Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][CH3:11])[C:3]([C:5]1[O:6][CH:7]=[CH:8][N:9]=1)=[O:4].Cl.[F:13][CH:14]([F:39])[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][CH2:24][C@H:25]([C@H:29]([OH:38])[C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:31])[C:26](O)=[O:27]>>[O:6]1[CH:7]=[CH:8][N:9]=[C:5]1[C:3]([C@@H:2]([NH:1][C:26](=[O:27])[C@@H:25]([C@H:29]([OH:38])[C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:31])[CH2:24][CH2:23][CH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH:14]([F:13])[F:39])[CH2:10][CH3:11])=[O:4]
Reactant: CC[C@H](N)C(=O)c1ncco1
Reactant: O=C(O)[C@H](CCCc1ccccc1OC(F)F)[C@H](O)C(=O)N1CCOCC1
Agent: Cl
Product: CC[C@H](NC(=O)[C@H](CCCc1ccccc1OC(F)F)[C@H](O)C(=O)N1CCOCC1)C(=O)c1ncco1

Procedure:
It is similarly prepared according to the general procedure for Example 10 using (S)-2-Amino-1-oxazol-2-yl-butan-1-one; hydrochloride as the amino component and (R)-5-(2-Difluoromethoxy-phenyl)-2-((S)-1-hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid as the acidic component but without further oxidation step.
Reaction SMILES: N(OCCC(C)C)=[O:2].[CH3:9][N:10]([CH3:27])[S:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](N)=[O:19])=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=1)(=[O:13])=[O:12].O>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:9][N:10]([CH3:27])[S:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:2])=[O:19])=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=1)(=[O:13])=[O:12]
Reactant: CC(C)CCON=O
Reactant: CN(C)S(=O)(=O)c1ccc(C(N)=O)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(C(=O)O)c(C(F)(F)F)c1

Procedure:
Isoamyl nitrite (150 ml) was added to a stirred mixture of 4-(N,N-dimethylaminosulphonyl)-2-trifluoromethylbenzamide (15.1 g) in acetic acid and concentrated sulphuric acid while maintaining the temperature at 70°-80° C. It was cooled, poured into water and extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered to give 4-(N,N-dimethylaminosulphonyl)-2-trifluoromethylbenzoic acid (11.2 g) as a white solid, m.p. 188.9°-189.4° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=2)[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].OC(C(F)(F)F)=O.[NH2:38][CH2:39][C:40]([CH3:45])([CH3:44])[C:41]([OH:43])=[O:42].C[O-].[Na+]>CCO>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=3)=[N:6][C:5]([C:3]([NH:38][CH2:39][C:40]([CH3:45])([CH3:44])[C:41]([OH:43])=[O:42])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(CN)C(=O)O
Reactant: COC(=O)c1nc(-c2cncc(F)c2)c2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1nc(-c2cncc(F)c2)c2c(=O)n(Cc3ccccc3)ccc2c1O)C(=O)O
Temperature: 140 °C
Yield: 34 %

