Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:20])[CH:3]=1.[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Br.C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN(C)C=O>[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:20])[CH:3]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)cc(O)cc2=O)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
Methyl 3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylbenzoate (from Step 1) (16.5 g, 60.4 mmol) 2,4-difluorobenzyl bromide (7.8 ml, 60.4 mmol) were taken up in 250 ml of N,N-dimethylformamide and the mixture was cooled to 0° C. K2CO3 (8.3 g, 60.4 mmol) was added and reaction stirred for 12 hours during which time the reaction was allowed to warm to room temperature. LC/MS indicated the presence of starting material after 12 hours. An excess of K2CO3 was added at room temperature along with 0.50 ml of 2,4-difluorobenzyl bromide. The reaction stirred for an additional two hours. Saturated NaHCO3 (aq.) was poured into reaction vessel. The solution was extracted with ethyl acetate and the organic layers were combined then washed with water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over Na2SO4, and evaporated. The product was carried on to the next step as a crude oil (24.1 g, quantitative yield). 1H NMR (300 MHz, CDCl3) δ 8.06 (dd, J=7.85, 1.61 Hz, 1H), 7.82 (d, J=1.61, 1H), 7.52 7.44 (m, 2H), 7.01-6.88 (m, 2H), 6.05 (d, J=2.62 Hz, 1H), 5.97 (dd, J=2.62, 0.81 Hz, 1H), 5.08 (s, 2H), 3.93 (s, 3H), 2.20 (s, 3H), 1.89 (s, 3H); ES-MS m/z 400 (M+H). ES-HRMS m/z 400.1374 (M+H calcd for C22H20F2NO4 requires 400.1355).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][OH:5].CC(C)([O-])C.[Na+].Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH2:29])[N:15]=1>COCCOC.O>[CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][O:5][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH2:29])[N:15]=1
Reactant: CC(C)CCO
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)CCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 110 °C

Procedure:
To 3-methyl-1-butanol (1.03 mL) in DME (5 mL) was added sodium tert-butoxide (912 mg) in portions over 5 mins with stirring. The mixture was stirred at room temperature until homogeneous. 2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (600 mg) was added followed by DME (4.6 mL). The reaction was heated at 110° C. overnight. The reaction was allowed to cool, was taken up in water (20 mL) and washed with EtOAc (2×20 mL). The organics were extracted with brine, separated, dried over MgSO4, filtered and concentrated in vacuo to give a viscous yellow oil. The crude material was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (30-80%) to afford the title compound as a yellow residue (266 mg).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C:12]([C:13]3[CH2:14][CH2:15][C@@H:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][CH:18]([OH:28])[C:17]4([CH3:30])[CH3:29])=[CH:11][CH2:10]1)[CH3:8])C>C(O)C.[OH-].[Na+]>[OH:28][C@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@@H:16]([CH2:15][CH2:14][C:13]3[C:12]4[C@:26]([CH3:27])([CH2:25][CH2:24][C:23]=32)[C@@H:9]([C@H:7]([CH3:8])[CH2:6][CH2:5][C:4]([OH:31])=[O:3])[CH2:10][CH:11]=4)[C:17]1([CH3:29])[CH3:30]
Reactant: CCOC(=O)CC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CCC(O)C(C)(C)[C@@H]1CC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](CCC(=O)O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 83.3 %

Procedure:
3-Hydroxy-4,4-dimethyl-5α-chola-8,14-dien-24-oic acid ethyl ester (1.9 g) is suspended in a mixture of 190 ml of 96% ethanol and 63 ml of 1M sodium hydroxide. The mixture is stirred for 3.5 h at room temperature. After aqueous work-up and crystallization from ethanol/water, the title compound (1.48 g) is isolated. 1H-NMR (CDCl3, 400 MHz): δ=5.36 (1H, s); 3.22 (1H, m); 1.03 (3H, s). 1.01 (3H, s); 0.97 (3H, d); 0.83 (3H, s); 0.81 (3H, s). MS: Calculated: 400.6. Found 400.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][C@@H:8]([C:15](N1[C@H](C)[C@H](C2C=CC=CC=2)OC1=O)=[O:16])[CH2:9][C@H:10]([CH3:14])[CH2:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].OO.S(=O)(O)[O-:36].[Na+].S([O-])([O-])=O.[Na+].[Na+]>O.C1COCC1.CCOCC.CCCCCC>[C:1]([O:5][C:6](=[O:30])[CH2:7][C@H:8]([CH2:9][C@H:10]([CH3:14])[CH2:11][CH2:12][CH3:13])[C:15]([OH:16])=[O:36])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Reactant: O=S([O-])O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Yield: 92.9 %

