Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N=C=NC(C)C)(C)C.[CH2:28]([O:35][C:36](=[O:49])[C@@H:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C1C=CN=CC=1)C.C(#N)C>[CH2:28]([O:35][C:36](=[O:49])[C@@H:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:17][C:16](=[O:18])[CH2:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:14][CH:13]=2)=[CH:41][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCO[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)O)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CCO[C@@H](Cc1ccc(OC(=O)Cc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (4-tert-butoxycarbonylamino-phenyl)-acetic acid (100 mg, 0.39 mmol), N,N′-diisopropylcarbodiimide (60 mg, 0.47 mmol) and DMAP (15 mg, 0.12 mmol) in dry acetonitrile (15 mL) was added (S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid benzyl ester (120 mg, 0.39 mmol). The mixture was stirred for 3 h at r.t. before the solvent was evaporated and the remaining crude product directly purified by HPLC. The title compound was obtained as a solid (48 mg, 22.6%). 1H NMR (400 MHz, CDCl3): δ 7.25-7.36 (m, 9H), 7.16-7.18 (d, 2H), 6.91-6.93 (d, 2H), 5.12 (s, 2H), 4.00-4.03 (dd, 1H), 3.77 (s, 2H), 3.55-3.29 (m, 1H), 3.30-3.36 (m, 1H), 2.97-2.99 (m, 2H), 1.51 (s, 9H), 1.11-1.14 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([NH2:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[CH2:28]Br)[CH3:25]>O>[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[CH2:28][NH:12][CH:10]([CH3:11])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:25]
Reactant: CCOC(CBr)OCC
Reactant: COc1cccc(CC(C)N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(CNC(C)Cc1cccc(OC)c1)OCC
Temperature: 130 °C
Yield: 68 %

Procedure:
(+)-2-(3-methoxyphenyl)-1-methylethylamine (472.8 g, 2.86 mol), potassium carbonate (sesquihydrate) (1133.8 g, 6.88 mol) and dimethylformamide (2400 ml) were mixed and heated to 130° C. in a reaction flask fitted with an efficient stirrer and a reflux condenser. Bromoacetaldehyde diethylacetal (630 g, 3.20 mol) was added dropwise over a 45 min period while maintaining the temperature at 130° C. The reaction was mildly exothermic. The temperature was maintained at 130° C. for 1 hr. The reaction mixture was cooled to 45° C., and 325 ml of water was added. After stirring at least 1 hr and after the temperature of the mixture reached 30°, it was filtered from the salts and the solvent evaporated under vacuum on a rotatory evaporator. The residual oil was filtered from some inorganic salts and distilled under vacuum; collected fractions boiling at 115°-130° C. at 0.05 mmHg, yield 68% of (+)-N-(2,2-diethoxyethyl)-2-(3-methoxyphenyl)-1-methylethylamine.
Reaction SMILES: [Li+].[CH3:2]CC[CH2-].[Cl:6][C:7]1[CH:15]=[C:14]([CH:16]([O:19][CH2:20][C:21]2([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH:17]=O)[C:13]2[C:9](=[CH:10][N:11]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:12]=2)[CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCOCC>[Cl:6][C:7]1[CH:15]=[C:14]([CH:16]([O:19][CH2:20][C:21]2([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:23][CH2:22]2)[CH:17]=[CH2:2])[C:13]2[C:9](=[CH:10][N:11]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:12]=2)[CH:8]=1
Reactant: [CH2-]CCC
Reactant: CC(C)(C)OC(=O)N1CCC(COC(C=O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Reaction time: 0.17 h
Yield: 30.4 %

