Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3([C:21]([NH:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[NH:29][CH:28]=[CH:27]5)=[O:22])[CH2:20][CH2:19]3)=[CH:17][C:12]=2[O:11][CH2:10]1.O>CN(C)C=O>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3([C:21]([NH:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[NH:29][CH:28]=[C:27]5[Br:1])=[O:22])[CH2:20][CH2:19]3)=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(Nc1ccc2[nH]ccc2c1)C1(c2ccc3c(c2)OCO3)CC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc2[nH]cc(Br)c2c1)C1(c2ccc3c(c2)OCO3)CC1
Reaction time: 0.08 h
Yield: 90.6 %

Procedure:
Freshly recrystallized N-bromosuccinimide (0.278 g, 1.56 mmol) was added portionwise to a solution of 1-(benzo[d][1,3]-dioxol-5-yl)-N-(1H-indol-5-yl)cyclopropanecarboxamide (0.500 g, 1.56 mmol) in N,N-dimethylformamide (2 mL) over 2 minutes. The reaction mixture was protected from light and was stirred bar for 5 minutes. The resulting green solution was poured into 40 mL of water. The grey precipitate which formed was filtered and washed with water to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-1H-indol-5-yl)cyclopropanecarboxamide (0.564 g, 91%). ESI-MS m/z calc. 398.0, found 399.3 (M+1)+. Retention time of 3.38 minutes. 1H NMR (400 MHz, DMSO-d6) 11.37 (s, 1H), 8.71 (s, 1H), 7.67 (d, J=1.8 Hz, 1H), 7.50 (d, J 2.6 Hz, 1H), 7.29 (d, J=8.8 Hz, 1H), 7.22 (dd, J=2.0, 8.8 Hz, 1H), 7.02 (d, J=1.6 Hz, 1H), 6.96-6.88 (m, 2H), 6.03 (s, 2H), 1.43-1.40 (m, 2H), 1.09-1.04 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:22](O)[CH2:23][OH:24]>C1(C)C=CC=CC=1>[CH3:10][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:24][CH2:23][CH2:22][O:9]1
Reactant: OCCO
Reactant: CC(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C2(C)OCCO2)cc1
Temperature: 25 °C
Yield: 79.1 %

Procedure:
A mixture of 4-methylacetophenone (1.00 g, 7.45 mmol), p-toluenesulfonic acid (133 mg, 0.745 mmol) and ethylene glycol (1.20 mL, 22.4 mmol) in dry toluene (20 mL) was heated at reflux with a Dean-Stark apparatus under nitrogen for 24 h. The mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was taken up in ether (20 mL) and the solution was washed with saturated sodium bicarbonate solution (2×10 mL) and brine (1×10 mL), then dried (Na2SO4) and concentrated under reduced pressure. Flash column chromatography of the residue, eluting with 37% aqueous ammonia:ether:hexane (0.02:1:6) afforded 2-methyl-2-(4-methylphenyl)-1,3-dioxolane (23) as a colourless oil (1.05 g, 59%). 1H nmr (200 MHz, CDCl3) 1.65 (s, 3H, CH3), 2.35 (s, 3H, ArCH3), 3.74-3.86 (m, 2H, OCH2), 3.94-4.06 (m, 2H, OCH2), 7.15 (d, J=8.2 Hz, 2H, 2×ArH), 7.37 (d, J=8.2 Hz, 2H, 2×ArH).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[N:12][C:5]2[NH:6][C:7](=[O:11])[CH2:8][NH:9][CH2:10][C:4]=2[CH:3]=1.[C:14]([O:18][C:19](=[O:22])[CH2:20]Br)([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>CN(C=O)C.O>[C:14]([O:18][C:19](=[O:22])[CH2:20][N:9]1[CH2:10][C:4]2[CH:3]=[C:2]([Br:1])[CH:13]=[N:12][C:5]=2[NH:6][C:7](=[O:11])[CH2:8]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C1CNCc2cc(Br)cnc2N1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CC(=O)Nc2ncc(Br)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
A solution of 7-bromo-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (2.29 g, 9.46 mmol) in DMF (100 mL) was treated with tert-butylbromoacetate (1.7 mL, 12 mmol) and triethylamine (1.5 mL, 11 mmol). After stirring at room temperature overnight, the mixture was diluted with H2O (300 mL) and then extracted with EtOAc (3×200 mL). The combined organic layers were washed with H2O (3×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, hexanes/EtOAc, 2:1) gave the title compound (1.61 g, 48%) as a white powder: MS (ESI) t/e 356 (M+H)+.
Reaction SMILES: C[NH:2][C@H:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[CH2:4]1.C(N[C@H]1CCC2C(=C(OC)C=CC=2)C1)C1C=CC=CC=1>[Pd]>[NH2:2][C@H:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[CH2:4]1
Reactant: CN[C@H]1CCc2cccc(OC)c2C1
Agent: [Pd]
Agent: COc1cccc2c1C[C@@H](NCc1ccccc1)CC2
Product: COc1cccc2c1C[C@@H](N)CC2

