Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1([N:7](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:6][O:5][CH2:4]1.C1CCCCC=1.[ClH:28]>C(O)C.[Pd].C(OCC)C>[ClH:28].[ClH:28].[NH2:1][CH2:2][C:3]1([NH2:7])[CH2:6][O:5][CH2:4]1
Reactant: NCC1(N(Cc2ccccc2)Cc2ccccc2)COC1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: C1=CCCCC1
Solvent: CCO
Product: NCC1(N)COC1

Procedure:
585 mg (2.07 mmol) of 3-(aminomethyl)-N,N-dibenzyloxetane-3-amine [synthesis described in: US2008/103183 A1, 2008; p. 48] were initially charged in ethanol (29.2 ml), and 441 mg (0.41 mmol) of 10% palladium on activated carbon and 6.3 ml (62.2 mmol) of cyclohexene were added. The reaction mixture was stirred under reflux for 8 h. Subsequently, the reaction mixture was filtered through a Millipore® filter and washed with methanol, and the filtrate was admixed with 2.6 ml (5.2 mmol) of 2 M hydrogen chloride in diethyl ether, concentrated and dried under high vacuum. This gave 423 mg (87% of theory, purity 75%) of the target compound.
Reaction SMILES: [CH:1]1([N:4]([CH:47]2[CH2:52][CH2:51][CH:50]([C:53]([O:55]CC)=[O:54])[CH2:49][CH2:48]2)[S:5]([C:8]2[CH:9]=[C:10]([CH:44]=[CH:45][CH:46]=2)[C:11]([NH:13][C:14]2[S:15][C:16]3[CH2:43][CH2:42][CH2:41][CH2:40][C:17]=3[C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]3[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)=[O:20])=[O:12])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[C:53]([C@H:50]1[CH2:51][CH2:52][C@H:47]([N:4]([CH:1]2[CH2:2][CH2:3]2)[S:5]([C:8]2[CH:9]=[C:10]([CH:44]=[CH:45][CH:46]=2)[C:11]([NH:13][C:14]2[S:15][C:16]3[CH2:43][CH2:42][CH2:41][CH2:40][C:17]=3[C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:38][CH:39]=3)=[CH:24][CH:23]=2)=[O:20])=[O:12])(=[O:6])=[O:7])[CH2:48][CH2:49]1)([OH:55])=[O:54].[C:53]([C@@H:50]1[CH2:51][CH2:52][C@H:47]([N:4]([CH:1]2[CH2:2][CH2:3]2)[S:5]([C:8]2[CH:9]=[C:10]([CH:44]=[CH:45][CH:46]=2)[C:11]([NH:13][C:14]2[S:15][C:16]3[CH2:43][CH2:42][CH2:41][CH2:40][C:17]=3[C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:38][CH:39]=3)=[CH:24][CH:23]=2)=[O:20])=[O:12])(=[O:6])=[O:7])[CH2:48][CH2:49]1)([OH:55])=[O:54]
Reactant: CCOC(=O)C1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)OC)cc5)cc3)CCCC4)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)N(C5CC5)[C@H]5CC[C@@H](C(=O)O)CC5)c4)sc4c3CCCC4)cc2)cc1
Product: O=C(O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)N(C5CC5)[C@H]5CC[C@H](C(=O)O)CC5)c4)sc4c3CCCC4)cc2)cc1

