Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]#[C:3][C:4]#[C:5][CH2:6][OH:7].[CH2:9]([N:11]=[C:12]=[O:13])[CH3:10].C[O:15][CH2:16][CH2:17]OC>[Cu].C(N(CC)CC)C>[CH2:1]([OH:8])[C:2]#[C:3][C:4]#[C:5][CH2:6][OH:7].[CH2:9]([N:11]([CH2:1][CH3:2])[C:12]([O:15][CH2:16][CH3:17])=[O:13])[CH3:10]
Reactant: CCN=C=O
Reactant: COCCOC
Agent: [Cu]
Agent: OCC#CC#CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)N(CC)CC
Yield: 95 %

Procedure:
The monomer 2,4-hexadiyne-1,6-diol-bis-ethylurethane is synthesized in 95% yield by the reaction of 11.0 gm (0.10 mole) 2,4-hexadiyne-1,6-diol with 26.5 gm (0.37 mole) ethyl isocyanate in the presence of 1,2-dimethoxyethane (50 ml), dibutyl-tin-2-ethylhexoate (0.1 gm), and triethylamine (2 ml). The monomer is recrystallized as approximately 3 cm long needles by the slow cooling of a 10:90 acetone/petroleum ether solution (75ml) containing 0.2 gm sample, as described in Example 4. These crystals rapidly turn pink upon exposure to light. Polymerization proceeded quantitatively by 60 Co α -ray irradiation at a dose rate of 1 Mrad/hr and a total dosage of 60 Mrad. The resulting polymer fibers are copper-like in appearance and strongly dichroic, with dichroic axis in the fiber axis direction. The polymer fibers are monoclinic monocrystals in which the polymer chain axis, with repeat length 4.9 A, is in a non-unique axis direction. The polymer fibers are annealed as described in Examples 4 and 5, in order to obtain reversible thermal-dimensional behavior. The annealed polymer fiber has a negative thermal expansion coefficient over the entire temperature range from -50° to 100°C. The average thermal expansion coefficient is -1.46 × 10-5 °C-1 between -50° and +100°C amd -1.31 × 10-5 °C-1 between -50° and +40°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[CH2:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:22].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][N:33]3[CH2:32][CH2:31][N:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH2:21][CH3:22])[CH2:35][CH2:34]3)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOc1ccccc1N1CCNCC1
Reactant: COc1ccc(C2=NOC(CCC=O)C2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccccc1N1CCN(CCCC2CC(c3ccc(OC)c(OC)c3)=NO2)CC1
Yield: 61.6 %

Procedure:
3-[3-(3,4-Dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]propanal (22.96 mg, 0.090 mmol), 1-(2-ethoxyphenyl)piperazine hydrochloride (20.0 mg, 0.082 mmol), molecular sieve (5 beads), NaBH(OAc)3 (52.4 mg, 0.247 mmol) and diisopropylethylamine (26.95 L, 0.082 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 22.9 mg (68.2%) of the target compound was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C[Sn](C)(C)[C:28]1[CH:29]=[N:30][CH:31]=[N:32][CH:33]=1.C(N(CC)CC)C.[Cl-].[Li+]>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:28]4[CH:29]=[N:30][CH:31]=[N:32][CH:33]=4)[CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: C[Sn](C)(C)c1cncnc1
Reactant: CN1CCC(c2cccc3ccc(OS(=O)(=O)C(F)(F)F)cc23)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCC(c2cccc3ccc(-c4cncnc4)cc23)CC1
Temperature: 115 °C

