Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]#[C:14][CH2:15][CH2:16][CH2:17][OH:18]>C(O)C.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]
Reactant: OCCCC#Cc1ccccc1C#CCCCO
Agent: [Pd]
Solvent: CCO
Product: OCCCCCc1ccccc1CCCCCO
Reaction time: 4 h
Yield: 91.4 %

Procedure:
5-[2-(5-Hydroxy-pent-1-ynyl)-phenyl]-pent-4-yn-1-ol (2.70 g, 11.14 mmol) was dissolved in ethanol (30 mL) and 10% Pd/C (2.5% w/w) was added. The resulting mixture was hydrogenated on a Parr hydrogenation apparatus (45 psi) for 4 hrs. The catalyst was removed by filtration through a Celite pad. The filter cake was rinsed with methanol, and the combined organic liquors were concentrated under reduced pressure. The crude product was purified by column chromatography (chloroform:methanol 20:1) to afford 2.55 g of the title compound. Yield: 91%. 1H NMR (300 MHz, CDCl3) δ 1.38-1.67 (m, 12H), 2.60 (t, J=7.8 Hz, 4H), 3.59 (t, J=6.6 Hz, 4H), 7.11 (m, 4H) ppm; 13C NMR (75 MHz, CDCl3) δ 26.0, 31.3, 32.6, 32.8, 62.6, 125.8, 129.1, 140.2 ppm.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])([CH3:3])=[CH2:2].[ClH:12]>C(O)C.C(O)(=O)C.CO.C(OCC)C.[Pd]>[ClH:12].[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([CH3:3])[CH3:2]
Reactant: C=C(C)c1cccc(C#N)c1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CCO
Product: CC(C)c1cccc(CN)c1
Reaction time: 12 h

Procedure:
A solution of 3-isopropenylbenzonitrile (6.0 g, 41.9 mmol) and 10% Pd/C (600 mg) in ethanol (65 mL) and acetic acid (2.4 mL) is degassed with nitrogen for 15 min, and shaken under an atmosphere of hydrogen at 50 psi for 12 h. The reaction mixture is filtered through diatomaceous earth and concentrated under reduced pressure to provide an oil. The oil is dissolved in methanol (5 mL) and hydrochloric acid (15 mL of a 1 M solution in diethyl ether) is added. The resulting precipitate is collected by filtration to provide the title compound. APCI MS m/z 149 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]2[C:13](=[O:14])[NH:12][C:10](=[O:11])[CH:9]([C:15]([OH:17])=[O:16])[CH2:8]2)=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:20][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[C:13](=[O:14])[NH:12][C:10](=[O:11])[CH:9]([C:15]([OH:17])=[O:16])[CH2:8]2)=[CH:18][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(OC2CC(C(=O)O)C(=O)NC2=O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1NC(=O)C(C(=O)O)CC1Oc1ccc(CBr)cc1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
A solution of 1.3 g (5.2 mmol) of 4-(4-methylphenoxy)carboxyglutarimide, 1.0 g (5.7 mmol) of N-bromosuccinimide and 0.02 g of benzoyl peroxide in 30 ml of carbon tetrachloride was refluxed for 16 hours, cooled to room temperature, evaporated and the residue dissolved in 200 ml of ethyl acetate. The EtOAc layer was washed with water, dried over Na2SO4 and evaporated to give 1.6 g of the crude product.
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@H:20]([C:24]([OH:26])=[O:25])[CH2:21][CH2:22][OH:23].C(=O)(O)[O-].[Na+]>O.CC(C)=O>[C:2]1([CH2:1][O:8][C:9]([NH:19][C@H:20]([C:24]([OH:26])=[O:25])[CH2:21][CH2:22][OH:23])=[O:11])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H](CCO)C(=O)O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(N[C@@H](CCO)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(Benzyloxycarbonyloxy)succinimide (23.57 g., 94.58 mmol.) was added to a solution of L-homoserine (10.24 g., 85.98 mmol.) and sodium bicarbonate (7.95 g., 94.58 mmol., 1.1 eq.) in a mixture of water (100 ml.) and acetone (100 ml.). The mixture was stirred at room temperature overnight. The acetone was removed under reduced pressure (rotovap) and the aqueous solution was washed with methylene chloride (2×75 ml.). The aqueous layer was then acidified to pH 2 by addition of 6N hydrochloric acid and extracted with ethyl acetate (2×250 ml.). The combined ethyl acetate layers were washed with water (2×100 ml.) and brine, dried over sodium sulfate, filtered, concentrated and dried in vacuo to afford 19.54 g. of title product as a white solid. TLC (ethyl acetate:n-butanol:acetic acid:water; 2:1:1:1) Rf =0.74
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[CH2:26][CH:27]1CC[CH2:28]1.[C-]#N.[K+]>C(O)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH:20]3[CH2:28][CH2:27][CH2:26]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: OCC1CCC1
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Product: O=C(OCC1CCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2

