Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.O[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.C(P(CCCC)(CCCC)=CC#N)CCC>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:20][CH2:19]3)[CH:10]=2)[O:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(CCn2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.500 g, 2.58 mmol), tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.593 g, 2.58 mmol) and 2-(tributylphosphoranylidene)acetonitrile (0.746 g, 3.09 mmol) were stirred together in toluene (10 ml) at 85° C. overnight. The reaction was concentrated and purified by normal phase chromatography to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].[CH3:11]I.[H-].[Na+].O>CS(C)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: CI
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(C)cc(C)c1C
Reaction time: 10 h

Procedure:
In 100 ml of dimethyl sulfoxide were dissolved 10 g of 2,3,5-trimethylphenol and 10.4 ml of methyl iodide and the solution was ice-cooled. To this solution was added 5.6 g of 60% oily sodium hydride and the mixture was stirred for 10 hours. Water was added and the resulting mixture was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off to give an oily substance. Yield 12.9 g (quantitative).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:12]=[C:11]([O:13][CH3:14])[C:10]3[O:15][C:16]4[C:21]([C@@:22]5([CH2:27][CH2:26][O:25][C:24]([NH2:28])=[N:23]5)[C:9]=3[CH:8]=2)=[CH:20][C:19]([NH2:29])=[CH:18][CH:17]=4)[CH2:3][CH2:2]1.[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1.CO>[NH2:28][C:24]1[O:25][CH2:26][CH2:27][C@:22]2([C:9]3[CH:8]=[C:7]([C:4]4[CH2:3][CH2:2][O:1][CH2:6][CH:5]=4)[N:12]=[C:11]([O:13][CH3:14])[C:10]=3[O:15][C:16]3[C:21]2=[CH:20][C:19]([NH:29][C:37](=[O:38])[C:34]2[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][N:35]=2)=[CH:18][CH:17]=3)[N:23]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: COc1nc(C2=CCOCC2)cc2c1Oc1ccc(N)cc1[C@@]21CCOC(N)=N1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc(C2=CCOCC2)cc2c1Oc1ccc(NC(=O)c3ccc(Cl)cn3)cc1[C@@]21CCOC(N)=N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.9 %

Procedure:
To a solution of (S)-3-(3,6-dihydro-2H-pyran-4-yl)-1-methoxy-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.080 g, 0.203 mmol) in THF/MeOH (20.3 mL) were added 5-chloro-2-pyridinecarboxylic acid (0.035 g, 0.223 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (0.066 g, 0.223 mmol). The resulting reaction mixture was stirred at RT for 2 h. The mixture was quenched with sat. NaHCO3 and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, concentrated, chromatographed on silica gel using 0-5% MeOH/DCM and repurified by HPLC to afford a white solid as (S)—N-(2′-amino-3-(3,6-dihydro-2H-pyran-4-yl)-1-methoxy-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-chloropicolinamide (0.0401 g, 0.075 mmol, 37.0% yield).
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24].[N:25]1[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1.C([BH3-])#N.[Na+].O>CO>[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH2:31][C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)[CH2:14]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24]
Reactant: O=Cc1ccncc1
Reactant: CCOC(=O)c1cn(C2CCCNC2)c2ccc(I)cc2c1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cn(C2CCCN(Cc3ccncc3)C2)c2ccc(I)cc2c1=O
Temperature: 23 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
Ethyl 6-iodo-4-oxo-1-(piperidin-3-yl)-1,4-dihydroquinoline-3-carboxylate hydrochloride (Intermediate 132, 500 mg, 1.08 mmol) was suspended in methanol (15 mL) then 4-pyridinecarboxaldehyde (520 μl, 5.4 mmol) and sodium cyanoborohydride (612 mg, 9.7 mmol) were added. The reaction was stirred at 23° C. for 16 h. The volume of the reaction was reduced by half and water (25 mL) was added. The suspension was extracted with 2:1 ethyl acetate: tetrahydrofuran (3×, 10 mL). The organic phases were combined, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was passed through a plug of silica gel (2 g) eluting with 10% methanol in dichloromethane to remove any remaining borohydride. The solid was then dried in a vacuum oven at 50° C. for 18 h to give 460 mg (82% yield) of ethyl 6-iodo-4-oxo-1-(1-(pyridin-4-ylmethyl)piperidin-3-yl)-1,4-dihydroquinoline-3-carboxylate as an off white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]2C(=O)OC(C)(C)[O:14][C:13]2=[O:21])[C:9]#[C:10][CH3:11])=[CH:4][CH:3]=1.O.Cl>C(C(CC)=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:9]#[C:10][CH3:11])[CH2:12][C:13]([OH:21])=[O:14])=[CH:6][CH:7]=1
Reactant: CC#CC(c1ccc(O)cc1)C1C(=O)OC(C)(C)OC1=O
Agent: Cl
Solvent: CCC(=O)CC
Solvent: O
Product: CC#CC(CC(=O)O)c1ccc(O)cc1
Yield: 100 %

