Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:16]1([CH3:28])[CH:21]=[CH:20][C:19]([S:22]([CH2:25][N+:26]#[C-:27])(=[O:24])=[O:23])=[CH:18][CH:17]=1.[H-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O>[CH2:12]([O:11][C:9](=[O:10])[C:8]([CH3:15])([CH3:14])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:25]([N+:26]#[C-:27])([S:22]([C:19]1[CH:18]=[CH:17][C:16]([CH3:28])=[CH:21][CH:20]=1)(=[O:23])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:14])([CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:13]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C(C)(C)CCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: [C-]#[N+]C(CCCCCCC(C)(C)C(=O)OCC)(CCCCCCC(C)(C)C(=O)OCC)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 99.7 %

Procedure:
To a solution of ethyl 8-bromo-2,2-dimethyloctanoate (35.0 g, 125.4 mmol), tetrabutylammonium iodide (4.6 g, 12.5 mmol), and p-toluenesulphonylmethyl isocyanide (TosMIC, 12.2 g, 62.7 mmol) in anhydrous DMSO (450 mL) was added sodium hydride (60% dispersion in mineral oil, 6.3 g, 158 mmol) under cooling with an ice-water bath and under N2 atmosphere. The reaction mixture was stirred for 23 h at room temperature, then carefully hydrolyzed with ice-water (500 mL) and extracted with MTBE (3×200 mL). The organic layers were washed with water (300 mL) and brine (150 mL), dried over MgSO4, and concentrated in vacuo to give crude 9-isocyano-2,2,16,16-tetramethyl-9-(toluene-4-sulfonyl)-heptadecanedioic acid diethyl ester (37.0 g, 100%). 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 7.88 (d, J=7.9 Hz, 2H), 7.42 (d, J=7.9 Hz, 2H), 4.10 (q, J=7.5 Hz, 4H), 2.48 (s, 3H), 2.05-1.75 (m, 3H), 1.65-1.20 (m, 21H), 1.15 (t, J=7.5 Hz, 6H), 1.10 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 177.89, 163.75, 146.23, 131.35, 130.28, 129.82, 81.79, 60.17, 42.09, 40.57, 33.09, 29.68, 25.17, 24.78, 23.66, 14.31. HRMS (LSIMS, gly): Calcd for C37H54NO6S (MH+): 592.3672. found: 592.3667.
Reaction SMILES: [C:1]([NH:4][C:5](=[CH2:9])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[CH3:10][NH2:11]>O>[C:1]([NH:4][CH:5]([CH2:9][NH:11][CH3:10])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CN
Reactant: C=C(NC(C)=O)C(=O)O
Solvent: O
Product: CNCC(NC(C)=O)C(=O)O

Procedure:
0.31 g of 2-acetamidoacrylic acid was stirred in 200 ml of 40% methylamine in water at 40° C. for 80 hours. Excess methylamine and water were evaporated under reduced pressure, and the residue was held under high vacuum overnight. The residue was recrystallized from a 1:1 v:v mixture of ether and methanol and dried to give 2-acetylamino-3-(methylamino)propionic acid (38A) as a white solid, m.p.: 166.5°-168.5° C. (with decomposition).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:49])[CH2:27][C:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:36][CH:37]=[C:38]([CH2:40][O:41]C3CCCCO3)[N:39]=2)[CH:30]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:11]1[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])=[CH:13][C:8]2[N:7]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[O:36][CH:37]=[C:38]([CH2:40][OH:41])[N:39]=4)[CH:30]=3)[CH2:27][C:26](=[O:49])[NH:19][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)co2)c1
Reactant: CCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)co3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(ethyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.15 g) (Example J7) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-2-yl]-phenyl]-propionic acid tert-butyl ester (0.22 g) (Example K11) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.10 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:32]=[CH:31][N:30]=[C:29]([CH3:28])[CH:34]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following procedures analogous to those described in Example 75 Step 1. LC-MS Method 2 tR=0.866 min, m/z=444.2; 1H NMR (CDCl3) 1.04-1.16 (d, 6H), 1.50 (d, 3H), 2.14-2.25 (m, 4H), 2.45 (m, 1H), 2.57 (s, 3H), 2.83 (m, 1H), 5.65 (m, 1H), 7.04 (d, 2H), 7.20-7.33 (m, 9H), 8.45 (d, 1H).
Reaction SMILES: [Br:1][CH2:2][CH:3]([Br:5])[CH3:4].[CH3:6][C:7]([CH3:9])=[O:8]>>[Br:1][CH2:2][CH:3]([Br:5])[CH3:4].[CH2:6]1[O:8][CH:7]1[CH3:9]
Reactant: CC(C)=O
Agent: CC(Br)CBr
Product: CC1CO1
Yield: 30 %

