Example 3, Parts B and C, and Example 1, Parts A and B, acetic acid 4-(tert-butoxy-carbonylprop-2-ynylamino)-but-2-enyl ester is converted to 4-acetoxymethyl-5-aminooctahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester. A solution of this material and benzyloxycarbonyl glycine in acetonitrile is treated sequentially with diisopropylethylamine and TBTU, and the resulting mixture is stirred at room temperature until the reaction is complete. The mixture is concentrated under vacuum yielding a residue. The residue is purified by flash column chromatography providing the title product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])[N:13]=2)[CH2:8][CH2:7]1)[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38]>C(#N)C>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][CH:42]=[C:34]([Cl:33])[CH:35]=3)=[CH:16][CH:15]=[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])[N:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CCN(c2nc(S(C)(=O)=O)ccc2N)CC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC1CCN(c2nc(S(C)(=O)=O)ccc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 49.8 %

Procedure:
To a mixture of 0.080 g (0.23 mmol) of (3′-amino-6′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester in acetonitrile (5 mL) is added 0.12 mL (0.70 mmol) of N,N-diisopropylethylamine followed by 0.032 mL (0.28 mmol) of 3-chlorobenzoyl chloride. The mixture is heated at 80° C. for 1 h then an additional 0.096 mL (0.84 mmol) of 3-chlorobenzoyl chloride is added. The mixture is stirred at 80° C. for an additional 10 minutes then cooled to room temperature and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 0.055 g (49%) of [3′-(3-chloro-benzoylamino)-6′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester as a colorless foam.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].Cl>CC(O)CCC(O)C>[F:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cccc(F)c1
Reactant: COCC1COc2cc3ncnc(Cl)c3cc2O1
Agent: CC(O)CCC(C)O
Agent: Cl
Product: COCC1COc2cc3ncnc(Nc4cccc(F)c4)c3cc2O1
Temperature: 25 °C

Procedure:
The titled compound of Example 7, 4-chloro-7-methoxy methyl-[1,4]dioxano[2,3-g]quinazoline (40 mg, 0.15 mmol) was dissolved in diisopropanol (2.5 ml), where was then added 3-fluoroaniline (33 mg, 0.3 mol) and concentrated hydrochloric acid of catalytic amount, followed by refluxing for 24 hours. Then, the reaction mixture was cooled down to a room temperature to obtain a solid, which was then filtered, washed with diisopropanol and dried under vacuum to prepare the titled compound (24 mg, 47%, m.p. 257-260° C.; mass (m/z;rel) 340.10).
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:15]2[C@:6]3([CH2:18][CH2:17][N:16]([CH3:19])[C@@H:14]2[CH2:13][C:12]2[CH:11]=[CH:10][C:9]([O:20][CH3:21])=[CH:8][C:7]3=2)[CH2:5][C:4](=[O:22])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].[N:29]#CBr>C(Cl)(Cl)Cl>[C:19]([N:16]1[CH2:17][CH2:18][C@@:6]23[C:7]4[CH:8]=[C:9]([O:20][CH3:21])[CH:10]=[CH:11][C:12]=4[CH2:13][C@@H:14]1[C@@H:15]2[C@@H:2]([CH3:1])[CH2:3][C:4](=[O:22])[CH2:5]3)#[N:29]
Reactant: N#CBr
Reactant: COc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@@H]1[C@@H](C)CC(=O)C3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)[C@]13CCN(C#N)[C@H](C2)[C@@H]1[C@@H](C)CC(=O)C3
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A rapidly stirred mixture of 8β,17-dimethyl-3-methoxymorphinan-6-one (free base; prepared in Part A) in chloroform (1.0 g/10 ml) containing 1.5 g finely powdered dry K2CO3 was treated dropwise with a solution of cyanogen bromide in chloroform (1.2 equivalents; 1.0 g/20 ml). The mixture was stirred rapidly for 30 minutes and then heated at reflux for an additional two hours. The solution was cooled, filtered, evaporated to dryness and azeotroped with alcohol. The crystalline, mp. 202°-205° C., product was obtained in 81% yield and was used without further pruification.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH:13]([CH2:26][C:27]2[NH:31][CH:30]=[N:29][CH:28]=2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH:13]2[CH2:26][C:27]2[NH:31][CH:30]=[N:29][CH:28]=2)=[CH:23][CH:22]=1)#[N:25]
Reactant: [H][H]
Reactant: N#Cc1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2Cc2cnc[nH]2)cc1
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccc(CN2CCNCC2Cc2cnc[nH]2)cc1