Procedure:
It is contemplated that (-)-N-methyl-(2S)-2-amino-8-methoxytetralin can be prepared as follows: (-)(2S)-2-benzylamino-8-methoxytetralin (prepared as described in Karlsson et al., Acta Chemica Scandinavica 1988, B42, 231-236) can be hydrogenated in a Parr apparatus in the presence of 10% palladium on carbon to afford (-)(2S)-2-amino-8-methoxy-tetralin. (-)(2S)-2-Amino-8-methoxytetralin can then be formylated as described in Example 6(g) to afford (-)-N-formyl-(2S)-2-amino-8-methoxytetralin which in turn can be reduced as described in Example 6 to afford (-)-N-methyl-(2S)-2-amino-8-methoxytetralin.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:36]3[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=3)(=[O:41])=[O:40])=[O:24])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1ccc(F)cc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(F)cc3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-fluorobenzenesulfonamide: 1H-NMR (CDCl3) δ 7.94-7.88 (2H, m), 7.47-7.15 (11H, m), 6.24 (1H, br.s), 3.48-3.42 (2H, m), 2.84 (2H, t, J=7.0 Hz), 2.32 (3H, s), 2.23 (3H, s).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.CS(O)(=O)=O.CS(O)(=O)=O.[NH2:36][CH:37]1[CH2:40][NH:39][CH2:38]1>>[NH2:36][CH:37]1[CH2:40][N:39]([C:15]2[C:16]([F:18])=[CH:17][C:10]3[C:11]([CH:14]=2)=[N:12][C:13]2[N:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:7](=[O:20])[C:8]=2[CH:9]=3)[CH2:38]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: NC1CNC1
Agent: CS(=O)(=O)O
Product: CCOC(=O)c1cn(C2CC2)c2nc3cc(N4CC(N)C4)c(F)cc3cc2c1=O
Yield: 53.6 %

Procedure:
8-(3-Amino-1-azetidinyl)-1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydrobenzo-[b][1,8]naphthyridine was prepared under the conditions of Example 2, but starting with 1.7 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine and 1.88 g of 3-aminoazetidine dimethanesulphonate. After 1 recrystallization in 50 cm3 of ethanol, 1.05 g of 8-(3-amino-1-azetidinyl)-1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine are obtained in the form of a yellow solid, melting point 178°-180° C.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][CH2:6][NH:7][C:8]([N:10]1[CH2:14][C@@H:13]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@@:12]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[C@H:11]1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[F:37])=[O:9])C.O.[OH-].[Li+]>>[Cl:36][C:32]1[C:31]([F:37])=[C:30]([C@@H:11]2[C@:12]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:13]([CH2:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH2:14][N:10]2[C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:38])=[O:3])=[O:9])[CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)CCNC(=O)N1C[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)C[C@@H]1CN(C(=O)NCCC(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Yield: 99.8 %

