Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:3]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:33]1[CH2:37]OC[CH2:34]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[C:4]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[C:3]=1[CH:18]([CH2:34][CH2:33][CH3:37])[C:19]([O:21][CH3:22])=[O:20]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sccc2c1-c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sccc2c1-c1ccc(C)cc1
Yield: 58.8 %

Procedure:
This compound was prepared according to the procedure C from methyl 2-(6-methyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.078 g; 0.250 mmol), LHMDS 1N in THF (0.276 mL; 0.276 mmol), 1-iodopropane (0.041 mL; 0.420 mmol) in DMF (3.6 mL) for 4 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.052 g (59%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1.C([O-])(=O)C.[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:13][C:14]2[CH:19]=[N:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N)cn1
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2nc(Cl)nc3ccccc23)cn1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 96.8 %

Procedure:
A mixture of 2,4-dichloroquinazoline (61 mg, 0.31 mmol), 5-amino-2-methoxy pyridine (40 mg, 0.32 mmol) and sodium acetate (38 mg, 0.46 mmol) in 3 mL of solvent (THF:water/1:1) was stirred at 60° C. for 45 min. The reaction mixture was diluted with 25 mL of ethyl acetate. It was washed with saturated NaCl, dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by chromatography (40% ethyl acetate/hexanes) on silica gel to give the title compound (86 mg, 0.30 mmol, 98%). 1H NMR (CDCl3): 8.38 (d, J=3.0 Hz, 1H), 8.07 (dd, J=8.7 and 3.0 Hz, 1H), 7.89-7.79 (d, J=8.4 Hz, 1H), 7.86 (m, 2H), 7.59-7.53 (m, 2H), 6.84 (d, J=8.7 Hz, 1H), 3.96 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]([C:33]2[O:34][CH:35]=[CH:36][C:37]=2[CH3:38])=[O:32])[CH:25]=1.[OH-].[K+].Cl>C1COCC1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]([C:33]2[O:34][CH:35]=[CH:36][C:37]=2[CH3:38])=[O:32])[CH:25]=1
Reactant: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3occc3C)c2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cc(C(=O)N=S(C)(=O)CCCCC(=O)O)cnc2N)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To the solution of methyl 5-(N-{[6-amino-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-methylsulfonimidoyl)pentanoate (367 mg, 0.68 mmol) in THF (13 mL) at 0° C. was added dropwise 1N aq KOH (3.42 mL, 5 eq). The reaction was stirred at 0° C. for 20 minutes and then at RT for 4 hours. It was then cooled back to 0° C. and 2N aq HCl was dropwise added to adjust the pH to about 5-6. The mixture was then evaporated at RT to remove the most of the THF. The oily residue was then partitioned between aq NH4Cl and CHCl3. The chloroform layer was isolated, followed by a wash with brine (1×) and then dried with anhydrous Na2SO4 overnight. The upper clear solution was decanted, concentrated, and subject to a gradient column chromatography (MeOH-DCM 1:500 to 1:9). The corresponding product fractions were collected, concentrated, and treated with EtOAc with stirring. The title compound was obtained upon filtration as white solid (238 mg, 67%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([CH2:20][CH2:21][CH2:22][OH:23])[CH:9]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1.CN(C1C=CC=CN=1)C>C(#N)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([CH2:20][CH2:21][CH2:22][O:23][C:36](=[O:37])[NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH3:27])[CH:30]=2)[CH:9]=1
Reactant: Cc1cccc(C=NNc2cc(CCCO)nc(N3CCOCC3)c2)c1
Reactant: COc1cccc(N=C=O)c1
Agent: CN(C)c1ccccn1
Solvent: CC#N
Product: COc1cccc(NC(=O)OCCCc2cc(NN=Cc3cccc(C)c3)cc(N3CCOCC3)n2)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
3-{4-[N′-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyrid-2-yl}-propan-1-ol (1 mmol) is dissolved in acetonitrile (4 mL). To the mixture is added m-methoxyphenylisocyanate (149 mg., 1 mmol) and a catalytic amount of dimethylaminopyridine. The reaction is stirred at 60° C. for 16 hours. The reaction is then cooled to 4° C., and the precipitate is filtered, washed with acetonitrile (1 mL) and dried to give Compound 102, (3-methoxy-phenyl)-carbamic acid 3-{4-[N′-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyrid-2-yl}-propyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH:30]1[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][OH:38])[CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:30]2[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][OH:38])[CH2:32][CH2:31]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: OCCC1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCC(CCO)CC3)ccc21
Yield: 110.3 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (30.0 mg, 0.0730 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 4-piperidineethanol (94 mg, 0.73 mmol), acetic acid (0.168 mL, 2.93 mmol) and sodium triacetoxyborohydride (54 mg, 0.26 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and ethyl acetate, followed by extracting with 1 mol/L hydrochloric acid. The aqueous layer was added with sodium carbonate to adjust the pH to 9. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)piperidinomethyl]indol-2-yl}isoindolinone (42.2 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([OH:45])[CH:41]=2)[O:36]1>>[F:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:45][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:41]=2)[O:36]1
Reactant: Oc1ccc2c(c1)CCC(c1cccc(F)c1F)O2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2cccc(F)c2F)O3)nc1