Procedure:
A mixture of 1-(1-methylpiperidin-4-yl)-7-trifluoromethanesulfonyloxynaphthalene (0.304 g, 0.819 mmol), 5-trimethylstannylpyrimidine (0.220 g, 0.905 mmol), triethylamine (0.55 mL, 3.95 mmol), lithium chloride (0.107 g, 2.53 mmol), bis(triphenylphosphine)palladium chloride (0.029 g, 0.041 mmol), and butylated hydroxytoluene (BHT, approx. 0.01 g, antioxidant) in dimethylformamide (15 mL) was heated to 115° C. for 1 hour. The reaction was cooled and diluted with ethyl acetate. The mixture was extracted with a mixture of 1N lithium chloride (25 mL) and 1N sodium hydroxide (3 mL), 1N lithium chloride and brine. The organic phase was dried over calcium sulfate and concentrated. The residue was flash chromatographed on silica gel (1×2.5 inches packed with 75% ethyl acetate/hexane). Elution proceeded as follows: 75% ethyl acetate/hexane, 225 mL, nil; ethyl acetate, 200 mL, nil; 1% methanol/ethyl acetate, 200 mL, nil; 5% methanol/ethyl acetate, 300 mL, nil; and 7% methanol/1% triethylamine/ethyl acetate, 250 mL, 0.130 g (52%) of 1-(1-methylpiperidin-4-yl)-7-pyrimid-5-yl-naphthalene as a tan foam. A sample triturated with ether afforded white crystals which had: Mp 121.5°-123° C.; 1H NMR (250 MHz, CDCl3) δ 9.27 (s, 1H), 9.08 (s, 2H), 8.26 (s, 1 H), 8.03 (d, J=8.5 Hz, 1H), 7.78 (dd, J=3, 6.5 Hz, 1H), 7.69 (dd, J=1.5, 8.5 Hz, 1H), 7.57-7.50 (m, 2H), 3.36 (sym m, 1H), 3.09 (br d, J=12 Hz, 2H), 2.40 (s, 3H), 2.28 (sym m, 2H), 2.06-1.90 (m, 4H). Analysis calculated for C20H21N3 : C, 79.17; H, 6.98;N, 13.85. Found: C, 78.46; H, 7.14; N, 13.89. HRMS m/e 303.1731. Observed m/e 303.1700.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].Cl.[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18](=[NH:20])[NH2:19].O=[C:22]([CH3:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C([O-])(=O)C.[Na+]>C(O)C>[CH3:29][C:22]1[NH:19][C:18]([C:14]2[S:13][CH:17]=[CH:16][N:15]=2)=[N:20][CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])[C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: N=C(N)c1nccs1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccccc1[N+](=O)[O-]
Temperature: 88 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
A mixture of 2-nitrobenzaldehyde (10 g, 66 mmol), thiazole-2-carboximidamide hydrochloride (10.8 g, 66 mmol), ethyl 3-oxobutanoate (8.6 g, 66 mmol) and sodium acetate (5.5 g, 66 mmol) in ethanol (250 mL) was stirred at 88° C. for 16 hours, then cooled to 25° C. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=3/1) to give the title compound as a light yellow solid (12 g, 48%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH2:9][CH2:10][C:11]3[C:12](=[N:13][N:14]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C:15](=[O:17])[CH:16]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH:25]O.O>C(O)(=O)C>[Cl:1][C:2]1[C:7]2[S:8](=[O:25])[CH2:9][CH2:10][C:11]3[C:12](=[N:13][N:14]([C:18]4[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=4)[C:15](=[O:17])[CH:16]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1cccc(Cl)c1SCC2
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1cccc(Cl)c1S(=O)CC2
Temperature: 25 °C

Procedure:
To a solution of 0.9 g of 8-chloro-2-(4-chlorophenyl)-5,6-dihydro[1]benzothiepino[5,4-c]pyridazin-3(2H)-one, prepared in Example 24, in 20 ml of acetic acid is added 0.6 ml of 35% hydrogen peroxide with stirring at room temperature and the mixture is stirred for 18 hours at the same temperature. To the residue is added water, and the precipitated crystals are collected by filtration and repeatedly washed with ethanol to give 0.7 g of 8-chloro-2-(4-chlorophenyl)-5,6-dihydro-[1]benzothiepino[5,4-c]pyridazin-3(2H)-one 7-oxide, melting at 217°-219° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17]12[CH2:22][CH:21]1[CH2:20][N:19]([CH2:23][C:24]1[S:25][CH:26]=[C:27](Br)[N:28]=1)[CH2:18]2.C(O)C>C1(C)C=CC=CC=1>[CH:17]12[CH2:22][CH:21]1[CH2:20][N:19]([CH2:23][C:24]1[S:25][CH:26]=[C:27]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:28]=1)[CH2:18]2
Reactant: Brc1csc(CN2CC3CC3C2)n1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Clc1ccc(-c2csc(CN3CC4CC4C3)n2)cc1
Temperature: 97.5 °C
Yield: 79.8 %

