Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[C:2]#[CH:3].[CH2:6]([O:13][N:14]1[C:20](=[O:21])[N:19]2[CH2:22][C@H:15]1[CH2:16][CH2:17][C@H:18]2/[C:23](/Cl)=[N:24]/[OH:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl.CCOC(C)=O>[CH2:6]([O:13][N:14]1[C:20](=[O:21])[N:19]2[CH2:22][C@H:15]1[CH2:16][CH2:17][C@H:18]2[C:23]1[CH:3]=[C:2]([C:1]([NH2:5])=[O:4])[O:25][N:24]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C#CC(N)=O
Reactant: O=C1N2C[C@@H](CC[C@H]2/C(Cl)=N/O)N1OCc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)c1cc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
Propiolamide (0.30 g, 4.37 mmol) was added to a solution of (2S,5R,Z)-6-(benzyloxy)-N-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbimidoyl chloride (3.64 mmol) in dry DCM (10 mL), followed by the addition of TEA (0.56 mL, 4.0 mmol) in DCM (2 mL) over a 30 minute period. The reaction mixture was stirred at rt overnight. Then the mixture was diluted with EtOAc, washed with water and saturated sodium chloride. The combined organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography (gradient elution 5:1 to 1:2, petroleum ether/EtOAc containing 1% TEA) to afford 3-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)isoxazole-5-carboxamide (0.4 g, 32%) as a yellow solid. ESI-MS (EI+, m/z): 343 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:12][OH:13])=[N:9][C:10]=2I)[CH:7]=1.[H-].[Na+].C([Mg]Cl)(C)C.[CH2:21]([Sn:25]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])Cl)[CH2:22][CH2:23][CH3:24]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:12][OH:13])=[N:9][C:10]=2[Sn:25]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:7]=1
Reactant: OCc1nc(I)c2ccc(F)cn12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nc(CO)n2cc(F)ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a round-bottomed flask, (6-fluoro-1-iodo-imidazo[1,5-a]pyridin-3-yl)-methanol (156 mg, 0.53 mmol) was dissolved in THF (4 ml). Sodium hydride (60% dispersion in mineral oil, 26 mg, 0.65 mmol) was added and the reaction mixture was stirred at room temperature for 10 min. The reaction mixture was cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride (2.0 M in THF, 0.32 ml, 0.64 mmol) was added dropwise. The reaction was stirred at −16° C. for 25 min then tributylchlorostannane (0.17 ml, 0.63 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 h then quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to afford (6-Fluoro-1-tributylstannanyl-imidazo[1,5-a]pyridin-3-yl)-methanol as a brown semisolid which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O)(=[O:11])=[O:10].[CH3:23][O:24][C:25](=[O:38])[C@@H:26]([NH2:37])[C@@H:27]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=1)[CH3:28]>>[CH3:23][O:24][C:25](=[O:38])[C@@H:26]([NH:37][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:13]=1[NH:12][S:9]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])(=[O:11])=[O:10])[C@@H:27]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=1)[CH3:28]
Reactant: COC(=O)[C@@H](N)[C@H](C)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F
Product: COC(=O)[C@@H](NC(=O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F)[C@H](C)c1ccc(Cl)c(Cl)c1

Procedure:
2-(2,6-Difluoro-benzenesulfonylamino)-4-iodo-benzoic acid was coupled to (2S,3R)-2-amino-3-(3,4-dichloro-phenyl)-butyric acid methyl ester as in EXAMPLE 1, Part C, to afford the title compound. HPLC: RT=12.39 min. MS (ESI+): mass calcd. for C24H19Cl2F2IN2O5S, 683.29; m/z found, 683/685 [M+H]+. 1H NMR (400 MHz, CDCl3): 11.29 (s, 1H), 8.11 (d, J=1.6, 1H), 7.52-7.47 (m, 1H), 7.42 (dd, J=8.3, 1.6, 1H), 7.37 (d, J=13.9, 1H), 7.24 (d, J=2.1, 2H), 7.11 (d, J=8.3, 1H), 7.02-6.98 (m, 3H), 6.65 (d, J=8.3, 1H), 4.95-4.91 (m, 1H), 3.26 (s, 3H), 3.31 (quin, J=7.2, 1H), 1.43 (d, J=7.2, 3H).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH2:12][CH2:13][C:14]([O:16]C)=[O:15])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[OH-].[Na+].CO>[C:1]1([C:7]2[O:11][C:10]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCc1nnc(-c2ccccc2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.6 %

