Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:7]([Si:10]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])Cl)([CH3:9])[CH3:8].N1C=CN=C1>CN(C=O)C.C(OC(=O)C)C>[CH:1]1([O:6][Si:10]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: OC1C=CCC1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[Si](OC1C=CCC1)(C(C)C)C(C)C

Procedure:
A solution of 2-cyclopentenol (K. Alder, F. H. Flock, Chem. Ber. 1956, 89, 1732.) (2.31 g, 27.5 mmol), (triisopropyl)chlorsilane (5.30 g, 5.9 mL, 27.5 mmol), imidazole (2.06 g, 30.2 mmol) in DMF (50 mL) was stirred at room temperature for 3 h and for an additional hour at 50° C. Then the solution was diluted with ethylacetate, washed 4 times with water and dried over sodium sulfate. Evaporation of the solvent yielded in 6.32 g (96%) of the silylether 513/13 as a colourless liquid. No major impurities were visible in the 1H-NMR-spectrum.
Reaction SMILES: [NH3:1].[C:2]1([C:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29]C)=O)[CH:25]=4)[NH:20][CH:19]=3)[CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C)C=O>[C:2]1([C:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([NH2:1])=[O:29])[CH:25]=4)[NH:20][CH:19]=3)[CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Reactant: N
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1

Procedure:
0.02 mol of concentrated ammonia (D=0.9) is added dropwise at 20° to a solution of 4.18 g of methyl 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-carboxylate in 30 ml of dimethylformamide. The mixture is stirred for a further hour at 20° and worked up in the customary manner to give 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-carboxamide, m.p. 207°-208°.
Reaction SMILES: N[C@@](C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)CO.[C:38]([C@H:42]1[CH2:47][CH2:46][C@H:45]([O:48][C:49]2[C:50]([Cl:66])=[C:51]3[C:56](=[CH:57][CH:58]=2)[CH:55]=[C:54]([C@:59]2([CH3:65])[CH2:63][O:62]C(=O)[NH:60]2)[CH:53]=[CH:52]3)[CH2:44][CH2:43]1)([CH3:41])([CH3:40])[CH3:39]>>[NH2:60][C@@:59]([C:54]1[CH:53]=[CH:52][C:51]2[C:56](=[CH:57][CH:58]=[C:49]([O:48][C@H:45]3[CH2:44][CH2:43][C@H:42]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:47][CH2:46]3)[C:50]=2[Cl:66])[CH:55]=1)([CH3:65])[CH2:63][OH:62]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2Cl)CC1
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2Cl)CC1

Procedure:
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-chloronaphthalen-2-yl)propan-1-ol was synthesized as per (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)propan-1-ol (Example 221) in 39% yield using (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-chloronaphthalen-2-yl)-4-methyloxazolidin-2-one as starting material. MS: m/z: 373.28 [M−NH2]+. 1H NMR (MeOD) δ: 8.14 (d, J=9.0 Hz, 1H), 7.93 (d, J=1.8 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.71 (dd, J=9.0, 2.0 Hz, 1H), 7.39 (d, J=9.0 Hz, 1H), 4.26-4.37 (m, 1H), 3.73 (d, J=11.0 Hz, 1H), 3.69 (d, J=11.0 Hz, 1H), 2.18-2.26 (m, 2H), 1.85-1.93 (m, 2H), 1.46-1.58 (m, 5H), 1.05-1.26 (m, 3H), 0.85-0.94 (m, 9H)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:21])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1.[H-].[Na+].Cl.Cl[CH2:26][CH2:27][N:28]([CH3:30])[CH3:29]>CN(C)C=O>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:21])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[CH:15]=1
Reactant: Cc1cc(O)c(C(=O)C=Cc2cccc(O)c2)c(=O)n1C
