Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18]2[N:22]=[CH:21][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:19]=2)[C:13](=[O:42])[C:12]3([CH3:50])[CH2:43][C:44]2[CH:45]=[N:46][CH:47]=[N:48][CH:49]=2)[CH:5]=[CH:6][C:7]=1[F:8]>CO.ClCCl.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18]2[N:22]=[CH:21][NH:20][N:19]=2)[C:13](=[O:42])[C:12]3([CH3:50])[CH2:43][C:44]2[CH:49]=[N:48][CH:47]=[N:46][CH:45]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC1(Cc2cncnc2)C(=O)N(c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c2ccc(-c3ccc(F)c(Cl)c3)cc21
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC1(Cc2cncnc2)C(=O)N(c2nc[nH]n2)c2ccc(-c3ccc(F)c(Cl)c3)cc21

Procedure:
5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1-trityl-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one (8.25 g, 12.2 mmol) in methanol (60 mL), dichloromethane (10 mL) and 1 N aqueous HCl solution (30 mL) was stirred at 50° C. for 1.5 hours. Most of the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and water (50 mL) was added. The pH of the mixture was adjusted to pH=7 with the addition of 1 N aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer further extracted with dichloromethane (2×100 mL). The organic extracts were combined, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane and hexane was then slowly added. The product recrystallized over 3 days. The crystalline product was filtered, washed with 50% dichloromethane/hexanes and dried under reduced pressure. The filtrate was collected, concentrated under reduced pressure and purified by column chromatography on silica gel Biotage 40S, eluting with 40-100% ethyl acetate/hexanes, to give additional product. The product from crystallization and the product from column chromatography were combined, dissolved in acetonitrile/water and lyophilized to afford 5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one as a white solid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17])(=O)C.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH3:35])[CH:28]=[C:29]([O:33]C)[C:30]=1[O:31][CH3:32].CO>ClCCCl>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:28]1[C:29]([OH:33])=[C:30]([O:31][CH3:32])[C:25]([O:24][CH3:23])=[CH:26][C:27]=1[CH3:35])=[O:17]
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: CC(=O)OCCCCCCCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCCl
Product: COc1cc(C)c(C(=O)CCCCCCCCCCCO)c(O)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
To a solution of 12-acetoxy-n-dodecanoyl chloride (8.5 g) in 1,2-dichloroethane (30 ml) is added aluminum chloride (8.2 g) and the mixture is stirred at room temperature for 2 hours. The mixture is cooled to 5° C. and a solution of 3,4,5-trimethoxytoluene (5.6 g) in 1,2-dichloromethane (20 ml) is added to the above mixture. The mixture is stirred at room temperature for 72 hours, and at 50° C.-60° C. for 30 minutes. Methanol (200 ml) is added to the reaction mixture and the mixture is stirred at 50° C. for 3 hours. The solvent is distilled off, and the residue is subjected to extraction with dichloromethane. The dichloromethane layer is washed with water and dried over magnesium sulfate. The solvent is distilled off to thereby leave crude crystals. The product is recrystallized from ether-hexane (1:1) to give 6-(12-hydroxy-1-oxododecyl)-2,3-dimethoxy-5-methylphenol (8.5 g) as colorless needles. Melting point 82° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:41])[NH:10][C:11]1[CH:16]=[C:15]([C:17]([C:19]2[C:24]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=3)(=[O:28])=[O:27])=[CH:23][C:22]([Cl:40])=[CH:21][N:20]=2)=[O:18])[CH:14]=[CH:13][N:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]([NH:10][C:11]1[CH:16]=[C:15]([C:17]([C:19]2[C:24]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([C:36]([F:37])([F:39])[F:38])[CH:30]=3)(=[O:28])=[O:27])=[CH:23][C:22]([Cl:40])=[CH:21][N:20]=2)=[O:18])[CH:14]=[CH:13][N:12]=1)=[O:41]
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccnc(NC(=O)CNC(=O)OC(C)(C)C)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccnc(NC(=O)CN)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ({4-[5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-pyridin-2-ylcarbamoyl}-methyl)-carbamic acid tert-butyl ester (45 mg) in CH2Cl2 was added TFA (200 μL). The resulting mixture was stirred at room temperature for 3 h, concentrated under reduced pressure and the residue was re-dissolved in MeCN and purified by HPLC to provide 2-amino-N-{4-[5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-pyridin-2-yl}-acetamide. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1 H), 8.48-8.46 (m, 1 H), 8.19 (s, 1H), 8.08 (br m, 3 H), 7.89 (s, 1 H), 7.78-7.76 (m, 2 H), 7.55 (d, J=7.6 Hz, 1 H), 7.28-7.26 (m, 1 H), 3.85 (s, 2 H), 2.43 (s, 3 H); MS m/z 528.0 (M+H)+.
