Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH2:11][CH2:12][S:13][CH2:14][CH:15]=3)=[C:7]([C:16]([NH:18][CH3:19])=[O:17])[C:6]=2[CH:20]=1.[F:27][C:28]1[C:29]2[CH:30]=[C:31]3[C:40]4[N:41]=[C:42]([Sn](C)(C)C)[CH:43]=[CH:44][C:39]=4[O:38][CH2:37][N:32]3[C:33]=2[CH:34]=[CH:35][CH:36]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:13]1[CH2:14][CH:15]=[C:10]([C:8]2[O:9][C:5]3[CH:4]=[C:3]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:2]([C:42]4[CH:43]=[CH:44][C:39]5[O:38][CH2:37][N:32]6[C:33]7[CH:34]=[CH:35][CH:36]=[C:28]([F:27])[C:29]=7[CH:30]=[C:31]6[C:40]=5[N:41]=4)=[CH:20][C:6]=3[C:7]=2[C:16]([NH:18][CH3:19])=[O:17])[CH2:11][CH2:12]1
Reactant: C[Sn](C)(C)c1ccc2c(n1)-c1cc3c(F)cccc3n1CO2
Reactant: CNC(=O)c1c(C2=CCSCC2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CNC(=O)c1c(C2=CCSCC2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 100 °C
Yield: 12.1 %

Procedure:
To a solution of 5-bromo-2-(3,6-dihydro-2H-thiopyran-4-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, 0.2 mmol), 11-fluoro-2-(trimethylstannyl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (105 mg, 0.26 mmol) in 1,4-dioxane (5 mL) was added Pd(PPh3)4(10 mg) under nitrogen. The reaction mixture was heated at 100° C. overnight, concentrated in vacuo to remove 1,4-dioxane and purified by prep-TLC (PE:EA=1:1) to give 2-(3,6-dihydro-2H-thiopyran-4-yl)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (15 mg, yield: 11%). 1H-NMR (CDCl3, 400 MHz) δ 7.97 (s, 1H), 7.58 (s, 1H), 7.47 (s, 2H), 7.18˜7.23 (m, 2H), 7.11 (d, J=8.4 Hz, 1H), 6.80˜6.86 (m, 2H), 6.05 (d, J=4.8 Hz, 1H), 5.99 (s, 2H), 3.41 (t, J=2.0 Hz, 2H), 3.35 (s, 3H), 3.00 (d, J=4.8 Hz, 3H), 2.90 (t, J=5.6 Hz, 2H), 2.80 (d, J=3.2 Hz, 2H), 2.71 (s, 3H). MS (M+H)+: 619.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1.C(N(CC)CC)C>C(O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:5]1[N:6]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:7]2[C:3]([N:4]=1)=[C:2]([NH:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)[N:10]=[CH:9][N:8]=2
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C1
Temperature: 80 °C
Yield: 86.1 %

Procedure:
To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (100 mg, 0.267 mmol, 1 eq.) in 3 mL of ethanol was added tert-butyl (3R)-3-aminopiperidine-1-carboxylate (64 mg, 0.32 mmol, 1.2 eq.) and triethylamine (0.06 mL, 0.4 mmol, 1.5 eq.). The reaction was heated to 80° C. for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 124 mg (86%) of tert-butyl (3R)-3-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidine-1-carboxylate. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.33 (br. s., 9 H) 1.49-1.67 (m, 2 H) 1.74 (d, J=6.97 Hz, 1 H) 2.00 (d, J=2.83 Hz, 1 H) 3.20 (br. s, 2 H) 3.50 (br. s, 1 H) 3.88 (br. s, 1 H) 4.32 (br. s., 1 H) 5.87 (d, J=7.44 Hz, 1 H) 7.02-7.54 (m, 8 H) 8.38 (s, 1 H), [M+H]+ 539.3.
Reaction SMILES: [BH4-].[Na+].[OH:3][C@@H:4]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C:24]([O:26][CH3:27])=[O:25])[CH2:5]1>O.CO>[OH:3][C@@H:4]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[C@@H:17]([OH:23])[CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C:24]([O:26][CH3:27])=[O:25])[CH2:5]1
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@]12C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
Sodium borohydride (1.24 g) in water (7 ml) was added to a solution of methyl 3α-hydroxy-11-oxo-5α-androstane-17β-carboxylate (2.58 g) in methanol (60 ml) and the mixture refluxed for 30 minutes. A further portion of sodium borohydride (200 mg) in a little water was added and refluxing continued for 10 minutes more. Most of the solvent was removed in vacuo and, after cooling, the crystalline product was collected by filtration. Recrystallization from aqueous methanol afforded title compound (1.662 g),
Reaction SMILES: O[C:2]1[C:6](=[O:7])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C:3]=1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].Cl.[NH2:23][OH:24].O>N1C=CC=CC=1>[OH:24][N:23]=[C:2]1[C:6](=[O:7])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH:3]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)C1=C(O)C(=O)N(Cc2ccccc2)C1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C1CN(Cc2ccccc2)C(=O)C1=NO
Reaction time: 96 h
Yield: 83.7 %