Procedure:
A mixture of 7-benzyl-1-(5-fluoro-pyridin-3-yl)-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (17 mg, 0.042 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (39 mg, 0.17 mmol), and NaOMe (18 mg, 0.34 mmol) in EtOH (2 mL) was heated at 140° C. for 6 h in a microwave reactor. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-40% EtOAc/CH2Cl2+1% AcOH). The product was then dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2, and the resulting precipitate was isolated by filtration to give 7 mg of the title compound. MS: (+) m/z 491.37 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][CH2:4][Mg]Cl.[F:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[C:18]1[C:19]([CH:34]=[O:35])=[CH:20][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:22][CH:23]=1.[Cl-].[NH4+]>C1COCC1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:20][C:19]=1[CH:34]([OH:35])[CH2:4][CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1]
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C=O)c2)cc1
Reactant: CC(C)(C)CC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(O)CCC(C)(C)C)c2)cc1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
A solution of (3,3-dimethylbutyl)magnesium chloride in THF (0.50 M, 13.1 mL) was added to a solution of 2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)-[1,1′-biphenyl]-2-carbaldehyde (800 mg) in THF (15 mL) at 0° C., and the mixture was stirred at 0° C. for 50 min. To the reaction mixture was added saturated aqueous ammonium chloride solution at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (788 mg) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][C:13](=O)[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].Cl.[NH2:22][OH:23].N1C=CC=CC=1>C(O)C>[CH2:1]([N:4]([CH2:12][C:13](=[N:22][OH:23])[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3]
Reactant: NO
Reactant: C=CCN(CC(=O)c1cnccn1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: C=CCN(CC(=NO)c1cnccn1)C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
tert-Butyl N-allyl-N-(2-oxo-2-pyrazin-2-yl-ethyl)carbamate (6.53 g, 23.55 mmol) is dissolved in ethanol (22 mL) with stirring under nitrogen. Hydroxylamine hydrochloride (3.80 g, 54.16 mmol) and pyridine (2.67 mL, 32.97 mmol) are added and the resulting solution is heated at 80° C. under nitrogen for 80 minutes. The reaction is then cooled to room temperature and is concentrated to a small volume under reduced pressure. Dichloromethane (200 ml) and 1 M aqueous sodium hydroxide (60 ml) are added and the phases are separated. The aqueous phase is re-extracted with dichloromethane (2×200 mL). The combined organic extracts are dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The crude product is purified by silica gel chromatography using a 0-5% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound as a mixture of E/Z isomers (6.61 g, 96%). ES/MS (m/e): 293 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:17])=[N:6][C:5]=2[N:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26](Cl)[CH3:27])=[CH:22][N:21]=1>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([S:17][C@H:26]([C:23]3[CH:22]=[N:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[CH3:27])=[N:6][C:5]=2[N:18]=1
Reactant: C[C@@H](Cl)c1ccc(Cl)nc1
Reactant: CCC[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Product: CCC[C@H](CO)Nc1nc(S[C@@H](C)c2ccc(Cl)nc2)nc2nc(N)sc12
Yield: 22.1 %

Procedure:
The title compound was prepared using General Method A starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]pentan-1-ol (70 mg, 0.245 mmol) and 2-chloro-5-[(1R)-1-chloroethyl]pyridine (Example 6b, 52 mg, 0.29 mmol). Purification by preparative HPLC yielded 23 mg (22% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.N1[CH2:41][CH2:40][CH2:39][CH2:38]C1.C1(C=O)CC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:38][CH:39]3[CH2:41][CH2:40]3)[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12
Reactant: C1CCNCC1
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3)cc2)c2c(N)ncnc21
Agent: O=CC1CC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 28.9 %

