Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(O)C>[O:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][NH:15][S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])[CH2:19][CH2:20]1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: NCCN1CCOCC1
Solvent: CCO
Product: O=C1Cc2cc(S(=O)(=O)NCCN3CCOCC3)ccc2N1
Temperature: 65 °C
Yield: 53.6 %

Procedure:
A solution of 5-chlorosulphonyloxindole (1 g, 4.3 mmol), (prepared as described for the starting material in Example 60), and 4-(2-aminoethyl)morpholine (620 μl, 4.7 mmol) in ethanol (20 ml) was heated at 65° C. for 1 hour. The solvent was removed by evaporation, the residue was partitioned between methylene chloride and water and the aqueous layer was adjusted to pH7-8 with 5% aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 5-(2-morpholinoethylaminosulphonyl)oxindole (750 mg, 54%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([N:19]2[C:23]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[N:22][N:21]=[C:20]2C(OCC)=O)=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[N:10]=[C:9]([O:15][CH3:16])[C:8]([O:17][CH3:18])=[N:7]2.C(O)(=O)C>O1CCOCC1.O>[Cl:3][C:4]1[C:5]([N:19]2[CH:20]=[N:21][N:22]=[C:23]2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[N:10]=[C:9]([O:15][CH3:16])[C:8]([O:17][CH3:18])=[N:7]2
Reactant: CCOC(=O)c1nnc(-c2cccnc2)n1-c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1nc2cc(Cl)c(Cl)c(-n3cnnc3-c3cccnc3)c2nc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.7 %

Procedure:
1M Aqueous sodium hydroxide solution (17.25 mL, 17.25 mmol) was added dropwise to a stirred solution of 6,7-dichloro-2,3-dimethoxy-5-[3-ethoxycarbonyl-5-(3-pyridyl)-4H-1,2,4-triazol-4-yl]quinoxaline (Preparation 94, 8.2 g, 17.25 mmol) in 1,4-dioxane (68 mL) and water (50 mL) at 10° C. The solution was warmed to room temperature and stirred for 20 hours, diluted with water (50 mL), acidified with glacial acetic acid and extracted with ethyl acetate (1×100 mL, 2×50 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using dichloromethane:methanol (1:0 changing to 9:1, by volume) to give the title compound (5.82 g, 84%) as a white solid, mp 206-207° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[CH:23]1([N:29]([CH3:37])[CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(NC(C)C)(C)C>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:34]3[CH2:35][CH2:36][CH:31]([CH2:30][N:29]([CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[CH3:37])[CH2:32][CH2:33]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CN(CC1CCNCC1)C1CCCCC1
Agent: Cl
Solvent: CC(C)NC(C)C
Product: CN(CC1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1)C1CCCCC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and cyclohexyl-methyl-piperidine-4-ylmethyl-amine, hydrochloride, 5 equivalent of diisopropylamine was added, preparative HPLC (Method C) (43%, white crystals). HPLC-MS m/z=492.3 (M+1), Rt: 3.22 min.
Reaction SMILES: [OH:1][C:2]([CH3:13])([CH3:12])[C@@H:3]([NH:5][C:6](=[O:11])C(Cl)(Cl)Cl)[CH3:4].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:4][C@H:3]1[C:2]([CH3:13])([CH3:12])[O:1][C:6](=[O:11])[NH:5]1
Reactant: C[C@H](NC(=O)C(Cl)(Cl)Cl)C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[C@@H]1NC(=O)OC1(C)C

Procedure:
To a solution of (4) (1.964 g, 7.92 mmol) in ethanol (140 ml) was added potassium carbonate (0.547 g, 3.96 mmol) and the solution was refluxed for 30 minutes. After concentration in vacuo, dichloromethane was added and the mixture was washed with saturated aqueous sodium. chloride solution. Concentration in vacuo gave crude crystalline solid which was purified by recrystallisation in toluene/60-80 petroleum ether giving the title compound (5) (0.968 g, 95%); mp 60° C.; νmax (CDCl3) 1758 cm-1 ; [α]D24 (c 2 in CHCl3)=+1.2; (Found: C, 56.13; H, 8.85; N, 10.79. C6H11NO2 requires C, 55.80; H, 8.58; N, 10.84%); δH (500 MHz; CDCl3) 1.12 (3H, d, J=6.6, CHCH3), 1.27 (3H, s, C(CH3)2), 1.39 (3H, s, C(CH3)2), 3.59 (1H, J=6.5, CHCH3), 7.27 (1H, s, NH); δC (125 MHz; CDCl3) 16.07 (CH3), 21.46 (CH3), 27.14 (CH3), 57.12 (CH), 83.50 (C), 159.00 (CO); m/z (CI+, NH3) 130 (M+ +1).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][C:18]2[N:22]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]3[CH:28]=[CH:29][C:30]([C:32](=[NH:34])[NH2:33])=[CH:31][C:20]=3[N:19]=2)[C:9]1=[O:35])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:32]([C:30]1[CH:29]=[CH:28][C:21]2[N:22]([CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])[C:18]([CH2:17][N:10]3[C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[N:8]([CH2:7][C:6]([OH:36])=[O:5])[C:9]3=[O:35])=[N:19][C:20]=2[CH:31]=1)(=[NH:33])[NH2:34]
Reactant: CC(C)CCn1c(Cn2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)nc2cc(C(=N)N)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CCn1c(Cn2c(=O)n(CC(=O)O)c3ccccc32)nc2cc(C(=N)N)ccc21
Reaction time: 48 h
Yield: 97.8 %

