Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O>C1COCC1>[C:15]([O:14][C:12](=[O:11])[NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Temperature: 0 °C

Procedure:
Suspend tyramine (10.0 g, 73.0 mmol) in THF (200 mL). Cool to 0° C. Add a solution of (BOC)2O (31.8 g, 145 mmol) in THF (43 mL). Allow reaction mixture to warm to room temperature overnight. After 20 hours concentrate. Purification through two Waters 500A columns on a PrepLC system 500A to give the title compound: MS FAB ES+ 238.3 (M+H)+, base peak 182.2 (M+2H—C(CH3)3)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=8.5 min, 100% purity.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=O)[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1.O>N1C=CC=CC=1>[N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[S:26])[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: S=C1Nc2cccnc2Nc2ccccc21
Temperature: 100 °C

Procedure:
A mixture of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (3.00 g, 14 mmol) and Lawesson's reagent (6.51 g, 16 mmol) in pyridine (40 mL) was heated to 100° C. for 18 hours. After cooling to room temperature the mixture was poured into water and stirred. The precipitate was collected on a filter paper and dried. The crude product (yellow solid) was carried on to the next step without further purification (96%). 1H NMR (DMSO-d6) 400 MHz δ: 11.99 (s, 1H), 8.37, (s, 1H), 7.98 (dd, J=4.6, 1.7 Hz, 1H), 7.96 (dd, J=8.0, 1.7 Hz, 1H), 7.44 (dd, J=7.7, 1.4 Hz, 1H), 7.35 (td, J=7.7, 1.7 Hz, 1H), 7.06 (dd, J=8.0, 1.2 Hz, 1H), 7.01 (dd, J=8.0, 4.6 Hz, 1H), 6.95 (td, J=8.0, 1.2 Hz, 1H); LC/MS [M+H]: 228.
Reaction SMILES: [I-].C[N+]([CH2:6][C:7]1[N:8]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][CH:11]=1)(C)C.CN1CCN(C)C1=O>ClCCl>[CH3:6][C:7]1[N:8]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1cccc(-n2cccc2C[N+](C)(C)C)c1
Agent: [I-]
Solvent: CN1CCN(C)C1=O
Solvent: ClCCl
Product: COC(=O)c1cccc(-n2cccc2C)c1
Temperature: 105 °C
Reaction time: 1.5 h
Yield: 93.9 %

Procedure:
To the mixture of methyl 3-(2-trimethylammoniomethyl-pyrrol-1-yl)benzoate iodide (2.0 g) and 1,3-dimethyl-imidazolidin-2-one (6 ml) was added borane-pyridine complex (1.1 ml) and the mixture was stirred for 1.5 hours at 105° C. To the mixture was added dichloromethane, and the mixture was washed with water, 1N-hydrochloric acid and water successively. The mixture was dried over magnesium sulfate and evaporated in vacuo to give methyl 3-(2-methylpyrrol-1-yl)benzoate (1.01 g) as an oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C:30](=[O:31])[N:4]2[C:5]([C:17]([O:19]CC3C=CC([N+]([O-])=O)=CC=3)=[O:18])=[C:6]([O:9][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[CH2:7][CH2:8][C@H:3]12.[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][C:38](Cl)=[O:39].C1OC1C>C(Cl)Cl>[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][C:38]([NH:1][C@@H:2]1[C:30](=[O:31])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([O:9][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:11])=[O:12])[CH2:7][CH2:8][C@H:3]12)=[O:39]
Reactant: N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OS(=O)(=O)C(F)(F)F)CC[C@H]12
Reactant: O=C(Cl)Cc1cccs1
Agent: CC1CO1
Solvent: ClCCl
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(OS(=O)(=O)C(F)(F)F)CC[C@H]12

Procedure:
p-Nitrobenzyl 7β-amino-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylate is acylated in methylene chloride with 2-thienylacetyl chloride in the presence of propylene oxide and then is deesterified to provide the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.O.NN>C(O)C.[C].[Pd]>[OH:14][C:11]1([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)NCC1(O)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCC1(O)CCNCC1
Temperature: 25 °C
Yield: 104.3 %

