Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[O:16]=[C:12]1[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:15][N:10]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:11]1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(=O)C1
Reaction time: 1 h

Procedure:
Sodium hydride (88 mg, 60% wt.) was added portionwise to a solution of 4-BOC-piperazinone (400 mg) in DMF (10 ml). The reaction mixture was stirred for 1 h, and then benzyl bromide (262 μl) was added dropwise and the mixture stirred at room temp for 16 h. The reaction was quenched with methanol and diluted with water, and then extracted with EtOAC. The organic extracts were concentrated in vacuo and the residue was purified by chromatography (silica, 20% ether/hexane as eluent) to give the sub-title compound (429 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+:16]([O-:18])=[O:17])[NH:9][C:8]=2[CH3:19])=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C1COCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+:16]([O-:18])=[O:17])[N:9]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:8]=2[CH3:19])=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2cccc([N+](=O)[O-])c2c1Oc1ccc(Cl)cc1
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2c([N+](=O)[O-])cccc21
Reaction time: 0.17 h

Procedure:
The product from step (ii) (6.0 g) was dissolved in THF (100 ml), sodium t-butoxide (2.1 g) added, stirred for 10 min, ethyl bromoacetate (2.45 ml) added and stirred for a further 20 min. The reaction was quenched with 1M hydrochloric acid, extracted with EtOAc, washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica eluting with 20% ethylacetate/iso-hexane. Yield 6 g.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].Br[CH:13]([C:15]1[N:20]2[N:21]=[CH:22][N:23]=[C:19]2[N:18]=[CH:17][CH:16]=1)[CH3:14]>COCCOC>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:13]([C:15]2[N:20]3[N:21]=[CH:22][N:23]=[C:19]3[N:18]=[CH:17][CH:16]=2)[CH3:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(Br)c1ccnc2ncnn12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(Oc1ccc(C#N)cc1)c1ccnc2ncnn12
Reaction time: 0.5 h

Procedure:
A solution of 4-cyanophenol (1.19 g) in dry 1,2-dimethoxyethane was added slowly to a stirred suspension of sodium hydride (0.48 g) in dry 1,2-dimethoxyethane (35 ml). The mixture was stirred for 30 minutes, then a solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (2.27 g, prepared in a similar manner to that described in Example 6 below) in dry 1,2-dimethoxyethane (85 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature. The sodium bromide was removed from the mixture by filtration. The solvent was evaporated from the mixture and the residue was dissolved in dichloromethane and washed with 200 ml of a 5% aqueous solution of sodium hydroxide followed by water. The organic layer was dried over magnesium sulphate. Evaporation of the solvent afforded a crude product which was purified by column chromatography on silica gel using as eluent a mixture of ethyl acetate and petroleum ether (in the ratio 6:4 respectively), followed by recrystallisation from ethyl acetate, to give 7-[1-(4-cyanophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 1.07 g, (m.p. 163°-164° C.).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][C:15]1[C:20]([CH2:21][OH:22])=[CH:19][CH:18]=[C:17]([CH3:23])[N:16]=1.[CH2:24]([O:26][C:27](=[O:39])[CH2:28][C:29]1[C:33]2[CH:34]=[CH:35][C:36](O)=[CH:37][C:32]=2[S:31][CH:30]=1)[CH3:25].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH2:24]([O:26][C:27](=[O:39])[CH2:28][C:29]1[C:33]2[CH:34]=[CH:35][C:36]([O:22][CH2:21][C:20]3[C:15]([CH3:14])=[N:16][C:17]([CH3:23])=[CH:18][CH:19]=3)=[CH:37][C:32]=2[S:31][CH:30]=1)[CH3:25]
Reactant: CCOC(=O)Cc1csc2cc(O)ccc12
Reactant: Cc1ccc(CO)c(C)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1csc2cc(OCc3ccc(C)nc3C)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a mixture of tri-n-butylphosphine (7.10 mL), (2,6-dimethylpyridin-3-yl)methanol (3.00 g), ethyl(6-hydroxy-1-benzothiophen-3-yl)acetate (5.43 g) and THF (150 mL) was added ADDP (7.17 g) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere overnight. The mixture was concentrated. To the residue was added IPE and the precipitate was filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (7.74 g)
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:3]=1[C:4]([NH2:6])=O.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl
Temperature: 25 °C

