Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[N:11]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[N:12]1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[N:11]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[N:12]1
Reactant: COC(=O)c1ccn(-c2ccc(OC)cc2OC)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1ccn(-c2ccc(O)cc2O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 1-(2,4-dimethoxyphenyl)-1H-pyrazole-3-carboxylate 2 (1.00 g, 3.82 mmol, 1.00 equiv) in DCM (20 mL) was added BBr3 (9.55 g, 38.2 mmol, 10 equiv) at −40° C. The resulting solution was stirred overnight at room temperature. The mixture was quenched by the addition of 10 mL of water and the reaction mixture was extracted with 3×200 mL of ethyl acetate. The combined organic layers were washed with 200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.8 g (90%) of methyl 1-(2,4-dihydroxyphenyl)-1H-pyrazole-3-carboxylate 3 as a white solid. LC-MS: m/z=235 (MH)+.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19](O)=[O:20])=[CH:11][N:10]=1.[O:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[C:12]([C:19]([NH:29][CH2:28][CH:25]2[CH2:26][CH2:27][O:22][CH2:23][CH2:24]2)=[O:20])=[CH:11][N:10]=1
Reactant: NCC1CCOCC1
Reactant: O=C(O)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC1CCOCC1)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.2 %

Procedure:
To a mixture of rac-2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (150 mg) and N,N-dimethyl formamide (3.0 mL) were added 1-(tetrahydro-2H-pyran-4-yl)methylamine (69 mg), 1-hydroxybenzotriazole (81 mg), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg) in this order at room temperature, and then the mixture was stirred at room temperature for 5 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine in this order, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate). The obtained colorless oily substance was solidified using ethanol-water to obtain rac-2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-N-(tetrahydro-2H-pyran-4-ylmethyl)-4-(trifluoromethyl)pyrimidine-5-carboxamide (173 mg) as a white solid.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]1[CH:19]=[N:20][NH:21][CH:22]=1)=[CH:13][CH:12]=2.[CH:23]12[O:28][CH:27]1[CH2:26][CH2:25][CH2:24]2>CN(C=O)C>[Cl:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]1[CH:22]=[N:21][N:20]([CH:26]3[CH2:25][CH2:24][CH2:23][CH:27]3[OH:28])[CH:19]=1)=[CH:13][CH:12]=2
Reactant: Clc1cc2cc(-c3cn[nH]c3)ccc2cn1
Reactant: C1CC2OC2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OC1CCCC1n1cc(-c2ccc3cnc(Cl)cc3c2)cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
A mixture of Cs2CO3 (45.4 mg, 0.139 mmol), 3-chloro-6-(1H-pyrazol-4-yl)isoquinoline (16 mg, 0.070 mmol) and 6-oxabicyclo[3.1.0]hexane (Preparation 37, 23.4 mg, 0.279 mmol) in DMF (3 mL) was stirred at 120° C. under microwave irradiation for 60 minutes. The reaction was cooled, concentrated in vacuo and purified using Biotage silica gel column chromatography eluting with 50-75% EtOAc/cyclohexane to give the title compound as white solid (11 mg, 50%).
Reaction SMILES: [N:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:14]([N:18]1[C:22](=[O:23])[C:21](Cl)=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[S:19]1(=[O:33])=[O:32])[CH2:15][CH2:16][CH3:17]>CN(C=O)C>[CH2:14]([N:18]1[C:22](=[O:23])[C:21]([NH:11][C:10]2[CH:12]=[CH:13][C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[CH:8][CH:9]=2)=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[S:19]1(=[O:32])=[O:33])[CH2:15][CH2:16][CH3:17]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CCCCN1C(=O)C(Cl)=C(c2cccc(Cl)c2)S1(=O)=O
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C(Nc2ccc(N3CCOCC3)cc2)=C(c2cccc(Cl)c2)S1(=O)=O
Temperature: 140 °C
Yield: 184.9 %