Procedure:
The product from Step 1 (6.17 mmol) was dissolved in absolute ethanol followed by the introduction of 10% Pd/C catalyst then hydrogen under atmospheric pressure. The catalyst was removed via filtration through filter-aid and the product was isolated by removing the solvent under reduced pressure. 1H—NMR (CD3OD): 7.8 (s, 1H); 7.75 (d, 2H); 7.3 (d, 2H); 6.9 (s, 1H); 5.45 (s, 2H); 3.3 (m, 4H); 2.6 (s, 2H); 2.3 (m, 4H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[I:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21])[N:12]=[CH:11]2.Br[CH2:27][CH:28]([CH3:30])[CH3:29]>CN1C(=O)CCC1>[I:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([O:22][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:21])[N:12]=[CH:11]2
Reactant: O=C(O)c1cccc(-n2ncc3cc(I)ccc32)c1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)COC(=O)c1cccc(-n2ncc3cc(I)ccc32)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A 50 mL.s flask was charged with sodium carbonate (0.700 g, 6.60 mmol), 3-(5-iodo-1H-indazol-1-yl)benzoic acid (I1a) (2.185 g, 6 mmol) and NMP (15 mL) at 40° C. with magnetic stirring. After a couple of minutes 1-bromo-2-methylpropane (0.971 mL, 9.00 mmol) was added in one portion. After one hour at 40° C., the temperature was raised to 55° C. and another portion of 1-bromo-2-methylpropane (0.971 mL, 9.00 mmol) was added. The stirring was continued overnight. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed twice with water, dried over Na2SO4, filtered and evaporated to dryness to afford the title compound as a syrup (2.5 g, 99%). The product solidified to a beige material upon standing.
Reaction SMILES: [H-].[Na+].[S:3]1([C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:8])[NH:6]1)(=[O:5])=[O:4].[C:15]([O:19][C:20](=[O:34])[C@H:21]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24]I)([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[C:15]([O:19][C:20](=[O:34])[C@H:21]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24][N:6]1[C:7](=[O:8])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[S:3]1(=[O:4])=[O:5])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCI)C(=O)OC(C)(C)C
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CCCN1C(=O)c2ccccc2S1(=O)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
Sodium hydride (0.311 g, 7.78 mmol) was added to a solution of saccharin (1.73 g, 9.44 mmol) and 18-crown-6 (0.025 g) in 10 mL of DMF. After stirring at RT for 30 min, (2R)-(t-butyloxycarbonylamino)-5-iodopentanoic acid t-butyl ester (2.78 g, 6.96 mmol) in 10 mL of DMF was added, and the solution was stirred at RT for 30 min, then at 60° C. for 6 h. The solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and 0.05M aqueous HCl. The organic phase was washed with water and brine, dried over MgSO4 and concentrated. The crude material was purified by silica gel chromatography (hexane/ethyl acetate=4/1˜3/1) to give the title compound (1.98 g, 63% yield): NMR (400 MHz, CDCl3) 1.44 (s, 9H), 1.46 (s, 9H), 1.68-1.96 (m, 4H), 3.81 (t, 2H, J=7.0 Hz), 4.19-4.29 (m, 1H), 5.09 (br d, 1H, J=7.9 Hz), 7.82-7.93 (m, 3H), 8.06 (d, 1H, J=7.3 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[N:15][NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19](Br)[C:18]=3[OH:24])[C:11]([CH3:25])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)([OH:28])=[O:27].[OH-].[K+]>C(O)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[N:15][NH:16][C:17]3[C:18]([OH:24])=[C:19]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([C:26]([OH:28])=[O:27])[CH:34]=4)[CH:20]=[CH:21][CH:22]=3)[C:11]([CH3:25])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=NNc1cccc(Br)c1O
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=NNc1cccc(-c2cccc(C(=O)O)c2)c1O
Reaction time: 20 h

