Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12](O)=[O:13])=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[CH:22]1([CH2:25][C:26]([NH2:34])([CH3:33])[C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)[CH2:24][CH2:23]1>>[CH:22]1([CH2:25][C:26]([NH:34][C:12]([C:9]2[CH:8]=[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:18])([F:20])[F:19])[C:6]([C:2]3([F:1])[CH2:5][O:4][CH2:3]3)=[CH:11][N:10]=2)=[O:13])([C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)[CH3:33])[CH2:24][CH2:23]1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1(F)COC1)C(F)(F)F
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3(F)COC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxylic acid (Example 142b) and 2-Cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (example 66e) as starting materials and isolated (31 mg, 26%); MS (ESI, m/z): 473.5 (M+H+).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-]>C1COCC1>[NH:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[CH2:12][C@@H:9]1[CH2:10][CH2:11][C@H:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCC(Cc2nc3ccccc3[nH]2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CC[C@@H](Cc2nc3ccccc3[nH]2)CC1
Temperature: 65 °C

Procedure:
The cis/trans mixture of 4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic acid ethyl esters (D) (600 mg, 2.1 mmol) was dissolved in a minimal amount of THF (5 mL) and mixed with concentrated aqueous LiOH (2 mL). The reaction was stirred vigorously and heated at 65° C. for 3 h. After cooling and concentration, the crude material was dissolved in 1:1 water/CH3CN and subjected to preparative reverse-phase HPLC to yield (E) cis-4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic acid (200 mg, 37%): 1H NMR (400 MHz, CD3OD) δ7.77 (m, 2 H), 7.60 (m, 2 H), 3.11 (d, 2 H), 2.62 (m, 1 H), 2.10 (m, 3 H), 1.65 (m, 4 H), 1.43 (m, 2 H); mass spectrum m/z 259 [(M+H)+; calcd for C15H19N2O2: 259].
Reaction SMILES: Br[CH2:2][C:3]([C@@H:5]1[CH2:7][C@@H:6]1[C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=O.[Cl:18][C:19]1[N:24]=[N:23][C:22]([NH2:25])=[C:21]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:20]=1>CN(C=O)C.C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:22]2[N:23]([CH:2]=[C:3]([C@@H:5]3[CH2:7][C@@H:6]3[C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)[N:25]=2)[N:24]=1
Reactant: O=C(CBr)[C@@H]1C[C@@H]1c1ccc2ccccc2n1
Reactant: Nc1nnc(Cl)cc1N1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1cc(N2CCOCC2)c2nc([C@@H]3C[C@@H]3c3ccc4ccccc4n3)cn2n1
Reaction time: 48 h

