Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([O:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=1)[NH2:5].Cl[S:17]([C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18].O.[Cl-].[NH4+]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][S:17]([C:20]2[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=2[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18])[CH:6]=[C:7]([O:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: Nc1cc(F)cc(Oc2cccnc2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccccc1S(=O)(=O)Nc1cc(F)cc(Oc2cccnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-fluoro-5-(pyridin-3-yloxy)aniline (1.10 g) in pyridine (22 ml), 1.92 g of methyl 2-(chlorosulfonyl)benzoate was added, and the reaction solution was stirred overnight at room temperature. Water and a saturated aqueous ammonium chloride solution were added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a 1N aqueous hydrochloric acid solution and a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by silica gel chromatography to yield the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[N:6]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:5]2=[O:22].CO[CH:25]1[CH:29]([CH2:30][O:31][CH:32]2[CH2:37]CCC[O:33]2)[CH2:28][CH:27](OC)O1>C(O)(=O)C>[CH3:21][S:18]([NH:17][N:6]1[C:5](=[O:22])[C:4]2[C:9](=[CH:10][C:11]([C:12]([F:13])([F:15])[F:14])=[C:2]([N:1]3[CH:27]=[CH:28][C:29]([CH2:30][O:31][C:32](=[O:33])[CH3:37])=[CH:25]3)[CH:3]=2)[NH:8][C:7]1=[O:16])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(N)cc2c1=O
Reactant: COC1CC(COC2CCCCO2)C(OC)O1
Solvent: CC(=O)O
Product: CC(=O)OCc1ccn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)c1

Procedure:
To a solution of 130 mg (0.39 mmol) of N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide in 5 ml of acetic acid a solution of 95 mg (0.39 mmol) of 2-(2,5-dimethoxy-tetrahydro-furan-3-ylmethoxy)-tetrahydro-pyran (prepared according to Frydman, Benjamin; Ojea, Maria I. 1,4-Diaminobutanes from furans: a new synthetic approach to substituted putrescines. Tetrahedron Letters (1998), 39(27), 4765-4768) is added and the reaction mixture is stirred at reflux for 3 hours. The solvent is evaporated at HV overnight to yield acetic acid 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-pyrrol-3-ylmethyl ester. 1H-NMR ; DMSO-d6 (400 MHz, ppm): 7.85 (s, 1H , aromatic); 7.62 (s, 1H , aromatic); 7.03 (s, 1H, N-CH═C(CH2) in pyrrol); 6.91 (m, 1H, N-CH═CH in pyrrol); 6.27 (m, 1H, CH═CH-C(CH2)-N in pyrrol); 4.96 (s, 2H, CH2-OCOCH3); 3.16 (s, 3H, SO2-CH3); 2.03 (s, 3H, CH2-OCOCH3); LC-MS: 459 [M-H]-; Agilent LC/MSD 1100 Series, LC-MS method: Column: SunFireC18, 4.6*50 mm, 3.5 μm; negative MS; water/acetonitril 95:5 to 5:95 in 5 min, flow: 1.5 ml/min.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C@H:6]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)=[CH:20][CH:19]=3)[C@H:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][O:9]2)=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[CH2:6]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C@H:6]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:20][CH:19]=3)[C@H:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][O:9]2)=[CH:4][CH:3]=1)[C:5]1[CH:10]=[CH:11][CH:2]=[CH:3][CH:4]=1
Reactant: Oc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(OCCCCCCCCCCBr)cc1
Reactant: C1COCCN1
Product: c1ccc(COc2ccc3c(c2)OC[C@@H](c2ccccc2)[C@H]3c2ccc(OCCCCCCCCCCN3CCOCC3)cc2)cc1

Procedure:
From (+,-) cis 7-Hydroxy-4-[4-(10-Bromodecyloxy)-phenyl]-3-phenyl-chroman (300 mg, 0.48 mmol) and morpholine (208 mg, 2.4 mmol).
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[NH2:9][C:10]1[CH:15]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:14](Br)[CH:13]=[CH:12][N:11]=1>>[NH2:9][C:10]1[C:15]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[N:14][C:13]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][N:11]=1
Reactant: [O-]c1ccccc1
Reactant: NC1=NC=CN(Br)C1N1CCOCC1
Agent: [Na+]
Product: Nc1ncc(Oc2ccccc2)nc1N1CCOCC1

