Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[NH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH2:9])=[CH:6][CH:5]=1.C([Mg]Br)C.[CH3:18][Si:19](Cl)([CH3:21])[CH3:20]>O1CCCC1>[CH3:13][Si:2]([CH3:1])([CH3:12])[N:3]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH2:9])=[CH:6][CH:5]=1)[Si:19]([CH3:21])([CH3:20])[CH3:18]
Reactant: C[Si](C)(C)Cl
Reactant: C=Cc1ccc(N[Si](C)(C)C)cc1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: C=Cc1ccc(N([Si](C)(C)C)[Si](C)(C)C)cc1
Temperature: 60 °C

Procedure:
4-(N-{trimethylsilyl}amino)styrene (3.5g, 18 mmol) in 20 ml tetrahydrofuran (thf) was added dropwise to ethylmagnesium bromide (1.0M/thf, 36.6 ml, 36.6 mmol). This mixture was heated at 60° C. for 6 hours then allowed to cool to room temperature. Trimethylsilyl chloride (6.35 g, 49 mmol) was added via syringe and the yellow solution heated to 60° C. for 16 hours. After removal of volatile components under reduced pressure, an off-white powder was obtained. Distillation of this at (5×10-3 mbar) yielded 4(N,N-bis {trimethylsilyl}amino) styrene as the only fraction. The colourless liquid product was stored at -30° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:16]C(=O)OC(C)(C)C)[CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.O1CCOCC1>C(Cl)Cl.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH2:16])[CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N[C@H](CCS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: CS(=O)(=O)CC[C@@H](N)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 151.1 %

Procedure:
To a stirred solution of 374 (395 mg, 1.03 mmol) in DCM (5 mL) was added a 4M HCl in dioxane (1.03 mL, 4.13 mmol) and stirring was continued overnight. The mixture was diluted with ether, filtered, dried and concentrated to afford 248 mg (75%) of (R)-1-(3,4-dichlorophenyl)-3-(methylsulfonyl)propan-1-amine hydrochloride (376) as white solid.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH3:18])[C:9](=[O:17])[C:10]3[C:15]([C:6]=2[CH:5]=[CH:4][C:3]=1[O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:14][CH:13]=[N:12][C:11]=3[CH3:16].C1C(=O)N([Cl:41])C(=O)C1>>[Cl:41][C:4]1[C:3]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:22][CH:23]([CH3:25])[CH3:24])=[C:2]([F:1])[C:7]2[N:8]([CH3:18])[C:9](=[O:17])[C:10]3[C:15]([C:6]=2[CH:5]=1)=[CH:14][CH:13]=[N:12][C:11]=3[CH3:16]
Reactant: Cc1nccc2c1c(=O)n(C)c1c(F)c(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc21
Reactant: O=C1CCC(=O)N1Cl
Product: Cc1nccc2c1c(=O)n(C)c1c(F)c(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(Cl)cc21

Procedure:
(S)-tert-butyl (1-((7-fluoro-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.08 g, 0.175 mmol), prepared as described in Example 29, Part G, was subjected to chlorination using NCS to afford (S)-tert-butyl (1-((9-chloro-7-fluoro-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2 yl)carbamate (80 mg, 0.104 mmol, 60% crude yield) as semi-solid. The material was carried forward without further purification. LC/MS (ESI) m/e 492.2 [(M+H)+, calcd for C25H32ClFN3O4 492.2].
Reaction SMILES: C(OC([NH:11][CH:12]1[CH2:15][N:14]([P:16](=[O:20])([O-:19])[O:17][CH3:18])[C:13]1=[O:21])=O)C1C=CC=CC=1.[K:22].[H][H]>C(O)C.[Pd]>[NH2:11][C@H:12]1[CH2:15][N:14]([P:16](=[O:19])([O-:20])[O:17][CH3:18])[C:13]1=[O:21].[K:22]
Reactant: COP(=O)([O-])N1CC(NC(=O)OCc2ccccc2)C1=O
Reactant: [H][H]
Agent: [Pd]
Agent: [K]
Solvent: CCO
Product: COP(=O)([O-])N1C[C@H](N)C1=O
Reaction time: 0.5 h

