Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[C:21]([O:33][CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[OH:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH3:34][O:33][C:21]1[CH:20]=[C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:39]4[CH2:40][CH2:41][CH:36]([OH:35])[CH2:37][CH2:38]4)[C:17]=23)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: OC1CCNCC1
Reactant: COc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccn1
Product: COc1cc(Nc2ncnc3[nH]nc(OCCN4CCC(O)CC4)c23)ccc1OCc1ccccn1
Yield: 54 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[3-methoxy-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate and 4-hydroxypiperidine to give the title compound in 54% yield; NMR Spectrum: 1.36 (d, 2H), 1.69 (d, 2H), 2.18 (t, 2H), 2.78 (m, 4H), 3.81 (s, 3H), 4.41 (t, 2H), 4.53 (d, 1H), 5.16 (s, 2H), 7.03 (d, 1H), 7.23 (dd, 1H), 7.37 (m, 2H), 7.54 (d, 1H), 7.85 (td, 1H), 8.26 (s, 1H), 8.30 (s, 1H), 8.58 (d, 1H); Mass Spectrum: 492 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.[CH:17]1([O:21][C:22](Cl)=[O:23])[CH2:20][CH2:19][CH2:18]1.C1(O)CCC1.C(Cl)(Cl)=O>CN(C=O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[CH:17]1([O:21][C:22]([N:10]2[C:4]3[CH:3]=[C:2]([Br:1])[N:7]=[CH:6][C:5]=3[CH:8]=[C:9]2[C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)=[O:23])[CH2:20][CH2:19][CH2:18]1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Reactant: O=C(Cl)OC1CCC1
Agent: O=C(Cl)Cl
Agent: OC1CCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3cnc(Br)cc3n2C(=O)OC2CCC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 122, 100 mg, 0.36 mmol) was dissolved in dry DMF (1 ml). The solution was degassed and a solution of sodium bis(trimethylsilyl)amide (0.54 ml of a 1M solution in THF, 0.54 mmol) was added. After 20 minutes reaction, a solution of cyclobutylchloroformate [freshly prepared by stirring 40 mg of cyclobutanol with one equivalent of a 20% phosgene solution in toluene (0.275 ml) for 3 h, 0.55 mmol] was added. The reaction was stirred for 2 hours at room temperature then was diluted with ethyl acetate and water. The organic solution was washed with brine, dried over sodium sulphate and concentrated in vacuum. The crude product was purified on silica gel column chromatography eluting with 20% hexane in ethyl acetate to afford the title compound as a white powder (95 mg, 70.2%). 1H-NMR (500 MHz, CDCl3): δ 1.69 (m, 1H), 2.12 (m, 1H), 2.15 (m, 2H), 2.4 (m, 2H), 3.94 (s, 3H), 5.17 (quin, J=7.2 Hz, 1H), 6.54 (s, 1H), 7.6 (s, 1H), 7.62 (s, 1H), 8.14 (s. 1H), 8.51 (s, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:6]([CH3:18])=[C:5]2[CH:19]=O.Cl.[NH2:22][OH:23].CO>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:6]([CH3:18])=[C:5]2[CH:19]=[N:22][OH:23]
Reactant: NO
Reactant: Cc1c(C=O)c2cc(Br)ccc2n1-c1ccc(O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1c(C=NO)c2cc(Br)ccc2n1-c1ccc(O)cc1
Yield: 66 %

Procedure:
A mixture of 5-bromo-1-(4-hydroxyphenyl)-2-methyl-1H-indole-3-carbaldehyde (0.16 g, 0.5 mmol), hydroxylamine hydrochloride (0.10 g, 1.4 mmol), methanol (10 mL) and pyridine (0.2 mL) was reacted according to the procedure used in Example 4 to afford a white solid (66%): mp 209-211° C.; 1H NMR (DMSO-d6): δ 2.29 (3H, s), 6.92-6.97 (3H, m), 7.20-7.25 (3H, m), 8.19 (1 H, d, J=1.9 Hz), 8.39 (1H, s), 9.94 (1H, br s), 10.76 (1H, s); MS m/z (M+H)+ 345/347 (1 Br). Anal. for C16H13BrN2O2·0.5H2O; Calc'd: C, 54.26; H, 3.98 N, 7.91. Found: C, 54.26; H, 3.68; N, 7.65.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: Cc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f40) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].N1C=CN=C1.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].O>CN(C)C=O>[Si:35]([O:25][C@@H:23]1[CH2:22][CH2:21][C@@:20]2([CH3:26])[C@H:19]([CH2:18][C@@H:17]([OH:27])[C@@H:16]3[C@@H:15]2[CH2:14][C@H:13]([OH:28])[C@@:12]2([CH3:29])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:24]1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reaction time: 8 h

