Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([CH:28]([O:31][CH3:32])[O:29][CH3:30])[CH:20]=1>CCCCCC.CN(C=O)C>[CH3:30][O:29][CH:28]([O:31][CH3:32])[C:21]1[CH:20]=[C:19]([C:9]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][CH2:8]2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10]#[N:11])[CH:24]=[CH:23][C:22]=1[N+:25]([O-:27])=[O:26]
Reactant: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: N#CC(c1ccccc1)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(OC)c1cc(C(C#N)(c2ccccc2)N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
NaH (0.975 mol) was washed with hexane. After the hexane was decanted off, the NaH was stirred in DMF (1950 mL) at room temperature. Morpholin-4-yl-phenyl-acetonitrile (0.70 mol) in DMF (300 mL) was added dropwise under N2 gas. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled in an ice bath and 4-chloro-2-dimethoxymethyl-1-nitrobenzene (0.86 mol) in DMF (150 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 2 hours and at room temperature overnight. The reaction mixture was poured on ice/water and extracted with diisopropyl ether. The organic layer washed with water, dried (MgSO4) and evaporated to yield the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[N:10]([CH3:35])[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH2:33][CH3:34])[N:12]=2.Cl[CH2:38][C:39]([NH2:41])=[O:40].CCN(CC)CC>C(Cl)Cl>[CH2:33]([C:25]1[N:24]([C:13]2[N:12]=[C:11]3[C:16]([N:17]=[C:9]([CH2:8][N:3]4[CH2:4][CH2:5][N:6]([CH2:38][C:39]([NH2:41])=[O:40])[CH2:7][C:2]4([CH3:1])[CH3:36])[N:10]3[CH3:35])=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:14]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH3:34]
Reactant: NC(=O)CCl
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCNCC3(C)C)n(C)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(CC(N)=O)CC3(C)C)n(C)c2n1
Reaction time: 84 h
Yield: 47.6 %

Procedure:
A mixture of 8-(2,2-dimethylpiperazin-1-ylmethyl)-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (120 mg, 0.25 mmol), 2-chloroacetamide (50 mg, 0.54 mmol) and NEt3 (50 μL, 0.36 mmol) in DCM (5 mL) was allowed to stir at r.t. for 5 h before further 2-chloroacetamide (100 mg, 1.07 mmol) and NEt3 (100 μL, 0.72 mmol) was added. The resulting mixture was allowed to stir for 84 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-5%) affording 717 (65 mg, 49%). LCMS (method I): RT 2.54 min, [M+H]+ 547.2. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.99 (1 H, m), 7.77-7.74 (1 H, m), 7.32-7.22 (2 H, m), 6.95 (1 H, brd s), 5.43 (1 H, brd s), 4.34 (4 H, brd s), 3.90 (3 H, s), 3.86 (6 H, t, J=4.76 Hz), 3.35 (2 H, q, J=7.48 Hz), 2.96 (2 H, s), 2.62-2.45 (4 H, m), 2.38 (2 H, s), 1.45 (3 H, t, J=7.48 Hz), 1.25 (6 H, s)
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].O=[C:12]([CH3:24])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.N1CCCCC1.O>C1C=CC=CC=1>[CH3:24][C:12]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[NH:10][C:1](=[O:9])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4]1
Reactant: NC(=O)c1ccccc1O
Reactant: CC(=O)COc1ccc([N+](=O)[O-])cc1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: O
Product: CC1(COc2ccc([N+](=O)[O-])cc2)NC(=O)c2ccccc2O1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
To a stirred mixture of salicylamide (6.85 g, 50 mmol) and 4-[2-oxo-propoxy]nitrobenzene (9.75 g, 50 mmol) in benzene (500 mL) was added piperidine (0.52 mL, 5 mmol). The reaction mixture was immersed in a pre-heated oil bath (˜100° C.) and refluxed for 10 h with continuous removal of water using Dean-Stark water separator. The reaction mixture was cooled to room temperature End the precipitated brown coloured solid was filtered, washed with benzene and dried to afford the title compound (13.5 g, 86%).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])(O)=O.[Na+].[CH3:25][O:26][C:27](Cl)=[O:28].Cl>O1CCOCC1>[CH3:25][O:26][C:27]([NH:16][CH:15]([CH2:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:17]([OH:19])=[O:18])=[O:28]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])c2ccccc12)C(=O)O
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)NC(Cc1ccc([N+](=O)[O-])c2ccccc12)C(=O)O
Reaction time: 3 h

