Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:20]1>CS(C)=O>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][N:21]2[CH2:22][CH2:23][CH2:24][C@@H:20]2[CH2:19][N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=3[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]2=3)=[CH:32][CH:31]=1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: Fc1ccc(CCN2CCC[C@H](Cl)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Fc1ccc(CCN2CCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
Four-hundred milligrams (9.9 mmols) of 60% sodium hydride were washed with petroleum ether, and then suspended in 40 ml of dimethyl sulfoxide. To the suspension were added 1.5 g (7.6 mmols) of 5,11-dihydrodibenzo[b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 1 hour. To this reaction solution was added dropwise a solution of 2.2 g (9.1 mmols) of (S)-(+)-3-chloro-1-(4-fluorophenethyl)piperidine [[α]D25 =+9.5° (c=1.0, ethano l)] in 10 ml of dimethyl sulfoxide, and the mixed solution was stirred at room temperature for 4 days. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:2. This mixed solvent was distilled off under reduced pressure to give 1.4 g of (R)-(+)-5,11-dihydro-5-[1-(4-fluorophenethyl)-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine as a pale yellow oil in a yield of 44%.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([Cl:16])[C:5]([NH:8][NH:9]C(=O)C(F)(F)F)=[N:6][CH:7]=1.Cl.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>O>[Br:1][C:2]1[N:3]=[C:4]([Cl:16])[C:5]([NH:8][NH2:9])=[N:6][CH:7]=1
Reactant: O=C(NNc1ncc(Br)nc1Cl)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NNc1ncc(Br)nc1Cl
Temperature: 80 °C
Yield: 59 %

Procedure:
A 250 mL round bottom flask was charged with N′-(5-bromo-3-chloropyrazin-2-yl)-2,2,2-trifluoroacetohydrazide (2.97 g, 9.4 mmol), concentrated HCl (6 mL) and ethanol (60 mL). The resulting mixture was heated at 80° C. for 4 h. The reaction mixture was then allowed to cool to room temperature and neutralized with Na2CO3. It was then diluted with water and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 20% EtOAc in petroleum ether, to afford 1.24 g (59%) of the product as a yellow solid.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[CH:7]=[C:6]([CH:17]([CH3:19])[CH3:18])[C:5]=1[N:20]1[CH2:24][CH2:23][N:22]=[C:21]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=O.[K+].CO>C(#N)C.ClCCl>[CH:1]([C:4]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[CH:7]=[C:6]([CH:17]([CH3:19])[CH3:18])[C:5]=1[N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1cc2oc3ccccc3c2c(C(C)C)c1N1CCN=C1c1ccccc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CO
Product: CC(C)c1cc2oc3ccccc3c2c(C(C)C)c1-n1ccnc1-c1ccccc1
Reaction time: 1 h
Yield: 44.2 %

Procedure:
1-(1,3-diisopropyldibenzo[b,d]furan-2-yl)-2-phenyl-4,5-dihydro-1H-imidazole (4.78 g, 12.05 mmol) in 70 mL of acetonitrile and 70 mL of dichloromethane were added to a 1 L round bottom flask. Potassium permanganate (3.81 g, 24.11 mmol) was ground in a mortar and pestle. Monmorilonite K was added and was ground together finely with the potassium permanganate. This mixture was added to the solution in portions over 0.5 hours. Reaction was done 1 h after first addition. 100 mL of methanol was added and stirred for 1 h. The solid was filtered through Celite. The material was purified using a 200 g Varian column eluting with 20% ethyl acetate/hexanes. 2.1 g (44% yield) of product was obtained after column.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:35])[CH2:5][C@@H:6]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Br[CH2:37][N:38]1[C:42](=[O:43])[N:41]([CH3:44])[N:40]([CH3:45])[C:39]1=[O:46]>CN(C)C=O>[CH3:3][CH:4]([CH3:35])[CH2:5][C@@H:6]([C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[C:7]([CH2:37][N:38]1[C:42](=[O:43])[N:41]([CH3:44])[N:40]([CH3:45])[C:39]1=[O:46])([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: Cn1c(=O)n(CBr)c(=O)n1C
Reactant: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(Cn1c(=O)n(C)n(C)c1=O)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.5 %