Procedure:
Cholic acid, 4.08 g, is dissolved in 10 ml of dry dimethylformamide and 3.40 g of imidazole is added, followed by 3.60 g of t-butyldimethylsilyl chloride. The reaction mixture is allowed to stand overnight at room temperature. The reaction mixture is poured into water, filtered and the precipitate is washed with water. This precipitate is dissolved in 30 ml of tetrahydrofuran and 3 ml of water and 2 ml of acetic acid is added. After 6.5 hours, the solvent is evaporated and the residue chromatographed on 200 g of silica gel with 5% methanol in methylene chloride as eluent, to provide 3α-(t-butyldimethylsilyloxy)-7α,12α-dihydroxy-5β-cholan-24-oic acid, mp 145.5-148, having the following structural formula: ##STR14##
Reaction SMILES: [N:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[C:11]3[N:10]=[C:9]([NH:22][NH2:23])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=O.C(O)(=O)C>C(O)C>[NH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]([CH:24]=[N:23][NH:22][C:9]2[CH:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:12]3[N:13]=[CH:14][C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[C:11]3[N:10]=2)=[CH:27]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: NNc1cc(N2CCOCC2)n2ncc(-c3ccccn3)c2n1
Solvent: CCO
Solvent: CC(=O)O
Product: C(=NNc1cc(N2CCOCC2)n2ncc(-c3ccccn3)c2n1)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
To a solution of (7-morpholin-4-yl-3-pyridin-2-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (25 mg, 0.080 mM) in ethanol (1.5 mL), there were added 3-formyl-indole (18 mg, 0.12 mM) and acetic acid (3 μL) and then the mixture was stirred at room temperature for 3 hours. The precipitated solid was recovered through filtration and then washed with ethanol to thus give the title compound (18 mg, yield: 51%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH3:38])[C:28]2[N:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([N:27]([C:28]2[N:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[N:29]=2)[CH3:38])=[CH:25][CH:26]=1
Reactant: COc1cc(OC)nc(N(C)c2ccc(I)cc2)n1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: COC(=O)C(C/C=C/c1ccc(N(C)c2nc(OC)cc(OC)n2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 63.7 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (80 mg) was reacted with N-(4-iodophenyl)-4,6-dimethoxy-N-methylpyrimidin-2-amine (118 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-((4,6-dimethoxy-pyrimidin-2-yl)-methyl-amino)phenyl]pent-4-enoic acid methyl ester (92 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=2/1) was used for purification.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4]1.O.[C:11]([C:13]1[CH:18]=[C:17](Cl)[N:16]=[C:15]([Cl:20])[CH:14]=1)#[N:12]>CN1CCCC1=O>[Cl:20][C:15]1[CH:14]=[C:13]([C:11]#[N:12])[CH:18]=[C:17]([O:9][CH2:8][C:5]2[CH:6]=[CH:7][S:3][CH:4]=2)[N:16]=1
Reactant: OCc1ccsc1
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cc(Cl)nc(OCc2ccsc2)c1
Reaction time: 1.5 h

