Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([F:27])[N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1)=[O:2].[OH-:28].[K+]>C(O)C.C(Cl)Cl.O.[N+]([O-])([O-])=O.[Ag+]>[C:1]([C:3]1[N:4]=[C:5]([F:27])[N:6]([C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=1)([OH:28])=[O:2]
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-formyl-2-fluoro-1-triphenylmethylimidazole (356 mg.) in ethanol (5 ml.) and CH2Cl2 (3 ml.) was treated with silver nitrate (0.37 g.) in water (0.5 ml.) followed by the dropwise addition of 5 ml. of potassium hydroxide solution (5 ml. of a solution of 2.1 g. KOH in 35 ml. water). The mixture was stirred at room temperature for two hours, filtered and the filtrate extracted with ether. The aqueous layer was acidified with concentrated HCl and extracted with CHCl3. The organic layer was dried over MgSO4, filtered and the solvent evaporated to give 4-carboxy-2-fluoro-1-triphenylmethylimidazole (261 mg.) as a white solid having the following n.m.r. in d6DMSO: 7.0-7.68 (m, 16H); 11.5-12.5 (br, 1H).
Reaction SMILES: CC([CH:5]1[CH2:10][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28](=[O:30])[CH3:29])[C@@H:23]([CH3:31])[CH2:22][C@H:21]4[NH:32][C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])=[CH:14][CH:13]=2)[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.[ClH:42]>CO>[ClH:42].[ClH:42].[C:28]([N:24]1[C:25]2[C:20](=[CH:19][C:18]([C:15]3[CH:16]=[CH:17][C:12]([CH2:11][N:9]4[CH2:8][CH2:7][NH:6][CH2:5][CH2:10]4)=[CH:13][CH:14]=3)=[CH:27][CH:26]=2)[C@H:21]([NH:32][C:33](=[O:34])[O:35][CH:36]([CH3:37])[CH3:38])[CH2:22][C@@H:23]1[CH3:31])(=[O:30])[CH3:29]
Reactant: CC(=O)N1c2ccc(-c3ccc(CN4CCN(C(=O)[O-])C(C(C)(C)C)C4)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: Cl
Solvent: CO
Product: CC(=O)N1c2ccc(-c3ccc(CN4CCNCC4)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 70 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl-4-({-4-[(cis)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}methyl)-1-piperazinecarboxylate (for a preparation see Intermediate 8) (98 mg, 0.174 mmol) was dissolved in methanol (2 mL) and to this was added 1.25M HCl in methanol. (0.305 mL, 0.382 mmol) and stirred overnight. 1.25M HCl in methanol. (0.305 mL, 0.382 mmol) was added and the reaction was heated in a sealed vessel to 70° C. in an optimiser microwave for 15 min followed by a further 30 min. 2 eqv of 1.25M HCl in methanol was added and the reaction mixture heated in the microwave under the same conditions for a further 1 hr. The reaction mixture was reduced in vacuo to give a white solid (86 mg). LCMS (Method A): Rt=0.92, MH+=465
Reaction SMILES: C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:20][C:21]1[C:26]([OH:27])=[C:25]([NH:28][C:29](=O)[C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([C:35]#[N:36])=[C:23]([CH3:37])[C:22]=1[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([OH:44])[CH:39]=1>O>[Br:20][C:21]1[C:22]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([OH:44])[CH:39]=2)=[C:23]([CH3:37])[C:24]([C:35]#[N:36])=[C:25]2[C:26]=1[O:27][C:29]([C:30]([CH3:32])([CH3:31])[CH3:33])=[N:28]2
Reactant: Cc1c(C#N)c(NC(=O)C(C)(C)C)c(O)c(Br)c1-c1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccc(O)c2)c(Br)c2oc(C(C)(C)C)nc2c1C#N
Yield: 94.5 %

Procedure:
Toluene (45 ml), p-toluenesulfonic acid monohydrate (21.0 mg, 111 μmol) were added to N-(2-bromo-5-cyano-3,3′-dihydroxy-6-methylbiphenyl-4-yl)-2,2-dimethylpropionamide (I-16) (446 mg, 1.11 mmol), followed by refluxing with a Dean-Stark condenser for 3 hours. After cooling, water (50 ml) was added to the reaction liquid, the product was extracted with ethyl acetate (50 ml×2). The organic layer was washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain the entitled compound (404 mg, 95%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][CH2:12][C:13]1[N:18]=[C:17]([Cl:19])[C:16]([C:20](OC)=[O:21])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:29]>C(O)C>[CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][CH2:12][C:13]1[N:18]=[C:17]([Cl:19])[C:16]([C:20]([NH2:29])=[O:21])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: COC(=O)c1ccc(CCc2cc(Br)ccc2OCc2ccccc2)nc1Cl
Solvent: CCO
Product: NC(=O)c1ccc(CCc2cc(Br)ccc2OCc2ccccc2)nc1Cl