Procedure:
(4-chlorophenyl) boronic acid (0.34 g, 2.17 mmol) and potassium carbonate (0.63 g, 4.53 mmol) were added to a solution of 2-(3-azabicyclo[3.1.0]hexan-3-ylmethyl)-4-bromothiazole (Step-1 of compound 102, 0.47 g, 1.81 mmol) in a mixture of toluene:ethanol (5:15 ml) in a tube at 25° C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. Tetrakis(triphenylphosphine)(0)palladium (0.10 g, 0.09 mmol) was then added to the reaction mixture under nitrogen atmosphere and the tube was sealed. The reaction mixture was heated at 95-100° C. for 18 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was washed with ethanol (20 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography using 5% ethyl acetate in hexanes as an eluent to obtain the title compound (0.42 g, 79.0%). MS: m/z 291 (M+1).
Reaction SMILES: [I:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[OH2:11].[C:12]1(C)C=[CH:16][C:15](S(O)(=O)=O)=[CH:14][CH:13]=1>CCOC(C)=O>[I:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:16]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1
Reactant: O
Reactant: Ic1ncnc2[nH]cnc12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: Ic1ncnc2c1ncn2C1CCCCO1
Temperature: 25 °C

Procedure:
In a RB flask were placed 6-iodo-9H-purine (2680 mg, 10894 μmol), 3,4-dihydro-2(H)-pyran (2982 μl, 32682 μmol), and p-toluenesulfonic acid monohydrate (34.0 mg, 218 μmol) in EtOAc (150 mL) and heated to reflux for 2 hours. After cooling to RT, the reaction mixture was washed with NaHCO3 (aq., sat., 100 mL), then brine (100 mL). The organic solution was concentrated in vacuo. The residue was redissolved in a small amount of DCM and then put on a layer of silica gel in a funnel. The silica was rinsed with EtOAc/hexane (1:1). A light yellow solution (filtrate) was collected and concentrated to give a waxy product. This product was treated with hexanes to give the titled compound as an off white solid. MS Found: (ESI pos. ion) m/z 331 (M+H+).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([NH:16][CH:17]([CH3:19])[CH3:18])(=[O:15])=[O:14])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].[CH3:20]S(O)(=O)=O.O1CCCOO1>ClCCl>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]2[NH:12][S:13](=[O:15])(=[O:14])[N:16]([CH:17]([CH3:18])[CH3:19])[CH2:20][C:10]=2[CH:11]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(NS(=O)(=O)NC(C)C)cc1
Reactant: CS(=O)(=O)O
Agent: C1COOOC1
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc2c(c1)CN(C(C)C)S(=O)(=O)N2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-(4-Ethylsulfonylphenyl)-N′-(1-methylethyl)sulfamide (5 g, 0.016 mol) was dissolved in dry dichloromethane (150 ml) and methanesulphonic acid (18.87 ml, 0.303 mol). The solution was cooled at 0° C. before the addition of trioxan (0.480 g, 0.005 mol) in dichloromethane (15 ml). After stirring at 0° C. for 1 hr, the reaction mixture was poured onto ice-water (250 ml), the layers separated, dried (MgSO4) and concentrated in vacuo to yield 3,4-dihydro-6-(ethylsulfonyl)-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide as a white solid. δ(1H NMR, DMSO, ppm): 1.10 (9H, m), 3.30 (2H, q), 4.10 (1H, m), 4.80 (2H, s), 6.95 (1H, d), 7.75 (1H, dd), 7.80 (1H, d).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:3]1=2.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:18]([Cl:33])=[CH:17][N:16]=1>CO.C(Cl)Cl>[Cl:33][C:18]1[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[N:20][C:15]([NH:13][C:10]2[CH:11]=[CH:12][C:3]3[N:2]([CH3:1])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[CH:9]=2)=[N:16][CH:17]=1
Reactant: CN1CCCCc2cc(N)ccc21
Reactant: CS(=O)(=O)Nc1ccccc1Nc1nc(Cl)ncc1Cl
Solvent: CO
Solvent: ClCCl
Product: CN1CCCCc2cc(Nc3ncc(Cl)c(Nc4ccccc4NS(C)(=O)=O)n3)ccc21