Procedure:
Sodium hydride (0.24 g (ca.60% in mineral oil), 0.006×1.0 mol) was suspended in 20 ml of N-methyl-2-pyrrolidinone, and 3-thiophenemethanol (0.69 g, 0.006×1.0 mol) was added thereto and the resultant solution was stirred for about 30 minutes at room temperature. The resultant mixture was cooled to 4° C. with iced water, then 4-cyano-2,6-dichloropyridine (1.04 g, 0.006 mol) was added thereto and stirred for about 1.5 hour while cooling with iced water.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]([CH3:21])[CH2:19][OH:20])[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:22]2[CH2:25][CH2:24][CH2:23]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:28][C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.Cl>CN(C)C=O.C(OC)(C)(C)C.O1CCOCC1.C(OCC)(=O)C.O>[ClH:28].[C:1]([C:5]1[N:6]=[C:7]([CH:22]2[CH2:25][CH2:24][CH2:23]2)[CH:8]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][C@@H:18]([CH3:21])[CH2:19][O:20][C:29]3[N:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:15][CH2:16]2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ncccn1
Reactant: C[C@@H](CO)CN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: C[C@@H](COc1ncccn1)CN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Reaction time: 0.17 h
Yield: 41.8 %

Procedure:
0.755 g of (R)-3-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-2-methyl-propan-1-ol (2.18 mmol) were stirred in 7.6 ml of dimethylformamide under argon. 0.105 g of 60% sodium hydride (2.6 mmol) were added and stirred for 10 min. A solution of 0.275 g of 2-chloro-pyrimidine (2.4 mmol) in 2.4 ml of dimethylformamide was added. The reaction mixture was stirred for 16 h, followed by the addition of 30 ml of water and 40 ml of ethyl acetate. The organic layer was separated and the aqueous phase extracted with a further portion of ethyl acetate. The combined extracts were concentrated to dryness and the crude product purified by flash column chromatography eluting with ethyl acetate. The fractions containing the product were combined and evaporated under reduced pressure to give a pale yellow oil. The oil was dissolved in tert-butyl methylether and 4 N hydrochloric acid in dioxan was added to the solution. A white solid separated. The precipitate was collected by filtration, washed with tert-butyl methyl ether and dried in a vacuum oven to yield 0.42 g of the title compound.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH2:5]([N:23]=[C:24]=[O:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CCOCC>[CH2:5]([NH:23][C:24]([NH:3][CH2:2][CH2:1][NH2:4])=[O:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: NCCN
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCNC(=O)NCCN
Reaction time: 2 h

Procedure:
20 grams (0.33 moles) ethylene diamine in 200 cc ether was reacted with 5.0 gms (.0168 mole) octadecylisocyanate in 25 cc ether. A white precipitate forms which is stirred for 2 hours, filtered and washed with ether and recrystallized from 2 propane, melting point 108°-127°C.
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][C:10]([OH:12])=O)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:13]1[CH:14]=[CH:15][C:16]2N(O)N=[N:19][C:17]=2[CH:18]=1.CCN=C=NCCCN(C)C.NC1C=CC=CC=1>C1COCC1>[C:1]([NH:5][S:6]([CH2:9][C:10]([NH:19][C:17]1[CH:18]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:12])(=[O:7])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)NS(=O)(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a solution of compound 2-(N-tert-butylsulfamoyl)acetic acid (5 g, 25.6 mmol.) in dry THF (20 mL) was added HOBt (13.8 g, 102.4 mmol.) and EDCI (18.3 g, 102.4 mmol.). Then aniline (3.6 g, 38.4 mmol.) was added successively. The reaction mixture was stirred overnight at room temperature. TLC analysis showed the reaction complete. The mixture was quenched by adding water and extracted with EtOAc (30 mL×3). The combined organic layer was dried over Na2SO4, concentrated. The residue was purified by column chromatography (PE:EtOAc=2:1) to afford 2-(N-tert-butylsulfamoyl)-N-phenylacetamide (3.5 g, 51%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([C:13]3[N:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=4)[C:23]#[N:24])[O:15][N:14]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.Cl[CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[C:23]([C:22]1[CH:25]=[C:18]([C:16]2[O:15][N:14]=[C:13]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH2:10][CH2:11][CH2:12][C@H:3]4[NH:2][S:33]([CH:32]=[CH2:31])(=[O:35])=[O:34])[N:17]=2)[CH:19]=[CH:20][C:21]=1[O:26][CH:27]([CH3:29])[CH3:28])#[N:24]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4N)no2)cc1C#N
Agent: Cl
Solvent: ClCCl
Product: C=CS(=O)(=O)N[C@@H]1CCCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a stirred solution of (R)-5-(3-(5-amino-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride 3 (100 mg, 0.24 mmol) in DCM (5 mL) at 0° C. were added TEA (170 μL, 1.2 mmol) and 2-chloroethanesulfonyl chloride (76 μL, 0.73 mmol). The reaction mixture was warmed to room temperature and stirred for 30 min. The solvent was removed and the product was purified by chromatography (EA/hexane) to give 83.0 mg (75%) of (R)-N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)ethenesulfonamide INT-16 as a white solid. LCMS-ESI (m/z) calculated for C24H24N4O4S: 464.5; found 465.1 [M+H]+, tR=3.83 min. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.2 Hz, 1H), 8.32 (dd, J=8.9, 2.2 Hz, 1H), 7.96 (dd, J=7.7, 1.2 Hz, 1H), 7.62 (t, J=11.0 Hz, 1H), 7.38 (t, J=7.7 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 6.66 (dt, J=26.0, 13.0 Hz, 1H), 6.38 (d, J=16.5 Hz, 1H), 6.03 (dd, J=10.1, 5.2 Hz, 1H), 4.86-4.73 (m, 1H), 4.68-4.57 (m, 1H), 4.50 (d, J=8.3 Hz, 1H), 3.18 (dt, J=18.1, 5.8 Hz, 1H), 3.02 (dt, J=18.1, 6.8 Hz, 1H), 2.15-1.96 (m, 2H), 1.97-1.79 (m, 2H), 1.48 (d, J=6.1 Hz, 6H).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([C:9]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:10]=1[N:11]([CH3:14])[CH:12]=[O:13])(=[O:8])[CH3:7].O>ClCCl>[Cl:4][CH2:7][C:6]([C:9]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:10]=1[N:11]([CH3:14])[CH:12]=[O:13])=[O:8]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)c1cc(F)ccc1N(C)C=O
Solvent: ClCCl
Solvent: O
Product: CN(C=O)c1ccc(F)cc1C(=O)CCl
Reaction time: 8 h