Procedure:
To a suspension of methyltriphenylphosphoniumbromide (470 mg, 1.314 mmol) in THF (17 ml) was added N-BUTYLLITHIUM (0.526 ml, 1.314 mmol). The ice bath was removed and the suspension was stirred for 10 min. To this was added tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-oxoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (277 mg, 0.438 mmol) in 2.5 mL THF. The reaction was allowed to stir 1 hour before diluted with ether (100 mL) and filtered out the solid, the ether layer was washed with water, brine and dried over magnesium sulfate, filtered and concentrated. It was then purified by Biotage LC (20-25% EtOAc/Hex) to give title compound (84 mg, 0.133 mmol, 30.4% yield) as light yellow foam solid. 1H-NMR (CDCl3, 500 MHz) δ 7.98 (s, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.29 (m, 2H), 7.00 T, J=8.8 Hz, 2H), 6.85 (s, 1H), 5.88 (ddd, J=17.2, 10.6, 5.9 Hz, 1H), 5.63(d, J=4.0 Hz, 1H), 5.60 (d, J=3.7 Hz, 1H), 5.30 (d, J=5.5 Hz, 1H), 5.23 (d, J=17.2 Hz, 1H), 5.02 (d, J=10.3 Hz, 1H), 3.69 (m, 2H), 3.58 (t, J=8.4 Hz, 2H), 3.42 (AB, Δν=28.5 Hz, J=8.8 Hz, 2H), 3.04 (m, 2H), 1.80-2.25 (m,4H), 1.41 (s, 9H), 0.88 (t, J=9.2 Hz, 2H), −0.07 (s, 9H). LC/MS (HPLC method 3): tR=4.43 min, 630.3(MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[CH2:13][C:14]([OH:16])=[O:15].[Li+].[Cl-].[CH2:19]=[CH:20][Sn](CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:19]([C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[CH2:13][C:14]([OH:16])=[O:15])=[CH2:20]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1cc(-n2cnnn2)ccc1CC(=O)O

Procedure:
To a solution of [2-bromo-4-(1H-tetrazol-1-yl)phenyl]acetic acid (100 mg, 0.35 mmol) in 10 mL of toluene was added LiCl (44 mg, 1.05 mmol), Pd(PPh3)4(10 mg), CH2═CHSnBu3 (222 mg, 0.7 mmol), and the mixture was heated to reflux overnight. After the reaction was completed, the reaction solution was diluted with EtOAc and filtered. The filtrate was concentrated and purified by prep-TLC to give [2-ethenyl-4-(1H-tetrazol-1-yl)phenyl]acetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=[C:4]2[CH:3]=1.O=S(Cl)Cl.[NH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[F:29])[C:22]([O:24][CH3:25])=[O:23].O>CC(N(C)C)=O>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:28]([F:29])=[C:19]([NH:18][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]3=[N:10][CH:9]=2)=[O:13])[CH:20]=1
Reactant: O=C(O)c1cnc2cc(Br)ccn12
Reactant: COC(=O)c1ccc(F)c(N)c1
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
To the solution of compound 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (Intermediate 1) (1.26 Kg, 5.23 mol) in DMAC (15 L) was added dropwise SOCl2 (1.86 kg, 15.6 mol) at 10° C. in 30 min. To the resulting mixture warmed to 20° C. was added compound methyl 3-amino-4-fluorobenzoate (884 g, 5.23 mol) in DMAC (3.0 L) over 30 min. After addition, the reaction temperature went up to 30° C. HPLC showed the reaction went to completion within 5 min. To the reaction mixture was added water (20 L) over 20 min. The mixture was filtered and dried under vacuum to afford the title compound as a white solid;
Reaction SMILES: [N+:1]([C:4]1[C:9]([F:10])=[C:8]([F:11])[C:7]([F:12])=[C:6](F)[C:5]=1[C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([O-:3])=[O:2].[CH2:22](OC(OCC)OCC)C.C(OC(=O)C)(=O)C.[CH:39]1([NH2:42])[CH2:41][CH2:40]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH:39]1([N:42]2[C:6]3[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[C:9]([F:10])=[C:8]([F:11])[C:7]=3[F:12])[C:14](=[O:21])[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:22]2)[CH2:41][CH2:40]1
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1[N+](=O)[O-]
Reactant: NC1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 24.2 %