Procedure:
{3-[5-Carbamimidoyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-2-oxo-2,3-dihydro-benzoimidazol-1-yl}-acetic acid tert-butyl ester (1.0 g, 2.0 mmol) was dissolved in CH2Cl2 (50 ml) treated with TFA (3 ml) and stirred for 48 h. The solvent was removed and the residue triturated with EtOAc to give 850 mg (98%) of {3-[5-Carbamimidoyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-2-oxo-2,3-dihydro-benzoimidazol-1-yl}-acetic acid as a with solid.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)[CH3:13].C1C=CC=CC=1>O>[C:9]1(=[N:22][C:19]2[CH:18]=[CH:17][C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:23])=[CH:21][CH:20]=2)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][CH2:11]1
Reactant: O=C1CCCc2ccccc21
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(N=C2CCCc3ccccc32)cc1

Procedure:
A solution of α-tetralone (40 ml), ethyl-p-amino-benzoate (42 g) and benzene (100 ml) was refluxed in the presence of molecular sieve (100 g) with the continuous removal of water. The crude product was crystallized from ethanol to give N-(1,2,3,4-tetrahydonaphthylidene)-p-carbethoxyaniline (XXVIII). XXVIII had a.m.p. of 108.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].O.[CH2:28](O)[CH2:29][OH:30]>S(=O)(=O)(O)O>[OH:30][CH2:29][CH2:28][O:19][C:18](=[O:20])[C@H:17]([CH3:21])[N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CC(C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: OCCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: C[C@@H](C(=O)OCCO)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 56 %

Procedure:
A solution of (S)-2-(4-chlorophenyl-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.00995 mole) and concentrated sulfuric acid (4 drops) in ethylene glycol (50 ml) was refluxed under nitrogen for three hours, and then poured into a saturated sodium bicarbonate solution (200 ml). Water (50 ml) was added and the product was extracted into two portions of ethyl acetate. The combined organic layers were washed twice with water and once with a saturated sodium chloride solution, dried over magnesium sulfate, treated with charcoal and filtered. Evaporation of the solvents under reduced pressure gave 1.9 g (56% yield) of solid which was dissolved in hot isopropyl ether (with a little isopropyl alcohol added). The solution was stirred and cooled to room temperature to precipitate a solid. The mixture was cooled in the freezer, the solid was collected by filtration, rinsed with isopropyl ether and dried under high vacuum at room temperature overnight to give 1.44 g of title compound, mp 112°-113.5° C.
Reaction SMILES: O.[NH2:2][NH2:3].C[O:5][C:6](=O)[C:7]([NH:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:12][CH:11]=1)=[O:8].CCOCC>CCO>[NH:2]([C:6](=[O:5])[C:7]([NH:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:12][CH:11]=1)=[O:8])[NH2:3]
Reactant: CCOC(=O)[C@H]1CC[C@H](Oc2ccc(NC(=O)C(=O)OC)cc2)CC1
Reactant: NN
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@H]1CC[C@H](Oc2ccc(NC(=O)C(=O)NN)cc2)CC1
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
Hydrazine monohydrate (0.15 mL, 3.34 mmol) was added in one portion to a stirred solution of ethyl trans-4-(4-{[methoxy(oxo)acetyl]amino}phenoxy)cyclohexanecarboxylate (150 mg, 3.04 mmol) in EtOH (3 mL) and the reaction mixture was stirred for 20 minutes. Ether (10 mL) was added and the mixture was cooled to 5° C. The mixture was filtered to give the title compound (Intermediate 80) (129 mg, 85%) as a solid that was used without further purification; MS m/e MH+ 350.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.NC(N)=[S:12].CC(CC)=O>O>[CH3:9][O:8][C:5]1[N:4]=[N:3][C:2]([SH:12])=[CH:7][CH:6]=1
Reactant: COc1ccc(Cl)nn1
Reactant: NC(N)=S
Solvent: CCC(C)=O
Solvent: O
Product: COc1ccc(S)nn1
Yield: 23.4 %