Procedure:
To a 250 mL 3-necked RB flask fitted with magnetic stirrer was charged with 5-[1-(4-hydroxyphenyl)but-2-yn-1-yl]-2,2-dimethyl-1,3-dioxane-4,6-dione (5.8 g, 20.13 mmol) in diethyl ketone was added water (13 mL), the reaction mixture was heated to refluxed for 48 h. The RM was acidified with 1N HCl and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphat. Finally removal of solvent under reduced pressure to obtain the product (4.11 g, yield: 100.0%).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[O:18])[CH2:8]1.ClC1C=CC=C(C(OO)=[O:28])C=1.C(=O)([O-])O.[Na+].N([O-])=O.[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N+:14]([O-:28])=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[O:18])[CH2:8]1
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Cc1cc[n+]([O-])c2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
In benzene (15 ml) was dissolved 7-(2,5-dichlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.09 g), and to the solution was added m-chloroperbenzoic acid (0.963 g). The mixture was stirred at room temperature for 1 hour, and to the mixture were added ethyl acetate (150 ml), saturated sodium hydrogen carbonate solution (200 ml) and sodium nitrite(200 mg). The mixture was shaken, and the separated upper layer was washed with water and concentrated under reduced pressure. The residue was washed with a mixture of isopropylether and ethyl acetate (2:1) to give 7-(2,5-dichlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one-1-oxide (1.04 g) as yellow crystals.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1)[CH2:3][C:4]#[N:5].[CH:15](=O)[CH2:16][CH2:17][CH2:18][CH3:19]>>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=1)[CH2:3][C:4]#[N:5]
Reactant: N#CCC(O)c1cccc([N+](=O)[O-])c1
Reactant: CCCCC=O
Product: CCCCCNc1cccc(C(O)CC#N)c1

Procedure:
Hydrogenation of nitrobenzene 11 (0.8 g, 4.2 mmol) and pentanal (0.45 ml, 4.2 mmol) following method described in Example 11 gave 3-hydroxy-3-(3-(pentylamino)phenyl)propanenitrile as a light yellow oil. Yield (0.90 g, 77%).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([C:18]2[CH:27]=[C:26]3[C:21]([C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][S:25]3)=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1.[OH-].[K+].C1COCC1.Cl>C(O)C.O>[CH3:28][C:22]1([CH3:29])[C:21]2[C:26](=[CH:27][C:18]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][O:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:30])=[O:2])=[CH:9][CH:8]=3)=[CH:19][CH:20]=2)[S:25][CH2:24][CH2:23]1
Reactant: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)SCCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC(COc1ccc(C(=O)O)cc1)c1ccc2c(c1)SCCC2(C)C
Temperature: 45 °C
Yield: 89 %

Procedure:
A solution of 4-[2-(4,4-dimethyl-thiochroman-7-yl)-heptyloxy]-benzoic acid methyl ester (0.715 g, 1.68 mmole) in 12 mL of ethanol was treated with a solution of potassium hydroxide (1.9 g) in 7.5 mL of water. THF (5 mL) was added and the mixture was heated at 45° C. for two hours, diluted with 30 mL of water and the pH adjusted to 2.0 with concentrated HCl. The mixture was extracted with three portions of 30 mL of ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a pale yellow foam. The product was purified by trituration in pentane, to yield 0.617 g of 4-[2-(4,4-dimethyl-thiochroman-7-yl)-heptyloxy]-benzoic acid as an off-white solid. M.p.: 123.0-123.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:18]([O-])=O.[Na+].[Sn](Cl)[Cl:23]>O.Cl>[ClH:23].[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)[NH2:18]
Reactant: Cl[Sn]Cl
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: NNc1ccc(CC(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.1 h