Procedure:
To a solution of the title compound of Example I (8.07 g, 27.9 mmol) in 150 ml of pyridine was added hydroxylamine hydrochloride (9.69 g, 139 mmol) and resulting solution was stirred for 4 d. Addition of H2O resulted in the formation of precipitate which was filtered to give the title compound (7.11 g, 84%) as a colorless solid. Calculated for C16H20N2O4 1/2H2O: C, 61.35; H, 6.76; N, 8.94. Found C, 61.35; H, 6.57, N, 9.34.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[N:9]=[N+:10]([O-:20])[C:11]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:12]=2[N:13]=1>COCCOC>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:11]2[N+:10]([O-:20])=[N:9][C:8]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[N:13][C:12]=2[CH:14]=1
Reactant: CN(C)CCN
Reactant: COc1ccc2c(c1)nc(Cl)n[n+]2[O-]
Solvent: COCCOC
Product: COc1ccc2c(c1)nc(NCCN(C)C)n[n+]2[O-]
Yield: 67.7 %

Procedure:
N,N-Dimethyl-1,2-ethanediamine (1.33 mL, 12.1 mmol) was added to a stirred solution of chloride 7 (0.85 g, 4.04 mmol) in DME (50 mL) and the solution stirred at reflux temperature for 16 h. The solvent was evaporated and the residue was partitioned between DCM (100 mL) and dilute aqueous NH3 (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give amine 8 (0.72 g, 68%) which was dissolved in HCl-saturated MeOH, the solvent evaporated and the residue crystallized as a tan solid, mp (MeOH/EtOAc) 236-239° C.; 1H NMR [(CD3)2SO] δ 10.68 (br s, 1 H, NH+Cl−), 8.07 (d, J=9.3 Hz, 1 H, H-8), 8.03 (br s, 1 H, NH), 6.95-6.99 (m, 2 H, H-5, H-7), 3.92 (s, 3 H, OCH3), 3.70-3.76 (m, 2 H, CH2N), 3.30-3.35 (m, 2 H, CH2N), 2.81 [d, J=4.9 Hz, 6 H, N(CH3)2]; 13C NMR [(CD3)2SO] δ 164.9, 159.0, 150.4, 125.4, 121.6, 117.3, 104.3, 55.2, 55.0, 42.3 (2), 35.8. Anal. Calcd for C12H18ClN5O2: C, 48.1; H, 6.1; N, 23.4; Cl, 11.8. Found: C, 48.3; H, 6.1; N, 23.6; Cl, 11.9%.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2]2=[O:8].[CH3:9][Mg]Br.C1COCC1>C(OCC)C>[CH3:9][C:2]1([OH:8])[CH2:3][CH:4]2[CH2:7][CH:1]1[CH2:6][CH2:5]2
Reactant: O=C1CC2CCC1C2
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)CC2CCC1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of bicyclo[2.2.1]heptan-2-one (25 g, 0.23 mol) in diethyl ether (250 mL) was added a solution of methylmagnesium bromide in THF (3 mol/L, 90 mL, 0.27 mol) over 1 h at 0° C. The reaction mixture was stirred for an additional 30 min as it was warmed to room temperature. Then the reaction was quenched with 40 mL saturated aqueous ammonium chloride solution. The resulting mixture was extracted with diethyl ether (3×80 mL). The organic layers were combined and concentrated to give the desired product (26 g, 0.205 mol, yield: 90%). 1H NMR (400 MHz, CDCl3) δ ppm 2.20 (s, 1H), 2.01 (s, 1H), 1.94 (s, 1H), 1.61-1.49 (m, 3H), 1.34-1.20 (m, 7H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[O:15][CH2:16][CH3:17])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:24][NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=1>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:16]([O:15]/[C:9](=[CH:8]\[C:5]1[CH:6]=[CH:7][C:2]([C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([NH:25][CH3:24])[CH:27]=2)=[CH:3][CH:4]=1)/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:17]
Reactant: CCOC(=O)/C(=C/c1ccc(Br)cc1)OCC
Reactant: CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(=C/c1ccc(-c2cccc(NC)c2)cc1)OCC
Yield: 89.4 %

