Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:5]3=[N:4][C:3]=2[C:11]([F:14])([F:13])[F:12])=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: FC(F)(F)c1nc2cnccn2c1Br
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Fc1ccc(-c2c(C(F)(F)F)nc3cnccn23)cc1

Procedure:
3-Bromo-2-(trifluoromethyl)imidazo[1,2-a]pyrazine (I12) (1.330 g, 5 mmol), (4-fluorophenyl)boronic acid (1.049 g, 7.50 mmol), sodium carbonate (2.65 g, 25.00 mmol) and Bis(triphenylphosphine)palladium (II) chloride (0.351 g, 0.500 mmol) were heated at 80° C. for 7 h in water (10 ml) and 1,2-dimethoxyethane (DME) (20 ml). The mixture was passed through a hydromatrix cartridge (Varian, 20 g) and washed through with dichloromethane. The filtrated was concentrated in vacuo to afford a tacky oil. The product was purified by flash chromatography (Isolera, 100 g, 0-100% 2M ammonia in methanol:dichloromethane (1:9)/dichloromethane) to afford product in 2.03 g. The compound was repurified by flash chromatography (Isolera, 100 g, 0-100% ethyl acetate/iso-hexane) to afford product in 1.42 g as beige solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Br:15])[C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:26](=S)=[S:27].OS(O)(=O)=O.S>C1COCC1.C(Cl)Cl.O>[Br:15][C:12]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]2[C:13]=1[O:14][C:26](=[S:27])[CH:2]=[C:1]2[OH:3]
Reactant: S=C=S
Reactant: COC(=O)c1cc(Br)c(O)c(C(C)=O)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(O)O
Agent: S
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c2oc(=S)cc(O)c2c1
Temperature: -5 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
To a suspension of methyl 3-acetyl-5-bromo-4-hydroxybenzoate (70 g, 243.52 mmol) in THF (700 mL) at −50° C. under nitrogen (flask equipped with a bleach trap) was added lithium bis(trimethylsilyl)amide (828 ml, 828 mmol). The dark solution was allowed to warm to −5° C. and stirred for 2 h. Carbon disulfide (22 mL, 365 mmol) was added in one portion to the solution at −20° C. then the mixture was stirred at room temperature overnight. Water (700 mL) was added, the THF layers was washed with water (2×350 mL). The aqueous phases were combined and cooled to 0° C. and quenched with H2SO4 (108 ml, 1948 mmol) in a vessel equipped with a bleach trap to neutralize the H2S formed. The mixture was stirred at room temperature for 3 h, DCM was added (700 mL) and mixture was stirred at room temperature overnight. The aqueous phase was extracted with DCM (2×). The organic phases were combined, washed with brine, dried over MgSO4, filtered and evaporated to afford an orange solid. This solid was triturated in diethyl ether, filtered and dried to give methyl 8-bromo-4-hydroxy-2-thioxo-2H-chromene-6-carboxylate (48.7 g, 63%) as a yellow/orange solid. Mass Spectrum: m/z [M+H]+=317.
Reaction SMILES: [OH:1]O.[Cl:3][CH2:4][CH2:5][S:6][CH2:7][C:8]1[C:17]2[O:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:14]([CH3:24])[C:13](=[O:25])[C:12]=2[CH:11]=[CH:10][CH:9]=1.O>C(O)(=O)C>[Cl:3][CH2:4][CH2:5][S:6]([CH2:7][C:8]1[C:17]2[O:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:14]([CH3:24])[C:13](=[O:25])[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:1]
Reactant: Cc1c(-c2ccccc2)oc2c(CSCCCl)cccc2c1=O
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(-c2ccccc2)oc2c(CS(=O)CCCl)cccc2c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
36 ml of aqueous 30% hydrogen peroxide was quickly added dropwise at 10° C. to a solution of 12 g of Intermediate XXI in 84 ml of glacial acetic acid. The reaction mixture was stirred for 4 hours at ambient temperature, and then poured into 220 ml of water. The title compound was collected by suction filtration, washed with water and desiccated. Yield 12.4 g, m.p. 142°-145° C. (methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:14](Cl)(Cl)=[S:15].O1CCOCC1>O>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]([N:1]=[C:14]=[S:15])=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccccc1-c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: S=C=Nc1ccccc1-c1ccccc1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
A mixture of 2-aminobiphenyl (10.2 g), thiophosgene (10.4 g), dioxane (50 ml) and water (100 ml) was prepared with cooling in an ice bath. The temperature was raised to 30° C. and stirred for 3 hours at 30° C. to yield 2-biphenylylisothiocyanate as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:18]2)=[O:14])=[CH:4][CH:3]=1.[Cl:27]N1C(=O)CCC1=O.O>C(O)C>[NH2:1][C:2]1[N:7]2[C:8]([Cl:27])=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22]2)=[O:14])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCN1CCC(CNC(=O)c2ccc(N)n3cc(CC)nc23)CC1
Solvent: CCO
Solvent: O
Product: CCCCN1CCC(CNC(=O)c2ccc(N)n3c(Cl)c(CC)nc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To a solution of 5-amino-N-[(1-butylpiperidin-4-yl)methyl]-2-ethylimidazo[1,2-a]pyridine-8-carboxamide (EXAMPLE 10, Step 4, 170 mg, 0.48 mmol) in ethanol (4 mL) was added N-chlorosuccinimide (76 mg, 0.57 mmol) at room temperature. After stirring at room temperature for 1 h, water (50 mL) was added to the mixture. The aqueous layer was extracted with dichloromethane (60 mL×3). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was suspended in diethyl ether and the insoluble solid was collected by filtration to give 71 mg (38%) of the title compound as a gray solid.
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([NH:4][C:5]3=O)[CH2:2]1)[CH2:9]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([NH:4][CH2:5]3)[CH2:2]1)[CH2:9]2
Reactant: O=C1NC2CC3CC(C2)CC1C3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C1NC2CC3CC1CC(C3)C2