Procedure:
A mixture of 66.0 gm. (0.235 mole) of 2,4-dichloro-3,5-dinitrobenzamide and 140 ml. of phosphorus oxychloride is heated at reflux for 1 hour. The solution is cooled to room temperature. The excess phosphorus oxychloride is distilled off in vacuo. The solid residue is triturated with ice-water and filtered. There is obtained 54.0 g. (88%) of a tan solid melting at 139°-141°.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]([C:11]#[N:12])=[C:4](F)[C:3]=1[F:14].[OH-:15].[Na+].Cl>O>[F:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([F:1])[C:3]([F:14])=[C:4]([OH:15])[C:5]=1[C:11]#[N:12]
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1c(O)c(F)c(F)c(C#N)c1F

Procedure:
A 2.0 g amount of tetrafluoroisophthalonitrile and 0.7 g of sodium hydroxide were added to 40 ml of water and the mixture was heated under reflux for 1.5 hours. After cooling, the mixture was neutralized with concentrated hydrochloric acid and was then extracted with ether. After the ether extract was washed with water, the extract was dried with magnesium sulfate. The solvent was distilled off and the resultant crude crystal was recrystallized to obtain 1.39 g of the desired compound No. 19.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([C:6]2[S:10][C:9]([C:11]3[S:15][CH:14]=[CH:13][CH:12]=3)=[CH:8][CH:7]=2)[S:4][CH:5]=1.ClS([N:20]=[C:21]=O)(=O)=O>C(Cl)Cl>[C:21]([C:14]1[S:15][C:11]([C:9]2[S:10][C:6]([C:3]3[S:4][CH:5]=[CH:1][CH:2]=3)=[CH:7][CH:8]=2)=[CH:12][CH:13]=1)#[N:20]
Reactant: c1csc(-c2ccc(-c3cccs3)s2)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc(-c3cccs3)s2)s1
Reaction time: 2 h

Procedure:
To a solution of α-terthienyl(2.46 g, 0.010 m) in methylene chloride (20 ml), was added chlorosulfonyl isocyanate (1.75 ml) in methylene chloride (15 ml). A yellow solid separated almost at once. The reaction mixture was stirred for 2 h and left overnight. Dimethyl formamide (5.0 ml) was added to the ice-cold reaction mixture dropwise. Addition of water (40 ml) precipitated a yellow solid insoluble in methylene chloride. The latter was removed in vacuo and the yellowish green solid was collected in a Buchner funnel and washed with water. Yield: 2 g; m.p. 122°-125° C. Recrystallization from the minimum amount of boiling ethanol-benzene(1:1) afforded 1.6 g of product(58.6% crude yield).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[CH3:5][C:6]([O:9][CH2:10][CH:11]1[O:13][CH2:12]1)([CH3:8])[CH3:7].[OH-].[Na+]>B(F)(F)F.CCOCC.ClCCl>[C:6]([O:9][CH2:10][CH:11]([OH:13])[CH2:12][O:3][CH2:2][CH2:1][OH:4])([CH3:5])([CH3:7])[CH3:8]
Reactant: OCCO
Reactant: CC(C)(C)OCC1CO1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OCC(O)COCCO
Reaction time: 15 h
Yield: 71 %

Procedure:
To a solution of ethylene glycol (248 g, 4 moles) and boron trifluoride etherate catalyst (1 ml) in dichloromethane (20 ml) preheated to 45° C. was added t-BGE (130 g, 1 mole) dropwise at such a rate so as to maintain a gentle reflux. After completion of addition, stirring was continued for about 15 hours. The solution was then adjusted to pH 7.5 by addition of sodium hydroxide and the product removed by distillation. Tertiary butoxymethyl diethylene glycol was obtained in 71 percent yield having a boiling point of 105° C.-115° C./1 mm.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH:12](OC(=O)C)=[O:13].[OH-].[Na+]>C1COCC1>[C:1]([N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:12]=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC=O
Reactant: CC(C)(C)Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)N(C=O)c1ccccc1
Yield: 74.2 %

