Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)Cl.[Br:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=1[O:14][CH3:15].[C:16](O)(=[O:21])[CH2:17][C:18](O)=[O:19]>O>[Br:6][C:7]1[CH:13]=[C:12]2[C:10](=[CH:9][C:8]=1[O:14][CH3:15])[NH:11][C:18](=[O:19])[CH:17]=[C:16]2[OH:21]
Reactant: O=C(O)CC(=O)O
Reactant: COc1cc(N)ccc1Br
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2[nH]c(=O)cc(O)c2cc1Br
Temperature: 105 °C
Reaction time: 0.08 h
Yield: 65.5 %

Procedure:
POCl3 (5.07 mL, 54.4 mmol) was added to a mixture of 4-bromo-3-methoxyaniline (10 g, 49.5 mmol) and malonic acid (5.15 g, 49.5 mmol) with thorough mixing, and the mixture was then heated to 105° C. After 5 minutes, the reaction began to bubble vigorously, and eventually formed a hard foam; heating was continued for 1 hour. After cooling, water (200 mL) was added, and the mixture was stirred for 30 minutes. The solid was filtered off and washed with water. 2N NaOH (300 mL) was added to the solid, and stirring was continued overnight. The remaining solid was filtered off; EtOH (5 mL) was then added to the filtrate; and the basic layer was then acidified with concentrated HCl to pH 2. The resulting solid was then filtered off, washed with water. The solid was then transferred to a flask, and the remaining water was removed by stripping off EtOH (200 mL×2). The solid was then further dried under high vacuum for 15 hours to yield 8.75 g (66%) of the title compound as an off-white solid. LRMS ESI+ (M+H)+ 270.2/272.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[OH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:3][C:4]2=[O:18])=[CH:11][CH:12]=1
Reactant: BrCc1ccncc1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1cc(OCc2ccncc2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 400 mg (1.63 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 20 mL DMF is added 0.45 g (1.79 mmol) 4-bromomethyl-pyridine and 0.68 g (4.89 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT, diluted with 60 mL of EtOAc and is washed twice with water. The organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Waters symmetry C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([I:12])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.I[CH2:15][CH3:16]>>[Cl:1][C:2]1[C:3]([F:13])=[C:4]([I:12])[C:5]([O:11][CH2:15][CH3:16])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CCI
Reactant: CC(=O)c1cc(Cl)c(F)c(I)c1O
Product: CCOc1c(C(C)=O)cc(Cl)c(F)c1I

Procedure:
This compound was prepared according to the procedure of Example 13 Step 3, using 1-(5-chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone and iodoethane as the starting materials. LCMS calculated for C10H10ClFIO2 (M+H)+: m/z=342.9; Found: 342.9.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][C:22]=3[N:28]([CH3:37])[S:29]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)(=[O:31])=[O:30])=O)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:54])=CC=1>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([S:54][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[CH:23][C:22]=4[N:28]([CH3:37])[S:29]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)(=[O:31])=[O:30])=[N:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN(c1cccc2cc(C(=O)NCC3(O)CCN(Cc4ccccc4)CC3)[nH]c12)S(=O)(=O)c1cccs1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC4(CCN(Cc5ccccc5)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Yield: 4.9 %

Procedure:
To a solution of N-[(1-benzyl-4-hydroxypiperidin-4-yl)methyl]-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.30 g) in a mixed solvent of toluene (60 ml) and tetrahydrofuran (30 ml) was added Lawesson's reagent (1.94 g), and the mixture was heated under reflux for 3 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=5:95-40:60), and recrystallized from ethyl acetate-hexane to give the title compound (0.063 g, yield 5%) as colorless crystals.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:10]([CH3:12])[CH:11]=1)=[O:6]>C(O)(=O)C>[Br:1][C:17]1[CH:18]=[C:13]([C:9]2[S:8][C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:11][C:10]=2[CH3:12])[CH:14]=[CH:15][C:16]=1[O:19][CH3:20]
Reactant: COC(=O)c1cc(C)c(-c2ccc(OC)cc2)s1
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1cc(C)c(-c2ccc(OC)c(Br)c2)s1
Reaction time: 16 h
Yield: 90 %