Procedure:
Compound 79c (67 mg, 0.23 mmol) was dissolved in DMF (2 mL) and compound 19a (50 mg, 0.23 mmol) was added in one portion. The reaction was allowed to stir for 48 h under an argon atmosphere, at which time it was diluted with DCM (50 mL) and washed with saturated sodium bicarbonate (50 mL). The organic layer was concentrated under reduced pressure and then purified by preparative TLC (5% MeOH/DCM) to afford compound 79d. Mass spectrum (LCMS, ESI pos.) Calcd. For C22H20ClN5O 406.1 (M+H). found 406.2.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:23]=O)[N:14]3[CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[C:10]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1)[CH3:2].Cl.[O:36]1[CH2:41][CH2:40][CH:39]([CH:42]2[CH2:45][NH:44][CH2:43]2)[CH2:38][CH2:37]1.COC(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:23][N:44]4[CH2:45][CH:42]([CH:39]5[CH2:40][CH2:41][O:36][CH2:37][CH2:38]5)[CH2:43]4)[N:14]3[CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[C:10]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C3CCCCO3)c2n1
Reactant: C1CC(C2CNC2)CCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: COC(OC)OC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)n(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 126.4 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 2-(2-ethylbenzoimidazol-1-yl)-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-9H-purine-8-carbaldehyde (0.22 g, 0.48 mmol), 3-(tetrahydropyran-4-yl)azetidine hydrochloride (0.093 g, 0.53 mmol) in DCE (5 mL), trimethoxymethane (0.518 mL, 4.8 mmol) and acetic acid (0.03 mL, 0.48 mmol). The reaction mixture was stirred for 4 h at room temperature. Sodium triacetoxyborohydride (0.152 g, 0.72 mmol) was added and the reaction mixture was stirred for a further 72 h at room temperature. The suspension was partitioned between DCM and water; the organic layer was separated and washed with brine, dried with sodium sulphate and concentrated to give 2-(2-Ethylbenzoimidazol-1-yl)-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-8-[3-(tetrahydropyran-4-yl)azetidin-1-ylmethyl]-9H-purine as an orange oil (0.356 g, 99%). LCMS (Method A): RT=2.97 min, [M+H]+ 587.4
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]=1[CH3:22].[CH3:23][C:24]1([CH3:39])[C:28]2=[N:29][CH:30]=[C:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:32]=[C:27]2[NH:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:23][C:24]1([CH3:39])[C:28]2=[N:29][CH:30]=[C:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:32]=[C:27]2[N:26]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:3]=2[CH3:22])[CH2:25]1
Reactant: Cc1c(CCc2ccccc2)nc2cc(F)cc(F)c2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(CCc2ccccc2)nc2cc(F)cc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
4-Chloro-5,7-difluoro-3-methyl-2-phenethylquinoline (40.9 mg, 0.129 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (30 mg, 0.129 mmol), Pd2dba3 (11.8 mg, 0.013 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (12.3 mg, 0.026 mmol), sodium tert-butoxide (37.1 mg, 0.386 mmol), and toluene (1.29 mL) were stirred at 105° C. for 2 h. The reaction mixture was then concentrated and the resulting residue partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and water, then dried (MgSO4) and concentrated. Purification of the crude product by reverse-phase HPLC (0-70% acetonitrile in water) gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]-pyridin-1-yl)-5,7-difluoro-3-methyl-2-(2-phenylethyl)quinoline. 1H NMR (400 MHz, chloroform-d) δ ppm 7.54-7.64 (1H, m), 7.45-7.54 (1H, m), 7.27-7.32 (2H, m), 7.15-7.27 (3H, m), 6.83-6.97 (1H, m), 5.52-5.62 (1H, m), 3.65-3.85 (5H, m), 3.49-3.61 (1H, m), 3.12-3.35 (4H, m), 2.88-3.06 (4H, m), 2.18-2.32 (3H, m), 1.40-1.61 (6H, m). Mass Spectrum (ESI) m/e=515.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=2)[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH2:28]([CH:30]1[O:32][CH2:31]1)Cl.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:28][CH:30]3[O:32][CH2:31]3)=[C:22]([CH3:27])[CH:21]=2)[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(c2ccc(O)c(C)c2)c2cccc3ccccc23)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc(C(c2ccc(OCC3CO3)c(C)c2)c2cccc3ccccc23)cc1
Temperature: 120 °C

Procedure:
A mixture of (4-methoxyphenyl)-(3-methyl-4-hydroxyphenyl)-1-naphth-1-yl methane (1.0 gm, 0.002 mol), epichlorohydrin (25 ml) and anhydrous K2CO3 (4.0 gm) was refluxed at 120° C. for 8 hrs. K2CO3 was filtered off and filtrate was concentrated. The residue obtained was dissolved in ethyl acetate, washed with water, dried over sodium sulphate and concentrated to give an oil which was chromatographed over silica gel using hexane-chloroform as the eluent to give the title compound of general formula I, yield 75 gm (66%).
Reaction SMILES: [CH2:1]([N:4]([CH2:31][CH2:32][CH3:33])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:10]([CH3:30])[C:11]2[CH:17]=[C:16]([CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[CH:15]=[CH:14][C:12]=2[N:13]=1)[CH2:2][CH3:3]>CN.CO>[NH2:19][CH2:18][C:16]1[CH:15]=[CH:14][C:12]2[N:13]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:31][CH2:32][CH3:33])[N:10]([CH3:30])[C:11]=2[CH:17]=1
Reactant: CCCN(CCC)CCCCc1nc2ccc(CN3C(=O)c4ccccc4C3=O)cc2n1C
Agent: CN
Solvent: CO
Product: CCCN(CCC)CCCCc1nc2ccc(CN)cc2n1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 10.3 %

