Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1COCC1.CO>Cl.O1CCOCC1>[ClH:1].[ClH:1].[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)nc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CO
Product: NC1CCN(c2ccc(Cl)nc2)CC1
Yield: 277.1 %

Procedure:
A solution of tert-butyl [1-(6-chloropyridin-3-yl)-piperidin-4-yl)carbamate (1.211 g, 3.88 mmol) in HCl in Dioxane (4M, 5 mL), THF (5 mL) and MeOH (4 mL) was stirred at rt for 20 h. The reaction mixture was filtered, the residue washed with EtOAc and dried to give the title compound (1.02 g, 92%) as a solid; 1H NMR (500 MHz, CD3OD): 8.36 (d, 1H), 7.97 (dd, 1H), 7.68 (d, 1H), 4.05-3.96 (m, 2H), 3.51-3.41 (m, 1H), 3.18 (dt, 2H), 2.24-2.17 (m, 2H), 1.85 (dq, 2H); 13C NMR (CD3OD): 145.8, 136.7, 133.3, 130.7, 126.5, 47.1, 28.9; Mass Spectrum: M+H 212.
Reaction SMILES: [ClH:1].Cl[C:3]1[CH:15]=[CH:14][C:6]([CH:7]=[N:8][NH:9][C:10](=[NH:13])SC)=[CH:5][CH:4]=1.[NH2:16][NH2:17]>C(O)C>[NH2:16][NH:17][C:10]([NH:9][NH:8][CH2:7][C:6]1[CH:14]=[CH:15][C:3]([Cl:1])=[CH:4][CH:5]=1)=[NH:13]
Reactant: Cl
Reactant: CSC(=N)NN=Cc1ccc(Cl)cc1
Reactant: NN
Solvent: CCO
Product: N=C(NN)NNCc1ccc(Cl)cc1

Procedure:
The same compound is synthesized by the reaction of equimolar quantities ofp-chlorobenzylhydrazine and methyl-3-(4-chlorobenzylidene)thiocarbazimidatehydrochloride (see Example 10) in hot ethanol. It is also prepared by the reaction of equimolar amounts of 1-(p-chlorobenzyl)-S-methylisothiosemicarbazide and hydrazine in warm ethanol, which affords 1-amino-3-(p-chlorobenzylamino)guanidine, followed by treatment of the latter with an equimolar quantity of p-chlorobenzaldehyde in hot isopropanol.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[F:6][C:7]([F:43])([F:42])[C:8]1[CH:9]=[C:10]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:11][N:12]1[C:16](Cl)=[C:15]([C:18]([C:20]2[O:24][C:23]([CH:25]3[CH2:27][CH2:26]3)=[N:22][C:21]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])=[O:19])[N:14]=[N:13]1.CCOC(C)=O>CS(C)=O>[F:41][C:38]([F:39])([F:40])[C:36]1[CH:35]=[C:10]([CH:9]=[C:8]([C:7]([F:6])([F:43])[F:42])[CH:37]=1)[CH2:11][N:12]1[C:16]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[C:15]([C:18]([C:20]2[O:24][C:23]([CH:25]3[CH2:26][CH2:27]3)=[N:22][C:21]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])=[O:19])[N:14]=[N:13]1
Reactant: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1Cl)c1oc(C2CC2)nc1-c1ccccc1Cl
Reactant: c1c[nH]cn1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-n1ccnc1)c1oc(C2CC2)nc1-c1ccccc1Cl
Temperature: 80 °C
Yield: 88.3 %

