Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1(Cl)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C1C=CC=CC=1>[CH:5]1([C:5]2[C:6]([CH:5]3[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)=[C:7]([CH:5]3[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[CH:8]=[CH:9][CH:10]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: ClC1CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: c1cc(C2CCCCC2)c(C2CCCCC2)c(C2CCCCC2)c1
Temperature: 3 °C
Yield: 50.7 %

Procedure:
Aluminum chloride (6.83 g) was added to 20.0 g of benzene, and the mixture was stirred under cooling at 3° C. Thereto, 40.4 g of cyclohexyl chloride was slowly added dropwise. After the dropwise addition, the mixture was stirred at room temperature for 5 hours and then poured in ice water. The organic layer was extracted with ethyl acetate, and the obtained organic layer was distilled at 40° C. under reduced pressure, further distilled at 170° C. under reduced pressure, then cooled to room temperature, and recrystallized by charging 50 ml of acetone. The precipitated crystal was collected by filtration to obtain 14 g of tricyclohexylbenzene.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17]C(=O)C)=[CH:13][CH:12]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[OH-].[NH4+]>B(F)(F)F.CO>[Cl:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(OCc2nc(Cl)ccc2Cl)cc1
Agent: FB(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(OCc2nc(Cl)ccc2Cl)cc1
Temperature: 0 °C

Procedure:
N-(4-((3,6-Dichloro-2-pyridinyl)methoxy)phenyl)acetamide (30.27 grams; 0.097 mole) was mixed with a 270 ml. solution of boron trifluoride-methanol (1 gram per 10 ml.) and the resulting reaction mixture refluxed for a period of 4 1/2 hours. The reaction mixture was then diluted and cooled with ice water to a temperature of between about 0° to about 10° C. Concentrated ammonium hydroxide was added until the reaction mixture was basic. The reaction mixture was then extracted with portions of methylene chloride, the extracts combined and the solvent removed by evaporation. The residue thus obtained was extracted with five 500 ml. portions of hexane. The crystalline material which precipitated from the hexane mixture upon cooling was recovered by filtration. As a result of these operations, the desired 4-((3,6-dichloro-2-pyridinyl)methoxy)benzenamine compound was recovered as a light yellow crystalline solid having a melting point of 74°-75° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1>>[NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:6][C:5]([C:24]2[CH:23]=[N:22][N:21]([CH3:20])[C:25]=2[CH3:26])=[CH:4][N:3]=1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C
Reactant: COC(=O)c1ccc(-c2cc(Br)cnc2N)cc1F
Product: Cc1c(-c2cnc(N)c(-c3ccc(C(=O)O)c(F)c3)c2)cnn1C

Procedure:
Following Steps 1 and 2 in Scheme 97, using methyl 4-(2-amino-5-bromopyridin-3-yl)-2-fluorobenzoate and 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 4-(2-amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-fluorobenzoic acid was obtained. LCMS (m/z): 327.1 (MH+), 0.45 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH2:12])[O:9][CH:8]=[N:7]1)=[O:5])[CH3:2].[OH2:30]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:5])[CH:6]([NH:7][CH:8]=[O:30])[CH:10]([OH:9])[C:11](=[CH2:12])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH3:2]
Reactant: O
Reactant: C=C(CCCCCCNC(=O)OCc1ccccc1)C1OC=NC1C(=O)OCC
Solvent: C1CCOC1
Product: C=C(CCCCCCNC(=O)OCc1ccccc1)C(O)C(NC=O)C(=O)OCC

