Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2.[H-].[Na+].C1(C)C=CC(S(O[CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])(=O)=O)=CC=1>CN(C)C=O>[C:34]([O:33][C:31]([NH:30][CH2:29][CH2:28][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[C:5]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: Cc1ccc(S(=O)(=O)OCCNC(=O)OC(C)(C)C)cc1
Reactant: CCOC(=O)c1cc2c(C)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C)cccc2n1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
A mixture of ethyl 4-methyl-1H-indole-2-carboxylate (42.9 g, 211 mmol), 60% sodium hydride (9.29 g, 232 mmol) and N,N-dimethylformamide (300 ml) was stirred at room temperature for 1 hour. A solution of 2-tert-butoxycarbonylaminoethyl 4-toluenesulfonate (86.6 g, 275 mmol) in N,N-dimethylformamide (200 ml) was added dropwise and the resulting mixture was stirred at room temperature for 9 hours. The reaction mixture was poured into ice water and extracted twice with ethyl acetate, and the extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent:ethyl acetate/n-hexobtain 2 3/97) to obtain 24.4 g of ethyl 1-(2-tert-butoxycarbonylaminoethyl)-4-methyl-1H-indole-2-carboxylate.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[NH:6][N:5]=2)[CH2:3][CH2:2]1.C(O)C.[Cl:13][C:14]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:15]=1[CH2:16][N:17]=[C:18]=[O:19].O>C(=O)([O-])O.[Na+]>[CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:18]([NH:17][CH2:16][C:15]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:14]=3[Cl:13])=[O:19])[NH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Reactant: Nc1cc(C2CC2)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1Cl)Nc1cc(C2CC2)n[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.7 %

Procedure:
1 g (8.13 mmol) of 3-cyclopropyl-5-amino-1H-pyrazole are dissolved in 10 ml of ethanol containing 1.37 g (16.26 mmol) of sodium hydrogen carbonate and 3.27 g (16.26 mmol) of 2,4-dichlorobenzyl isocyanate. After 3 hours at room temperature 50 ml of water were added and the solid was filtered. The filtrate was evaporated to dryness and then redissolved with 10 ml of methanol. 8.2 ml of 1M sodium hydrate were added and the mixture stirred 4 h at room temperature. Methanol is evaporated and the residue is dissolved with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to afford 1.5 g (60% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([O:12]C(C)C)=[O:11].S(=O)(=O)(O)O>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[OH:9]
Reactant: CC(C)O[N+](=O)[O-]
Reactant: Oc1ccc(F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(F)cc(F)c1O
Yield: 83.4 %

Procedure:
To a stirred solution of 2,4-difluorophenol (0.65 g, 5 mmol) in dichloromethane (7 mL) at room temperature was added tetrabutylammoniumhydrogen sulphate (0.085 g, 5 mol %) followed by isopropyl nitrate (1.31 g, 12.5 mmol). Sulphuric acid (96%, 0.65 mL) was then added dropwise to the mixture causing gentle reflux of the solvent. The reaction mixture was then stirred for fifteen minutes and then poured onto water (50 mL). The phases were separated and the aqueous phase was extracted by dichloromethane (10 mL). The combined organic layers were washed by brine, dried over anhydrous sodium sulphate and filtered through a short pad of silica gel. Evaporation of the solvent (40° C., water aspirator pressure) afforded a yellow solid, identified by NMR as the title compound (0.73 g, 83%). (ortho-selectivity 100%, no nitro-isomers detected).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH2:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[F:27][CH:28]([F:32])[C:29](O)=[O:30].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:26][C:29](=[O:30])[CH:28]([F:32])[F:27])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: O=C(O)C(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(NC(=O)C(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 120 h
Yield: 32 %

Procedure:
A mixture of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (150 mg, <0.366 mmol), difluoroacetic acid (0.0346 mL, 0.55 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (158 mg, 0.824 mmol), 1-hydroxybenzotriazole monohydrate (126 mg, 0.823 mmol) and triethylamine (0.15 mL, 1.07 mmol) in N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 5 days. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-75% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/diisopropyl ether to give the title compound (56.3 mg, 0.115 mmol, 32%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:13]([CH3:21])[CH2:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:55][C@H:56]1[CH2:60][NH:59][C@H:58]([C:61]([O:63][CH3:64])=[O:62])[CH2:57]1>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]([C@H:13]([CH3:21])[CH2:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([N:59]1[CH2:60][C@H:56]([OH:55])[CH2:57][C@H:58]1[C:61]([O:63][CH3:64])=[O:62])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoic acid (2 g, 6.6 mmole), synthesized using Scheme 1, in dichloromethane (20 mL) was added DIPEA (11.5 mL, 33.0 mmole), HATU (2.7 g, 7.2 mmole) followed by (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate (1.3 g, 7.2 mmole) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mass was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude (2S,4R)-methyl 1-((3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate. The crude product was taken to the next step without further purification (2.2 g, 80%). MS: MS m/z 427.2 (M++1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[N:26][C:25]=1Cl.C(N(CC)CC)C>C(#N)C>[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[N:26][C:25]=1[NH:1][CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cnc1NCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Yield: 36.7 %