Procedure:
A mixture of methyl 3-(5-phenyl-1,3,4-oxadiazol-2-yl)propanoate (600 mg, 2.0 mmol) in 1 M of aqueous NaOH (10 mL) and Methanol (10 mL) was stirred at room temperature overnight. The reaction solution was adjusted to pH 5 and extracted with ethyl acetate three times. The combined organic layers were dried, filtered and concentrated to yield the desired product (0.50 g, 83%). LCMS calculated for C11H11N2O3 (M+H): 219.1. found 219.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:18](O)=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][OH:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)O
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CO)CCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
N-tert-butoxycarbonyl-D-homophenylalanine (36 mmol) was dissolved in THF (300 mL) and cooled to 0° C. Borane-THF complex (0.32M in THF, 320 mL, 9 equivalents) was added dropwise over 2 hours and the solution was stirred for an additional 2 hours at 0° C. The reaction mixture was quenched over several hours by the slow addition of MeOH (300 mL) and the solution was concentrated to dryness. The residue was dissolved in EtOAc (200 mL), washed with 1 N NaOH (2×100 mL) and brine (1×75 mL). The organic layer was dried over NASO4, filtered and the filtrate concentrated to dryness. Recrystallization from hexanes gave the title compound (6.5g, 84%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 1.57 (9H, s), 1.91-1.93 (2H, m), 2.77-2.85 (2H, m), 3.68-3.82 (3H, m), 7.29-7.42 (5)H, m); MS (relative intensity) nme 288 (100, M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:8]([CH2:18]OS(C)(=O)=O)[CH2:7]1.[CH3:30][NH2:31]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C@H:8]([CH2:18][NH:31][CH3:30])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Oc2cc(F)cc([N+](=O)[O-])c2)C[C@H]1COS(C)(=O)=O
Reactant: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC[C@@H]1C[C@@H](Oc2cc(F)cc([N+](=O)[O-])c2)CN1C(=O)OC(C)(C)C
Temperature: 55 °C

Procedure:
To a solution of (2S,4R)-tert-butyl 4-(3-fluoro-5-nitrophenoxy)-2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate (1.0 equiv) in THF (0.4 M) was added 40% aq. methylamine (90 equiv). The resulting solution was heated to 55° C. overnight. The reaction mixture was cooled to room temperature and diluted with EtOAc (20 volume equivalents) and washed twice with sat. aq. NaHCO3 (10 volume equivalents) and once with brine (10 volume equivalents). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a dark oil with 119% mass balance; the material was used without further purification.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:5]=[C:6]([C@@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:19]=[CH:18]3)[C@@H:11]([NH2:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)[CH3:3].C([O:34][CH2:35][C:36](Cl)=[O:37])(=O)C>>[CH2:2]([C:4]1[CH:5]=[C:6]([C@@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[N:19]=[CH:18]3)[C@@H:11]([NH:13][C:35](=[O:34])[CH2:36][OH:37])[CH3:12])[CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: CCc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: CCc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)CO)c1