Procedure:
To a solution of 10.8 g (36.1 mmol) of ethyl (Z)-3-(4-bromophenyl)-2-ethoxyacrylate prepared beforehand as described in Example 1c and 108 mL (217 mmol) of aqueous 2 M sodium carbonate solution in 120 mL of toluene, 1.5 g (1.8 mmol) of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium are added. The reaction medium is stirred and a solution of 9.25 g (39.7 mmol) of methyl[3-(4,4,5,5-tetramethyl[1.3.2]dioxaborolan-2-yl)phenyl]amine in 90 mL of ethanol is then added dropwise. After stirring at 80° C. for 2 hours, the reaction medium is hydrolyzed and diluted with ethyl acetate. After separation of the phases by settling, the ethyl acetate phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 90/10 and then 80/20 heptane/ethyl acetate mixture. 10.5 g (94%) of ethyl (Z)-2-ethoxy-3-(3′-methylaminobiphenyl-4-yl)acrylate are obtained in the form of a yellow oil. After taking up the product in pentane, 9.5 g (85%) of ethyl (Z)-2-ethoxy-3-(3′-methylaminobiphenyl-4-yl)acrylate are obtained in the form of a pale yellow solid with a melting point of 52° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-])=O)[N:3]=1.O.O.Cl[Sn]Cl.O.C([O-])(O)=O.[Na+]>C(O)C>[Br:1][C:2]1[N:3]=[C:4]([NH2:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc([N+](=O)[O-])nc1Br
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(N)nc1Br
Temperature: 25 °C
Yield: 63 %

Procedure:
To a solution of 2-bromo-3-methoxy-6-nitropyridine (2.0 g, 8.6 mmol) in ethanol (20 mL) was added SnCl2.2H2O (3.9 g, 17 mmol) at room temperature. The reaction was heated at reflux for 2 h. After cooling to room temperature, the reaction mixture was poured into water (50 mL), basified to pH to 8 with saturated NaHCO3 and extracted with ethyl acetate (50×3 mL). The combined organic layers were dried over Na2SO4, evaporated in vacuo and purified by chromatography on silica gel (20% ethyl acetate in petroleum ether) to afford 6-bromo-5-methoxypyridin-2-amine (1.1 g, 65%). 1H-NMR (300 MHz, CDCl3) δ 7.09 (d, J=8.4, 1H), 6.43 (d, J=8.4, 1H), 4.27 (br s, 2H), 3.82 (s, 3H).
Reaction SMILES: N(C1CCCC1)=C=S.[CH:9]1([NH:14][C:15]([NH2:17])=[S:16])[CH2:13][CH2:12][CH2:11][CH2:10]1.Br[CH2:19][C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)=O>N.CO.C1COCC1>[CH:9]1([NH:14][C:15]2[S:16][CH:19]=[C:20]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)[N:17]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NC(=S)NC1CCCC1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Agent: N
Agent: S=C=NC1CCCC1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2csc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Isothiocyanato-cyclopentane (4 g) in ammonia (37% in water, 8 mL) and methanol (32 mL) was stirred for 16 hours, filtered of and dried. The Cyclopentyl-thiourea (2.06 mmol) and 4-(2-Bromo-acetyl)-benzoic acid (2.06 mmol) were mixed in THF (12 mL). After stirring at room temperature for 5 minutes the mixture was heated to 80° C. for 2 hours. The mixture was then cooled to room temperature and filtered. The solid was washed with a small amount of diethylether and dried. m/z=289.05 in MS ES+, which was characterized by hplc and MS and used in the next step without any further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C@H:33]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:43]=[C:44]([NH:48][C:49](=[O:53])[CH:50]([CH3:52])[CH3:51])[CH:45]=[CH:46][CH:47]=2)[CH2:38][CH2:37]1.[CH3:60][O:61][C:62]1[CH:63]=[C:64](O)[CH:65]=[CH:66][C:67]=1[O:68][CH3:69]>C1COCC1>[CH3:60][O:61][C:62]1[CH:63]=[C:64]([CH:65]=[CH:66][C:67]=1[O:68][CH3:69])[O:32][C@@H:33]([C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:43]=[C:44]([NH:48][C:49](=[O:53])[CH:50]([CH3:52])[CH3:51])[CH:45]=[CH:46][CH:47]=2)[CH2:38][CH2:37]1
Reactant: COc1ccc(O)cc1OC
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(O[C@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.1 %