Procedure:
A solution of 1a (1.2212 g, 8.18 mmol) and acetic formic anhydride (1.2 mL, 15 mmol) in THF (10 mL) was stirred for 7 h at room temperature. To the reaction solution was added an aqueous NaOH solution (1.0 M, 20 mL) The organic phase was extracted with Et2O (30 mL×2) and was chromatographed (4:1 hexanes/EtOAc) to give 2a (1:1 mixture of isomers, 1.076 g, 74.2%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.72 (s, 0.5H), 8.16 (s, 0.5H), 7.51-7.29 (m, 3H), 7.19-6.99 (m, 2H), 1.40 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 163.4, 162.6, 141.0, 138.2, 130.3, 130.1, 129.3, 129.2, 128.4, 57.7, 56.7, 31.0, 29.2. HRMS-ESI (m/z): [M+H]+ calcd for C11H15NO, 178.1226. found: 178.1228.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17]([CH3:19])=O)[N:3]=1.SC[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccc(C#N)o2)c1C#N
Reactant: SCCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1ccc(-c2nc(N)nc(SCCc3ccccn3)c2C#N)o1

Procedure:
From 2-amino-4-(5-cyano-furan-2-yl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 347 ([M—H]−, 100).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:24][C@@H:25]1[C:31](=[O:32])[N:30]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:29]2[CH:41]=[CH:42][CH:43]=[CH:44][C:28]=2[O:27][CH2:26]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1C(=O)C2=CC=CC=C2[C:14]1=[O:23])=[O:5])[CH3:2].[OH2:45].NN>C(O)C>[C:37]([O:45][C:14]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([NH:24][C@@H:25]1[C:31](=[O:32])[N:30]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:35])[C:29]2[CH:41]=[CH:42][CH:43]=[CH:44][C:28]=2[O:27][CH2:26]1)[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:23])([CH3:40])([CH3:39])[CH3:38]
Reactant: O
Reactant: CCOC(=O)[C@H](CCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: NN
Solvent: CCO
Product: CCOC(=O)[C@H](CCCCCCNC(=O)OC(C)(C)C)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reaction time: 8 h
Yield: 153.3 %

Procedure:
In 10 ml of ethanol is dissolved 0.7 g of tert-butyl 3(S)-[1(S)-ethoxycarbonyl-7-phthalimidoheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate obtained in Example 64, and hydrazine hydrate (0.29 g) is added to the solution. After standing overnight, the solution is concentrated under reduced pressure, diluted with 50 ml of water and extracted five times with 30 ml each of ethyl acetate. To the ethyl acetate layer are added 50 ml of water and 0.7 g of sodium bicarbonate and 0.38 g of di-tert-butyl dicarbonate is added dropwise to the resulting mixture with stirring. After the mixture is stirring at room temperature for 0.5 hour, the ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 0.51 g of tert-butyl 3(S)-[7-tert-butoxycarbonylamino-1(S)-ethoxycarbonylheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate as a colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[CH3:34])[CH2:29]Br>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:29][C:28]3[CH:31]=[CH:32][C:33]([CH3:34])=[C:26]([F:25])[CH:27]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: Cc1ccc(CBr)cc1F
Product: Cc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1F
Yield: 2.8 %

Procedure:
The title compound (0.003 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 3-fluoro-4-methylbenzyl bromide (0.9 g) in place of benzyl chloride. MS (ESI): exact mass calculated for C21H21ClFN3, 369.14; found, m/z 370.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.50-7.47 (m, 2H), 7.44-7.42 (m, 2H), 7.19 (t, J=7.6 Hz, 1H), 6.84-6.81 (m, 1H), 6.78-6.75 (m, 1H), 5.33 (s, 2H), 2.95-2.92 (m, 4H), 2.87-2.84 (m, 2H), 2.81-2.78 (m, 2H), 2.22 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:14]N1C(=O)CCC1=O>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[I:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccsc1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccsc1I
Yield: 92.3 %