Procedure:
4-Azatricyclo[4.3.1.13,8 ]undecan-5-one, 2.45 grams (14 mmol), was added to a suspension of lithium aluminum hydride (2.12 grams, 56 mmol) in 200 ml of anhydrous ether. The mixture was refluxed for 6 hours then worked up to give compound 3 as a white solid material recrystallized from hexane (melting point 290° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH:25]4[CH2:29][CH2:28][CH2:27][O:26]4)=[C:18]([O:30][CH3:31])[CH:17]=3)=[O:14])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.Br[CH2:33][CH2:34]Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:13](=[O:14])[N:15]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH:25]5[CH2:29][CH2:28][CH2:27][O:26]5)=[C:18]([O:30][CH3:31])[CH:17]=4)[CH2:34][CH2:33][N:11]3[CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1OCCC1CCCO1
Reactant: BrCCBr
Product: COc1cc(N2CCn3cc(-c4ccc(Cl)cc4)cc3C2=O)ccc1OCCC1CCCO1

Procedure:
Following the procedure described in Example 1 step D, the product of step B (120 mg) was alkylated with 1,2-dibromoethane to yield 20 mg of the title compound. MS (ESI) 467 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[C:16]([C:18]([OH:34])([C:30]([F:33])([F:32])[F:31])[CH:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][C:22]=3[Cl:29])[CH3:20])[CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[C:16]([C:18]([OH:34])([C:30]([F:31])([F:32])[F:33])[CH:19]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=3[Cl:29])[CH3:20])[CH:15]=[CH:14][N:13]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2cc(C(O)(C(C)c3ccc(OC)cc3Cl)C(F)(F)F)ccn2)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2cc(C(O)(C(C)c3ccc(O)cc3Cl)C(F)(F)F)ccn2)CC1
Yield: 74 %