Procedure:
To ester 101 (10.8 g, 0.025 mol) in H2O (73 mL) and THF (244 mL) at 0° C. was added a premixed solution of LiOH (51.2 mL of a 0.8 M solution) and H2O2 (14.6 mL of a 30% solution). After 4 hours a further 12.8 mL LiOH (0.8 M solution) and 3.65 mL of H2O2 (30% solution) was added. After 30 minutes sodium bisulfite (7 g), sodium sulfite (13 g), and water (60 mL) was added followed by hexane (100 mL) and ether (100 mL). The two layers were separated and the aqueous layer extracted with ether. The combined organic phases were concentrated to an oil that was dissolved in heptane (300 mL). The resultant solid was filtered off and the filtrate dried (MgSO4) and concentrated to afford an oil (6 g, 93%) which was used without further purification. MS, m/z (relative intensity): 257 [M+H, 100%].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[CH3:9].[OH-:10].[K+].O>CO>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: Cc1c(Cl)cccc1Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1c(O)cccc1Cl

Procedure:
8.1 g (0.05 mol) of 2,6-dichlorotoluene and 9.9 g (0.15 mol) of potassium hydroxide (85%) are heated in 40 ml of methanol in an autoclave at 200° C. for 20 hours, which results in a pressure of 30 bar. After cooling, the reaction mixture is poured into 250 ml of water and extracted three times with 70 ml of dichloromethane. The aqueous phase is acidified to pH 1-2 with 30% hydrochloric acid and again extracted three times with 70 ml of dichloromethane each time. The united organic phases are dried over sodium sulphate and evaporated under reduced pressure to give a solid. 3-Chloro-2-methylphenol is obtained as a solid (6.2 g, content by HPLC: 93.5%, 82% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](/[C:16](/[CH2:29]C)=[C:17](/[F:28])\[CH:18]=[CH:19]\[C:20](\[CH3:27])=[CH:21]\[C:22]([O:24]CC)=[O:23])=[CH:6][C:7]2[CH:8]=[CH:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2].[OH-].[Na+]>>[CH2:1]([O:3][C:4]1[C:5](/[C:16](/[CH3:29])=[C:17](/[F:28])\[CH:18]=[CH:19]\[C:20](\[CH3:27])=[CH:21]\[C:22]([OH:24])=[O:23])=[CH:6][C:7]2[CH:8]=[CH:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(cc1OCC)C(C)(C)CC=C2
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)O)C=CCC2(C)C

Procedure:
Following General Procedure J-1, ethyl (2E,4E,6E)-7-(3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-6-fluoro-3-methyl-nona-2,4,6-trienoate (Compound A-68, 23 mg, 0.056 mmol) was hydrolyzed with 1M NaOH to yield the title compound as a yellow solid after purification by column chromatography (silica gel, 10% ethyl acetate in hexanes) followed by recrystallization from acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH:9]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:17][C:18]1C(NC2CCCCC2)=NC=CC=1>>[CH:9]1([N:8]2[C:3]3=[N:4][CH:5]=[CH:6][CH:7]=[C:2]3[N:1]=[C:18]2[NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1cccnc1NC1CCCCCCC1
Reactant: Nc1cccnc1NC1CCCCC1
Product: Nc1nc2cccnc2n1C1CCCCCCC1