Procedure:
15.1 g (10.0 mmol) 4-aminophenylacetic acid are placed in a solution of 10.6 g (10.0 mmol) sodium carbonate in 100 ml of water. The mixture is cooled to 0° C., then 6.9 g (10.0 mmol) sodium nitrite in 50 ml of water are added. This mixture is added dropwise to 100 ml of conc. hydrochloric acid while being cooled, then stirred for 0.1 hours. 45.1 g (20.0 mmol) tin(II)-chloride in 40 ml of conc. hydrochloric acid are added dropwise with vigorous stirring, during which time a precipitate is formed. The reaction mixture is stirred for 1 hour at ambient temperature, then suction filtered. The precipitate is washed with water and dried.
Reaction SMILES: CN(CCN(C)C)C.[CH2:9]([O:11][C:12](=[O:21])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1)[CH3:10].N#N.[Li]CCCC.[I:29]I>C1COCC1>[CH2:9]([O:11][C:12](=[O:21])[NH:13][C:14]1[C:19]([I:29])=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1)[CH3:10]
Reactant: CCOC(=O)Nc1cccc(F)n1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)Nc1nc(F)ccc1I
Temperature: -78 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
28.6 ml (0.18 mol) TMEDA was added to a solution of compound 56 (13.41 g, 72.9 mmol) dissolved in 300 ml anhydrous THF. The mixture was cooled to −78° C. (under N2). To the stirred reaction mixture was added 76 ml (2.5 M n-BuLi) and the mixture was stirred for 2 hours at −78° C. After the addition of I2(48 g, 0.17 mol), the mixture was stirred for 1 hour at −78° C. The reaction mixture was subsequently quenched with a saturated Na2S2O3 solution and allowed to warm to ambient temperature. Ethyl acetate was added to the mixture and the organic layer was washed with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether/PE (1/3) to 1/1) and afforded (6-fluoro-3-iodo-pyridin-2yl)-carbamic acid ethyl ester (57) (amorphous, 15.86 g, 70%). 1H-NMR (400 MHz, CDCl3): δ 8.07 (bt, J=8 Hz, 1H), 7.24-7.14 (bs, 1H), 6.49 (dd, J=8 Hz, 3 Hz, 1H), 4.29 (q, J=8 Hz, 2H), 1.35 (t, J=8 Hz, 3H). (TLC diethyl ether/PE 1/1 Rf 0.27).
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH:6]2[C:19](=[O:20])[N:8]3[CH:9]([C:15]([O:17][CH3:18])=[O:16])[C:10]([CH3:14])([CH3:13])[S:11](=O)[C@H:7]23)[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.S(Cl)(Cl)=[O:28]>C(Cl)(Cl)(Cl)Cl>[C:4]1(=[O:21])[N:5]([CH:6]2[C:19](=[O:20])[N:8]3[CH:9]([C:15]([O:17][CH3:18])=[O:16])[C@:10]([CH3:14])([OH:28])[CH2:13][S:11][C@H:7]23)[C:1](=[O:26])[C:2]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:3]12
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C1N2C(=O)C(N3C(=O)c4ccccc4C3=O)[C@H]2S(=O)C1(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C1N2C(=O)C(N3C(=O)c4ccccc4C3=O)[C@H]2SC[C@@]1(C)O