Procedure:
10.35 g (0.03 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 25 ml of hydroxymethylcyclobutane and 0.5 g of powdered potassium cyanide are heated to 165° for 2 hours, the ethanol formed being distilled off continuously. The mixture is subsequently evaporated in vacuo, the residue is taken up in chloroform, the chloroform solution is washed three times with water, dried over magnesium sulphate and evaporated. By recrystallization of the resulting material from ethyl acetate there is obtained cyclobutylmethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 204°-205°.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=3[F:19])[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:10]=2[CH3:27])=[CH:6][C:5]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:4][N:3]=1.[OH:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[F:19][C:17]1[CH:16]=[C:15]([F:20])[CH:14]=[C:13]2[C:18]=1[C:9]([NH:8][C:7]1[C:2]([C:38]3[CH:39]=[CH:40][C:35]([OH:34])=[CH:36][CH:37]=3)=[N:3][CH:4]=[C:5]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:6]=1)=[C:10]([CH3:27])[C:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[N:12]2
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1Cl
Reactant: OB(O)c1ccc(O)cc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1-c1ccc(O)cc1
Temperature: 90 °C
Reaction time: 19 h

Procedure:
N-(2-chloro-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-amine (60.6 mg, 0.13 mmol), 4-hydroxyphenylboronic acid (36.7 mg, 0.27 mmol), tricyclohexylphosphine (7.7 mg, 0.027 mmol), and tris(dibenzylideneacetone)dipalladium (0) (12.1 mg, 0.013 mmol) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (2.0 mL) and aq. 1.3M potassium phosphate tribasic (0.3 mL, 0.39 mmol) were added by syringe. The resulting reaction was heated to 90° C. and monitored with TLC and LC-MS. After 19 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-55% of a premixed solution of 89:9:1 DCM:MeOH:ammonium hydroxide in DCM) to afford a film that was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a yellow solid as 4-(3-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinopyridin-2-yl)phenol. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.49 (1H, s), 8.70 (1H, dq, J=4.8, 0.9 Hz), 8.01 (1H, td, J=7.7, 1.7 Hz), 7.94 (1H, d, J=2.4 Hz), 7.83 (1H, d, J=7.6 Hz), 7.65 (2H, m), 7.54 (4H, m), 6.79 (2H, m), 6.45 (1H, d, J=2.4 Hz), 3.76 (4H, m), 3.14 (4H, m), 2.13 (3H, s). Mass Spectrum (pos.) m/e: 526.2 (M+1).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1B(O)O>>[Cl:11][C:9]1[N:10]=[C:3]2[CH:2]=[CH:7][CH:6]=[C:5]([C:15]3[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:14]=3[O:13][CH3:12])[N:4]2[N:8]=1
Reactant: COc1ccc(C(F)(F)F)cc1B(O)O
Reactant: Clc1nc2c(Br)cccn2n1
Product: COc1ccc(C(F)(F)F)cc1-c1cccc2nc(Cl)nn12