Procedure:
A suspension of 0.1 mole of sodium phenoxide and 0.1 mole of 2-amino-3-morpholino-4-bromopyrazine is refluxed 10- 20 hours. The cooled mixture is extracted with diethyl ether, washed with cold 2N sodium hydroxide solution, dried and evaporated to give 2-amino-3-morpholino-5-phenoxypyrazine.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@H:13]([NH:26][C:27](=[O:36])[C@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:16][CH:15]=1.NN>CCO.CCOC(C)=O>[NH2:3][CH2:12][C@H:13]([NH:26][C:27](=[O:36])[C@H:28]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH3:29])[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:18][CH:19]=1
Reactant: CC[C@H](C)COc1ccc([C@H](CN2C(=O)c3ccccc3C2=O)NC(=O)[C@@H](C)c2ccccc2)cc1
Agent: NN
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC[C@H](C)COc1ccc([C@H](CN)NC(=O)[C@@H](C)c2ccccc2)cc1
Temperature: 55 °C
Yield: 96 %

Procedure:
To a solution of (S)-N-{(R)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1-[4-((S)-2-methyl-butoxy)-phenyl]-ethyl}-2-phenyl-propionamide dissolved in 10 mL of EtOH, was added anhydrous hydrazine. The resulting mixture was heated to 55° C. 1.5 h. It was cooled to rt, and diluted with EtOAc. The solids were filtered off, and the filtrate concentrated and was purified by column chromatography on silica gel using 0%→10% MeOH/DCM to obtain 109 mg (96%) of the desired product. 1H NMR (400 MHz, MeOD) δ 7.19-7.33 (m, 5H), 7.05-7.12 (m, 2H), 6.79-6.88 (m, 2H), 5.12 (dd, J=8.8, 5.8 Hz, 1H), 3.77-3.86 (m, 1H), 3.69-3.77 (m, 2H), 3.21-3.29 (m, 2H), 1.81 (s, 1H), 1.57 (ddd, J=13.4, 7.6, 5.8 Hz, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.22-1.35 (m, 1H), 1.02 (d, J=6.8 Hz, 3H), 0.96 (t, J=7.5 Hz, 3H); LCMS m/e calcd 355.2 [(M+H)+, for C22H31N2O2 355.2].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH2:17][O:18][C:19]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=5)[N:22]=[CH:21][CH:20]=4)=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:4][C:3]=1[C@@H:31]([NH:36][S@](C(C)(C)C)=O)[C:32]([F:35])([F:34])[F:33]>CO.Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH2:17][O:18][C:19]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=5)[N:22]=[CH:21][CH:20]=4)=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:4][C:3]=1[C@@H:31]([NH2:36])[C:32]([F:33])([F:35])[F:34]
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc([C@@H](N[S@@](=O)C(C)(C)C)C(F)(F)F)c(Cl)c5)nn34)ccnc2c1
Agent: Cl
Solvent: CO
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc([C@@H](N)C(F)(F)F)c(Cl)c5)nn34)ccnc2c1
Reaction time: 2 h

Procedure:
A solution of (S)—N—((R)-1-(2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (62 mg, 100 μmol) in MeOH (2 mL) and 5M HCl (2 mL) was stirred at 35° C. for 18 h. LCMS suggests full conversion. Solvents removed under reduced pressure and residue dissolved in MeOH (20 mL). Si-Carbonate (1.3 g; 0.9 mmol) added to solution and stirred for 2 h. Filtrated isolated by filtration and reduced to a film under reduced pressure. Product purified on silica (4 g) eluting with 7% 2M NH3 in MeOH/DCM. MS (ESI pos. ion) m/z: 515 (MH+). Calc'd exact mass for C24H18ClF3N6O2: 514.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br.[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:12][CH2:11][Br:10]
Reactant: Cc1ccc(O)c(Br)c1
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(OCCBr)c(Br)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 2-bromo-4-methylphenol (5.0 g, 26 mmol), 1,2-dibromoethane (7.0 g, 37 mmol) in water (20 mL) and NaOH (1.1 g, 28 mmol) was stirred at 100° C. for 24 h. The mixture was extracted with DCM (150 mL), washed with water, brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (20:1) to give the title compound (1a).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH:25]([C:28](OC)=[O:29])[CH2:24][CH2:23]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[Si:1]([O:18][CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][OH:29])[CH2:24][CH2:23]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCC(OCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)[Si](OCCOC1CCC(CO)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.90 g (3.75 mmol, 87% pure) of the compound from Example 3A are dissolved in 15 ml of diethyl ether and added dropwise to a suspension of 170.9 mg (4.50 mmol) of lithium aluminum hydride in 15 ml of diethyl ether. The mixture is then stirred at RT for 20 h. A further 136.7 mg (3.60 mmol) of lithium aluminum hydride are then added, and the mixture is stirred at RT for another 20 h. The mixture is then triturated with 257 μl of water and 257 μl of 15% strength aqueous potassium hydroxide solution. A further 10 ml of water are added, and the phases are separated. The organic phase is dried over magnesium sulfate. The solvent is removed on a rotary evaporator and the residue is purified chromatographically on silica gel 60 (mobile phase: gradient cyclohexane/ethyl acetate 50:1→10:1).
Reaction SMILES: [Br:1]Br.[C:3]1([S:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH4+].[Cl-]>CN(C=O)C>[C:3]1([S:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[C:14]([Br:1])=[CH:13]2)(=[O:11])=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(F)ccc21
Reactant: BrBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.5 %