Procedure:
2-[2-(2,3-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 1.88 g of 2-(2,3-difluorophenyl)chroman-6-ol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 3.0 Hz), 8.60 (dd, 1H, J 9.1, 3.0 Hz), 7.45 (m, 1H), 7.38 (m, 1H), 7.30 (m, 1H), 7.21 (d, 1H, 9.1 Hz), 7.03 (d, 1H, J 2.7 Hz), 6.98 (dd, 1H, J 8.8, 2.7 Hz), 6.92 (d, 1H, 8.8 Hz), 5.42 (dd, 1H, J 10.4, 2.3 Hz), 3.04 (m, 1H), 2.79 (m, 1H) 2.21 (m, 1H), 2.08 (m, 1H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O)[CH:2]=[CH2:3].ClC(N(C)C)=C(C)C.C(N(CC)CC)C>ClCCl>[CH2:3]1[CH:2]2[CH2:1][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH:10]2[C:11]1=[O:13]
Reactant: C=CCc1ccccc1CC(=O)O
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CC2Cc3ccccc3C12
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a solution of 2-allyl phenyl acetic acid (Example I2, Step 2, 0.095 g, 0.539 mmol) in dichloromethane (25 mL) was added at 0° C. 1-chloro-N,N,2-trimethyl-1-propenylamine (0.078 mL, 0.593 mmol). The solution was stirred for 1 h and then heated to reflux. Then, a solution of triethylamine (0.082 mL, 0.593 mmol) in dichloromethane (4 mL) was added slowly over two hours to the solution of the acid chloride at reflux. The reaction mixture was stirred for another 2 h and then cooled down. The solvents were removed in vacuo and the residue was purified by flash chromatography eluting with cyclohexane and ethyl acetate (20/1) to give 1,2a,7,7a-tetrahydro-2H-Cyclobut[a]inden-2-one (colourless oil, 56 mg, 66%) The analytical data were identical to the product obtained with the method A.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:23]([O:25]CC)=[O:24])[C:7](=[O:22])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1.[Li+].[OH-].Cl.C(OCC)(=O)C>C1COCC1.O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:23]([OH:25])=[O:24])[C:7](=[O:22])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:10]=[CH:9]3)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(F)cc3)ccn2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(F)cc2)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 60 °C