Procedure:
3-Benzyloxycarbonylamino-2-oxo-1-azetidinylphosphonic acid, methyl ester, potassium salt (250 mg; see example 4) in ethanol (7 ml) was added to a pre-hydrogenated suspension of 10% palladium on charcoal (125 mg) in ethanol (3 ml). The mixture was vigorously stirred under a hydrogen atmosphere for 0.5 hour, the atmosphere was exchanged for fresh hydrogen, and stirring was continued for an additional 0.5 hour. The catalyst was then replaced and the mixture was stirred for another 15 minutes under hydrogen, filtered through Celite on a Millipore filter and solvent was removed in vacuo giving (S)-3-amino-2-oxo-1-azetidinylphosphonic acid, methyl ester, potassium salt.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(C)(C)C.[Li]C(C)(C)C.CCCCC.CON(C)[C:28]([CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:29]>CCOCC>[NH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[C:28]([CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:29]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1
Reactant: CON(C)C(=O)C1CCCC1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: Nc1ccccc1C(=O)C1CCCC1
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 87.8 %

Procedure:
To a stirred solution of phenyl-carbamic acid tert-butyl ester (1.2 g, 6.2 mmol) in Et2O (12 mL) under a nitrogen atmosphere was added dropwise a 1.7 M solution of t-BuLi in pentan (8.4 mL, 14.3 mmol) over a 10-min period at −20° C. The mixture was stirred at −10° C. for 2.5 h and then cyclopentanecarboxylic acid methoxy-methyl-amide (1.07 g, 6.8 mmol) was added over 5 min. The mixture was allowed to warm to room temperature and stirred for further 1 h before it was quenched with aqueous NH4Cl. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo. The crude material was dissolved CH2Cl2 (18 mL) and TFA (6 mL) and stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo, and added aqueous NaHCO3 to pH 7 and extracted with CH2Cl2. The combined organic phases were dried and concentrated in vacuo to give 1.03 g (68%) of (2-amino-phenyl)-cyclopentyl-methanone as an oil.
Reaction SMILES: [CH2:1]([CH:4]([CH2:13][CH2:14][CH3:15])[C:5]([O:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:6])[CH2:2][CH3:3].[CH2:16]1[O:21][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][CH2:18][CH:17]1O.C(N(CC)CC)C>C(Cl)Cl>[CH2:13]([CH:4]([CH2:1][CH2:2][CH3:3])[C:5]([O:7][CH2:8][CH2:9][C:10](=[O:12])[O:11][CH:17]1[CH2:18][O:19][CH:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:21][CH2:16]1)=[O:6])[CH2:14][CH3:15]
Reactant: CCCC(CCC)C(=O)OCCC(=O)O
Reactant: OC1COC(c2ccccc2)OC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(CCC)C(=O)OCCC(=O)OC1COC(c2ccccc2)OC1
Reaction time: 72 h
Yield: 83 %

Procedure:
3-(2-propylpentanoyloxy)propanoic acid (2.05 g, 9.5 mmol) was dissolved in anhydrous CH2Cl2 (200 ml) under argon. 1,3-O-benzylideneglycerol (2.50 g, 13.67 mmol triethylamine (4.04 g, 40.0 mmol) and O-benzotriazol-1-yl-N,N, N′,N′-trimethyluronium hexafluorophosphate (4.2 g, 11.0 mmol) were added successively. The reaction mixture was stirred under argon for 72 h. The reaction mixture was washed with saturated NaHCO3 solution (1×90 ml), water (1×90 ml) and dried over Na2SO4. The organic solvent was removed under reduced pressure giving a pale, pink solid (2.99 g, 7.9 mmol, 83%).
Reaction SMILES: [NH2:1][OH:2].[C:3]([O:12][CH2:13][CH3:14])(=[O:11])/[CH:4]=[CH:5]\[C:6]([O:8][CH2:9][CH3:10])=[O:7]>ClCCl>[OH:2][NH:1][C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][C:3]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: NO
Reactant: CCOC(=O)/C=C\C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)C[C@H](NO)C(=O)OCC
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Hydroxylamine free base (50% aqueous solution, 45.0 g, 0.68 mol) was added dropwise to diethyl maleate (100.0 g, 0.56 mol) under nitrogen. The reaction temperature was maintained below 55° C. with an ice bath. The mixture was stirred for 30 minutes. Dichloromethane (100 ml) was added to the reaction mixture and the organic layer was collected. The organic layer was concentrated under reduced pressure to give crude diethyl N-hydroxyaspartate (103 g, 89% yield). The product was analyzed by NMR spectroscopy and found to be greater than 95% pure.
Reaction SMILES: [C:1]1([C:7]2([C:13]#[N:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:15]1[CH2:24][CH:16]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[OH:15][CH:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:24][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:13]#[N:14])[CH2:12][CH2:11]1
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: c1ccc(CC2CO2)cc1
Solvent: C1COCCO1
Product: N#CC1(c2ccccc2)CCN(CC(O)Cc2ccccc2)CC1