Procedure:
Liquid bromine (1.8 g, 0.57 ml, 11.43 mmol) was added drop wise to a stirred solution of methyl-5-(4-methoxyphenyl)-4-methylthiophene-2-carboxylate (prepared according to the procedure reported in WO 2007/092751, 2.0 g, 7.62 mmol) in acetic acid (20 ml) at a temperature of about 25° C. The resulting mixture was stirred at the same temperature for 16 hours. The progress of reaction was monitored by TLC. The reaction mixture was poured onto ice water (100 ml). The mixture so obtained was extracted with ethyl acetate (3×100 ml). The separated combined organic layer was washed with 10% aqueous sodium bicarbonate solution (2×50 ml). The organic layer was then dried over anhydrous Na2SO4. The solvent was evaporated form the organic layer under reduced pressure to obtain a crude product. The crude product was further purified by flash chromatography using 15-25% ethyl acetate in hexanes as an eluent to obtain the title compound (2.35 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[NH2:26][C:27]1[CH:28]=[CH:29][C:30]2[N:34]=[C:33]([CH2:35][OH:36])[NH:32][C:31]=2[CH:37]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:26][C:27]4[CH:28]=[CH:29][C:30]5[N:34]=[C:33]([CH2:35][OH:36])[NH:32][C:31]=5[CH:37]=4)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc3cnc(OS(=O)(=O)C(F)(F)F)nn23)cn1
Reactant: Nc1ccc2nc(CO)[nH]c2c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1ccc(-c2ccc3cnc(Nc4ccc5nc(CO)[nH]c5c4)nn23)cn1

Procedure:
{6-[7-(6-Methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-1H-benzoimidazol-2-yl}-methanol was prepared from trifluoro-methanesulfonic acid 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester and (6-amino-1H-benzoimidazol-2-yl)-methanol; dihydrochloride in an analogous manner to Example 1061. Product isolated as a yellow solid (35 mg, 34%). m.p.=182-187° C.; LCMS (m/e) 388 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 12.16 (bs, 1H), 9.36 (s, 1H), 8.97 (s, 1H), 8.92 (s, 1H), 8.60 (dd, 1H, J=1.8 and 8.7 Hz), 7.87 (bs, 1H), 7.50-7.35 (m, 2H), 7.18 (d, 1H, J=4.6 Hz), 6.99 (d, 1H, J=8.7 Hz), 6.94 (d, 1H, J=4.6 Hz), 5.63 (bs, 1H), 4.66 (s, 2H), 3.93 (s, 3H).
Reaction SMILES: [CH3:1][NH2:2].[C:3]1([S:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH2:19][C@@H:18]([CH2:21]OS(C)(=O)=O)[O:17][C:16]=3[CH:27]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[C:3]1([S:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH2:19][C@@H:18]([CH2:21][NH:2][CH3:1])[O:17][C:16]=3[CH:27]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)OC[C@@H]1COc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Reactant: CN
Solvent: CO
Product: CNC[C@@H]1COc2ccc(S(=O)(=O)c3ccccc3)cc2O1

Procedure:
A 2M solution of methyl amine in methanol (10 mL) and methansulfonic acid 7-benzenesulfonyl-2,3-dihydro-benzo[1,4]dioxin-2(S)-yl-methyl ester (0.87 g, 2.26 mmol) were heated in a microwave at 100° C. for 3 hours. The solvent was removed under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluting with dichloromethane—methanol; 98:2, v/v) to give (7-Benzenesulfonyl-2,3-dihydro-benzo[1,4]dioxin-2(R)-ylmethyl)-methyl-amine as a white solid (0.557 g; 77%), which was converted to a hydrochloride salt: MS (M)+ 319; m. p. 240.0-243.6° C., [α]=+40.5° (methanol; c=1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[C:24]([F:27])([F:26])[F:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[C:24]([F:27])([F:25])[F:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2C(F)(F)F)CC1

