Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([N:7]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6].O>C(O)(=O)C>[N+:1]([C:11]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:5][CH3:6])[C:19]3[C:14]([C:13]=2[CH:12]=1)=[CH:15][CH:16]=[CH:17][CH:18]=3)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCn1c2ccccc2c2ccccc21
Solvent: CC(=O)O
Solvent: O
Product: CCn1c2ccccc2c2cc([N+](=O)[O-])ccc21
Temperature: 40 °C
Yield: 70.9 %

Procedure:
A solution of 7.3 g of 70% nitric acid (81.1 mmol) in 50 ml acetic acid was added dropwise to a cooled (19°-21° C) acetic acid (200 ml) solution of 15.0 g of N-ethylcarbazole (76.9 mmol). The green reaction solution was then heated on a water bath at 40° C for 2 hours. Upon cooling, addition to 400 ml of water gave a light green precipitate wgich was filtered and air dried. Recrystallization from acetone/methanol gave 13.1 g (71% yield) of 3-nitro-N-ethylcarbazole, mp 118.5°-20° C; the sulfur content (X-ray) was found to be <20 ppm, so that the sulfur in N-ethylcarbazole must be in the elemental or organic (no inorganic) form, most likely the latter, and is easily oxidized to a water soluble form.
Reaction SMILES: C([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH2:30][N:29](CC5C=CC=CC=5)[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[N:9]1[NH:8][CH:16]=[C:15]2[C:10]=1[CH:11]=[C:12]([C:17]1[CH:18]=[C:19]([CH:27]3[O:32][CH2:31][CH2:30][NH:29][CH2:28]3)[N:20]3[C:25]=1[C:24]([NH2:26])=[N:23][CH:22]=[N:21]3)[CH:13]=[CH:14]2
Reactant: Nc1ncnn2c(C3CN(Cc4ccccc4)CCO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ncnn2c(C3CNCCO3)cc(-c3ccc4c[nH]nc4c3)c12
Yield: 27 %

Procedure:
A solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(4-benzylmorpholin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (200 mg, 0.388 mmol) and 25 mg 10% by wt. palladium on carbon in acetic acid (5 mL) was stirred under an atmosphere of hydrogen for 52 h. The reaction was filtered through Celite® and concentrated in vacuo. The residue was purified by preparative RP-HPLC to provide 35.1 mg (27%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.10 (s, 1 H), 7.92 (s, 1 H), 7.83 (d, 1 H, J=8 Hz), 7.52 (s, 1 H), 7.19 (d, 1 H, J=8 Hz), 6.73 (s, 1 H), 4.98 (dd, 1 H, J=10, 2 Hz) (m, 1 H), 3.81 (d, 1H, J=11 Hz), 3.55-3.66 (m, 2H), 3.31 (bs, 3H), 3.05 (dd, 1H, J=12, 3 Hz), 2.86 (dd, 1H, J=12, 10 Hz), 2.71-2.78 (m, 2H); ES-MS m/z 336.4 [M+H]+, HPLC RT (min) 1.10.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([I:9])[CH:3]=1.[CH:10](O)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(#N)C.C1(S(O)(=O)=O)C=CC=CC=1>[CH:10]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[I:9])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(Cl)cc1I
Reactant: OC(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)c1ccccc1
Solvent: CC#N
Solvent: O
Product: Clc1ccc(NC(c2ccccc2)c2ccccc2)c(I)c1
Reaction time: 4 h
Yield: 88.1 %

Procedure:
To a nitrogen purged 2 L three necked flask equipped with addition funnel, overhead stirrer and reflux condenser was charged 150 g(0.591 mol) 4-Chloro-2-iodo-phenylamine, 3 g(0.018 mol, 0.03 eq) benzenesulfonic acid and 500 mL acetontrile. The mixture was warmed to 70 C and 120 g (0.652 mol, 1.1 eq) benzhydrol dissolved in 500 mL acetonitrile was added to the stirred warm solution over a period of 7.5 h. After another 4 h, LC analysis showed 95% product and 5% starting material remaining. The mixture was cooled to 25 C and 290 mL water was added dropwise over a period of 30-40 min. Stirring was continued over night at 23 C. The dark purple solid was collected by filtration, washed with 2× withMeCN/water 1/1 dried at 50 C in vacuo for 15 h to give 218.5 g (88%) product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].Cl[C:34]1[CH:44]=[CH:43][C:37]([C:38]([N:40]([CH3:42])[CH3:41])=[O:39])=[CH:36][N:35]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:34]3[CH:44]=[CH:43][C:37]([C:38](=[O:39])[N:40]([CH3:41])[CH3:42])=[CH:36][N:35]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(N(CC)CC)cc1
Reactant: CN(C)C(=O)c1ccc(Cl)nc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(=O)N(C)C)cn3)ccc2n1-c1ccc(N(CC)CC)cc1