Procedure:
In a manner analogous to Campaigne, E. and Monroe, P. A. J.A.C.S., 76, 2447-2450 (1954), to a boiling solution of (tert-butoxy)-N-(3-thiophenyl)carboxamide (21.0 g, 0.1 mol) in methylene chloride (400 mL) add N-iodosuccinimide (23.7 g, 0.1 mol) in small portions. Set the heating bath to 65° C. for 20 min. Take the reaction to room temperature, evaporate the solvent and purify the crude by flash chromatography (Silica gel-Hexane/EtOAc 9:1) to obtain 30.0 g (88%) of (tert-Butoxy)-N-(2-iodo(3-thiophenyl))carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C@H:7]([C:9]([N:11]2[CH:16]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH:14]([N:19]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])[CH2:15]3)=[O:10])[NH2:8])=[CH:4][CH:3]=1.[O:35]1[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@H:7]([C:9]([N:11]2[CH:16]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH:14]([N:19]([CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[C:20]([N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])=[O:21])[CH2:15]3)=[O:10])[NH:8][CH:38]2[CH2:39][CH2:40][O:35][CH2:36][CH2:37]2)=[CH:33][CH:34]=1
Reactant: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@H](N)Cc1ccc(Cl)cc1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@@H](Cc1ccc(Cl)cc1)NC1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.9 %

Procedure:
0.30 g of the N-[8-(4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N′,N′-diethylurea endo compound, obtained in step 1.5, is dissolved in 3 ml of dichloromethane under N2 in the presence of 0.061 g of tetrahydro-4H-pyran-4-one and of 0.17 g of sodium triacetoxyborohydride. The reaction medium is stirred at ambient temperature for 3 days. After evaporation and hydrolysis with a saturated aqueous sodium hydrogen carbonate solution, extraction is carried out with ethyl acetate until the aqueous phase is completely depleted. The organic phase is washed with H2O and then with a saturated aqueous sodium chloride solution. Drying over MgSO4 and concentration to dryness are carried out. The crude is chromatographed on silica gel, elution being carried out with a 99/1 and then 98/2 mixture of dichloromethane and methanol. 0.23 g of N-{8-[4-chloro-N-(tetrahydro-2H-pyran-4-yl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N′,N′-diethylurea is then obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([Br:20])[C:18]=1[Cl:19])[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:20][C:17]1[CH:16]=[C:11]([CH:10]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:18]=1[Cl:19])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(Br)c(Cl)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Br)c(Cl)c(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 97.1 %

Procedure:
Methyl 3-(bis(tert-butoxycarbonyl)amino)-5-bromo-4-chlorobenzoate (3.06 g, 6.58 mmol) was dissolved in a solution of TFA (1.015 ml, 13.17 mmol) in CH2Cl2 (32.9 ml). The reaction was stirred at rt for 45 min, and then sat. NaHCO3 solution was added. The reaction mixture was diluted with a little more CH2Cl2 and washed 2× with sat. NaHCO3 to remove any residual TFA. The organic layer was dried over Na2SO4, filtered, and concentrated to provide methyl 3-bromo-5-(tert-butoxycarbonylamino)-4-chlorobenzoate (2.33 g) as a cream solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C@@H:18]([NH2:20])[CH3:19])=[C:14]([CH:23]([CH3:28])[C:24]([F:27])([F:26])[F:25])[CH:13]=1.[CH3:29][C:30]1[N:31]=[CH:32][N:33]([C:35]2[C:44](=[O:45])[N:43]3[C:38]([C:39](=[O:46])[O:40][CH2:41][CH2:42]3)=[CH:37][CH:36]=2)[CH:34]=1>O1CCCC1>[F:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C@@H:18]([NH:20][C:39]([C:38]2[N:43]([CH2:42][CH2:41][OH:40])[C:44](=[O:45])[C:35]([N:33]3[CH:34]=[C:30]([CH3:29])[N:31]=[CH:32]3)=[CH:36][CH:37]=2)=[O:46])[CH3:19])=[C:14]([CH:23]([CH3:28])[C:24]([F:25])([F:26])[F:27])[CH:13]=1
Reactant: CC(c1cc(F)ccc1OC[C@H](C)N)C(F)(F)F
Reactant: Cc1cn(-c2ccc3n(c2=O)CCOC3=O)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cn(-c2ccc(C(=O)N[C@@H](C)COc3ccc(F)cc3C(C)C(F)(F)F)n(CCO)c2=O)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diisobutylaluminum hydride (1.5 M in toluene, 1.63 mL, 2.44 mmol) was added to a solution of (2S)-1-[4-fluoro-2-(1,1,1-trifluoropropan-2-yl)phenoxy]propan-2-amine (P13) (fractions that were enriched in the lower Rf diastereomer were used, see step 4 of Preparation 13; 324 mg, 1.22 mmol) in tetrahydrofuran (5 mL). After the vigorous bubbling subsided, the reaction mixture was stirred for 2 hours at room temperature. 7-(4-Methyl-1H-imidazol-1-yl)-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,6-dione (P14) (299.7 mg, 1.222 mmol) was added, and the reaction mixture was heated to 60° C. for 24 hours. It was then cooled to room temperature, carefully quenched with 1 M aqueous sodium hydroxide solution, and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the product as a sticky orange-tan oil. This was used in the following step without additional purification. Yield: 430 mg, 0.84 mmol, 69%. LCMS m/z 511.3 (M+1). On large scale, use of diisobutylaluminum hydride was less successful; in this case, simply dissolving P13 and P14 in methanol, boiling the solution down to a thick homogeneous oil and heating at 110° C. provided superior results.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1.C(N(C(C)C)C(C)C)C>CC(O)C>[Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([N:16]3[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]3)=[CH:24][CH:23]=2)=[N:4][CH:3]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Brc1ncc(Br)n2ncnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cc2)CC1
Yield: 50.4 %