Procedure:
In a manner similar to the method described in Example 8, rac-3-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-propionic acid ethyl ester (99 mg, 0.175 mmol, example 72) was reacted with lithium hydroxide hydrate (44 mg, 1.047 mmol, Aldrich) to give rac-3-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-propionic acid (94 mg, 99%). HRMS (ES+) m/z Calcd for C26H27Cl2F2N3O3+H [(M+H)+]: 538.1471; Found: 538.1470.
Reaction SMILES: I[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:3]2[O:4][C:5]3[C:10]([C:11](=[O:12])[CH:2]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[N:14]1
Reactant: O=c1c(I)coc2ccccc12
Reactant: c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2n[nH]c3ccccc23)oc2ccccc12
Temperature: 0 °C
Yield: 86.6 %

Procedure:
To an eggplant type flask (25 ml), 3-iodochromone (136 mg) prepared in Example 1, indazole (236 mg), potassium carbonate (1382 mg), and dimethylformamide (15 mg) were added and the mixture was reacted at 80° C. for 30 hours with stirring. The reaction mixture was added to ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography, and the purified product was recrystallized from benzene/hexane to give the titled compound (113.6 mg; yield=88.5%) as crystals. Melting point: 237°-238° C. 1H-NMR(CDCl3, δ ppm): 6.94 (s, H3), 8.26 (dd, H5), 7.58-7.68 (m, H6), 7.75 (t, H7), 7.58-7.68 (m, H8), 8.30 (s, H3'), 7.82 (m, H4'), 7.35-7.53 (m, H5'), 7.35-7.53 (m, H6'), 8.26 (m, H7') .
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[NH:15][NH:16]C(OC(C)(C)C)=O.[Cl:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([N:31]=[C:32]=[O:33])=O)=[C:27]([F:36])[CH:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[N:15]1[C:32](=[O:33])[NH:31][C:29]([C:28]2[CH:34]=[CH:35][C:25]([Cl:24])=[CH:26][C:27]=2[F:36])=[N:16]1
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C2CC2)ccc1Cl
Reactant: O=C=NC(=O)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(Cl)cc3F)[nH]c2=O)c1)C1CC1
Yield: 55.9 %

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl)hydrazinecarboxylate (step-7 of Intermediate-48, 0.060 g, 0.17 mmol), 4-chloro-2-fluorobenzoyl isocyanate (Intermediate-58, 0.035 g, 0.71 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.040 g of desired product. 1H NMR (400 MHz, DMSO d6): δ 0.67-0.69 (m, 4H), 1.59-1.60 (m, 1H), 4.31 (d, J=5.9 Hz, 2H), 7.36 (dd, J=6.24 Hz, 1H), 7.45 (dd, J=8.5 Hz, 2H), 7.59 (d, J=8.3 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.83 (t, J=8.3 Hz, 1H), 7.64 (t, J=6 Hz, 1H), 12.51 (br s, 1H); MS (m/z): 421.08 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([N:16]3[CH2:20][CH2:19][CH:18]([N:21]4[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:23]=[C:22]4[CH3:30])[C:17]3=[O:31])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].CI.[NH4+].[Cl-].[C:38](O)(C(F)(F)F)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([CH3:14])[CH3:15])=[C:11]([N:16]3[CH2:20][CH2:19][C:18]([CH3:38])([N:21]4[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[N:23]=[C:22]4[CH3:30])[C:17]3=[O:31])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc(C(F)(F)F)cn1C1CCN(c2cnn(-c3ccc(Cl)cc3)c2C(C)C)C1=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1nc(C(F)(F)F)cn1C1(C)CCN(c2cnn(-c3ccc(Cl)cc3)c2C(C)C)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27 %