Procedure:
A solution of 6.8 g (22 mmoles) of 2-nitro-3,4,5,6-tetrafluoro-β-oxobenzenepropanoic acid, ethyl ester, 4.9 g (33 mmoles) of triethylorthoformate and 50 ml of acetic anhydride was heated at reflux for two hours. The solvent was removed in vacuo and then in high vacuo at 80° C. for 1.5 hours. The residue was dissolved in 25 ml of t-butanol and treated with 1.43 g (25 mmoles) of cyclopropylamine. The mixture was heated at 45° C. for four hours, cooled to room temperature and treated dropwise with a solution of 2.47 g (25 mmoles) of potassium t-butoxide in 25 ml of t-butanol. The reaction was heated at 60° C. for six hours and the solvent was removed in vacuo. The residue was dissolved in chloroform, washed with water, dried (MgSO4), and evaporated in vacuo. The residue was chromatographed over silica gel eluting with chloroform/ethyl acetate (80/20) to give 1.9 g of the title compound as an oil which was used without further purification.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8](=[O:15])[N:9]2[CH2:12][CH2:13][CH3:14])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[OH:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.[OH-].[K+].Cl>O.CS(C)=O>[N+:17]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:24]1[CH:25]=[CH:26][C:21](=[O:20])[CH:22]=[CH:23]1)[N:9]([CH2:12][CH2:13][CH3:14])[C:8](=[O:15])[C:7](=[O:16])[NH:6]2)([O-:19])=[O:18]
Reactant: CCCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc21
Reactant: Oc1ccncc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccc(=O)cc3)cc21
Temperature: 130 °C
Reaction time: 3.5 h
Yield: 67.8 %

Procedure:
First, 1.244 g of 7-fluoro-6-nitro-1-(n-propyl)-1,4-dihydroquinoxaline-2,3-dione, 952 mg of 4-hydroxypyridine, and 711 mg of powdered potassium hydroxide were added to 10 ml of dry dimethylsulfoxide. The mixture was stirred at 130° C. for 3.5 hours in a nitrogen atmosphere. Then, 50 ml of water was added to the reaction mixture and the mixture was made acidic (pH 2 to 3) with 4N hydrochloric acid to give a yellow precipitate. The precipitate was filtered and recrystallized with dimethylformaldehyde to give 1.08 g of 6-nitro-7-(4-oxo-4H-pyridin-1-yl)-1-(n-propyl)-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Br:15][C:16]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:19]2[N:20]([CH3:26])[C:21]([CH2:23][CH2:24]Cl)=[N:22][C:18]=2[CH:17]=1.[OH-].[Na+].O>CO>[Br:15][C:16]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:19]2[N:20]([CH3:26])[C:21]([CH2:23][CH2:24][N:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)=[N:22][C:18]=2[CH:17]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Cn1c(CCCl)nc2cc(Br)c3ccccc3c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(CCN2CCN(Cc3ccccc3)CC2)nc2cc(Br)c3ccccc3c21

Procedure:
4 cc (0.022 mole) of 1-benzylpiperazine is added to a solution of 7.2 g (0.02 mole) of 5-bromo-2-(2-chloroethyl)-1-methyl-1H-naphth[1,2-d]imidazole hydrochloride and 40 cc (0.04 mole) of 1 N NaOH in 100 cc of hot methanol, and the obtained reaction mixture is heated under an argon atmosphere at reflux temperature for several hours. When the reaction, which is followed by thin layer chromatography, is completed, the solvent is boiled off and the obtained residue is taken up with a small amount of water, filtered and dried. Yield 8.87 g. M.p. 155°-157° C.
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][N:24]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][C:25]2=[O:35])[C:10](=[O:36])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39]>N1C=CC=CC=1>[CH2:41]([O:40][C:38](=[O:39])[N:15]([CH2:14][CH2:13][CH2:12][N:11]1[C:10](=[O:36])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1])[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:21][CH2:22][CH2:23][N:24]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][C:25]1=[O:35])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:42]
Reactant: CCOC(=O)Cl
Reactant: O=c1[nH]c2ccccc2c(=O)n1CCCNCCCCNCCCn1c(=O)[nH]c2ccccc2c1=O
Solvent: c1ccncc1
Product: CCOC(=O)N(CCCCN(CCCn1c(=O)[nH]c2ccccc2c1=O)C(=O)OCC)CCCn1c(=O)[nH]c2ccccc2c1=O
Reaction time: 2 h

Procedure:
3-(3-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butylamino}propyl)-1H-quinazoline-2,4-dione (2 g, 4.1 mmol) was dissolved in 40 mL pyridine and ethyl chloroformate (0.46 mL, 4.9 mmol) was added thereto. After 2 hours, pyridine was removed under reduced pressure and dichloromethane and water was added to the remaining residue. After each layer was separated, dichloromethane was removed and silica gel column-chromatography of the remaining residue was performed to give the title compound of yellow solid (0.61 g, 24%).
Reaction SMILES: [N:1]1([NH:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.C(=O)(O)[O-].[Na+].Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>ClCCl>[CH2:22]([O:21][C:19](=[O:20])[N:6]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[N:1]1[CH:2]=[CH:3][CH:4]=[CH:5]1)[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: c1ccn(Nc2ccncc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)N(c1ccncc1)n1cccc1