Procedure:
A solution of methyl 6-phthalimido-2,2-dimethylpenam-3-carboxylate-1-oxide (2.25 g., 6 mmol) and thionyl chloride (0.47 ml., 6.5 mmol) in 90 ml. dry carbon tetrachloride was refluxed for 1 hour, cooled and evaporated in vacuo to dryness. An nmr spectrum of the crude product showed a 2:3:3 mixture of methyl 7-phthalimido-3α-methyl-3β-hydroxycepham-4-carboxylate, methyl 6-phthalimido-2β-chloromethylpenam-2α-methyl-3-carboxylate, and methyl 6-phthalimido-2α-chloromethylpenam-2β-methyl-3-carboxylate, respectively. The products were separated by chromatography on silica gel and fully characterized by spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:14][O:15][C:16](=[O:31])[C@H:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH2:21].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CC1C=CC=CC=1)N>CO.C(Cl)(Cl)Cl>[CH3:14][O:15][C:16](=[O:31])[C@H:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH:21][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure C and using 3,5-difluorophenylacetic acid (Oakwood) and N-(L-alaninyl)-L-phenylalanine methyl ester hydrochloride (prepared from N-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester hydrochloride (Sigma) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp=173-175° C.). The reaction was monitored by tlc (Rf=0.6 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 4% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[C:8]([C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)=[CH:7][N:6]=1.Cl[C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[S:34](C1C=CC([N+]([O-])=O)=CC=1Cl)(=[O:36])=[O:35].CCN(C(C)C)C(C)C>CC(N(C)C)=O.C(OCC)(=O)C>[NH:20]1[CH:21]=[CH:22][N:23]=[C:19]1[C:8]1[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)=[N:10][C:5]([NH:4][CH2:3][CH2:2][NH:1][S:34]([C:26]2[CH:25]=[CH:30][C:29]([N+:31]([O-:33])=[O:32])=[CH:28][CH:27]=2)(=[O:35])=[O:36])=[N:6][CH:7]=1
Reactant: N#Cc1ccc(-c2nc(NCCN)ncc2-c2ncc[nH]2)cc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2Cl)c(Cl)c1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2nc(NCCNS(=O)(=O)c3ccc([N+](=O)[O-])cc3)ncc2-c2ncc[nH]2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 56.2 %

Procedure:
A mixture of 4-{2-[(2-aminoethyl)amino]-5-imidazolylpyrimidin-4-yl}benzenecarbonitrile (30 mg, 0.098 mmol), chloro(4-nitrophenyl)sulfone (22 mg, 0.1 mmol), and Hünig's base (70 uL, 0.4 mmol) in DMA (500 uL) were heated to 80° C. After stirring for 12 hours, the reaction was diluted with ethyl acetate (10 ml) and extracted with sat. aq. NaHCO3 (2×5 ml), water (3×5 ml), brine (5 ml), dried with Na2SO4, filtered, and concentrated. The resulting product, 4-{5-imidazolyl-2-[(2-{[(4-nitrophenyl)sulfonyl]amino}ethyl)amino]pyrimidin-4-yl}benzenecarbonitrile weighing 27 mg (56% yield) was approximately 90% pure by LCMS and HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[N:12]=[CH:11][CH:10]=[N:9]1.[H][H].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(OCC)(=O)C.CO.[Ni].O>[F:1][C:2]1[CH:3]=[C:4]([NH:13][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:5]=[CH:6][C:7]=1[N:8]1[N:12]=[CH:11][CH:10]=[N:9]1
Reactant: [H][H]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(-n2nccn2)c(F)c1
Agent: [Ni]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1ccc(-n2nccn2)c(F)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
A solution of 6.0 g (28.82 mmol) of 3-fluoro-1-nitro-4-(2H-1,2,3-triazol-2-yl)benzene in 150 mL ethyl acetate and 25 mL methanol was treated with 750 mg of W-2 Raney Nickel. The mixture was hydrogenated on a Paar shaker under 45 psi hydrogen pressure for 24 h. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was dissolved in 150 mL acetone, treated with 72 mL saturated sodium bicarbonate solution, followed by cooling to 0° C. The mixture was treated with 6.15 g (5.14 mL, 36.08 mmol) of benzyl chloroformate, followed by stirring at 0° C. for 1 h, and then warming to ambient temperature for 3 h. The mixture was diluted with 500 mL water and 400 mL ethyl acetate. The aqueous phase was washed with 250 mL ethyl acetate and the combined organic layers were extracted with 300 mL saturated NaCl solution. Drying (Na2SO4) and concentration in vacuo afforded an amber oil which was recrystallized from hot chlorform-hexane to afford 7.52 g (84%) of the title compound as a white solid, mp 99.5-101° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([F:8])[CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.[OH-].[Na+]>CO>[CH2:9]([N:5]1[CH2:6][C@@H:7]([F:8])[C@@H:3]([CH2:2][NH:1][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:4]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC[C@H]1CN(Cc2ccccc2)C[C@H]1F
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: F[C@@H]1CN(Cc2ccccc2)C[C@@H]1CNCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3S,4S)-3-Aminomethyl-1-benzyl-4-fluoropyrrolidine (186 mg) was dissolved in methanol (4 mL). To this solution, molecular sieves 4A (80.0 mg) and then benzaldehyde (90.8 μL) were added. The mixture was stirred at room temperature for 1 hour, followed by addition of a borane/pyridine complex (90.2 μL) and further stirring at room temperature for 3 hours. Subsequently, 6 mol/L hydrochloric acid (1.5 mL) was added and the mixture was stirred for 1 hour. A 6 mol/L aqueous solution of sodium hydroxide was then added to make the mixture basic. The mixture was extracted with diethyl ether (3×10 mL). The diethyl ether layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane:ethyl acetate=4:1) to give (3S,4S)-1-benzyl-3-benzylaminomethyl-4-fluoropyrrolidine as a pale brown oil (179 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][C:26]4[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: N#Cc1cc(CCl)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1ccnc(C#N)c1
Temperature: 80 °C
Yield: 4 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (600 mg, 2 mmol), (prepared as described for the starting material in Example 24), 4-chloromethyl-2-cyanopyridine hydrochloride (620 mg, 3 mmol) and potassium carbonate (1.0 g 7 mmol) in DMF (8 ml) was heated at 80° C. for 30 minutes. The mixture was allowed to cool, poured into water and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and the solvent removed by evaporation and azeotroped with toluene. The residue was triturated with ethyl acetate/hexane, the solid product collected by filtration and purified by column chromatography eluting with ethyl acetate and further chromatography eluting with methylene chloride/methanol (99/1). The purified product was recrystallised from ethyl acetate/hexane to give 4-(4-chloro-2-fluoroanilino)-7-((2-cyano-4-pyridyl)methoxy)-6-methoxyquinazoline (35 mg, 4%).
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:7]=1[O:15][CH3:16]>C(O)C>[CH3:16][O:15][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=1[CH2:5][C:1]#[N:2]
Reactant: COc1cccc([N+](=O)[O-])c1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: COc1cccc([N+](=O)[O-])c1CC#N
Yield: 61 %