Procedure:
A mixture of 4-phenyl-piperidine-4-carbonitrile (6.3 g, 34 mmol) and (2.3-epoxypropyl)benzene (5.0 g, 37 mmol) in dioxane was refluxed for seven days. The solvent was evaporated and the residue was shaken between dilute sodium hydroxide and diethyl ether. The ether extract was dried over potassium carbonate, filtered and the product was converted to the hydrochloride as described in Example 5. Recrystallization from a mixture of ethanol and acetonitrile gave 10.0 g with m.p. 246°-249° C.
Reaction SMILES: N1C=CN=CC=1N=C=O.[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14].[F:20][C:21]([F:32])([F:31])[C:22]1[N:23]=[CH:24][C:25]([N:28]=[C:29]=[O:30])=[N:26][CH:27]=1>>[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:15][C:29]([NH:28][C:25]1[CH:24]=[N:23][C:22]([C:21]([F:32])([F:20])[F:31])=[CH:27][N:26]=1)=[O:30])=[O:14]
Reactant: O=C=Nc1cnc(C(F)(F)F)cn1
Reactant: NC(=O)c1ccccc1Cl
Agent: O=C=Nc1cnccn1
Product: O=C(NC(=O)c1ccccc1Cl)Nc1cnc(C(F)(F)F)cn1

Procedure:
A compound of formula I may also be prepared by allowing a 2-substituted benzamide to react with a 2-pyrazinylisocyanate utilizing the appropriate solvents, times of reaction and general reaction conditions hereinabove described. For example, 2-chlorobenzamide is allowed to react with 5-trifluoromethylpyrazin-2-ylisocyanate to yield 1-(2-chlorobenzoyl)-3-(5-trifluoromethyl-2-pyrazinyl)urea, having a melting point of about 219°-220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH3:13])[C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[CH3:14][N:15]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH3:13])[C:5]2[O:9][C:8]([N:18]3[CH2:19][CH2:20][CH2:21][N:15]([CH3:14])[CH2:16][CH2:17]3)=[N:7][C:6]=2[CH:11]=1
Reactant: CN1CCCNCC1
Reactant: CCc1cc(Cl)cc2nc(S)oc12
Solvent: Cc1ccccc1
Product: CCc1cc(Cl)cc2nc(N3CCCN(C)CC3)oc12