Procedure:
Add imidazole (0.37 g, 5.44 mmol) to a solution of [1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-[4-(2-chloro-phenyl)-2-cyclopropyl-oxazol-5-yl]-methanone (0.16 g, 0.28 mmol) in DMSO (1.0 mL) and heat to 80° C. for 18 h. Dilute reaction mixture with EtOAc and wash with water and brine, then dry, filter, and concentrate. Purify by flash chromatography using a linear gradient of 30% to 70% EtOAc in hexane to give the title compound (0.15 g, 76%). MS (ES) 607.1 (M+H). 1H NMR (400 MHz, CHCl3) δ 7.88 (s, 1H), 7.61 (s, 1H) 7.51 (m, 3H), 7.21–7.33 (m, 4H), 6.92 (s, 1H), 5.43 (s, 2H), 2.20 (m, 1H), 1.17–1.31 (m, 4H).
Reaction SMILES: CC(O)=O.Cl[C:6]1[N:7]=[N:8][CH:9]=[C:10]([Cl:13])[C:11]=1[NH2:12].[CH:14]([NH2:17])([CH3:16])[CH3:15]>CO>[Cl:13][C:10]1[C:11]([NH2:12])=[C:6]([NH:17][CH:14]([CH3:16])[CH3:15])[N:7]=[N:8][CH:9]=1
Reactant: CC(C)N
Reactant: Nc1c(Cl)cnnc1Cl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Nc1nncc(Cl)c1N
Temperature: 0 °C
Yield: 74 %

Procedure:
HOAc (2.47 mL, 42.7 mmol) was added dropwise to a mixture of 3,5-dichloropyridazin-4-amine (Preparation 4, 1000 mg, 6.098 mmol) and isopropylamine (7.27 mL, 85.4 mmol) cooled to 0° C. The resulting solid/suspension was heated under microwave irradiation at 105° C. for 5 hours. The reaction mixture was dissolved in minimum amount of MeOH and purified by silica gel column chromatography eluting with EtOAc:heptane: 10%-90% to provide the title compound as a slightly brownish solid in 74% yield, 2.52 g.
Reaction SMILES: N(OCCCCC)=O.[C:9]([C@@:12]1([OH:37])[C@:16]([C:18](=[O:20])[CH3:19])([OH:17])[C@@H:15]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:14][C@H:13]1[N:26]1[CH:34]=[N:33][C:32]2[C:27]1=[N:28][C:29](N)=[N:30][C:31]=2[Cl:35])(=[O:11])[CH3:10].C1(C([Cl:57])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:9]([C@@:12]1([OH:37])[C@:16]([C:18](=[O:20])[CH3:19])([OH:17])[C@@H:15]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:14][C@H:13]1[N:26]1[CH:34]=[N:33][C:32]2[C:27]1=[N:28][C:29]([Cl:57])=[N:30][C:31]=2[Cl:35])(=[O:11])[CH3:10]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@@](O)(C(C)=O)[C@@]1(O)C(C)=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCCON=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@@](O)(C(C)=O)[C@@]1(O)C(C)=O
Temperature: 25 °C
Yield: 74.3 %

Procedure:
n-Pentyl nitrite (98 g, 838 mM) is added over one hour at room temperature under nitrogen to a mixture of the compound of Example 2 (350 g, 819 mM), triphenylmethyl chloride (500 g, 1.79 M) and potassium carbonate (65 g) in CH2Cl2 (3 L). The resulting mixture is heated at reflux for 20 minutes, cooled to room temperature and filtered. The filtrate is concentrated in vacuo, and the resulting residue is purified by column chromatography on silica gel (2.5 kg, ethyl acetate/hexane 1:4-3:7) to yield the title compound as a pale yellow solid (272 g, 74%).
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.[CH2:40]([O:42][C:43](=[O:63])[C@H:44]([OH:62])[CH2:45][C@H:46]([NH2:61])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([Cl:60])[CH:55]=2)=[CH:50][CH:49]=1)[CH3:41].CCN(C(C)C)C(C)C>>[CH2:40]([O:42][C:43](=[O:63])[C@H:44]([OH:62])[CH2:45][C@H:46]([NH:61][C:8]([C:4]1[CH:3]=[C:2]([OH:1])[N:6]([CH3:7])[N:5]=1)=[O:10])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([Cl:60])[CH:55]=2)=[CH:50][CH:49]=1)[CH3:41]
Reactant: Cn1nc(C(=O)O)cc1O
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
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: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)n(C)n1
Reaction time: 0.17 h
Yield: 27.3 %