Procedure:
2-Chloro-5-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro[1,2,4]triazolo[1,5-a]pyridine (0.5 g, 2.15 mmol) and 2-methoxy-5-trifluoromethylbenzeneboronic acid (0.71 g, 3.23 mmol) in a manner analogous to Example 2c. Product was isolated as a foam (0.7 g, 82%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.80 (d, J=8.8 Hz, 1H), 7.75-7.70 (m, 2H), 7.68-7.62 (m, 1H), 7.16 (d, J=8.8 Hz, 1H), 7.09 (d, J=6.8 Hz, 1H), 3.87 (s, 3H). MS=328 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:23][C:24]([CH3:28])([CH3:27])[C:25]#[CH:26]>C1COCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:26]#[C:25][C:24]([CH3:28])([CH3:27])[CH3:23])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C#Cc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4-Iodo-phenyl)-carbamic acid tert-butyl ester (37a, 1.0 g, 3.13 g) was dissolved in THF (30 mL) and treated with Et3N (2.2 mL, 15.7 mmol), 3,3-dimethyl- 1-butyne (0.58 mL, 4.70 mmol), bis(triphenylphosphine) palladium (II) chloride (0.218 g, 0.31 mmol), and copper (I) iodide (0.03 g, 0.16 mmol). The reaction was stirred overnight at room temperature, then filtered and concentrated. The residue was chromatographed on silica gel eluting with 8:1 hexanes/EtOAc to give 0.7 g (82%) of the mostly clean desired product which was carried on without further purification.
Reaction SMILES: [CH:1]1([N:4]([CH2:28][C:29]2[CH:34]=[C:33]([CH2:35][CH2:36][CH2:37][CH2:38][OH:39])[CH:32]=[C:31]([Cl:40])[C:30]=2[Cl:41])[C:5]([C@H:7]2[C@H:12]([C:13]3[CH:18]=[CH:17][N:16]([CH3:19])[C:15](=[O:20])[CH:14]=3)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.Cl>C(Cl)Cl>[CH:1]1([N:4]([CH2:28][C:29]2[CH:34]=[C:33]([CH2:35][CH2:36][CH2:37][CH2:38][OH:39])[CH:32]=[C:31]([Cl:40])[C:30]=2[Cl:41])[C:5]([C@H:7]2[C@H:12]([C:13]3[CH:18]=[CH:17][N:16]([CH3:19])[C:15](=[O:20])[CH:14]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:2][CH2:3]1
Reactant: Cn1ccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2C(=O)N(Cc2cc(CCCCO)cc(Cl)c2Cl)C2CC2)cc1=O
Agent: Cl
Solvent: ClCCl
Product: Cn1ccc([C@@H]2CCNC[C@H]2C(=O)N(Cc2cc(CCCCO)cc(Cl)c2Cl)C2CC2)cc1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a CH2Cl2 solution (0.05 M) of trans-1,1-dimethylethyl 3-[(cyclopropyl{[2,3-dichloro-5-(4-hydroxybutyl)phenyl]methyl}amino]carbonyl}-4-(1-methyl-2-oxo-1,2-dihydro-4-pyridinyl)-1-piperidinecarboxylate (1 eq.) from the previous step was added HCl (4.0 M dioxane solution, 30 eq.). The resulting solution was stirred at RT for 3 h. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a SiO2 column packed with 93:7 (v/v) CH2Cl2:2.0 M NH3 in MeOH. Elution with the same solvent system furnished the title compound as a white froth. MS (ESI+, M+H): 508.
Reaction SMILES: C[Mg]Cl.[CH3:4][N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH2:15][CH3:16])[C:9]=2[C:8](=[O:17])[N:7]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23])[C:6]1=[O:25].[CH3:26]COCC.[Cl-].[NH4+]>O1CCCC1>[OH:24][C:22]([CH3:26])([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:7]1[C:8](=[O:17])[C:9]2[N:10]([CH2:14][CH2:15][CH3:16])[CH:11]=[N:12][C:13]=2[N:5]([CH3:4])[C:6]1=[O:25]
Reactant: CCCn1cnc2c1c(=O)n(CCCCC(C)=O)c(=O)n2C
Reactant: CCOCC
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2C