Procedure:
5-Chloro-7-ethyl-2-mercaptobenzoxazole (200 mg) was dissolved in toluene (10 ml), N-methylhomopiperazine (1.17 ml) was added dropwise to the solution and then the mixture was stirred with heating for 5 hours. After evaporation of the solvent, the thus obtained mixture was purified by a silica gel column chromatography (methylene chloride:methanol=10:1) to obtain the title compound 5-chloro-7-ethyl-2-(4-methyl-1-homopiperazinyl)benzoxazole (211 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]2[C:9]([C:11]3[C:30]([C:31](=[O:32])[C:5]2=[CH:4][C:3]=1[OH:36])=[C:29]([OH:33])[C:14]1[C:15]2[C:20]([CH2:21][CH2:22][C:13]=1[C:12]=3[O:34][CH3:35])=[CH:19][C:18]1[CH:23](O)[O:24][C:25](=O)[C:17]=1[C:16]=2[OH:28])=[O:10].[C:37]1([NH:43][NH2:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(O)(=O)C>[C:37]1([N:43]2[C:25](=[O:24])[C:17]3[C:16]([OH:28])=[C:15]4[C:14]5[C:13]([CH2:22][CH2:21][C:20]4=[CH:19][C:18]=3[CH:23]=[N:44]2)=[C:12]([O:34][CH3:35])[C:11]2[C:9](=[O:10])[C:6]3[C:5](=[CH:4][C:3]([OH:36])=[C:2]([CH3:1])[C:7]=3[OH:8])[C:31](=[O:32])[C:30]=2[C:29]=5[OH:33])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NNc1ccccc1
Reactant: COc1c2c(c(O)c3c1C(=O)c1c(cc(O)c(C)c1O)C3=O)-c1c(cc3c(c1O)C(=O)OC3O)CC2
Solvent: CC(=O)O
Product: COc1c2c(c(O)c3c1C(=O)c1c(cc(O)c(C)c1O)C3=O)-c1c(cc3cnn(-c4ccccc4)c(=O)c3c1O)CC2
Reaction time: 12 h
Yield: 83 %

Procedure:
A 5% mixture of madurahydroxylactone in glacial acetic acid is mixed with 2 mole equivalents of phenylhydrazine and boiled under reflux for 30 min. The reaction mixture is then left to stand at room temperature for about 12 hours. The red solid which has crystallized out is filtered off with suction, washed with glacial acetic acid and dried. The crude product is extracted with tetrahydrofuran (THF) in a Soxhlet. On cooling, the product crystallizes out and is filtered off with suction and dried. The yield is about 83% of theory.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:11][C:12]1[CH:13]=[C:14]([CH:18]=O)O[C:16]=1[CH3:17].O(C)[Na]>C1COCC1>[C:12]1([CH:11]=[CH:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:13]=[CH:14][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc(C=O)oc1C
Reactant: O=C(CO)c1ccccc1
Agent: CO[Na]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)c1ccccc1
Yield: 58.2 %

Procedure:
2.0 g (14.7 mmol) of 2-hydroxyacetophenone, 1.75 g of 4,5-dimethylfuran-2-carbaldehyde (14.1 mmol), and 10 ml of 25% wt NaOCH3 were reacted in 50 ml of dry THF to give 1.71 g (50%) of chalcone after purification. 1H NMR (300 MHz. CDCl3): δ 13.07 (s, 1H). 7.95 (d, J=7.8 Hz, 1H), 7.61 (d, J=15.0 Hz, 1H), 7.51-7.42 (m, 2H), 7.02 (d, d, J=0.9, 8.4 Hz, 1H), 6.94 (d, d, d, J=1.2, 8.4, 9.0 Hz, 1H), 6.60 (s, 1H), 2.34 (s, 3H), 2.00 (s, 3H).
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][N:6]1[C:10](=[O:11])[CH2:9][CH:8]([C:12](OC)=[O:13])[CH:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[OH:13][CH2:12][CH:8]1[CH2:9][C:10](=[O:11])[N:6]([CH3:5])[CH:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C1CC(=O)N(C)C1c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1C(=O)CC(CO)C1c1ccccc1
Reaction time: 2 h

Procedure:
To 82.6 g of sodium borohydride in 950 ml. of methanol at -5° to 0° C. was slowly added in portions 63 g. of methyl 1-methyl-5-oxo-2-phenylpyrrolidin-3-carboxylate. After the addition, the reaction mixture was then allowed to come to ambient temperature over 2 hours. Concentration in vacuo gave a semisolid which was suspended in water at 50° C. and stirred for 30 minutes. The solid was then dissolved in 3:1 chloroform-ether, dried (Na2SO4) filtered, and concentrated in vacuo to yield 40 g. of an oil.
Reaction SMILES: Cl[CH:2]1[CH2:8][CH:7]([CH:9]([CH3:11])[CH3:10])[CH2:6][CH2:5][NH:4][C:3]1=[O:12].[N-:13]=[N+:14]=[N-:15].[Na+].C(Cl)Cl>CS(C)=O.O>[N:13]([CH:2]1[CH2:8][CH:7]([CH:9]([CH3:11])[CH3:10])[CH2:6][CH2:5][NH:4][C:3]1=[O:12])=[N+:14]=[N-:15]
Reactant: CC(C)C1CCNC(=O)C(Cl)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: CC(C)C1CCNC(=O)C(N=[N+]=[N-])C1
Temperature: 25 °C