Procedure:
To a solution of 1-[1-(4-chlorophenyl)-5-isopropylpyrazol-4-yl]-3-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]pyrrolidin-2-one (50 mg, 0.11 mmol) was added DMF (2 mL) and NaH (60% in mineral oil, 16 mg, 0.33 mmol) slowly at room temperature under nitrogen atmosphere. After stirring for 10 min at room temperature, MeI (34 μL, 0.55 mmol) was added and further stirred for 2 h. Saturated NH4Cl solution (10 mL) was then added at 0° C. slowly to the reaction mixture followed by extraction with EtOAc (2×25 mL). The combined EtOAc layers were dried (MgSO4), concentrated in vacuo, and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give 1-[1-(4-chlorophenyl)-5-isopropyl-pyrazol-4-yl]-3-methyl-3-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]pyrrolidin-2-one (17 mg, 0.029 mmol, 27% yield) as a TFA salt. 1H NMR (400 MHz, Methanol-d4) δ 7.88 (s, 1H), 7.70 (s, 1H), 7.59 (d, J=11.76 Hz, 2H), 7.42 (d, J=11.76 Hz, 2H), 3.86-3.95 (m, 2H), 2.99-3.08 (m, 1H), 2.58-2.80 (m, 2H), 2.52 (s, 3H), 1.96 (s, 3H), 1.22 (d, J=23.4 Hz, 3H), 1.20 (d, J=23.4 Hz, 3H); MS: (ES) m/z calculated for C22H23ClF3N5O [M+H]+466.9. found 466.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([O:23]CC)=[O:22])[N:9]=1.[OH-].[Na+].Cl>CO>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([OH:23])=[O:22])[N:9]=1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.6 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) is dissolved in 20 ml of methanol with 0.4 g of sodium hydroxide and the mixture is stirred at room temperature for 2 h. It is acidified with 0.1 N hydrochloric acid and the precipitated crystals are filtered off. After washing with water and drying, [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetic acid remains as colorless crystals of m.p. 231-233° C.
Reaction SMILES: C(OC(=O)[N:7]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:30])[NH2:29])=[C:24]([OH:31])[CH:23]=2)=[C:16]([F:32])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.Cl>ClCCl.O1CCOCC1>[F:20][C:18]1[CH:19]=[C:14]([CH2:13][NH:7][CH2:8][CH2:9][CH:10]([CH3:11])[CH3:12])[CH:15]=[C:16]([F:32])[C:17]=1[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([NH2:29])=[O:30])=[C:24]([OH:31])[CH:23]=1
Reactant: CC(C)CCN(Cc1cc(F)c(Oc2ccc(C(N)=O)c(O)c2)c(F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)CCNCc1cc(F)c(Oc2ccc(C(N)=O)c(O)c2)c(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
[4-(4-Carbamoyl-3-hydroxy-phenoxy)-3,5-difluoro-benzyl]-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-1e-3: 0.8 g) was dissolved in 5 mL of dichloromethane and treated with 2.5 ml of a 4.0 M hydrogen chloride solution in dioxane. After stirring 24 hours at room temperature, the volatiles were removed under reduced pressure and the resulting crude material was suspended in methanol, heated at reflux for 20 minutes, and stirred overnight at room temperature. The resulting slurry was collect via filtration, rinsing with chilled methanol, and dried under vacuum to provide the title compound (4A).
Reaction SMILES: [F:1][C:2]([F:22])([C:15]1[N:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9])=O.Cl[Si](C)(C)C>ClCCCl>[F:1][C:2]([F:22])([C:15]1[N:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:3]1[N:10]=[C:8]([OH:9])[C:7]2[C:6](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=1
Reactant: NC(=O)c1ccccc1NC(=O)C(F)(F)c1ncc(F)cn1
Agent: C[Si](C)(C)Cl
Solvent: ClCCCl
Product: Oc1nc(C(F)(F)c2ncc(F)cn2)nc2ccccc12
Temperature: 85 °C
Yield: 69.8 %

