Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([O:19][CH3:20])([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[NH2:5].[C:21]1([CH2:27][CH2:28][CH2:29][NH:30][C:31](N2C=CN=C2)=[O:32])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:21]1([CH2:27][CH2:28][CH2:29][NH:30][C:31]([NH:5][CH:4]([C:6]2[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=2)[C:3]([O:2][CH3:1])([O:19][CH3:20])[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[O:32])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(OC)(c1ccncc1)C(N)c1ccc(F)cc1
Reactant: O=C(NCCCc1ccccc1)n1ccnc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(OC)(c1ccncc1)C(NC(=O)NCCCc1ccccc1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of 2,2-dimethoxy-2-(4-pyridyl)-1-(4-fluorophenyl)ethanamine (51.12 g, 0.185 mol) and N-(3-phenylpropyl)-1H-imidazole-1-carboxamide (42.42 g, 0.185 mol) in toluene (300 mL) under N2, was stirred and heated to reflux temperature for 3 h. The solution was cooled to room temperature and the dark brown solution was diluted with ethyl acetate (200 mL). The mixture was washed with water (2×200 mL), brine (200 mL), and dried with Na2SO4. The solvents were removed in vacuo to yield a brown solid which was recrystallized from a solvent mixture of ethyl acetate/hexane (1:1) to yield an off-white solid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:10]1[CH:11]=[C:12]([CH:21]=[O:22])[N:13]2[C:17]3[CH2:18][CH2:19][CH2:20][C:16]=3[S:15][C:14]=12>C1COCC1>[C:4]1([CH2:3][CH2:2][CH:21]([C:12]2[N:13]3[C:14]([S:15][C:16]4[CH2:20][CH2:19][CH2:18][C:17]=43)=[N:10][CH:11]=2)[OH:22])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1cnc2sc3c(n12)CCC3
Reactant: BrCCc1ccccc1
Solvent: C1CCOC1
Product: OC(CCc1ccccc1)c1cnc2sc3c(n12)CCC3

Procedure:
The Grignard reagent generated during 18 hours, from (2-bromoethyl)benzene (2.2 g) an Mg (0.291 g) in THF (70 mL) was treated with solid 6,7-Dihydro-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-carboxaldehyde (FIG. E-6) (0.58 g) and reacted for 1.5 hours. The supernate solution was decanted into cold 5% ammonium chloride solution and precipitated 6,7-Dihydro-α-(2-phenylethyl)-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-methanol (FIG. E-7) (0.80 g) was filtered. Crystallization from acetonitrile solution gave pure 6,7-Dihydro-α-(2-phenylethyl)-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-methanol (FIG. E-7), m.p. 117-118°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH2:11][CH:10]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>CCOCC>[C:19]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH2:11][CH:10]=1)(=[O:21])[CH3:20]
Reactant: OCCCCCCCC1=CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)OCCCCCCCC1=CC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 2.5 mmol of 1-(7-hydroxyheptyl)-cyclopropene in 5 ml of ether was cooled in an ice bath. Triethylamine (0.44 ml) and 0.21 g (2.7 mmol) of acetyl chloride were added, and the reaction mixture was stirred 1 hour at 5° C. Additional acetyl chloride (0.11 g), ether and triethylamine were added, and the reaction was stirred at 5° C. until GC analysis indicated 95% conversion. The reaction was worked up by adding more ether and washing the organic phase with water, dilute HCl solution (diluted 1M aqueous HCl), potassium carbonate solution (2×), water and brine. The ether phase was dried over magnesium sulfate and stripped. Hexane was added and the reaction was stripped again to give 1-(7-acetoxyheptyl)-cyclopropene.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([N:11]1[C:16](=[O:17])[C:15]([Cl:18])=[C:14](Cl)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-:21].[Na+].Cl>C(OCC)(=O)C>[Cl:18][C:15]1[C:16](=[O:17])[N:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:2])=[O:20])[N:12]=[CH:13][C:14]=1[OH:21]
Reactant: COC(=O)C(CC1CCCC1)n1ncc(Cl)c(Cl)c1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(O)C(CC1CCCC1)n1ncc(O)c(Cl)c1=O
Reaction time: 0.17 h
Yield: 90 %