Procedure:
The compound (232 mg) obtained in Example 13-5 was dissolved in a 40% methylamine/methanol solution (3.0 ml) and the whole was stirred at room temperature for 20 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and then washed with a 1 mol/l sodium hydroxide aqueous solution, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining the subject compound (17.0 mg) as a pale-yellow oily substance.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH2:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]1[CH2:31][CH2:30][N:29]([C:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)=[O:18])[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCc1cc(-c2ccc(C(=O)O)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(C(=O)N3CCN(Cc4ccccc4)CC3)s2)c(C)[nH]c1=O
Yield: 60 %

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophene-2-carboxylic acid and 4-benzyl-piperazine to afford the title compound (60% yield). LC/MS: RT 2.07 min; m/e 422 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=[O:7].CCN(CC)CC.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH4+].[Cl-].[Li+].[OH-].Cl>C1COCC1.O.C(Cl)Cl>[C:17]1([S:23]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CCCCN
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)CCCCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a solution of 41 (3 g, 22.90 mmol), in a solvent mixture of CH2Cl2 (100 mL) and THF (50 mL) at room temperature were added Et3N (7.96 mL, 57.25 mmol), followed by benzenesulfonyl chloride (6.13 mL, 48.09 mmol). The mixture was stirred overnight at room temperature and then treated with a saturated aqueous solution of NH4Cl. The phases were separated and the aqueous layer was extracted several times with CH2Cl2. The combined organic extracts were dried over (MgSO4) and evaporated under reduced pressure giving a mixture of mono- and bis-alkylated products. The residue was dissolved in THF (50 mL) and water (50 mL), and LiOH was added. The resulting mixture was stirred for 4 h at room temperature, and then was treated with 1N HCl until pH 1. The phases were separated and the aqueous layer was extracted several times with AcOEt. The combined organic extracts were dried over (MgSO4) and then evaporated under reduced pressure, yielding compound 42 (2.95 g, 48%) as a white powder: 1H NMR (300 MHz, acetone-d6) δ 7.86 (d, J=7 Hz, 2H), 7.64-7.57 (m, 3H), 6.47 (br. s, 1H), 2.96-2.89 (m, 2H), 2.27-2.23 (m, 2H), 1.60-1.50 (m, 4H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH2:9][CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:8]1[C:6]2=[N:7][C:2]([C:33]3[CH:32]=[CH:31][N:30]=[C:29]([N:26]4[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]4)[CH:34]=3)=[CH:3][N:4]=[C:5]2[NH:11][CH2:10][CH2:9]1
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1Cl
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CN1CCN(c2cc(-c3cnc4c(n3)N(Cc3c(F)ccc(F)c3Cl)CCN4)ccn2)CC1

Procedure:
The entitled compound was prepared from 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine and 2-(4-Methylpiperazin-1-yl)pyridine-5-boronic acid pinacol ester using Suzuki coupling conditions as described in Scheme 1.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[C:30]([S:31][CH3:32])=[CH:29][CH:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][CH:25]=[N:26]2.OP(O)(O)=O>CN(C=O)C.C(Cl)Cl.C(OCC)(=O)C>[CH3:32][S:31][C:30]1[C:21]([NH:20][C:3](=[O:5])[CH:2]([Br:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2
Reactant: CCCCCCCCC(Br)C(=O)O
Reactant: CSc1ccc2ncccc2c1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=P(O)(O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCCCC(Br)C(=O)Nc1c(SC)ccc2ncccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a stirred solution of 2-bromodecanoic acid (184 mg, 0.73 mmol) in CH2C12 (3.0 ml) was injected by syringe oxalyl chloride (0.06 ml, 105 mol %) and then DMF (1 drop). After stirring at room temperature for 1 hour, N-methyl morpoline (0.24 ml, 300 mol %) was added. To this mixture was injected a solution of 5-amino-6-methylthioquinoline (139 mg, 100 mol %) in CH2Cl2 (2.0 ml). After stirring at room temperature for an additional 30 min. the reaction mixture was diluted with CH2Cl2 (30 ml), poured over 1.0M H3PO4 (100 ml), and extracted with CH2Cl2 (3×30 ml). The combined extracts were dried (Na2SO4), evaporated, and chromatographed using 1% triethylamine:ethyl acetate as eluants to give the title compound (192 mg, 62% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16]2[C@@H:15]3[CH2:17][C@@H:14]3[CH2:13][C:12]=2[C:11]([C:18](O)=[O:19])=[N:10]1.[NH2:21][C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][N:23]=1>>[OH:28][C:26]1[CH:25]=[CH:24][N:23]=[C:22]([NH:21][C:18]([C:11]2[C:12]3[CH2:13][C@H:14]4[CH2:17][C@H:15]4[C:16]=3[N:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[N:10]=2)=[O:19])[CH:27]=1
Reactant: Nc1cc(O)ccn1
Reactant: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Product: O=C(Nc1cc(O)ccn1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21