Procedure:
5-Hydroxy-1-methyl-1h-pyrazole-3-carboxylic acid (122 mg, 862 μmol) and HATU (361 mg, 949 μmol) were combined in DMF (1.0 mL, 13 mmol) and stirred for 10 minutes. (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (30.0 mg, 86 μmol) and DIPEA (165 μL, 949 μmol) were added, and the resulting mixture was stirred at room temperature overnight. The mixture was then concentrated under reduced pressure and the residue was dissolved in 50% AcOH-water (1.5 mL), filtered, purified by reverse phase preparative HPLC, and lyophilized to yield the title compound (11.1 mg). MS m/z [M+H]+ calc'd for C24H26ClN3O5, 472.16. found 472.2.
Reaction SMILES: [F:1][S:2]([C:5]([C:8]([C:11]([O:14][C:15](C(F)=O)([C:17]([F:20])([F:19])[F:18])[F:16])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])(=[O:4])=[O:3].[C:24](=[O:27])(O)[O-:25].[K+:28]>C(COC)OC>[F:1][S:2]([C:5]([C:8]([C:11]([O:14][C:15]([C:24]([O:25][K:28])=[O:27])([C:17]([F:20])([F:19])[F:18])[F:16])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])(=[O:4])=[O:3]
Reactant: [K+]
Reactant: O=C([O-])O
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)S(=O)(=O)F)C(F)(F)F
Solvent: COCCOC
Product: O=C(O[K])C(F)(OC(F)(F)C(F)(F)C(F)(F)S(=O)(=O)F)C(F)(F)F
Reaction time: 0.5 h

Procedure:
FSO2(CF2)3OCF(CF3)COF is added dropwise to a flask under cooling with ice, into which potassium bicarbonate and monoglyme are charged, with stirring. After completion of the dropwise addition, stirring is continued further for 30 minutes, and then the solvent is distilled off. Vacuum drying is further carried out to obtain FSO2(CF2)3OCF(CF3)COOK.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].[Cl:14][C:15]1[CH:16]=[C:17]([O:21][CH3:22])[CH:18]=[CH:19][CH:20]=1.Cl>C(Cl)Cl>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([Cl:14])[CH:20]=[CH:19][C:18]=1[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][Br:5])=[O:12]
Reactant: COc1cccc(Cl)c1
Reactant: O=C(Cl)CCCCCBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(Cl)ccc1C(=O)CCCCCBr

Procedure:
Aluminum chloride (70 g.) was added portionwise to a solution of 110 g. of 6-bromocaproyl chloride in 250 ml. of methylene dichloride. To the resulting solution was added slowly, with cooling and stirring, 72 g. of m-chloroanisole in 250 ml. of methylene dichloride. The reaction mixture was stirred for 1 hour and poured into 500 ml. of 2N hydrochloric acid and 500 ml. of ice. The organic layer was separated and the aqueous layer extracted with ether. The combined organic layers were washed with sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated. The product containing isomeric mixtures was chromatographed on silica gel and eluted with ethyl acetate-hexane. The first compound eluted (72 g.) was the desired isomer, 5-(2-methoxy-4-chlorobenzoyl)pentyl bromide.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6]CC.[OH-].[Na+]>CO>[NH2:1][CH2:2][CH:3]([C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1)[CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:6])[OH:9]
Reactant: CCOC(OCC)P(=O)(CC(CN)c1ccc(Cl)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(OCC)P(=O)(O)CC(CN)c1ccc(Cl)cc1