Procedure:
The experimental protocol is identical with that used in Example 1, starting in Step a from 3-amino-2-cyclooctylaminopyridine of Preparation 3 instead of 3-amino-2-cyclohexylaminopyridine.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:6][CH:5]=[CH:4][C:3]=1[C:16]1[NH:17][CH2:18][C:19]([CH3:25])([C:21]([O:23]C)=[O:22])[N:20]=1.[OH-].[Na+]>CO.O>[OH:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:6][CH:5]=[CH:4][C:3]=1[C:16]1[NH:17][CH2:18][C:19]([CH3:25])([C:21]([OH:23])=[O:22])[N:20]=1
Reactant: COCCOCCOc1cccc(C2=NC(C)(C(=O)OC)CN2)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCOCCOc1cccc(C2=NC(C)(C(=O)O)CN2)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of methyl 2-(2-hydroxy-3-(2-(2-methoxyethoxy)ethoxy)phenyl)-4-methyl-4,5-dihydro-1H-imidazole-4-carboxylate (0.85 g, 0.25 mmol) in MeOH (5 mL) was added NaOH (20 mg, 0.5 mmol) and water (one drop). The resulting mixture was stirred for 2 h at room temperature. The solvent was evaporated under vacuum and the residue was purified by Combi Flash to obtain the title compound as colorless oil (50 mg, 60%). 1H NMR (300 MHz, CD3OD, n=2): δ 7.40-7.50 (m, 1H), 7.10-7.25 (m, 1H), 6.75-6.95 (m, 1H), 4.30-4.40 (m, 1H), 4.15-4.25 (m, 2H), 3.75-3.95 (m, 2H), 3.45-3.75 (m, 5H), 3.35 (s, 3H), 1.67 (s, 3H). LC-MS (ES, m/z): 339 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:34][CH3:35])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[CH:33]=[CH:32][S:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36].ClC1C=C(C=CC=1)C(OO)=[O:42]>C(Cl)Cl.CN(C=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:34]([CH3:35])=[O:42])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[CH:33]=[CH:32][S:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(-c2cc(NC(=O)c3ccsc3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
N-{3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophene-carboxamide (0.052 g, 0.1 mmol) was dissolved in a mixture of CH2Cl2 (10 mL) and DMF (0.5 mL). Then 3-chloroperoxybenzoic acid (50-60%) (0.03 g, ˜0.1 mmol) was added and the mixture stirred for 45 min at room temperature. Solvent was pumped off in vacuo to give the title compound plus a small amount of the corresponding sulfone. The mixture was used without further purification. LC-MS m/z 540 (M+H)+, 1.76 min (ret. time).
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=[O:6])[CH3:5].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:9]1([NH:8]/[C:2](/[CH3:1])=[CH:3]\[C:4](=[O:6])[CH3:5])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1
Reactant: CC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)/C=C(/C)Nc1ccccc1

Procedure:
A solution of 2,4-pentanedione (51.5 mL), aniline (45.6 mL) and a catalytic amount of para-toluenesulfonic acid monohydrate (0.95 g) in toluene (500 ml) was refluxed for 3.5 h in a round bottom flask equipped with a Dean-Stark apparatus and condenser. The solution was concentrated to dryness to give the desired compound as an orange oil (89.3 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]4[CH3:26])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:27]([O:29]C)=[O:28])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:31]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]4[CH3:26])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:27]([OH:29])=[O:28])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:31]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(F)ccc4o3)c(N3CCCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H]1CCCCN1c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(F)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a solution of (S)-methyl 2-(5-fluorobenzofuran-2-yl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate (120 mg, 0.29 mmol) in MeOH (20 mL) was added sodium hydroxide (46 mg, 1.15 mmol) and water (3 mL). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (10 mL) and adjusted to pH 5 with hydrochloric acid (1N). The solids were collected by filtration to afford (S)-2-(5-fluorobenzofuran-2-yl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (113 mg, 97%).
Reaction SMILES: ClN([C:10]1[C:19]2[C:14](=[CH:15][C:16](O)=[C:17](OC)[CH:18]=2)[N:13]=[CH:12][N:11]=1)C1C=CC=CC=1F.BrCCCOC1CCCCO1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[N:11][CH:12]=1
Reactant: COc1cc2c(N(Cl)c3ccccc3F)ncnc2cc1O
Agent: BrCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2ncncc2c1
Temperature: 90 °C
Yield: 172.9 %