Procedure:
1,2-dibromopropane (1.00 ml/hour) and helium (2.0 ml/minute) were passed through a reactor packed with M at 100° C. Within the first 2 hours, an average 1,2-dibromopropane conversion of 40%, with 30% propylene oxide average selectivity and 70% acetone selectivity was obtained.
Reaction SMILES: C([Li:5])CCC.[CH2:6]([C:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9]>CCCCCC.C(OCC)C>[CH2:6]([C:10]1([Li:5])[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCC1=CC=CC1
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: [Li]C1(CCCC)C=CC=C1

Procedure:
Being cooled in an ice-water bath, a solution of 49.8 ml of butyl lithium(0.125 mol) in 2.5M hexane was slowly dripped to a solution of 15.2 g(0.125 mol) of butyl-cyclopentadiene in 200 ml diethylether with stirring. After the dripping was finished, the resultant mixture was continuously stirred for 1 hour, a white muddy solution of butyl-cyclopentadienyl lithium was then obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[C:15]([CH3:17])[C:14]([C:18](=O)[CH2:19]Br)=[C:13]([CH3:22])[CH:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:23][C:24]([NH2:26])=[S:25]>CCO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[C:15]([CH3:17])[C:14]([C:18]4[N:23]=[C:24]([NH2:26])[S:25][CH:19]=4)=[C:13]([CH3:22])[CH:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NC(N)=S
Reactant: Cc1cc(Oc2ccc3c(c2)OCO3)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(Oc2ccc3c(c2)OCO3)cc(C)c1-c1csc(N)n1
Yield: 95.6 %

Procedure:
A mixture of 1-(4-(benzo(d)(1,3)dioxol-5-yloxy)-2,6-dimethylphenyl)-2-bromoethanone (6.13 g, 16.9 mmol) and thiourea (1.29 g, 16.9 mmol) in 95% EtOH (24.1 mL) was heated at reflux for 90 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4-(benzo(d)(1,3)dioxol-5-yloxy)-2,6-dimethylphenyl)thiazol-2-amine (5.50 g) as yellow solids 20 in 96% yield: 1H NMR (500 MHz, CDCl3) δ 6.75 (d, J=8.5 Hz, 1 H), 6.66 (s, 2 H), 6.58 (m, 1 H), 6.49 (m, 1 H), 6.28 (s, 1 H), 5.98 (s, 2 H), 5.05 (s, 2 H), 2.13 (s, 6 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11](OS(C1C=CC(C)=CC=1)(=O)=O)[C@@H:12]1[O:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C@H:12]2[CH2:13][O:14]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1OC[C@H]1CO1
Yield: 91.2 %