Procedure:
To a solution containing 9 g of N-(1H-pyrrol-1-yl)-4-pyridinamine and 15 g of sodium bicarbonate in 350 ml of dichloromethane was added to a solution containing 6.7 g of ethyl chloroformate in 50 ml of dichloromethane.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([NH2:18])=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:37]([N:44]1[CH2:49][CH2:48][CH:47](N)[CH2:46][CH2:45]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[CH2:37]([N:44]1[CH2:49][CH2:48][CH:47]([NH:18][C:16]([C:15]2[CH:14]=[C:13]3[C:9]([CH:10]=[N:11][N:12]3[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:8][C:7]=2[O:6][C:5]2[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=2)=[O:17])[CH2:46][CH2:45]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(N)=O)cc21
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)NC3CCN(Cc4ccccc4)CC3)cc21
Reaction time: 18 h
Yield: 97 %

Procedure:
A solution of 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (compound 10g, prepared as described in Example 46) in THF was treated with carbonyldiimidazole (1.2 equivalents) at room temperature under nitrogen atmosphere. After stirring for 18 hours, the reaction was treated with 1-benzyl-piperidin-4-yl-amine (1 equivalent). After an additional 18 hours, the solvent was allowed to slowly evaporate and the residue was purified in a Sep Pak cartridge eluting with a gradient of 100% CH2Cl2 to 5% MeOH/CH2Cl2 to provide compound 11g-4 as an oil in 97% yield.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[Na].Br[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>CO.O>[CH:2]([C:1]([O:8][CH3:9])=[O:7])([C:3]([O:5][CH3:6])=[O:4])[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CC(=O)OC
Reactant: COC(=O)CCC/C=C\CBr
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)CCC/C=C\CC(C(=O)OC)C(=O)OC
Reaction time: 0.25 h