Procedure:
To 2-(2,2-difluoro-2-(5-fluoropyrimidin-2-yl)acetamido)benzamide (230 mg, 1.03 mmol) were added 1,2-dichloroethane (8 mL), TEA (5.75 mL, 41.2 mmol) and chlorotrimethylsilane (2 mL, 15.45 mmol) and the mixture was heated at 85° C. in a sealed vessel overnight. The mixture was allowed to cool and then was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with saturated aq NaHCO3 and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-12% MeOH/DCM to afford 2-(difluoro(5-fluoropyrimidin-2-yl)methyl)quinazolin-4-ol (210 mg, 69%). LC-MS (ESI) m/z 293 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]([OH:16])=O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.[CH2:48]([N:55]1[CH2:60][CH2:59][O:58][C@@H:57]([CH2:61][NH2:62])[CH2:56]1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C)C=O>[CH2:48]([N:55]1[CH2:60][CH2:59][O:58][C@@H:57]([CH2:61][NH:62][C:14](=[O:16])[CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])[CH2:56]1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: NC[C@H]1CN(Cc2ccccc2)CCO1
Reactant: Cc1oc(-c2ccccc2)nc1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(-c2ccccc2)nc1CC(=O)NC[C@H]1CN(Cc2ccccc2)CCO1
Reaction time: 0.08 h
Yield: 104.4 %

Procedure:
A mixture of (5-methyl-2-phenyl-oxazol-4-yl)-acetic acid (0.263 g), 1-hydroxylbenzotriazole (0.163 g), and N,N-diisopropylethylamine (0.211 ml) in N,N-dimethylformamide (3 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.232 g). The mixture was stirred for 5 min, treated with 1-[(2S)-4-benzylmorpholin-2-yl]methanamine (prepared in accordance with EP 0 995 746 A1; 0.192 g), and the solution was stirred at 22° C. for 18 h. The mixture was partitioned between dichloromethane (20 ml) and saturated aqueous sodium hydrogen carbonate (10 ml). The phases were separated in a hydrophobic frit; the organic phase was loaded onto a solid phase extraction cartridge (10 g SCX) and eluted with methanol, followed by 0.880 ammonia:methanol 10:90 to give the title compound as a colourless gum (0.394 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:16][O:17][CH2:18][CH2:19]O>>[CH3:16][O:17][CH2:18][CH2:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: COCCO
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Product: COCCOC(=O)c1ccc(O)cc1

Procedure:
A mixture of 25.0 g of p-hydroxybenzoic acid, 170 g of methyl glycol (methoxyethanol) and 1 ml of sulfuric acid (conc.) was heated for 8 hours to 110°-115° C. and, after the excess methyl glycol had been distilled off under reduced pressure, was poured onto ice/water. After neutralization with sodium hydrogen carbonate, the aqueous phase was extracted by shaking several times with methylene chloride. The methylene chloride solution was treated with active carbon, concentrated by evaporation and the residue recrystallized from toluene. p-hydroxybenzoic acid 2-methyloxy-ethyl ester melting at 90°-93° C. was obtained in a yield of 27.6 g (78%).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][CH:31]=1)[C:8]([NH:10][C:11]1[CH:28]=[CH:27][C:14]([C:15]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:13][CH:12]=1)=[O:9])(=O)C.[OH-].[Na+]>CO>[OH:4][C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][CH:31]=1)[C:8]([NH:10][C:11]1[CH:28]=[CH:27][C:14]([C:15]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:13][CH:12]=1)=[O:9]
Reactant: CC(=O)Oc1cccc(C(=O)Nc2ccc(C(=O)N3CCCc4ccccc43)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccc(C(=O)N2CCCc3ccccc32)cc1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of 1-[4-(3-acetyloxybenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (1.5 g) in methanol (20 ml) is added 5% aqueous sodium hydroxide solution (10 ml) and the mixture is stirred at room temperature overnight. Methanol is distilled off under reduced pressure and the resulting residue is acidified with diluted aqueous hydrochloric acid solution. The precipitated crystal is collected by filtration and recrystallized from methanol to give 1-[4-(3-hydroxybenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (1.22 g) as white powder, m.p. 217-218° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](O)(=O)[CH3:11]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:10]([CH3:11])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Nc1cc(Br)cnc1N
Product: Cc1nc2cc(Br)cnc2[nH]1
Yield: 82 %