Procedure:
A solution of methyl 6-[2-benzyloxy-5-bromophenethyl]-2-chloro-3-pyridinecarboxylate (2.0 g) in ethanol (60 ml) saturated with ammonia was heated at 177° C. under pressure for 6 hours. The solvent was evaporated and the residue subjected to chromatography on silica gel (7734). Two products were isolated. The first was eluted with 2.5% ethyl acetate/CH2Cl2 and the second with 5% MeOH/CH2Cl2. The first product was identified as a mixture of the methyl and ethyl esters of 6-[2-benzyloxy-5-bromophenethyl]-2-amino-3-pyridinecarboxylic aicd (0.3 g). The second produce was identified as the title compound (0.6 g) mpt. 142°-144° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:40][CH3:41])=[C:8]([NH:31][C:32]([C:34]2[S:35][CH:36]=[CH:37][C:38]=2[CH3:39])=[O:33])[C:9](/[CH:12]=[CH:13]/[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16](C(C3SC=CC=3C)=O)[N:15]=2)=[CH:10][CH:11]=1.[CH2:42]([NH:44][CH2:45][CH2:46][OH:47])[CH3:43].[I-].[Na+].[OH-].[Na+]>CN(C)C(=O)C.O>[CH2:42]([N:44]([CH2:45][CH2:46][OH:47])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:40][CH3:41])=[C:8]([NH:31][C:32]([C:34]2[S:35][CH:36]=[CH:37][C:38]=2[CH3:39])=[O:33])[C:9](/[CH:12]=[CH:13]/[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][N:15]=2)=[CH:10][CH:11]=1)[CH3:43]
Reactant: COc1c(OCCCCl)ccc(/C=C/c2nn(C(=O)c3sccc3C)c3ccccc23)c1NC(=O)c1sccc1C
Reactant: CCNCCO
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCN(CCO)CCCOc1ccc(/C=C/c2n[nH]c3ccccc23)c(NC(=O)c2sccc2C)c1OC
Temperature: 90 °C
Reaction time: 3 h
Yield: 34.7 %

Procedure:
A solution of (E)-N-(3-(3-chloropropoxy)-2-methoxy-6-{2-[1-(3-methylthiophene-2-carbonyl)-1H-indazol-3-yl]vinyl}phenyl)-3-methylthiophene-2-carboxamide (0.30 g, 0.49 mmol) obtained in Step 4 in N,N-dimethylacetamide (6.0 mL) was added with 2-(ethylamino)ethanol (0.97 mL, 9.9 mmol) and sodium iodide (0.11 g, 0.74 mmol), followed by stirring at 90° C. for 3.0 hours. After cooling the reaction mixture to room temperature, aqueous sodium hydroxide solution (2.0 mol/L, 3.0 mL) was added and the mixture was stirred for 1.0 hour. The mixture was added with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography [amino-silica gel chromatorex (trade mark) NH, manufactured by Fuji Silysia; hexane/ethyl acetate=60/40 to ethyl acetate] and crystallized from hexane/ethyl acetate (1/1) to obtain Compound 339 (91 mg, 34%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].I[C:16]1[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=1
Reactant: Cn1ccnc1I
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1onc(-c2ccccc2)c1C#Cc1nccn1C
Yield: 30 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (73 mg, 0.40 mmol) was converted (using 2-iodo-1-methyl-1H-imidazole instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 32 mg, 30%) which was obtained as a light brown solid. MS: m/e=264.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C@@H:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[C@@H:16]([CH:22]([CH3:24])[CH3:23])[CH2:15]1.[O:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:25]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[C@@H:14]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[C@@H:16]([CH:22]([CH3:23])[CH3:24])[CH2:15]2)=[CH:26]1
Reactant: OB(O)c1ccoc1
Reactant: CC(C)[C@H]1C[C@H](c2c[nH]c3c(C(N)=O)cc(Br)cc23)CCS1(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)[C@H]1C[C@H](c2c[nH]c3c(C(N)=O)cc(-c4ccoc4)cc23)CCS1(=O)=O
Reaction time: 0.08 h
Yield: 37.9 %