Procedure:
A solution the compound prepared in Example 250 (0.68 g) in ethanol (11 mL) was treated with hydrazine monohydrate (0.208 mL), followed by 10% palladium-carbon (0.238 g). The mixture was refluxed for 18 hours. After allowing mixture to cool to room temperature, the catalyst was filtered off and washed with methanol. The filtrate was evaporated in vacuo to obtain the title compound (0.510 g) having the following physical data.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[CH:4][CH:3]=1.[C:14]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>O=S(Cl)Cl>[C:14]([C:18]1[CH:19]=[CH:20][C:21]([NH:22][C:6]([C:5]2[CH:4]=[CH:3][C:2]([C:1]([O:12][CH3:13])=[O:11])=[CH:10][CH:9]=2)=[O:8])=[CH:23][CH:24]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)Nc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
mono-Methyl terephthalate (1.02 g, 5.67 mmol) was refluxed in SOCl2 (10 mL) for 1 hour, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was taken up in tetrahydrofuran (30 mL) and treated with 4-tert-butylaniline (0.9 mL, 5.65 mmol) and DIEA (5 mL, 28.8 mmol) at room temperature. After stirring overnight, the mixture was concentrated under reduced pressure and the residue was taken up in ethyl acetate. The ethyl acetate was washed with H2O and brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with 3:2 hexanes:ethyl acetate and the solid air-dried to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.08 (m, 4H), 7.69 (m, 2H), 7.39 (m, 2H), 3.90 (s, 3H), 1.29 (s, 9H); MS (ESI+) m/z 312 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6][C:7]=1[CH2:8][CH2:9][CH3:10].[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:11]1([C:5]2[O:6][C:7]([CH2:8][CH2:9][CH3:10])=[C:3]([CH2:2][O:17][C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)[N:4]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCc1oc(-c2ccccc2)nc1CCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1oc(-c2ccccc2)nc1COc1ccc(C=O)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
A mixture of 4-chloromethyl-2-phenyl-5-propyloxazole (2.26 g), 4-hydroxybenzaldehyde (1.33 g), anhydrous potassium carbonate (1.76 g) and N,N-dimethylformamide (50 mL) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water, and the precipitated solid was collected by filtration and dried with air to give crystals (2.75 g, 89%) of 4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzaldehyde. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 76-77° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][CH:10]=[O:11])=[C:4]([Cl:12])[N:3]=1.[O:13]1[CH2:17][CH2:16][C@H:15]([O:18][CH2:19][C:20]2[N:25]=[C:24]([CH2:26][NH2:27])[CH:23]=[CH:22][CH:21]=2)[CH2:14]1.C(N(CC)CC)C>CC(O)C>[NH2:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]([NH:9][CH:10]=[O:11])=[C:6]([NH:27][CH2:26][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:19][O:18][C@H:15]3[CH2:16][CH2:17][O:13][CH2:14]3)[N:25]=2)[N:7]=1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: NCc1cccc(CO[C@H]2CCOC2)n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)c(NC=O)c(NCc2cccc(CO[C@H]3CCOC3)n2)n1
Yield: 72.5 %

Procedure:
A mixture of N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide (17.24 g, 82.46 mmol), 6-[(S)-(tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethylamine (18.89 g, 90.70 mmol) and triethylamine (12.64 mL, 90.70 mmol) in propan-2-ol (165 mL) was heated at reflux for 2 h, cooled and the resulting precipitate was filtered, washed with cold propan-2-ol and dried to give the title compound (22.66 g, 73%) as a pink solid; LC-MS retention time 1.46 min, (M+H)+ 379.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].O>C(O)(=O)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCCc1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a stirred solution of 1-acetoxy-2-[(3,4-methylenedioxy)-phenyl]ethane (1.7 g, 8.09 mmol) in acetic acid (10 ml) was added, dropwise, concentrated HNO3 (4.5 ml). This was stirred at room temperature for 30 min. The reaction mixture was poured into water (100 ml). The precipitated solid was filtered, washed with water and dried under high vacuum to get 1-acetoxy-2-[(3,4-methylenedioxy)-6-nitrophenyl]ethane (1.8 g, 88% yield).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[F:11])#[N:2].[CH3:12][Mg+].[Br-]>C1COCC1.CCOCC>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]([OH:8])[CH3:12])=[CH:5][C:4]=1[F:11])#[N:2]
Reactant: C[Mg+]
Reactant: N#Cc1ccc(C=O)cc1F
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1ccc(C#N)c(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4-cyano-3-fluorobenzaldehyde, as described above in Step B, (250 mg, 1.68 mmol) in THF, under argon, at −78° C. was added MeMgBr dropwise (0.59 mL of a 3.0 M solution in Et2O, 1.77 mmol). The reaction mixture was stirred at −78° C. for 1 hour, then quenched with saturated aqueous NH4Cl, allowed to warm to ambient temperature, and extracted with CH2Cl2 (2×40 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexane—20% to 40% EtOAc, to yield the titled product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][C:5]([F:9])=[C:6]([F:8])[CH:7]=1.O.[NH2:12][NH2:13].C(O)CC>ClC>[Cl:1][C:2]1[C:3]([NH:12][NH2:13])=[N:4][C:5]([F:9])=[C:6]([F:8])[CH:7]=1
Reactant: NN
Reactant: Fc1cc(Cl)c(F)nc1F
Agent: CCl
Solvent: CCCO
Solvent: O
Product: NNc1nc(F)c(F)cc1Cl
Yield: 85.24 %