Procedure:
0.284 g of 60% sodium hydride was added to a stirred ice-cold solution of 3.01 g of 1,2-dibenzyl 1-tert.butyl 4-methyl-1,1,2(R)-pentanetricarboxylate in 50 ml of dry dimethylformamide under a nitrogen atmosphere. The mixture was stirred for 30 minutes at 0° and for an additional 1.5 hours at ambient temperature, and again cooled to 0° before the addition of 1.6 g of 4-bromomethyl-1,2-dimethylurazole. The mixture was allowed to return to ambient temperature and was stirred for 3 hours. The volatiles were evaporated under high vacuum and the residue was dissolved in ethyl acetate and washed with 5% aqueous citric acid solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography on silica gel using hexane/ether (1:1) followed by ether for the elution. There were obtained 2.464 g of 1,2-dibenzyl 1-tert.butyl 4-methyl-1-[(1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl)methyl]-1,1,2(R)-pentanetricarboxylate in the form of a colorless oil.
Reaction SMILES: [CH3:1][Mg]Br.CON[C:7]([CH:9]1[CH2:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH3:16])[CH2:10]1)=[O:8].Cl>C(OCC)C.CC1CCCO1>[C:7]([CH:9]1[CH2:10][N:11]([C@H:15]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH3:16])[C:12](=[O:14])[CH2:13]1)(=[O:8])[CH3:1]
Reactant: CONC(=O)C1CC(=O)N([C@@H](C)c2ccc(OC)cc2)C1
Reactant: C[Mg]Br
Agent: Cl
Solvent: CC1CCCO1
Solvent: CCOCC
Product: COc1ccc([C@H](C)N2CC(C(C)=O)CC2=O)cc1
Temperature: 20 °C
Reaction time: 1.25 h

Procedure:
530 mL of a 3 M solution of methylmagnesium bromide in diethylether is added slowly to a cooled solution of 271 g of (R/S)—N-Methoxy-5-oxo-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-3-carboxamide (mixture of diastereoisomers) in 1.4 L of 2-methyltetrahydrofuran so that the temperature remains under 0° C. After complete addition the temperature is kept for 75 minutes at 0° C. and then warmed up to 20° C. The suspension is stirred 16 hours at 20° C. Under cooling 650 mL of a 4 M hydrochloric acid are added. The organic phase is separated and washed with 500 mL saturated sodium carbonate solution and with 500 mL saturated brine. The organic phase is dried over sodium sulfate. After filtration the solvent is evaporated under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.C(O)C.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Reactant: COc1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3c(N4CCN(Cc5csc(C)n5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.062 g, 0.15 mmol), ethanol (0.85 mL), DMF (0.15 mL) and 4-methoxybenzaldehyde (0.022 g, 0.165 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85° C. for 17 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on preparative silica TLC plates, which were eluted with dichloromethane/methanol (v/v; 9:1). The isolated compound was further purified by column chromatography on a Biotage SP1 system eluting with methanol (2-10%) in dichloromethane. The title compound was obtained as a yellow solid after trituration with diethyl ether (0.010 g, 13%); 1H-NMR (500 Mz, DMSO-d6): δ 2.62-2.73 (m, 4H, piperazine N(CH2)2), 3.18 (s, 3H, Me), 3.60-3.74 (m, 4H, piperazine N(CH2)2), 3.85 (s, 3H, OMe), 4.00-4.20 (br s, 2H, NCH2), 7.11 (d, J=8.5 Hz, 2H, ArH), 7.33 (s, 1H, thiazole 5-H), 8.15 (d, J=9.0 Hz, 2H, ArH), 8.21 (s, 1H, imidazo[4,5-b]pyridine 5-H); LC (Method B)-MS (ESI, m/z) 3.14 min—499/501 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 499.0916, calculated for C22H23BrN6OS (M+H)+: 499.0915.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[C:7]([CH3:9])[N:8]=1)=[N+:2]=[N-:3].[C:20]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:21][C:22]([CH3:24])=O.C(N(CC)CC)C>CN(C)C=O.ClCCl>[CH2:13]([NH:12][C:10]([C:6]1[S:5][C:4]([N:1]2[C:22]([CH3:24])=[C:21]([C:20]([O:26][CH2:27][CH3:28])=[O:25])[N:3]=[N:2]2)=[N:8][C:7]=1[CH3:9])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1nnn(-c2nc(C)c(C(=O)NCc3ccccc3)s2)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
To a solution of 2-azido-N-benzyl-4-methylthiazole-5-carboxamide (0.53 g, 1.92 mmol) and ethyl acetoacetate (0.50 g, 3.85 mmol) in N,N-dimethylformamide (2 mL) was added triethylamine (0.54 mL, 3.85 mmol). The reaction mixture was stirred at ambient temperature for 24 hours, diluted with dichloromethane (30 mL) and washed with saturated aqueous sodium bicarbonate (5 mL) and brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford the title compound as a white solid in 49% yield (0.36 g): 1H NMR (300 MHz, DMSO-d6) δ 9.03 (t, J=6.0 Hz, 1H), 7.36-7.34 (m, 5H), 4.46 (d, J=6.0 Hz, 2H), 4.35 (q, J=6.0 Hz, 2H), 2.89 (s, 3H), 2.64 (s, 3H), 1.34 (t, J=6.0 Hz, 3H); MS (ES+) m/z 386.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=3[CH3:24])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[C:21]([NH:23][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][CH:34]=[C:26]([F:25])[CH:27]=4)[CH:20]=[CH:19][C:18]=3[CH3:24])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CCOC(=O)c1cncc2c(COc3cc(N)ccc3C)csc12
Product: CCOC(=O)c1cncc2c(COc3cc(NC(=O)c4cccc(F)c4)ccc3C)csc12