Procedure:
(racemic)-5-Bromo-3-[trans-2-(1-methylethyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl]-1H-indole-7-carboxamide (60 mg, 0.145 mmol) was placed in a microwave vial and dissolved in 1,4-Dioxane (2 mL) and Water (1 mL). 3-Furanylboronic acid (16.24 mg, 0.145 mmol) and K2CO3 (60.2 mg, 0.435 mmol) were added. Argon was bubbled in the mixture for 10 mins, stirring. PdCl2(dppf) (5.60 mg, 0.012 mmol) was added, and argon was bubbled another 10 mins. The vial was sealed and put under microwave 5 mins at 100° C. with high absorption parameter. The crude was run through a thiol-SPE cartridge eluting with 2 mL of methanol and the eluted solvents are evaporated. The residue was dissolved in 2-3 mL of DMSO, filtered through a syringe filter (Acrodisc CR 13 mm; 45 um PTFE filter), and purified on a Gilson HPLC. The desired fractions were concentrated, giving 22 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@H:10]([NH:12][CH2:13][CH:14]=[CH2:15])[C@@H:9]([NH2:16])[C@H:8]([O:17][CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:7]=1)=[O:5])[CH3:2].[C:23](O)(=[O:25])[CH3:24].CS(O)(=O)=O.C(OC(=O)C)(=O)C>COC(C)(C)C.CCCCCC.O>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@H:10]([NH:12][CH2:13][CH:14]=[CH2:15])[C@@H:9]([NH:16][C:23](=[O:25])[CH3:24])[C@H:8]([O:17][CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(=O)O
Reactant: C=CCN[C@H]1CC(C(=O)OCC)=C[C@@H](OC(CC)CC)[C@@H]1N
Agent: CS(=O)(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: COC(C)(C)C
Product: C=CCN[C@H]1CC(C(=O)OCC)=C[C@@H](OC(CC)CC)[C@@H]1NC(C)=O
Temperature: 2.5 °C
Yield: 83 %

Procedure:
In a 4 l 4-necked round bottom flask equipped with a thermometer, a mechanical stirrer, a Claisen condenser and an inert gas supply 278.0 g of (3R,4R,5S)-5-allylamino-4-amino-3-(1-ethyl-propoxy)-cyclohex-1-enecarboxylic acid ethyl ester obtained according to (d) were dissolved at room temperature with stirring under argon in 2800 ml of tert.-butyl methyl ether. From the red solution 1400 ml of tert.-butyl methyl ether were distilled. Again 1400 ml of tert.-butyl methyl ether were added and distilled off. The red solution was cooled to 0-5° C. and treated with 512 ml of acetic acid (9.0 mol) whereby the temperature rose to about 23° C. After cooling to 0° C.-5° C. 58.1 ml of methanesulfonic acid (d=1.482, 0.90 mol) were added dropwise in the course of 27 min followed by 84.7 ml of acetic anhydride (d=1.08, 0.90 mol) added dropwise in the course of 40 min keeping the temperature in the range of 0° C. to 5° C. The brown reaction mixture was stirred without cooling for 14 h then treated with vigorous stirring with 1400 ml of water (deionized) for 30 min and the brown organic phase was extracted with 450 ml of 1M aqueous methanesulfonic acid. The combined aqueous phases (pH=1.6) were treated with stirring with about 694 ml of 50% aqueous potassium hydroxide until pH=10.0 was reached, keeping the temperature in the range of 10 to 25° C. The brown, turbid mixture was extracted first with 1000 ml then with 400 ml, in total with 1400 ml of tert.-butyl methyl ether, the combined organic extracts were stirred over 32 g of charcoal and filtered. The filter cake was washed with about 200 ml tert.-butyl methyl ether and the combined filtrates were evaporated in a rotary evaporator at 47° C./380 to 10 mbar to yield 285.4 g of brown-red, amorphous crystals which were dissolved with stirring in a mixture of 570 ml of tert.-butyl methyl ether and 285 ml of n-hexane at 50° C. The brown solution was cooled in 45 min with stirring to −20° C. to −25° C. and stirred for 5 h whereby brown crystals precipitated. The suspension was filtered over a pre-cooled (−20° C.) glass filter funnel and the filter cake was washed with a pre-cooled (−20° C.) mixture of 285 ml of tert.-butyl methyl ether and 143 ml of n-hexane and dried in a rotary evaporator at 48° C.<10 mbar to yield 200.33 g (83%) of (3R,4R,5S)-4-acetylamino-5-allylamino-3-(1-ethyl-propoxy)-cyclohex-1-enecarboxylic acid ethyl ester; m.p. 100.2° C.-104.2° C.
Reaction SMILES: O=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[S:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2.O.NN.C(O)C.[OH-].[Na+]>C(O)(=O)C.C(O)COCCO>[N:12]1[C:6]2[S:5][C:4]3[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]=3[CH2:2][CH2:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)Cc1cccnc1S2
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: OCCOCCO
Product: O=C(O)Cc1ccc2c(c1)CCc1cccnc1S2
Temperature: 135 °C
Reaction time: 1.5 h
Yield: 76.2 %