Procedure:
A solution of ethyl 1-cyclopropyl-8-(4-fluoro-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (120 mg, 0.329 mmol) in THF (6 mL) and water (2 mL) was treated with LiOH (55 mg, 1.31 mmol). The reaction was heated to 60° C. for 2 h and acidified with 1N HCl to pH 4. The precipitate was dissolved with ethyl acetate (50 mL) and washed with brine (2×20 mL). The organic phase was separated, dried, and concentrated. The precipitate was filtered to afford the title compound EXAMPLE 44 as a yellow solid (110 mg, 99%). ESI-MS m/z: 338 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.37 (d, J=7.5 Hz, 1H), 8.30 (s, 1H), 7.70-7.61 (m, 3H), 7.51-7.45 (m, 2H), 2.89 (s, 3H), 2.53-2.51 (m, 1H), 1.13-1.10 (m, 2H), 0.83-0.82 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12](Cl)=[O:13].N1C=CC=CC=1.[NH2:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([CH:40]3[CH2:45][CH2:44][C:43](=[O:46])[CH2:42][CH2:41]3)[N:29]=[C:30]([C:31]3[CH:36]=[CH:35][C:34]([NH2:37])=[C:33]([O:38][CH3:39])[CH:32]=3)[C:23]=12>ClCCl>[NH2:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([CH:40]3[CH2:45][CH2:44][C:43](=[O:46])[CH2:42][CH2:41]3)[N:29]=[C:30]([C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:12](=[O:13])[C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=4[F:1])=[C:33]([O:38][CH3:39])[CH:32]=3)[C:23]=12
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Reactant: COc1cc(-c2nn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A solution of 2-fluoro-4-trifluoromethyl-1-benzenecarbonyl chloride (0.87 g, 3.83 mmol) in dichloromethane (5 mL) was added into a mixture of pyridine (15 mL) and 4-[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclohexanone (1.00 g, 2.56 mmol) in dichloromethane (5 mL) at 0° C. over 5 minutes. The mixture was stirred at 0° C. for 10 minutes and at ambient temperature overnight. The solvent was removed under reduced pressure. The residue was partitioned between water and dichloromethane. The dichloromethane layer was washed with saturated aqueous ammonium chloride twice and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography on silica using Isco system to provide N1-{4-[4-amino-1-(4-oxocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-trifluoromethylbenzamide (0.95 g, 1.76 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 9.90 (dd, 1H), 8.30(d, 1H), 8.28 (s, 1H), 7.99 (t, 1H), 7.89 (d, 1H), 7.75 (d, 1H), 7.34 (s, 1H), 7.30 (d, 1H), 6.90 (br, 2H), 5.27 (m, 1H), 3.94 (s, 3H), 2.70 (m, 2H), 2.47 (m, 4H), 2.17 (m, 2H); RP-HPLC (Hitachi HPLC, Hypersil C18, 5 μm, 100A, 250×4.6 mm; 25%-100% acetonitrile—0.05M ammonium acetate over 10 min, 1 mL/min) Rt 9.23 min. MS: MH+ 543.
Reaction SMILES: [C:1]([C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:10]12[CH3:11])[C:23]1[CH:22]=[CH:21][C:20]([C:27]([O:29]C)=[O:28])=[CH:19][C:18]=1[CH2:17][CH2:16]3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].O>CO>[C:1]([C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:10]12[CH3:11])[C:23]1[CH:22]=[CH:21][C:20]([C:27]([OH:29])=[O:28])=[CH:19][C:18]=1[CH2:17][CH2:16]3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)c3ccccc3)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(C(=O)O)cc4CC[C@H]3[C@@H]1CC[C@@H]2C(=O)c1ccccc1

Procedure:
A mixture of methyl 17β-benzoyl-estra-1,3,5(10)-triene-3-carboxylate, K2CO3, water and methanol is heated at reflux for about 5 hours. Acidifications followed by conventional workup yields title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](C(OCC)=O)=[CH:10][NH:11][C:12]=2[S:13][C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.Cl>[OH-].[Na+].C(CN)O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][NH:11][C:12]=2[S:13][C:14]([F:16])([F:15])[F:17])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c[nH]c(SC(F)(F)F)c1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: NCCO
Product: FC(F)(F)Sc1[nH]ccc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
A solution of ethyl 4-(p-chlorophenyl)-5-[(trifluoromethyl)thio]pyrrole-3-carboxylate (8.0 g, 0.023 mol) in 10% aqeuous sodium hydroxide solution is refluxed for several hours, stirred at room temperature overnight, poured into ice-water, treated with concentrated hydrochloric acid and extracted with ether. The combined organic extracts are washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a brown semi-solid. A solution of the semi-solid (6.9 g) in ethanolamine is heated at 110° C. for several hours, poured into ice-water and extracted with chloroform. The combined organic extracts are washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a brown oil. The oil is dissolved in methylene chloride, filtered through a bed of silica gel and the filtrate is concentrated in vacuo to obtain the title product as a grey semi-solid (4.8 g, mp 44°-46° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]2.CN(C=O)C.C([Li])(C)(C)C.CCCCC>C1COCC1.CCOC(C)=O.CC(O)=O>[C:14]([O:13][C:11]([N:7]1[C:8]2[C:4](=[CH:3][CH:2]=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)ccc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccccc21
Temperature: -78 °C
Yield: 18.4 %