Procedure:
16.6 g of the compound obtained in Step 1 and 20.12 ml of hydrazine monohydrate were added to 100 ml of n-propanol, and the resulting mixture was refluxed 3 hours, and distilled under a reduced pressure to remove the solvent. The residue thus obtained was dissolved in 100 ml of chloromethane, washed with water, and dried over anhydrous magnesium sulfate. The dried organic layer was concentrated under a reduced pressure to obtain 15.9 g (yield: 85.24%) of the title compound.
Reaction SMILES: [OH:1][P:2]1(=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:15])=O>>[Cl:15][P:2]1(=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=P1(O)CCCc2ccccc21
Reactant: O=S(Cl)Cl
Product: O=P1(Cl)CCCc2ccccc21

Procedure:
1-Hydroxy-1-oxo-1,2,3,4-tetrahydrophosphinoline (2.7g, 15 mmole) was refluxed with redistilled thionyl chloride (12 ml, 170 mmole) for 2 hr, and the excess of thionyl chloride removed by distillation. Distillation of the residue (bulb to bulb) at 150°/0.005 mm gave 1-chloro-1-oxo-1,2,3,4-tetrahydrophosphinoline (34), a light yellow fuming solid (2.3g, 76%). This was used without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1([N:35]2[CH:39]=[C:38]([C:40](Cl)=[O:41])[C:37]([CH2:43][CH2:44][CH3:45])=[N:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:40]([C:38]3[C:37]([CH2:43][CH2:44][CH3:45])=[N:36][N:35]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:39]=3)=[O:41])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: CCCc1nn(-c2ccccc2)cc1C(=O)Cl
Product: CCCc1nn(-c2ccccc2)cc1C(=O)N[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-phenyl-3-propyl-1H-pyrazole-4-carbonyl chloride: ESMS m/e: 592.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18].Cl.C(N(CC)CC)C>O1CCCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([NH:1][C:17](=[O:19])[CH3:18])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1cc(Cl)ccc1O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Cl)ccc1O

Procedure:
To a solution of 100 grams of 2 amino-4-chlorophenol (0.70 mole) in 1 liter of tetrahydrofuran is added 71 grams of triethylamine (0.70 mole). The resulting solution is cooled with an ice bath. To the solution is then slowly added 55 grams of acetyl chloride (0.70 mole) in 200 ml. of tetrahydrofuran. A precipitate forms (triethylamine hydrochloride). The solution is then filtered and the filtrate evaporated under reduced pressure, yielding a dark solid residue. Recrystallization of the residue from methylene chloride and petroleum ether (1:1) yields 4-chloro-2-acetamidophenol.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[CH:6]2O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:11][C:9]1[CH:8]=[C:7]2[C:3](=[C:2]([F:1])[CH:10]=1)[CH2:4][C:5]([CH3:13])=[CH:6]2
Reactant: CC1Cc2c(F)cc(F)cc2C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=Cc2cc(F)cc(F)c2C1
Yield: 85.2 %