Procedure:
4-Morpholin-4-ylaniline (53 mg, 0.30 mmol) was added to a solution of 2-butyl-4-chloro-5-(3-chlorophenyl)isothiazol-3(2H)-one 1,1-dioxide (50 mg, 0.15 mmol) in dry DMF (1.0 mL) at rt and under an atmosphere of nitrogen. The reaction mixture was heated in a microwave reactor at 140° C. for 25 mins, whereafter the solvents were removed. Another portion of 4-morpholin-4-ylaniline (160 mg, 0.90 mmol) was added to a solution of 2-butyl-4-chloro-5-(3-chlorophenyl)isothiazol-3(2H)-one 1,1-dioxide (150 mg, 0.45 mmol) in dry DMF (2.0 mL) at rt and under an atmosphere of nitrogen. The reaction mixture was heated in a microwave reactor at 140° C. for 25 mins, whereafter the solvents were removed. The obtained two mixtures were combined and purified using preparative HPLC (column ACE C8, 0.1M NH4OAc/MeCN, gradient) followed by column chromatography (Horizons Biotage, Heptane:EtOAc, 3:1, isocratic run) to give the title compound (132 mg, 62%) as a yellow solid; 1H NMR (500 MHz, CDCl3): δ 7.22 (bs, 1H), 7.13-7.19 (m, 2H), 7.06-7.11 (m, 1H), 6.93-6.96 (m, 1H), 6.65-6.69 (m, 2H), 6.55-6.60 (m, 2H), 3.82-3.86 (m, 4H), 3.75-3.80 (t, 2H), 3.04-3.08 (m, 4H), 1.83-1.91 (m, 2H), 1.44-1.52 (m, 2H), 1.01 (t, 3H); 13C NMR (125 MHz, CDCl3): δ 159.3, 149.8, 134.2, 132.6, 130.3, 129.3, 129.0, 127.9, 127.3, 126.8, 124.3, 115.6, 107.8, 66.9, 49.6, 40.5, 30.4, 20.3, 13.8; Mass Spectrum: M−H 474.
Reaction SMILES: N=[C:2]1[N:7]2[CH:8]=[CH:9][C:10]3[C:15]([C:6]2=[N:5][CH:4]=[C:3]1[C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3.C(O)(=[O:23])C>Cl.O>[O:23]=[C:2]1[N:7]2[CH:8]=[CH:9][C:10]3[C:15]([C:6]2=[N:5][CH:4]=[C:3]1[C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: CCOC(=O)c1cnc2c3ccccc3ccn2c1=N
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: O=C(O)c1cnc2c3ccccc3ccn2c1=O

Procedure:
A solution of ethyl 4-imino-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (1.0 g.) in acetic acid (20 ml.) and 37% hydrochloric acid (20 ml.) was refluxed for 35 minutes. The solution was cooled and diluted with H2O to precipitate the crude acid (760 mg.), m.p. 219°-231° (prior softening). Recrystallized material (2-methoxyethanol) and a m.p. of 249°-252° and mixed melting point of 252°-255° with product from Example 2.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]12[C:17](=[O:18])O[C:14](=[O:15])[C:12]3=[C:13]1[C:8](=[CH:9][CH:10]=[CH:11]3)[CH:7]=[CH:6][CH:5]=2>N1C=CC=CC=1>[CH:6]1[CH:5]=[C:4]2[C:17]([N:2]([OH:3])[C:14]([C:12]3=[CH:11][CH:10]=[CH:9][C:8](=[C:13]23)[CH:7]=1)=[O:15])=[O:18]
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C1c2cccc3cccc(c23)C(=O)N1O
Temperature: 40 °C
Yield: 80.9 %