Procedure:
3-Chloro-5-isopropyl-azepan-2-one (3.4 g, 18 mmol) and sodium azide (3.51 g, 53.9 mmol) were reacted in dry dimethyl sulfoxide (50 ml) overnight at 80° C. under an argon atmosphere. The reaction mixture was allowed to cool to r.t. diluted with water (200 ml) and extrated with CH2Cl2 (4×). The combined organic fractions were washed with water (3×), brine and dried (MgSO4) filtered and evaporated under reduced pressure. The crude yellow oil was purified over silica gel (ethyl acetate/n-heptane 1:2): yellow oil 2.6 g (70%); MS: m/e=197.4 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([C:10]([O:12]CC)=[CH2:11])[C:7]([C:15]([F:18])([F:17])[F:16])=[CH:6][C:5]=1[NH:19][C:20](=[O:22])[CH3:21].Cl.CCOC(C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[C:7]([C:15]([F:18])([F:17])[F:16])=[CH:6][C:5]=1[NH:19][C:20](=[O:22])[CH3:21]
Reactant: C=C(OCC)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(C)=O)c(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of crude 2-acetylamino-5-(1-ethoxy-vinyl)-4-trifluoromethyl-benzoic acid methyl ester from above in THF (100 mL) was treated with aqueous hydrochloric acid (1N, 50 mL), and the mixture was stirred at r.t. for 1 h under nitrogen. The mixture was then poured into EtOAc and washed once with water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica gel 60, hexanes/EtOAc 2:1) to give 5-acetyl-2-acetylamino-4-trifluoromethyl-benzoic acid methyl ester (10.7 g, 35.1 mmol, 76% over two steps) as a white powder, m.p. 66-69° C., ESI-MS: m/z 326 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[N:31]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[N:30]=[CH:29]3)[C@@H:9]([NH:19][C:20](=[O:24])[CH2:21][O:22][CH3:23])[CH2:10][O:11]CC2C=CC=CC=2)[CH:5]=[CH:6][CH:7]=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[N:31]([C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)[N:30]=[CH:29]3)[C@@H:9]([NH:19][C:20](=[O:24])[CH2:21][O:22][CH3:23])[CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: COCC(=O)N[C@@H](COCc1ccccc1)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(F)c1
Agent: [Pd]
Solvent: CCO
Product: COCC(=O)N[C@@H](CO)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[(1S)-2-(3-Fluorophenyl)-2-{[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy}-1-(benzyloxymethyl)ethyl]-2-methoxyacetamide (15 mg, 0.027 mmol) is dissolved in 10 mL ethanol and Pd (10% on charcoal, 0.29 mg, 0.0027 mmol) is added. The reaction mixture is charged with hydrogen and stirred for 2 h at r.t. After filtration of the reaction mixture via a glass microfibre filter, the solvent evaporated and the residue purified by chromatography (silicagel, eluents: ethylacetate/hexane). 7.5 mg (59.6%) of the title compound as a mixture of stereoisomers are obtained.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:18]([CH:19]([CH3:22])[CH2:20][OH:21])[N:17]=[C:16]([CH3:23])[N:15]=1)[N:7]=3.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:34]1(B2OC(C)(C)C(C)(C)O2)[CH2:36][CH2:35]1>O1CCCC1.O.C(Cl)Cl.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:34]1([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:10]([CH:9]=[C:8]([C:14]5[N:18]([CH:19]([CH3:22])[CH2:20][OH:21])[N:17]=[C:16]([CH3:23])[N:15]=5)[N:7]=4)[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH2:36][CH2:35]1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)CO)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C4CC4)cc2OCC3)n(C(C)CO)n1
Temperature: 120 °C
Yield: 27.7 %