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:15])[CH2:4][C@H:5]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:6]([OH:8])=O.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH2:45]([N:52]1[CH2:56][C@H:55]2[C@H:57]([NH2:60])[CH2:58][CH2:59][C@H:54]2[CH2:53]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>ClCCl>[CH2:45]([N:52]1[CH2:56][C@H:55]2[C@H:57]([NH:60][C:6](=[O:8])[C@@H:5]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[CH2:4][CH:3]([CH3:2])[CH3:15])[CH2:58][CH2:59][C@H:54]2[CH2:53]1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CC(C)C[C@@H](C(=O)O)N1CCOCC1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N1CCOCC1
Reaction time: 0.25 h

Procedure:
(S)-4-Methyl-2-morpholinopentanoic acid hydrochloride (363 mg, 1.526 mmol) and triethylamine (0.387 mL, 2.77 mmol) were combined in dichloromethane (10 mL). 1-Hydroxybenzotriazole hydrate (234 mg, 1.526 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.270 mL, 1.526 mmol) were added, and the reaction was stirred for 15 minutes. Then (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine (300 mg, 1.387 mmol) from Example 16 Step E was added, and the reaction mixture was stirred at ambient temperature for 24 hours. The reaction was quenched with aqueous sodium bicarbonate and extracted with dichloromethane. The solvent was removed in vacuo and the crude material was purified by silica gel chromatography using 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.27 (d, J=7.3, 1H), 7.44 (d, J=7.4, 2H), 7.37 (t, J=7.5, 2H), 7.27 (dd, J=9.8, 17.3, 1H), 4.51-4.39 (m, 1H), 3.74 (t, J=4.5, 4H), 3.62 (d, J=13.1, 1H), 3.45 (d, J=13.1, 1H), 3.29-3.21 (m, 1H), 2.87 (dd, J=2.4, 9.0, 1H), 2.79 (dt, J=4.5, 9.3, 2H), 2.75-2.68 (m, 2H), 2.55 (d, J=14.8, 2H), 2.49-2.43 (m, 1H), 2.35 (dd, J=2.6, 8.9, 1H), 2.32-2.26 (m, 1H), 2.11 (dq, J=6.1, 12.1, 1H), 1.86 (dd, J=6.6, 12.2, 3H), 1.67-1.55 (m, 2H), 1.41 (dt, J=6.2, 20.1, 1H), 0.94 (dd, J=6.2, 11.1, 6H); MS (HI+) m/z 400 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1.[C:21](=O)([O:25]CC)[O:22][CH2:23][CH3:24].CN(C)P(N(C)C)(N(C)C)=O>C1COCC1>[Cl:13][C:14]1[CH:19]=[C:18]([CH2:20][C:21]([O:22][CH2:23][CH3:24])=[O:25])[CH:17]=[CH:16][N:15]=1
Reactant: Cc1ccnc(Cl)c1
Reactant: CCOC(=O)OCC
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)Cc1ccnc(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
In a 1000 mL round-bottom flask, diisopropylamine (80.21 mL, 567.5 mmol) was combined with THF (250 mL) and cooled to −78° C. Butyllithium (227.0 mL, 567.5 mmol) (2.5M in hexane) was added and the mixture was stirred for 30 minutes. 2-Chloro-4-methylpyridine (36.20 g, 283.8 mmol) in THF (100 mL) was added, and the mixture was stirred for 2 hours. A mixture of diethyl carbonate (37.82 mL, 312.1 mmol) and hexamethylphosphoramide (54.31 mL, 312.1 mmol) was added, and the mixture was stirred at −78° C. for one hour and then stirred at ambient temperature. The reaction was quenched with 25% ammonium chloride solution and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried and evaporated. The crude oil was purified by silica gel chromatography, eluting with 5% ethyl acetate/hexane to provide the desired product as clear oil (42.75 g, 75.47% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2(O)[C:21]3[CH:20]=[C:19]([S:22][C:23]([F:26])([F:25])[F:24])[CH:18]=[CH:17][C:16]=3[S:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:4][CH2:3]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.FC(F)(F)C(O)=O>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:21]3[CH:20]=[C:19]([S:22][C:23]([F:25])([F:24])[F:26])[CH:18]=[CH:17][C:16]=3[S:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:4][CH2:3]1
Reactant: CN1CCC(C2(O)c3ccccc3Sc3ccc(SC(F)(F)F)cc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CN1CCC(=C2c3ccccc3Sc3ccc(SC(F)(F)F)cc32)CC1

Procedure:
A solution of 3.29 g. of 1-methyl-4-(2-trifluoromethylthio-9-hydroxythioxanthen-9yl)piperidine in 15 ml. of trifluoroacetic anhydride and 30 ml. of trifluoroacetic acid is stirred and refluxed for 2.5 hours. The solution is evaporated to dryness. The residue is dissolved in benzene and is washed with 10% sodium hydroxide to make the free base form. The benzene is washed with water, dried over magnesium sulfate, filtered, and the benzene is removed on a rotary evaporator. The residue is recrystallized from acetonitrile to give 1-methyl-4-[2-(trifluoromethylthio)thioxanthen-9-ylidene]piperidine, m.p. 104°-106° C.