Procedure:
Preparation according to Preparation 1 using 5-bromo-2-hydroxybenzaldehyde (6 g, 29 mmol), (R)-glycidyltosylate (6.7 g, 29 mmol), K2CO3 (4.9 g, 35 mmol) and DMF (12 ml). The combined organic phases were washed with LiCl (5%, 100 ml), HCl (1 N, 100 ml), brine (100 ml) and were evaporated to dryness. The residue was purified by flash column chromatography (isooctane/EtOAc) to give the crude title compound (6.8 g). MS m/z (rel. intensity, 70 eV) 257 (M+, 38), 256 (M+, 39), 200 (bp), 199 (87), 57 (88).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH:22]2[C:27](=[O:36])[NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:44]([CH3:46])[CH3:45]>CC(C)=O>[NH2:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH:22]2[C:27](=[O:36])[NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:44]([CH3:46])[CH3:45])=[C:14]([O:19][CH3:20])[CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: COc1cc(-c2ccc3nc(N)nc(N4CCNCC4C(=O)Nc4ccc(F)cc4)c3n2)ccc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(-c2ccc3nc(N)nc(N4CCNCC4C(=O)Nc4ccc(F)cc4)c3n2)ccc1OC(C)C
Reaction time: 24 h
Yield: 39.2 %

Procedure:
A suspension of 2-amino-4-[(N-4-fluoro-phenyl-carbamoyl)-piperazin-1-yl]-6-(4-hydroxy-3-methoxy-phenyl)-pyrido[3,2-d]pyrimidine (96 μmole), anhydrous potassium carbonate (0.22 mmole) and 2-iodopropane (0.96 mmole) in acetone (7 ml) was refluxed under a nitrogen atmosphere for 20 hours. Then, another aliquot of 2-iodopropane was added and the reaction was continued for another 24 hours. Upon cooling, the reaction mixture was partitioned between ethyl acetate and brine and the aqueous layer was extracted several times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and evaporated under reduced pressure. Purification of the crude residue by silica gel flash chromatography, using 10% methanol in CH2Cl2 as mobile phase, afforded the pure title compound (20 mg, yield 39%) which was characterized by its mass spectrum as follows: MS (m/z): 532 ([M+H]+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:11].Br[C:13]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>C(O)(C)C.CN1CCOCC1.[Cu].[Cu]I>[CH3:11][N:6]1[C:7]2[C:3](=[C:2]([NH:1][C:13]3[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=[O:16])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[N:5]1
Reactant: Cn1ncc2c(N)cccc21
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Agent: [Cu]
Agent: [Cu]I
Solvent: CC(C)O
Solvent: CN1CCOCC1
Product: Cn1ncc2c(Nc3c(C(=O)O)cccc3[N+](=O)[O-])cccc21
Yield: 5 %

Procedure:
A solution of 4-nitroindazole (prepared according to the literature procedures Davies, R. R. J.C.S., 1955, 2412-2423; Porter, H. D. Org. Synth. Collect. Vol I, 20, 73-74.) (2.01 g, 12.3 mmol) was added slowly to a cold (ice/water), stirred suspension of NaH (440 mg, 18.4 mmol) in DMF (20 mL) under N2. The mixture was stirred for 30 min, and a solution of MeI (1.91 g, 13.5 mmol) in DMF (10 mL) was then added. Workup gave 1-methyl-4-nitroindazole (1.79 g, 82%); mp (EtOAc/petroleum ether) 138-139° C. Hydrogenation of this (6.70 g, 37.9 mmol) in absolute EtOH (300 mL) in the presence of Pd/C (1.00 g) gave 4-amino-1-methylindazole (4.23 g, 76%). A mixture of 4-amino-1-methylindazole (4.10 g, 27.9 mmol) and 2-bromo-3-nitrobenzoic acid (6.86 g, 27.9 mmol) were then reacted in a mixture of isopropanol/N-methylmorpholine in the presence of copper powder and CuI as above, giving 2-[(1-methyl-1H-indazol-4-yl)amino]-3-nitrobenzoic acid (439 mg, 5 %); mp (EtOAc/n-hexane) 257-260° C.; Reductive cyclisation of 2-[(1-methyl-1H-indazol-4-yl)amino]-3-nitrobenzoic acid with NaBH4 in 2 M NaOH as above gave 3-methyl-3H-pyrazolo[4,3-a]phenazine-10-carboxylic acid as a dark yellow solid (54%); mp (acetone) 320-323° C. [(CD3)2SO] δ 4.28 (s, 3 H, NCH3), 8.07 (t, J=7.9 Hz, 1 H, H-8), 8.10 (d, J=9.6 Hz 1H, H-4 or H-5), 8.39 (d, J=9.6 Hz 1H, H-4 or H-5), 8.52-8.60 (m, 2H, H-7 and H-9), 8.76 (s, 1 H, H-2), 14.90 (br s, 1 H, COOH).
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH:26]=[CH2:27])[S:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=1)(=[O:17])=[O:16])(=[O:7])=[O:6])[CH:2]=[CH2:3].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][C:34]=1[O:35][CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[CH2:1]([N:4]([CH2:25][CH:26]=[CH2:27])[S:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:31]2[CH:32]=[N:33][C:34]([O:35][CH3:36])=[C:29]([Cl:28])[CH:30]=2)[CH:19]=1)(=[O:17])=[O:16])(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: COc1ncc(B(O)O)cc1Cl
Reactant: C=CCN(CC=C)S(=O)(=O)c1cnccc1NS(=O)(=O)c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: C=CCN(CC=C)S(=O)(=O)c1cnccc1NS(=O)(=O)c1cccc(-c2cnc(OC)c(Cl)c2)c1
Temperature: 100 °C
Yield: 58 %