Procedure:
A microwave vial was charged with a solution of 2-[5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-3-methyl-[1,2,4]triazol-1-yl]-propan-1-ol (0.140 g, 0.000346 mol) and Potassium phosphate (0.220 g, 0.00104 mol) in Tetrahydrofuran (2.0 mL) and Water (2.0 mL). The mixture was thoroughly purged with N2. 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.189 mL, 0.00104 mol) and Tetrakis(triphenylphosphine)palladium(0) (0.0400 g, 0.0000346 mol) were added and the vial was sealed immediately. The reaction was heated in the microwave to 120° C. for 20 minutes. The reaction was diluted with methylene chloride and filtered through celite. Saturated NH4Cl was added and the mixture was extracted 3 times with methylene chloride. The organic layers were combined, dried with MgSO4 and concentrated. The crude was purified by reverse-phase HPLC to give 35 mg of 270 as a white solid. MS (ESI+) 366.2. 1H NMR (500 MHz, DMSO) δ 8.26 (d, J=8.3 Hz, 1H), 7.82 (s, 1H), 6.86 (dd, J=8.4, 1.7 Hz, 1H), 6.75 (d, J=1.7 Hz, 1H), 5.73-5.57 (m, 1H), 4.85 (t, J=5.4 Hz, 1H), 4.50-4.43 (m, 4H), 3.76 (ddd, J=10.7, 7.5, 6.0 Hz, 1H), 3.68-3.62 (m, 1H), 2.24 (s, 3H), 1.97-1.85 (m, 1H), 1.39 (d, J=6.7 Hz, 3H), 1.02-0.93 (m, 2H), 0.75-0.67 (m, 2H)
Reaction SMILES: [C:1]([NH:20][C@@H:21]1[CH2:27][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[NH:23][C:22]1=[O:32])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH:36]([CH3:38])[CH3:37]>CN(C)C=O>[CH:36]([N:23]1[C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[CH2:26][CH2:27][C@@H:21]([NH:20][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:22]1=[O:32])([CH3:38])[CH3:37]
Reactant: O=C1Nc2ccccc2CC[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)CCc2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A 35 mL heavy-walled sealable tube was fitted with a stirbar and septa. The tritylated benzolactam from Step 4 (2.02 g, 4.83 mmol) and N,N-dimethylformamide (20 mL) were added, giving a solution that was cooled to 0° C. Sodium hydride (1.08 g, 60%/oil, 27.0 mmol) was added cautiously, giving a mixture that was stirred 5 minutes at 0° C., then removed from the cold bath and allowed to warm to room temperature. After 30 minutes, 2-iodopropane (1.0 mL, 10.0 mmol) was added, and the resulting mixture was stirred at room temperature for 18 hours. The rubber septa was then removed, the reaction vessel was sealed with a plastic screwcap, placed in an oil bath and warmed to 60° C. After 4 hours, the reaction was cooled to room temperature, diluted with H2O (100 mL) and extracted three times with diethyl ether (100 mL, then 2×50 mL). The organic extracts were combined, washed with saturated aqueous NaCl solution (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The resulting oil was purified via flash chromatography on silica gel (0% to 25% ethyl acetate/hexanes linear gradient) to give the desired product.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:15]([C:17]4[CH:24]=[CH:23][C:20]([CH:21]=O)=[C:19]([F:25])[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[N:4]1)[CH3:2].[NH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)(=[O:27])=[O:28])[C:15]([C:17]4[CH:24]=[CH:23][C:20]([CH2:21][N:44]5[CH2:48][CH2:47][CH2:46][CH2:45]5)=[C:19]([F:25])[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:35]2[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3c2cc(-c2ccc(C=O)c(F)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: C1CCNC1
Product: CCn1cc(-c2ccnc3c2cc(-c2ccc(CN4CCCC4)c(F)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 101 using 4-[4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-fluorobenzaldehyde and pyrrolidine provided the title compound. ESMS[M+H]+: 651.4.