Procedure:
8.15 g (20.25 mmol) of 5-[8-(N-benzyloxycarbonylamino)oct-1-en-2-yl]-oxazoline-4-carboxylic acid ethyl ester are heated under reflux in 40 ml of tetrahydrofuran and 20 ml of water for 4 hours with stirring. The reaction mixture is concentrated to dryness by evaporation in vacuo at 45°, and the honey-like residue is concentrated by evaporation twice more after the addition of toluene. The crude product is dissolved in dichloromethane, dried with sodium sulfate, filtered and concentrated by evaporation. Drying under a high vacuum at room temperature yields 9.03 g of 10-(N-benzyloxycarbonylamino)-2-formylamino-3-hydroxy-4-methylene-decanoic acid ethyl ester in the form of a yellowish honey.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]([CH3:14])=[CH:12][C:11](Cl)=[CH:10][CH:9]1[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Li+].[Li+].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:13]([CH3:14])=[CH:12][CH2:11][CH2:10][CH:9]1[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCC1C=C(Cl)C=C(C)N1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CO
Product: CCCCCC1CCC=C(C)N1C(=O)OC(C)(C)C
Yield: 97.9 %

Procedure:
To a stirred solution of 1-(tert-Butoxycarbonyl)-4-chloro-6-methyl-2-n-pentyl-1,2-dihydropyridine (3.48 g, 11.61 mmol) in 220 mL of MeOH at 0° C. was added of lithium carbonate 0.857 g, 11.61 mmol) followed by 5% Pd/C. The mixture was placed under a positive pressure of hydrogen gas from a balloon, and the reaction progress was monitored by removing aliquots with a syringe, concentrating the aliquot in vacuo, and examining its 1H NMR spectrum. Upon completion, the mixture was filtered through Celite and evaporated. The residue was dissolved in ether (100 mL) and water (50 mL) was added, and the aqueous phase was extracted twice with ether. The combined organic extracts were washed with 1M NaOH and brine. The organic phase was dried with potassium carbonate, filtered through Celite, and concentrated in vacuo to give the crude product. Purification by column chromatography (silica gel, 5% EtOAc in hexanes) afforded 3.04 g (98%) of the product which was homogeneous by TLC analysis. 1H NMR (300 MHz) d 4.86 (br s, 1 H), 4.39-4.31 (m, 1 H), 2.02 (s, 3 H), 1.98-1.92 (m, 2 H), 1.91-1.28 (m, 21 H), 0.9-0.85 (t, 3 H); 13C NMR (75 MHz) 153.8 (s), 132.5 (s), 110.9 (s), 79.9 (s), 51.9 (s), 31.7 (s), 29.4 (s), 28.3 (s), 26.0 (s), 25.8 (s), 23.1 (s), 22.6 (s), 19.5 (s), 13.9 (s) ppm. FT-IR (neat) 2956, 2927, 2856, 1693, 1658, 1454, 1349, 1253, 1169, 1124, 1072 cm−1.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:11][C:10](=[O:12])[N:9]([CH2:13][CH3:14])[C:8]=1[CH3:15])=O.[N+]([O-])(O)=O.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([NH:29][C:30]([NH2:32])=[NH:31])=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>COCCO>[CH2:13]([N:9]1[C:8]([CH3:15])=[C:7]([C:5]2[CH:4]=[CH:3][N:32]=[C:30]([NH:29][C:26]3[CH:27]=[N:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[N:31]=2)[S:11][C:10]1=[O:12])[CH3:14]
Reactant: CCn1c(C)c(C(=O)C=CN(C)C)sc1=O
Reactant: COc1ccc(NC(=N)N)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: COCCO
Product: CCn1c(C)c(-c2ccnc(Nc3ccc(OC)nc3)n2)sc1=O
Temperature: 120 °C
Yield: 39.4 %