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(O)c(C(=O)C=Cc2cccc(OCCN(C)C)c2)c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a solution of 0.58 g of 4-hydroxy-3-[3-(3-hydroxyphenyl)-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone in 10 ml of dimethylformamide was added 0.32 g of sodium hydride (60% oily), and this was stirred at room temperature for 1 hour. To the reaction mixture was added 0.25 g of 2-chloroethyldimethylamine hydrochloride, and this was heated at 60° C. for 4 hours. The solvent was distilled off under reduced pressure, and the precipitated crystals were filtered, washed with t-butyl methyl ether, and dried to obtain 0.21 g of 4-hydroxy-3-[3-[3-(2-dimethylaminoethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (56a)] as a yellow crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1([C:28]([O-:30])=O)[CH2:27][CH2:26]1)=[O:24].[Li+].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[F:63][C:64]1[CH:70]=[CH:69][C:67]([NH2:68])=[CH:66][CH:65]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1([C:28]([NH:68][C:67]2[CH:69]=[CH:70][C:64]([F:63])=[CH:65][CH:66]=2)=[O:30])[CH2:27][CH2:26]1)=[O:24]
Reactant: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)C4(C(=O)[O-])CC4)cc3F)ccn2)cn1
Reactant: Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a solution of Example B5 (9.91 g, 23.58 mmol) in DMF (80 mL), under an atmosphere of argon, were added TBTU (11.36 g, 35.4 mmol), DIPEA (20.59 ml, 118 mmol) and 4-fluoroaniline (3.93 g, 35.4 mmol). The reaction mixture was stirred at RT overnight. An additional portion of TBTU (7.5 g, 17.8 mmol) was added and stirring was continued. After 2 h, an additional portion of TBTU (3.5 g, 8.33 mmol) was added and stirring was continued for 2 h. The solvent was removed under high vacuum and the residue was dissolved in EtOAc (700 mL) and washed with sat. aq. NaHCO3 (2×200 mL) and brine (50 mL), dried (MgSO4), concentrated to dryness and purified by silica gel chromatography (MeOH-DCM) to provide N-(2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (7.2 g, 59% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.14 (s, 1H), 9.76 (s, 1H), 8.39 (d, J=5.6 Hz, 1H), 8.28 (s, 1H), 8.13 (dd, J=12.1, 7.1 Hz, 1H), 7.99 (s, 1H), 7.62-7.53 (m, 3H), 7.27 (d, J=2.6 Hz, 1H), 7.22-7.15 (m, 2H), 6.71 (dd, J=5.6, 2.4 Hz, 1H), 3.86 (s, 3H), 1.69-1.56 (m, 4H); MS (ESI): m/z 508.1 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]O)=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.CS([Cl:22])(=O)=O>C(Cl)Cl>[Cl:22][CH2:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncccc1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncccc1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-methoxy-pyridin-3-yl)-methanol (0.38 g, 2.74 mmol) from example 42 step A and triethylamine (0.5 mL, 3.56 mmol) in 6 mL of CH2Cl2 was added methanesulfonyl chloride (0.26 mL, 3.29 mmol) at 0° C. After 1 hr, the reaction was warmed to room temperature and stirred overnight. The reaction mixture was brought to the usual work-up to give the crude product, which was purified by chromatography (silica gel, 25% EtOAc/hexanes). 1H NMR (300 MHz, CDCl3) 8.15 (m, 1H), 7.67 (m, 1H), 6.91 (m, 1H), 4.60 (s, 2H), 4.02 (s, 3H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=2)=[C:8]([F:28])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].Cl[C:30]1[C:31]2[N:38]=[CH:37][N:36]([CH:39]([CH3:41])[CH3:40])[C:32]=2[N:33]=[N:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]([C:30]3[C:31]4[N:38]=[CH:37][N:36]([CH:39]([CH3:41])[CH3:40])[C:32]=4[N:33]=[N:34][CH:35]=3)[CH:13]=2)=[C:8]([F:28])[CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CC(C)n1cnc2c(Cl)cnnc21