Procedure:
Into a 10-mL round-bottom flask, was placed 3-[(2R)-2-([4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile (150 mg, 0.32 mmol, 1.00 equiv), piperidine (27 mg, 0.32 mmol, 1.00 equiv), cyclopropanecarbaldehyde (44.5 mg, 0.63 mmol, 2.00 equiv), methanol (5 mL). The resulting solution was stirred for 12 h at 25° C. and then concentrated under vacuum. The residue was loaded on a silica gel column and eluted with dichloromethane/methanol (50/1) to give 48.5 mg (29%) of the title compound as a off-white solid. LC-MS: (ES, m/z): MS (ESI, pos. ion) m/z: 524 (M+1). 1H-NMR: (CDCl3, ppm): 1HNMR (300 MHz, CD3OD, ppm), 8.253 (1H, s), 7.686˜7.749 (2H, t), 7.363˜7.440 (1H, t), 7.185˜7.232 (2H, t), 6.833˜6.941 (3H, m), 6.450˜6.600 (1H, d), 4.301˜4.555 (3H, m), 3.604˜3.638 (2H, m), 1.868˜2.005 (5H, m), 1.200˜1.294 (3H, m), 0.798˜0.810 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:4]([Cl:12])[CH:3]=1.[H-].[Na+].[CH3:15]I.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:11][CH3:15])([CH3:10])[CH3:9])=[C:4]([Cl:12])[CH:3]=1
Reactant: CI
Reactant: CC(C)(O)c1ccc(Br)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)(C)c1ccc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 370 mg (1.48 mmol) of 2-(4-bromo-2-chloro-phenyl)-propan-2-ol in 2 ml DMF was added to a suspension of sodium hydride (65 mg, ˜60% dispersion in oil) in 2 ml DMF at 0° C. The mixture was stirred at 0° C. for 30 min and then 111 μl (1.78 mmol) of methyl iodide were added. The reaction mixture was then warmed to rt and stirring was continued overnight. Then water was added and the mixture was extracted with ether. The organic phase was washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo to give a residue which was purified by flash column chromatography (1:9 ether/pentane). The title compound was obtained as a colorless liquid (310 mg, 79%). 1H NMR (CDCl3, 300 MHz): δ 1.64 (s, 6H), 3.13 (s, 3H), 7.35 (m, 2H), 7.54 (d, J=1.7 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]=[C:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].O>CC(O)=O.[Pd].[H][H]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1=CNCCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1CNCCN1C(=O)OC(C)(C)C
Yield: 97.9 %

Procedure:
Ethyl 1-tert-butoxycarbonyl-1,4,5,6-tetrahydropyrazinecarboxylate (60 g) was dissolved in AcOH (400 ml), and the solution was subjected to catalytic reduction using 10% palladium on carbon (12 g)-H2O (30 ml), in hydrogen at 3 atm for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in AcOEt (1000 ml), and the organic layer was washed with saturated aqueous NaHCO3 solution by stirring carefully to avoid foaming. The organic layer was further washed with saturated brine, and dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure to give 59.2 g of ethyl 1-tert-butoxycarbonyl-2-piperazinecarboxylate as an oil (yield 97.9%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(F)cc2)c(CCCCO)o1
Reactant: Cc1ccccc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccccc1OCCCCc1oc(-n2ccnc2C)nc1-c1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-fluorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanol (315 mg), 2-methylphenol (216 mg), tributylphosphine (405 mg) and tetrahydrofuran (5ml) was added 1,1′-(azodicarbonyl)dipiperidine (505mg) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(4-fluorophenyl)-2-(2-methyl-1-imidazolyl)-5-[4-(2-methylphenoxy)butyl]oxazole was obtained as an oil (367 mg, 91%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]2[CH:13]=[N:14][C:15]([Cl:17])=[N:16][C:5]1=2)[CH:2]=[CH2:3].I[CH3:19].[H-].[Na+]>CN(C)C=O>[CH2:1]([N:4]1[CH2:10][CH:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:19])[C:6]2[CH:13]=[N:14][C:15]([Cl:17])=[N:16][C:5]1=2)[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCN1CC(C)C(=O)Nc2cnc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CC(C)C(=O)N(C)c2cnc(Cl)nc21
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a mixture of 1.37 g (0.00542 mole) of (rac)-9-allyl-2-chloro-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-65), 0.51 mL (0.00813 mole) of iodomethane and 15 mL of N,N-dimethyl-formamide at 0 degrees, was added 0.33 g (0.00813 mole) of 60% oil dispersion of sodium hydride. The mixture was stirred at 0 degrees for 2 hours and then partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-60:40) to give 1.45 g of (rac)-9-allyl-2-chloro-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-65). HRMS (ES+) m/z Calcd for C12H15CIN4O+H [(M+H)+]: 267.1007. Found: 267.1007.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.[H-].[Na+]>O>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ccccn1
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(CN2CCC(Oc3ccccn3)CC2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 106.3 %