Procedure:
Following the procedure of Example 101b, 1-Methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamine (48 mgs, 0.27 mmol) and N-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenyl]-methanesulfonamide (0.9 eq) were reacted except that the ISCO chromatography gradient was 0% to 10% MeOH/CH2Cl2 and the final product was triturated from 4 mL of EtOAc with hexane to give N-{2-[5-Chloro-2-(1-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (30.6 mgs) as an off-white/grey solid. MP=170-172° C. 1H-NMR (CDCl3) δ δ 7.88 (s, 1H), 7.50-7.48 (m, 1H), 7.36-7.33 (m, 1H), 7.23 (s, 1H), 7.17-7.13 (m, 2H), 6.95-6.89 (m, 3H), 6.68 (s, 1H), 6.63 (br s, 1H), 2.71-2.68 (m, 8H), 2.50-2.47 (m, 2H), 1.63-1.55 (m, 2H), 1.42-1.38 (m, 2H); LC/MS (ESI+): 273 (M+H).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C.C(OCC)(=O)C>[CH2:21]([O:20][C:18]([C:17]1[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH:1]=1)=[O:19])[CH3:22]
Reactant: O=Cc1ccccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc2ccccc2o1
Yield: 33.1 %

Procedure:
A mixture of salicylaldehyde (53.10 g), K2CO3 (97 g) and ethyl bromoacetate (73.30 g) in ethanol (200 ml) was refluxed for 6 hours. The reaction mixture was diluted with ethyl acetate, washed with water, 1N NaOH and brine, dried and concentrated to give the titled compound (27.40 g) as a colorless oil
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[Br:22][C:23]1[N:28]=[CH:27][C:26]([C:29](Br)=[O:30])=[CH:25][CH:24]=1.O>ClCCl>[Br:22][C:23]1[N:28]=[CH:27][C:26]([C:29]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:30])=[CH:25][CH:24]=1
Reactant: O=C(Br)c1ccc(Br)nc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Br)nc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.0 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 10 ml of triethylamine in 50 ml of dichloromethane under argon is added 3 g of 6-bromopyridine-3-carbonyl bromide. The mixture is stirred at room temperature for 16 hours and then poured into 100 ml of water. The organic layer is separated and washed with 2% HCl, water, saturated NaHCO3 and dried (Na2SO4), the solvent removed under vacuum and the residue chromatographed on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:34]=2)[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:34]=3)[CH2:27][CH2:28]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CCCC(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Product: CCCC(=O)Nc1cc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)ccc1F

Procedure:
Example 104 was prepared from bis(4-fluorophenyl)acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.33–8.14 (m, 1H), 7.89–7.67 (br, 1H), 7.51–6.60 (m, 10H), 4.98–4.79 (br, 1H), 4.75 (s, 1H), 3.46–3.29 (m, 2H), 3.29–3.08 (m, 2H), 2.79–2.63 (m, 2H), 2.63–2.46 (m, 1H), 2.46–2.21 (m, 4H), 1.97–1.60 (m, 8H), 1.01 (t, 3H, J=7.2 Hz); ESMS m/e: 552.3 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3O[C:36](C)=[C:37](C)[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH:41]([NH:44][CH:45]=O)([CH3:43])[CH3:42].[CH:47](N)(C)C>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:44]([CH:41]([CH3:42])[CH3:43])[C:45]([CH3:47])=[C:37]([CH3:36])[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CC(C)N
Reactant: CC(C)NC=O
Reactant: CCCc1nc2c(C)cc(-c3nc(C)c(C)o3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Product: CCCc1nc2c(C)cc(-c3nc(C)c(C)n3C(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 146 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and N-isopropyl-formamide/isopropylamine.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1.CC#N.O>CCCCO>[Br:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:23]2)=[C:4]2[C:10]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccc(F)c1
Solvent: O
Solvent: CCCCO
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccc(F)c4)c23)C1
Temperature: 155 °C
Yield: 27 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-fluorobenzamide (306 mg, 0.869 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (522 mg, 2.61 mmol) were placed in n-BuOH (5 mL) and heated to 155° C. for 42 hours in a sealed tube. The reaction was cooled to room temperature and concentrated to dryness. The crude residue was purified by C-18 reverse phase flash chromatography (Biotage Horizon unit, C-18 25M column, 5-80% CH3CN/water gradient) to give (R)-tert-butyl 1-(5-bromo-3-(3-fluorobenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (125 mg, 27% yield).
Reaction SMILES: C(OC(=O)[NH:7][C:8](=[NH:43])[C:9]1[S:10][C:11]([S:41][CH3:42])=[C:12]([S:14]([C:17]2[CH:18]=[C:19]([C:23]3[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=3[NH:30][C:31]([NH:33][CH2:34][CH2:35][C:36]3[N:37]=[N:38][NH:39][N:40]=3)=[O:32])[CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH:13]=1)(C)(C)C.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46].C(Cl)Cl>>[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[CH3:42][S:41][C:11]1[S:10][C:9]([C:8]([NH2:43])=[NH:7])=[CH:13][C:12]=1[S:14]([C:17]1[CH:18]=[C:19]([C:23]2[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=2[NH:30][C:31]([NH:33][CH2:34][CH2:35][C:36]2[N:40]=[N:39][NH:38][N:37]=2)=[O:32])[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCc2nn[nH]n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCc2nn[nH]n2)c1
Yield: 46 %