Procedure:
A mixture of 300 mg of methyl 4-(2-{4-[({2-[(3-{cyclopropyl[4-(ethoxycarbonyl)cyclohexyl]sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate, 1.0 mL of a 1.0 M aqueous sodium hydroxide solution, and 3.0 mL of ethanol was heated and refluxed for 3 days. The reaction mixture was concentrated under reduced pressure and the residue was neutralized with 1.0 M hydrochloric acid, and then the precipitate was collected by filtration. The obtained solid was purified by silica gel column chromatography (chloroform-methanol) to obtain 4-{2-[4-({[2-({3-[(trans-4-carboxycyclohexyl)(cyclopropyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoic acid (high polarity product) and 4-{2-[4-({[2-({3-[(cis-4-carboxycyclohexyl)(cyclopropyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoic acid (low polarity product). The products were each suspended in ethyl acetate-hexane to obtain 114 mg of 4-{2-[4-({[2-({3-[(trans-4-carboxycyclohexyl)(cyclopropyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoic acid (Example 4) and 56 mg of 4-{2-[4-({[2-({3-[(cis-4-carboxycyclohexyl)(cyclopropyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoic acid (Example 5), respectively, as colorless crystals.
Reaction SMILES: CO[C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].[CH3:14]C(C)C(=O)C(OC)=O.[C:23]1([CH2:29][C:30](=O)[C:31]([O:33]C)=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:29]([C@H:30]1[CH2:14][C@H:3]([OH:13])[C@H:4]([CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:5][C:31]1=[O:33])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: COC(=O)C(=O)C(C)C
Reactant: COC(=O)C(=O)Cc1ccccc1
Product: O=C1N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H]1Cc1ccccc1

Procedure:
Following the procedures outlined in Examples 2-6, and replacing L-cyclohexylalanine methyl ester with L-phenylalanine methyl ester in Example 2 and methyl 3-methyl-2-oxobutyrate with methyl 3-phenyl-2-oxopropionate in Example 4 provides the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[O:12]=[C:13](Cl)OC(Cl)(Cl)Cl>O1CCOCC1>[C:4]12[C:3](=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH:2][C:13](=[O:12])[O:7][C:5]2=[O:6]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccccc1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2ccccc2c(=O)o1

Procedure:
7.5 g of 2-amino benzoic acid hydrochloride was mixed with 10 ml of diphosgene and the mixture was stirred in 150 ml of dioxane for 40 minutes at reflux. The resulting mixture was cooled and filtered. Yield: 5.7 g of title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[CH2:15][CH2:14]3)[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:24]([CH3:31])=[N:25][N:26]([CH2:28][CH2:29][OH:30])[CH:27]=1.CCOC(C)=O>CO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[CH2:15][CH2:14]3)=[CH:7][C:2]([NH:22][C:23]2[C:24]([CH3:31])=[N:25][N:26]([CH2:28][CH2:29][OH:30])[CH:27]=2)=[N:3][CH:4]=1
Reactant: Cc1nn(CCO)cc1N
Reactant: CN1CCc2cccc(Nc3cc(Cl)ncc3Cl)c2C1=O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nn(CCO)cc1Nc1cc(Nc2cccc3c2C(=O)N(C)CC3)c(Cl)cn1