Procedure:
A 3-L flask equipped with a stirrer, cooling tube and thermometer was purged by nitrogen gas. 55.2 g (770 mmol) of hydroxylamine-hydrochloride (purity of 97%) and 1.2 L of pyridine were added to the flask and were stirred to dissolve at room temperature under nitrogen atmosphere. To the stirred mixture, 138.7 g (700 mmol) of 1,8-naphthalenedicarboxylic anhydride was added. The stirred mixture was heated at 40° C. for 1 hour and subsequently was heated at 70° C. for 1 hour. After stirring at 90° C. for 1 hour, the reaction mixture was cooled to room temperature with stirring. The resulting crystalline solid was filtered off and washed with 5% by weight of acetic acid aqueous solution and dried at 80° C. for 20 hours under a reduced pressure to yield 120.7 g (81%) of N-hydroxynaphthalimide with yellow color.
Reaction SMILES: O[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13].P(Cl)(Cl)(Cl)=O>>[Cl:13][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1nc(O)ccc1[N+](=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 1 h
Yield: 277.5 %

Procedure:
A mixture of 2.42 gm (15.7 mMol) 6-hydroxy-3-nitro-2-picoline, 1.0 gm phosphorus pentachloride, and 0.5 mL phosphorus oxychloride was heated at 110° C. for 2.5 hours. The reaction mixture was cooled to room temperature and then an additional 0.5 gm of phosphorus pentachloride and 0.5 mL phosphorus oxychloride were added. Heating was resumed for one hour at which point the reaction mixture poured into 100 mL of an ice/water slurry. The resultant slurry is filtered and the solid dried under vacuum to provide 2.3 gm (85%) of the desired compound as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]=[N:8][NH:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.O=P(Cl)(Cl)[Cl:21]>ClC1C=CC=CC=1>[Cl:21][C:6]1[C:5]2[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:9]=[N:8][CH:7]=1
Reactant: Cc1ccc2c(=O)cn[nH]c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: Clc1ccccc1
Product: Cc1ccc2c(Cl)cnnc2c1
Yield: 69.1 %

Procedure:
7-Methyl-1-H-cinnolin-4-one (1.3 g, 8.1 mmol) is treated with about 80 mL of chlorobenzene and heated until the solid dissolves. The resulting solution is cooled and treated with pyridine (0.16 mL, 2 mmol) and POCl3 (1.13 mL, 12.2 mmol). The solution is heated to reflux for 1 h then concentrated to dryness. The residue is chromatographed (20% ethyl acetate/hexane) to yield the title compound as a tan solid (˜1 g, 5.6 mmol). MS m/z (M+=178); 1H NMR (CDCl3, 300 MHz) δ9.3 (s, 1H), 8.35 (s, 1H), 8.1 (d, 1H), 7.7 (d, 1H), 2.68 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[C:13]([N+:19]([O-])=O)[CH:12]=3)=[O:5])[CH3:2].[ClH:22].[H][H]>C(O)C.[Pt](=O)=O>[ClH:22].[ClH:22].[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[C:13]([NH2:19])[CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1cc([N+](=O)[O-])ccc12
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc2c(cn1)[nH]c1cc(N)ccc12

Procedure:
0.1 g of 7-nitro-β-carbolin-3-carboxylic acid ethyl ester is suspended in 30 ml of ethanol and, after the addition of 1 ml of 5N hydrochloric acid, is hydrogenated at normal pressure over 25 mg of platinum dioxide until the theoretical amount of hydrogen has been absorbed. The catalyst is filtered off and washed well with warm ethanol. The filtrate is treated with active carbon and concentrated until turbidity commences. After cooling, 95 mg of 7-amino-β-carbolin-3-carboxylic acid ethyl ester dihydrochloride of melting point 270° C. (decomposition) is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[N:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:21]1[CH:22]=[C:23]2[C:28]([CH:27]=[CH:26][CH:25]=[CH:24]2)=[N:20]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: c1ccc2[nH]ncc2c1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)Cn1cc2ccccc2n1

Procedure:
Using general procedure 4 and purification method E with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.25 g, 0.95 mmol) and indazole (0.56 g, 4.74 mmol) gives the title compound.
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH2:12]([OH:16])[C@H:13]([OH:15])[CH3:14].N1C=CN=C1>CN(C=O)C>[CH:1]([Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[O:16][CH2:12][C@H:13]([OH:15])[CH3:14])([CH3:3])[CH3:2]
Reactant: C[C@@H](O)CO
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](OC[C@@H](C)O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.7 %