Procedure:
5-(3-Dimethylamino-acryloyl)-3-ethyl-4-methyl-3H-thiazol-2-one (80 mg, 0.333 mmol), N-(6-methoxy-pyridin-3-yl)-guanidine nitrate (76 mg, 0.333 mmol) and K2CO3 (185 mg, 1.332 mmol) were combined in of 2-methoxyethanol (4 mL) and the mixture was heated at 120° C. for 22 h. After cooling, the inorganics were filtered off and the filtrate was concentrated to dryness. The crude product was purified by SiO2 gel chromatography. Pooling of the desired fractions afforded the title compound (45 mg, 39%). 13C-NMR (d6-DMSO) δ: 14.5, 14.7, 37.3, 53.7, 109.0, 110.3, 128.4, 131.82, 132.4, 137.8, 138.4, 152.7, 159.5, 160.3, 164.7, 170.1. Remaining analytical data in Table 2.
Reaction SMILES: [N+](C1C=CC([O:8][C:9]([P:11](=[O:20])([O:16][CH:17]([CH3:19])[CH3:18])[O:12][CH:13]([CH3:15])[CH3:14])=O)=CC=1)([O-])=O.[C:23]1([C:29]([NH:42][C@@H:43]([CH2:46][NH2:47])[CH2:44][OH:45])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH:13]([O:12][P:11]([C:9]([NH:47][CH2:46][C@H:43]([NH:42][C:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:44][OH:45])=[O:8])([O:16][CH:17]([CH3:19])[CH3:18])=[O:20])([CH3:15])[CH3:14]
Reactant: CC(C)OP(=O)(OC(C)C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)OP(=O)(OC(C)C)C(=O)NC[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of diisopropyl 4-nitrophenoxycarbonylphosphonate (i-Pr-NPPF) (9.27 g, 28 mmol) in dry CH2Cl2 (50 mL) was added dropwise to a solution of (S)-2-triphenylmethylamino-3-aminopropanol (9.3 g, 28 mmol) in dry CH2Cl2 (100 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 h. Workup was done by washing the reaction mixture successively with 0.5 M NaOH and water. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue obtained was purified by column chromatography (silica gel, 70% EtOAc in pet. ether) to provide (S)-3-diisopropylphosphonoformamido-2-(tritylamino)propanol as gummy solid in 82% (12.0 g) yield.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:6]2[C:7]3[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]=3[CH:15]=[CH:16][CH:17]=2)(=[O:4])=[O:3].[H-].[Na+].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>CN(C)C=O>[CH:22]1([CH2:21][N:10]2[C:11]3[C:7]4[C:6](=[CH:17][CH:16]=[CH:15][C:8]=4[C:9]2=[O:14])[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=3)[CH2:24][CH2:23]1
Reactant: BrCC1CC1
Reactant: CS(=O)(=O)c1ccc2c3c(cccc13)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2c3c(cccc13)C(=O)N2CC1CC1
Reaction time: 17 h

Procedure:
A mixture of 2.5 g of 6-(methylsulfonyl)-benz[cd]indol-2(1H)-one (Example 3) in 50 ml of N,N-dimethylformamide is treated with 0.35 g of sodium hydride and 1.5 ml of (bromomethyl)cyclopropane at 75° C. in a pressure bottle for 24 hours. An additional 1.5 ml of (bromomethyl)cyclopropane is added and heating continued at 75° C. for 17 hours in a pressure bottle. The reaction mixture is cooled then evaporated. The concentrate is chromatographed on silica gel using 1:1 ethyl acetate-hexane to afford 0.72 g of the desired product as yellow crystals, m.p. 148°-150° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([S:24](Cl)(=[O:26])=[O:25])[N:5]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[CH3:28][NH2:29]>CC(C)=O.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([S:24]([NH:29][CH3:28])(=[O:26])=[O:25])[N:5]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CN
Reactant: CC(C)(C)[Si](C)(C)OCc1c(Cl)nc(S(=O)(=O)Cl)n1COCC[Si](C)(C)C
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1nc(Cl)c(CO[Si](C)(C)C(C)(C)C)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A solution of 4-chloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-sulfonyl chloride (0.341 g, 0.72 mmol) in acetone (4.5 mL) and THF (2.5 mL) was added to a 0° C. solution of methylamine (3.6 mL of a 2M solution in THF, 7.2 mmol) in THF (2 mL). The reaction mixture was stirred at RT for 1 h and evaporated. The residue was taken up in EtOAc and washed with brine. The organic phase was dried (Na2SO4), filtered evaporated, and purified by silica gel chromatography (0-25% EtOA/hexanes) to give the title compound (0.23 g, 68%) as a light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.85 (br. s., 1H), 5.73 (s, 2H), 4.75 (s, 2H), 3.59-3.68 (m, 2H), 2.86 (d, J=5.1 Hz, 3H), 0.93 (d, J=8.4 Hz, 2H), 0.89 (s, 9H), 0.10 (s, 6H), −0.01 (s, 9H).
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].Cl.Cl[C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)[CH:12]=1)=[O:10]>CO>[C:20]1([N:13]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:19]3[C:11]([C:9]([NH:5][C:4]([NH2:6])=[NH:3])=[O:10])=[CH:12]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][N:21]=1
Reactant: N=C(N)N
Reactant: O=C(Cl)c1cn(-c2nccc3ccccc23)c2ncccc12
Agent: Cl
Agent: [Na]
Solvent: CO
Product: N=C(N)NC(=O)c1cn(-c2nccc3ccccc23)c2ncccc12