Procedure:
A mixture of 400 mg of (5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]thiepin-8-yl)-acetic acid, 800 mg of hydrazine hydrate and 30 ml of ethanol was refluxed for 3 hours. The solvent was distilled off to obtain a solid substance, to which were added 1 g of sodium hydroxide and 8 ml of diethylene glycol, and the mixture was stirred under a nitrogen atmosphere at 135° C. for 1.5 hours. After cooling, ice water was added to the mixture, and the resulting mixture was acidified with acetic acid and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain an oil, which was chromatographed over silica gel and eluted with chloroform ethanol (100/1) to obtain a powder. This was recrystallized from 290 mg (yield: 76%) of (5,6-dihydro benzo[b]pyrido[3,2-f]thiepin-8-yl)-acetic acid as colorless needle crystals.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1([CH2:26][O:27][C:28](=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[O:24][C:23](=[O:25])[CH2:22][CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[C:28]([O:27][CH2:26][C:20]1([CH2:19][OH:18])[O:24][C:23](=[O:25])[CH2:22][CH2:21]1)(=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCCCC(=O)OCC1(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCC(=O)O1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC(=O)OCC1(CO)CCC(=O)O1
Yield: 71.5 %

Procedure:
A solution of 3d (0.118 g, 0.2 mmol) in THF (3 mL) at room temperature was stirred with a solution of n-tetrabutylammonium fluoride in THF (1M, 0.3 mL) for 40 min. The solution was evaporated under vacuum, dissolved in EtOAc (20 mL), dried (Na2SO4) and concentrated. The residue obtained was purified by flash column chromatography over silica gel using hexane:EtOAc (7:3) as eluant to give 3e (0.051 g, 72%) as a white solid; mp 65°-66° C. (EtOAc/hexane); IR (KBr) 3448.1, 1763.2, 1728.1 cm-1 ; 1H NMR (CDCl3) δ 0.88 (distorted t, 3 H, CH3), 1.30 (m, 20 H, CH3 (CH2)10CH2CH2CO); 1.60 (m, 2 H, CH3 (CH2)10CH2CH2CO), 2.00-2.12 (m, 2 H, H-4a), 2.20-2.30 (m, 2 H, H-4b), 2.33 (t, J=7.6 Hz, 2 H, CH3 (CH2)10CH2CH2CO), 2.45 (t, J=6.4 Hz, 1 H, OH), 2.65 (m, 2 H, H-3), 3.60 (dd, J=12.1, 5.9 Hz, 1 H, CHHOH), 3.75 (dd, J=12.1, 6.1 Hz, CHHOH), 4.10 (d, J=12.0 Hz, 1 H, CHHOCO), 4.30 (d, J=12.0 Hz, 1 H, CHHOCO); 13C NMR δ 14.09, 22.65, 24.81, 25.47, 28.79, 29.07, 29.19, 29.32, 29.41, 29.56, 29.60, 31.89, 34.03, 64.82, 65.45, 86.02, 173.48, 176.47; FAB MS (m/z, relative intensity) 357 (MH+, 100), 211 (C13H27CO+, 35). Anal. Calcd for C20H36O5 : C,67.37; H,10.18. Found: C,67.30; H,10.17.
Reaction SMILES: [I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([O:14][C:15]([C:17]1([NH2:27])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:26])[CH:23]=2)[CH2:18]1)=[O:16])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:12]([O:14][C:15]([C:17]1([NH:27][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[I:1])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:26])[CH:23]=2)[CH2:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1(N)Cc2ccc(F)cc2C1
Reactant: Cc1cccc(C(=O)O)c1I
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
To a solution of 2-iodo-3-methyl-benzoic acid (3.85 g, 14.7 mmol), 2-amino-5-fluoro-indan-2-carboxylic acid ethyl ester (3.00 g, 13.4 mmol), HATU (6.10 g, 16.1 mmol) in anhydrous DMF (6 mL) is added DIPEA (3.30 mL, 20.1 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is recrystallized from EtOAc to give a pure product (147) as white solid (3.90 g, 62%).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19][CH2:20][C:21]1[N:25]=[CH:24][O:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19][CH2:20][C:21]1[N:25]=[CH:24][O:23][N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1SCc1ncon1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1SCc1ncon1)OCc1ccccc1