Procedure:
A mixture of N,N-diallyl-4-(3-bromophenylsulfonamido)pyridine-3-sulfonamide (0.29 g, 0.62 mmol), 5-chloro-6-methoxypyridin-3-ylboronic acid (0.15 g, 0.81 mmol), (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.026 g, 0.030 mmol), cesium carbonate (0.30 g, 0.93 mmol), 1,2-dimethoxyethane (4.5 mL) and water (0.5 mL) under an atmosphere of argon was heated at 100° C. for 15 min in a microwave reactor. The reaction mixture was partitioned between ethyl acetate and diluted hydrochloric acid, the organic phase was dried over magnesium sulfate and the solvent was evaporated. Purification by column chromatography, using chloroform/methanol (98:2) as the eluent, gave the title compound in 58% yield.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].[NH2:12][CH2:13][CH2:14][CH2:15][OH:16].Cl>>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])=[O:4])=[CH:6][CH:7]=1
Reactant: NCCCO
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Product: O=C(NCCCO)c1ccc(O)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
Methyl p-hydroxybenzoate (11.5 g) was added to 17.0 g of 3-aminopropanol, and the mixture was stirred at 120° C. for 8 hours. Then, the reaction mixture was added to 1 N hydrochloric acid and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried. Evaporation of the solvent gave a crude product. The crude product was purified by silica gel column chromatography to give 9.3 g (yield 63.7%) of 4-hydroxy-N-(3-hydroxypropyl)benzamide.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[CH2:5][O:4]1.O.[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8]>>[Cl:1][CH2:2][CH:3]([OH:4])[CH2:5][N:9]([CH2:10][CH3:11])[CH2:7][CH3:8]
Reactant: CCNCC
Reactant: ClCC1CO1
Solvent: O
Product: CCN(CC)CC(O)CCl
Temperature: 31.5 °C
Reaction time: 6 h