Procedure:
0.397 g (17.28 mmol) of sodium (washed beforehand in toluene) was gradually added to 40 cm3 of methanol at a temperature in the region of 20° C. under an argon atmosphere. After dissolving with stirring, 1.685 g (17.28 mmol) of guanidine hydrochloride were added and the mixture was stirred at a temperature in the region of 20° C. for 1 h 30. The reaction mixture was filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue was subsequently taken up in a mixture of 70 cm3 of tetrahydrofuran and 70 cm3 of dichloromethane under an argon atmosphere at a temperature in the region of 20° C. and then 3.46 mmol of 3-chlorocarbonyl-1-(isoquinolin-1-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride were added thereto with stirring. After stirring at a temperature in the region of 20° C. for 15 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The solid residue was taken up in 100 cm3 of water and stirred for 2 h, and then the insoluble material was filtered off. The solid was dried and then triturated in 20 cm3 of cyclohexane. The solid was filtered off and then dried at a temperature in the region of 20° C. under reduced pressure (2.7 kPa) and 0.784 g of N-[1-(isoquinolin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine was thus obtained in the form of a light yellow solid melting at 250° C. 1H N.M.R. spectrum (300 MHz, (CD3)2SO, δ in ppm): 7.31 (dd, J=8 and 5 Hz, 1H), 7.58 (broad d, J=8.5 Hz, 1H), 7.66 (ddd, J=8.5, 7.5 and 1 Hz, 1H), 7.89 (ddd, J=8.5, 7.5 and 1 Hz, 1H), 8.09 (d, J=5.5 Hz, 1H), from 8.10 to 8.25 (mt, 2H), 8.29 (s, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.90 (dd, J=8 and 1.5 Hz, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:37]=[CH:36][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)(Cl)Cl>[CH3:45][S:46]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:37]=[CH:36][C:18]([C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[CH:26][CH:27]=2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[N:13]([S:46]([CH3:45])(=[O:48])=[O:47])[CH:12]=[CH:11][N:10]=1)(=[O:48])=[O:47]
Reactant: CS(=O)(=O)Cl
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3nccn3S(C)(=O)=O)Cc3nccn3S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The compound (52.9 mg) obtained in Example 19-3 was dissolved in anhydrous chloroform (2.0 ml). The solution was added with triethylamine (0.054 ml) and then added with methanesulfonyl chloride (manufactured by Kanto Kagaku) (0.027 ml), followed by stirring at room temperature for 17 hours. After completion of the reaction, chloroform (3.0 ml) was added to the solution, and the whole was washed with water. The organic layer was dried with anhydrous magnesium sulfate. Subsequently, the solvent was distilled off and the residue was then purified through silica gel column chromatography (manufactured by Fuji Silysia Chemical Ltd.) (hexane/ethyl acetate), thereby obtaining the subject compound (31.7 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[N:16]=[C:6]2[N:7]=[C:8]3[CH2:15][CH2:14][CH2:13][S:12][C:9]3=[C:10](Cl)[N:5]2[N:4]=1.CC(O)C.[NH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl.C(N(CC)CC)C>C(N(CC)CC)C>[CH3:1][N:2]([CH3:17])[C:3]1[N:16]=[C:6]2[N:7]=[C:8]3[CH2:15][CH2:14][CH2:13][S:12][C:9]3=[C:10]([NH:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:5]2[N:4]=1
Reactant: NCCN1CCOCC1
Reactant: CN(C)c1nc2nc3c(c(Cl)n2n1)SCCC3
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CN(C)c1nc2nc3c(c(NCCN4CCOCC4)n2n1)SCCC3
Reaction time: 1 h