Procedure:
This compound was prepared from 8-[(2,5-dichloropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one and 2-(4-amino-3-methyl-pyrazol-1-yl)ethanol. Column chromatography (SiO2, 50 equiv.; 95:5; EtOAc:MeOH) followed by prep. TLC (SiO2: 20×20 cm; 1000 μM, Analtech, EtOAc:MeOH; 95:5) furnished 45 mg of the desired compound. 1H NMR spectrum (CDCl3) 2.09 (s, 3H), 2.91 (t, 2H), 3.11 (s, 3H), 3.25 (bs, 1H), 3.51 (t, 2H), 3.86-3.95 (m, 2H), 4.05-4.10 (m, 2H), 5.89 (s, 1H), 6.44 (s, 1H), 6.68 (d, 1H), 7.14-7.29 (m, 2H), 7.44 (s, 1H), 7.88 (s, 1H), 11.09 (s, 1H); Mass spectrum: ESI+ MH+ 427
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:7](=[C:10]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH2:11][OH:12])([CH3:9])[CH3:8].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(#N)C>[C:1]([O:12][CH2:11][C:10](=[C:7]([CH3:9])[CH3:8])[CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: CC(C)=CCC(CO)=C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCC(=O)OCC(CC=C(C)C)=C(C)C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
In a nitrogen atmosphere, 64.0 g of butyryl chloride was added dropwise to a mixture of 94.1 g of 2-isopropylidene-5-methyl-4-hexenol (3) having a purity of 81.1% and an α,β-isomer purity of 98.1%, 50 g of pyridine and 500 ml of acetonitrile over 55 minutes which was stirred under cooling with ice. The reaction mixture was stirred for 2 hours under cooling with ice. To the reaction mixture was added an aqueous solution of saturated sodium bicarbonate, followed by extraction with diethyl ether. The diethyl ether solution was subjected to work-up including washing, drying and concentration to obtain 131.22 g of the crude product. The crude product was purified by distillation under reduced pressure to obtain, as the intended product, 23.54 g of a fraction having a purity of 92.8% and an α,β-isomer purity of 97.0% and 82.05 g of a fraction having a purity of 92.2% and an α,β-isomer purity of 98.3%. The yield of fractions including the other fractions was 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)([OH:11])[CH:9]=[CH2:10])=[CH:4][CH:3]=1.C(N([CH2:23][CH3:24])CC)C.C[OH:26]>CN(C)C1C=CN=CC=1.C(OC(=O)C)(=O)C>[C:23]([O:11][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH:9]=[CH2:10])(=[O:26])[CH3:24]
Reactant: CO
Reactant: C=CC(O)(c1ccc(Cl)cc1)c1cccnc1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: C=CC(OC(C)=O)(c1ccc(Cl)cc1)c1cccnc1
Yield: 90 %

Procedure:
A mixture of 1-(4-chlorophenyl)-1-(3-pyridyl)-2-propen-1-ol (0.692 g, 2.8 mmol), triethylamine (3.3 ml) and 4-dimethylaminopyridine (85 g) was stirred in acetic anhydride (0.9 ml) at 25° C. for 20 h. Methanol (1 ml) was added and after 10 min the mixture was concentrated in vacuo. Ether (25 ml) was added and the ether phase was washed with saturated NaHCO3 solution (3×15 ml) and dried over MgSO4. Evaporation of the solvent gave 0.725 g (90%) of the title compound, which was used in the palladium catalyzed amination according to Example 16.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:8]([NH:12][C:13](=[O:16])[CH2:14][Cl:15])([CH3:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[K].CCSC([N:23](CC(C)C)CC(C)C)=O>[Pd]>[ClH:15].[NH2:23][C:2]1[CH:3]=[C:4]([C@@:8]2([CH3:11])[NH:12][C:13](=[O:16])[CH2:14][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCSC(=O)N(CC(C)C)CC(C)C
Reactant: C[C@@](CO)(NC(=O)CCl)c1cccc(Br)c1
Agent: [Pd]
Agent: [K]
Product: C[C@@]1(c2cccc(N)c2)COCC(=O)N1
Product: Cl

Procedure:
In close analogy to the reaction sequence described for the preparation of Building block A, the cyclization of the (R)-N-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide with potassium tent-butylate, followed by the palladium-catalyzed amination, and, finally, by the hydrolysis yielded the (R)-5-(3-amino-phenyl)-5-methyl-morpholin-3-one hydrochloride as a light yellow solid. Mass (calculated) C11H15ClN2O2 [242.707]; (found) [M+H]+=207.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH:20]=[CH:21][C:22](Cl)=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:53]([OH:58])(=[O:57])[C:54]([OH:56])=[O:55]>C(OCC)(=O)C>[C:53]([OH:58])(=[O:57])[C:54]([OH:56])=[O:55].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[CH:20]=[CH:21]/[C:22]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: COc1ccc(C=CC(=O)Cl)cc1OC
Reactant: Nc1ccccc1Nc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(/C=C/c2nc3ccccc3n2-c2ccccn2)cc1OC