Procedure:
4-(N-(t-butoxycarbonyl)piperidin-4-yl)oxy-3-trifluoromethyl-1-nitrobenzene was dissolved in methanol in the presence of Pd/C. The solution was hydrogenated at 50 psi for 1 hour until hydrogen intake was completed. The catalyst was filtered off and the filtrate was concentrated to afford 4-[(N-(t-butoxycarbonyl)piperidin-4-yl)oxy]-3-trifluoromethylbenzenamine, >95%.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[N:11]1[CH2:20][CH:19]=[CH:18][C:17]2[N:16]=[CH:15][C:14]([N+:21]([O-:23])=[O:22])=[CH:13][C:12]1=2.[NH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>ClCCl.NCCNC(=O)OC(C)(C)C>[N+:21]([C:14]1[CH:15]=[N:16][C:17]2[C:12]([C:13]=1[NH:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[N:11][CH:20]=[CH:19][CH:18]=2)([O-:23])=[O:22]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=[N+]([O-])c1cnc2c(c1)N(Cl)CC=C2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A solution of diisopropylethylamine (13.47 g, 0.10 mole) in dichloromethane (25 mL) was added to a solution of 5-chloro-3-nitro[1,5]naphthyridine (18.2 g, 0.086 mol) in dichloromethane (250 mL). A solution of tert-butyl N-(2-aminoethyl)carbamate (16.7 g, 0.10 mol) in dichloromethane (75 mL) was slowly added to the reaction mixture. The reaction mixture was heated at reflux overnight. Additional tert-butyl N-(2-aminoethyl)carbamate (1 g) was added and the reaction mixture was heated at reflux for an additional 3 hours. The reaction mixture was allowed to cool to ambient temperature and then it was diluted with additional dichloromethane, washed with water and with brine, dried, and then concentrated under vacuum to provide a dark solid. This solid was purified by flash chromatography (silica gel eluting with dichloromethane) to provide 24.8 g of 1,1-dimethylethyl N-{2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethyl}carbamate as a canary yellow solid. A portion (0.3 g) was recrystallized from toluene (10 mL) and heptane (10 mL) to provide 0.2 g of canary yellow needles, m.p. 149-151° C. Analysis: Calculated for C15H19N5O4: %C, 54.05; %H, 5.75; %N, 21.01. Found: %C, 54.17; %H, 5.73; %N, 20.90.
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[Na].CN(C)P(N(C)C)(N(C)C)=O.Br[CH2:32][CH2:33][CH3:34]>O>[C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13]([O:15][CH2:32][CH2:33][CH3:34])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCBr
Reactant: CC(C(=O)O)c1ccc(C(=O)c2cccs2)cc1
Agent: [Na]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCOC(=O)C(C)c1ccc(C(=O)c2cccs2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 28.2 parts of p-(2-thenoyl)hydratropic acid, sodium salt in 250 parts of hexamethylphosphoramide are added 49.2 parts of 1-bromopropane and the whole is stirred for 2 hours at room temperature. The reaction mixture is poured onto 1000 parts of water and the product is extracted three times with diisopropylether. The combined extracts are washed with 200 parts of water, dried, filtered and evaporated. The viscous residue is filtered off over hyflo, yielding propyl p-(2-thenoyl)hydratropate as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:9](F)=[N:8][CH:7]=2)#[N:2].[NH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>O1CCCC1>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:9]([NH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[N:8][CH:7]=2)#[N:2]
Reactant: COC(=O)c1cccc(Nc2c(C#N)cnc3cnc(F)cc23)c1
Reactant: NCCN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(Nc2c(C#N)cnc3cnc(NCCN4CCOCC4)cc23)c1
Yield: 159.8 %

Procedure:
Following the procedure described above in Example 1, methyl 3-(3-cyano-6-fluoro-1,7-naphthyridin-4-ylamino)benzoate (0.25 g, 0.78 mmol, 1 eq) was reacted with 4-(2-aminoethyl)morpholine (1 mL, 7.62 mmol, 9.8 eq) in tetrahydrofuran (4 mL). Workup and flash column chromatography eluting with 2-5% methyl alcohol in dichloromethane yielded 539 mg product (54% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 2.40-2.46 (m, 4 H) 2.55 (t, J=6.44 Hz, 2 H) 3.34-3.39 (m, 2 H) 3.54-3.60 (m, 4 H) 3.87 (s, 3 H) 6.67 (t, J=5.18 Hz, 1 H) 7.01 (s, 1 H) 7.56 (dt, J=4.36, 1.23 Hz, 2 H) 7.79-7.83 (m, 2 H) 8.32 (s, 1 H) 8.87 (s, 1 H) 9.73 (s, 1 H).
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[O:15][C:14](=[O:16])[CH:13]=[CH:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:31]([O:34][CH2:35][CH3:36])(=[O:33])C.C(Cl)(Cl)Cl>O1CCOC1>[C:1]([O:9][CH2:10][C@H:11]1[O:15][C:14](=[O:16])[CH2:13][C@@H:12]1[CH:31]1[O:34][CH2:35][CH2:36][O:33]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: O=C1C=C[C@@H](COC(=O)c2ccccc2)O1
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1COCO1
Product: O=C1C[C@H](C2OCCO2)[C@@H](COC(=O)c2ccccc2)O1
Yield: 80 %