Procedure:
According to Scheme 3, step 3: A mixture of 4,6-Difluoro-2-methyl-indan-1-ol (8a) (0.65 g, 3.53 mmol) and para-toluene sulfonic acid monohydrate (30 mg, 0.18 mmol) in toluene was heated at reflux for 1 h. The solution was washed with aqueous saturated NaHCO3 and brine, dried over MgSO4 and solvents evaporated. The crude product was purified by silica gel chromatography (eluting with 0% to 100% ethyl acetate in heptane to give 0.50 g of 5,7-Difluoro-2-methyl-1H-indene (9a) which was used immediately in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH-].[Na+].Cl.Cl[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.CCOC(C)=O>C(#N)C>[N+:8]([C:7]1[CH:6]=[CH:5][C:4]([O:11][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:3][C:2]=1[NH2:1])([O-:10])=[O:9]
Reactant: ClCc1ccc2ccccc2n1
Reactant: Nc1cc(O)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Nc1cc(OCc2ccc3ccccc3n2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-amino-4-nitrophenol (5.0 g, 32 mmol) in acetonitrile (162 mL) was added 4N NaOH (16.2 mL, 4 N) followed by 2-(chloromethyl)quinoline hydrochloride (7.6 g, 34 mmol) and the resulting mixture was stirred at RT for 2 h. The reaction was then heated to 80° C. for 4 h. The reaction mixture was cooled to RT and concentrated to dryness. Water was added to the residue to give a dark orange solid that was isolated by filtration. Trituration using EtOAc then afforded the title compound. MS (ESI): mass calcd. for C16H13N3O3, 295.10; m/z found, 296.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 8.42 (d, J=8.5, 1H), 8.02 (dd, J=10.0, 9.2, 2H), 7.83-7.75 (m, 1H), 7.68 (d, J=8.5, 1H), 7.66-7.60 (m, 1H), 7.55 (d, J=3.0, 1H), 7.32 (dd, J=9.2, 3.0, 1H), 7.28 (s, 2H), 7.03 (d, J=9.3, 1H), 5.34 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:14][OH:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[OH-:16].[Na+].C(Cl)(Cl)Cl>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH2:14][O:15][C:5]([CH3:6])([CH3:4])[C:8]([OH:9])=[O:16])=[C:11]([CH3:13])[N:12]=2)=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: Cc1nc(-c2ccc(Cl)cc2)oc1CO
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1nc(-c2ccc(Cl)cc2)oc1COC(C)(C)C(=O)O
Yield: 65 %