Procedure:
A mixture of 1-(3,4-dimethylphenyl)-3-methyl-4-(3-bromo-2-hydroxyphenyl)hydrazono-5-pyrazolone (2 g) prepared as in Example 10, 3-carboxyphenylboronic acid (1 g), bis(triphenylphosphine)palladium(II)chloride [PdCl2(PPh3)2] (0.2 g), potassium hydroxide (1.50 g) in ethanol (50 mL) and water (20 mL) was heated to about reflux temperature and stirred for about 20 hours. The hot mixture was filtered to remove the catalyst. The clear filtrate was concentrated under vacuum. To the residue, water (100 mL) was added, acidified to pH 3-5 using hydrochloric acid and stirred for about 30 minutes at about room temperature. The slurry was filtered to give an orange solid, which was washed with water (20 mL) and dried in an oven at about 55° C. to about 60° C. for about 12 hours.
Reaction SMILES: Cl/[C:2](/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3]/[O-].[K+].Cl.O1CCOCC1.[Br:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH2:25])[CH:20]=1>C1(C)C=CC=CC=1>[Br:18][C:19]1[CH:24]=[CH:23][N:22]2[C:2]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][N:25]=[C:21]2[CH:20]=1
Reactant: Nc1cc(Br)ccn1
Reactant: CCOC(=O)/C(Cl)=C\[O-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc2cc(Br)ccn12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.3 %

Procedure:
Potassium (E)-2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (4.4 g, 23 mmol; prepared as in Example 65, step B1) was suspended in toluene (40 mL) and a 4M solution of HCl in dioxane (2.0 mL, 8.1 mmol). The mixture was stirred at ambient temperature for 5 minutes. 4-Bromopyridin-2-amine (2.0 g, 12 mmol) was added to the mixture and heated to 40° C. for 22 hours. The mixture was cooled to ambient temperature and extracted with 2M HCl (3×75 mL). Solid K2CO3 was added to the combined aqueous extracts until CO2 evolution ceased. The aqueous phase was extracted with MTBE (2×50 mL), dried over MgSO4, filtered and concentrated to give the product (2.4 g). MS (ES+APCI) m/z=268.7 (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][OH:14]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[OH:14][CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[NH:6][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: Nc1ccccc1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccccc1CO
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.8 %

Procedure:
A solution of methane sulfonyl chloride (10.2 ml, 0.13 mol) in chloroform (100 mL) was added dropwise to a solution of (2-aminophenyl)methanol (15.0 g, 0.12 mol) in pyridine (100 mL) and chloroform (150 mL) under nitrogen over 1 h at 0° C. The reaction mixture was stirred for 12 h at ambient temperature and then washed with hydrochloric acid (2N, 200 ml×2). The organic phase was dried over anhydrous MgSO4 and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane=1:3) to afford N-[2-(hydroxymethyl)phenyl]methanesulfonamide (13.0 g, 53% yield) as a yellow oil.
Reaction SMILES: C(S)CS.[Br:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([AsH2:17]=O)=[CH:13][CH:12]=1)=[O:9]>CO>[Br:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([AsH2:17])=[CH:15][CH:16]=1)=[O:9]
Reactant: O=[AsH2]c1ccc(NC(=O)CCBr)cc1
Agent: SCCS
Solvent: CO
Product: O=C(CCBr)Nc1ccc([AsH2])cc1
Reaction time: 0.08 h