Procedure:
A mixture of 3-chloro-6-methoxy-pyridazine (100 g), thiourea (105 g) and ethyl methyl ketone (1.8 L) was prepared and refluxed for three hours. The reaction mixture was then cooled and the supernatant was poured into water and extracted with 1M sodium hydroxide (4×100 mL). The sodium hydroxide solution was washed with ethyl acetate (2×50 mL) and the aqueous extract was acidified with sufficient concentrated hydrochloric acid to lower the pH to 5. The resulting yellow solid was collected and air dried to afford the title compound (24%, 23 g); mp, 198-200° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[CH:3]1.C([Li])CCC.C(OC([N:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)=O)(C)(C)C.[ClH:32]>O1CCCC1.C(Cl)Cl.[Cl-].[Na+].O.O1CCOCC1.CO>[ClH:32].[ClH:32].[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]=[C:3]1[C:28]1([OH:31])[CH2:29][CH2:30][NH:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cn1cnc(-c2ccccc2)c1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1cc(-c2ccccc2)nc1C1(O)CCNCC1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Dissolve 1-methyl-4-phenyl-1H-imidazole (9.05 mmoles; 1.43 g) in anhydrous tetrahydrofuran (30.00 mL) and the mixture cooled to −78° C. Slowly add n-butyl lithium (1.30 equiv; 11.77 mmoles; 7.35 mL) (1.6M in hexanes) and the reaction stirs at −78° C. for 30 minutes then add a THF (20 mL) solution of N-T-butoxycarbonyl-4-piperidone (11.77 mmoles; 2.34 g) dropwise over 20 min. Allow to stir overnight with warming to room temperature. Dilute with DCM and saturated aq. sodium chloride/water (50/50), (2×DCM), then dry over MgSO4. Filter and concentrate to 3.8 g crude yellow oil. Purify the reaction by using ISCO chromatography over a Biotage 40M column eluting with 50:50 EtOAc:Hex at a flow rate of 40 mL/min. Concentrate product fractions to 2.00 g of 4-hydroxy-4-(1-methyl-4-phenyl-1H-imidazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid. ES-MS (M+H)=358.3. Dissolve it in 5 mL dichloromethane and add hydrogen chloride (20.00 mmoles; 5.00 mL)(4M in dioxane) slowly at room temperature. After approximately 5 min the solution becomes cloudy and add 3 mL of methanol to get the reaction back into solution. After 1 h the reaction is 95% complete. Add 1 mL of 4M HCl in dioxane and stir 15 min. Concentrate to 2.1 g of 4-(1-Methyl-4-phenyl-1H-imidazol-2-yl)-piperidin-4-ol dihydrochloride as a light yellow solid. MS(ES): (m/z)=258.3 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][C:6]=12.C(=O)(O)[O-].[Na+].[N:22]#[C:23]Br>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:23]#[N:22])[CH2:13][CH2:12]3)=[N:7][C:6]=12
Reactant: Brc1cnn2ccc(N3CCNCC3)nc12
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#CN1CCN(c2ccn3ncc(Br)c3n2)CC1
Temperature: 0 °C