Procedure:
A mixture of 4-(chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (3.28 g, 10 mmol), (prepared as described for the starting material in Example 2), 1-bromo-3-tetrahydropyranyloxypropane (2.5 g, 11 mmol) and potassium carbonate (5.0 g, 36 mmol) in DMF (50 ml) was stirred and heated at 90° C. for 3 hours. The reaction mixture was allowed to cool, was diluted with water (500 ml) and extracted with ethyl acetate (3×100 ml). The extracts were combined, washed with water (×3), and then brine, and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by column chromatography eluting with ethyl acetate. The purified product was recrystallized from ethyl acetatethexane to give 4-(chloro-2-fluoroanilino)-6-methoxy-7-tetrshydropyran-2-yloxypropoxy)quinazoline (2.25 g, 49%).
Reaction SMILES: [F:1][C:2]1([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[CH2:5][O:4][CH2:3]1.Cl.[NH2:15][OH:16].C(N(CC)CC)C>C(O)C.O>[F:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:10](=[N:15][OH:16])[NH2:11])=[CH:12][CH:13]=2)[CH2:3][O:4][CH2:5]1
Reactant: N#Cc1ccc(C2(F)COC2)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=NO)c1ccc(C2(F)COC2)cc1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
A solution of 4-(3-fluorooxetan-3-yl)benzonitrile (Step 2, 450 mg, 2.54 mmol), hydroxylamine hydrochloride (388 mg, 5.59 mmol) and triethylamine (779 μL, 5.59 mmol) in ethanol (12.5 mL) was stirred and heated at reflux over night. After being cooled to rt, the reaction mixture was diluted with water (75 mL) whereupon the product precipitated. Filtration, washing with water and drying in a vacuum oven afforded a first crop of the title compound (360 mg, 67%). A second crop was obtained after concentration of the filtrate (122 mg, 21%, purity 90%): 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.77 (d, 2H), 7.54 (d, 2H), 5.87 (broad s, 2H), 4.97 (dd, 2H), 4.91 (dd, 2H); DCI(NH3)-MS m/z 211 (MH)+; HPLC RT (Method I) 2.64 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][C:13]1[CH:14]=[N:15][NH:16][C:17]=1[CH:18]=O>CC(N(C)C)=O>[Br:12][C:13]1[CH:14]=[N:15][NH:16][C:17]=1[C:18]1[NH:6][C:4](=[O:5])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][C:7]=2[F:11])[N:1]=1
Reactant: NC(=O)c1c(N)cccc1F
Reactant: O=Cc1[nH]ncc1Br
Solvent: CC(=O)N(C)C
Product: O=c1[nH]c(-c2[nH]ncc2Br)nc2cccc(F)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 19.4 %

Procedure:
2-Amino-6-fluorobenzamide (77 mg, 0.50 mmol) was dissolved under argon in dimethylacetamide (5 ml), 4-bromo-1H-pyrazole-5-carbaldehyde (88 mg, 0.50 mmol) and Na2S2O5 (143 mg, 0.75 mmol) were added, and the mixture was stirred under reflux conditions for 5 h. After cooling to room temperature, the reaction mixture was concentrated and taken up with a mixture of acetonitrile and N,N-dimethylformamide. Filtration with suction and thorough drying of the remaining solid gave 2-(4-bromo-1H-pyrazol-5-yl)-5-fluoroquinazolin-4(3H)-one (30 mg, 19% of theory) as a colorless solid. 1H NMR (400 MHz, d6-DMSO δ, ppm) 13.91 (br. s, 1H, NH), 12.03 (br. s, 1H, NH), 8.22 (s, 1H), 7.80 (dd, 1H), 7.51 (d, 1H), 7.27 (dd, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[CH:25]([C@@H:28]1[C:32]([CH3:34])([CH3:33])[O:31][C:30](=[O:35])[NH:29]1)([CH3:27])[CH3:26]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:29]4[C@H:28]([CH:25]([CH3:26])[CH3:27])[C:32]([CH3:33])([CH3:34])[O:31][C:30]4=[O:35])=[CH:3][C:4]=3[CH3:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC(C)[C@H]1NC(=O)OC1(C)C
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC(C)(C)[C@H]4C(C)C)cc3C)CC2)c(C)c1
Yield: 3.4 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (867 mg) described in Preparation Example 67 and (R)-(+)-4-isopropyl-5,5-dimethyloxazolidin-2-one (409 mg), the title compound (35 mg) was obtained.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:15])[CH:10]=[C:11]([CH2:13]O)[N:12]=2)=[CH:4][CH:3]=1.[N-:16]=[N+:17]=[N-:18].[Na+].O.CCOC(C)=O>O=S(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:15])[CH:10]=[C:11]([CH2:13][N:16]=[N+:17]=[N-:18])[N:12]=2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1cc(CO)nc1-c1ccc(I)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=S(Cl)Cl
Product: Cn1cc(CN=[N+]=[N-])nc1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of (2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methanol prepared above (46 mg, 0.15 mmol) in SOCl2 (2 mL) was stirred at room temperature for 15 min. It was concentrated in vacuo to give a residue, which was then partitioned between EtOAc and 5% aq. NaHCO3. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was dissolved in DMF (2 mL). To the solution, NaN3 (70 mg, 1.1 mmol) was added. After the mixture was stirred at room temperature for 2 days, water and EtOAc were added. The organic layer was separated, dried over Na2SO4, concentrated in vacuo to give (2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methyl azide (46 mg). MS 340.0 (M+H).
Reaction SMILES: Cl.C1(C(C2C=CC=CC=2)[N:9]2[CH2:12][CH:11]([OH:13])[CH2:10]2)C=CC=CC=1.Cl.P([O-])([O-])(O)=O.[K+].[K+].[F:28][C:29]1[CH:30]=[C:31]([N+:36]([O-:38])=[O:37])[CH:32]=[CH:33][C:34]=1F>CO.O.[OH-].[OH-].[Pd+2].CO.C(Cl)(Cl)Cl>[F:28][C:29]1[CH:30]=[C:31]([N+:36]([O-:38])=[O:37])[CH:32]=[CH:33][C:34]=1[N:9]1[CH2:12][CH:11]([OH:13])[CH2:10]1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [Pd+2]
Agent: Cl
Agent: O=P([O-])([O-])O
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CC(O)C2)c(F)c1
Reaction time: 16 h
Yield: 64.7 %