Procedure:
A solution of 3-cyclopentyl-2-(4,5-dichloro-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester (Intermediate 79 step 1, 18.0 g, 56.4 mmol) in a 4N aqueous sodium hydroxide solution (140 mL) was stirred at 60° C. overnight. The reaction solution was acidified with a 6N aqueous hydrochloric acid solution to pH=2˜3. Ethyl acetate was added to the solution and was stirred for 10 min. The aqueous phase was extracted with ethyl acetate, the combined organics were washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was washed with diethyl ether (50 mL) to afford 2-(5-chloro-4-hydroxy-6-oxo-6H-pyridazin-1-yl)-3-cyclopentyl-propionic acid as a white solid (14.5 g, 90%).
Reaction SMILES: [CH2:1]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[Li]CCCC.[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=[O:26]>C1COCC1>[Br:21][C:22]1[CH:23]=[C:24]([CH:25]([CH:9]2[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[CH2:2][CH2:1][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=3)[OH:26])[CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc2c(c1)CCc1ccccc1C2
Reactant: O=Cc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1cccc(Br)c1)C1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.5 %

Procedure:
Under nitrogen, cool a THF (300 mL) solution of dibenzosuberane (23.9 g, 123 mmol) to 0° C. and add n-BuLi (1.6M, 90 mL, 144 mmol). Remove the cooling bath and the reaction stir at ambient temperature for 1 h. Cool the orange solution to 5° C. and add a solution of 3-bromobenzaldehyde (22.8 g, 123 mmol) in THF (100 mL). After 30 min., quench the reaction with saturated NH4Cl (200 mL) and remove most of the THF under reduced pressure. Shake the residue with brine/EtOAc. Dry the organic layer (MgSO4) and concentrate to give 49.2 g colorless oil. HPLC shows 86% purity. The compound is sufficiently pure to carry on to the next reaction. Purify a small portion on silica gel using EtOAc/hexane to give a colorless oil that rapidly crystallized, mp 93.9° C., 1H NMR (CDCl3) δ3.00 (m,2H), 3.57 (m,2H), 3.94 (d,1H), 5.30 (d,1H), 6.38 (d,1H), 6.76-7.34 (m,12H); MS (EI) 360 (M−H2O).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Br:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.CN(C=O)C.[H-].[Na+]>O>[Br:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][C:2]1[CH:3]=[C:4]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: COc1cccc(Sc2cc(Br)cnc2C#N)c1
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(Sc2cc(Oc3cccc(Br)c3)cnc2C#N)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.7 %

Procedure:
A 10 mL round-bottomed flask was charged with 5-bromo-3-(3-methoxyphenylthio)picolinonitrile (214 mg, 0.666 mmol), 3-bromophenol (138 mg, 0.800 mmol), and DMF (6 mL). NaH (24.0 mg, 0.999 mmol) was added and reaction stirred at room temperature for 24 hours. The reaction was poured into water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was purified on silica gel (10% EtOAc in Hexanes) to afford the title compound (225 mg, 81.7% yield).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][C:10]=1[F:22])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:22][C:10]1[CH:11]=[C:12]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:13]=[CH:14][C:9]=1[CH2:8][NH2:7]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Oc2ccccc2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(Oc2ccccc2)cc1F
Yield: 33.2 %

Procedure:
Dissolve (2-fluoro-4-phenoxy-benzyl)-carbamic acid tert-butyl ester (2.44 g, 7.72 mmol) in DCM (200 mL). Add trifluoroacetic acid (50 mL) then stir at ambient temperature for 16 h. Evaporate the solvent, dissolve the residue in DCM and wash with 1N aqueous NaOH. Dry over Na2SO4 and concentrate in vacuo. Purify by SCX chromatography to obtain the title compound (557 mg, 33%). MS (ES+) m/z: 201 (M+H—NH3)+.
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1>CO.C(CN)O>[OH:11][CH2:10][CH2:7][NH:6][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][OH:20])[CH2:16][CH2:17]2)=[O:11])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)N2CCN(CCO)CC2)nc1
Solvent: NCCO
Solvent: CO
Product: O=C(NCCO)c1ccc(C(=O)N2CCN(CCO)CC2)nc1
Yield: 79 %

Procedure:
6-[1-(2-hydroxyethyl)piperazin-4-yl-carbonyl]nicotinic acid methyl ester (2 g) was dissolved in methanol (20 ml) and with the addition of ethanolamine (2 ml), the mixture was heated to reflux for 8 hours and concentrated under reduced pressure. The concentrated residue was dissolved in isopropanol (14 ml), and with the addition of isopropyl ether to precipitate. After 2-hours stirring, the filtered solid was recrystallized with ethyl acetate and hexane to give a desired compound of 1.74 g (yield: 79%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].CCCCCC.C([Li])CCC.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23]>C(OCC)C>[CH3:23][Si:22]([CH3:25])([CH3:24])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1ccc(C)c(Br)c1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1ccc(C)c([Si](C)(C)C)c1
Reaction time: 5 h