Procedure:
To 2-chloromethyloxirane (95 g, 1.03 mole) was added a mixture of water (3.08 g, 0.17 mole) and diethylamine (106.2 mL, 1.03 mole) at 30° C. The reaction mixture was then stirred at 28-35° C. for 6 hour and cooled to 20-25° C. to give 1-chloro-3-diethylamino-propan-2-ol.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:43])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:42])[CH2:21][CH2:22][NH:23][C:24]([C:26]3[N:27]=[C:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[F:41])[O:29][C:30]=3[C:31]([F:34])([F:33])[F:32])=[O:25])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>C1COCC1.CO.O>[F:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:28]1[O:29][C:30]([C:31]([F:34])([F:32])[F:33])=[C:26]([C:24]([NH:23][CH2:22][CH2:21][C:20]([NH:19][C:16]2[CH:15]=[CH:14][C:13]([C@H:10]3[CH2:9][CH2:8][C@H:7]([CH2:6][C:5]([OH:43])=[O:4])[CH2:12][CH2:11]3)=[CH:18][CH:17]=2)=[O:42])=[O:25])[N:27]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4F)oc3C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4F)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
NaOH (22.6 mg, 0.57 mmol) was added to trans-{4-[4-(3-{[2-(2-fluoro-phenyl)-5-trifluoromethyloxazole-4-carbonyl]amino}propionylamino)phenyl]cyclohexyl}acetic acid methyl ester (65 mg, 0.11 mmol) dissolved in THF/MeOH/water (20 mL, 3:2:1). The reaction mixture was stirred at 25° C. for 15 hours and concentrated under vacuum. The residue was acidified with 1M HCl up to pH of 2, stirred for 30 minutes, and filtered. The filtrate was eluted with a gradient of methanol/DCM (5-10%) on a silica gel by column chromatography and purified to obtain the desired compound (60 mg, 94%) as a white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=2)[N:12]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[N:11]=1.[H][H]>C(O)C.[Pd]>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=2)[N:12]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[N:11]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Yield: 60 %

Procedure:
3-(1H-Benzo[d]imidazol-2-yl)-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (50 mg, 0.137 mmol) was added to 10% Pd/C (10 mg) in ethanol (40 mL) and then pressurized with hydrogen (60 psi) for 6 h at room temperature. The reaction mixture was filtered through Celite, and the solvent was removed in vacuo. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound in 60% yield. 1H NMR (400 MHz, CD3OD): δ 7.69 (m, 2H), 7.55 (m, 2H), 7.26 (m, 2H), 7.05 (m, 1H), 5.84 (d, 1H, J=9.2 Hz), 4.00 (m, 1H), 3.82 (m, 1H), 2.65 (m, 1H), 2.14 (m, 2H), 1.78 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH:9]=[CH:10][CH2:11]Cl)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:23]([O:27][C:28]([N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[CH2:39][NH:40][CH:41]1[C:50]2[N:49]=[CH:48][CH:47]=[CH:46][C:45]=2[CH2:44][CH2:43][CH2:42]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(#N)C.[I-].[K+]>[C:23]([O:27][C:28]([N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[CH2:39][N:40]([CH2:11]/[CH:10]=[CH:9]\[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:13])[C@@H:41]1[C:50]2[N:49]=[CH:48][CH:47]=[CH:46][C:45]=2[CH2:44][CH2:43][CH2:42]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Reactant: CC(C)(C)OC(=O)NCC=CCCl
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC/C=C\CN(Cc1nc2ccccc2n1C(=O)OC(C)(C)C)[C@H]1CCCc2cccnc21
Temperature: 60 °C
Reaction time: 17 h
Yield: 161.1 %