Procedure:
Bromine (0.187 mL, 3.632 mmol) was added dropwise to a room temperature solution of 1-benzenesulfonyl-5-fluoro-1H-indole (1.0 g, 3.632 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 5 hours. A saturated solution of NH4Cl was added, and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with water and with brine; dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc, 95/5) to give 0.676 g (53% yield) of 1-benzenesulfonyl-3-bromo-5-fluoro-1H-indole as a white solid.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(N(CC)CC([N:15]1[C:28]2[CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH:33]([CH3:36])[CH2:34][CH3:35])=[O:30])[CH:25]=[CH:24][C:23]=2[S:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)C)C>CC(O)C>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH3:36][CH:33]([CH2:34][CH3:35])[CH2:32][NH:31][C:29]([C:26]1[CH:25]=[CH:24][C:23]2[S:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:28]=2[CH:27]=1)=[O:30]
Reactant: CCC(C)CNC(=O)c1ccc2c(c1)N(C(C)CN(CC)CC)c1ccccc1S2
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)O
Product: CCC(C)CNC(=O)c1ccc2c(c1)Nc1ccccc1S2
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
Fumaric acid (0.07 g) dissolved in 2-propanol (1 cc) under reflux is added to a solution of 10-[(2RS)-1-diethylamino-2-propyl]-N-[(2RS)-2-methylbutyl]-2-phenothiazinecarboxamide (0.25 g) in boiling 2-propanol (2.5 cc). Crystallization is primed by scratching, and the mixture is stirred for 2 hours at 25° C. and then left to stand for 12 hours at 0° C. The crystals are filtered off and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 40° C. to give 10-[(2RS)]-l-diethylamino-2-propyl]-N-[(2RS)-2-methylbutyl]-2-phenothiazinecarboxamide fumarate (0.19 g), m.p. at 110° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11].CCN(CC)CC.[CH3:20][C:21](OC(C)=O)=[O:22]>CCOCC.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:21](=[O:22])[CH3:20])=[CH:6][C:5]=1[OH:11]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC(C)=O)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.4 %

Procedure:
2,4-Dihydroxy-benzoic acid methyl ester (11.76 g, 70 mmol) was dissolved in Et2O (175 mL). Then Et3N (10.78 mL, 77 mmol), Ac2O (7.28 mL, 77 mmol), and DMAP (catalytic amount) were added. The reaction solution was then stirred for one hour at room temperature. Then the reaction solution was concentrated by rotary evaporation and the resulting residue was purified with a silica gel column and dichloromethane as eluent. Obtained 3.44 g 4-Acetoxy-2-hydroxy-benzoic acid methyl ester in 23% yield.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:15][CH2:14]2)[CH2:5][CH2:4][CH:3]3[CH2:2]1.CC(N(C)C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][CH2:43][CH2:44][OH:45]>O>[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]([CH2:42][CH2:43][CH2:44][OH:45])[C:20]4=[O:28])[CH2:15][CH2:14]2)[CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: OCCCBr
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C2CCC3CCc4cccc2c43)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=c1n(CCCO)c2ccccc2n1C1CCN(C2CCC3CCc4cccc2c43)CC1
Temperature: 85 °C