Procedure:
6.9 g (30.8 mmol) of 2-(4-chlorophenyl)-4-methyl-5-oxazolemethanol were combined with 6.2 g (155 mmol) of powdered sodium hydroxide in 45 ml of acetone and the suspension was heated to reflux. 4.9 g (41.1 mmol) of chloroform in 10 ml of acetone were added dropwise during 30 minutes and the suspension was heated at reflux for 4 hours. The solvent was removed by evaporation under reduced pressure, and the residue was partitioned between 150 ml of diethyl ether and 400 ml of water. The organic phase was separated and the aqueous phase was extracted twice with diethyl ether. The aqueous phase was acidified to pH 2 with concentrated hydrochloric acid and extracted three times with 50 ml of dichloromethane each time. The combined dichloromethane extracts were dried over magnesium sulphate, filtered and evaporated to yield 3.7 g of crude product. Recrystallization from ethyl acetate yielded 3.1 g (32.5%) of 2-[[2-(4-chlorophenyl)-4 -methyl-5-oxazolyl]methoxy]-2-methylpropionic acid of melting point 166°-167° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:15]3[C:11](=[N:12][N:13]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])[C:14]=3[CH:24]([CH3:26])[CH3:25])[C:10]2=[O:35])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:36][Si]([N-][Si](C)(C)C)(C)C.[K+].CI>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:16]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:36])[C:15]3[C:11](=[N:12][N:13]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])[C:14]=3[CH:24]([CH3:26])[CH3:25])[C:10]2=[O:35])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1ccccc1-n1nc2c(c1C(C)C)C(c1ccc(Cl)cc1)N(c1ccc(F)c(Cl)c1)C2=O
Agent: [K+]
Solvent: CI
Product: COc1ccccc1-n1nc2c(c1C(C)C)C(C)(c1ccc(Cl)cc1)N(c1ccc(F)c(Cl)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared in analogy to the procedure described for example 74 but using the compound prepared in example 88, 3 equivalents of KHMDS and 2 equivalents of methyl iodide. The reaction mixture was stirred for 2 h at rt. The crude material was purified by silica gel column chromatography (hexane/EtOAc, 4:1) followed by preparative HPLC (Column: AG/PP/C-18-15/025. Flow: 20 mL/min. Gradient: 25% B; A=0.1% TFA in water, B=acetonitrile/MeOH, 1:1). tR: 6.92 min (HPLC 2); ESI-MS: 524.1 [M+H]+ (LC-MS 2).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][B:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[O:4][C:3]1([CH3:17])[CH3:16].[NH2:19][C@@H:20]([CH:28]([CH3:30])[CH3:29])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:29][CH:28]([CH3:30])[C@H:20]([NH:19][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([B:5]2[O:4][C:3]([CH3:17])([CH3:16])[C:2]([CH3:1])([CH3:18])[O:6]2)=[CH:15][CH:14]=1)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (2.0 g, 8.1 mmol) and (S)-tert-butyl 2-amino-3-methylbutanoate (2.0 g, 9.5 mmol) in DMF (10 mL) were added HATU (6.1 g, 16 mmol) and DIEA (4.2 g, 33 mmol). The reaction mixture was stirred at rt overnight. The reaction was then quenched with water (100 mL). The resulting mixture was extracted with DCM (2×100 mL), and the organic layer was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:50)) to obtain compound 43a as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C22H34BNO5: 404.3 (M+H). Found 404.1.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:14]3[CH3:17])=[C:10]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1)[CH3:2].[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1.CCN(CC)CC>C(Cl)Cl>[CH:35]1([C:38]([N:22]2[CH2:21][CH2:20][CH:19]([CH2:18][C:13]3[N:14]([CH3:17])[C:15]4[C:11]([N:12]=3)=[C:10]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:9]=[C:8]([N:7]3[C:6]5[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=5[N:4]=[C:3]3[CH2:1][CH3:2])[N:16]=4)[CH2:24][CH2:23]2)=[O:39])[CH2:37][CH2:36]1
Reactant: O=C(Cl)C1CC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(C(=O)C4CC4)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 17.4 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-8-piperidin-4-ylmethyl-9H-purine (230 mg, 0.50 mmol), cyclopropyl carbonyl chloride (50 μL, 0.55 mmol) and NEt3 (140 μL, 1.00 mmol) in DCM (10 mL) was allowed to stir at r.t. for 5 h then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-5%) then further purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 40-98%) affording 852 as a white solid (46 mg, 17%). LCMS (method I): RT 3.59 min, [M+H]+ 529.4. 1H NMR (DMSO, 400 MHz): δ 8.03-7.99 (1 H, m), 7.64-7.63 (1 H, m), 7.25-7.24 (2 H, m), 4.45-4.10 (6 H, m), 3.77-3.75 (6 H, m), 3.27-3.24 (3 H, m), 3.16-3.00 (1 H, m), 2.86 (2 H, d, J=7.07 Hz), 2.64-2.47 (1 H, m), 2.20-2.08 (1 H, m), 2.01-1.93 (1 H, m), 1.79-1.71 (2 H, m), 1.33 (3 H, t, J=7.43 Hz), 1.30-1.07 (2 H, m), 0.74-0.66 (4 H, m)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][O:24][CH2:23][O:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[C:27]1(B(O)O)[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1>C([O-])([O-])=O.[Na+].[Na+].COCCOC.C(OCC)(=O)C.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>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][O:24][CH2:23][O:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1COCOC1
Reactant: OB(O)C1=CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1COCOC1

Procedure:
Nitrogen was bubbled through a solution of 5-bromo-3-[[1,3]dioxan-5-yl-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (15 mg, 0.034 mmol) containing cyclohexen-1-ylboronic acid (8 mg, 0.063 mmol) in 2M aqueous Na2CO3 (0.9 mL) and DME (1.8 mL) for 10 min. Pd(PPh3)4 (3 mg) was added and the mixture was refluxed for 1 h 10 min. It was cooled, diluted with ethyl acetate (50 mL), washed with water and brine, dried and evaporated yielding the crude 5-cyclohex-1-enyl-3-[[1,3]dioxan-5-yl-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (24 mg) which was used in the next step without further purification.