Procedure:
A solution containing 180 mg (0.825 mmol) compound (2e) and 22.5 mg (0.123 mmol) benzophenone in 110 mL [1,3]-dioxolane was irradiated at 20° C. for 7 hours according to the general procedure. Column chromatography (silica gel 40 g, ethyl acetate in hexanes 40%) gave compound (3e) (193 mg. 80%) as a colorless solid, Rf=0.29, [α]25D 35.2°, c 1.2, CHCl3, IR (neat) 2360, 2342, 1779, 1721, 1272, 1118 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 2.53 (d, 1H J=11.6 Hz), 2.62-2.73 (m, 2H), 3.83 (mc, 2H), 3.94 (mc, 2H), 4.37 (dd, 1H, J=5.1 Hz, J=12.3 Hz), 4.53 (dd, 1H, J=2.9 Hz, J=12.3 Hz), 4.74 (ddd, 1H, J=2.9 Hz, J=5.1 Hz, J=6.9 Hz), 4.88 (d, 1H, J=3.4 Hz), 7.37 (dd, 2H, J=7.7 Hz, J=7.9 Hz), 7.49 (dd, 1H, J=1.0 Hz, J=7.7 Hz), 7.92 (dd, 2H, J=1.0 Hz, J=7.9 Hz). 13C-NMR (100.6 MHz, CDCl3, Dept) δ: 29.77 (−), 40.06 (+), 65.37 (−), 65.50 (−), 65.99 (−), 77.56 (+), 103.14 (+), 128.51 (+), 129.31 (quat), 129.57 (+), 133.30 (+), 166.00 (quat) 175.62 (quat). C15H16O6; Exact Mass: 292.09; Mol. Wt.: 292.28; C, 61.64, H, 5.52, O, 32.84.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C:4]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1>CCOC(C)=O.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:32][C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@H:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:18][CH:19]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: COC(=O)C(=Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-tert-Butoxycarbonylamino-3-{(R)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-acrylic acid methyl ester (4.9 g) was suspended in 300 mL EtOAc. 400 mg (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(I)trifluoromethanesulfonate in 30 mL DCM was added. The mixture was then degassed and a hydrogen balloon was added. The mixture was stirred at room temperature for 2 hours and the solvent was evaporated. The residue was purified by silica gel flash chromatography (hexanes to 8:2 hexanes/EtOAc) to give 4.8 g after drying. 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.46 (d, 1H), 7.34 (m, 2H), 7.24-7.28 (m, 1H), 6.98 (m, 2H), 6.87 (d, 1H), 6.69 (d, 1H), 6.62 (m, 1H), 5.07-4.96 (m, 4H), 4.54 (m, 1H), 4.30 (m, 1H), 4.0 (m, 1H), 3.74 (s, 3H), 3.0 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]#[N:12])=[CH:4][N:3]=1.[NH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]1>CN(C)C=O.C(OCC)(=O)C>[C:11]([C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)=[N:3][CH:4]=1)#[N:12]
Reactant: N#Cc1cnc(Cl)c([N+](=O)[O-])c1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cnc(N[C@H]2CC[C@H](O)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-chloro-5-cyano-3-nitropyridine (3.5 g)(obtained according to International Patent Application No.WO9410171) in N,N-dimethylformamide (35 mL) was added trans-4-aminocyclohexanol (4.39 g) at 0° C. The mixture was stirred at room temperature under nitrogen atmosphere for 45 minutes and diluted with ethyl acetate. The mixture was washed with water (3 times) and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual solid was washed with diethyl ether to give 5-cyano-2-(trans-4-hydroxycyclohexylamino)-3-nitropyridine (3.38 g) as a yellow sold.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].N[OH:17].C(N(CC)CC)C>CO>[C:1]([O:5][C:6]([C:7]1[CH:8]=[CH:9][C:10]([CH:13]=[N:14][OH:17])=[CH:11][CH:12]=1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(C#N)cc1
Reactant: NO
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(C=NO)cc1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
In 100 ml of methanol were dissolved 20.5 g of 4-cyanobenzoic acid t-butyl ester and 13.9 g of hydroxylamine. To the solution was added, while stirring at room temperature, 128 g of triethylamine, and the mixture was stirred for one hour at 85° C. The reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate, and the solution was washed with water. The organic layer was concentrated under reduced pressure to give a crude product, which was recrystallized from isopropyl ether to afford 11.45 g of the title compound as a colorless crystalline product.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([O:3][CH2:28][C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[C:25]([F:24])([F:34])[F:35])=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: FC(F)(F)c1ccccc1CBr
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OCc3ccccc3C(F)(F)F)(CC1)CC2
Yield: 89.3 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) and 2-trifluoromethylbenzyl bromide (25.4 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-(2-trifluoromethylbenzyl)oxycarbonyl bicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (39.9 mg).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:14]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[N+:19]([O-])=O)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[H][H]>O>[NH2:19][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([S:15](=[O:18])(=[O:17])[NH2:16])[C:6]=1[NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:10]([OH:12])=[O:11]
Reactant: [H][H]
Reactant: CCCCNc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCNc1c(N)cc(C(=O)O)cc1S(N)(=O)=O