Reactant: CCS(=O)(=O)c1ccc(-c2cc(B3OC(C)(C)C(C)(C)O3)ccc2F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)c1ccc(-c2cc(-c3cnnc4c3ncn4C(C)C)ccc2F)c(F)c1
Temperature: 120 °C
Yield: 80 %

Procedure:
To a solution of 2-[4′-(ethylsulfonyl)-2′,6-difluorobiphenyl-3-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 47, 48 mg, 0.12 mmol) and 4-chloro-7-isopropyl-7H-imidazo[4,5-c]pyridazine (Preparation 6, 22 mg, 0.11 mmol) in anhydrous dioxane (0.56 mL) was added aqueous Na2CO3 solution (2M, 0.17 mL, 0.34 mmol) and a stream of nitrogen gas was bubbled through the suspension for 5 minutes. Tetrakistriphenylphosphine palladium(0) (2.3 mg, 0.002 mmol) was added and the mixture was heated under microwave irradiation at 120° C. for a total of 15 minutes. The reaction mixture was cooled, diluted with water (20 mL) and extracted with EtOAc (3×15 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered and the filtrate was evaporated in vacuo to leave a tan sticky solid that was purified by silica gel column chromatography eluting with heptane:EtOAc to afford the title compound as a tan solid in 80% yield, 40 mg.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[S:21]1[CH:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22]1.C(N(CC)CC)C>C(Cl)Cl>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3](=[O:20])[CH:2]([NH:1][C:26]([C:23]2[CH:24]=[CH:25][S:21][CH:22]=2)=[O:27])[N:8]=1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: O=C(Cl)c1ccsc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1N=C(c2ccccc2F)c2ccccc2NC1=O)c1ccsc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (75 mg, 0.229 mmol), thiophene-3-carbonyl chloride (44.9 mg, 0.306 mmol) and triethylamine (42.5 μl, 0.306 mmol) were combined in CH2Cl2 (4 ml) and stirred 10 min. at 25° C. The reaction was concentrated and chromatographed on silica gel (2% MeOH in CH2Cl2) to give the title compound as a white solid from Et2O: (m.p. 238°-239°).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[C:35]([Br:40])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[Br:40][C:35]1[CH:34]=[C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])[CH:38]=[CH:37][C:36]=1[F:39]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CN(C[C@@H](N)c1ccc(F)c(Br)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(F)c(Br)c1

Procedure:
Compound 28 was prepared following general synthesis scheme 8 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(3-bromo-4-fluoro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a beige solid. LC/MS [419 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.40 (d, 1H), 9.02 (dd, 1.9 Hz, 1H), 8.60 (d, 1H), 8.40 (dd, 1H), 8.19 (s, 1H), 8.04-7.76 (m, 1H), 7.55 (ddd, 4.7, 2.1 Hz, 1H), 7.36 (td, 1H), 5.88-5.57 (m, 1H), 3.48 (t, 1H), 3.21 (dd, 1H), 2.54 (d, 1H), 2.50 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([CH3:14])[C@@H:3]([C:5]1[CH:13]=[CH:12][C:8]2[CH2:9][CH2:10][O:11][C:7]=2[CH:6]=1)[OH:4].[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:30]3[C:25](=[CH:26][C:27](I)=[CH:28][CH:29]=3)[CH:24]=[N:23]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)CCC.[Cu]I>[O:11]1[C:7]2[CH:6]=[C:5]([C@@H:3]([O:4][C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[N:22]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=3)[N:23]=[CH:24]4)[C@@H:2]([NH2:1])[CH3:14])[CH:13]=[CH:12][C:8]=2[CH2:9][CH2:10]1
Reactant: Fc1ccc(-n2ncc3cc(I)ccc32)cc1