Procedure:
A mixture of 60.65 H (318 mmoles) 1-phenylmethyl-4-piperidinol, 500 ml dimethylformamide, 46.25 g, that is 41 ml (475 mmoles) 2-fluoropyridine and 17 g 50% sodium hydride in mineral oil is heated at 100° C. for 1 h. The mixture is cooled in an ice bath, 20 ml water are added, the mixture is stirred for 30 min and concentrated to a residual volume of about 200 ml. 1 1 iced water is added, the mixture is stirred at 0° C. for 30 min, and the precipitate is filtered off, washed and dried. 90.71 g 1-phenylmethyl-4-(2-pyridinyloxy)piperidine are thus isolated. Melting point: 75° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([OH:17])=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1.CC1C=CC=C(C)N=1.FC(F)(F)S(O[Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])(=O)=O.Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([OH:17])=[CH:12][C:13]([O:16][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])=[CH:14][CH:15]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: COc1ccc(F)c(-c2ccc(O)cc2O)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: COc1ccc(F)c(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2O)c1
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
Under a nitrogen atmosphere, to a solution of 2′-fluoro-5′-methoxy-[1,1′-biphenyl]-2,4-diol (14.6 g) and 2,6-dimethylpyridine (10.2 mL) in toluene (100 mL) was added triisopropylsilyl trifluoromethanesulfonate (21.1 mL) at −15° C., and the mixture was stirred at −15° C. for 20 min. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound as a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:29]=[CH:28][C:11]3[NH:12][C:13]([NH:15][C:16]([C:18]4[N:19]=[C:20]5[CH:25]=[CH:24][C:23](Cl)=[N:22][N:21]5[CH:27]=4)=[O:17])=[N:14][C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O1CCCCC1[O:36][CH2:37][CH2:38][OH:39]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:29]=[CH:28][C:11]3[NH:12][C:13]([NH:15][C:16]([C:18]4[N:19]=[C:20]5[CH:25]=[CH:24][C:23]([O:36][CH2:37][CH2:38][OH:39])=[N:22][N:21]5[CH:27]=4)=[O:17])=[N:14][C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1nc2cc(-c3cccc(Cl)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Reactant: OCCOC1CCCCO1
Product: O=C(Nc1nc2cc(-c3cccc(Cl)c3)ccc2[nH]1)c1cn2nc(OCCO)ccc2n1

Procedure:
6-(2-Hydroxy-ethoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-phenyl)-1H-benzoimidazol-2-yl]-amide (41 mg) was prepared from 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-phenyl)-1H-benzoimidazol-2-yl]-amide (80 mg) and 2-(tetrahydro-pyran-2-yloxy)-ethanol as described in Example 122. LCMS (m/z): 449.7. 1H NMR (400 MHz, DMSO-d6): δ 12.38 and 11.4 (1H, s) 8.84 (1H, s) 8.15 (1H, d) 7.78 1H, s) 7.71 (1 h, s) 7.56-7.66 (2H, m) 7.45-7.51 (2H, m) 7.39 (1H, d) 7.07 (1H, d) 4.98 (1H, t) 4.38 (2H, t) 3.79 (2H, q).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:19])[C:7]=3[CH3:20])=[CH:4][C:3]=1[F:21].BrC1C(=O)C(Br)=C(Br)C(C)([N+:30]([O-:32])=[O:31])C=1Br>FC(F)(F)C(O)=O.CCOC(C)=O>[NH2:1][C:2]1[C:14]([N+:30]([O-:32])=[O:31])=[C:13]2[C:5]([C:6]3[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:19])[C:7]=3[CH3:20])=[CH:4][C:3]=1[F:21]
Reactant: CC1([N+](=O)[O-])C(Br)=C(Br)C(=O)C(Br)=C1Br
Reactant: CCCCC12CCC(=O)C(C)=C1c1cc(F)c(N)cc1C2
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCC12CCC(=O)C(C)=C1c1cc(F)c(N)c([N+](=O)[O-])c1C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 7-amino-9a-butyl-6-fluoro-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (243 mg, 0.845 mmol) in trifluoroacetic acid (1.7 mL) was treated with 2,3,5,6-tetrabromo-4-methyl-4-nitro-2,5-cyclohexadien-1-one (396 mg, 0.845 mmol). The resulting mixture was placed under a N2 atmosphere, sonicated briefly, and stirred at room temperature for 3 hours. The mixture was diluted with EtOAc (50 mL), washed successively with water, 5% NaHCO3 and brine, dried over MgSO4, filtered, and evaporated under vacuum to a brown oil (659 mg). The crude product was purified by flash chromatography on a Biotage 40S KP-Sil column, eluting with 10:1 hexanes-EtOAc. The product containing fractions were evaporated under vacuum to an orange gum (113 mg, 40%) which was lyophilized from benzene to provide 7-amino-9a-butyl-6-fluoro-4-methyl-8-nitro-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:3]=1[CH2:4][N:5]([CH2:6][CH3:7])[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Br
Reactant: O=C(Cl)c1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(=O)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine and benzoyl chloride.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]([NH:9][C:10]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[O:8])(=[O:3])[CH3:2].[C:25]([O:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32])(=[O:27])[CH3:26].C(N(CC)CC)C>O1CCCC1>[C:1]([O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]([NH:9][C:10]1[CH:19]=[C:18]([NH:20][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=2[O:28][C:25](=[O:27])[CH3:26])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(N)cc1NC(=O)c1ccccc1OC(C)=O
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)c2ccccc2OC(C)=O)cc1NC(=O)c1ccccc1OC(C)=O
Yield: 66.9 %