Procedure:
A mixture of 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (2 g, 7.20 mmol), 4-(4-methyl-piperazin-1-yl)-phenylamine (1.65 g, 8.64 mmol) and N-ethyldiisopropyl-amine (1.5 mL, 8.64 mmol) is heated at 80° C. in 2-propanol (50 mL) for 8 hours. The reaction mixture is evaporated to dryness and the residue partitioned between dichloromethane and water. The aqueous phase is extracted twice with dichloromethane. The organic layers are washed with brine, dried over MgSO4, filtered and evaporated to furnish the title compound (1.41 g) as a grey solid. 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.27 (3H, s), 2.54 (4H, m), 3.14 (4H, m), 6.97 (2H, d), 7.80 (2H, d), 7.87 (1H, s), 8.72 (1H, s), 9.92 (1H, br s). LCMS: Rt 2.07 min (77.4%), m/z (APCI) 388 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].N1C(C)=CC(C)=CC=1C>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[CH2:4][CH2:3]1
Reactant: CC1(C)CCNc2ccccc21
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: ClC(Cl)Cl
Solvent: Cc1cc(C)nc(C)c1
Product: CC1(C)CCN(c2ccccc2[N+](=O)[O-])c2ccccc21
Temperature: 250 °C
Reaction time: 1 h

Procedure:
1b (0.762 g, 4.73 mmol), ortho-fluoronitrobenzene (0.88 g, 5.67 mmol, 1.19 eq), and 2,4,6-collidine (0.66 mL, 1.05 eq) were pre-stirred 40s in a conical microwave container. It was then heated with stirring at a Personal Chemistry Microwave reactor with normal absorption at 250° C. for 1 h. The crude mixture was dissolved in CHCl3, and was purified by flash chromatography (hexanes/EtOAc) to give 0.66 g of crude 1c. LC-MS ESI 283 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7]OS(C)(=O)=O)[CH:4]=[N:3]1.[C:13]([NH:17][C:18]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[C:26]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH:39]([F:41])[F:40])[CH:36]=4)[NH:31][N:30]=3)[N:27]=2)[N:22]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:21]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:13]([NH:17][C:18]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[C:26]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH:39]([F:40])[F:41])[CH:36]=4)[N:31]([CH2:7][C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[N:30]=3)[N:27]=2)[N:22]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:21]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cn1cc(COS(C)(=O)=O)cn1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1cc(Cn2nc(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)c3cc(OC(F)F)ccc32)cn1
Temperature: 90 °C
Yield: 50.5 %

Procedure:
To a solution of methanesulfonic acid 1-methyl-1H-pyrazol-4-ylmethyl ester (108 mg, 0.57 mmol) in DMF (2 mL) were added 2-(5-difluoromethoxy-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (100 mg, 0.19 mmol) and Cs2CO3 (184 mg, 0.57 mmol). The bright yellow reaction mixture was heated at 90° C. for 2 h then cooled to room temperature, quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×) dried over MgSO4 and concentrated. The residue was chromatographed with 50% to 100% EtOAc/hexanes to afford 60 mg (51%) of 2-[5-difluoromethoxy-1-(1-methyl-1H-pyrazol-4-ylmethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a light yellow solid.