Procedure:
A mixture of 3-(4-nitro-1-naphthyl)alanine (0.65 g, 2.5 mmol), aqueous NaHCO3 (5 mL) and methylchloroformate (230 uL, 3 mmol, 1.2 eq) in dioxane (10 mL) was stirred for 3 hours, acidified to a ph <3 with aqueous 2N HCl and extracted with ethyl acetate. The combined organic layers was washed with water (1×25 mL), brine(1×25 mL), dried (MgSO4), filtered and concentrated under reduce pressure to provide the titled compound. MS (APCI(+)) m/e 319 (M+H)+.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:19])[CH:16]=3)[CH2:11]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1.Br.C(O)(=O)CC>O>[Cl:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][NH:10][CH2:18]2
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccc(Cl)cc3C2)cc1
Agent: Br
Solvent: O
Solvent: CCC(=O)O
Solvent: Oc1ccccc1
Product: Clc1ccc2c(c1)CNC2
Yield: 51.3 %

Procedure:
1.0 g of 2-(p-toluenesulfonyl)-5-chloroisoindoline and 1.0 g of phenol were added to a mixture of 8 ml of 48% hydrobromic acid and 1.4 ml of propionic acid, and the mixture was refluxed for 6 hours. The resultant reaction mixture was diluted with 10 ml of water and extracted 2 times with 50 ml of ether. The water layer was basified with aqueous sodium hydroxide solution and extracted with 50 ml of ether 4 times. The extract was concentrated and the residue was purified by vacuum distillation (bath temperature: 130°-140 ° C., pressure: 7 mmHg) to obtain 256 mg of 5-chloroisoindoline.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][CH:9]([C:12](OCC)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[BH4-].[Li+].B(OC)(OC)OC>O1CCCC1.O>[CH:1]1([C:4]([N:6]2[CH2:7][CH2:8][CH:9]([CH2:12][OH:13])[CH2:10][CH2:11]2)=[O:5])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1CCN(C(=O)C2CC2)CC1
Agent: COB(OC)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(C1CC1)N1CCC(CO)CC1
Reaction time: 48 h
Yield: 63.7 %

Procedure:
A solution of 1-(cyclopropylcarbonyl)-4-carboethoxy piperidine (35 g, 156 mmol) in anhydrous tetrahydrofuran (350 mi) was stirred at ambient temperature under a nitrogen atmosphere. A solution of lithium borohydride in tetrahydrofuran (2M, 78 mL, 156 mmol) was added dropwise. Trimethyl borate (1.77 mL, 15.7 mmol) was added, then the reduction mixture was stirred for about 48 hours. Water was added dropwise with vigorous stirring until the vigorous gas evolution ceased. The mixture was diluted twofold with water and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Vacuum distillation (bp 165° C., 0.5 mm Hg) gave a clear, colorless liquid (18.2 g): IR (neat): 3410 (br s), 3094 (w), 3008 (s), 2918 (s), 2858 (s), 1738 (m), 1613 (s), 1448 (s), 1375 (s), 1316 (s); 1H-NMR: 4.7-4.5 (m, 1H), 4.4-4.1 (m, 1H), 3.6-3.4 (m, 2H), 3.2-2.5 (m, 3H), 2.0-1.7 (m, 4H), 1.4-1.1 (m, 1H), 1.0-0.8 (m, 2H), 0.8-0.65 (m, 2H); HRMS: Calcd for C10H17NO2 : 183.1259; Found: 183.1250; Anal.: Calcd for C10H17NO2 : C, 65.54, H, 9.35, N, 7.64; Found: C, 65.83, H, 9.43, N, 7.50.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:27])[C:17]#[C:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)#[C:7][CH3:8].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]#[C:17][C:16](=[O:27])[NH:15][C:12]2[CH:11]=[CH:10][C:9]([C:6]#[C:7][CH3:8])=[CH:14][CH:13]=2)=[CH:24][CH:23]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC#Cc1ccc(NC(=O)C#Cc2ccc(CO)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#Cc1ccc(NC(=O)C#Cc2ccc(COS(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.14 mL (1.8 mmol) of methanesulfonic acid chloride is slowly added dropwise at ambient temperature to a solution of 0.5 g (1.72 mmol) of 3-(4-hydroxymethylphenyl)propynoic acid (4-prop-1-ynylphenyl)amide and 0.49 mL (3.6 mmol) of triethylamine in 20 mL of dichloromethane and the reaction mixture is stirred for 2 hours at ambient temperature. It is extracted three times with water and the organic phase is dried over sodium sulfate. The solvent is distilled off and the residue is stirred with diisopropyl ether. Yield: 0.48 g (75.6% of theory); C20H17NO4S (M=367.42); calc.: molecular ion peak (M+H)+: 368; found: molecular ion peak (M+H)+: 368; Rf value: 0.48 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[CH3:24][C:25]1[CH:26]=[C:27]([SH:31])[CH:28]=[CH:29][CH:30]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:4][C:3](=[O:23])[C:2]=1[S:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=1
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: Cc1cccc(S)c1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cc1cccc(SC2=C(O)CC(CCc3ccccc3)(c3ccccc3)OC2=O)c1