Procedure:
22.4 g (0.3 mol) of methylmagnesium chloride in the form of a 20% strength solution in tetrahydrofuran are added dropwise with vigorous stirring at room temperature to a suspension of 61.3 g (0.2 mol) of 3-methyl-1-(5-oxohexyl)-7-propylxanthine in 2 1 of anhydrous ether, the internal temperature rising to approximately 30° C. The mixture is then warmed with stirring and under reflux for 2 hours, treated with saturated aqueous ammonium chloride solution to decompose the alkoxide formed, and the organic phase is separated off and washed twice with 500 ml of water each time. The collected water phases are extracted thoroughly with dichloromethane again. The dichloromethane extract is combined with the ethereal phase, dried over sodium sulfate, filtered and evaporated under reduced pressure, 59.0 g of crude product (91.5% of theory) being obtained, which is purified by recrystallization from diisopropyl ether.
Reaction SMILES: [N+](C(C)C)([O-])=[O:2].C[O-].[Na+].[Br:10][C:11]1[C:12]([CH2:25]Br)=[CH:13][C:14]([O:23][CH3:24])=[C:15]([CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:16]=1>CO>[Br:10][C:11]1[C:12]([CH:25]=[O:2])=[CH:13][C:14]([O:23][CH3:24])=[C:15]([CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:16]=1
Reactant: CC(C)[N+](=O)[O-]
Reactant: COC(=O)C(C)c1cc(Br)c(CBr)cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)c1cc(Br)c(C=O)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a solution of 2-nitropropane (210 mg) in methanol (5 ml) was added sodium methoxide (130 mg), and the solution was refluxed by heating for 0.5 hour, and then cooled on ice. To this reaction mixture was added a solution of methyl 2-(5-bromo-4-bromomethyl-2-methoxyphenyl)propionate (860 mg) obtained above in methanol (4 ml), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1.0 M aqueous hydrochloric acid, water, and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by column chromatography (hexane/ethyl acetate=7/1) to give the title compound (540 mg).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=4[F:36])=[C:24]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:23]=3)[C:19](=[O:21])[CH3:20])[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[C:19]([N:18]([CH2:17][C:13]1[CH:12]=[C:11]([CH:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][C:6]([OH:8])=[O:7])[CH:16]=[CH:15][CH:14]=1)[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=2[F:36])=[C:24]([CH2:37][C:38]([CH3:39])([CH3:41])[CH3:40])[CH:23]=1)(=[O:21])[CH3:20]
Reactant: CCOC(=O)CC(c1cccc(CN(C(C)=O)c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(F)c(-c2ccc(N(Cc3cccc(C(CC(=O)O)C4CC4)c3)C(C)=O)cc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-((N-(2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)acetamido)methyl)phenyl)propanoate (104 mg) in ethanol (1.9 mL) was added 2N aqueous sodium hydroxide solution (466 μL) at room temperature, and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was neutralized with 1N hydrochloric acid at 0° C., and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound (99 mg) as a white amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:69]1([NH:74][CH2:75][CH2:76][C:77]#[N:78])[CH2:73][CH2:72][CH2:71][CH2:70]1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[N:74]([CH2:75][CH2:76][C:77]#[N:78])[CH:69]2[CH2:73][CH2:72][CH2:71][CH2:70]2)[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: N#CCCNC1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCC#N)C2CCCC2)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 146.2 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.100 g), TBTU (0.080 g) and HOBt (0.034 g) in DMF (3 ml) was added DIPEA (0.087 ml) followed by 3-(cyclopentylamino)propionitrile (0.035 g) after 15 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was washed with water and extracted with ethyl acetate. The organic layer was dried with brine and MgSO4, filtered and concentrated to give the title compound (0.190 g) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][NH:11]C(OC(C)(C)C)=O)=[O:9])=[N:6][CH:7]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][NH2:11])=[O:9])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1cnc(Cl)cn1
Agent: Cl
Solvent: C1COCCO1
Product: NNC(=O)c1cnc(Cl)cn1
Reaction time: 4 h