Procedure:
The title compound was prepared in accordance with step (c) Example 38 from 1-(4-diethylaminophenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (120 mg, 0.28 mmol, see step (b) Example 1) and 6-chloro-N,N-dimethyl-nicotinamide (78 mg, 0.42 mmol). Yield 79 mg (48%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17](OC)=[O:18])=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[C:3]([CH:17]=[O:18])=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)[CH:6]=1
Reactant: COC(=O)c1cn(-c2cccc(C(F)(F)F)c2)cc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
Methyl 4-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate (3.0 g) synthesized above was dissolved in tetrahydrofuran (10 mL) and added dropwise to a solution (15 mL) of lithium aluminum hydride (0.40 g) in tetrahydrofuran at 0° C. The reaction mixture was stirred at 0° C. for 30 min, water (0.40 mL) was carefully added dropwise, 1N aqueous sodium hydroxide solution (2.0 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran (30 mL). The extracts were combined, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in toluene (50 mL), manganese dioxide (6.0 g) was added, and the mixture was heated under reflux under dehydrating conditions for 1 hr. After cooling, manganese dioxide was filtered off, and the residue was evaporated under reduced pressure to give the title compound (2.3 g, 86%) as a slightly yellow solid.
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[C:5]2[N:6]([C:10](I)=[C:11]([CH:13]([CH3:15])[CH3:14])[N:12]=2)[CH:7]=[CH:8][CH:9]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]2=[C:23]([CH:39]=1)[O:24][CH2:25][C:26]1[CH:36]=[C:35]([CH:37]=[O:38])[CH:34]=[CH:33][C:27]=1/[C:28]/2=[C:29](/[CH3:32])\[C:30]#[N:31]>>[F:1][CH:2]([F:17])[O:3][C:4]1[C:5]2[N:6]([C:10]([CH:37]([OH:38])[C:35]3[CH:34]=[CH:33][C:27]4/[C:28](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:22]5[CH:21]=[CH:20][C:19]([F:18])=[CH:39][C:23]=5[O:24][CH2:25][C:26]=4[CH:36]=3)=[C:11]([CH:13]([CH3:15])[CH3:14])[N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Reactant: CC(C)c1nc2c(OC(F)F)cccn2c1I
Product: C/C(C#N)=C1/c2ccc(C(O)c3c(C(C)C)nc4c(OC(F)F)cccn34)cc2COc2cc(F)ccc21
Yield: 96.5 %

Procedure:
[step 3] Using 8-(difluoromethoxy)-3-iodo-2-isopropylimidazo[1,2-a]pyridine (600 mg, 1.71 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (250 mg, 0.85 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8A, step 3, (E)-2-(8-{[8-(difluoromethoxy)-2-isopropylimidazo[1,2-a]pyridin-3-yl](hydroxy)methyl}-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (426 mg, 96%) was obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[S:15]([OH:18])(=[O:17])=[O:16]>C(O)C>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[S:15]([OH:18])(=[O:17])=[O:16].[CH2:7]([O:5][C:4](=[O:6])[C@H:2]([CH3:3])[NH2:1])[CH3:8]
Reactant: C[C@H](N)C(=O)O
Agent: Cc1ccc(C)c(S(=O)(=O)O)c1
Solvent: CCO
Product: CCOC(=O)[C@H](C)N
Temperature: 70 °C