Procedure:
Into a 25-mL RB-flask was added triphenylphosphine (9.80 mg, 0.0375 mmol), diethyl azodicarboxylate (5.22 mg, 0.0300 mmol), N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 3,4-dimethoxyphenol (7.70 mg, 0.0500 mmol) and THF (1.00 mL) at room temperature. The reaction mixture was stirred at room temperature overnight (16 h). The solvent was removed under reduced pressure and the residue was purified by preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] to afford the desired product (4.40 mg, 34.1% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.40–7.30 (m, 4H), 7.25 (m, 3H), 6.97 (d, 1H, J=7.8 Hz), 6.64 (d, 1H, J=9.1 Hz), 6.51 (d, 1H, J=2.6 Hz), 6.29 (d, 1H, J=2.6, 9.1 Hz), 5.20 (apparent dd, 1H, J=4.4, 8.5 Hz), 3.80 (s, 3H), 3.77 (s, 3H), 3.23 (m, 2H), 2.77 (m, 2H), 2.5 (m, 2H), 2.3–2.1 (m, 6H), 1.80 (m, 2H), 1.25 (d, 6H, J=7.9 Hz); ESMS m/e: 517.4 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[C:22]([C:29]5[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=5[Cl:36])=[N:23][O:24][C:25]=4[CH:26]4[CH2:28][CH2:27]4)=[CH:15][C:14]=3[Cl:37])([OH:12])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:80][N:81](C=O)C>O.[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:80]([C:2]1[CH:3]=[C:4]([CH:8]2[CH2:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[C:22]([C:29]5[C:30]([Cl:36])=[CH:31][CH:32]=[CH:33][C:34]=5[Cl:35])=[N:23][O:24][C:25]=4[CH:26]4[CH2:28][CH2:27]4)=[CH:15][C:14]=3[Cl:37])([OH:12])[CH2:11]2)[CH:5]=[CH:6][CH:7]=1)#[N:81]
Reactant: CN(C)C=O
Reactant: OC1(c2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C3CC3)cc2Cl)CC(c2cccc(Br)c2)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#Cc1cccc(C2CC(O)(c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)cc3Cl)C2)c1
Temperature: 115 °C
Reaction time: 10 h
Yield: 42 %