Procedure:
To a solution of 1,1-dimethylethyl 2-[(5-chloro-2-pyrazinyl)carbonyl]hydrazine carboxylate (I48) (2.182 g, 8 mmol) in 1,4-dioxane (20 mL) was added 4M HCl in 1,4-dioxane (20.00 mL, 80 mmol). The solution was then stirred under argon for 4 hours. Analysis by LCMS showed some sign of starting material still present thus 4M HCl in 1,4-dioxane (8.00 mL, 32.0 mmol) was added. The solvent was then evaporated in vacuo and the remaining solid was loaded onto an SCX cartridge (2×10 g). The solid was then washed with methanol (2×30 mL) before being eluted from the cartridge by 2M NH3/MeOH. TLC confirmed product location and the solvent from the combined fractions was evaporated in vacuo. The solid was triturated with diethyl ether, filtered, and washed with diethyl ether to afford product in 1.02 g.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH:7]=1)=[O:5].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][N:28]=1.C([Mg]Cl)(C)C>C1COCC1>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:8]1[C:9]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4](=[O:5])[C:6]([C:15]([C:30]2[CH:29]=[N:28][C:27]([Cl:26])=[CH:32][CH:31]=2)=[O:16])=[CH:7]1
Reactant: Clc1ccc(I)cn1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)nc1)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 600 mg (1.68 mmol) of 1-(3-chloro-benzyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 4 mL THF and 887 mg (3.70 mmol) of 2-chloro-5-iodo-pyridine in 4 mL THF with 1.93 mL 2M isopropylmagnesium chloride. Yield: 418 mg of a white powder. LC-MSD, m/z for C22H14Cl2N2O2 [M+H]+=409.0, 411.0; HPLC retention time: 3.3 min.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C=O)C.[O:42]1[CH2:47][CH2:46][CH:45]([C:48](Cl)=[O:49])[CH2:44][CH2:43]1>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][N:21]([C:48]([CH:45]5[CH2:46][CH2:47][O:42][CH2:43][CH2:44]5)=[O:49])[CH2:20][C:18]=4[N:19]=3)=[CH:12][CH:13]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Reactant: O=C(Cl)C1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CN(C(=O)C1CCOCC1)C2
Temperature: 25 °C

Procedure:
To a solution of (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (Example 3) (100 mg, 0.37 mmol) and triethyamine (42.4 μL, 0.30 mmol) in DCM (3 mL, anhydrous), and DMF (1 mL, anhydrous) was added tetrahydro-2H-pyran-4-carbonyl chloride (45.2 mg, 0.30 mmol). The reaction mixture was stirred at room temperature until LCMS indicated reaction was complete. Solvent was then removed in vacuo.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[CH:7]=[C:8]([C:12](OCC)=[O:13])[O:9]2)=[CH:4][CH:3]=1.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].Cl>C(O)C.O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[CH:7]=[C:8]([CH2:12][OH:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: O
Solvent: CCO
Product: O=c1cc(CO)oc2cc(O)ccc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
To a suspension of 5 g (21 mmoles) of ethyl 7-hydroxy-4-oxo-chromen-2-carboxylate and 5 g (45 mmoles) of anhydrous calcium chloride in 100 mL of absolute ethanol, cooled at 0° C., were added 3 g of sodium borohydride in several portions and the mixture was stirred at room temperature for 16 hours. Further 1 g of sodium borohydride was added and stirred for an additional 2 hours. The reaction mixture was suspended in 200 mL of water and acidified slowly with HCl. The precipitate was filtered, washed with water and dried at vaccum to give 2.7 g de 7-hydroxy-2-(hydroxymethyl)-chromen-4-one as a solid, yield 66%, mp 250-252° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[C:15](Cl)=[CH:14][C:13]([NH2:17])=[C:12]([N+:18]([O-:20])=[O:19])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOC(C)=O>[Cl:9][C:10]1[C:15]([S:8][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=2)=[CH:14][C:13]([NH2:17])=[C:12]([N+:18]([O-:20])=[O:19])[CH:11]=1
Reactant: Cc1cccc(S)c1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(Sc2cc(N)c([N+](=O)[O-])cc2Cl)c1
Temperature: 90 °C
Yield: 80.8 %

Procedure:
A mixture of 3-methyl-benzenethiol (2.30 mL, 19.3 mmol), 4,5-dichloro-2-nitro-phenylamine (2.00 g, 9.66 mmol), potassium carbonate (2.67 g, 19.3 mmol), and DMF (48 mL) was heated at 90° C. for 16 h. The reaction mixture was cooled to 23° C. EtOAc was added and the organic layer was washed with saturated aqueous NaHCO3 (2×80 mL) and brine (1×80 mL). The aqueous layers were extracted with EtOAc (3×80 mL). The organic layers were combined, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (0-100% EtOAc/hexanes) to yield the titled compound (2.30 g, 81%). 1H NMR (400 MHz, CDCl3): 8.12 (s, 1H), 7.41-7.36 (m, 3H), 7.34-7.30 (m, 1H), 5.95 (s, 1H), 5.88 (br s, 2H), 2.41 (s, 3H).