Procedure:
To a solution of 2-amino-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.27 g, 0.97 mmol) in acetonitrile (5 mL) was added 2,5-dichloro-nicotinic acid methyl ester (0.20 g, 0.97 mmol) and triethylamine (0.135 mL, 0.97 mmol). The reaction was refluxed for 2 hours. The reaction was concentrated and purified by chromatography on silica gel to give the title compound (0.16 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][N:30]4[C:34]5=[N:35][C:36]([CH3:40])=[CH:37][C:38]([CH3:39])=[C:33]5[N:32]=[C:31]4[CH2:41][CH3:42])=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C.Cl>C(Cl)(Cl)Cl>[CH2:41]([C:31]1[N:30]([CH2:29][C:26]2[CH:25]=[CH:24][C:23]([NH:22][C@H:19]3[CH2:18][CH2:17][C@H:16]([C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[O:15])[CH2:21][CH2:20]3)=[CH:28][CH:27]=2)[C:34]2=[N:35][C:36]([CH3:40])=[CH:37][C:38]([CH3:39])=[C:33]2[N:32]=1)[CH3:42]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(N[C@H]2CC[C@H](C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)CC2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(N[C@H]2CC[C@H](C(=O)N3CCNCC3)CC2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Compound 113 (261 mg, 0.454 mmol) was dissolved in chloroform (1.7 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (4.5 mL) was added to the solution, followed by stirring at 0° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added with a 2 mol/L aqueous sodium hydroxide solution, then extracted with ethyl acetate three times. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The residue was recrystallized from ethanol-diisopropyl ether (1:20) to obtain Compound 114 (201 mg, 0.423 mmol, 93.3%).
Reaction SMILES: [C:1]([C:8]1NC=CN=1)([C:3]1NC=CN=1)=O.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=1.C(O)(C)C>ClCCl>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([O:20][CH:1]([CH3:8])[CH3:3])=[O:19])=[CH:16][N:15]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)OC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 114 %

Procedure:
Carbonyl diimidazole (18.6 g, 0.115 mol) was added to a suspension of 6-chloronicotinic acid (16.6 g, 0.105 mol) in dichloromethane (250 mL). After all of the solid had dissolved the reaction solution was stirred at ambient temperature for 1 hour and then isopropyl alcohol (100 mL) was added. The dichloromethane was removed under vacuum. A catalytic amount of sodium isopropoxide was added to the solution and the solution was heated at reflux for 1 hour. The solution was then concentrated under vacuum. The resulting residue was slurried with water and then extracted with diethyl ether. The extract was dried over magnesium sulfate and then concentrated under vacuum to provide 23.9 g of isopropyl 6-chloronicotinate.
Reaction SMILES: [C:1]1([NH:7][C:8]([C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B>C1COCC1>[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:10]([CH2:8][NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11]1)([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)Nc2ccccc2)C1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](CNc2ccccc2)C1
Yield: 91.5 %