Procedure:
Triisopropylsilyl chloride (83.8 mL, 390 mmol) was added slowly over 15 minutes to a solution of (2R)-propane-1,2-diol (29.7 g, 390 mmol) in DMF at 0° C. (100 mL) keeping the internal temperature below 15° C. This was followed by addition of imidazole (66.4 g, 975 mmol) and the reaction mixture was allowed to warm to RT and stirred under argon for 20 hours. The reaction was quenched with 1M hydrochloric acid/diethyl ether (300 mL/800 mL). The organic layer was separated and washed with 1M hydrochloric acid followed by saturated brine solution. The organic layer was dried (MgSO4), filtered and evaporated. Purification by distillation at 10 mmHg, 90-104° C., afforded the title compound as colourless oil (69.5 g).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH2:10][C@@H:11]([C@@H:19]([OH:22])[CH2:20][CH3:21])[CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[C:23]([N:27]=[C:28]=[S:29])([CH3:26])([CH3:25])[CH3:24]>C(O)C>[C:23]([NH:27][C:28]([NH:10][C@H:11]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C@@H:19]([OH:22])[CH2:20][CH3:21])=[S:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC[C@H](O)[C@H](N)Cc1ccncc1
Reactant: CC(C)(C)N=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC[C@H](O)[C@@H](Cc1ccncc1)NC(=S)NC(C)(C)C
Temperature: 50 °C

Procedure:
4.3 cm3 of triethylamine are added to a solution of 3.6 g of (2R,3S)-2-amino-1-(4-pyridyl)-3-pentanol dihydrochloride in 60 cm3 of ethanol, followed by addition of 2.6 cm3 of tert-butyl isothiocyanate. The mixture is heated at a temperature in the region of 50° C. for 18 hours. After cooling, the reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. and the residue is taken up in 50 cm3 of water and 100 cm3 of dichloromethane. The organic phase is washed with 30 cm3 of water, dried over sodium sulphate, filtered and concentrated under the above conditions. 4.3 g of N-tert-butyl-N′-[(1R,2S)-1-(4-pyridylmethyl)-2-hydroxybutyl]thiourea are obtained in the form of a thick colourless oil [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 0.80 (t, J=7.5 Hz: 3H); from 1.25 to 1.55 (mt: 2H); 1.37 (s: 9H); 2.72 (dd, J=14 and 9 Hz: 1H); 2.93 (dd, J=14 and 4.5 Hz: 1H); 3.37 (mt: 1H); 4.60 (mt: 1H); 4.88 (unresolved complex: 1H); 7.11 (s: 1H); 7.16 (d, J=8.5 Hz: 1H); 7.26 (broad d, J=5.5 Hz: 2H); 8.43 (broad d, J=5.5 Hz: 2H)].
Reaction SMILES: [C:1]1([CH2:6][SH:7])[S:5][CH:4]=[CH:3][CH:2]=1.C(N1C(=O)C2=CC=CC=[C:12]2[C:11]1=[S:20])C>>[CH2:11]([S:20][S:7][CH2:6][C:1]1[S:5][CH:4]=[CH:3][CH:2]=1)[CH3:12]
Reactant: CCN1C(=O)c2ccccc2C1=S
Reactant: SCc1cccs1
Product: CCSSCc1cccs1