Procedure:
Dimethyl malonate (39.6 g) is added slowly with cooling and stirring to a solution of 6.9 g of sodium dissolved in 100 ml of absolute methanol and the mixture stirred for 15 min. The bromoester of formula 9, methyl cis-7-bromo-5-heptenoate (65.7 g) is added dropwise. The mixture is heated at reflux for 1 hr., cooled and diluted with water. The mixture is extracted with ether. The ether extracts are dried (Na2SO4) and concentrated. The residue is distilled under reduced pressure to give the title compound, b.p. 140° - 150° C/0.7 mm.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[N:7]=[CH:8][C:9]([C:12]#[N:13])=[N:10][CH:11]=1.N1C=CC=CC=1>C1COCC1.C(Cl)Cl>[N:5]([C:6]1[N:7]=[CH:8][C:9]([C:12]#[N:13])=[N:10][CH:11]=1)=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: N#Cc1cnc(N)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1cnc(N=C=S)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of thiophosgene (1.86 g, 15 mmol) in THF (4 mL) is added dropwise to a solution of 5-aminopyrazine-2-carbonitrile (1.20 g, 10 mmol) and pyridine (2 mL) in CH2Cl2 (200 mL) and THF (25 mL) at room temperature. The reaction mixture is stirred at room temperature for 3 h. The mixture is concentrated and the crude product is diluted with ethyl acetate, filtered and concentrated to give the title compound.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:7][CH:6]=1.O.[CH3:25][N:26]([CH:28]=[O:29])C>>[CH:19]1([CH:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][N:26]3[CH2:25][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[C:28]3=[O:29])=[CH:6][CH:7]=2)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)C(c1ccc(CN2Cc3ccccc3C2=O)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
At 0° C., 611.3 mg (15.3 mmol, 60%) of sodium hydride were added to 2.035 g (15.3 mmol) of 1-oxoindoline in 12 ml of DMF. The mixture was stirred for 25 min, and 6.0 g (12.7 mmol, about 75% pure) of tert-butyl(+/−)-[4-(bromomethyl)phenyl](cyclopentyl)acetate were then added at 0° C. The reaction mixture was stirred for a further 4 h while slowly warming to RT, water was then added and the mixture was extracted twice with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. In an ultrasonic bath, the crude product was treated with diethyl ether, and the solid was filtered off with suction and dried. This gave 3.40 g (65.2% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](/[N:11]=[CH:12]/[C:13]2[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=2)[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[CH:7][CH:6]=1)=[O:4].[C:29](OCC)(=O)C.[O:35]1[CH2:39][CH2:38][CH2:37]C1>FC(F)(F)S([O-])(=O)=O.[Y+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH2:19]([O:18][C:16]([C:15]1[CH:14]=[C:13]([CH:12]2[C:38]([CH3:29])([CH3:37])[CH:39]([OH:35])[C:7]3[C:8](=[CH:9][CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=3)[NH:11]2)[CH:28]=[CH:27][CH:26]=1)=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(/N=C/c2cccc(C(=O)OCc3ccccc3)c2)cc1
Reactant: CCOC(C)=O
Reactant: C1CCOC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Y+3]
Product: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cccc(C(=O)OCc3ccccc3)c1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
To a solution of (E)-benzyl 3-((4-(methoxycarbonyl)phenylimino)methyl)benzoate (15.0 g, 40.1 mmol, 1.0 eq.), yttrium(III) trifluoromethanesulfonate (0.5 g, 0.8 mmol, 0.02 eq.) in Tetrahydrofuran (85 mL) in a four-necked flask was added Isobutyl aldehyde (3.18 g, 44.2 mmol, 1.1 eq.) via syringe. The reaction mixture was stirred at room temperature under nitrogen overnight. Thin layer chromatography (Petroleum ether:ethyl acetate=6:1) showed the reaction was complete. The reaction mixture was washed with water and the aqueous layer was extracted with ethyl acetate (twice). The organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography (Petroleum ether:ethyl acetate=5:1, then 2:1) to afford 14.2 g of methyl 2-(3-(benzyl oxycarbonyl)phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid, which was used in next step without further purification. Yield: 78.9%. MS (ESI+APCI) M−17=428.1.
Reaction SMILES: [CH2-]C(C)=[O:3].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.[CH2:22]1[CH2:27][CH2:26][CH:25]([N:28]=[C:29]=[N:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:24][CH2:23]1>CC(C)=O.C1COCC1>[C:29]([NH:28][CH:25]1[CH2:24][CH2:23][CH2:22][CH2:27][CH2:26]1)([NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:3]
Reactant: [CH2-]C(C)=O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of freshly prepared acetonide-protected amino acid (0.2 mmol, 1 equiv) in acetone (1.5 ml) was added 3 ml of THF, N-methylmorpholine (0.22 mmol, 1.1 equiv), 1-hydroxybenzotriazole (0.44 mmol, 2.2 equiv), and hexapeptide amine (0.22 mmol, 1.1 equiv). The resultant mixture was cooled to 0° C. and DCC (0.22 mmol, 1.1 equiv) was added. The mixture was allowed to warm up to room temperature and stirred under N2 for 20 h, after which time the precipitated dicyclohexylurea (DCU) was removed by filtration and washed with small portion of CH2C2. The combined filtrate was washed with saturated NaHCO3 solution and dried over MgSO4. Concentration in vacuo and dissolving the residue in EtOAc yielded more DCU. The residue remaining after a second filtration and concentration in vacuo was purified by chromatography with 10-40% acetone in freshly distilled n-hexane to give the N,O-Isopropylidene protected heptapeptide 1-7.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[C:20]([I:23])=[N:21][NH:22][C:16]=2[CH2:15]1)=[O:13].[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC(Cl)C.C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[C:20]([I:23])=[N:21][N:22]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][O:24]3)[C:16]=2[CH2:15]1)=[O:13].[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[CH:20]([I:23])[N:21]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][O:24]3)[NH:22][C:16]=2[CH2:15]1)=[O:13]
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(I)n[nH]c2C1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCC2=C(C1)NN(C1CCCCO1)C2I
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(I)nn(C3CCCCO3)c2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-iodo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (40 mg, 0.09 mmol) in dichloroethane (1 mL) was added 3,4-dihydropyran (24 mL, 0.26 mmol) and para-toluenesulfonic acid (2 mg, 0.009 mmol). After stirring for 4 h at rt the reaction was diluted with CH2Cl2 and washed with aqueous saturated sodium bicarbonate. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. Chromatography on silica gel (0-50% ethyl acetatehexanes) provided the desired product as a mixture of regioisomers (45 mg, 95%). MS (ESI) mass calcd. C19H18ClF31N3O2, 539.0. m/z found, 540.0 [M+H]+.