Procedure:
1-(Diphenylmethyl)-3-azetidinol hydrochloride (2.000 g, 7.29 mmol) was dissolved in methanol (75 mL) and treated with 6N HCl (1.20 mL, 7.29 mmol). Palladium hydroxide on carbon (0.200 g) was then added under a nitrogen stream. The reaction mixture was then shaken on a Parr apparatus under 40 psi of H2. After 16 h, TLC analysis (5% methanol/chloroform) revealed the starting material was consumed. The reaction mixture was filtered through Celite® and concentrated under reduced pressure to an amber oil. This material was dissolved in dimethylsulfoxide (29 mL) and the atmosphere replaced with nitrogen. Dipotassium hydrogen phosphate (5.07 g, 29.2 mmol) was added followed by 3,4-difluoronitrobenzene (0.966 mL, 8.75 mmol). The mixture was stirred at ambient temperature under nitrogen. After 3 h, TLC analysis (5% methanol/chloroform) revealed the reaction to be complete. The reaction mixture was diluted with water (250 mL) and extracted with chloroform (4×50 mL). The combined organic extracts were washed with water (2×50 mL) and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow solid. Chromatography over silica gel (100 g), eluting with a gradient of 3-7% acetonitrile/chloroform afforded, after concentration of appropriate fractions, 1.00 g (65%) of the title compound as an orange solid with mp 130.5°-132° C. and MS(EI) 212 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([OH:12])([CH3:11])[CH3:10].[Cl:13][CH2:14][C:15](Cl)=[O:16]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15](=[O:16])[CH2:14][Cl:13])=[C:3]([C:9]([OH:12])([CH3:10])[CH3:11])[CH:4]=1
Reactant: CC(C)(O)c1cc(Br)ccc1N
Reactant: O=C(Cl)CCl
Product: CC(C)(O)c1cc(Br)ccc1NC(=O)CCl

Procedure:
Prepared from 2-(2-amino-5-bromophenyl)propan-2-ol and chloro acetyl chloride generally according to the procedure described in example 1. An off-white solid: mp 133-134° C. 1H-NMR (DMSO-d6) δ 11.21 (s, 1H), 8.12 (d, J=8.6 Hz, 1H), 7.46 (dd, J=8.6, 2.3 Hz, 1H), 7.44 (d, J=2.3 Hz, 1H), 6.28 (s, 1H), 4.43 (s, 2H), 1.53 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]1.[C:15]1([C:21]2[O:25][CH:24]=[N:23][C:22]=2[C:26](O)=[O:27])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH:12][C:26]([C:22]2[N:23]=[CH:24][O:25][C:21]=2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:27])[CH:9]=[N:8]1
Reactant: CC(F)(F)CCCCn1cc(N)cn1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(F)(F)CCCCn1cc(NC(=O)c2ncoc2-c2ccccc2)cn1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)=[O:8]>[Pd].C1COCC1>[NH2:15][C:11]1[CH:10]=[C:9]([C:7]([C:6]2[S:5][C:4]([NH:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:3][C:2]=2[NH2:1])=[O:8])[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1nc(Nc2ccccc2)sc1C(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc(C(=O)c2sc(Nc3ccccc3)nc2N)c1

Procedure:
A mixture of the title compound from Example A(1) ((4-amino-2-phenylamino-thiazol-5-yl)-(3-nitrophenyl)-methanone, 520 mg, 1.53 mmol) and 10% palladium on carbon (80 mg) in THF (10 mL) was stirred under a hydrogen atmosphere overnight. The catalyst was filtered off and the filtrate concentrated in vacuo to give 470 mg of a crude solid that recrystallized from ethyl acetate/benzene to provide 100 mg (19% yield) of light yellow powder, mp 162-164° C.