Procedure:
A solution of 4-methoxypyridin-2-amine (100 mg, 0.806 mmol) in DCM (1.6 mL) under N2 atmosphere was cooled in an dry ice/IPA bath, and tribromoborane (0.305 mL, 3.23 mmol) was added with a syringe. After removing the cold bath, the reaction was stirred overnight at room temperature. The reaction mixture was diluted with water (5 mL) and stirred for an additional 30 min. It was then washed with saturated NaHCO3 (20 mL) to pH=7 and extracted with DCM (3×20 mL). The combined organic layer was dried over MgSO4 and concentrated to provide 2-aminopyridin-4-ol. The title compound was prepared in a manner similar to that described in Method EE using Intermediate 1 (see Example 1.1) and 2-aminopyridin-4-ol. LCMS m/z=369.3 [M+H]+; 1H NMR: (400 MHz, CD3CN) δ ppm 0.50 (td, J=4.7 and 3.5 Hz, 1H), 1.22 (td, J=7.8 and 4.9 Hz, 1H), 2.21-2.26 (m, 1H), 2.31-2.38 (m, 1H), 2.93 (d, J=16.7 Hz, 1H), 3.05 (dd, J=16.6 and 6.3 Hz, 1H), 6.80 (dd, J=7.1 and 2.2 Hz, 1H), 6.95 (d, J=2.2 Hz, 1H), 7.15-7.21 (m, 1H), 7.22-7.29 (m, 1H), 7.52 (s, 1H), 7.70 (td, J=8.8 and 5.9 Hz, 1H), 7.82 (d, J=7.1 Hz, 1H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:26])[C@H:19]([C:23](O)=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:27][O:28][C@@H:29]([C@@H:38]([N:43]([CH3:51])[C:44](=[O:50])[C@H:45]([CH:47]([CH3:49])[CH3:48])[NH2:46])[C@@H:39]([CH3:42])[CH2:40][CH3:41])[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:26])[C@H:19]([C:23]([NH:46][C@H:45]([C:44]([N:43]([C@@H:38]([C@@H:39]([CH3:42])[CH2:40][CH3:41])[C@H:29]([O:28][CH3:27])[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[CH3:51])=[O:50])[CH:47]([CH3:49])[CH3:48])=[O:24])[CH:20]([CH3:21])[CH3:22])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
396 mg (1.1 mmol) of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N-methyl-L-valine were dissolved in 20 ml of DMF, and 365 mg (1 mmol) of tert-butyl (3R,4S,5S)-3-methoxy-5-methyl-4-[methyl(L-valyl)amino]heptanoate (Intermediate 2), 234 mg (1.2 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 187 mg (1.2 mmol) of 1-hydroxy-1H-benzotriazole hydrate were added in succession. The mixture was stirred at RT overnight. The reaction was then poured into a mixture of semisaturated aqueous ammonium chloride solution and ethyl acetate. The organic phase was separated off, washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. The residue was used directly, without further purification, for the next step.
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:4]=1.C[O-].[Na+]>CO>[F:9][C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][C:5]=1[NH:10][C:11](=[O:12])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1cc(OC(=O)OC(C)(C)C)ccc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(O)ccc1F
Temperature: 40 °C
Reaction time: 15 h
Yield: 99.3 %