Procedure:
4′-[2-(2-Chloro-4-methoxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester (Example 154, 57 mg) in dichloromethane (0.5 mL) under argon, was treated with 1M-BBr3 in dichloromethane (0.341 mL). The solution was poured into ice-water/NaHCO3, extracted twice with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash chromatography (4 g silica gel, heptane/ethyl acetate 2/1) to give the title compound as amorphous colorless solid (41 mg). MS (m/e)=487.2 (MH+).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[I:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29]>C(Cl)Cl.CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([I:20])=[C:22]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)=[O:19])=[CH:14][CH:15]=2)[CH:2]=1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: Nc1ccc(I)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CO
Product: O=C(Cc1ccc(-n2cnc3cccnc32)cc1)Nc1ccc(I)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 1 but using (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 7.1) and 4-iodo-3-trifluoromethyl-phenylamine. Title compound: ES-MS: 522.7 [M+H]+; single peak at tR=4.72 min (System 1); Rf=0.25 (CH2Cl2/MeOH, 95:5).
Reaction SMILES: C(OC(=O)[NH:7][N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]1)(C)(C)C.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[NH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]1
Reactant: CN1CCN(NC(=O)OC(C)(C)C)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(N)CC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(4-Methyl-3-oxo-piperazin-1-yl)-carbamic acid t-butyl ester (67 mg, 292 μmol) was at 0° C. combined with dichloromethane (2 mL) and trifluoroacetic acid (1 mL) to give a light yellow solution. The reaction mixture was stirred for 2 h at 0° C. and subsequently concentrated in vacuo to give the title compound as yellow oil, which was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([CH2:9][NH:10][C:11](=[O:31])[C@@H:12]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([NH2:30])=[N:26][N+:27]([O-:29])=[O:28])[NH:13]C(OC(C)(C)C)=O)=[CH:4][C:3]=1[Br:32].[ClH:33]>>[ClH:33].[NH2:1][C:2]1[C:3]([Br:32])=[CH:4][C:5]([CH2:9][NH:10][C:11](=[O:31])[C@@H:12]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([NH2:30])=[N:26][N+:27]([O-:29])=[O:28])[NH2:13])=[CH:6][C:7]=1[Br:8]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc1cc(Br)c(N)c(Br)c1
Agent: Cl
Product: NC(=N[N+](=O)[O-])NCCC[C@@H](N)C(=O)NCc1cc(Br)c(N)c(Br)c1

Procedure:
Prepared analogously to Example 36b) from (R)-N-[(4-amino-3,5-dibromophenyl)methyl]-N5 -[amino(nitroimino)methyl]-N2 -[(tert.-butyloxy)carbonyl]-ornithinamide by treating with methanolic hydrochloric acid in a quantitative yield.
Reaction SMILES: OC1O[C@H](CO)[C@@H](O)[C@H]1O.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:20]([O:28][C@:29]1([CH3:54])[C@H:34]([O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:33]([CH2:44][O:45][C:46](=[O:53])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[O:32][CH:30]1[OH:31])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.COC(C)(C)C>CN(C1C=CN=CC=1)C.COCCOC.O.CCCCCCC>[C:11]([O:31][C@@H:30]1[O:32][C@H:33]([CH2:44][O:45][C:46](=[O:53])[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C@@H:34]([O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@:29]1([CH3:54])[O:28][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@]1(OC(=O)c2ccccc2)C(O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: OC[C@H]1OC(O)[C@H](O)[C@@H]1O
Solvent: COCCOC
Solvent: COC(C)(C)C
Solvent: CCCCCCC
Product: C[C@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reaction time: 8 h
Yield: 52 %

Procedure:
The protective group at C-1 of the ribofuranose is made in the immediately preceding step. Benzoyl chloride is added to a 5° C. solution of 2,3,5-tri-O-benzoyl-2-C-methyl-D-ribofuranose in approximately a 2:1 molar ratio, along with DMAP and TEA in anhydrous DME. The reaction is stirred and allowed to run overnight, after which it is quenched with ice water and aqueous sodium carbonate solution. THF is then removed, and the mixture is extracted with ethyl acetate. Washing, drying and solvent removal produces a thick, oily product. The latter has added to it tert-butyl methyl ether, heptane and water, and is stirred for approximately 2 hours at about 20° C. The final product, 1,2,3,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose, is obtained in 52% yield and greater than 98% purity, after washing and vacuum drying (see FIG. 1, compound 4, Scheme 1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:31][C:32]([NH:34][C:35](=[O:43])[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[S:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)[S:17][C:10]=12.CCN(CC)CC.[N:51]([CH3:54])=[C:52]=[O:53]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:31][C:32]([NH:34][C:35](=[O:43])[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[S:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][N:28]([C:52]([NH:51][CH3:54])=[O:53])[CH2:27][CH2:26]4)=[CH:22][CH:23]=3)[S:17][C:10]=12
Reactant: CN=C=O
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCNCC5)cc4)sc23)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)N1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=S)NC(=O)Cc6ccccc6)cc5F)c4s3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39.9 %