Procedure:
3-[5-(3-Fluoro-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester was prepared from 3-(5-amino-2-methyl-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 23 supra) and 3-fluorobenzoyl chloride (Aldrich) following the procedure described in Example 10 as an off-white solid.
Reaction SMILES: O=[C:2]1O[C:6]2[C:8]3[C:13]([CH2:14][C:5]=2[C:4]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:3]1[C:21]#[N:22])=[CH:12][CH:11]=[CH:10][CH:9]=3.[H-].[Na+].[CH2:25]1[CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:27][O:28][C:29]1[CH:25]=[CH:26][C:4]2[CH2:5][C:6]3[C:2](=[C:3]([C:21]#[N:22])[C:4]([N:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)=[C:5]4[CH2:14][C:13]5[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=5)[C:6]4=3)[C:3]=2[CH:2]=1
Reactant: N#Cc1c(N2CCCCC2)c2c(oc1=O)-c1ccccc1C2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(c1)-c1c(C#N)c(N3CCCCC3)c3c(c1C2)-c1ccccc1C3

Procedure:
A mixture of 2-oxo-4-(piperidin-1-yl)-2,5-dihydroindeno[1,2-b]pyran-3-carbonitrile (292 mg), 6-methoxyindanone-1 (162 mg) and NaH (48 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 216-218° C.; IR (KBr) 2213 cm−1 (CN); MS (ESI) 392 (M+); 13C NMR (150 MHz, CDCl3) δ 24.39, 26.94, 35.47, 36.96, 53.14, 55.54, 99.39, 110.62, 113.05, 118.84, 122.72, 123.26, 124.94, 127.11, 127.93, 131.65, 132.25, 134.54, 140.38, 142.59, 144.41, 144.74, 146.32, 152.27, 160.02.
Reaction SMILES: C(C1(C(C)C)[O:8][C@@H:7]([CH2:9][CH2:10][OH:11])[CH2:6][O:5]1)(C)C.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:15]([O:11][CH2:10][CH2:9][C@H:7]([OH:8])[CH2:6][OH:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)C1(C(C)C)OC[C@H](CCO)O1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Product: OC[C@@H](O)CCOCc1ccccc1
Temperature: 110 °C
Reaction time: 18 h
Yield: 92.3 %