Procedure:
The title compound was prepared analogous to the method described in Example 21 starting from (1R,2S)-1-(3-ethylphenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine hydrochloride (22a) (50 mg, 0.12 mmol), and Acetoxyacetyl chloride (14 μL, 0.13 mmol). Yield 37 mg (70%).
Reaction SMILES: C([O:3][CH2:4][C:5]1[N:6]([CH2:17][C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:19]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH2:15])[C:8]=2[N:16]=1)C.B(Br)(Br)Br>ClCCl.CO>[NH2:15][C:9]1[C:8]2[N:16]=[C:5]([CH2:4][OH:3])[N:6]([CH2:17][C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[CH:19]=3)[C:7]=2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1Cc1cc(-c2ccc(F)cc2)no1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(N)c2nc(CO)n(Cc3cc(-c4ccc(F)cc4)no3)c2c1C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
Under a nitrogen atmosphere, a solution of 2-(ethoxymethyl)-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (0.8545 g, 2.161 mmol) in dichloromethane (50 mL) was cooled to about 6° C., and boron tribromide (5.4 mL of a 1 M solution in dichloromethane) was added dropwise. The reaction was heated at reflux under nitrogen for two hours and diluted with dichloromethane and methanol. The resulting solution was washed sequentially with aqueous potassium carbonate, water, and brine; dried over sodium sulfate; filtered; and concentrated under reduced pressure. The resulting solid was stirred in water overnight, isolated by filtration, purified by column chromatography on silica gel (eluting with 3% to 5% CMA in chloroform), and dried to provide 0.283 g of (4-amino-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-2-yl)methanol as a tan powder, mp 164.0-165.0° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[NH:26][CH:25]=[CH:24]5)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Cl:37])C(=O)C1>C(Cl)Cl>[Cl:37][C:24]1[C:23]2[C:27](=[CH:28][CH:29]=[C:21]([C:18]3[N:17]=[C:16]([C:9]4[S:10][C:11]([C:12]([F:15])([F:14])[F:13])=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=4)[O:20][N:19]=3)[CH:22]=2)[NH:26][CH:25]=1
Reactant: FC(F)(F)c1sc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1-c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: FC(F)(F)c1sc(-c2nc(-c3ccc4[nH]cc(Cl)c4c3)no2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
D2 (200 mg) and NCS (65 mg) were dissolved in DCM (5 ml) and stirred overnight at room temperature. The reaction mixture was then partitioned between DCM and H2O. The DCM solution was evaporated to dryness and purified on a Biotage silica cartridge, eluting with a 25-75% mixture of diethyl ether in hexane. This gave the title compound (36 mg) as a brown solid. A second batch of the title compound was also obtained from this purification (86 mg) as a brown solid. δH (CDCl3, 400 MHz): 7.28 (1H, m), 7.45-7.54 (6H, m), 7.93 (1H, s), 8.05 (1H, d), 8.28 (1H, br s), 8.49 (1H, s). MS (ES): C21H11ClF3N3OS requires 445; found 444 (M−H+).
Reaction SMILES: [CH2:1](N)C.Cl[C:5]1[C:14]([C:15]([C:17](=[CH:23][N:24](C)[CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])=[CH:13][C:12]2[C:7](=[CH:8][C:9]([Cl:28])=[C:10]([F:27])[CH:11]=2)[N:6]=1.C1CCN2C(=NCCC2)CC1>C(O)C>[Cl:28][C:9]1[C:10]([F:27])=[CH:11][C:12]2[C:7]([CH:8]=1)=[N:6][C:5]1[N:24]([CH2:25][CH3:1])[CH:23]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15](=[O:16])[C:14]=1[CH:13]=2
Reactant: CCN
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2nc3cc(Cl)c(F)cc3cc2c1=O
Reaction time: 2 h
Yield: 85.1 %

Procedure:
16 g of ethylamine are added, in the course of 5 minutes, at between 10° and 15° C., to a stirred suspension of 13.5 g of ethyl 2-(2,7-dichloro-6-fluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate in 135 cm3 of ethanol, the temperature is allowed to rise to about 20° C., 0.5 g of DBU is added and the mixture is heated, with stirring, for 2 hours at a temperature close to 75° C. After cooling to a temperature close to 20° C., the precipitate is drained and washed with twice 100 cm3 of ethanol and twice 100 cm3 of diethyl ether. 10.4 g of 8-chloro-3-ethoxycarbonyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-benzo-[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 300°-301° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[C:28]([C:34]2[O:35][C:36]([CH3:39])=[CH:37][N:38]=2)[CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:20])[CH3:21])=[O:23])=[C:28]([C:34]2[O:35][C:36]([CH3:39])=[CH:37][N:38]=2)[CH:27]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: Cc1cnc(-c2cc(F)ccc2CN)o1
Product: Cc1cnc(-c2cc(F)ccc2CNC(=O)c2nc3n(c(=O)c2OCc2ccccc2)CCOC3(C)C)o1