Procedure:
(R)-1-Boc-piperidine-3-carboxylic acid phenyl amide 26 (5.26 g, 17.28 mmol) in 20 mL of dry THF was added slowly to 34.5 mL of 1.0 M borane in THF while stirring in an ice bath. The mixture was refluxed for 2 hours, then cooled in an ice bath, and quenched with 20 mL of aqueous HCl (10%), then treated with NaOH (10%) to pH˜10. The mixture was extracted with ethyl acetate (3×100 mL). The extracts were combined and washed with brine (2×50 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was passed through a short column (silica gel, ethyl acetate) to afford (R)-N-(1-Boc-piperidin-3-ylmethyl)-aniline 28 as a colorless oil (4.59 g, 91%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:75][CH:76]1[CH2:81][CH2:80][O:79][CH2:78][CH2:77]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:75][CH:76]5[CH2:81][CH2:80][O:79][CH2:78][CH2:77]5)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Reactant: NC1CCOCC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCOCC4)cc3F)ncc21
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
To a mixture of 0.070 g (0.161 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-benzoic acid (I-182) and 4 mL of dimethylformamide was added 0.0346 g (0.256 mmole) of 1-hydroxybenzotriazole, 0.0950 g (0.250 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1253 g (0.936 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0248 g (0.246 mmole) of 4-aminotetrahydropyran was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0504 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-N-(tetrahydro-pyran-4-yl)-benzamide (I-225).
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8]([C:10]1[C:11]([NH:19][C:20]([C:22]2[N:23]([C:31]3[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][N:32]=3)[N:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=2)=[O:21])=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][N:16]=[CH:15]2)=[O:9])([CH3:6])[CH2:3][S:4][CH3:5].ClC1C=CC=C(C(OO)=[O:46])C=1>C(Cl)Cl.C(OCC)(=O)C>[CH3:5][S:4]([CH2:3][C:2]([NH:7][C:8]([C:10]1[C:11]([NH:19][C:20]([C:22]2[N:23]([C:31]3[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][N:32]=3)[N:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=2)=[O:21])=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][N:16]=[CH:15]2)=[O:9])([CH3:1])[CH3:6])=[O:46]
Reactant: CSCC(C)(C)NC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)ccc2cn[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)CC(C)(C)NC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)ccc2cn[nH]c12
Temperature: 25 °C
Yield: 65.4 %