Procedure:
To a stirred solution of 1.0M of 2-bromo-p-xylene in diethyl ether at 0° C. was added n-butyllithium hexane solution solwly, and the mixture was stirrd for 5 hr. To the above reaction mixture was added 1.0M of chlorotrimethylsilane as dropwise and it was stirred for 24 hr. The solvent was removed under reduced pressure, and the residne was redistilled in vacuo to afford titled compound(TSTX) in colorloss state. The structure of product was identified by infrared and nuclear magnetic resonance spectrum, and the result is summarized in Table 1.
Reaction SMILES: C1(C)C=CC=C(C2OC=NC=2C(NC2C=NN(CC[O:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=O)=[O:24])C=2)=O)C=1.[OH:34][CH2:35][CH2:36][N:37]1[C:41]([CH3:42])=[C:40]([NH:43][C:44]([C:46]2[N:47]=[CH:48][O:49][C:50]=2[C:51]2[CH:52]=[C:53]([CH3:57])[CH:54]=[CH:55][CH:56]=2)=[O:45])[C:39]([CH3:58])=[N:38]1>>[CH3:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([O:34][CH2:35][CH2:36][N:37]2[C:41]([CH3:42])=[C:40]([NH:43][C:44]([C:46]3[N:47]=[CH:48][O:49][C:50]=3[C:51]3[CH:52]=[C:53]([CH3:57])[CH:54]=[CH:55][CH:56]=3)=[O:45])[C:39]([CH3:58])=[N:38]2)(=[O:24])=[O:22])=[CH:27][CH:28]=1
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2c(C)nn(CCO)c2C)c1
Reactant: Cc1ccc(S(=O)(=O)OCCn2cc(NC(=O)c3ncoc3-c3cccc(C)c3)cn2)cc1
Product: Cc1ccc(S(=O)(=O)OCCn2nc(C)c(NC(=O)c3ncoc3-c3cccc(C)c3)c2C)cc1

Procedure:
The title compound was synthesized according to above mentioned procedure for 2-(4-(5-(m-tolyl)oxazole-4-carboxamido)-1H-pyrazol-1-yl)ethyl-4-methylbenzenesulfonate, starting from N-(1-(2-hydroxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide. LC-MS conditions A: tR=0.93 min, [M+H]+=467.46.
Reaction SMILES: [F:1][CH:2]([F:15])[C:3]1[CH:4]=[C:5]([N+:12]([O-])=O)[C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=1>CCO.[Ni]>[NH2:12][C:5]1[C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=[C:3]([CH:2]([F:15])[F:1])[CH:4]=1
Reactant: O=C(O)c1ncc(C(F)F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(C(F)F)cnc1C(=O)O
Reaction time: 16 h

Procedure:
To a solution of 265 mg (1.22 mmol) 5-difluoromethyl-3-nitro-pyridine-2-carboxylic acid in EtOH was added 50 mg Raney-Nickel (Degussa B113W) and the reaction mixture was kept shaking under a hydrogen atmosphere for 16 h. The catalyst was filtered off (Celite) and washed with EtOH and the filtrate was evaporated to provide the title compound as off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](Cl)=[O:13])[CH:6]=[CH:5]2.[NH2:15][C:16]1[CH:17]=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>>[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[C:16]([NH:15][C:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[CH:8]=2)=[O:13])[CH:17]=1
Reactant: O=C(Cl)c1ccc2cc(Br)ccc2c1
Reactant: Nc1cnc2ccccc2c1
Product: O=C(Nc1cnc2ccccc2c1)c1ccc2cc(Br)ccc2c1

Procedure:
This material was prepared analogous to the procedure described for Example 1(b). 6-Bromo-naphthalene-2-carbonyl chloride, Example 1(a), reacted with 3-aminoquinoline (Aldrich) to give the title compound as a green amorphous solid. MS (ESI, pos. ion.) m/z: 377 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:40])[CH:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28](=[O:39])[NH:29][C:30]3[C:31]4[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=4[S:33][CH:34]=3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:33]1[CH:34]=[C:30]([NH:29][C:28]([O:27][C:24]2[CH:25]=[CH:26][C:21]([C:18]3[CH:17]=[CH:16][C:15]([S:12]([NH:11][CH:7]([CH:8]([CH3:9])[CH3:10])[C:6]([OH:40])=[O:5])(=[O:14])=[O:13])=[CH:20][CH:19]=3)=[CH:22][CH:23]=2)=[O:39])[C:31]2[CH:38]=[CH:37][CH:36]=[CH:35][C:32]1=2
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(OC(=O)Nc3csc4ccccc34)cc2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(OC(=O)Nc3csc4ccccc34)cc2)cc1)C(=O)O
Reaction time: 4 h
Yield: 66 %