Procedure:
A solution of sulphuryl chloride (3.2 ml) in dichloromethane (20 ml) was added dropwise over a period of 10 minutes to the solution of 2'-acetyl-4'-fluoro-N-methylformanilide at 0° under a nitrogen atmosphere and the mixture stored overnight at 0 to 5°. Water (25 ml) was added whilst maintaining the temperature below 1 0°. The dichloromethane layer was separated, washed with water (1 25 ml) and dried over magnesium sulphate to give a solution of 2'-(2-chloroacetyl)-4'-fluoro-N-methylformanilide.
Reaction SMILES: C(OC(=O)C)C.Cl.[CH3:8][O:9][C:10]([C:12]1[N:13]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([O:43]C(C)(C)C)=[O:42])=[CH:37][CH:36]=2)[C:14](=[O:33])[C:15]2[C:20]([C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:19][C:18]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])=[CH:17][CH:16]=2)=[O:11]>>[CH3:8][O:9][C:10]([C:12]1[N:13]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]([OH:43])=[O:42])=[CH:39][CH:40]=2)[C:14](=[O:33])[C:15]2[C:20]([C:21]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[CH:19][C:18]([C:28](=[O:32])[N:29]([CH3:30])[CH3:31])=[CH:17][CH:16]=2)=[O:11]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(C(=O)N(C)C)ccc2c(=O)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2ccccc2)c2cc(C(=O)N(C)C)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.5 %

Procedure:
To a 4N-hydrochloric acid ethyl acetate solution (4 ml) was added 2-(4-tert-butoxycarbonylbenzyl)-6-dimethylcarbamoyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (140 mg), and the mixture was stirred at room temperature for 4 hrs. The reaction mixture was concentrated under reduced pressure, and the obtained residue was crystallized from methanol-diisopropyl ether to give the title compound (86 mg).
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[C:13](=O)[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:22]=[C:13]1[CH:12]2[CH2:15][CH2:16][N:9]([CH2:10][CH2:11]2)[C:8]1=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccccc1CN
Reactant: O=C1C(=Cc2ccccc2)N2CCC1CC2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: COc1ccccc1CN=C1C(=Cc2ccccc2)N2CCC1CC2
Temperature: 116 °C