Reactant: C[C@@H](N)[C@H](O)c1ccc2c(c1)OCC2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCC#N
Product: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2c(c1)OCC2
Temperature: 105 °C
Yield: 21.3 %

Procedure:
A stirred mixture of (1R,2R)-2-amino-1-(2,3-dihydrobenzofuran-6-yl)propan-1-ol (306b, 180 mg, 0.93 mmol), 1-(4-fluorophenyl)-5-iodo-1H-indazole (346 mg, 1.02 mmol), and cesium carbonate (0.910 g, 2.79 mmol) in butyronitrile (2 mL) was degassed for 5 min. Then copper(I) iodide (35 mg, 190 μmol) was added. The tube was sealed and heated at 105° C. for 12 h. The solvent was removed, the residue was taken in dichloromethane (20 mL), and filtered on a prepact silica column (10 g), washed with dichloromethane (50 ml) followed by ethyl acetate (50 ml). Than the product was eluted with a mixture of 0.35M ammonia solution in ethylacetate/methanol (5:95) (100 ml) to give 80 mg (22%) of subtitle compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH3:12])[C:5]([OH:7])=[O:6].[N:13](OC(C)(C)C)=O.C([O-])(=O)C.[K+].C1OCCOCCOCCOCCOCCOC1>O1CCCC1.C(Cl)(Cl)Cl>[C:5]([C:4]1[CH:3]=[C:2]2[C:10]([C:11]([CH3:12])=[N:13][NH:1]2)=[CH:9][CH:8]=1)([OH:7])=[O:6]
Reactant: CCc1ccc(C(=O)O)cc1N
Reactant: CC(C)(C)ON=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cc1n[nH]c2cc(C(=O)O)ccc12
Temperature: -12 °C
Reaction time: 0.33 h
Yield: 17.3 %

Procedure:
To chloroform (75 ml), which had been passed through an alumina column, was added boron trifluoride diethyl ether complex (3.75 g, 26.4 mmol) and the mixture was cooled at −12° C. A solution of 3-amino-4-ethylbenzoic acid (2.5 g, 15.1 mmol) in tetrahydrofuran (25 ml) was dropwise added thereto for 20 min. After the completion of the addition, t-butyl nitrite (1.87 g, 18.1 mmol) was added and the mixture was heated to 5° C. The mixture was stirred at 5° C. for 1.5 hr. Then potassium acetate (7.4 g, 75.4 mmol) and 18-crown-6-ether (400 mg, 1.51 mmol) were added and the mixture was stirred at room temperature for 40 hr. The brown reaction mixture was concentrated under reduced pressure. Ethyl acetate/acetone (7/3, 100 ml) and 1N hydrochloric acid (25 ml) was added to the residue and the mixture was stirred at room temperature for 1 hr. Saturated brine (25 ml) was added thereto. The insoluble matter was filtered off and the filtrate was partitioned. The water layers were extracted with ethyl acetate/acetone (7/3, 40 ml) and the combined organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained brown oil (4.3 g) was dissolved in ethyl acetate, and then hydrogen chloride-diethyl ether (6 of hydrogen chloride in 40 ml of ether) and diethyl ether (100 ml) were added. The precipitated solid was collected by filtration. The obtained solid was extracted with ethyl acetate/acetone (7/3, 100 ml) and saturated brine (25 ml), and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained solid was washed with diethyl ether to give the objective compound (0.46 g, 17%) as brown crystals.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:13]1([C:19]#[CH:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(C)C(=N)N(C)C.CN(C=O)C>[Cu]I.O>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[O:12][C:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:20][C:2]=2[CH:3]=1)=[O:6]