Procedure:
To 1-[1-(1,2,2a,3,4,5-hexahydroacenaphthylen-5-yl)piperidin-4-yl]-1,3-dihydro-2H -benzimidazol-2-one (500 mg), dimethylacetamide (3 ml) and potassium carbonate (370 mg) was added 3-bromopropanol (0.242 ml), and the mixture was stirred with heating at 85° C. for 2 hr. The reaction mixture was cooled to room temperature, water was added, and the precipitate was collected by filtration to give 1-[1-(1,2,2a,3,4,5-hexahydroacenaphthylen-5-yl)piperidin-4-yl]-3-(3-hydroxypropyl)-1,3-dihydro-2H-benzimidazol-2-one.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12](=[N:20][C:21]#[N:22])OC2C=CC=CC=2)[CH:7]=[C:8]([I:10])[CH:9]=1)=[N+:2]=[N-:3].[F:23][C:24]1[CH:25]=[C:26]([C:30]2([NH2:34])[CH2:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>C(O)(C)C>[N:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12]([NH:20][C:21]#[N:22])=[N:34][C:30]2([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=3)[CH2:33][CH2:32][CH2:31]2)[CH:7]=[C:8]([I:10])[CH:9]=1)=[N+:2]=[N-:3]
Reactant: N#CN=C(Nc1cc(I)cc(N=[N+]=[N-])c1)Oc1ccccc1
Reactant: NC1(c2cccc(F)c2)CCC1
Solvent: CC(C)O
Product: N#CNC(=NC1(c2cccc(F)c2)CCC1)Nc1cc(I)cc(N=[N+]=[N-])c1
Temperature: 82 °C
Yield: 46.6 %

Procedure:
Step B-2. To a stirred suspension of N-(3-azido-5-iodophenyl)-N'-cyanocarbamimidic acid, phenyl ester (B-1, 472 mg 1.16 mmol) in isopropanol was added 1-(3-fluorophenyl)cyclobutanamine (227 mg, 1.40 mmol). The reaction mixture was heated in a sealed tube at 82° C. overnight. The cooled reaction mixture was concentrated. The residue was purified by medium pressure liquid chromatography using 30% ethyl acetate in hexane as the eluent to afford 0.257 g of N-(3-azido-5-iodophenyl)-N'-cyano-N"-[1-(3-fluorophenyl)cyclobutyl]guanidine. (B-2). Mp=171°-173° C. (dec). IR (mull) 3195, 3135, 3078, 3002, 2953, 2925, 2854, 2188, 2110, 1614, 1608, 1587, 1573, 1542, 1448, 1440, 1430, 1365, 1309, 1292, 1245, 1221, 1162, 1041, 874 cm-1 ; 1H NMR (CDCl3) δ7.42 (m, 1 H), 7.26 (m, 2 H), 7.17 (m, 2 H), 7.06 (m, 1 H), 6.78 (m, 1 H), 2.59 (m, 4 H), 2.15 (m, 1 H), 2.00 (m, 1 H), 1.61 2, 2 H); 13C NMR (CDCl3) δ156.4, 138.0, 131.3, 124.9, 120.6, 116.3, 114.7, 114.4, 112.8, 112.5, 94.9, 59.6, 34.7, 14.8; Mass Spec (FAB) m/z 476 (M+1), 448, 434, 421, 350, 328, 300, 273, 216, 173, 149 (base). Exact mass calculated for C18H16FIN7 : 476.0498. Found: 476.0514. Analysis calculated for C18H15FIN7 : C, 45.49; H, 3.18; N, 20.63. Found: C, 45.23; H, 3.16; N, 20.37.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:41])[C:18]=1/[CH:19]=[C:20](\[O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)/[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1>>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH:39][C:36]2[CH:37]=[CH:38][C:33]([C:32]([O:31]/[C:20](/[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)=[CH:19]\[C:18]3[C:17]([Cl:41])=[CH:16][N:15]=[CH:14][C:13]=3[Cl:12])=[O:40])=[CH:34][CH:35]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(/C(=C/c2c(Cl)cncc2Cl)OC(=O)c2ccc(N)cc2)cc1OC
Product: COc1ccc(/C(=C/c2c(Cl)cncc2Cl)OC(=O)c2ccc(NS(=O)(=O)c3ccc(C)cc3)cc2)cc1OC