Procedure:
To a 12 L three neck round bottom flask (3nrbf) fitted with mechanical stirrer, thermometer, condenser, and Dean Stark trap, was charged 5.9 L toluene, 791.8 g (3.7 moles) of 2-phenylmethylene-1-azabicyclo[2.2.2]octan-3-one, 764 g (5.6 moles, 1.5 equivalents) 2-methoxybenzylamine, and 8.8 g (0.039 moles) (+)camphor sulfonic acid. The solution was heated to reflux (116° C.) and refluxed for 42 hours. A total of 75 ml water was collected in the Dean Stark trap showing that the reaction was proceeding. The solution containing the title product was cooled to room temperature.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl>N1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:16][C:13]2[S:14][CH:15]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[N:12]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(-c2csc(NS(=O)(=O)c3ccc(Cl)cc3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrochloride with 0.45 g of 4-chlorobenzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 50 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 40 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 40 ml of 50% ethanol yielded 0.43 g of 4-chloro-N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35](=[O:40])[CH2:34]2.CN1C=CN=C1.CCN=C=NCCCN(C)C.[ClH:58]>CN(C=O)C.O.C(OCC)(=O)C>[ClH:58].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][C:35](=[O:40])[CH2:34]4)=[O:23])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)nc1OC
Reactant: Nc1ccc2c(c1)CC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2cc(-c3cccc(C(=O)Nc4ccc5c(c4)CC(=O)N5)c3)nn3ccnc23)nc1OC
Temperature: 50 °C
Reaction time: 48 h
Yield: 2 %

Procedure:
A mixture of 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (100 mg, 0.26 mmol), 5-aminoindolin-2-one (38 mg, 0.26 mmol), 1-methyl-1H-imidazole (84 mg, 1.02 mmol) and EDCI (196 mg, 1.02 mmol) in DMF (3 mL) was stirred at 50° C. for 48 h. Ethyl acetate (5 mL) and water (5 mL) were added. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phases were combined and washed with brine (10 mL) then dried over Na2SO4. The residue was concentrated and purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 25% acetonitrile/75% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give a residue that was treated with 0.5 mL HCl and the suspension stirred for 5 min. Concentration gave 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(2-oxoindolin-5-yl)benzamide hydrochloride (2.3 mg, 2%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.67 (s, 1H), 10.36 (s, 1H), 10.31 (s, 1H), 8.88 (s, 1H), 8.51-8.47 (m, 2H), 8.20-8.12 (m, 3H), 7.75-7.68 (m, 2H), 7.54-7.44 (m, 2H), 7.09 (d, 1H, J=8.1 Hz), 6.81 (d, 1H, J=7.8 Hz), 4.03 (s, 3H), 3.78 (s, 3H), 3.08 (s, 2H). LC-MS: [M+H]+, 522, tR=1.48 min, HPLC: 99.05% at 214 nm, 96.91% at 254 nm, tR=5.184 min.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:13][CH2:12][O:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[CH2:14]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]1)[CH3:15]>>[CH2:14]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH:22]([CH2:12][CH2:13][CH:10]([OH:11])[C@H:7]2[CH2:8][CH2:9][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]2)[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:18][CH2:17]1)[CH3:15]
Reactant: CC[C@H]1CC[C@H](CC(=O)OC(C)(C)C)CC1
Reactant: CCC[C@H]1CC[C@H](C2CCO2)CC1
Product: CCC[C@H]1CC[C@H](C(O)CCC(C(=O)OC(C)(C)C)[C@H]2CC[C@H](CC)CC2)CC1

Procedure:
Reaction operations were carried out according to the first step of Example 1 by using 1-(trans-4-propylcyclohexyl)oxetane (37) (3.1 g, 17.0 mmol) and tert-butyl 2-(trans-4-ethylcyclohexyl)acetate (40) (12.3 g, 54.4 mmol) as starting materials to obtain tert-butyl 2-(trans-4-ethylcyclohexyl)-5-hydroxy-5-(trans-4-propylcyclohexyl)pentanoate (41) (6.8 g, 14.5 mmol). The yield based on the compound (37) was 85%.