Procedure:
A solution of {imino-[5-methylsulfanyl-4-(6′-methyl-2′-{3-[2-(2H-tetrazol-5-yl)-ethyl]-ureido}-biphenyl-3-sulfonyl)-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester (10 mg, 15.3 μmol) in TFA/DCM (2.0 mL, 1:1) was stirred at ambient temperature for 1.5 h. The reaction mixture was concentrated to dryness, and flash chromatographed on silica gel column, eluting with 10% MeOH/DCM containing 0.1% TFA to give the title compound (4.7 mg, 46% yield) as a white solid.
Reaction SMILES: Br[CH:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3]1.[CH2:16]([NH:23][CH2:24][CH2:25][NH2:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3][CH:2]([NH:26][CH2:25][CH2:24][NH:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]=2[CH:8]=1)#[N:13]
Reactant: CC1(C)CC(Br)c2cc(C#N)ccc2O1
Reactant: NCCNCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(NCCNCc2ccccc2)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 216.7 %

Procedure:
A solution of 4-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (1.50 g, 5.64 mmole, from Example 8, part B) and N-benzylethylenediamine (8.48 g, 10 eq.) containing NaHCO3 (4.80 g, 5 eq.) in N,N-dimethylformamide (30 ml) was stirred for 48 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and distilled H2O. The organic phase was washed with distilled H2O, saturated NaCl solution, dried over Na2SO4 and evaporated in vacuo to obtain 4.10 g of an orange oil. The crude product was chromatographed on silica eluting with 9:1 methylene chloride/methanol (trace of NH4OH) to obtain 0.91 g (48%) of the title compound as a colorless gum. 1H NMR (CDCl3) δ 8.00 (s, 1H). 7.49-7.34 (m, 6H), 6.88 (d, J=8.80 Hz, 1H), 3.93-3.82 (m, 3H), 3.03-2.80 (m, 5H), 2.25 (dd, J=5.57 and 13.20 Hz, 1H), 1.67 (m, 1H), 1.53 (s, 3H), 1.35 (s, 3H); 13C NMR (CDCl3) δ 157.66, 139.89, 132.52, 132.03, 128.43, 128.14, 127.05, 125.55, 119.65, 118.06, 102.89, 76.86, 53.73, 49.38, 49.01, 45.32, 39.25, 36.40, 29.72, 25.02; MS: (M+H)+ @334.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](Br)=[CH:10][CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([CH:21]=[O:22])[CH:15]=2)[N:7]=1)=[O:5])[CH3:2].[C:23]([Cu])#[N:24].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11]([C:23]#[N:24])=[CH:10][CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([CH:21]=[O:22])[CH:15]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(Oc2ccc(Br)c(C=O)c2)ccc1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(Oc2ccc(Br)c(C=O)c2)ccc1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19.1 %

Procedure:
To a solution of 3-bromo-6-(4-bromo-3-formyl-phenoxy)-pyridine-2-carboxylic acid ethyl ester (23, 1.8 g, 4.19 mmol) in DMF (6 mL) was added CuCN (0.75 g, 8.38 mmol) in portions at 130° C. and heated for 4 hour. The mixture was cooled to room temperature and ethyl acetate (100 mL) was added. The mixture was stirred for 10 minutes, filtered, and washed with ethyl acetate (2×50 mL). The filtrate was washed with water (2×50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified by column chromatography (25% ethyl acetate/hexanes) to yield compound 24 (0.3 g, 19%) as a white solid. 1H NMR 400 MHz (DMSO-d6) δ: 10.20 (s, 1H), 8.51 (d, J=8.6 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 7.76 (s, 1H), 7.59 (d, J=2.7 Hz, 1H), 7.55 (dd, J=8.5, 2.7 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 1.26 (t, J=7.0 Hz, 3H); MS (ES) m/z: 377 (M+1)+.