Procedure:
2-[4′-(Benzo[b]thiophen-3-ylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester (180 mg, 0.31 mmol) was dissolved in methylene chloride under N2 atmosphere, added with TFA (2 mL) at 0° C. and stirred for 4 hrs. Solvent was evaporated and the product dried under high vacuum to give 2-[4′-(Benzo[b]thiophen-3-ylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid in 66% yield (108 mg).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C@@:10]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:15][C@H:14](O)[CH:13]3[CH:11]2[C@H:12]3[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COCCN(S(F)(F)[F:37])CCOC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]1([C@H:7]([NH:9][C@@:10]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:15][C@@H:14]([F:37])[CH:13]3[CH:11]2[C@H:12]3[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@H]1C2C1[C@](N[C@H](C)c1ccccc1)(C(=O)OCC)C[C@@H]2O
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)[C@H]1C2C1[C@](N[C@H](C)c1ccccc1)(C(=O)OCC)C[C@H]2F
Yield: 84 %

Procedure:
To a solution of ethyl 2-[((1R)-1-phenylethyl)amino](2S,4S,6R)-2-(ethoxycarbonyl)-4-hydroxybicyclo[3.1.0]hexane-6-carboxylate (59.0 g crude, 0.163 mol) in CH2Cl2 (690 mL) at −20° C. is added Deoxo-Fluor® (45.1 mL, 0.245 mol) over 15 minutes, maintaining the temperature between −15 and −20° C. The mixture is stirred for 20 minutes at this temperature and at 0° C. for 15 minutes before aqueous 15% Na2CO3 (650 ml) is slowly added while maintaining the temperature below 10° C. The layers are separated and the aqueous layer back extracted with CH2Cl2 (150 mL). The combined organic layers are dried (Na2SO4) and concentrated to a brown oil (73 g). The oil is purified on a pad of silica gel (400 g) eluting with EtOAc/heptane (1:6) to afford the title compound as a yellow oil (49.7 g, 84%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1([CH2:31][CH2:32][N:33]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[C:36]([CH3:44])([CH3:43])[O:35][C:34]2=[O:45])[CH2:30][CH2:29]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH2:21][NH:27][C:28]2([CH2:31][CH2:32][N:33]3[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[C:36]([CH3:43])([CH3:44])[O:35][C:34]3=[O:45])[CH2:30][CH2:29]2)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)N(CCC2(N)CC2)c2ccccc21
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Product: CC1(C)OC(=O)N(CCC2(NCC(O)c3cc(OCc4ccccc4)cc4c3OCC(=O)N4)CC2)c2ccccc21

Procedure:
Prepared from 900 mg (2.5 mmol) of 6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 700 mg (2.7 mmol) of 1-[2-(1-aminocyclopropyl)ethyl]-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one analogously to the method described for Example 16a. White solid. Yield: 630 mg (45%); mass spectroscopy: [M+H]+=558.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][C:18]([F:17])([F:29])[F:30])=[CH:21][CH:22]=2)=[O:28])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1c(Br)cnn1C
Yield: 63.6 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.032 g, 0.11 mmol) was treated with 4-(trifluoromethoxy)phenyl isocyanate (0.025 g, 18.4 μL, 0.12 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 19 (0.032 g, 0.07 mmol, 58%) as a white solid. LCMS m/z (%)=485 (M+H79Br, 92), 487 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.31 (s, 1H), 8.19 (s, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.51 (s, 1H), 7.45 (s, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.9 Hz, 1H), 3.83 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[CH:33]([C:37]2[CH:42]=[CH:41][C:40]([O:43]S(C4C=CC(C)=CC=4)(=O)=O)=[CH:39][CH:38]=2)[N:32]([C:54](=[O:59])[C:55]([F:58])([F:57])[F:56])[CH2:31][CH2:30]3)[CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1>[F:57][C:55]([F:56])([F:58])[C:54]([N:32]1[CH2:31][CH2:30][C:29]2[C:34](=[CH:35][CH:36]=[C:27]([O:26][CH2:25][CH2:24][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:28]=2)[CH:33]1[C:37]1[CH:38]=[CH:39][C:40]([OH:43])=[CH:41][CH:42]=1)=[O:59]
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C3c4ccc(OCCN5CCCC5)cc4CCN3C(=O)C(F)(F)F)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(N1CCc2cc(OCCN3CCCC3)ccc2C1c1ccc(O)cc1)C(F)(F)F
Yield: 183.5 %