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and 3,4-dimethoxycinnamoyl chloride (Ramamurthy, B.; Sugumaran, M. Synthesis, 1987, 523) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound. MW: 447.45; mp: 178.0-179.0° C.; 1H-NMR (DMSO) δ: 8.79-8.76 (1H, m), 8.18 (1H, td, J=7.7, 1.8 Hz), 7.83 (1H, d, J=16.1 Hz), 7.72 (2H, d, J=6.8 Hz), 7.63 (1H, dd, J=7.5, 5.0 Hz), 7.44 (1H, d, J=7.3 Hz), 7.34-7.15 (4H, m), 7.04 (1H, d, J=16.1 Hz), 6.99 (1H, t, J=8.1 Hz), 3.78 (6H, s).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.[F:20]C1C=CC=C(OC)C=1C=O>>[F:20][C:7]1[CH:2]=[CH:3][CH:4]=[C:5]([O:18][CH3:19])[C:6]=1[CH:8]([OH:17])[C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(F)c1C=O
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Product: COc1cccc(F)c1C(O)C#Cc1ccccc1
Yield: 77 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2-fluoro-6-methoxy-benzaldehyde (947 mg, 6.14 mmol) was reacted to give the title compound (1.21 g, 77%). 1H NMR (400 MHz, DMSO-d6): δ 7.41-7.30 (m, 6H), 6.91-6.79 (m, 2H), 5.97-5.94 (m, 1H), 5.90-5.87 (d, 1H), 3.86 (s, 3H).
Reaction SMILES: Cl.[S:2]1[C:6]([C:7](=[NH:9])[NH2:8])=[N:5][CH:4]=[N:3]1.[Br:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[CH:13]=O.O=[C:21]([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Br:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[CH:13]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:21]([CH3:28])[NH:8][C:7]([C:6]2[S:2][N:3]=[CH:4][N:5]=2)=[N:9]1
Reactant: O=Cc1ccc(F)cc1Br
Reactant: N=C(N)c1ncns1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Product: CCOC(=O)C1=C(C)NC(c2ncns2)=NC1c1ccc(F)cc1Br
Yield: 35.2 %

Procedure:
1,2,4-thiadiazole-5-carboximidamide hydrochloride (1.43 g, 8.69 mmol) was reacted with 2-bromo-4-fluorobenzaldehyde (1.76 g, 8.69 mmol) and ethyl 3-oxobutanoate (1.36 g, 10.5 mmol) according to the procedure as described in Example 1, Step A to give the title compound as a yellow solid (1.3 g, 35%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[NH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[NH2:11]>>[C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:11]=1)([CH3:9])([CH3:8])[CH3:1]
Reactant: NNc1ccccn1
Reactant: CC(C)(C)C(=O)CC#N
Product: CC(C)(C)c1cc(N)n(-c2ccccn2)n1
Yield: 99 %

Procedure:
The title compound was prepared from 4,4-dimethyl-3-oxopentane nitrile and 2-hydrazinopyridine, using the same method as that described for preparation 7, as a solid in 99% yield.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[O:11][C:12](=[O:34])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(C(C)(C)C)(C)C.C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[C:12]([O:11][CH:10]([CH2:9][OH:8])[CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])(=[O:34])/[CH:13]=[CH:14]\[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)OC(COCCCCCCCCCCCCCCCC)CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCCCCCC=CC=CC=CC=CC=C/C=C\C(=O)OC(CO)COCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.7 %