Procedure:
To a solution of 1.0 g of ethyl 3-amino-2-(p-chlorophenyl)propyl(diethoxymethyl)phosphinate in 5 ml of methanol are added 2.5 ml of a 2 normal sodium hydroxide solution and the mixture is heated to a temperature of 80° for a period of 5 hours. After this time, the reaction is concentrated under reduced pressure, and the oily residue is passed down an Ion Exchange Resin (DOWEX® 50W-X8 H+) using de-ionised water as eluant. Ninhydrin-positive fractions are combined and evaporated to give 3-amino-2-(4-chlorophenyl)-propyl(diethoxymethyl)phosphinic acid, m.p. 175°-185° (dec.), 31P-NMR: δ=+31.6 ppm (D2O).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].O>C1COCC1>[Si:17]([O:10][CH2:9][C:5]1[CH:4]=[C:3]([CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1cccc(CO)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCc1cccc(CO)c1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
Under a nitrogen atmosphere, to a suspension of 60% sodium hydride (1.40 g) in THF (70 mL) was slowly added 1,3-phenylenedimethanol (4.84 g) at 0° C., and the mixture was stirred at 0° C. for 1 hr. tert-Butylchlorodiphenylsilane (9.63 g) was added, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.97 g) as a colorless oil.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([C:19]([F:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])=[CH:18][C:12]=2[N:11]=1)[CH3:2].[CH3:29]N(C=O)C.[H-].[Na+].IC>O>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]([CH3:29])[C:12]2[CH:18]=[C:17]([C:19]([F:28])([C:20]([F:21])([F:22])[F:23])[C:24]([F:27])([F:25])[F:26])[CH:16]=[CH:15][C:13]=2[N:14]=1)[CH3:2].[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:14]([CH3:29])[C:13]2[CH:15]=[CH:16][C:17]([C:19]([F:28])([C:20]([F:21])([F:22])[F:23])[C:24]([F:27])([F:25])[F:26])=[CH:18][C:12]=2[N:11]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCSc1ccccc1-c1nc2cc(C(F)(C(F)(F)F)C(F)(F)F)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCSc1ccccc1-c1nc2cc(C(F)(C(F)(F)F)C(F)(F)F)ccc2n1C
Product: CCSc1ccccc1-c1nc2ccc(C(F)(C(F)(F)F)C(F)(F)F)cc2n1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 2-(2-ethylsulfanyl-phenyl)-5-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-1H-benzimidazole (97 mg) and DMF (10 mL), sodium hydride (11 mg) and iodomethane (16 μL) were added under ice-cooling. The mixture was heated to room temperature, and stirred for 5 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 35 mg of 2-(2-ethylsulfanyl-phenyl)-1-methyl-6-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-1H-benzimidazole (hereinafter, Present Compound 304) and 80 mg of 2-(2-ethylsulfanyl-phenyl)-1-methyl-5-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-1H-benzimidazole (hereinafter, Present Compound 305).
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][C:6](=O)[C:5]=12.I[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>>[N:15]1[CH:16]=[CH:17][C:12]([CH:6]2[CH2:7][CH2:8][CH2:9][N:4]3[CH:3]=[N:2][CH:1]=[C:5]23)=[CH:13][CH:14]=1
Reactant: Ic1ccncc1
Reactant: O=C1CCCn2cncc21
Product: c1cc(C2CCCn3cncc32)ccn1

Procedure:
In analogy to Example 1 6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one [426219-51-4] and 4-iodopyridine [15854-87-2] are reacted. The title compound is obtained as a light brown foam. Rt=2.26 (Gradient I).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[O:8][C:9]1[CH:10]=[C:11]([C:17]2(O)[CH:22]=[CH:21][NH:20][C:19](=[O:23])[NH:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].Cl>C(O)C>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[O:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:22]=[CH:21][NH:20][C:19](=[O:23])[N:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(C2(O)C=CNC(=O)N2)cc1OC1CC2CCC1C2
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2cc[nH]c(=O)n2)cc1OC1CC2CCC1C2
Temperature: 25 °C
Yield: 31.5 %

Procedure:
The hydroxypyrimidinone of Example 60 (0.2 g, 0.61 mmol) is dissolved in 5 ml ethanol, treated with 2.5 ml 1N HCl and refluxed for 6 hours. The reaction is cooled to room temperature, quenched with water and the product extracted 3×ethyl acetate. The organics are washed, dried, filtered and concentrated in vacuo to yield a crude substance which is crystallized from ethyl acetate to give 60 mg (31.5%) of the pyrimidinone as a crystalline solid. This material is a 7:3 mixture of endo/exo bicycloalkyl isomers.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][O:17][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)=O.[Br:22]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([Br:22])[O:17][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCc2ccoc2CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2cc(Br)oc2CC1
Reaction time: 1 h