Procedure:
The compound was obtained starting from 4-toluenesulfonyl chloride and 4-amino -benzoic acid (Z)-2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy -phenyl)vinyl ester, following the procedure of Example 16.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][CH2:9][CH2:10][C:11]2[N:12]([CH3:22])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)=[C:5]([C:24]([OH:26])=O)[N:4]=[N:3]1.[NH:27]1[CH2:30][CH2:29][CH2:28]1>>[CH3:22][N:12]1[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=[C:11]1[CH2:10][CH2:9][NH:8][C:7]([C:6]1[N:2]([CH3:1])[N:3]=[N:4][C:5]=1[C:24]([N:27]1[CH2:30][CH2:29][CH2:28]1)=[O:26])=[O:23]
Reactant: C1CNC1
Reactant: Cn1cc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)O)nnn1C
Product: Cn1cc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)N2CCC2)nnn1C

Procedure:
The product was obtained starting from 1-methyl-5-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethylcarbamoyl)-1H-1,2,3-triazole-4-carboxylic acid (30 mg, 84.7 μmol) and azetidine (6.8 mg, 8 μL, 119 μmol) according to the method described in example 37, step 3 as colorless solid (11 mg, 28 μmol, 33%).
Reaction SMILES: [F:1][C:2]1[C:22]([CH:23]=[CH2:24])=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11](O)=[O:12])[C:7](=[O:18])[CH:6]=1.[CH3:25][C:26]1([CH3:38])[O:30][C@H:29]([CH2:31][N:32]2[CH:36]=[CH:35][C:34]([NH2:37])=[N:33]2)[CH2:28][O:27]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:25][C:26]1([CH3:38])[O:30][C@H:29]([CH2:31][N:32]2[CH:36]=[CH:35][C:34]([NH:37][C:11](=[O:12])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:19]=[CH:20][CH:21]=[C:22]([CH:23]=[CH2:24])[C:2]=4[F:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:33]2)[CH2:28][O:27]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: C=Cc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=Cc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Temperature: 0 °C
Yield: 65.2 %

Procedure:
To a solution of (S)-2-[4-(2-fluoro-3-vinyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.215 g, 0.64 mmol) in N,N-dimethylformamide (5 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.153 g, 0.78 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.530 g, 1.20 mmol). The mixture was stirred at 0° C. and triethylamine (0.122 g, 1.21 mmol) was added. The mixture was stirred at room temperature for 4 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 10% to 80% ethyl acetate/hexanes) which afforded (S)-2-[4-(2-fluoro-3-vinyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.214 g, 65%) as a white solid: HR-ES-MS m/z calculated for C27H33FN4O5 [M+H]+ 513.2508, observed 513.2505, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.45 (br. s., 1H), 1.49-1.67 (m, 1H), 1.67-1.84 (m, 1H), 3.73 (dd, J=8.4, 5.7 Hz, 1H), 4.00 (dd, J=8.4, 6.5 Hz, 1H), 4.04-4.18 (m, 2H), 4.23 (d, J=18.4 Hz, 1H), 4.35 (dq, J=6.0, 5.7 Hz, 1H), 4.60 (d, J=18.4 Hz, 1H), 4.81-4.93 (m, 1H), 4.91 (s, 1H), 5.52 (d, J=11.4 Hz, 1H), 6.00 (d, J=17.8 Hz, 1H), 6.44 (d, J=2.1 Hz, 1H), 6.86 (dd, J=17.8, 11.4 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 7.42 (td, J=7.8, 1.2 Hz, 1H), 7.57-7.64 (m, 2H), 10.81 (s, 1H).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([NH:26][C:27](=[O:29])[CH3:28])[CH3:25])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1.Cl.CN(C)CC(O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]I.O1CCOCC1>[N:4]1[CH:3]=[C:2]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([NH:26][C:27](=[O:29])[CH3:28])[CH3:25])=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH:7]=[N:6][CH:5]=1
Reactant: Ic1cncnc1
Reactant: CC(=O)NC(C)Cc1ccc(C#Cc2ccc(O)cc2)cc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)NC(C)Cc1ccc(C#Cc2ccc(Oc3cncnc3)cc2)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
28.1 mg (0.14 mmol) 5-iodopyrimidine, 40.0 mg (0.14 mmol) N-(1-(4-((4-hydroxy-phenyl)ethynyl)phenyl)propan-2-yl)acetamide (I76.1), 1.30 mg (0.07 mmol) CuI, 1.9 mg (0.14 mmol) N,N-dimethylglycine hydrochloride and 58.7 mg (0.18 mmol) Cs2CO3 are added to 1 mL dioxane. The reaction mixture is stirred at 90° C. for 2 h then filtered through a plug of silica gel and washed with DMF. The filtrate is purified by HPLC (MeOH/H2O/TFA).