Procedure:
A solution of 1M TBAF in THF (2.8 ml, 2.82 mmol) and toluene-4-sulfonic acid 4-[6-(2-pyrrolidin-1-yl-ethoxy)-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-1-yl]phenyl ester (0.415 g, 0.71 mmol) in anhydrous THF (50 ml) was refluxed under N2 for 18 hr, then concentrated in vacuo to a green oil. This was suspended in sat. NaHCO3 solution (25 ml), then extracted with EtOAc (3×40 ml). The combined extracts were dried over MgSO4 and concentrated in vacuo to give 0.566 g of green oil. Purification by flash chromatography, eluting with EtOAc:MeOH (8:2) gave 0.241 g (79% yield) of yellow oil.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:13]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH:31]([CH3:33])[CH3:32]>CN(C=O)C>[CH2:19]([O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][CH2:10][C:2]1[N:3]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CBr
Reactant: CC(C)COc1cccc(OCc2nc3ccccc3[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)COc1cccc(OCc2nc3ccccc3n2CC(C)C)c1
Temperature: 90 °C
Yield: 84 %

Procedure:
A 100 mL flask fitted with a stir-bar, condenser, and an Ar inlet was charged with benzimidazole 73 (1.73 g, 5.84 mmol) and K2CO3 (1.62 g, 11.7 mmol). DMF (25 mL) was added followed by 1-bromo-2-methylpropane (1.20 g, 0.95 mL, 8.73 mmol), and the mixture was heated in a 90° C. bath for 5 hr. Another 0.3 mL of 1-bromo-2-methylpropane was added and the mixture was heated overnight. The suspension was cooled, and the solids were filtered off and rinsed with EtOAc (100 mL). The filtrate was washed with saturated aqueous NH4Cl (2×60 mL), H2O (2×60 mL), and brine (50 mL), filtered through phase separation paper, and concentrated in vacuo to a yellow oil. The crude oil was chromatographed on silica gel with the product eluting with 10-12% EtOAc in hexanes. The product fractions were concentrated to give 1.73 g of Compound #17 as a colorless oil (84%). 1H NMR (300 MHz, CDCl3): δ 7.81 (m, 1H), 7.40 (m, 1H), 7.36-7.24 (m, 2H), 7.20 (t, 1H), 6.71-6.63 (m, 2H), 6.56 (dd, 1H), 5.37 (s, 2H), 4.12 (d, 2H), 3.72 (d, 2H), 2.36 (nonet, 1H), 2.08 (nonet, 1H), 1.03 (d, 6H), 0.98 (d, 6H) ppm. HPLC analysis (5:10:85 H2O:A1:MeOH) showed a purity of 99% with a retention time of 8.0 min.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][N:8]([C:11]([C@@H:13]([C@H:23]([CH2:36][OH:37])[O:24][CH2:25][P:26]([O:32][CH:33]([CH3:35])[CH3:34])([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[O:14]C(=O)C2C=CC=CC=2)=[O:12])[C:7](=[O:38])[N:6]=1)(=O)C.N>CO>[N:8]1([C:11]([C@@H:13]([C@H:23]([CH2:36][OH:37])[O:24][CH2:25][P:26]([O:32][CH:33]([CH3:35])[CH3:34])([O:28][CH:29]([CH3:30])[CH3:31])=[O:27])[OH:14])=[O:12])[CH:9]=[CH:10][C:5]([NH2:4])=[N:6][C:7]1=[O:38]
Reactant: CC(=O)Nc1ccn(C(=O)[C@H](OC(=O)c2ccccc2)[C@H](CO)OCP(=O)(OC(C)C)OC(C)C)c(=O)n1
Agent: N
Solvent: CO
Product: CC(C)OP(=O)(CO[C@@H](CO)[C@@H](O)C(=O)n1ccc(N)nc1=O)OC(C)C
Yield: 85.7 %

Procedure:
A solution of 14 (450 mg, 0.84 mmol) in MeOH saturated with ammonia (100 mL) was stirred at room temperature overnight. The mixture was concentrated, and the residue was purified by column chromatography (CH2Cl2:MeOH=20:1) to give compound 18 (281 mg, 0.72 mmol) as a white powder in 86% yield which was characterized as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[F:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([F:48])[C:34]=1[OH:49]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:22][CH2:23]2)=[CH:3][C:2]([C:37]2[CH:38]=[C:33]([F:32])[C:34]([OH:49])=[C:35]([F:48])[CH:36]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(F)c(O)c(F)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(F)c4)cc23)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexylcarbamate (49 mg, 0.100 mmol) was reacted with 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (50 mg, 0.196 mmol) to afford the desired product (26.2 mg, 49%) as an off-white solid: ESI MS m/z 538 [C30H33F2N3O4+H]+.