Procedure:
Compound 450 (0.367 g, 0.60 mmol) was dissolved in dichloromethane (2 mL) at RT and then Et3N (0.25 mL, 1.803 mmol) was added. The reaction mixture was cooled to 0° C., treated with isocyanatomethane (0. 16 mL, 3.43 mmol) and stirred for 10 min at 0° C. The reaction mixture was then warmed to RT over a 30 min period, and then was quenched with MeOH. It was then concentrated to dryness and the residue was purified by flash chromatography (eluent 9/1/10 MeOH/NH4Cl/DCM) to give title compound 455 as a pale yellow solid (0.16 g, 39% yield). 1H NMR δ (400 MHz, DMSO-d6): 12.48 (s, 1H), 11.83 (s, 1 H), 8.51 (dd, J=1.2, 5.5 Hz, 1H), 8.01 (m, 2H), 7.84 (m, 2H), 7.53 (m, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.23-7.38 (m, 5H) 6.65 (dd, J=0.8, 5.5 Hz, 1H), 6.39 (q, J=4.2 Hz, 1 H), 3.81 (s, 2 H), 3.51 (s, 2H), 3.25 (m, 4H), 2.53 (d, J=4.3 Hz, 3H), 2.31 (m, 4H). LCMS: 669 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=1[Cl:38])=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=3[Cl:38])=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1cccc(Cl)c1Cl
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cccc(Cl)c2Cl)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(2,3-dichlorophenyl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(2,3-dichlorophenyl)-6-oxohexyl)piperidine-4-yl)methyl)benzamide.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:17]([OH:27])=[CH:16][N:15]=2)=[N:6]1.[CH3:32][C:33]1([CH3:40])[O:37][CH:36]([CH2:38]Br)[CH2:35][O:34]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:32][C:33]1([CH3:40])[O:37][C@@H:36]([CH2:38][O:27][C:17]2[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:19][C:14]([C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:5]([CH2:4][C:3]4[CH:28]=[CH:29][CH:30]=[CH:31][C:2]=4[F:1])[N:6]=3)=[N:15][CH:16]=2)[CH2:35][O:34]1
Reactant: Oc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1
Reactant: CC1(C)OCC(CBr)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COc2cnc(-c3nn(Cc4ccccc4F)c4ccccc34)nc2Nc2ccncc2)O1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
200 mg of 2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-ol (3-3, 0.49 mmol, 1 eq.), 94.6 mg of 2,2-dimethyl-4(R)-4-bromomethyl-1,3-dioxalane (0.49 mmol, 1 eq.) and 134 mg of potassium carbonate (0.97 mmol, 2 eq.) were suspended in 3.7 ml of dry DMF. The reaction mixture was stirred at 50° C. oil bath temperature for 18 hours. 201 mg of potassium carbonate (1.46 mmol, 3 eq.) were added and the mixture was stirred at 90° C. oil bath temperature for further 24 hours. Then the mixture was partitioned between half saturated aq. ammonium chloride solution and dichloromethane/isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloromethane/isopropanol 4:1. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo. The residue was purified by flash chromatography to yield 126 mg (0.27 mmol, 44%) of the analytically pure target compound.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[CH:5]=[C:4]([Br:13])[CH:3]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:12][CH2:11][CH:8]2[CH2:7][C:6]3[CH:5]=[C:4]([Br:13])[CH:3]=[C:2]([F:1])[C:10]=3[O:9]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1Cc2cc(Br)cc(F)c2O1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Br)cc(F)c3O2)cc1
Yield: 74.8 %