Procedure:
Sodium cyanide (165 mg, 3.36 mmol) was added to a solution of 2-(bromomethyl)-1-methoxy-3-nitro-benzene (680 mg, 2.56 mmol) in ethanol (5 mL) and the mixture was heated at reflux for 16 h. The solvent was removed in vacuo, water (30 mL) was added and the mixture was extracted with dichloromethane (25 mL). The organic phase was washed with water (2×20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel (100-200 mesh) using 8% ethyl acetate in petroleum ether to afford 2-(2-methoxy-6-nitro-phenyl)acetonitrile (300 mg, 61%).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[N:14]=[C:13]([CH:16]=[O:17])[NH:12][C:11]=3[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O.O>CN(C=O)C>[CH3:24][N:12]1[C:11]2[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:9][CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:15]=2[N:14]=[C:13]1[CH:16]=[O:17]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1nc2c(-c3ccccc3)ccc(-c3ccccc3)c2[nH]1
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: Cn1c(C=O)nc2c(-c3ccccc3)ccc(-c3ccccc3)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3.3 g (11.07 mmol) 4,7-diphenyl-1H-benzimidazole-2-carbaldehyde, 8.60 g (62.0 mmol) anhydrous K2CO3 and 1.1 ml (11.07 mmol) dimethyl sulfate in 30 ml anhydrous DMF was stirred at room temperature for 30 min. The reaction mixture was then poured into 300 ml water, stirred for 10 min and extracted with dichloromethane (3×100 ml). The combined extracts were washed with water (3×50 ml) and dried over anhydrous Na2SO4. The solvent was evaporated to give an yellow oil which was triturated with 20 ml methanol at 0° C., filtered while cold, washed with cold (0° C.) methanol (2×10 ml) and dried under reduced pressure. Yield 3.1 g (89.6%). 1H NMR (250 MHz, CDCl3), δ, ppm: 3.74 (s, 3H), 7.47 (m, 10H) 8.04 (d, JHH=7.8 Hz, 2H), 10.1 (s, 1H).