Procedure:
L-alanine (1.50 g, 16.84 mmol) and 2,5-dimethylbenzenesulfonic acid (2,5-DMBS) (3.76 g, 20.20 mmol) were added to ethanol (15 ml), and the mixture was heated overnight at 70° C. to perform esterification. To complete the esterification reaction, the mixture was heated to 90° C., and ethanol (200 ml) was added over 3.5 hours, while distilling away almost the same amount of ethanol. Thereafter, the solvent was evaporated under reduced pressure, and the residue was dried under reduced pressure. The obtained oily residue was cooled in a refrigerator to allow partial crystallization. Ethyl acetate (7 ml) was added, and the residue was dissolved almost entirely at 50° C. The mixture was stirred at room temperature, diethyl ether (40 ml) was further added, and the mixture was stirred at room temperature to give a slurry. The obtained slurry was cooled overnight in a refrigerator, and the crystals were separated and dried to give 3.77 g of L-alanine ethyl ester 2,5-dimethylbenzenesulfonate (L-Ala-OEt 2,5-DMBS salt) dry crystals (L-Ala-OEt 2,5-DMBS salt content 95.6%,11.88 mmol, yield 70.5%).
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]([C:8]3[O:12][N:11]=[C:10](N)[N:9]=3)CN(C2)[CH2:2]1.[Cl:14][C:15]1[C:16]([CH3:30])=[C:17](C2C=CC(NO)=CC=2)[CH:18]=[CH:19][C:20]=1N>>[CH2:6]([C:8]1[O:12][N:11]=[C:10]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[C:16]=2[CH3:30])[N:9]=1)[CH2:5][C:1]#[CH:2]
Reactant: Cc1c(-c2ccc(NO)cc2)ccc(N)c1Cl
Reactant: Nc1noc(C2CN3CCC2C3)n1
Product: C#CCCc1nc(-c2cccc(Cl)c2C)no1
Yield: 46 %

Procedure:
According to the general protocol for oxadiazole synthesis described in Example 40(C) the conversion of 3-chloro-N′-hydroxy-2-methylbenzidine (628 mg, 3.4 mmol) afforded 387 mg of 5-(but-3-ynyl)-3-(3-chloro-2-methylphenyl)-1,2,4-oxadiazole (Yield: 46%) as yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:21]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[CH:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:21]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[CH:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCC=C(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Br)cc1)C2
Solvent: CCO
Product: O=C(O)CCCC=C(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Br)cc1)C2

Procedure:
3.7 g of methyl 6-(2-(4-bromobenzenesulphonylamino)-indan-5-yl)-6-(3-pyridyl)hex-5-enoate are refluxed for 15 minutes in 30 ml of ethanol and with 1N of 15N sodium hydroxide solution. After cooling the solution is rotary evaporated and the residue is taken up in water and washed with 30 ml of methylene chloride. Then the aqueous phase is adjusted to pH 4 using hydrochloric acid. The precipitate formed is washed and dried.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][SH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]1([CH2:7][CH2:8][CH2:9][S:10][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCCCc1ccccc1
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(SCCCc2ccccc2)cc1

Procedure:
A mixture of 174.6 grams (1.15 mole) of 3-phenylpropyl thiol, 158.8 grams (1.15 mole) of p-fluoroacetophenone and 158.8 grams (1.15 mole) of potassium carbonate in 500 ml. of dry dimethylformamide is stirred at its reflux temperature for approximately 24 hours. The reaction mixture is cooled, water added and extracted with methylene chloride. The extract is washed with water, a solution of 2 N sodium hydroxide, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is recrystallized from isopropyl alcohol to yield the desired p-(3-phenylpropylthio)acetophenone having a m.p. of 76°-8° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([NH:19][CH3:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:23][O:24][C:25](=[O:33])[CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CN(C)C=O>[CH3:23][O:24][C:25](=[O:33])[CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][N:19]([C:10]1[CH:9]=[N:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:11]=1)[CH3:20]
Reactant: CNc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: COC(=O)COCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COCCCCN(C)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 20.3 %

Procedure:
Under an argon atmosphere, to a solution of 763 mg of 5,6-diphenyl-2-(methylamino)pyrazine in 4 ml of N,N-dimethylformamide, 140 mg of 60% sodium hydride was added, followed by stirring at 80° C. for 30 minutes. The reaction solution was ice-cooled and a solution of 657 mg of 2-(4-bromobutyloxy)acetic acid methyl ester in 2 ml of N,N-dimethylformamide was slowly added. After an ice bath was removed, the mixture was stirred at room temperature for 14 hours. The reaction solution was combined with ice water and extracted with ethyl acetate and, after the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 240 mg of the desired compound as a pale yellow oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[NH:12]1[CH:16]=[CH:15][N:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O.[Cu]=O>[N:12]1[N:13]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[N:14]=[CH:15][CH:16]=1
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: c1c[nH]nn1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2cc(-n3nccn3)ccc21
Temperature: 80 °C
Reaction time: 15 h
Yield: 54.4 %