Procedure:
Treatment of 4-bromo-2-fluorophenol (25.0 g, 130.9 mmol) with potassium carbonate (72.35 g, 523.53 mmol) and allyl bromide (19.00 g, 157.06 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-4-bromo-6-fluorophenol. Treatment of 2-allyl-4-bromo-6-fluorophenol (25.6 g, 110.8 mmol) with 3-chloroperoxybenzoic acid (57.36 g, 332.38 mmol, 77%) followed by potassium carbonate (38.28 g, 277.0 mmol) generally according to the procedure described for Intermediate 9 afforded 19.1 g (70%) of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methanol (18.61 g, 75.3 mmol) with p-toluenesulfonyl chloride (17.22 g, 90.34 mmol) generally according to the procedure described for Intermediate 10 gave 22.6 g (75%) of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.25 mmol) and 2-methylphenylboronic acid (0.254 g, 1.87 mmol) generally according to the procedure described for Intermediate 35 afforded 0.282 g, (55%) of (±)-([7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.19 g, 3.0 mmol) generally according to the procedure described for Intermediate 98 afforded 0.17 g (99%) of (±)-2-(azidomethyl)-7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.30 g, 3.0 mmol) according to the procedure described in Example 154 afforded 0.038 g (22%) of (±)-([7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]amine as a white solid, hydrochloride salt. mp >250° C.
Reaction SMILES: NC(N)=O.[CH:5]1([NH:10][S:11]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([NH2:21])[C:15]=2[OH:22])(=[O:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31]([NH:21][C:16]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([S:11]([NH:10][CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9]2)(=[O:13])=[O:12])[C:15]=1[OH:22])=[O:32]
Reactant: Nc1ccc(Cl)c(S(=O)(=O)NC2CCCC2)c1O
Reactant: O=C=Nc1ccccc1Cl
Agent: NC(N)=O
Product: O=C(Nc1ccccc1Cl)Nc1ccc(Cl)c(S(=O)(=O)NC2CCCC2)c1O
Yield: 43.3 %

Procedure:
Following the general procedure for urea formation outlined in example 15, (N-cyclopentyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (0. 15 g, 0.52 mmol) and 2-chlorophenylisocyanate (62 μL, 0.52 mmol) were coupled to form the desired urea (0.1 g, 43%). LC-MS n/z 444(M+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:15]([Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:14]=1)=[O:12])[CH3:2].[H-].[Na+].Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][C:37]=1[Cl:46].O>O1CCCC1>[Cl:46][C:37]1[CH:38]=[C:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH:40]=[CH:41][C:36]=1[CH2:35][O:10][C:9]1[C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([Si:22]([CH:23]([CH3:24])[CH3:25])([CH:29]([CH3:30])[CH3:31])[CH:26]([CH3:28])[CH3:27])[CH:14]=2)=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Reactant: CCOc1c(O)cccc1C(=O)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1c(OCc2ccc(S(C)(=O)=O)cc2Cl)cccc1C(=O)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (2-ethoxy-3-hydroxy-phenyl)-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (665, 40 mg, 0.064 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (3.32 mg, 0.083 mmol) at room temperature under an atmosphere of nitrogen. The mixture was stirred at room temperature for 40 minutes, then 1-bromomethyl-2-chloro-4-methanesulfonyl-benzene (21.72 mg, 0.077 mmol) was added to the reaction mixture. It was stirred at room temperature overnight. The mixture was then poured into water and was extracted with ethyl acetate. The organic layer was collected and washed with brine, dried over magnesium sulfate. After removal of the solvent, a crude compound as light yellow oil was obtained (666, 84 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH2:13](OS(C1C=CC(C)=CC=1)(=O)=O)[C@@H:14]1[O:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([O:11][CH2:13][C@H:14]2[CH2:15][O:16]2)=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Br)cc(F)c1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Br)cc(F)c1OC[C@H]1CO1
Yield: 39.9 %

Procedure:
Preparation according to Preparation 1 using 1-(5-bromo-3-fluoro-2-hydroxyphenyl)ethanone (16.8 g, 72 mmol), (R)-glycidyltosylate (18.1 g, 79 mmol), K2CO3 (15.0 g, 108 mmol) and DMF (60 ml). The combined organic phases were washed with LiCl (5%), HCl (1 N). Flash column chromatography (isooctane/EtOAc) yielded the title compound (8.3 g). MS m/z (rel. intensity, 70 eV) 290 (M+, 9), 288 (M+, 9), 217 (bp), 81 (47), 57 (46).