Procedure:
To a mixture of 144 mg (0.26 mmol) of 6-{[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-1H-indazole-7-carboxylic acid (1,1-dimethyl-2-methylsulfanylethyl)-amide, prepared in example 7 in 2.88 mL of methylene chloride at 0° C. is added dropwise 64 mg (0.26 mmol) of m-chloroperbenzoic acid dissolved in 0.5 mL of methylene chloride. The mixture is stirred and let warm-up to ambient temperature within 1 hour. The reaction is quenched by the addition of an aqueous saturated sodium carbonate solution. The product is extracted with ethyl acetate (3 times) and the combined organic extracts are dried on Na2SO4, filtrated and evaporated. After a flash chromatography with hexanes and ethyl acetate as eluents, 111 mg (0.17 mmol, 75%) of a white solid are obtained; LC/MS: 568/570 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[C:5]([OH:10])=[N:6][CH:7]=[CH:8][CH:9]=1.C([O-])(=O)C.[Na+].[Br:17]Br>C(O)(=O)C>[Br:17][C:8]1[CH:9]=[C:4]([O:3][CH:2]([F:1])[F:11])[C:5]([OH:10])=[N:6][CH:7]=1
Reactant: BrBr
Reactant: Oc1ncccc1OC(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1ncc(Br)cc1OC(F)F
Temperature: 12.5 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
As shown in step 3-iv of Scheme 3, 3-(difluoromethoxy)pyridin-2-ol (986 mg; 6.12 mmol) was dissolved in 25 mL of glacial acetic acid and sodium acetate (79 mg; 9.6 mmol) was added. The mixture was cooled in an ice bath and bromine (780 μL; 1.63 g; 10.22 mmol) in 10 mL of glacial acetic acid was added over 10 minutes. The reaction was stirred for 30 minutes at 10-15° C. The volatiles were removed under reduced pressure and the residue was partitioned between brine/saturated sodium carbonate solution and ethyl acetate. After the evolution of gas ceased, the organic and aqueous layers were separated and the aqueous solution extracted three additional times with EtOAc. The combined organics were dried over Na2SO4, filtered, and the volatiles removed under reduced pressure. The residue was purified twice by silica gel chromatography (first a DCM to 10% MeOH/DCM gradient then 1:1 EtOAc/hexanes) to provide 5-bromo-3-(difluoromethoxy)pyridin-2-ol as a light yellow powder (Compound 1009, 810 mg, 55% yield): ESMS (M+H) 241.9/243.9; 1H NMR (CDCl3) δ 13.2 (br m, 1H), 7.44 (d, 1H, J=2.1 Hz), 7.18 (d, 1H, J=2.1 Hz), 6.92 (t, 1H, J=75 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:4][C:3]=1[CH3:18].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[Li+].[Cl-].[CH2:35]([C@@H:42]1[CH2:46][O:45][C:44](=[O:47])[NH:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([N:43]2[C@H:42]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:46][O:45][C:44]2=[O:47])=[O:17])=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1cc(CCCCCCCC(=O)O)ccc1F
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(CCCCCCCC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)ccc1F
Temperature: -10 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a cooled (−10° C.) solution of 8-(4-fluoro-3-methylphenyl)octanoic acid (0.452 g, 1.791 mmol) in 15 mL of THF, were added stepwise triethylamine (0.67 mL, 4.836 mmol) and pivaloyl chloride (0.24 mL, 1.971 mmol). The reaction mixture was stirred at −10° C. for 1 h and then LiCl (0.084 g, 1.971 mmol) and (R)-4-benzyloxazolidin-2-one (0.349 g, 1.971 mmol) were added stepwise. After warming slowly to room temperature and stirring overnight, the reaction mixture was diluted with ethyl acetate (80 mL) and washed with saturated NaHCO3 solution and brine. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-100% dichloromethane/hexanes to give the title compound as colorless oil (0.666 g, 90% yield). GC-MS: tR=9.6 min; m/z 411 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:16])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH3:15])[CH:9]=1)[CH3:6])[CH3:2].[CH2:18]([C:22]1[C:27]([CH2:28][C:29](O)=[O:30])=[CH:26][N:25]=[C:24]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[N:23]=1)[CH2:19][CH2:20][CH3:21].C(OC(=O)CC(=O)CCCC)C>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]([C:29](=[O:30])[CH2:28][C:27]2[C:22]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:23][C:24]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([F:40])([F:41])[F:39])=[CH:36][CH:37]=3)=[N:25][CH:26]=2)[CH3:15])[CH:9]=1)([CH3:16])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(NC)c1
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CC(=O)O
Agent: CCCCC(=O)CC(=O)OCC
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CC(=O)N(C)c1cccc(OC(C)(C)C(=O)OCC)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-methyl-2-(3-methylamino-phenoxy)-propionic acid ethyl ester (example 26 A]) was reacted with [4-butyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetic acid (prepared starting from 3-oxo-heptanoic acid ethyl ester in analogy to the sequences described in examples 27C] to 27F] and examples 26D] and 26E]) to give 2-[3-({2-[4-butyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetyl}-methyl-amino)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow amorphous solid.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:29]=[CH:28][C:10]2[C:11]3[N:12]([CH:16]=[C:17]([C:19]4[N:23]([CH:24]([CH3:26])[CH3:25])[N:22]=[C:21]([CH3:27])[N:20]=4)[N:18]=3)[CH2:13][CH2:14][O:15][C:9]=2[CH:8]=1)=O.FC(F)(F)C(O)=O.[CH2:38]([N:45]1[CH2:50][CH2:49][CH2:48][CH:47]([NH:51][NH2:52])[CH2:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)C(C)C)(C)C.C(O)C>>[CH2:38]([N:45]1[CH2:50][CH2:49][CH2:48][CH:47]([N:51]2[C:5]([C:7]3[CH:29]=[CH:28][C:10]4[C:11]5[N:12]([CH:16]=[C:17]([C:19]6[N:23]([CH:24]([CH3:25])[CH3:26])[N:22]=[C:21]([CH3:27])[N:20]=6)[N:18]=5)[CH2:13][CH2:14][O:15][C:9]=4[CH:8]=3)=[CH:4][CH:3]=[N:52]2)[CH2:46]1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: NNC1CCCN(Cc2ccccc2)C1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C(=O)/C=C/N(C)C)cc2OCC3)n(C(C)C)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4ccnn4C4CCCN(Cc5ccccc5)C4)cc2OCC3)n(C(C)C)n1
Reaction time: 8 h

Procedure:
(E)-3-(dimethylamino)-1-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)prop-2-en-1-one (0.366 g, 0.000901 mol), 1-benzyl-3-hydrazinylpiperidine trifluoroacetic acid salt (0.376 g, 0.00135 mol), and N,N-Diisopropylethylamine (0.392 mL, 0.00225 mol) was mixed in Ethanol (9 mL, 0.2 mol). The reaction mixture was heated to reflux and was stirred overnight. LCMS showed complete conversion to desired product. The reaction mixture was cooled to room temperature and concentrated to dryness and purified by rHPLC to give 9-(1-(1-benzylpiperidin-3-yl)-1H-pyrazol-5-yl)-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[CH:11]=[N:12][C:13]=2[O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:26](O)=[O:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:19][C:26]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][N:20]=3)=[O:27])[CH:11]=[N:12][C:13]=2[O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)c1cnccn1
Product: O=C(Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1)c1cnccn1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-cyclobutoxy-pyridin-3-ylamine (example 78 d) and 2-pyrazinecarboxylic acid (CAN 98-97-5) as starting materials; MS (EI) 381.2(M+H)+.