Procedure:
To a suspension of 5.40 g (0.02 mole) of 2-(dimethylamino)-5-chloro-7,8-dihydro-9H-thiopyrano[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidine in 20 ml of 2-propanol 2,125 g (0.021 mole) of triethylamine and 2.73 g (0.021 mole) of 2-aminoethylmorpholine are successively added, and the reaction mixture is boiled for one hour. Upon cooling triethylamine hydrochloride gets separated, which is filtered and washed with 2-propanol. The filtrate is evaporated to dryness in vacuo and the residue is dissolved in chloroform. The solution thus obtained is extracted twice with water, dried over anhydrous Na2SO4 and evaporated in vacuo. The oily product is suspended in ethyl acetate, the crystalline product thus obtained is filtered off and washed with ethyl acetate.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]([F:30])([F:29])[CH2:24][S:25](Cl)(=[O:27])=[O:26]>>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[S:25]([CH2:24][C:23]([F:30])([F:29])[F:22])(=[O:27])=[O:26])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: c1ccc(Oc2ccc(NCc3cccnc3)cc2)cc1
Product: O=S(=O)(CC(F)(F)F)N(Cc1cccnc1)c1ccc(Oc2ccccc2)cc1

Procedure:
Using the method of Example 343 using N-(4-phenoxypheny)pyridin-3-ylmethylamine and 2,2,2-trifluoroethanesulfonyl chloride (Aldrich) and purifying via preparative HPLC eluting with 90:10 to 70:30 DCM/ethyl acetate gave the title compound. Anal Calcd for C20H17F3N2O3S: C, 56.87; H, 4.06; N, 6.63. Found: C, 56.76; H, 4.09; N, 6.69. MS found 423.1 [M+H]+
Reaction SMILES: C(OC([N:8]=[C:9]([N:11](C(OC(C)(C)C)=O)[O:12][CH2:13][CH2:14][NH:15][C:16](=[O:39])[CH2:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[C:20]([NH:26][CH2:27][C:28]([F:37])([F:36])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=2)[C:19]=1[F:38])[NH2:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:9]([NH:11][O:12][CH2:13][CH2:14][NH:15][C:16](=[O:39])[CH2:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[C:20]([NH:26][CH2:27][C:28]([F:36])([F:37])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=2)[C:19]=1[F:38])(=[NH:8])[NH2:10]
Reactant: Cc1ccc(C(F)(F)CNc2ccc(C#N)c(CC(=O)NCCON(C(=O)OC(C)(C)C)C(N)=NC(=O)OC(C)(C)C)c2F)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(F)(F)CNc2ccc(C#N)c(CC(=O)NCCONC(=N)N)c2F)nc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 71.9 %

Procedure:
N-[2-(N′,N″-Bis(tert-butoxycarbonyl)amidinoaminooxy)ethyl]-2-{3-[(2,2-difluoro-2-(5-methylpyridyl)ethyl)amino]-6-cyano-2-fluorophenyl}acetamide (832 mg, 1.28 mmol), as prepared in the previous step, was dissolved into CH2Cl2 (6 mL), cooled to 0° C. and treated with TFA (2 mL), then allowed to warm to rt. After 12 h, the reaction was concentrated in vacuo to afford a yellow oil. Purification via flash chromatography (inactivated with NH3, 10% MeOH/CH2Cl2) afforded the product as a white solid (413 mg, 0.92 mmol, 72% yield). 1H NMR (300 Hz, CD3OD) δ 8.49 (s, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.27 (d, J=8.6 Hz, 1H), 6.82 (t, J=8.2 Hz, 1H), 4.07 (t, J=13.8 Hz, 2H), 3.79 (t, J=5.3 Hz, 2H), 3.72 (d, J=1.98 Hz, 2H), 3.42 (t, J=5.3 Hz, 2H), 2.39 (s, 3H); LC/MS (m/z) [M+1]+ 450.2 (calculated for C20H23F3N7O2, 450.4).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:6]=1[CH:14](C(OC)=O)[C:15]([O:17]C)=O)=[O:4]>Cl>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[CH2:14][C:15](=[O:17])[NH:11]2)([OH:2])=[O:4]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C(C(=O)OC)C(=O)OC
Agent: Cl
Product: O=C1Cc2c(cccc2C(=O)O)N1
Yield: 38.1 %