Procedure:
In 80 ml of tetrahydrofuran were dissolved 2 g of methyl 2-(2'-acetoxybenzamido)-4-aminobenzoate and 11.8 g of 2-acetoxybenzoylchloride, and to the solution was added dropwise a solution of 0.6 g of triethylamine in 5 ml of tetrahydrofuran while stirring under cooling with ice. Ten minutes after completion of the addition, the mixture was returned to room temperature, followed by stirring at that temperature for one hour. The reaction mixture was then poured into diluted hydrochloric acid-ice to precipitate crystals. The crystals were recovered by filtration and recrystallized from methanol to obtain 2.0 g of methyl 2,4-bis(2'-acetoxybenzamido)-benzoate having a melting point between 143° - 145°C. This product was confirmed to be identical to that obtained in Example 6.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.CC(O)=O.C(O[C:37]1(O[Si](C)(C)C)[CH2:39][CH2:38]1)C.[NH4+].[Cl-]>CO>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH:37]4[CH2:39][CH2:38]4)[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C5CC5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
To a solution of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (30 mg, 0.072 mmol) in MeOH (0.7 mL) was added AcOH (35 mg, 0.58 mmol), (1-ethoxycyclopropoxy)trimethylsilane (37 mg, 0.216 mmol) and a small amount of 4 Å molecular sieves. The mixture was stirred at room temperature for 1 h before the addition of Na(CN)BH3 (14 mg, 0.216 mmol). The resulting mixture was then stirred at 60° C. for 14 h and cooled to room temperature. Saturated aqueous NH4Cl (2 mL) was added and the mixture was extracted with EtOAc (3×3 mL). The combined organic layers were concentrated and purified by preparative RP-HPLC to provide 5-chloro-N2-(4-(1-cyclopropylpiperidin-4-yl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; 1H NMR (400 MHz, MeOD-d4) δ 7.97 (s, 1H), 7.84 (d, 1H), 7.50 (s, 1H), 6.93 (d, 1H), 6.29 (s, 1H), 5.33 (s, 1H), 2.80 (m, 1H), 2.58 (s, 2H), 2.28 (s, 3H), 2.24 (s, 3H), 1.96 (m, 1H), 1.80-1.85 (m, 2H), 1.65-1.75 (m, 2H), 0.2-0.7 (m, 6H); ESMS m/z 456.2 (M+H+).