Reactant: COC(=O)c1ccc(O)c(I)c1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: CN(C)C(=N)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2oc(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A mixture of methyl 3-iodo-4-hydroxybenzoate 26 (1 g, 3.6 mmol), phenylacetylene (2 ml, 18 mmol), tetramethylguanidine (4.5 ml, 36 mmol), copper(I)iodide (34 mg, 1.8 mmol), bis(triphenylphosphine)palladium (II)chloride (130 mg, 1.8 mmol) and DMF (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, extracted, washed and dried. After evaporation of the solvent, the residue was purified by chromatography to give about 0.9 g of 2-phenyl-benzofuran-5-carboxylic acid methyl ester 27.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)[CH2:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[N:7][CH:8]=1)[CH3:2].S(Cl)([Cl:36])(=O)=O>C(OCC)C>[Cl:36][C:18]1[CH:19]=[C:14]([C:11]([CH3:13])([CH3:12])[CH2:10][N:9]([C:6]2[N:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=2)[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:26][CH:27]=2)[CH:15]=[CH:16][C:17]=1[OH:20]
Reactant: CCc1cnc(N(Cc2ccc(OC(F)(F)F)cc2)CC(C)(C)c2ccc(O)cc2)nc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOCC
Product: CCc1cnc(N(Cc2ccc(OC(F)(F)F)cc2)CC(C)(C)c2ccc(O)c(Cl)c2)nc1
Yield: 24.9 %

Procedure:
To a solution 4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)phenol (300 mg; 0.67 mmol) in ethyl ether (0.1M) was added sulfuryl chloride (0.060 ml; 0.74 mmol). After 10 minutes an additional 0.3 eq of sulfuryl chloride were added. Stirred 20 more minutes. Partitioned between ethyl acetate and dilute sodium bicarbonate solution. Organic phase was washed with saturated brine, dried over sodium sulfate and concentrated. Purification by radial chromatography on silica gel using a dichloromethane-hexane gradient (30–90%) provided the title compound (80 mg; 25% yield).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[O:31][C:14]4=[C:15]([NH2:30])[N:16]=[CH:17][C:18]([C:19]5[CH:20]=[N:21][N:22]([CH:24]6[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]6)[CH:23]=5)=[C:13]4[CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36].CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:30][C:15]1[N:16]=[CH:17][C:18]([C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:25][CH2:26][N:27]([C:35](=[O:36])[CH2:34][O:33][CH3:32])[CH2:28][CH2:29]3)[CH:23]=2)=[C:13]2[CH:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][N:2]=[CH:1]4)[O:31][C:14]=12
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)c2cc(-c3cccc4cnccc34)oc12
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5cccc6cnccc56)cc34)cn2)CC1
Yield: 59.2 %

Procedure:
A solution of 2-isoquinolin-5-yl-4-(1-piperidin-4-yl-1H-pyrazol-4-yl)-furo[2,3-c]pyridin-7-ylamine (30 mg, 0.07 mmol), methoxyacetyl chloride (8.02 μL, 0.0877 mmol), and DIPEA (28.0 μL, 0.161 mmol) in DCM (0.94 mL) stirred overnight at RT. The reaction was diluted with DCM, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (10% 7 N NH3/MeOH:EtOAc) afforded 20 mg (60%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.97-2.21 (m, 4 H) 2.31 (br s, 2 H) 2.81-2.94 (m, 1 H) 3.17-3.32 (m, 1 H) 3.41-3.51 (m, 3 H) 4.06-4.25 (m, 3 H) 4.46 (tt, J=11.34, 4.07 Hz, 1 H) 4.76 (d, J=12.88 Hz, 1 H) 5.01 (br s, 2 H) 7.22 (s, 1 H) 7.69-7.80 (m, 2 H) 7.84-7.91 (m, 1 H) 8.03 (s, 1 H) 8.08-8.18 (m, 2 H) 8.22 (d, J=6.06 Hz, 1 H) 8.61-8.70 (m, 1 H) 9.37 (s, 1 H); MS (ESI): 483.11 [M+H]+; HPLC tR=0.89 min (TOF, polar—3 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([O:32][CH3:33])[C:30]=1[OH:31])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]#[CH:16])=[CH:9][C:8]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=1)=O.[O-:34][C:35]#[N:36].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([O:32][CH3:33])[C:30]=1[OH:31])[CH2:5][N:6]1[C:7]2[C:8](=[CH:9][C:10]([O:13][CH2:14][C:15]#[CH:16])=[CH:11][CH:12]=2)[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[N:36][C:35]1=[O:34]