Procedure:
A mixture of 3-[(tert-butoxycarbonyl)amino]-4-fluorophenyl tert-butyl carbonate (33.1 g, 101 mmol), sodium methoxide (6.55 g, 121 mmol) and methanol (500 mL) was stirred at 40° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and water were added to the residue. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was dried to give the title compound (22.8 g, quant.) as a yellow oil.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([NH2:17])=[S:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrBr.O.[OH-].[Na+]>C(Cl)(Cl)Cl>[NH2:17][C:15]1[S:16][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]=2[N:14]=1
Reactant: NC(=S)Nc1ccccc1Oc1ccccc1
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1nc2c(Oc3ccccc3)cccc2s1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
To a mixture of 1-(2-phenoxyphenyl)thiourea (53.4 g) in chloroform (100 ml) was added dropwise a solution of bromine (35.0 g) in chloroform (50 ml) with stirring under ice-cooling during 40 minutes. After refluxing for 1 hour and 40 minutes, the mixture was cooled to ambient temperature. To the resultant mixture was added water and then the mixture was alkalified with 5% sodium hydroxide aqueous solution. The chloroform layer was washed with water, dried over magnesium sulfate, concentrated under reduced pressure to give crystals, which were recrystallized twice from isopropyl alcohol to give 2-amino-4-phenoxybenzothiazole (25.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.O.O.O.C([O-])(=O)C.[Na+].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)([O-:22])=[O:21].Cl>C(#N)C.O>[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:1][C:2]2[CH:3]=[C:4]([S:8]([OH:11])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: Nc1cccc(S(=O)(=O)O)c1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccc(CNc2cccc(S(=O)(=O)O)c2)cc1
Yield: 57.3 %

Procedure:
After 52.0 g (0.30 mole) of 3-aminobenzenesulfonic acid in 225 ml of warm (65° C.) water and 83.0 (0.61 mole) of sodium acetate trihydrate in 75 ml of acetonitrile was combined and the temperature stabilized at approximately 68°-70° C., 43.2 g (0.20 mole) of 4-nitrobenzyl bromide in 85 ml of warmed acetonitrile was added dropwise over 70 minutes. The orange-red solution was then refluxed for 2 hrs, then acidified with 42 ml of conc. HCl over 40 minutes while simultaneously distilling off 110 ml of acetonitrile. The mixture was filtered hot (70° C.) which gave a light yellow powder. The powder was slurried in 275 ml of hot (75° C.) water for 20 minutes and then filtered. The slurrying process was repeated with water and then with methanol which gave a cream-colored powder. The cream-colored powder was dried in vacuo overnight at 50° C. to afford 35.33 g (57.3% yield) of purified 3-(((4-nitrophenyl)methyl)amino)benzenesulfonic acid as a cream-colored powder having a melting point greater than 275° C.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[CH:16]=[C:17]([CH3:19])[N:18]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>>[CH:20]([N:15]1[CH:16]=[C:17]([CH3:19])[N:18]=[C:14]1[C:12]1[N:13]=[C:6]2[C:5]3[CH:23]=[CH:24][C:2]([C:31]4[CH:30]=[N:29][N:28]([CH2:27][C:26]([CH3:42])([OH:43])[CH3:25])[CH:32]=4)=[CH:3][C:4]=3[O:10][CH2:9][CH2:8][N:7]2[CH:11]=1)([CH3:22])[CH3:21]
Reactant: Cc1cn(C(C)C)c(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cc1cn(C(C)C)c(-c2cn3c(n2)-c2ccc(-c4cnn(CC(C)(C)O)c4)cc2OCC3)n1
Yield: 22 %

Procedure:
Following the procedure in Example 182, 9-bromo-2-(1-isopropyl-4-methyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine was coupled with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol to give 195. Yield 22%. MS (ESI+): 447.1. 1H NMR (400 MHz, DMSO) δ 8.34 (d, J=8.4, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.63 (s, 1H), 7.36 (dd, J=8.4, 1.7, 1H), 7.25 (d, J=1.7, 1H), 7.00 (d, J=0.6, 1H), 5.68-5.57 (m, 1H), 4.72 (s, 1H), 4.48 (s, 4H), 4.03 (s, 2H), 2.10 (s, 3H), 2.07 (s, 1H), 1.42 (d, J=6.7, 6H), 1.09 (s, 6H).