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and (4-fluoro-2-(5-methyloxazol-2-yl)phenyl)methanamine. White crystals; mp 186° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.61 (6H, s, 2×CH3), 2.43 (3H, s, CH3), 4.02 (4H, m, 2×CH2), 4.80 (2H, d, J=6.3 Hz, NCH2), 5.25 (2H, s, OCH2), 6.82 (1H, s, CH), 7.11 (1H, m, aromatic), 7.29-7.34 (3H, m, aromatics), 7.52 (2H, m, aromatics), 7.65 (1H, dd, J=2.5 Hz and J=9.6 Hz, aromatic), 7.69 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 9.32 (1H, broad t, NH). HRMS (ESI+) calculated for C28H28FN4O5 [M+H+]: 519.2044: found: 519.2024.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[F:7][CH2:8]Br.[CH3:10][C:11]1([CH3:25])[C:15]([CH3:17])([CH3:16])[O:14][B:13]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[O:12]1>CC#N>[F:7][CH2:8][O:24][C:21]1[CH:20]=[CH:19][C:18]([B:13]2[O:14][C:15]([CH3:17])([CH3:16])[C:11]([CH3:25])([CH3:10])[O:12]2)=[CH:23][CH:22]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: FCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)OB(c2ccc(OCF)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cs2CO3 (651.6 mg, 2.0 mmol) and then FCH2Br (446.6 mg, 4.0 mmol) were added to a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (220 mg, 1.0 mmol)) in CH3CN (10 ml). After stirring at room temperature overnight, the mixture was filtered and concentrated. Purification by column chromatography afforded 2-(4-(fluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: LCMS tR=1.39 Min (5 min run, UV254nm). Mass calculated for, M+ 252.1, observed LC/MS m/z 253.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:14])([CH3:13])[C:11](=N)[N:10]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=3)[C:9]2=[S:28])=[CH:4][CH:3]=1.C[OH:30].O>Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])([CH3:14])[C:11](=[O:30])[N:10]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:25])([F:26])[F:27])[CH:17]=3)[C:9]2=[S:28])=[CH:6][CH:7]=1
Reactant: CO
Reactant: CC1(C)C(=N)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(O)cc1
Agent: Cl
Solvent: O
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(O)cc1
Temperature: 25 °C

Procedure:
A mixture of 3b (0.202 g, 0.5 mmol) in HCl aq., 2N (2 ml) and methanol (5 ml) was heated to reflux for 2 h. After being cooled to room temperature, the reaction mixture was poured into cold water (10 ml) and extracted with ethyl acetate (10 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane/acetone, 9:1) to yield 4-[3-(4 -hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile, 3c, [RD8] (0.198 g, 0.49 mmol, 98%) as a white powder.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:38])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])=[CH:24][CH:23]=1.[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:21][C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:38])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[CH:26][CH:27]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: COc1ccccc1C(=O)Nc1ccc(O)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1C(=O)Nc1ccc(OCCCOc2ccc(C[C@H](OC)C(=O)O)cc2)cc1

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester, from Example 173, Step A was treated with N-(4-Hydroxy-phenyl)-2-methoxy-benzamide from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C27H29NO7 [+H]+: 480.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:34]([O:36][C:37](=[O:63])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][C:45]2[C:50]([C:51](=[O:62])[NH:52][CH2:53][C:54]3[CH:59]=[CH:58][C:57]([CH2:60][NH2:61])=[CH:56][CH:55]=3)=[CH:49][CH:48]=[CH:47][N:46]=2)[CH:39]=1)[CH3:35].CN1CCOCC1>CN(C)C=O>[CH2:34]([O:36][C:37](=[O:63])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][C:45]2[C:50]([C:51](=[O:62])[NH:52][CH2:53][C:54]3[CH:55]=[CH:56][C:57]([CH2:60][NH:61][C:5](=[O:6])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([OH:1])[CH:3]=4)=[CH:58][CH:59]=3)=[CH:49][CH:48]=[CH:47][N:46]=2)[CH:39]=1)[CH3:35]
Reactant: CCOC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccc(CN)cc2)c1
Reactant: O=C(O)c1cccc(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccc(CNC(=O)c3cccc(O)c3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
3-Hydroxy-benzoic acid (27 mg, 0.19 mmol), 1-hydroxybenzotriazole (31 mg, 0.23 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (45 mg, 0.23 mmol) were added to a solution of 3-[3-(4-aminomethyl-benzylcarbamoyl)-pyridin-2-yloxy]-benzoic acid ethyl ester hydrochloride (100 mg, 0.19 mmol) (see Preparation 9) and N-methyl morpholine (0.11 ml, 0.97 mmol) in N,N-dimethylformamide (15 ml). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours, concentrated in vacuo and the residue partitioned between dichloromethane (20 ml) and water (20 ml). The organic phase was separated, washed with a saturated aqueous solution of sodium chloride (20 ml), dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The residue was then purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (99:1 changing to 98:1, by volume) giving 3-(3-{4-[(3-hydroxy-benzoylamino)-methyl]-benzylcarbamoyl}-pyridin-2-yloxy)-benzoic acid ethyl ester (45 mg) as an off-white foam.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[C:7]3[CH:13]=[C:12]([C:14]4[N:15]([CH2:19][C:20]([OH:22])=O)[CH:16]=[CH:17][CH:18]=4)[NH:11][C:8]3=[N:9][CH:10]=[C:5]2[CH:4]=[N:3]1.C(Cl)(=O)C([Cl:26])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]2=[C:7]3[CH:13]=[C:12]([C:14]4[N:15]([CH2:19][C:20]([Cl:26])=[O:22])[CH:16]=[CH:17][CH:18]=4)[NH:11][C:8]3=[N:9][CH:10]=[C:5]2[CH:4]=[N:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1ncc2cnc3[nH]c(-c4cccn4CC(=O)O)cc3c21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1ncc2cnc3[nH]c(-c4cccn4CC(=O)Cl)cc3c21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a flask was added 2-(2-(1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-pyrrol-1-yl)acetic acid (0.125 g, 0.423 mmol, Example #AN.1.2) and oxalyl chloride (0.275 mL, 0.550 mmol) in DCM (4 mL) followed by a drop of DMF. The mixture was stirred for about 40 min at rt and then concentrated to dryness to afford 2-(2-(1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-pyrrol-1-yl)acetyl chloride. The mixture was used immediately in the next step. Analytics were performed by quenching a sample with MeOH and methyl ester is the observed (M+H)+: LC/MS (Table 2, Method c) Rt=1.30 min; MS m/z 310 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]([C:14]([NH2:17])([CH3:16])[CH3:15])[CH:11]=[CH:12][CH:13]=2)=[CH:6][C:5]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:4]1)[CH3:2].CCN(CC)CC.[CH:34]1([NH:38][S:39](Cl)(=[O:41])=[O:40])[CH2:37][CH2:36][CH2:35]1>>[CH:34]1([NH:38][S:39]([NH:17][C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:7]3[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH2:18][O:19][C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH:6]=3)[CH:9]=2)([CH3:16])[CH3:15])(=[O:41])=[O:40])[CH2:37][CH2:36][CH2:35]1
Reactant: CCn1nc(COc2ccc(F)cc2)cc1-c1cccc(C(C)(C)N)c1
Reactant: O=S(=O)(Cl)NC1CCC1
Solvent: CCN(CC)CC
Product: CCn1nc(COc2ccc(F)cc2)cc1-c1cccc(C(C)(C)NS(=O)(=O)NC2CCC2)c1