Procedure:
To a mixture of 4a (348.4 mg, 0.4704 mmol) and glacial acetic acid (120 μL) was added 1.0 M TBAF in 2 mL THF over a period of 15 min at 5-10° C. (ice-water bath) with constant stirring. The reaction mixture was stirred at RT for 48 hours. It was then poured into water (100 mL), extracted with diethyl ether (100 mL, 2×), washed successively with saturated aqueous NaHCO3 (100 mL) and water (100 mL), and dried over anhydrous Na2SO4. After removal of solvent, the crude product was chromatographed on silica gel using dichloromethane-methanol to obtain 5a (140.8 mg, 48% yield). TLC: RF=0.65 (CH2Cl2:MeOH, 95:5 v/v); NMR (in CDCl3): δ in ppm 0.85 (3H, t, J=7.5 Hz), 0.95 (3H, t, J=7.0 Hz) 1.23 (26H, m), 1.54 (2H, m), 2.05 (2H, m), 2.38 (4H, m), 2.80 (10H, m), 3.44-3.50 (5H, m), 3.62-3.68 (2H, m), 3.85 (1H, br s, D2O exchangeable), 5.29-5.35 (12H, m); 13C NMR (in CDCl3): δ in ppm 14.3, 18.3, 22.7, 22.9, 25.7, 25.8 (2), 26.3, 29.6, 29.7 (2), 29.8 (2), 29.9 (2), 32.1, 64.4, 70.7, 72.1, 72.7, 127.2, 127.8, 128.1, 128.2, 128.3 (2), 128.4, 128.5, 128.8, 129.7 (2), 132.2, 177.9; FT-IR (cm−1) 3370 (br), 3013, 2954, 2918, 2850, 1712, 1470, 1397, 1382, 1326, 1239, 1123, 1060, 719; HRAPCI-MS m/z: measured 627.5349 ([M+H]+, calcd. 627.5352 for C41H71O4).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][CH:8]=[O:9])[CH:4]=[C:3]1[C:10]([OH:12])=O.S(Cl)([Cl:15])=O>C1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][CH:8]=[O:9])[CH:4]=[C:3]1[C:10]([Cl:15])=[O:12]
Reactant: Cn1cc(NC=O)cc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cn1cc(NC=O)cc1C(=O)Cl

Procedure:
A suspension of 1-methyl-4-formylamino-2-pyrrolecarboxylic acid (V) in benzene is heated at 80° C. in presence of an excess of thionyl chloride until a solution is obtained. The reaction is then stopped. By repeatedly evaporating from benzene at reduced pressure and temperature, there is obtained the crude chloride (II) which is stocked and used without further purification following determination of the title (generally not below 60%) by conversion to an ester and quantitative analysis of the resulting ester derivative. IR: 1740 cm−1.
Reaction SMILES: [CH2:1]([O:21][CH:22]([CH2:30][CH3:31])[C:23]([O:25]C(C)(C)C)=[O:24])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].FC(F)(F)C(O)=O.O>ClCCl>[CH2:1]([O:21][CH:22]([CH2:30][CH3:31])[C:23]([OH:25])=[O:24])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOC(CC)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOC(CC)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
tert-Butyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)butanoate (19.6 g, 45.5 mmol) was dissolved in dichloromethane (200 mL) and placed under nitrogen. Trifluoroacetic acid (50 mL) was added and the reaction mixture was stirred at room temperature for one hour. Water was added and the aqueous phase was extracted twice with dichloromethane. The combined organic extract was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was subjected to flash chromatography on silica gel using increasingly polar mixtures of heptane, ethyl acetate and formic acid (90:10:1→80:20:1) as eluent. Concentration of the appropriate fractions afforded 12.1 g (71% yield) of the title compound as an oil. 1H-NMR (300 MHz, CDCl3): δ 0.90-1.00 (m, 6H), 1.50 (m, 2H), 1.70 (m, 2H), 1.80 (m, 2H), 2.10 (m, 4H), 2.80-2.90 (m, 8H), 3.50 (m, 1H), 3.60 (m, 1H), 3.75 (t, 1H), 5.30-5.50 (m, 10H); MS (electro spray): 373.2 [M-H]−.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:33])([F:32])[C:10]1[N:14]2[CH:15]=[C:16]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1>ClCCl>[N:19]1([C:16]2[CH:17]=[CH:18][C:13]3[N:14]([C:10]([C:9]([F:8])([F:33])[F:32])=[N:11][N:12]=3)[CH:15]=2)[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3nnc(C(F)(F)F)n3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1nnc2ccc(N3CCNCC3)cn12
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 85.8 %