Procedure:
Starting from thenylmercaptan and N-ethylthiophthalimide there is obtained ethyl-thenyl-disulphide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:15]=[C:14]([CH2:16][O:17][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[N:13]=[CH:12]2)=[CH:6][CH:5]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]2[CH:15]=[C:14]([CH2:16][OH:17])[N:13]=[CH:12]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(Cn2cnc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cn2cnc(CO)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4-tert-Butyldiphenylsilyloxymethylimidazol-1-yl-methyl)benzoic acid methyl ester (1.6 g, 3.3 mmol) and tetrabutylammonium fluoride 1M in THF (3.3 ml, 3.3 mmol) in THF (10 ml) was stirred under argon at room temperature for 2 h. Water (15 ml) was added, the mixture was extracted with AcOEt, the organic phase washed with water, brine and dried over MgSO4.
Reaction SMILES: C([O:8][C:9]1[C:14]2[C:15]([CH2:22][C:23]([O:25][CH2:26]C)=[O:24])([OH:21])[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:13]=2[CH:12]=[C:11]([C:28]([CH3:36])([CH3:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:10]=1)C1C=CC=CC=1.[H][H]>CO>[OH:21][C:15]1([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:14]2[C:9]([OH:8])=[CH:10][C:11]([C:28]([CH3:35])([CH3:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:12][C:13]=2[O:18][C:17]([CH3:19])([CH3:20])[CH2:16]1
Reactant: [H][H]
Reactant: CCCCCCC(C)(C)c1cc(OCc2ccccc2)c2c(c1)OC(C)(C)CC2(O)CC(=O)OCC
Solvent: CO
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)CC2(O)CC(=O)OC
Yield: 33.3 %

Procedure:
A mixture of 655 mg (1.37 mmole) 5-benzyloxy-4-ethoxycarbonylmethyl-4-hydroxy-2,2-dimethyl-7(1,1-dimethylheptyl)-3,4-dihydro-2H-benzopyran, 133 mg 5% palladium-on-calcium carbonate and 50 ml methanol was hydrogenated at 38 psi (2.7 kg/cm2) until hydrogen uptake ceased. The mixture was filtered, the filtrate evaporated in vacuo and the residual oil taken up in hexane. Upon cooling, crystals formed which were collected by filtration, 66 mg. The mother liquor was evaporated in vacuo to an oil, pentane added and the mixture refrigerated overnight. Filtration gave an additional 179 mg of product. 1H-NMR(CDCl3)ppm(delta): 3.00 (dd, 2H), 3.20 (s, 2H), 3.70 (s, 3H), 4.90 (s, 1H), 6.35 (m, 2H), 7.65 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][CH:9]3[CH2:14][CH:10]3[C:11]=2[NH:12][N:13]=1)=O)C.[OH-].[NH4+:16]>O1CCOCC1>[CH2:14]1[CH:9]2[CH2:8][C:7]3[C:6]([C:4]([NH2:16])=[O:3])=[N:13][NH:12][C:11]=3[CH:10]12
Reactant: CCOC(=O)c1n[nH]c2c1CC1CC21
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: NC(=O)c1n[nH]c2c1CC1CC21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of the ester from Step C (14.2 g, 73.9 mmol) in dioxane (140 mL) was added ammonium hydroxide (28% NH3 in H2O, 750 mL). The mixture was placed in a 1000 mL pyrex bottle and agitated on a shaker plate for 22 h at rt. The mixture was concentrated in vacuo to a total volume of 100 mL at which time a light yellow precipitate was evident. The mixture was filtered and the solid was washed with H2O (2×100 mL). Further drying of the solid in vacuo gave 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid amide [HPLC/MS: Discovery® C18 column (5 μ, 50×2.1 mm), 5% v/v CH3CN (containing 1% v/v TFA) in H2O (containing 1% v/v TFA) gradient to 99% v/v CH3CN in H2O, 0.75 mL/min, tr=1.09 min, ESI+=164.0 (M+H)] as a white solid.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH3:10][N:11]([CH3:17])[C@@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([N:14]2[CH2:15][CH2:16][C@@H:12]([N:11]([CH3:17])[CH3:10])[CH2:13]2)=[N:3][CH:4]=1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: Cc1cc(Br)cnc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cnc1N1CC[C@@H](N(C)C)C1
Yield: 92.3 %