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[S:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](=[O:18])[N:17]=2)[N:7]=1)(=O)=O.[CH2:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])C.[C:30]1([CH:36]2CCNCC2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(OCC)(=O)C>CN(C=O)C.O>[C:30]1([CH:36]2[CH2:29][CH2:28][N:25]([CH2:23][C:6]3[N:7]=[C:8]([C:12]4[S:13][C:14]5[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=5[C:16](=[O:18])[N:17]=4)[CH:9]=[CH:10][CH:11]=3)[CH2:26][CH2:27]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCN(CC)CC
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CS(=O)(=O)Oc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc(-c2cccc(CN3CCC(c4ccccc4)CC3)n2)sc2ccccc12
Temperature: 70 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (0.30 g, 0.86 mmol), triethylamine (0.20 ml, 1.42 mmol) and 4-phenylpiperidine (0.15 g, 0.95 mmol) were dissolved in DMF (30 ml), and the mixture was stirred at 70° C. for 18 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.16 g, 76%) as pale yellow crystals.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:13]([NH:14][S:15](=[O:21])(=[O:20])[NH:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=[C:10]([F:22])[C:5]=1[C:6]([O:8]C)=[O:7].C1COCC1>CO>[F:3][C:4]1[C:13]([NH:14][S:15](=[O:20])(=[O:21])[NH:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=[C:10]([F:22])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCCNS(=O)(=O)Nc1ccc(F)c(C(=O)OC)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCNS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
NaOH (1M, 3.20 mL, 3.20 mmol) was added to methyl 2,6-difluoro-3-(N-propylsulfamoylamino)benzoate (0.24 g, 0.80 mmol) in 2:1 THF:MeOH (3 mL). The solution was stirred at room temperature for 16 hours, and then the solution was stirred at 70° C. for 16 hours. The solution was concentrated under reduced pressure to about half volume and then washed with EtOAc. The pH was adjusted to about 5, and the mixture was extracted with EtOAc (3×5 mL). The organic layers were dried over sodium sulfate, decanted and concentrated to provide 2,6-difluoro-3-(N-propylsulfamoylamino)benzoic acid.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=[O:17])[NH:6][C:7]1[N:8]([CH3:16])[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[Cl:20][C:21]1[CH:26]=[C:25]([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:24]=[C:23]([Cl:35])[C:22]=1[C:36]1[N:40]2[CH:41]=[C:42]([O:45][C@H:46]3[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[C@@H:49]([NH2:56])[CH2:48][CH2:47]3)[CH:43]=[CH:44][C:39]2=[N:38][N:37]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH:5]([OH:17])=[O:4].[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:56][C@@H:49]2[C:50]3[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@H:46]([O:45][C:42]3[CH:43]=[CH:44][C:39]4[N:40]([C:36]([C:22]5[C:21]([Cl:20])=[CH:26][C:25]([CH2:27][N:28]6[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]6)=[CH:24][C:23]=5[Cl:35])=[N:37][N:38]=4)[CH:41]=3)[CH2:47][CH2:48]2)=[O:17])[N:8]([CH3:16])[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CN1CCN(Cc2cc(Cl)c(-c3nnc4ccc(O[C@@H]5CC[C@H](N)c6ccccc65)cn34)c(Cl)c2)CC1
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1CCN(Cc2cc(Cl)c(-c3nnc4ccc(O[C@@H]5CC[C@H](NC(=O)Nc6cc(C(C)(C)C)nn6C)c6ccccc65)cn34)c(Cl)c2)CC1
Product: O=CO
Temperature: 70 °C
Reaction time: 8 h

Procedure:
(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (US 2004/0192653, which is incorporated herein by reference in its entirety; 17 mg, 0.051 mmol) was treated with a solution of Intermediate 13e (25 mg, 0.047 mmol) in 1,4-dioxane (0.4 mL) then DIPEA (10 μL, 0.058 mmol) was added. The mixture was stirred at 70° C. overnight. The mixture was treated with another portion of (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (7.8 mg, 0.024 mmol) in 1,4-dioxane (0.1 mL) and stirred at 70° C. for 6 h. The mixture was evaporated in vacuo and the residue was partitioned between DCM and water. The aqueous layer was then extracted with DCM (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by HPLC in 4 portions (Method 6, 5-95% MeCN in H2O, 0.1% HCO2H over 30 min), and the isolated product triturated (diethyl ether) to give a solid. The solid was collected by filtration, washed with ether and dried at 50° C. in vacuo to give the title compound. (5.4 mg, 16%). LCMS (Method 5): Rt 3.27 min, m/z 716.3 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.20 (9H, s), 1.82-1.99 (2H, m), 1.99-2.05 (1H, m), 2.05-2.14 (1H, m), 2.18 (3H, s), 2.29-2.42 (4H, br s), 2.42-2.52 (4H, br s, partially obscured by DMSO), 3.56 (3H, s, partially obscured by water), 3.60 (2H, s, partially obscured by water), 4.79-4.88 (1H, m), 5.54 (1H, t, J=4.3 Hz), 6.01 (1H, s), 6.91 (1H, d, J=8.4 Hz), 7.23-7.30 (1H, m), 7.33-7.39 (4H, m), 7.66 (2H, s), 7.91 (1H, d, J=10.2 Hz), 7.97 (1H, d, J=1.7 Hz), 8.21 (1H, s), 8.29 (1H, s).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([NH:18][C:19]([N:21]3[CH:25]=[CH:24]N=C3)=[O:20])=[N:15][C:14]=2[CH3:26])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].[CH2:27]([C:29]1[O:33][C:32](CCN)=[N:31][CH:30]=1)[CH3:28].C(N(CC)CC)C>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([NH:18][C:19]([NH:21][CH2:25][CH2:24][C:32]3[O:33][C:29]([CH2:27][CH3:28])=[CH:30][N:31]=3)=[O:20])=[N:15][C:14]=2[CH3:26])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2]
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccc(S(C)(=O)=O)c(C#N)c1
Reactant: CCc1cnc(CCN)o1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3ccc(S(C)(=O)=O)c(C#N)c3)s2)o1
Temperature: 70 °C

Procedure:
To a stirred solution of imidazole-1-carboxylic acid [5-(3-cyano-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide (Intermediate BD) (0.05 g, 1.29 mmol) in DMF (1.5 ml) under an inert atmosphere is added 2-(5-ethyl-oxazol-2-yl)-ethylamine (Amine) (0.018 g, 1.29 mmol) followed by triethylamine (0.02 ml, 0.14 mmol). The reaction mixture is heated to 70° C. for 2.5 hours and then allowed to cool to room temperature. The solvent is removed in vacuo and the resulting crude residue is dissolved in THF and passed through a 0.5 g polymer supported isocyanate resin (pre-washed with THE). The solution is concentrated in vacuo and the crude residue is dissolved in DCM and washed with water, brine, dried over MgSO4 and concentrated in vacuo again. Triturating with ether affords the titled compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1.O1CCCC1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[NH:12]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:18]2[C:10]([C:8]([C:5]2[CH:6]=[N:7][C:2]([NH:26][CH2:25][C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=3)=[CH:3][CH:4]=2)=[O:9])=[CH:11]1
Reactant: O=C(c1ccc(Cl)nc1)c1c[nH]c2ncccc12
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccc(NCc2ccc(C(F)(F)F)cc2)nc1)c1c[nH]c2ncccc12
Temperature: 180 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
Into a pressure flask was added (6-Chloro-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 7 (3.5 g, 0.014 mol, prepared as described in Example 3), 4-(trifluoromethyl)benzylamine (30, 9.0 g, 0.051 mol), tetrahydrofuran (30.0 mL, 0.37 mol), palladium acetate (200.0 mg, 0.890 mmol) and 2-(di-t-butylphosphino)biphenyl (200.0 mg, 0.67 mmol). The reaction mixture was stirred at 180° C. overnight, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. To the residue was added acetic acid (15.0 mL) and H2O (5.0 mL). The reaction mixture was stirred at 100° C. for 5 hours and concentrated to remove the acetic acid. The residue was then treated with aqueous Na2HCO3 and extracted with ethyl acetate. The organic layer was washed, dried, concentrated and purified to give compound P-0017 (1.0 g, yield=18.5%) as a light yellow solid. MS (ESI) [M+H+]+=397.