Procedure:
To a solution of 5-bromo-1-indanone (5.0 g, 24 mmol) and 1H-triazole (4.90 g, 71.1 mmol) in 20 mL of DMF was added Fe(acac)3 (838 mg, 2.37 mmol), copper (II) oxide (188 mg, 2.36 mmol) and potassium carbonate (3.27 g, 23.7 mmol). The reaction mixture was degassed with nitrogen for 10 minutes. The mixture was stirred at 90° C. for 6.5 hours and at 80° C. for 15 hours. The cooled reaction mixture was diluted with ethyl acetate and water. The biphasic mixture was passed through a thin Celite® pad, which was washed thoroughly with ethyl acetate. The combined organic layers were washed with water, brine and dried over anhydrous magnesium sulfate. Filtration and solvent removal afforded the crude product which was purified by silica chromatography using an ISCO (Teledyne Isco Inc., Lincoln Nebr.) column eluting with a 0-40% ethyl acetate/heptanes gradient to give the desired product as a pale yellow solid (2.60 g, 55%). MS (ES+) 200.1 (M+H)+. 1H NMR (CDCl3) δ 2.85 (t, 2H), 3.24 (t, 2H), 7.83-7.90 (m, 3H), 8.15 (d, 1H), 8.21 (s, 1H).
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl>[N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:31](=[O:33])[CH3:32])[CH2:22][CH2:23]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CC1
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of cis-(octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone (CC-033) (0.026 g, 0.08 mmol) in DCM (1 mL) was added triethylamine (0.27 mmol) and acetyl chloride (0.11 mmol). The reaction mixture was stirred for 1 hour, and then the solvent evaporated. The product was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound as a colourless oil (0.02 g). LCMS m/z 375.15 [M+H]+RT=9.73 min (Analytical Method 2). 1H NMR (400 MHz, CHCl3-d): δ 7.3 (s, 1H), 6.9 (s, 1H), 4.7 (m, 2H), 3.90-3.7 (m, 2H), 3.2-3.10 (m, 3H), 2.9-2.6 (m, 2H), 2.2 (s, 3H), 2.1-1.1 (m, 16H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:12][S:11]3)=[CH:6][CH:5]=[CH:4][N:3]=1.BrC1C(C2N=C3N(C=2)C(CN2CCOCC2)=CS3)=CC=CN=1.[CH3:45][O:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][NH2:52])=[CH:49][CH:48]=1>C1(C)C=CC=CC=1>[CH3:45][O:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][NH:52][C:2]2[C:7]([C:8]3[N:9]=[C:10]4[N:14]([CH:15]=3)[C:13]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:12][S:11]4)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:49][CH:48]=1
Reactant: Clc1ncccc1-c1cn2c(CN3CCOCC3)csc2n1
Reactant: COc1ccc(CN)cc1
Agent: Brc1ncccc1-c1cn2c(CN3CCOCC3)csc2n1
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2ncccc2-c2cn3c(CN4CCOCC4)csc3n2)cc1
Temperature: 25 °C