Procedure:
To 5.06 g of 5-bromo-2,3-diaminopyridine 46 (Ryabukhin et al (2006) Synthesis 21:3715-3726; Oguchi et al (2000) J. Med. Chem. 43(16):3052-3066; Seki et al (1995) J. Hetero. Chem. 32(3):1071-73; Fray et al (1995) J. Med. Chem. 38(18):3524-35) was added 50 mL acetic acid under N2 and the reaction was heated to reflux overnight. Complete reaction was confirmed by LCMS. The solution was concentrated in vacuo and purified by flash chromatography (DCM/MeOH) to give 4.68 g of 6-bromo-2-methyl-3H-imidazo[4,5-b]pyridine 51 (82% yield), which may also be prepared by the methods of Cee et al (2007) J. Med. Chem. 50(4):627-40; Itoh et al (1982) J. Hetero. Chem. 19(3):513-17. 6-Bromo-2-methyl-3H-imidazo[4,5-b]pyridine (4.68 g) in 150 mL THF was added to 0.63 g (1.1 eq) NaH in 10 mL THF under N2 at −78° C. The reaction was stirred at −78° C. for 30 minutes followed by the addition of 3.86 g of SEM-Cl(1.05 eq) and allowed to warm up to room temperature. The reaction was stirred at room temperature 4.5 hours and complete reaction was confirmed by LCMS. The reaction was quenched with water followed by the addition of NaCl (not saturated) and the two products extracted with EtOAc and concentrated in vacuo. The two regioisomers were separated by flash chromatography (EtOAc/Hexanes) to give 2.84 g 6-bromo-2-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine 52 and 1.94 g 6-bromo-2-methyl-1-((2-trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine 53 (63% overall yield). 6-Bromo-2-methyl-34(2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine 52 (2.08 g) was dissolved in 50 mL toluene followed by the addition of 2.32 g (1.5 eq) of bis(pinacolato)diboron, 0.24 g (0.05 eq) of PdCl2(dppf), and 1.79 g (3.0 eq) of KOAc. The reaction mixture was heated to 95° C. under N2 and let stir overnight. Complete reaction confirmed by LCMS. The mixture was cooled to room temperature, rotovapped and purified by flash chromatography (EtOAc/Hexanes) to give 1.83 g of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine 54 (77% yield). MS (Q1) 390.2 (M)+
Reaction SMILES: [C-:1]#[N:2].[K+].[N+:4]12[CH2:11][CH2:10][CH2:9][C:8]=1[CH2:7][CH2:6][CH2:5]2>O>[C:1]([C:8]12[CH2:9][CH2:10][CH2:11][N:4]1[CH2:5][CH2:6][CH2:7]2)#[N:2]
Reactant: C1CC2=[N+](C1)CCC2
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Product: N#CC12CCCN1CCC2
Temperature: 20 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of potassium cyanide (0.191 g, 2.86 mmol) in 1.0 ml of water was added over 20 minutes 0.284 g (1.35 mmol) of 1-azoniabicyclo[3.3.0]oct-1(5)-ene (Example 3). The mixture was stirred at 20° C. for 1 hour. To the reaction mixture was added 2 ml of water and extracted with methylene chloride (3×10 ml). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was distilled out in vacuo to afford 171 mg (Yield: 93.3%) of the desired compound.