Procedure:
(4-Chloro-but-2-enyl)-carbamic acid tert-butyl ester (1.81 g, 7.47 mmol), potassium iodide (59 mg, 0.36 mmol) and diisopropylethylamine (1.80 mL, 10.3 mmol) were added to a solution of 2-[(5,6,7,8-tetrahydroquinolin-8-ylamino)-methyl]-benzimidazole-1-carboxylic acid tert-butyl ester (2.57 g, 6.79 mmol)) in acetonitrile (70 mL) and warmed to 60° C. and stirred for 17 h under nitrogen. The solvent was removed in vacuo. The residue was dissolved in methylene chloride (100 mL) and washed with brine (100 mL). The aqueous layer was extracted with methylene chloride (2×150 mL). The combined organic layers were dried (Na2SO4) and concentrated. The crude mixture was purified by column chromatography on silica gel (150 g) to afford 2-{[(S)-((Z)-4-tert-butoxycarbonylamino-but-2-enyl)-5,6,7,8-tetrahydro-quinolin-8-yl-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester (5.99 g, 88%) as a white foamy solid. 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.72 (s, 9H), 1.95-2.08 (m, 4H), 2.09-2.20 (m, 1H), 2.61 (d, 1H, J=16.2 Hz), 3.28 (dd, 1H, J=14.1, 5.4 Hz), 3.62 (dd, 1H, J=13.7, 7.2 Hz), 3.69-3.85 (m, 2H), 4.29 (dd, 1H, J=9.2, 6.6 Hz), 4.42 (d, 1H, J=14.9 Hz), 4.48 (d, 1H, J=14.9 Hz), 5.43-5.63 (m, 2H), 6.19 (s, 1H), 6.87 (dd, 1H, J=7.5, 4.8 Hz), 7.17 (d, 1H, J=7.7 Hz), 7.23-7.28 (m, 1H), 7.65-7.71 (m, 1H), 7.75-7.80 (m, 1H), 8.34 (d, 1H, J=4.4 Hz).
Reaction SMILES: [C:1]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[OH-].[Na+:24]>C(O)C>[CH2:3]([OH:4])[CH3:2].[C:1]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O-:22])=[O:21])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Na+:24].[Na+:24].[C:1]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O-:22])=[O:21])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(O)CCCCCCCCCNC(=O)c1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])CCCCCCCCCNC(=O)c1ccccc1O
Temperature: 40 °C

Procedure:
A 1 L Pyrex glass, four-neck, round bottom flask was equipped with an overhead stirrer, reflux condenser, thermocouple temperature read out, and heating mantle. The flask was purged with dry nitrogen and the following reaction conducted under an atmosphere of dry nitrogen. The flask was charged with 100 g of N-salicyloyl-10-aminodecanoic acid and 500 mL absolute ethanol. The slurry was heated to about 40° C. with stirring and all of the solids were dissolved. An addition funnel was attached to the reactor and charged with 232.5 g of 11.2 wt % sodium hydroxide dissolved in absolute ethanol. The sodium hydroxide solution was added to the stirred reaction mixture over a fifteen minute period. The reflux condenser was removed from the reactor and replaced with a distillation head and receiver. The reaction mixture was distilled at atmospheric pressure until about 395 g of distillate was collected. The reaction mixture had become a thick slurry during this distillation. The mixture was allowed to cool to room temperature. The thick mixture was transferred to a sintered glass funnel and the solids recovered by vacuum filtration. The ethanol wet cake was placed in a 45° C. vacuum oven and dried to constant weight at full vacuum. The dried material had a weight of about 124.6 g.
Reaction SMILES: O.Cl.O[C:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:8][CH2:7][C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)=[C:5]1[CH3:19].N>O1CCCC1>[CH3:19][C:5]1[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:8][CH2:7][C:6]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2
Reactant: CC1=C(c2cccc3cccnc23)CCC1(O)c1ccccc1
Agent: Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: CC1=C(c2cccc3cccnc23)CC=C1c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.3 %

Procedure:
A mixture of 5 ml of water and 5 ml of concentrated hydrochloric acid was added to a solution of 1.717 g (5.7 mmol) of 3-hydroxy-2-methyl-3-phenyl-1-(8-quinolyl)cyclopentene in 100 ml of tetrahydrofuran. The mixture was stirred at room temperature for 90 minutes and ammonia solution was then added until the pH was 12. The aqueous phase was then separated off from the organic phase and the aqueous phase was extracted twice with diethyl ether. The organic phases were combined, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue obtained in this way was distilled at 157-170° C. and 2×10−2 mbar to give 1.12 g (3.95 mmol, 69.3%) of 2-methyl-3-phenyl-1-(8-quinolyl)cyclopentadiene.