Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:15]=[C:14]2[C:4]([CH:5](O)[C:6]3[C:11]([CH:12]=[CH:13]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:3][CH:2]=1.[N+:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])([O-:19])=[O:18].C(OCC)C.C>CO>[N+:17]([CH:20]([CH:5]1[C:4]2[CH:3]=[CH:2][CH:1]=[CH:15][C:14]=2[CH:13]=[CH:12][C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])([O-:19])=[O:18]
Reactant: OC1c2ccccc2C=Cc2ccccc21
Reactant: CCOC(=O)C[N+](=O)[O-]
Solvent: CO
Solvent: CCOCC
Product: CCOC(=O)C(C1c2ccccc2C=Cc2ccccc21)[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 41.3 %

Procedure:
Dibenzosuberenol (42 g, 0.2 mol) is combined with ethyl nitroacetate (25 mL, 0.23 mol) and the mixture is heated at 120° C. (oil bath) until melted and then kept at 110° C. for 2.5 hours. The oil bath is removed and the cooled reaction mixture is dissolved in 50 mL of methanol and taken up into 350 mL of boiling diethyl ether. The dark solution is treated with charcoal, filtered, and cooled overnight. A precipitate is collected by filtration, washed with hexane, diethyl ether, dried under vacuum at room temperature to give 26.7 g of the title compound; mp 101°-103° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][P:5]([CH2:9][C:10](=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:8])[O:6][CH3:7].[H][H].[Br:20]N1CCCCCC1=O>C1C=CC=CC=1>[CH3:3][O:4][P:5]([CH:9]([Br:20])[C:10](=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:8])[O:6][CH3:7]
Reactant: O=C1CCCCCN1Br
Reactant: [H][H]
Reactant: CCCCCCC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCCCC(=O)C(Br)P(=O)(OC)OC