Reactant: N#C[O-]
Reactant: C#CCOc1ccc(NCc2cc(Cl)c(O)c(OC)c2)c(C(=O)c2ccc(C(C)C)cc2)c1
Agent: [Na+]
Solvent: CC(=O)O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cc(Cl)c(O)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 43.1 mg (0.093 mmol) of [2-(3-Chloro-4-hydroxy-5-methoxy-benzyl-amino)-5-prop-2-ynyloxy-phenyl]-(4-isopropyl-phenyl)-methanone in 1 ml of acetic acid is added 12.1 mg (0.186 mmol) of sodium cyanate. After stirring for 12 h at r.t. the solvent is removed in vacuo and the residue partitioned between saturated NaHCO3 solution and ethyl acetate. The organic layer is separated and the aqueous phase extracted twice with ethyl acetate. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo. Flash chromatography (SiO2, hexane/ethyl acetate) affords the title compound as an amorphous yellow solid.
Reaction SMILES: [S:1]1[N:5]=[CH:4][C:3]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:2]1.[N:12](OCCC(C)C)=[O:13]>>[OH:13][N:12]=[C:6]([C:3]1[CH:4]=[N:5][S:1][N:2]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)Cc1cnsn1
Reactant: CC(C)CCON=O
Product: CCOC(=O)C(=NO)c1cnsn1

Procedure:
Ethyl 2-(1,2,5-thiadiazol-3-yl)acetate (9.5 g.) and isopentyl nitrite (10 ml.) were reacted according to a similar manner to that of Example 3(a) (1) to give ethyl 2-hydroxyimino-2-(1,2,5-thiadiazol-3-yl)acetate (a mixture of syn and anti isomers) (10.5 g.), mp 60° to 66° C.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:2]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH3:24][OH:25]>>[CH3:24][O:25][C:3]1([CH2:2][OH:1])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: C1CC2(CCO1)CO2
Reactant: CO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: COC1(CO)CCOCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1,6-dioxaspiro[2.5]octane (600 mg, 5.26 mmol) in methanol (10 ml) at 0° C. (ice-water) under nitrogen was added camphorsulfonic acid (50 mg, 0.21 mmol) and the resulting mixture was stirred at about 0° C. for 2 hours. The mixture was concentrated in vacuo and the crude residue was used in the next step without purification. The desired product was obtained as a light yellow oil (707 mg).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][NH:5]1)[C:2]#[CH:3].[Cl-:19].[Mn+2:20].[Cl-:21]>CO.C(O)C>[Cl:19][C:4]1([CH2:1][C:2]#[CH:3])[CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][N:5]1[Cl:21].[Mn+2:20]
Reactant: [Cl-]
Reactant: C#CCC1CNCCNCCNCCNCCN1
Agent: [Mn+2]
Solvent: CO
Solvent: CCO
Product: C#CCC1(Cl)CNCCNCCNCCNCCN1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 2-propargyl-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 29G (310 mg, 1.22 mmol) and anhydrous manganese(II) chloride (154 mg, 1.22 mol) in methanol (50 ml) were refluxed under a dry nitrogen atmosphere for 2 h and then stirred overnight at room temperature. The solution was taken to dryness, redissolved in absolute ethanol (15 ml) and filtered through celite. Concentration and recrystallization from ethanol-ether afforded 370 mg (80% yield) of white microcrystalline product: FAB mass spectrum (NBA) m/z (relative intensity) 378 (M+, 2), 343/345 ((M-Cl)+, 100/30); Anal. calcd. for C13H27Cl2MnN5 : C, 41.14; H, 7.18; N, 18.47. Found: C, 40.49; H, 6.56; N, 18.14.