Procedure:
3-bromo-5-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine (500 mg, 1.77 mmol) taken up in 20 mL DCM and stirred at 0° C. in an ice bath. Sodium bicarbonate (744 mg, 8.86 mmol) in 6 mL water added and stirred. Cyanogen bromide (225 mg, 2.12 mmol) added and stirred at 0° C. for 30 minutes then allowed to reach room temperature and stirred overnight. Reaction diluted with DCM washed with water, DCM layer dried over magnesium sulfate reduced in vacuo for 500 mg crude product for further reaction as is. LRMS (ESI) m/z 307/309 [(M+H)]+, calc'd for C11H11BrN6: 307.15.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.[C:10]1([C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][C:22](B(O)O)=[CH:23]3)=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C>[CH3:8][C:7]1[C:2]([C:22]2[CH:21]=[CH:20][C:19]3[C:24](=[CH:25][C:16]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:17][CH:18]=3)[CH:23]=2)=[N:3][CH:4]=[C:5]([CH3:9])[N:6]=1
Reactant: OB(O)c1ccc2ccc(-c3ccccc3)cc2c1
Reactant: Cc1cnc(Cl)c(C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cnc(-c2ccc3ccc(-c4ccccc4)cc3c2)c(C)n1
Yield: 65 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were placed 0.62 g of 2-chloro-3,5-dimethylpyrazine, 1.07 g of 7-phenylnaphthalene-2-boronic acid, 0.46 g of sodium carbonate, 0.020 g of bis(triphenylphosphine)palladium(II) dichloride (abbreviation: Pd(PPh3)2Cl2), 10 mL of water, and 10 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was irradiated with microwaves (2.45 GHz, 100 W) for 15 minutes, so that heating was performed. Then, the reaction container was cooled to 50° C. or less. Water was added to the reaction solution, and the organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and dried with magnesium sulfate. The solution which had been dried was filtered. The solvent of this solution was distilled, and the obtained residue was purified by silica gel column chromatography with a developing solvent of dichloromethane, whereby Hdm7p2npr, which is the pyrazine derivative to be produced, was found to be obtained (as a white powder in 65% yield). Note that the microwave irradiation was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). The synthesis scheme of Step 4 is illustrated in the following (d-5).
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].[CH3:7][C:8]1([CH3:15])[O:12][C@H:11]([CH:13]=O)[CH2:10][O:9]1.[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1[CH2:20]/[N:21]=[CH:13]/[C@@H:11]1[CH2:10][O:9][C:8]([CH3:7])([CH3:15])[O:12]1
Reactant: CC1(C)OC[C@@H](C=O)O1
Reactant: COc1ccc(CN)c(OC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1ccc(C/N=C/[C@@H]2COC(C)(C)O2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Prepared according to the procedure described by Hubschwerlen, C. and Schmid, G. Helv. Chim. Acta 1983, 66, 2206-2209 with the addition of MgSO4. To a suspension of (S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (Carbosynth LLC, 346 g, 43% in DCM, 1.143 mol) and MgSO4 (278 g) in DCM (1.5 L) at 0° C. was added 2,4-dimethoxybenzylamine (193 g, 1.154 mol) over 20 min. After stirring at rt for 2 h it was filtered, washing the filter cake with DCM (2×250 mL). The mother liquor was used directly in step 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[S:9][C:10]([NH2:12])=[N:11][C:6]2=[CH:5][CH:4]=1.[CH:13]1([CH2:18][CH:19]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[C:20](Cl)=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14]1>N1C=CC=CC=1>[CH:13]1([CH2:18][CH:19]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[C:20]([NH:12][C:10]2[S:9][C:7]3[C:6]([N:11]=2)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=3)=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1ccc2nc(N)sc2n1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc2nc(NC(=O)C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)sc2n1
Temperature: 25 °C

Procedure:
To a solution of the title A compound, 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine (1.22 mmol, 222 mg) in 3 mL of pyridine at 0° C. is added 3-cyclopentyl-2-(4-methansulfonyl-phenyl)-propionyl chloride (1.02 mmol, prepared as described for the preparation of the title C compound in Example 1). The reaction is allowed to warm to RT over 12 h, then evaporated and the residue is partitioned between MTBE and aqueous 0.1 N HCl. The organic solution is washed with water, saturated aqueous NaHCO3 and brine, dried and evaporated to an oil. Chromatography over silica affords 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-propionamide; 1H NMR δ 9.7 (s, 1H), 7.85 (m, 3H), 7.38 (d, J=8, 2H), 6.83 (d, J=8, 1H), 4.05 (s, 3H), 3.63 (t, J=7.5, 1H); 3.09 (s, 3H), 2.2 (m, 1H), 1.1-1.9 (m, 10H); e/z (ES) 460 (M+1, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C@@H:9]2[CH2:13][N:12]([C@H](C3C=CC=CC=3)C)[CH2:11][C@H:10]2[F:22])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>ClCCl>[CH2:27]([O:26][C:24]([N:12]1[CH2:13][C@@H:9]([C:6]2([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8][CH2:7]2)[C@H:10]([F:22])[CH2:11]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)C1([C@@H]2CN([C@@H](C)c3ccccc3)C[C@H]2F)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C1([C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2F)CC1
Temperature: 25 °C
Reaction time: 25 h
Yield: 89.4 %