Procedure:
To a benzene suspension of 194 mg of 80% NaH in mineral oil, a solution of 1.62 g of dimethyl-(2-oxo-octyl)phosphonate in 5 ml of benzene was added dropwise and continually stirred until there was no more evolution of hydrogen. The 1.24 g of N-bromo-caprolactam were added to form the carbanion of dimethyl-(1-bromo-2-oxo-octyl)-phosphonate. After 15 minutes the solution of the aldehyde, prepared as described above, was added and the reaction mixture stirred for 15 minutes.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[Na+].Br[CH2:13][CH2:14][CH2:15][CH3:16]>O.CCCCCCC>[CH2:13]([O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH2:14][CH2:15][CH3:16]
Reactant: Oc1cccc(F)c1F
Reactant: CCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCCC
Product: CCCCOc1cccc(F)c1F
Temperature: 30 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
2,3-Difluorophenol (21) (100.0 g) and sodium hydroxide (NaOH; 36.9 g) were added to water (300 ml) under a nitrogen atmosphere, and the stirring was continued at 70° C. 1-Bromobutane (158.0 g) was added thereto, and the stirring was continued at 70° C. for 2 hours. The reaction mixture obtained was cooled to 30° C., heptane (100 ml) and water (100 ml) were added, and mixed. The mixture was then allowed to separate into organic and aqueous phases. The extraction into an organic phase was carried out. The organic phase obtained was washed with brine and dried over anhydrous magnesium sulfate. Then, fractional distillation was carried out under reduced pressure, giving 114.4 g of 4-butoxy-2,3-difluorobenzene (22). The compound (22) obtained was a colorless oil having a boiling point of 109° C. to 110° C./20 mmHg. The yield based on the compound (21) was 80.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1([P:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:19]C2C=CC=CC=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH:32](=O)[CH2:33][CH2:34][CH3:35]>C1(C)C=CC=CC=1>[C:26]1([P:18](=[O:19])([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:32]([NH:11][C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:10])[CH2:33][CH2:34][CH3:35])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCCC=O
Reactant: NC(=O)Nc1ccc(Cl)cc1
Reactant: c1ccc(OP(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCC(NC(=O)Nc1ccc(Cl)cc1)P(=O)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 0.15 mole each of p-chlorophenylurea, phenyl diphenylphosphinite, and n-butyraldehyde in 150g of toluene is warmed at reflux for 5.5 hr, giving a reaction mixture having a 31P nmr signal only at -36.8 ppm. When the toluene is removed at reduced pressure, the residue solidifies. Recrystallization of a portion from benzene gives a white solid: mp 275°-278°C; 31P nmr -37.4 ppm; 1H nmr δ9.1 (s, 1, NHC6H4C1), 6.4-8.1 (m, 15, aryl and CHNH), 5.1 (m, 1, PCH), 0.6-2.0 (m, 7, CH2CH2CH3).
Reaction SMILES: CN(C)C=O.Cl.[NH:7]([CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([OH:20])[CH2:16][C:17]([NH2:19])=[O:18])[C:8]([NH2:10])=[NH:9].[C:21]([Cl:29])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[ClH:29].[NH:7]([CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([O:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][C:17]([NH2:19])=[O:18])[C:8]([NH2:10])=[NH:9]
Reactant: O=C(Cl)c1ccccc1
Reactant: N=C(N)NCCCC[C@H](O)CC(N)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N=C(N)NCCCC[C@@H](CC(N)=O)OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into 2.5 ml of dimethylformamide, was dissolved 2.09 of (S)-7-guanidino-3-hydroxyheptanamide hydrochloride followed by 1.7 ml of pyridine. To the solution, while being cooled in ice, was added slowly and dropwise 2.6 ml of benzoyl chloride. The mixture was stirred for 30 minutes while cooling in ice and for further two hours at room temperature. The reaction mixture was diluted with 20 ml of ice water, the separated oily layer was separated, and the aqueous layer was admixed with 600 mg of sodium chloride. The aqueous layer was passed through a column of Diaion® HP-20 which had been equilibrated with 0.5 M aqueous sodium chloride solution, and the column was washed successively with 0.5 M, 0.2 M and 0.1 M aqueous sodium chloride solutions, and with water. The fractions eluted with 20 to 40% (v/v) aqueous methanol were collected and concentrated under reduced pressure to yield 820 mg of (S)-7-guanidino-3-benzoyloxyheptanamide hydrochloride in oily form. NMR: 1.4-2.0 (CH2 x3), 2.65 (CH2), 3.17 (CH2), 5.50 (CH), 7.2-8.1 (COC6H5).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([OH:28])=O)[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:74][C@H:75]1[CH2:79][CH2:78][N:77]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[CH2:76]1>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:74][C@H:75]4[CH2:79][CH2:78][N:77]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[CH2:76]4)=[O:28])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)COc2cccc(-c3nc(Nc4ccc5[nH]ncc5c4)c4ccccc4n3)c2)C1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (50 mg, 0.098 mmol), PyBOP® (28 mg, 0.054 mmol), DIEA (17 μL, 0.098 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (16 mg, 0.084 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalent of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalent of (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo to afford the crude (3S)-tert-butyl 3-(2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamido)pyrrolidine-1-carboxylate.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=3)[C@@H:13]([CH2:33][N:34]([CH:39]([CH3:41])[CH3:40])[S:35]([CH3:38])(=[O:37])=[O:36])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[NH4+:43]>CCO>[NH2:43][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=3)[C@@H:13]([CH2:33][N:34]([CH:39]([CH3:41])[CH3:40])[S:35]([CH3:38])(=[O:37])=[O:36])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)N(C[C@H]1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)S(C)(=O)=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)N(C[C@H]1CN(S(=O)(=O)c2ccc(N)nc2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)S(C)(=O)=O
Temperature: 140 °C
Yield: 55.8 %

Procedure:
A 5-mL microwave reaction vial charged with N-(((2R)-4-((6-chloro-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-(1-methylethyl)methanesulfonamide (0.161 g, 0.246 mmol), concentrated ammonium hydroxide (0.65 mL, 5.0 mmol) and EtOH (2 mL). The vial was heated in an Initiator microwave reactor (Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 2.5 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The crude product was purified by column chromatography (25 g of silica gel, 30 to 100% EtOAc in hexanes) to afford N-(((2R)-4-((6-amino-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-(1-methylethyl)methanesulfonamide (0.0873 g) as a white solid.
Reaction SMILES: F[B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+]([F:21])(CC1)CC2.[C:22]1([CH:29]=[CH:28][CH:27]=[C:25]([OH:26])[CH:24]=1)[OH:23]>C(#N)C.C(OCC)C>[F:21][C:27]1[CH:28]=[CH:29][C:22]([OH:23])=[CH:24][C:25]=1[OH:26]
Reactant: Oc1cccc(O)c1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: CC#N
Product: Oc1ccc(F)c(O)c1
Temperature: 100 °C

Procedure:
[1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)] (SELECTFLUOR) (1.61 g., 4.54 mmoles) in anhydrous acetonitrile (50 mL) was treated with resorcinol (0.500 g., 4.54 mmoles) and heated at 100° C. overnight. The reaction was diluted with diethyl ether, washed with H2O (2×), saturated NaHCO3 (2×), brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. MS (DCI) m/z 129 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13]([OH:15])=O)=[CH:8][C:9]=1[CH:10]([CH3:12])[CH3:11])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:57][CH2:58][C:59]1[CH:60]=[C:61]([OH:65])[CH:62]=[CH:63][CH:64]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13](=[O:15])[NH:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([OH:65])[CH:60]=2)=[CH:8][C:9]=1[CH:10]([CH3:11])[CH3:12])=[O:4]
Reactant: NCc1cccc(O)c1
Reactant: COC(=O)c1sc(C(=O)O)cc1C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.7 %