Procedure:
5-Bromo-1-t-butyloxycarbonylindoline (2.0 g, 6.7 mmol) and DMF (0.53 mL, 6.7 mmol), were dissolved in THF (30 mL) and the resulting solution was cooled to −78° C. with stirring under a nitrogen atmosphere. A solution of t-butyllithium in pentane (1.7 M, 10.3 mL, 17.5 mmol) was added dropwise over 5 min. The reaction mixture was stirred for 2 h; then HOAc (3 mL) was added. The cloudy mixture was warmed to ambient temperature over 30 min and diluted with EtOAc (100 mL). Successive washings with a saturated Na2CO3 solution (2×10 mL) and then brine (10 mL) were performed. Drying over Na2SO4, filtration and removal of solvent in vacuo gave an oil. Column chromatography (EtOAc:hexane: 1:9, then 1:1) and removal of solvent in vacuo provided two products, both were white solids: (1) 1-t-butyloxycarbonylindoline (270 mg, 18% yield): 1H NMR (CDCl3, 300 MHz): 7.18–7.10 (m, 2H), 6.92 (t, 1H, J=7), 3.97 (t, 2H, J=7), 3.08 (t, 3H, J=7), 1.57 (s, 9H); MS (APCI+): 220 (C13H18NO2, M++H) and (2) the title product (650 mg, 39% yield): 1H NMR (CDCl3, 300 MHz): 9.86 (s, 1H), 7.9 (br s, 1H), 7.70–7.65 (m, 2H), 4.06 (t, 2H, J=7), 3.15 (t, 2H, J=7), 1.58 (s, 9H); MS (ES+): 248 (C14H18NO3, M++H).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH2:13][CH2:14][CH3:15]>CCOCC.CCCCCC>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([N:12]([CH2:13][CH2:14][CH3:15])[C:5]2[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=2[C:3]([OH:27])=[O:2])(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: CCCN(c1c(C)cc(C)cc1C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCN(c1c(C)cc(C)cc1C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Yield: 79.3 %

Procedure:
In the same amn as described in Example 109, 0.602 g (1.54 mmol) of the product of Example 105 provided 0.461 g (79%) of the desired carboxylic acid as a white solid after trituration with ether/hexane. Electrospray Mass Spec 378.2(M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]([C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([OH:25])=[C:20]([CH3:26])[CH:19]=2)[N:13]=[N:14][C:15]=1[O:16]C.C[Si](Cl)(C)C.[I-].[K+]>C(#N)C.O>[OH:25][C:21]1[C:22]([CH3:24])=[CH:23][C:18]([C:12]2[CH:11]=[C:10]([C:2]3[NH:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:15](=[O:16])[NH:14][N:13]=2)=[CH:19][C:20]=1[CH3:26]
Reactant: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1cc2ccccc2[nH]1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(-c2cc(-c3cc4ccccc4[nH]3)c(=O)[nH]n2)cc(C)c1O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
100 mg of 4-[5-(1H-Indol-2-yl)-6-methoxy-pyridazin-3-yl]-2,6-dimethyl-phenol is suspended in 2 ml acetonitrile and 40 μl of trimethylsilyl chloride and 53 mg of potassium iodide are added. The solution is heated to 80° C. for 3h, then a further 120 μl of trimethylsilyl chloride and 159 mg of potassium iodide are added. The solution is heated to 80° C. for 3 h then stirred at RT for 16 h. The reaction solution is diluted with water and the product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][CH:13]([CH2:29][CH2:30][CH3:31])[C:14]([NH:16][C:17]2[N:18]=[CH:19][N:20]([CH2:22][CH2:23]OS(C)(=O)=O)[CH:21]=2)=[O:15])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:32]([O:34][CH2:35][CH2:36][CH2:37][NH2:38])[CH3:33]>>[CH2:32]([O:34][CH2:35][CH2:36][CH2:37][NH:38][CH2:23][CH2:22][N:20]1[CH:21]=[C:17]([NH:16][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[CH2:9][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[CH2:29][CH2:30][CH3:31])[N:18]=[CH:19]1)[CH3:33]
Reactant: CCOCCCN
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(CCOS(C)(=O)=O)cn1
Product: CCC[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(CCNCCCOCC)cn1