Procedure:
Trifluoroacetic acid (5 mL, 64.90 mmol) was added to a mixture of tert-butyl 4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)piperazine-1-carboxylate (0.86 g, 2.32 mmol) and dichloromethane (20 mL). The resulting solution was stirred at 20° C. for 90 minutes and then evaporated to leave an involatile residue. The residue was purified by ion-exchange chromatography on an SCX column using aqueous ammonia (7M) in methanol as eluant to give 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (0.540 g, 86%) as a yellow solid that was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9]C)=O.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>CCOCC>[OH:1][C:2]1[C:3]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([Cl:16])[CH:18]=1)=[O:9]
Reactant: Nc1cccc(Cl)c1
Reactant: COC(=O)c1sc2ccc(Cl)cc2c1O
Solvent: CCOCC
Product: O=C(Nc1cccc(Cl)c1)c1sc2ccc(Cl)cc2c1O
Temperature: 170 °C
Yield: 56.3 %

Procedure:
A mixture of methyl 3-hydroxy-5-chlorobenzo[b]thiophene-2-carboxylate (1.21 g; 0.005M) and 3-chloroaniline (1.28 g; 0.010M) is heated under a nitrogen atmosphere at 170° C. for 90 minutes. The reaction mixture was cooled to room temperature, taken up in 10 ml of ether, collected the solid, washed with 10 ml of ether, air dried, and recrystallized from ethyl acetate to give 0.95 g (56% yield) of the title compound as a light grey solid, m.p. 233°-235° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32]Cl)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.[F:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(N(C(C)C)CC)(C)C>COCCO.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:40]3[CH2:41][CH2:42][N:37]([CH2:36][CH2:35][F:34])[CH2:38][CH2:39]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1
Reactant: FCCN1CCNCC1
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Solvent: COCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(CCF)CC4)c(OC)cc23)c2c1OCO2
Temperature: 110 °C
Yield: 46.7 %

Procedure:
N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (0.165 g) was dissolved in 2-methoxyethanol (5 ml) and then fluoroethyl piperazine (0.821 g) was added followed by diisopropylethylamine (0.83 ml) and the mixture heated to 110° C. for 15 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of dichloromethane and methanol with methanolic ammonia as eluent. There was thus obtained the title compound (0.092 g) as a white powder, contaminated with approximately 5 wt. % diisopropylethylamine; NMR Spectrum: (CDCl3) 2.15 (quin, 2H), 2.63 (m(broad), 12H, ), 2.69 (t, 1H), 2.76 (t, 1H), 3.46 (s, 3H), 3.99 (s, 3H), 4.35 (s, 2H), 4.52 (t, 1H), 4.64 (t, 1H), 6.07 (s, 2H), 6.96 (s, 1H), 7.07 (s, 1H), 7.12 (s, 1H), 7.28 (s, 1H), 8.62 (s, 1H); Mass Spectrum: M+H+ 586/588.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:14]([F:19])([F:18])C([O-])=O.[Na+]>COCCOCCOC.C(Cl)Cl>[F:18][C:14]1([F:19])[C:2]2([CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH2:1]1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: C=C1CCC(C(=O)OCC)CC1
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: ClCCl
Product: CCOC(=O)C1CCC2(CC1)CC2(F)F
Temperature: 25 °C

Procedure:
To a solution of ethyl 4-methylenecyclohexanecarboxylate (0.15 g, 0.892 mmol) in diglyme (3 mL) was added a solution of sodium 2-chloro-2,2-difluoroacetate (0.544 g, 3.57 mmol) in 5 ml of diglyme via syringe pump at 0.5 ml/h at 150° C. The reaction was cooled to rt, then diluted with DCM and washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was charged to a 40 g silica gel cartridge which was eluted with a 20 min gradient of 0-20% EtOAc in hexane to yield ethyl 1,1-difluorospiro[2.5]octane-6-carboxylate. 1H NMR (400 MHz, CDCl3) ppm 4.09-4.19 (2H, m), 2.29-2.45 (1H, m), 1.89-2.03 (2H, m), 1.55-1.72 (5H, m), 1.45-1.54 (1H, m), 1.31-1.39 (1H, m), 1.21-1.30 (3H, m), 0.84-0.94 (1H, m).