Procedure:
To a solution of 3-Isopropyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (110 mg, 0.48 mmol) in anhydrous DMF (5 mL) was added triethylamine (0.20 mL, 1.45 mmol), HBTU (0.27 g, 0.72 mmol), HOBT (78 mg, 0.58 mmol), and 3-Aminomethyl phenol (65 mg, 0.53 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-60% EtOAc in hexane to afford the desired product (0.070 g, 44% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[C:18]3[C:14]([CH:15]=[CH:16][N:17]3[CH3:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:21](Cl)(=[O:25])[C:22](Cl)=[O:23].[CH2:27]([OH:29])[CH3:28]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:19]=[C:18]3[C:14]([C:15]([C:21](=[O:25])[C:22]([O:29][CH2:27][CH3:28])=[O:23])=[CH:16][N:17]3[CH3:20])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1ccc2ccc(-c3ccc(C(C)(C)C)cc3)cc21
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCO
Product: CCOC(=O)C(=O)c1cn(C)c2cc(-c3ccc(C(C)(C)C)cc3)ccc12

Procedure:
Ethyl 2-{6-[4-(tert-butyl)phenyl]-1-methyl-1H-indol-3-yl}-2-oxoacetate was prepared from 6-[4-(tert-butyl)phenyl]-1-methyl-1H-indole (0.230 g, 0.874 mmol), oxalyl chloride (0.16 mL, 1.8 mmol), and ethanol (2 mL) following the procedure described in Step 3 of Example 1. The compound was purified by HPLC using 30% ethyl acetate in hexane as the mobile phase and dried for 20 minutes at 60° C. to yield a light yellow solid (0.141 g, 44%). 1HNMR (300 MHz, DMSO-d6): δ 8.5 (s, 1H), 8.2 (d, 1H, J=8.3 Hz), 7.9 (s, 1H), 7.7 (d, 2H, J=7.5 Hz), 7.65 (d, 1H, J=9.0 Hz), 7.5 (d, 2H, J=7.5 Hz), 4.35 (q, 2H, J=7.5 Hz), 3.95 (s, 3H), and 1.3-1.4 ppm (m, 12H).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)=O.[NH4+:17].[Cl-]>N.CO>[NH2:17][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)([CH3:7])[C:5]#[N:6]
Reactant: C[Si](C)(C)C#N
Reactant: [NH4+]
Reactant: CC(=O)c1cccc(Br)c1
Agent: N
Agent: [Cl-]
Solvent: CO
Product: CC(N)(C#N)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 88.9 %

Procedure:
Trimethylsilylcyanide (20 g, 200 mmol) was added to a stirred solution of 3-bromoacetophenone (20 g, 100 mmol) and NH4Cl (11 g, 200 mmol) in NH3/MeOH (400 mL). The mixture was stirred at room temperature for 4 days. Then the solvent was evaporated in vacuo and the residue was taken up in AcOEt (100 mL). The solid was filtered off and the filtrate was evaporated in vacuo to yield rac-2-amino-2-(3-bromo-phenyl)-propionitrile (20 g, 86% yield) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4]O.[CH3:7][C:8]([C:11]1[N:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][N:12]=1)([CH3:10])[CH3:9]>>[CH3:10][C:8]([C:11]1[N:12]=[CH:13][C:14]([CH2:17][C:18]([O:20][CH2:4][CH:3]=[C:2]([CH3:6])[CH3:1])=[O:19])=[CH:15][N:16]=1)([CH3:7])[CH3:9]
Reactant: CC(C)=CCO
Reactant: CC(C)(C)c1ncc(CC(=O)O)cn1
Product: CC(C)=CCOC(=O)Cc1cnc(C(C)(C)C)nc1

Procedure:
Prepared according to the esterification process described in Example 19 l, Method 1 from 3-methylbut-2-en-1-ol and 2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]acetic acid
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][CH:18]1[CH2:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[NH:20][C:19]1=[O:29]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:17][CH:18]1[CH2:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[NH:20][C:19]1=[O:29])=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CCc2ccccc2NC1=O
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Product: CC(C)(C)OC(=O)NCCCCCC(=O)NC1CCc2ccccc2NC1=O