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 2.2 mmol of 3-methylbenzenethiol, and 2.2 mmol of piperidine in 30 mL of dichloromethane. The crude product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 68°-70° C.). 1H NMR (DMSO-d6) δ2.06 (s, 3H), 2.18-2.36 (m, 3H), 2.60 (m, 1H), 3.38 (2H+H2O), 6.26 (d, 1H), 6.46 (s, 1H), 6.75 (m, 1H), 6.83 (t, 1H), 7.15 (m, 3H), 7.24 (m, 2H), 7.45 (m, 5H).
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.[C:15](=[S:17])=[S:16].[C:18]([OH:25])(=[O:24])/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22]>O1CCCC1>[C:2]1([CH2:1][C:15]([S:17][CH:20]([CH2:19][C:18]([OH:25])=[O:24])[C:21]([OH:23])=[O:22])=[S:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: S=C=S
Reactant: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)CC(SC(=S)Cc1ccccc1)C(=O)O
Reaction time: 0.25 h
Yield: 33 %

Procedure:
A solution of benzylmagnesium chloride in ether (1.0 M, 200 mL, 0.20 mol) was added to dry tetrahydrofuran (200 mL) under nitrogen. Carbon disulfide (20 mL, 25 g, 0.33 mol) was then added slowly with stirring. After 15 min, fumaric acid (23.2 g, 0.20 mol) was added and the ether was mostly removed by distillation. More tetrahydrofuran (100 mL) was added, and the solution was heated under reflux for 14 h. The reaction was cooled and poured into ether (1 L), then extracted with water (3×100 mL) followed by saturated sodium bicarbonate (5×200 mL). The bicarbonate extracts were combined and extracted with ether (2×100 mL), then acidified slowly to pH<1 with concentrated hydrochloric acid, and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water (200 mL) and saturated sodium chloride (100 mL), and then evaporated. The crude mixture was crystallized by trituration with 50:50 ether/light petroleum (100 mL). The solid was collected and placed in water (150 mL) at 65° whereupon most of the solid dissolved. The mixture was then quickly cooled in an ice bath and the resulting crystals were collected and washed with cold water (3×33 mL). The solid was then dissolved in a mixture of water (150 mL), ethyl acetate (600 mL) and tetrahydrofuran (50 mL). The water was removed and the organic phase was washed with water (3×100 mL), saturated sodium chloride (100 mL), dried over magnesium sulfate, and evaporated to give the title compound (21) as a yellow solid (18.4 g, 33%).
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:30]3[N:29]=[C:27]([NH2:28])[NH:26][C:24](=[O:25])[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:31])[C@@H:16]1[OH:32])([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2].S(OC)(O[CH3:37])(=O)=O>>[CH3:37][N:22]1[C:23]2[C:24]([N:26]=[C:27]([NH2:28])[NH:29][C:30]=2[N+:20]([C@@H:18]2[O:19][C@H:15]([CH2:14][O:13][P:1]([O:4][P:5]([O:8][P:9]([OH:11])([OH:12])=[O:10])([OH:7])=[O:6])([OH:2])=[O:3])[C@@H:16]([OH:32])[C@H:17]2[OH:31])=[CH:21]1)=[O:25].[CH2:30]([NH+:20]([CH2:18][CH3:17])[CH2:21][CH3:37])[CH3:23]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: COS(=O)(=O)OC
Product: CC[NH+](CC)CC
Product: Cn1c[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c2[nH]c(N)nc(=O)c21