Procedure:
A solution of the product from step h) (50 mg, 0.21 mmol) in CHCl3 (527 μl) and AcOH (527 μl) was treated with N-bromosuccinimide (38.1 mg, 0.21 mmol) at 22° C. After 1 hour, the contents were poured into sat. NaHCO3 and extracted with EtOAc (2×5 ml). The organic layer was washed with brine (1×5 ml), dried (MgSO4) and purified by preparative TLC (80% hexanes:20% EtOAc) providing 2-bromo-4,5,7,8-tetrahydro-furo[2,3-d]azepine-6-carboxylic acid tert-butyl ester which was directly treated with 4M HCl in dioxane (2 ml). The dioxane was evaporated and the residue was dissolved in MeOH and purified by preparative LC/MS providing 1.3 mg of the title compound. 1H NMR (CDCl3) 6.08 (s, 1H); 3.02-3.07 (m, 4H); 2.89-2.92 (m, 2H); 2.57-2.70 (m, 3H); MS: ESI (positive): 216, 218 (M+H).
Reaction SMILES: C([O-])([O-])=O.[Ca+2].[C:6]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)(=[O:8])[CH3:7].[I:16]Cl>O.CO.CCOCC>[NH2:13][C:12]1[CH:14]=[CH:15][C:9]([C:6](=[O:8])[CH3:7])=[CH:10][C:11]=1[I:16]
Reactant: ClI
Reactant: CC(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: CC(=O)c1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 44.4 %

Procedure:
To a stirred suspension of CaCO3 (4.5 g, 45.27 mmol) in H2O (15 mL) was added a solution of 4-acetylaniline (4.1 g, 30.18 mmol) in MeOH (25 mL), followed by a solution of iodine monochloride (5.2 g, 31.88 mmol) in MeOH (20 mL) dropwise. The reaction was stirred at r.t. for 45 minutes, then diluted with Et2O (150 mL). The organic fraction was separated, washed with water (100 mL), then brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (3.5 g, 44%) as a brown oil that was used without further purification. δH (DMSO-d6) 8.14 (1H, d, J 1.8 Hz), 7.70 (1H, dd, J 8.3 and 1.8 Hz), 6.75 (1H, d, J 8.3 Hz), 6.10 (2H, s), 2.41 (3H, s). LCMS (ES+) 261 (M)+, 283 (M+Na)+, RT 3.026 minutes (Method 4).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:20])([CH3:19])[O:6][C@@H:7]([CH3:18])[C:8](O[Si](C(C)(C)C)(C)C)=[O:9])([CH3:4])[CH3:3].C(Cl)(=O)C([Cl:24])=O>CN(C)C=O.C(Cl)Cl>[CH3:1][C:2]([Si:5]([CH3:20])([CH3:19])[O:6][C@@H:7]([CH3:18])[C:8]([Cl:24])=[O:9])([CH3:4])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a solution of 41.0 g (0.13 mol) of 2-(1,1-dimethylethyl)dimethylsilyl (2S)-2-((1,1-dimethylethyl)dimethylsilyloxy)propanoate (7) and five drops of N,N-dimethylformamide in methylene chloride at 0° C. was added 70.8 mL (0.14 mol) of a 2.0M solution of oxalyl chloride in methylene chloride over a 30 minute period. The cooling bath was removed and the reaction mixture was allowed to stir at room temperature for 18 hours. The solvent and excess oxalyl chloride were removed by rotary evaporation resulting in a yellow liquid. Purification by vacuum distillation afforded 25.6 g (88%) of (2S)-2-((1,1 -dimethylethyl)dimethylsilyloxy)propanoyl chloride (8) as a clear liquid: bp 42°-45° C. (1.5 mm Hg); 1H NMR (CDCl3) δ0.0920 (s, 3 H), 0.118 (s, 3 H), 0.909 (s, 9 H), 1.50 (d, J=6.7 Hz, 3 H), 4.49 (q, J=6.7 Hz, 1 H); 13C NMR (CDCl3) δ176.6, 76.0, 25.7, 25.6, 25.3, 20.9, 18.1, -1.57, -5.04, -5.28.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]([CH3:46])[C:25]([CH:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=2)[O:28]1)=[O:26]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:32]3[CH:33]=[C:34]4[C:29](=[CH:30][CH:31]=3)[O:28][CH:27]([C:25]([N:24]([CH3:46])[CH3:23])=[O:26])[CH2:36][CH2:35]4)[C:16]2=[CH:15][N:14]=1
Reactant: CN(C)C(=O)C1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2O1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CCC(C(=O)N(C)C)O5)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1, Step 7 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and N,N-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chromane-2-carboxamide. LCMS (M+H)+=496.0.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[O:10][C:9]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16]C)=[O:15])=[N:8][CH:7]=1.O.[OH-].[Li+].Cl>O1CCCC1.CO.O>[C:3]([CH2:4][CH2:5][C:6]1[O:10][C:9]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([OH:16])=[O:15])=[N:8][CH:7]=1)([OH:21])=[O:2]
Reactant: COC(=O)CCc1cnc(-c2cccc(C(=O)OC)c2)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1cnc(-c2cccc(C(=O)O)c2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To methyl 3-[5-(3-methoxy-3-oxopropyl)-1,3-oxazol-2-yl]benzoate (400 mg, 1.3 mmol) in 2:1:1 tetrahydrofuran/methanol/water (8 mL) is added lithium hydroxide monohydrate (112 mg, 2.7 mmol), and the reaction is stirred 2 h at room temperature. More lithium hydroxide monohydrate (225 mg, 5.4 mmol) is added and the reaction is stirred 16 h at room temperature. The reaction is treated with excess concentrated hydrochloric acid resulting in a precipitate. The precipitate is filtered to give the title compound. ESI MS m/z 260.1 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:31])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:30])[CH2:20][CH2:21]C2C=CC(OC)=CC=2)[CH2:14][CH2:13]1.CO[C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Cl)=[CH:36][CH:35]=1>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:31])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:30])[CH2:20][CH2:21][CH2:38][C:37]2[CH:40]=[CH:41][CH:34]=[CH:35][CH:36]=2)[CH2:14][CH2:13]1
Reactant: COc1ccc(CCC(O)CN2CCN(CC(=O)Nc3c(C)cccc3C)CC2)cc1
Reactant: COc1ccc(CCl)cc1
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)CCCc2ccccc2)CC1