Procedure:
Prepared from 6-(t-butoxycarbonylamino)hexanoic acid and 3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (Example 1, Step A) by the procedure described in Example 25, Step A. 1H NMR (200 MHz, CDCl3): 1.2-1.7 (m,14 H), 1.92 (m,2 H), 2.16 (t,5 Hz,1 H), 2.5-3.1 (m,6 H), 4.53 (m,2 H), 6.54 (d,7 Hz,1 H), 6.96 (m,1 H), 7.18 (m,3 H), 8.00 (s,1 H). FAB-MS: calculated for C21H31N3O4 389; found 390 (M+H,18%).
Reaction SMILES: [C:1]([OH:6])(=O)[C:2](O)=O.[CH3:7][C:8]([NH:13][NH2:14])([CH3:12])[CH2:9][CH:10]=[CH2:11].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.[OH-].[Na+].CCCCCC>[CH3:7][C:8]([N:13]([C:1](=[O:6])[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:12])[CH2:9][CH:10]=[CH2:11]
Reactant: O=C(O)C(=O)O
Reactant: C=CCC(C)(C)NN
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: C=CCC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
The 1,1-dimethyl-3-butenylhydrazine oxalate (2 g) was dissolved in toluene and neutralized with 50% aqueous sodium hydroxide. To this solution was added benzoyl chloride (2.8 g) and sodium hydroxide (50% Aq. solution) (3.2 g) at 25° C. The reaction mixture was warmed to room temperature and stirred. The mixture was diluted with hexane and filtered to afford an oily product which solidified upon standing. (m.p. 105-112° C.)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C@H:12]([CH:17]([CH3:19])C)C(OC)=O)[CH2:5]2.BrC1C=CC([C:25]([O:27][CH3:28])=[O:26])=C(CBr)C=1.Cl.NCCCC(OC)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH2:17][CH2:19][C:25]([O:27][CH3:28])=[O:26])[CH2:5]2
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2cc(Br)ccc2C1=O
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: COC(=O)CCCN
Agent: Cl
Product: COC(=O)CCCN1Cc2cc(Br)ccc2C1=O

Procedure:
The compound of example 374 was prepared analogous to compound of example 359 by reaction of the compound of example 358 and methyl 4-aminobutanoate hydrochloride.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([N:12]1[CH2:100][CH2:99][CH2:98][C@H:13]1[C:14]([NH:16][C@H:17]([C:25]([NH:27][C@H:28]([C:33]([NH:35][C@H:36]([C:39]([NH:41][C@H:42]([C:49]([NH:51][C@H:52]([C:58]([NH:60][CH2:61][C:62]([N:64]1[CH2:97][CH2:96][CH2:95][C@H:65]1[C:66]([NH:68][C@H:69]([C:74]([N:76]1[CH2:94][CH2:93][CH2:92][C@H:77]1[C:78]([NH:80][C@H:81]([C:89]([OH:91])=[O:90])[CH2:82][C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1)=[O:79])=[O:75])[CH2:70][CH2:71][S:72][CH3:73])=[O:67])=[O:63])=[O:59])[CH2:53][CH2:54][CH2:55][CH2:56][NH2:57])=[O:50])[CH2:43][C:44]1[N:48]=[CH:47][NH:46][CH:45]=1)=[O:40])[CH2:37][OH:38])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])=[O:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[NH:101](C(OC(C)(C)C)=O)[C@H:102]([C:108](O)=[O:109])[CH2:103][CH2:104][C:105](=[O:107])[NH2:106]>>[NH2:101][C@H:102]([C:108]([NH:1][C@H:2]([C:10]([N:12]1[CH2:100][CH2:99][CH2:98][C@H:13]1[C:14]([NH:16][C@H:17]([C:25]([NH:27][C@H:28]([C:33]([NH:35][C@H:36]([C:39]([NH:41][C@H:42]([C:49]([NH:51][C@H:52]([C:58]([NH:60][CH2:61][C:62]([N:64]1[CH2:97][CH2:96][CH2:95][C@H:65]1[C:66]([NH:68][C@H:69]([C:74]([N:76]1[CH2:94][CH2:93][CH2:92][C@H:77]1[C:78]([NH:80][C@H:81]([C:89]([OH:91])=[O:90])[CH2:82][C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1)=[O:79])=[O:75])[CH2:70][CH2:71][S:72][CH3:73])=[O:67])=[O:63])=[O:59])[CH2:53][CH2:54][CH2:55][CH2:56][NH2:57])=[O:50])[CH2:43][C:44]1[N:48]=[CH:47][NH:46][CH:45]=1)=[O:40])[CH2:37][OH:38])=[O:34])[CH2:29][CH:30]([CH3:31])[CH3:32])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])=[O:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:109])[CH2:103][CH2:104][C:105](=[O:107])[NH2:106]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Reactant: CSCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CSCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The resin of Example 25 was further condensed with Boc-Gln, followed by the same treatment and purification procedure and lyophilization from diluted aqueous hydrochloric acid, to give 21 mg of a white powder.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3](B(O)O)=[N:2]1.Br[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])=[CH:12][CH:11]=1.Br[C:29]1C=C2C(=CC=1)CN(C(NC1C=CC(C(=O)NCCC)=CC=1)=O)C2>>[CH3:29][N:1]1[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)[CH:3]=[N:2]1
Reactant: O=C(Nc1ccc(Br)cc1)N1Cc2ccccc2C1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(Br)cc3C2)cc1
Reactant: OB(O)c1cc[nH]n1
Product: Cn1cc(-c2ccc(NC(=O)N3Cc4ccccc4C3)cc2)cn1