Procedure:
Dimethyl 2-methoxycarbonyl-6-nitrophenylmalonate (3.0 g) was refluxed in 50 mL of 6 N hydrochloric acid overnight. The mixture was concentrated to dryness and refluxed for 2 hours with 1.1 g of tin(II) chloride in 20 mL of ethanol. The mixture was filtered through Celite, concentrated and chromatographed on silica gel (ethyl acetate:hexane:acetic acid) to give 0.65 g (37% yield) of 4-carboxy-2-oxindole as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[C:12](=[N:13]O)[CH2:11][CH2:10][CH2:9][C:7]=3[O:8][C:4]=2[CH:3]=1.[OH-:17].[Na+]>O>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[C:12](=[O:17])[NH:13][CH2:11][CH2:10][CH2:9][C:7]=3[O:8][C:4]=2[CH:3]=1
Reactant: ON=C1CCCc2oc3cc(Br)ccc3c21
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C1NCCCc2oc3cc(Br)ccc3c21
Temperature: 110 °C
Yield: 82 %

Procedure:
A mixture of the product of step B (1.05 g, 3.74 mmol) and polyphosphoric acid (15 g) was heated to 110° C. for 5 h. After cooling to ambient temperature, the reaction mixture was diluted with water, basified with 10 N NaOH and filtered. The solid obtained was washed with water and dried in vacuo at 70° C. to give 8-bromo-2,3,4,5-tetrahydro-1H-benzofuro[3,2-c]azepin-1-one (858 mg, 82%) as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ 8.06-7.95 (m, 2H), 7.86 (d, J=1.8 Hz, 1H), 7.45 (dd, J=8.4, 1.8 Hz, 1H), 3.28-3.20 (m, 2H), 3.15 (t, J=6.6 Hz, 2H), 2.07-1.93 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12]OS(C)(=O)=O)=[CH:5][CH:4]=1.[N-:18]=[N+:19]=[N-:20].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][N:18]=[N+:19]=[N-:20])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(COS(C)(=O)=O)CC2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)C(CN=[N+]=[N-])CC2
Reaction time: 1 h

Procedure:
12.8 g (50 mmol) of methanesulphonic acid (6-methoxyindan-1-ylmethyl) ester and 5.2 g (80 mmol) of sodium azide are dissolved in 130 ml of dimethyl sulphoxide and stirred at 80° for 1 hour. The reaction mixture is poured onto ice-water and extracted by shaking with diethyl ether. The organic phases are washed twice with saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness by evaporation under reduced pressure. 9.7 g of crude, oily 6-methoxyindan-1-ylmethylazide are obtained as residue.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2].[C:11](Cl)(=[O:14])[CH2:12][CH3:13]>>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[C:11](=[O:14])[CH2:12][CH3:13])[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CCNc1cccc(C)c1
Product: CCC(=O)N(CC)c1cccc(C)c1

Procedure:
N-Ethyl-N-(3-methylphenyl)propionamide was prepared on a laboratory scale by acylation of N-ethyl-m-toluidine with propionyl chloride. The reaction was carried out in a 5 litre 3 necked round bottomed flask equipped with a mechanical stirrer, a thermometer (0°-250° C.), an addition vessel and a condenser.