Procedure:
1,2-Ethanedithiol (Aldrich; 25 μl, 0.30 mmol) was added to 4-(bromopropionamido)-phenylarsineoxide (Example 1.1; 100 mg, 0.30 mol) dissolved in 1 ml of hot methanol. After 5 min, a white solid precipitated and was collected. Yield: 63.7 mg, 0.16 mmol, 53%.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][CH:12]2[CH2:16][C:15](=[O:17])[N:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[CH2:13]2)[CH:10]=1)=[O:5])C.[OH-].[K+]>CO.O>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[N:14]1[C:15](=[O:17])[CH2:16][CH:12]([CH2:11][N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[CH2:13]1
Reactant: CCOC(=O)c1cnn(CC2CC(=O)N(c3ccc(F)cc3F)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnn(CC2CC(=O)N(c3ccc(F)cc3F)C2)c1
Temperature: 52.5 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.222 g, 0.62 mmol) was dissolved in a mixture of solvents Methanol:water (3:1, 5 ml) and KOH (0.07 g, 125 mmol) was added to the reaction mixture and then stirred at 50-55° C. for 3 hours. Solvents were removed and the residue was diluted with water (3 ml) and washed with DCM (3×10 ml) and acidified with dil. HCl. It was extracted with ethyl acetate (3×15 ml), organic layers were mixed and washed with brine (20 ml), dried over Na2SO4 and evaporated to dryness to obtain 1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylic acid (0.18 g, 90%) as a brownish sticky mass.
Reaction SMILES: [C:1]1([CH:11]=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:15]=1O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CCO>[C:1]1([C:11]2[O:12][C:15]3[CH:16]=[C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:19][C:14]=3[N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)Cc1ccc(N)c(O)c1
Reactant: O=Cc1cccc2ccccc12
Solvent: CCO
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc2nc(-c3cccc4ccccc34)oc2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41.8 %

Procedure:
In EtOH (8 ml), 1-naphthaldehyde (263 mg, 1.68 mmol) and methyl 4-amino-3-hydroxyphenylacetate (305 mg, 1.68 mmol) were stirred at room temperature for 12 hours. Iodobenzene diacetate (651 mg, 2.02 mmol) was added to the reaction mixture, followed by stirring at room temperature for 5 minutes. After removal of the solvent by distilling the reaction mixture under reduced pressure, the residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (6:1, v/v) eluate fractions, methyl (2-(1-naphthyl)-6-benzoxazolyl)acetate (223 mg, 42%) was obtained as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][C:12]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[C:17]#[N:18])=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][C:12]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH2:17][NH2:18])=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#Cc1cccc(-c2cnc(-c3ccc(Cl)c(Cl)c3)[nH]2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cccc(-c2cnc(-c3ccc(Cl)c(Cl)c3)[nH]2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
A solution of 3-[2-(3,4-dichloro-phenyl)-3H-imidazol-4-yl]-benzonitrile (4.1 g, 13 mmol), in THF (130 ml) was slowly added to an ice-cooled mixture of lithium aluminum hydride (0.99 g, 26 mmol) in THF (130 ml). The mixture was stirred for 30 min. at r.t., then saturated Seignette-salt solution (5 ml) was added slowly and stirring was continued for 30 min. The precipitate was filtered and the organic phase evaporated and chromatographed over SiO2 with CH2Cl2—CH3OH—NH4OH (140:10:1) to obtain 3-[2-(3,4-dichloro-phenyl)-3H-imidazol-4-yl]-benzylamine (1.77 g, 43%) as a foam. The hydrochloride salt was then prepared which was crystallized to an off-white solid. Mp. >250° C. (MeOH/Et2O), MS: m/e=318 (M+H+).
Reaction SMILES: [CH3:1][C:2]([Si:17]([CH3:20])([CH3:19])[CH3:18])([O:4][C@@H:5]1[CH2:8][C@H:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6]1)[CH3:3].[H-].[Na+].I[CH3:24]>C1COCC1>[CH3:24][N:9]([C@H:7]1[CH2:6][C@@H:5]([O:4][C:2]([CH3:1])([Si:17]([CH3:20])([CH3:19])[CH3:18])[CH3:3])[CH2:8]1)[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](OC(C)(C)[Si](C)(C)C)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1C[C@@H](OC(C)(C)[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of crude tert-butyl {cis-3-[1-methyl-1-(trimethylsilyl)ethoxy]cyclobutyl}carbamate (108 g) in THF (1 L) was added NaH (60% in oil, 39.6 g, 0.99 mol) in portions and the resulting mixture was stirred at rt for 30 min. The mixture was then cooled to 0° C. and iodomethane (140.58 g, 0.99 mol) was added dropwise. After addition, the mixture was stirred from 0° C. to rt overnight. The mixture was quenched with sat. NH4Cl, and water was added (200 mL), and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, then evaporated to give crude product which was purified via silica gel chromatography to give the title compound (68.9 g, 87% yield) as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:23]=[C:22]([CH3:32])[C:10]=1[O:11][C:12]1[C:13]2[NH:21][N:20]=[N:19][C:14]=2[N:15]=[C:16](Cl)[N:17]=1.[NH2:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1.FC(F)(F)CO>>[CH3:8][C:9]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:23]=[C:22]([CH3:32])[C:10]=1[O:11][C:12]1[C:13]2[NH:21][N:20]=[N:19][C:14]=2[N:15]=[C:16]([NH:33][C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=2)[N:17]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(-c2ccncc2)cc(C)c1Oc1nc(Cl)nc2nn[nH]c12
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccncc2)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2nn[nH]c12
Temperature: 90 °C