Procedure:
(S)-2,2-Diisopropyl-4-(2-hydroxyethyl)dioxolane (76.2 g, 0.377 mol), benzylbromide (129 g, 0.753 mol) and tetrabutylammonium iodide (7 g, 19 mmol) were mixed with a concentrated sodium hydroxide solution (40 g in 90 mL of water, 2.26 mol) in a 3-neck flask equipped with a mechanic stirrer and a condenser. After stirred at 110° C. for 18 hours, the mixture was cooled to room temperature and the organic layer was separated. The aqueous layer was extracted with methylene chloride (100 mL×2). The combined methylene chloride extrats were dried over magnesium sulfate. The solvent was evaporated, and the residue was treated with 300 mL of 1.5M sulfuric acid. After stirred at 100° C. for 8 hours, the mixture was cooled to room temperature, and hexane (300 mL) was added. The aqueous layer was washed with hexane twice (200 mL×2), and then ajusted pH to 8-9 with concentrated sodium sodium hydroxide. The solution was extrated with ethyl acetate (200 mL×3). The combined ethyl acetate extrates were dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by fractional distillation in vacuo (0.1 mmHg, bp 150°-170° C.) to give 68.3 g (92% yield) of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)=[O:5].[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20].O>CC(C)=O>[Cl:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:4]([C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[NH:1][C:19](=[O:20])[CH:18]([Cl:22])[Cl:17])=[O:5]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Nc1ccccc1C(=O)c1cccc(Cl)c1
Solvent: CC(C)=O
Solvent: O
Product: O=C(c1cccc(Cl)c1)c1ccccc1NC(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-Amino-3'-chlorobenzophenone (6.12 g) was stirred and cooled at 15°C in solution in acetone (25 ml) while dichloroacetyl chloride (4.86 g) was added dropwise. After stirring at room temperature for 20 minutes the reaction mixture was poured into water, the acetone was removed under reduced pressure and the resulting oil extracted into chloroform. After drying over magnesium sulphate the chloroform was removed under reduced pressure and the product crystallized from ethanol. 2'-(m-Chlorobenzoyl)-2,2-dichloroacetanilide was obtained as yellow needles (6.88 g),m.p. 73°-75°C after recrystallization from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][C:7]=2[C:6]([O:15][CH3:16])=[CH:5][CH:4]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:17]([NH:24][CH:11]1[CH2:12][CH2:13][C:7]2[C:6]([O:15][CH3:16])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[CH2:9][CH2:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(OC)c2c1CCC(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(OC)c2c1CCC(NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 1,4-dimethoxy-5,6,8,9-tetrahydrobenzo-cyclohepten-7-one (670 mg) and benzylamine (0.5 ml) in toluene (60 ml) in the presence of a catalytic amount of p-toluenesulfonic acid monohydrate was refluxed for 2 hours to remove water as the toluene azeotrope, and then the mixture was evaporated in vacuo. To the residue in methanol (60 ml) was added sodium borohydride (0.5 g) under nitrogen at 5° C., and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into ice-cold water and stirred for 30 minutes before adding ethyl acetate and brine. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate-methanol) over silica gel to afford N-benzyl-(1,4-dimethoxy-5,6,8,9-tetrahydrobenzocyclohepten-7-yl)amine (600 mg).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:21][C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([Cl:33])[CH:24]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([Br:19])=[CH:17][CH:16]=[CH:15][N:14]3[CH:20]=2)=[CH:7][CH:6]=1.CC(OC([NH:42][C@@H:43]([C:45](O)=[O:46])[CH3:44])=O)(C)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH2:42][C@@H:43]([C:45]([NH:1][CH2:2][C@@H:3]([NH:21][C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([Cl:33])[CH:24]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([Br:19])=[CH:17][CH:16]=[CH:15][N:14]3[CH:20]=2)=[CH:7][CH:6]=1)=[O:46])[CH3:44]
Reactant: CC(C)Oc1ccc(C(=O)N[C@H](CN)Cc2ccc(-c3cn4cccc(Br)c4n3)cc2)cc1Cl
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(C(=O)N[C@H](CNC(=O)[C@@H](C)N)Cc2ccc(-c3cn4cccc(Br)c4n3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
A solution of N-((1S)-2-amino-1-{[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide (0.28 mmol), N-{[(1,1-dimethylethyl)oxy]carbonyl}-D-alanine (0.56 mmol), EDCI (0.56 mmol), and TEA (1.12 mmol) stirred in methylene chloride (2 mL) at RT for 18 h. The reaction was then treated with 4 M HCl in 1,4-dioxane (2 mL) and stirred at RT for 1 h. The mixture was then concentrated in vacuo, redissolved in ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate solution (1×10 mL). The organic layer was concentrated in vacuo, and purification of the residue by Gilson reverse phase HPLC afforded the title product as a white solid (25%). ESMS [M+H]+: 613.2.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10](I)=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[F:17][C:18]([F:33])([F:32])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][NH:28][C:27](=[O:31])[CH:26]=2)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu]I>[CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:28]3[CH:29]=[CH:30][C:25]([C:22]4[CH:21]=[CH:20][C:19]([C:18]([F:32])([F:33])[F:17])=[CH:24][CH:23]=4)=[CH:26][C:27]3=[O:31])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc[nH]1
Reactant: COC(Cn1ncc2cc(I)ccc21)OC
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: COC(Cn1ncc2cc(-n3ccc(-c4ccc(C(F)(F)F)cc4)cc3=O)ccc21)OC
Temperature: 115 °C
Reaction time: 15 h
Yield: 78.8 %