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N+:29]([CH3:32])([O-:31])=[O:30]>O1CCCC1.C(OCC)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[CH2:32][N+:29]([O-:31])=[O:30])=[O:4]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C1=CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C1CCCCC1C[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of cyclohex-1-enecarboxylic acid methyl ester 1 (5.15 g; 36.7 mmol), tetrabutyl ammonium fluoride (55.10 mL; 1 M in THF; 55.1 mmol) and nitromethane (3.97 mL; 73.5 mmol) in tetrahydrofuran (60 mL) was heated to reflux for 4 hours. After cooling to room temperature, the reaction mixture was diluted with diethyl ether (500 mL), washed with 2N HCl (2×100 mL) and then with brine (2×100 mL). The phases were separated. The organic phase was dried over MgSO4 and concentrated in vacuo. The crude mixture was purified over silica gel chromatography (EtOAc/heptane 1:4) to give 2 (5.46 g; cis and trans isomers; 73%) as a pale yellow liquid.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:12][C:13]1[CH:18]=[C:17]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccn2c(Br)cnc2c1
Reactant: Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2c(-c3cccc(N)c3)cnc2c1
Yield: 100.8 %

Procedure:
3-Bromo-7-methylimidazo[1,2-α]pyridine (4.2 g, 20.0 mmol) and 3-aminophenylboronic acid (4.0 g, 25.8 mmol) were suspended in 1,2-dimethoxyethane (80 ml) and sodium carbonate (40 ml of a 2M solution) and the resulting solution degassed for 25 minutes. Tetrakis(triphenylphosphine)palladium(0) (250 mg, 0.2 mmol) was added and the mixture heated at reflux for 17 hours. The cooled reaction mixture was poured into water (150 ml), extracted with ethyl acetate (3×70 ml) and the combined organics dried over anhydrous magnesium sulphate. The solution was filtered and concentrated in vacuo to yield 3-(3-aminophenyl)-7-methylimidazo[1,2-α]pyridine as a colourless oil (4.5 g, 100%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δH 2.38 (3H, s), 3.58 (2H, br s), 6.60 (1H, d, J 7), 6.70 (1H, d, J 8), 6.81 (1H, s), 6.91 (1H, d, J8), 7.24-7.28 (1H, m), 7.39 (1H, s), 7.57 (1H, s), 8.23 (1H, d, J 7); m/z (ES+) 224 (M++H).
Reaction SMILES: C[Si](C)(C)[O:3][CH2:4][CH2:5][O:6][C:7]1([C:11]#[N:12])[CH2:10][CH2:9][CH2:8]1.[NH2:15][OH:16].[C:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])#[C:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CCO>[CH2:22]([O:21][C:19](=[O:20])[C:18]([O:16][NH:15][C:11]([C:7]1([O:6][CH2:5][CH2:4][OH:3])[CH2:10][CH2:9][CH2:8]1)=[NH:12])=[CH:17][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:23]
Reactant: NO
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: C[Si](C)(C)OCCOC1(C#N)CCC1
Solvent: CCO
Product: CCOC(=O)C=C(ONC(=N)C1(OCCO)CCC1)C(=O)OCC
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A solution of 1-(2-trimethylsilanyloxyethoxy)cyclobutanecarbonitrile (3.5 g, 16.4 mmol) and 50% aqueous hydroxylamine (1.08 g, 16.4 mmol) in EtOH (16 mL) was stirred in an oil bath heated at 80° C. for 2.5 hrs and then cooled to room temperature. To a solution was added drop-wise diethyl acetylenedicarboxylate (2.93 g, 17.2 mmol) in an ice-bath and the mixture stirred at room temperature for 5 hrs. This mixture was concentrated in vacuo to obtain 6.16 g of a crude brownish oil containing intermediate 25: 1H NMR (500 MHz, CDCl3) δ: 1.19-1.38 (6 H, m) 1.72-1.86 (2 H, m) 2.06-2.24 (2 H, m) 2.29-2.49 (2 H, m) 3.26-3.38 (2 H, m) 3.65-3.76 (2H, m) 4.11-4.19(2 H, m) 4.24-4.38(2 H, m) 5.67(0.25 H, s) 5.85 (0.5 H, s). HRMS (M+H) calcd for C15H25N2O7 345.1662, found 345.1648.