Procedure:
A solution of benzylchloroformate (3.79 g) and 3-(2-aminophenylthiomethyl)-1,2,4-oxadiazole (3.1 g) in dioxan (75 ml) containing potassium carbonate (3.15 g) was refluxed for 1 hour. Solvent was then removed by evaporation under reduced pressure to give a colourless solid which was re-crystallised from hexane to give 3-(2-benzyloxycarbonylaminophenylthiomethyl)-1,2,4-oxadiazole, m.p. 41°.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)=[O:3].FC(F)(F)S(O[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23][CH2:22]2)(=O)=O.N#N.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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.O>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23][CH2:22]3)[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3cccc(C(N)=O)c3)ccc2C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 3-(aminocarbonyl)phenyl boronic acid (0.663 g; 4.0 mmol), 1,1-dimethylethyl 6-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydro-2(1H)-isoquinoline carboxylate (1.28 g; 3.35 mmol; Ex V-16) in DMF (10 mL) was sparged with N2 for 10 min, K3PO4 (1.7 g; 8.0 mmol) and Pd(PPh3)4 (0.193 g; 0.17 mmol) were added and the mixture was stirred at 100° C. for 2 h. Upon cooling, the mixture was poured into water and extracted with EtOAc (×3). Combined organics were washed (H2O, brine), and dried over Na2SO4. Residual solids were collected from the aqueous layer by filtration, air-dried, dissolved in hot EtOH and combined with the dried EtOAc extracts. The whole was adsorbed onto a minimal amount of silica gel and purified by flash chromatography (EtOAc/hexanes), affording the title compound as a as a colorless solid. LC/MS (method B) 2.69 min; m/z 297 ([M−C4H8]+H, 70%), 253 ([M−Boc]+H, 74%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][CH:10]=O)=[N:4][CH:5]=[CH:6][N:7]=1.CC#N.O=P(Cl)(Cl)Cl.CN(C=O)C>O>[Cl:1][C:2]1[C:3]2[N:4]([CH:10]=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=CNCc1nccnc1Cl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1nccn2cncc12
Temperature: 75 °C

Procedure:
In an oven dried flask filled with nitrogen was added N-(3-Chloro-pyrazin-2-ylmethyl)-formamide (3.8 g, 0.022 mol) followed by MeCN (60 mL, 1 mol) and the reaction mixture was degassed 3×. POCl3 (10 mL, 0.1 mol) was added to the reaction mixture dropwise and the reaction mixture was stirred at rt for 5 min before DMF (couple of drops) was added in one portion. The reaction mixture was heated at 75° C. overnight under a consistent N2 flow. The excess of POCl3 was removed under reduced pressure and the residue was quenched with 2 N NH3 in i-PrOH at 0° C. with vigorous stirring to adjust the pH to 9. The crude reaction mixture was then charged with water and the aqueous layer was washed with DCM. The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the title compound as a brown solid.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([NH:10][CH:11]([C:13]2[N:18]=[N:17][C:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:15][CH:14]=2)[CH3:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH:1]1([CH2:7][C:8]2[N:18]3[C:13]([CH:14]=[N:15][C:16]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)=[N:17]3)=[C:11]([CH3:12])[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)CC3CCCCC3)nn2)cc1
Agent: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2ncc3c(C)nc(CC4CCCCC4)n3n2)cc1
Yield: 71.7 %

Procedure:
Applying the Cyclization Procedure 2, using 2-cyclohexyl-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]acetamide (Intermediate 69) (100 mg, 0.27 mmol), pyridine (25 mL), 1,2,4 triazole (56 mg, 0.81 mmol) and phosphorus oxychloride (0.040 mL, 0.43 mmol), to afford 7-(cyclohexylmethyl)-5-methyl-N-[4-(methyloxy)phenyl]-imidazo[5,1-f][1,2,4]triazin-2-amine (68 mg) as a yellow solid. MS m/z 352 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]3[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=3)[C:32]#[N:33])=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(C#N)c1)=N2

Procedure:
The title compound was prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionyl-amino]-5-dimethylamino-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M66) (180 mg, 1.0 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (41 mg).