Procedure:
A suspension of 1-(2,2-dimethoxyethyl)-5-iodo-1H-indazole (458 mg, 1.38 mmol), 4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (330 mg, 1.38 mmol), Cs2CO3 (997 mg, 3.06 mmol), 8-hydroxyquinoline (42 mg, 0.29 mmol) and CuI (311 g, 163 mmol) in DMSO (5 mL) was evacuated for 30 minutes under high vacuum then backfilled with argon. The mixture was stirred under argon at 115° C. for 15 h and then allowed to cool. The mixture was diluted with 10% NH4OH in H2O (40 mL) and extracted with EtOAc (4×50 mL). The organics were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to dryness. Purification by flash chromatography (silica gel, CH2Cl2/MeOH, 95:5) followed by a second purification by flash chromatography (silica gel, CH2Cl2/MeOH, 97.5:2.5) gave the title compound (482 mg, 79%) as a light brown solid: 1H NMR (500 MHz, CDCl3) δ 8.08 (s, 1H), 7.75-7.73 (m, 5H), 7.61 (d, J=8.9 Hz, 1H), 7.52 (d, J=7.1 Hz, 1H), 7.45 (dd, J=8.9, 1.8 Hz, 1H), 6.92 (d, J=1.8 Hz, 1H), 6.52 (dd, J=7.1, 1.9 Hz, 1H), 4.78 (t, J=5.3 Hz, 1H), 4.52 (d, J=5.3 Hz, 2H), 3.39 (s, 6H); ESI MS m/z 444 [M+H]+.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:16]#[C:17][NH2:18]>ClCCCl>[C:17]([NH:18][C:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:16]
Reactant: N#CN
Reactant: C(=Nc1ccccc1)=NC1CCCCC1
Solvent: ClCCCl
Product: N#CNC(=Nc1ccccc1)NC1CCCCC1

Procedure:
A solution of 1.8 g N-cyclohexyl-N'-phenylcarbodiimide [prepared in accordance with Tetrahedron Letters 26, 1661 (1985) in 20 ml of 1,2-dichloroethane is reacted with 0.42 g of cyanamide and the reaction mixture is worked up as described in Example 1. The viscous oily crude product is chromatographed on silica gel (elution with a 4:1 mixture of methylene chloride/diethyl ether), affording a crystalline product which melts at 147°-147.5° C. (recrystallisation from ethyl acetate).
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C(NC(C)C)(C)C.[Li].C1COCC1.CCCCCCC.[CH:29]1(/[C:32](=[N:34]/[S:35]([C:37]([CH3:40])([CH3:39])[CH3:38])=[O:36])/[CH3:33])[CH2:31][CH2:30]1>C1COCC1>[C:37]([S:35]([NH:34][C:32]([CH:29]1[CH2:31][CH2:30]1)([CH3:33])[CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3])=[O:36])([CH3:38])([CH3:39])[CH3:40]
Reactant: C/C(=N\S(=O)C(C)(C)C)C1CC1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)CC(C)(NS(=O)C(C)(C)C)C1CC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 74.5 %

Procedure:
To a solution of tert-butyl acetate (1.29 g, 1.48 ml, 11.1 mmol) in THF (20 ml) cooled to −78° C. was added a 2M solution of lithium diisopropylamine in THF/n-heptane (5.55 ml, 11.1 mmol) over 10 minutes. The reaction mixture was stirred for 40 minutes at −78° C. followed by addition of a solution of (E)-N-(1-cyclopropylethylidene)-2-methylpropane-2-sulfinamide (CAN 1426425-10-6, 1.6 g, 8.54 mmol) in THF (5 ml) to the reaction cooled at −78° C. The reaction was stirred at −78° C. for 90 minutes and then let to warm up to 0° C. After stirring 1 hour at 0° C. the reaction was quenched by addition of water. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (1.93 g, 75%). MS (ESI, m/z): 304.5 (M+H+).