Procedure:
Guanosine triphosphate (GTP) (300 mg, 0.5 mmol) was methylated using dimethyl sulfate according to the procedure of Hendler et al. ((1970) Biochemistry 9, 414) with modification. The reaction mixture was neutralized and the product purified on a DEAE Sephadex A-25 (Sephadex is a registered trademark of Pharmacia Fine Chemicals, Inc.) column (3×50 cm). The column was washed with water and then eluted with a linear gradient of 0 to 0.8M triethylammonium bicarbonate (TEAB), pH 7.8 (2 l total volume). Twenty-milliliter fractions were collected and assayed spectrophometrically at 260 nm. m7GTP eluted at approximately 0.4M, and the peak was pooled and repeatedly evaporated to dryness from water vacuo. m7GTP-triethylammonium salt was obtained as a white solid (0.25 mmol, 50% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[CH3:24][NH2:25].O>CS(C)=O>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5]([NH:25][CH3:24])=[N:6][CH:7]=1
Reactant: CN
Reactant: Fc1cccc(CNc2cccc(-c3cc(F)ncc3Cl)n2)c1
Solvent: CS(C)=O
Solvent: O
Product: CNc1cc(-c2cccc(NCc3cccc(F)c3)n2)c(Cl)cn1

Procedure:
A mixture of 5′-chloro-2′-fluoro-N-(3-fluorobenzyl)-2,4′-bipyridin-6-amine (Intermediate B) (15 mg, 0.045 mmol) was added DMSO (0.4 ml) and methyl amine 40% in water (200 μl, 2.293 mmol) in a microwave tube was microwaved at 145° C. for 900 seconds and the reaction progress was followed by LCMS. Most of the amine was removed under vacuum, 0.5 ml of DMSO was added, filtered and purified by prep LC. After lyapholization 13.9 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 343.0 (MH+), retention time=0.67 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 2.97 (s, 3H) 4.62 (s, 2H) 6.81 (d, J=8.50 Hz, 1H) 6.91-7.02 (m, 3H) 7.09 (d, J=9.96 Hz, 1H) 7.17 (d, J=7.62 Hz, 1H) 7.27-7.39 (m, 1H) 7.69 (dd, J=8.50, 7.33 Hz, 1H) 8.03 (s, 1H).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[C@@H:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:2]2.C(N(CC)CC)C.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:2]2[C@H:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C@@H:4]3[CH2:7][C@H:1]2[CH2:6][CH2:5]3)(=[O:30])=[O:29])=[CH:26][CH:27]=1
Reactant: CCOC(=O)[C@H]1N[C@@H]2CC[C@H]1C2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)N1S(=O)(=O)c1ccc(OC)cc1
Yield: 71.6 %

Procedure:
To a solution of ethyl (1R, 3S, 4S)-2-azabicyclo[2.2.1]heptane-3-carboxylate (0.724 g, 4.28 mmol) in chloroform (8 ml) was added triethylamine (0.60 ml, 4.28 mmol) and 4-methoxybenzenesulfonyl chloride (0.973 g, 4.71 mmol) while being cooled with ice. After a reaction at room temperature for 4 hours, the reaction mixture was washed with 1N hydrochloric acid, saturated sodium bicarbonate water and saturated brine successively, and dried over magnesium sulfate. The solvent was evaporated and the residue was recrystallized (hexane/ethyl acetate), to give ethyl (1R, 3S, 4S)-2-[(4-methoxyphenyl)sulfonyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate (1.04 g, 71%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:26]([O:28]CC)=O)=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:14][CH:15]=1.O.[NH2:32][NH2:33]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:26]([NH:32][NH2:33])=[O:28])=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:14][CH:15]=1
Reactant: NN
Reactant: CCOC(=O)c1cc(OCc2ccc(OC)cc2)ccc1-c1cc(OC)ccc1F
Solvent: O
Solvent: CCO
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(=O)NN)c2)cc1