Procedure:
Prepared by the procedure of Example 1 Step 3 using the amine from Step 5 (100 mg, 0.28 mmol), Et3N (114 mg, 1.1 mmol) and cyclobutylsulfamoyl chloride (192 mg, 1.1 mmol) to yield, after purification by column chromatography on silica using 70% Et2O/iso-hexanes and then by normal phase preparative HPLC, the sulfamide (17.5 mg, 12%). 1H NMR (CDCl3, 360 MHz) δ 7.60-7.52 (2H, m), 7.44 (1H, t, J=7.6 Hz), 7.30 (1H, d, J=7.6 Hz), 6.97 (4H, app. d, J=6.3 Hz), 6.37 (1H, s), 5.06 (2H, s), 4.55 (1H, s), 4.12 (2H, q, J=7.3 Hz), 3.78 (1H, app. sextet, J=8.3 Hz), 2.45-2.35 (2H, m), 1.93-1.82 (2H, m), 1.75 (6H, s), 1.72-1.60 (2H, m), 1.44 (3H, J=7.3 Hz). MS (ES+) C25H31FN4O3S requires: 486, found: 487 (M+H+, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[N:14](CC3C=CC=CC=3)[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7]1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>[Pd].C(O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH:8]2[NH:14][CH:12]([CH2:11][CH2:10][CH2:9]2)[CH2:13]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC2CCCC(C1)N2Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C1CC2CCCC(C1)N2

Procedure:
To a 125 mL round-bottomed flask equipped with a condenser and N2 inlet were added 8.14 g (28.36 mmol) ethyl-N-benzyl-9-azabicyclo[3.3.1]nonane-3-carboxylate, 60 mL ethanol, 8.93 g (141.8 mmol) ammonium formate, and 5 g 10% palladium-on-carbon. The reaction was refluxed and fresh catalyst and ammonium formate were added until the starting material disappeared (about 4 hr, a total of 8 g catalyst). The reaction was cooled, filtered through diatomaceous earth (Celite [trademark]), and evaporated. The residue was partitioned between methylene chloride and an aqueous sodium hydroxide solution, and the organic layer separated, dried over sodium sulfate, and evaporated. The resulting oil was used directly in the next step.