Procedure:
The title compound was prepared as described in Example 280, substituting 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1H-pyrazol-3-ylboronic acid and N-(4-bromophenyl)isoindoline-2-carboxamide for 5-bromo-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.84 (s, 3H), 4.77 (s, 4H), 7.24-7.40 (m, 4H), 7.40-7.49 (m, 2H), 7.50-7.60 (m, 2H), 7.77 (s, 1H), 8.02 (s, 1H), 8.33 (s, 1H); MS (ESI(+)) m/e 319 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[C:21]1=O>C(O)C>[Cl:33][C:27]1[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:26]=1[CH:22]1[C:21]2[N:18]=[C:16]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[S:17][C:20]=2[CH2:25][CH2:24][CH2:23]1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: O=C1C(Br)CCCC1c1ccc(Cl)cc1Cl
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccc(Cl)cc2Cl)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 36.9 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (62 mg, 0.24 mmol) and of crude 2-bromo-6-(2,4-dichloro-phenyl)-cyclohexanone (79 mg, 0.25 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 3 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound (43 mg, 37%) as an off-white solid. MS ISP (m/e): 485.3/487.3 (100/73) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.00 (s, 1H), 7.47 (s, 1H), 7.39 (s, 1H), 7.11 (m, 2H), 6.89 (m, 2H), 6.75 (d, 1H), 4.47 (m, 1H), 3.60 (s, 3H), 2.76 m, 2H), 2.38 (s, 3H), 2.22 (m, 1H), 1.86 (m, 3H).
Reaction SMILES: NC(CCCCCCCCC(N)C(C)C)C(C)C.C(C1CC=CCCC=CCC(C(C)C)N=N1)(C)C.[CH3:37][CH:38]([CH:42]1[CH2:53][CH:52]=[CH:51][CH2:50][CH2:49][CH:48]=[CH:47][CH2:46][CH:45]([CH:54]([CH2:56][CH2:57][CH3:58])[CH3:55])[N:44]=[N:43]1)[CH2:39][CH2:40][CH3:41]>>[NH2:43][CH:42]([CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH:45]([NH2:44])[CH:54]([CH3:55])[CH2:56][CH2:57][CH3:58])[CH:38]([CH3:37])[CH2:39][CH2:40][CH3:41]
Reactant: CCCC(C)C1CC=CCCC=CCC(C(C)CCC)N=N1
Agent: CC(C)C(N)CCCCCCCCC(N)C(C)C
Agent: CC(C)C1CC=CCCC=CCC(C(C)C)N=N1
Product: CCCC(C)C(N)CCCCCCCCC(N)C(C)CCC

Procedure:
If there are used in the manner described under (a), instead of 250 g (1 mol) of 3,12-diisopropyl-1,2-diaza- 1,5,9-cyclododecatriene, 61 g (0.2 mol) of 3,12-di-(2-pentyl)-1,2-diaza-1,5,9-cyclododecatriene (diastereoisomeric mixture) and correspondingly reduced amounts of catalyst and solvent, using otherwise the same procedure, there is obtained, as the main fraction, 48.4 g (77%) of theory) of 5,14-diamino-4,15-dimethyloctadecane in the form of colourless oil [b.p. 155°-159° C./0.03 Torr; nD20 =1.4632; IR (liquid) inter alia bands at 3246, and 1613 cm-1 ].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:18](Cl)(=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22]>>[C:18]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CCCCC(=O)Cl
Product: CCCCC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 94 %

Procedure:
Beginning with 0.01 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.0066 mL (0.048 mMol) pentanoyl chloride, 0.013 gm (91%) of the title compound were prepared essentially by the procedure described in Example 7.