Procedure:
A solution of ethyl 2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)-[1,1′-biphenyl]-2-carboxylate (2.04 g) and hydrazine monohydrate (4.82 mL) in ethanol (20 mL) was stirred at 95° C. for 12 days. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.43 g) as a white solid.
Reaction SMILES: [NH2:1][C:2](SC)=[C:3]([N:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH:32][C:33]([NH:35][CH2:36]CC)=O)(=[O:31])=[O:30])=[CH:19][CH:18]=1)[C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])[C:4]([O:6][CH2:7][CH3:8])=[O:5].O.[CH3:42]OC>C(O)CO.S(=O)(=O)(O)O>[C:2]([CH:3]([N:9]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([N:32]=[CH:33][N:35]([CH3:36])[CH3:42])(=[O:30])=[O:31])=[CH:21][CH:22]=1)[C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:1]
Reactant: COC
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)NCCC)cc1)C(C(=O)OCC)=C(N)SC
Agent: O=S(=O)(O)O
Solvent: OCCO
Solvent: O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2S(=O)(=O)N=CN(C)C)cc1)C(C#N)C(=O)OCC
Reaction time: 1 h

Procedure:
200 mg of the product of Stage C of Example 3 were dissolved in 5 ml of dimethyl ether of ethylene glycol and 1 ml of concentrated sulfuric acid was added at ambient temperature. After stirring for one hour, water was added while cooling in an ice bath. Extraction was carried out with dichloromethane and the organic phases .were washed and dried. The solvent was evaporated under reduced pressure to obtain 180 mg of crude product which was crystallized from ethyl acetate to obtain 140 mg of the expected product melting at 130°-132° C.
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH2:14])[C:8]([O-:10])=[O:9].C([O-])([O-])=O.[Na+].[Na+]>O>[NH2:1][C:2]1[NH:4][C:5]2[CH:6]=[C:7]([C:8]([OH:10])=[O:9])[CH:11]=[CH:12][C:13]=2[N:14]=1
Reactant: N#CBr
Reactant: Nc1ccc(C(=O)[O-])cc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Nc1nc2ccc(C(=O)O)cc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of cyanogen bromide (5M, 1.44 mL, 7.22 mmol) was slowly added to a suspension of 3,4-diaminobenzoate (1.0 g, 6.02 mmol) in water (10 mL). The mixture was stirred at room temperature for 24 hours. An aqueous solution of Na2CO3 (10%) was added slowly until the product had precipitated as a brown solid (890 mg).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][N:3]=1.[H-].[Na+].Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.CO.C(Cl)Cl>CN(C)C=O>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([NH:1][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:3][O:4][C:5]=2[CH:10]=1
Reactant: COc1ccc2c(N)noc2c1
Reactant: ClCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(NCCN3CCOCC3)noc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
To a solution of 3-amino-6-methoxy-1,2-benzisoxazole (5.5 g) in N,N-dimethylformamide (DMF) (100 ml) was added sodium hydride (1.2 g) under nitrogen. The reaction was stirred one hour at ambient temperature. A solution of 4-(2-chloroethyl)morpholine (5.4 g) in DMF (50 ml) was added to the reaction and heated to 125° C. for one hour. TLC (5% MeOH/DCM) revealed the absence of starting material. The reaction was quenched with water (1 l) and extracted with EtOAc (2 l). The organic layer was washed with water, dried (MgSO4), and concentrated in vacuo. Flash column chromatography (silica gel) eluting with 3-4% MeOH/DCM afforded the product (4.5 g), m.p. 85-86° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][C:8](=O)[C:7]=2[CH:12]=1.[C:13]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:15])=[O:14].[C:36]1(C)C=CC=C[CH:37]=1>>[CH2:36]([O:15][C:13](=[O:14])[CH2:16][C:8]1[C:7]2[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:10][CH:9]=1)[CH3:37]
Reactant: O=C(O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2c(c1)C(=O)CO2
Reactant: Cc1ccccc1
Product: CCOC(=O)Cc1coc2ccc(OC)cc12

Procedure:
A mixture of 5-methoxy-benzofuran-3 (2H)-one (1.64 g, 10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixture was concentrated and loaded over a silica-gel column. The column was eluted with hexane (500 ml) and then with 25% ethyl acetate. The product, ethyl(5-methoxy-1-benzofuran-3-yl)acetate, was obtained as a white oil. Yield: 1.6 g (68%); (M+H): 235.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14]2)[N:3]=1.SC[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14]2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:7]=1
Reactant: SCCc1ccccn1
Reactant: Cc1cnn(-c2nc(N)nc(S(C)=O)c2C#N)c1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cnn(-c2nc(N)nc(SCCc3ccccn3)c2C#N)c1

Procedure:
From 2-amino-4-methanesulfinyl-6-(4-methyl-pyrazol-1-yl)-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 338 (M+H+, 100).