Procedure:
The 1:1 mixture of 6-(2-Chloro-pyridin-3-yl)-3-morpholin-4-ylmethyl-imidazo[2,1-b]thiazole and 6-(2-bromo-pyridin-3-yl)-3-morpholin-4-ylmethyl-imidazo[2,1-b]thiazole (600 mg) was mixed with 15 mL of toluene along with 0.47 mL of 4-methoxybenzylamine and stirred under reflux for 5 days. The reaction mixture was cooled to room temperature and partitioned between CH2Cl2 and brine. The organic layer was separated, dried (Na2SO4) and concentrated to afford the crude product. Purification by chromatography (Isco, gradient elution, CH2Cl2 to 95% CH2Cl2, 4% MeOH and 1% Et3N) afforded 200 mg of (4-methoxy-benzyl)-[3-(3-morpholin-4-ylmethyl-imidazo[2,1-b]thiazol-6-yl)-pyridin-2-yl]-amine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[N:6]=[CH:5]2.[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[C:29]([F:35])[C:28]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[C:29]([F:35])[C:28]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[N:6]=[CH:5]2
Reactant: COc1ccc(F)c(B(O)O)c1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1Nc1ncc2cc(Br)ccc2n1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(F)c(-c2ccc3nc(N[C@@H]4CCC[C@@H]4NC(=O)OC(C)(C)C)ncc3c2)c1F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
A mixture of tert-butyl ((1S,2R)-2-((6-bromoquinazolin-2-yl)amino)cyclopentyl)carbamate (25 mg, 0.06 mmol), (2,6-difluoro-3-methoxyphenyl)boronic acid (24 mg, 0.12 mmol), Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (3 mg, 0.003 mmol) and potassium phosphate (40 mg, 0.19 mmol) in 1,4-dioxane/water (1 mL/0.2 mL) was degassed with nitrogen for 5 min and stirred at 100° C. for 30 min under microwave. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with saturated ammonium chloride solution and dried with sodium sulfate. The residue was purified by silica gel column chromatography to afford tert-butyl ((1S,2R)-2-((6-(2,6-difluoro-3-methoxyphenyl)quinazolin-2-yl)amino)cyclopentyl)carbamate (21 mg, 37%). MS (ES+) C26H30N4O5 requires: 470, found: 471 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:44])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([CH:10]2[CH2:14][CH:13]([C:15]([O:17]C)=[O:16])[CH:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:11]2[C:26](=[O:43])[CH2:27][NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][C:39]([O:41]C)=[O:40])[CH:33]=2)=[O:30])=[O:9])[CH2:3]1.[OH-].[K+]>O.CO>[C:39]([CH2:38][C:34]1[CH:33]=[C:32]([NH:31][C:29](=[O:30])[NH:28][CH2:27][C:26]([N:11]2[CH:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH:13]([C:15]([OH:17])=[O:16])[CH2:14][CH:10]2[C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C:2]([CH3:1])([CH3:44])[CH2:3]2)=[O:9])=[O:43])[CH:37]=[CH:36][CH:35]=1)([OH:41])=[O:40]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)N3CCCC(C)(C)C3)CC(C(=O)OC)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CCCN(C(=O)C2CC(C(=O)O)C(c3ccccc3F)N2C(=O)CNC(=O)Nc2cccc(CC(=O)O)c2)C1
Yield: 36 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 1.6 g of methyl (2RS,4RS,5SR)-2-(3,3-dimethylpiperidinocarbonyl)-5-(2-fluorophenyl)-1-{2-[3-(3-(methoxycarbonylmethyl)phenyl)ureido]acetyl}pyrrolidine-4-carboxylate and 0.3 g of potassium hydroxide in a mixture of 20 cm3 of distilled water and 40 cm3 of methanol. After treatment, there is obtained 0.55 g of (2RS,4SR,5SR)-1-{2-[3-(3-(carboxymethyl)phenyl)ureido]acetyl}-2-(3,3-dimethylpiperidinocarbonyl)-5-(2-fluorophenyl)pyrrolidine-4-carboxylic acid, melting at 173° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.FC(F)(F)S([O-])(=O)=O.[N:16]1([S:21](N2C=C[NH+](C)C2)(=[O:23])=[O:22])[CH:20]=[CH:19][N:18]=[CH:17]1>>[N:16]1([S:21]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)(=[O:23])=[O:22])[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: OC1CCNCC1
Reactant: C[NH+]1C=CN(S(=O)(=O)n2ccnc2)C1
Agent: O=S(=O)([O-])C(F)(F)F
Product: O=S(=O)(N1CCC(O)CC1)n1ccnc1

Procedure:
1-(Imidazole-1-sulfonyl)-piperidin-4-ol was prepared in accordance with step A of the general method described in example 76 from 4-hydroxypiperidin and 3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium trifluoromethanesulfonate; MS: m/e=232.5 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)C>[C:25]([O:24][C:22]([N:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:29])=[O:2])=[CH:9][CH:8]=1)[C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:16][CH2:17]1)=[O:23])([CH3:26])([CH3:27])[CH3:28]
Reactant: COC(=O)c1ccc(CN(C(=O)OC(C)(C)C)[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1ccc(C(=O)O)cc1)[C@H]1CC[C@H](C(C)(C)C)CC1
Temperature: 70 °C

Procedure:
The crystalline residue from step 2 was re-dissolved in ethanol (200 mL) and aqueous sodium hydroxide solution (100 mL, 4N) was added whereafter the mixture was heated to 70° C. for 4 hours. After cooling, the reaction volume was reduced to one third by rotary evaporation, and water (300 mL) was added. The mixture was extracted with diethyl ether (2×200 mL) to remove traces of non-hydrolysed material. The aqueous phase was then acidified to pH 3.0 by addition of aqueous 4N HCl, whereupon the title material separated out of solution as compact crystals. The crystals were washed once with water and dried overnight in a vacuum oven (40° C.). Yield: 24.3 g (93%).