Procedure:
Combine 2,5-dibromo-3-methyl-pyridine (2.00 g, 7.97 mmol) with dimethyl-(R)-pyrrolidin-3-yl-amine (2.40 g, 20.72 mmol) and p-toluenesulfonic acid monohydrate (0.39 g, 2.07 mmol) in a sealed tube and heat at 100° C. overnight. Dilute with EtOAc (100 mL), wash with saturated NaHCO3 (3×40 mL), dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography, eluting with 2% NH3H2O in 1:1 CH3OH:EtOAc to give 2.09 g (99%) of the title compound. LC-MS/ES m/z (79Br) 284.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([O:16]C)=[O:15])=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[Li+].[OH-].Cl>C1COCC1>[NH2:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(C2CCCCC2)ccc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ccc(C2CCCCC2)nc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 18 %

Procedure:
To a solution of methyl 3-amino-6-cyclohexylpicolinate (1.0 equiv) in THF, at a concentration of 0.5 M, was added 1M LiOH (4.0 equiv). After stirring for 4 hours at room temperature, 1 N HCl (4.0 equiv.) was added and the THF was removed in vacuo. The resulting solid was filtered, rinsed with cold H2O (3×20 mL) yielding 3-amino-6-cyclohexylpicolinic acid (18%). LCMS (m/z): 221.0 (MH+); LC Rt=4.1 min
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1.[C:13]([NH2:16])(=[O:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>O>[C:13]([NH:16][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1)(=[O:15])[CH3:14]
Reactant: CC(N)=O
Reactant: Cc1ccc2nc(Cl)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)Nc1ccc2cc(C)ccc2n1
Temperature: 230 °C
Yield: 73.9 %

Procedure:
Chloride 44 (0.300 g, 1.69 mmol) was diluted with molten anhydrous acetamide (8 g, 135 mmol), and K2CO3 (1.17 g, 8.45 mmol) was added. The mixture was heated in a sand bath, at reflux (˜230° C.) for 16 h. The mixture was cooled, poured into H2O (120 mL) and extracted with EtOAc (4×30 mL). The organic layers were washed with H2O (3×100 mL) and sat. aq. NaCl (50 mL) and dried over anhydrous sodium sulfate and concentrated. Purification of the residue by flash column chromatography (SiO2), eluting with a gradient of 10% EtOAc in CH2Cl2 to 30% EtOAc in CH2Cl2 afforded the desired compound as a white solid (0.250 g, 74%). 1H NMR chemical shifts for this compound are consistent with those reported in the literature. 1H-NMR (500 MHz; CDCl3): δ 8.36 (br d, J=8.6 Hz, 1 H), 8.27 (br s, 1 H), 8.09 (d, J=8.9 Hz, 1 H), 7.70 (d, J=8.6 Hz, 1 H), 7.55 (s, 1 H), 7.50 (dd, J=8.6, 1.9 Hz, 1 H), 2.51 (s, 3 H), 2.24 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[C:30]([NH:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:32])[CH3:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:20])([F:19])[F:21])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:6][C:7]=1[C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([NH:33][C:30](=[O:32])[CH3:31])[CH:35]=1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: O=S(=O)(Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F)C(F)(F)F
Product: CC(=O)Nc1cccc(-c2cc(-c3ccnc4nc(C(F)(F)F)ccc34)ccc2F)c1
Yield: 41.5 %

Procedure:
Trifluoromethanesulfonic acid 2-fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenyl ester (30.0 mg, 0.068 mmol) was coupled to 3-acetamidophenyl-boronic acid (15.9 mg, 0.089 mmol) as described in Example 35 part c), affording N-[2′-fluoro-5′-(7-trifluoromethyl[1,8]naphthyridin-4-yl)biphenyl-3-yl]acetamide (12.0 mg, 41%). δH (360 MHz, CDCl3) 2.20 (3H, s), 7.35-7.47 (5H, m), 7.54-7.60 (2H, m), 7.84 (1H, d, J 8.4), 7.87 (1H, s), 8.56 (1H, d, J 8.8), 9.28 (1H, d, J 4.6). m/z (ES+) 426 [MH]+.