Procedure:
A suspension of 4-butylamino-3-nitro-5-sulphamyl-benzoic acid (8.6 g) in water (175 ml) was adjusted to pH 9.5 by addition of 2N sodium hydroxide. The resulting solution was hydrogenated after additon of Pd-on-carbon catalyst (0.5 g catalyst containing 10% Pd). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the 3-amino-4-butylamino-5-sulphamyl-benzoic acid was precipitated from the filtrate by addition of 4N hyrochloric acid until pH 3. After recrystallization from aqueous methanol the melting point was 211°-211.5° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]3[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=3[N:7]([CH2:11][CH3:12])[CH:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:41]=[N+:42]=[N-:43])(=O)=O)(C)C.C(O)(=O)C>C1COCC1>[N:41]([C:9]1[N:10]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]2[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=2[N:7]([CH2:11][CH3:12])[CH:8]=1)=[N+:42]=[N-:43]
Reactant: CCN1C=CN=C(C2CC2)c2ccccc21
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN1C=C(N=[N+]=[N-])N=C(C2CC2)c2ccccc21
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
To a stirring solution of 5-cyclopropyl-1-ethyl-1H-benzo[e][1,4]diazepine (6.4 g, 0.028 mol) in THF (125 ml) cooled to −78° C. was added potassium tert-butoxide (2.05 eq, 0.057 mol, 57.2 ml of a 1 M solution in THF) dropwise over 15 min. A solution of 2,4,6-triisopropylphenyl-sulfonylazide (9.5 g, 0.031 mol) in THF (100 ml) was added over 5 min. The solution was stirred for 10 min, acetic acid (7.7 ml,0.123 mol) was added and the reaction warmed to 30° C. for 2 hour. The reaction was concentrated the residue dissolved in dichloromethane (200 mL) and washed with satd. NaHCO3 (200 ml). The aqueous layer was back extracted with dichloromethane (100 ml). The organic layers were combined, dried with Na2SO4 and evaporated to a foam. The foam was chromatographed over silica eluting with 30% ethyl acetate:hexane. The appropriate fractions were collected and evaporated under reduced pressure to give 5.83 g of a powder. MP=158-160° C.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=O)[C:6](=[O:20])[N:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:4]=2[N:3]=1.O[NH:27][C:28](=[NH:35])[CH2:29][C:30]1[CH:34]=[CH:33][S:32][CH:31]=1.CC[O-].[Na+]>CCO>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][C:15]3[O:17][N:35]=[C:28]([CH2:29][C:30]4[CH:34]=[CH:33][S:32][CH:31]=4)[N:27]=3)[C:6](=[O:20])[N:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:4]=2[N:3]=1
Reactant: CCCCCn1c(=O)n(CCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Reactant: N=C(Cc1ccsc1)NO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCn1c(=O)n(CCCc2nc(Cc3ccsc3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 140 °C
Yield: 30.7 %

Procedure:
A mixture of ethyl 4-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (70 mg, 0.19 mmol), N-hydroxy-2-(3-thienyl)ethanimidamide (36 mg, 0.23 mmol), 21% solution of NaOEt in EtOH (78 μl, 0.21 mmol) and EtOH (1.5 ml) was heated in the microwave at 140° C. for 10 min. After cooling the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated and the aqueous layer extracted again with EtOAc. The combined extracts were concentrated and purified by MDAP. The title compound was freeze dried from 1,4-dioxane to give a white solid (27 mg, 31%).