Procedure:
Compound 25 was prepared in a manner similar to that of 16, substituting phenethyl chloride for 4-methoxybenzyl chloride in part A. (M+1)=410.4.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:8]([O:29][CH3:30])=[C:9]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:28])=[C:18]([N:20]3[CH:24]=[C:23]([C:25]([OH:27])=O)[CH:22]=[N:21]3)[CH:19]=2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[N:40]1[CH:41]=[CH:42][CH:43]=[C:38]([CH2:37][NH:36][C:25]([C:23]2[CH:22]=[N:21][N:20]([C:18]3[CH:19]=[C:14]([C:12](=[O:13])[NH:11][C:9]4[CH:10]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:6]=[C:7]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:8]=4[O:29][CH3:30])[CH:15]=[CH:16][C:17]=3[CH3:28])[CH:24]=2)=[O:27])[CH:39]=1
Reactant: NCc1cccnc1
Reactant: COc1c(NC(=O)c2ccc(C)c(-n3cc(C(=O)O)cn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(C(=O)NCc4cccnc4)cn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reaction time: 8 h
Yield: 54.2 %

Procedure:
The above carboxylic acid (75 mg, 0.15 mmol), 3-(aminomethyl)pyridine (25 mg, 0.23 mmol) and HATU (85 mg, 0.23 mmol) were dissolved in DMF (1.5 mL). N,N-Diisopropylethylamine (78 μL, 0.45 mmol) was added and the reaction was stirred overnight. Water was added and the resulting solution was extracted with CH2Cl2 (4×30 mL). The combined organic extracts were washed with 5% LiCl solution, dried over MgSO4, filtered, and concentrated. The residue was purified by semi-prep HPLC. The product fractions were concentrated and sodium bicarbonate added. The resulting solid was collected by vacuum filtration, washed with water, and dried under vacuum at 55° C. to provide the title compound (48 mg, 54%) as white solid: mp 127-133° C.; ESI MS m/z 591 [C30H34N6O5S+H]+; HPLC>95%, tR=15.03 min.