Procedure:
Trifluoroacetic acid (8 eq) is added to a suspension of 7-(2,6-dimethyl-4-(pyridin-4-yl)phenoxy)-5-chloro-1H-[1,2,3]triazolo[4,5-d]pyrimidine (1 eq) and 4-aminobenzonitrile (4 eq) in 2,2,2-trifluoroethanol (1 ml/0.1 mmol) in a sealed tube. The resulting mixture is heated at 90° C. for 3 days. The reaction is cooled to room temperature, concentrated to dryness and purified by silica gel chromatography.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][N:12]1[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][C:17]=2[N:16]=[CH:15][C:14]2=[CH:23][CH:24]=[CH:25][N:13]12.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH3:11][N:12]1[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][C:17]=2[NH:16][CH:15]([CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:14]2=[CH:23][CH:24]=[CH:25][N:13]12
Reactant: BrCCc1ccccc1
Reactant: CN1c2ccncc2N=Cc2cccn21
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1c2ccncc2NC(CCc2ccccc2)c2cccn21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2.8 g of magnesium turnings in 20 ml of diethyl ether and 20 ml of tetrahydrofuran was added 1 ml of 1,2-dibromoethanne followed by 13.94 ml of 2-bromoethylbenzene (dropwise). After initiating the reaction with external heat, the mixture was stirred at room temperature for one hour and then treated, dropwise, with a solution of 10.0 g of 5-methyl-5H-pyrido[3,4-f]-pyrrolo[1,2-b][1,2,5] triazepine in 100 ml of tetrahydrofuran. The reaction mixture was then stirred at room temperature for two hours, poured into an iced ammonium chloride solution, stirred for five minutes, and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrate was purified by means of high pressure liquid chromatography (silica gel; elution with ethyl acetate). Flash chromatography of the resultant oil (silica gel; elution with 10% methanol/dichloromethane) afforded a solid which was recrystallized from diethyl ether/ethyl acetate (10:1) to yield 1.25 g of 10,11-dihydro-5-methyl-10-(2-phenylethyl)-5H-pyrido-[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine, mp 92°-94° C.