Procedure:
4-(R)-(1-Ethoxycarbonylcyclopropyl)-3-(S)-fluoro-1-[1-(S)-phenylethyl]pyrrolidine (3.786 g, 12.40 mmol) was dissolved in dry dichloromethane (120 ml), and benzyl chloroformate (3.37 ml, 25.0 mmol) was added dropwise to the thus prepared solution which was cooled in an ice bath. After stirring the reaction solution for 25 hours at room temperature, dichloromethane was evaporated under reduced pressure. Thereafter, the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=4:1, to thereby obtain 3.718 g (89.4%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:13]=[C:14]([N+]([O-])=O)[C:15]([C:18]#[N:19])=[N:16][CH:17]=1.[NH4+].[Cl-]>O.CN(C=O)C>[Br:11][C:12]1[CH:13]=[C:14]([O:8][C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[C:15]([C:18]#[N:19])=[N:16][CH:17]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: Cc1ncccc1O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncccc1Oc1cc(Br)cnc1C#N
Reaction time: 0.08 h
Yield: 97.5 %

Procedure:
A flask was charged with 2-methylpyridin-3-ol (3.0 g, 27.5 mmol) and DMF (100 mL). Sodium hydride (0.760 g, 30.2 mmol) was added and stirred for 5 minutes. 5-Bromo-3-nitropicolinonitrile (6.26 g, 27.5 mmol) was added and stirred for 10 minutes. The reaction was poured into a flask containing 300 mL saturated NH4Cl and 300 mL water with vigorous stirring. The solids were filtered and dried under high vacuum to afford 5-bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (7.78 g, 97.6% yield) as light tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[OH-].[K+].[I:13]I>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:13])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cn[nH]c2c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1ccc2c(I)n[nH]c2c1
Temperature: 30 °C
Yield: 82.2 %

Procedure:
A mixture of 6-chloro-1H-indazole (2 g, 13.1 mmol), KOH (2.2 g, 39.3 mmol) and I2 (6.6 g, 26.2 mmol) in dry DMF (20 mL) was heated to 30° C. for 16 hours. Reaction quenched with water, product was extracted with ethyl acetate (150 mL), organic phase washed with water (3×10 mL), brine (2×10 mL) and dried over Na2SO4, then filtered and concentrated to afford 6-chloro-3-iodo-1H-indazole (3.0 g, 83%) as a yellow solid. LCMS: (M+H)+=279.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]2=[O:15])=[CH:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>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>[N:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:17]=[CH:16][C:5]([CH2:6][N:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]3=[O:15])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccncc1
Reactant: COc1cccn(Cc2ccc(Br)cc2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccn(Cc2ccc(-c3ccncc3)cc2)c1=O
Yield: 81.7 %

Procedure:
Reaction of 145 (0.25 g, 0.85 mmol), pyrdin-4-ylboronic acid (0.12 g, 1.02 mmol), 2M aq. K2CO3 (0.23 g, 1.69 mmol), Pd(PPh3)4 (2.5 mol %) according to method described for synthesis of 146a within 18 h afforded 203 mg of 146i (82%) of white solid. 1H NMR (400 MHz, CDCl3) δ 8.54 (dd, J=4.5, 1.6 Hz, 2H), 7.48 (m, 2H), 7.36 (m, 4H), 6.87 (dd, J=6.9, 1.7 Hz, 1H), 6.53 (dd, J=7.4, 1.6 Hz, 1H), 6.03 (t, J=7.2 Hz, 1H), 5.13 (s, 2H), 3.72 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 157.82, 150.32, 150.01, 149.90, 147.40, 137.31, 137.28, 128.57, 127.68, 127.04, 121.22, 111.90, 104.98, 55.57, 51.42. HRMS (EI) calcd for C18H16N2O2 [M]+ 292.1212. found 292.1205.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[N:17]2[C:26]=1[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH3:13])=O)C1C=CC=CC=1.CSC>C(O)(C(F)(F)F)=O>[NH2:11][C@H:12]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[N:17]2[C:26]=1[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH3:13]
Reactant: COC(=O)c1cccc2nc([C@H](C)NC(=O)OCc3ccccc3)c(-c3cccnc3)n12
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Product: COC(=O)c1cccc2nc([C@H](C)N)c(-c3cccnc3)n12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of (S)-methyl 2-(1-(((benzyloxy)carbonyl)amino)ethyl)-3-(pyridin-3-yl)imidazo[1,2-a]pyridine-5-carboxylate (450 mg, 1.04 mmol) and dimethylsulfide (0.4 mL) in TFA (1.2 mL)) was stirred at rt overnight. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc. The organic layer was washed with satd. sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo to provide (S)-methyl 2-(1-aminoethyl)-3-(pyridin-3-yl)imidazo[1,2-a]pyridine-5-carboxylate: LC-MS (ESI) m/z 297.2 [M+H]+. The crude product was used without further purification.