Procedure:
Methanesulfonic acid 2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-ethyl ester was reacted with 3-ethoxypropyl amine to provide the title compound: MS 446.2 m/z (M+1).
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[CH:8]=[C:7]([CH3:11])[O:6][C:5]=1[CH3:12])([OH:3])=[O:2].[C:13](Cl)(=O)C.CO.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:1]([C:4]1[C:9](=[O:10])[CH:8]=[C:7]([CH3:11])[O:6][C:5]=1[CH3:12])([O:3][CH3:13])=[O:2]
Reactant: Cc1cc(=O)c(C(=O)O)c(C)o1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1c(C)oc(C)cc1=O

Procedure:
42 g of 3-carboxy-2,6-dimethylpyr-4-one is dissolved in 250 ml of methylene chloride. In a second flask, 20 ml of acetyl chloride is cautiously added to 400 ml of methanol. The two solutions are mixed and refluxed for 5 hours. Solid sodium carbonate is added and the solvent removed after a water wash. The residue is distilled (115°-125° at 0.1 mm) to give 40 g of 3-carbomethoxy-2,6-dimethylpyr-4-one as a waxy solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1/[CH:14]=[CH:15]/[C:16]1[N:17]=[C:18]2[N:22]([C:23]=1[C:24](O)=[O:25])[CH:21]=[CH:20][S:19]2)[CH:2]([CH3:4])[CH3:3].[F:27][C:28]([F:36])([F:35])[C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH2:1]([O:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1/[CH:14]=[CH:15]/[C:16]1[N:17]=[C:18]2[N:22]([C:23]=1[C:24]([NH:34][C:31]1[S:32][CH:33]=[C:29]([C:28]([F:36])([F:35])[F:27])[N:30]=1)=[O:25])[CH:21]=[CH:20][S:19]2)[CH:2]([CH3:3])[CH3:4]
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC(C)C
Reactant: Nc1nc(C(F)(F)F)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C(F)(F)F)cs2)c1OCC(C)C

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 2 (150 mg, 0.403 mmol) with 4-(trifluoromethyl)-1,3-thiazol-2-amine (79 mg, 0.484 mmol) in the presence of EDCI hydrochloride (154 mg, 0.807 mmol) and DMAP (73 mg, 0.605 mmol) in a mixture of DCM and DMF (4:1, 5 mL) to give 10 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.97 (d, J=6.3 Hz, 6H), 1.98-2.04 (m, 2H), 3.65-3.71 (m, 2H), 3.81 (s, 3H), 6.97-7.03 (m, 1H), 7.07-7.14 (m, 1H), 7.30-7.36 (m, 1H), 7.42-7.52 (m, 2H), 7.83 (d, J=16.2 Hz, 1H), 7.97-8.07 (m, 2H), 13.00 (br s, 1H); APCI-MS (m/z) 523.12 (MH)+.
Reaction SMILES: [CH2:1]([C:8](=[CH2:25])[C:9]([NH:11][N:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(Cl)Cl>[CH2:25]=[C:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([NH:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:10]
Reactant: C=C(Cc1ccccc1)C(=O)NN1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: C=C(Cc1ccccc1)C(=O)NN1CCNCC1
Reaction time: 2 h
Yield: 68.5 %

Procedure:
Under an inert atmosphere, 7.4 g of the product of Step A were cooled to -15° C. in 20 ml of methylene chloride and then 13 ml of trifluoroacetic acid were added dropwise. After allowing to return to ambient temperature and stirring for 2 hours, neutralizing with a saturated aqueous solution of sodium bicarbonate, extractin was done with ethyl acetate. The extracts were washed with salted water, dried and the solvents were eliminated under reduced pressure to obtain 3.6 g of the expected product melting at 78° C.