Procedure:
To a solution of compound 2b (3.1 g, 5 mmol) in DMF (50 mL) were added under argon atmosphere Zn(CN)2 (500 mg, 4.3 mmol), Pd2(dba)3 (300 mg, 0.33 mmol) and Xantphos (150 mg, 0.31 mmol). The mixture was stirred for 10 h at 115° C. under microwave irradiation. After cooling to rt the reaction mixture was diluted with water (250 mL) and extracted with EA (250 mL×2). The combined organic layers were washed with brine (100 mL×3) and dried over Na2SO4. The residue was purified by CC (EA/PE) to give the title compound 2c (1.2 g, 42%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7](/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH:17]([O:20][Si](C(C)C)(C(C)C)C(C)C)[CH2:16][CH2:15]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7](/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][CH:17]([OH:20])[CH2:18][CH2:19]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](/C=C/CCC2CCC(O[Si](C(C)C)(C(C)C)C(C)C)CC2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@H]1CC[C@H](/C=C/CCC2CCC(O)CC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(E)-(4-(trans-4-Propylcyclohexyl)but-3-en-1-yl)-4-triisopropylsilyloxycyclohexane (s43) (8.3 g) and THF (50 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to 0° C. Tetrabutylammonium fluoride (TBAF; 1.0 M; in THF; 38.0 ml) was added in the temperature range of 0° C. to 5° C. After 1 hour of stirring at 0° C., the reaction mixture was allowed to come to room temperature, and the stirring was continued for another 8 hours. After the completion of the reaction had been confirmed by means of GC analysis, the reaction mixture was treated with water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder to give (E)-4-(4-(trans-4-propylcyclohexyl)but-3-en-1-yl)cyclohexanol (s44) (4.7 g). The yield based on the compound (s43) was 88.4%.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]2[N:27]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[S:29][C:30]=2[Br:31])=[CH:20][CH:19]=1)[NH:9]C(=O)OC(C)(C)C)(C)(C)C.[ClH:37]>O1CCOCC1>[ClH:37].[NH2:9][C:8]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]2[N:27]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[S:29][C:30]=2[Br:31])=[CH:20][CH:19]=1)=[NH:7]
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)c(Br)s1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(CCc2ccc(NC(=N)N)cc2)c(Br)s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Di-tert-butyl{[(4-{2-[2-(acetylamino)-5-bromo-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamate (113 mg) and 4N hydrochloric acid in 1,4-dioxane solution (2 ml) were combined under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo. The residue was washed with ethyl acetate to give N-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-bromo-1,3-thiazol-2-yl}acetamide hydrochloride (16.8 mg) as a pale yellow amorphous solid.
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[OH-].[Na+:13].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Cl.Cl>O>[Cl:14][C:15]1[CH:16]=[C:17]([CH2:18][NH:9][C:6]2[CH:5]=[CH:4][C:3]([S:1]([O-:11])(=[O:10])=[O:2])=[CH:8][CH:7]=2)[CH:20]=[CH:21][CH:22]=1.[Na+:13]
Reactant: ClCc1cccc(Cl)c1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)([O-])c1ccc(NCc2cccc(Cl)c2)cc1
Temperature: 50 °C
Reaction time: 120 h

Procedure:
A mixture of 17.2 g of sulfanilic acid, 100 ml of 5 Normal (N) sodium hydroxide solution, 100 ml of water and 16.1 g of 3-chlorobenzyl chloride was stirred in a 500-ml Erlenmeyer flask and heated to about 40°-50° C. After 5 days, a small portion of the reaction mixture was poured into dilute hydrochloric acid. A white precipitate formed which was insoluble in boiling water. The remaining portion of the reaction mixture was poured over 800 ml of ice-water, acidified with concentrated hydrochloric acid, and then filtered through a sintered glass funnel. After filtering, about 50 ml of slurry remained in the funnel. This slurry was put in a beaker, 200 ml of ethanol was added and the mixture was warmed to about 50° C. A solution of 5N sodium hydroxide was added dropwise until solution was achieved. The solution was carbon treated and filtered. Concentration of the filtrate gave a gummy semisolid which was recrystallized from 200 ml of acetic acid containing a small quantity of water. After vacuum oven drying, 5.4 g of the purified product, sodium 4-(((3-chlorophenyl)methyl)amino)benzenesulfonate, was obtained as an off-white solid having a melting point (mp) greater than 280° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:16]=[C:17]([C:25]([OH:27])=[O:26])[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO.CCOCC>[OH:14][C:11]1([C:15]2[CH:16]=[C:17]([C:25]([O:27][CH3:28])=[O:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(C(=O)O)c3ccccc3c2)CC1
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc2ccccc12

Procedure:
To a solution of 1.3 g (3.5 mmol) of the above 3-[1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl]-1-naphthoic acid in 10 mL of methanol and 10 mL of ether was added 2.0 mL (4.0 mmol) of a 2.0 M solution of (trimethylsilyl)diazomethane in ether. Glacial acetic acid was the added dropwise until gas evolution ceased and then the reaction was concentrated in vacuo to yield the crude title compound as a yellow oil. LC/MS 408.1 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=[N:10]1.[Br:19]Br.O>C(O)(=O)C>[Br:19][C:12]1[CH:11]=[N:10][N:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: BrBr
Reactant: CCOC(=O)c1ccnn1-c1c(Cl)cccc1Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(Br)cnn1-c1c(Cl)cccc1Cl
Reaction time: 60 h

Procedure:
14.3 g of ethyl 1-(2,6-dichlorophenyl)-pyrazole-5-carboxylate from Example 4 were dissolved in 100 ml of glacial acetic acid, 10 g of Na acetate were added, and 4.5 g of bromine were added dropwise at room temperature. After 60 hours, the reaction mixture was poured into 1 liter of water, washed with water and recrystallized from ethanol.