Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [FH:1].F.F.C(N(CC)CC)C.C(N(CC)CC)C.[CH2:18]([O:20][C:21]([CH:23]1[CH2:26][C:25](O)([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH2:37][C:36]([C:42]4[CH:47]=[C:46]([Cl:48])[C:45]([Cl:49])=[C:44]([Cl:50])[CH:43]=4)([C:38]([F:41])([F:40])[F:39])[O:35][N:34]=3)=[CH:29][CH:28]=2)[CH2:24]1)=[O:22])[CH3:19]>C(Cl)Cl>[CH2:18]([O:20][C:21]([CH:23]1[CH2:24][C:25]([F:1])([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH2:37][C:36]([C:42]4[CH:43]=[C:44]([Cl:50])[C:45]([Cl:49])=[C:46]([Cl:48])[CH:47]=4)([C:38]([F:40])([F:41])[F:39])[O:35][N:34]=3)=[CH:29][CH:28]=2)[CH2:26]1)=[O:22])[CH3:19]
Reactant: F
Reactant: CCOC(=O)C1CC(O)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of triethyl amine trihydrofluoride (4.21 g, 26.16 mmol, 4 eq.) in DCM (25 mL) was added triethyl amine (1.32 g, 13.08 mmol) in drop wise manner at −78° C. After 15 minutes was added X-TalFluoro-M (4.74 g, 19.62 mmol) followed by addition of pre-dissolved solution of 3-hydroxy-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid ethyl ester (Preparation 3, 3.5 g, 6.54 mmol) in DCM (15 mL) at −78° C. Resulting reaction mixture was stirred at room temperature for 16 hours. After consumption of starting material, reaction mixture was quenched with saturated aqueous solution of sodium bicarbonate (50 mL) and stirred at room temperature for 0.5 hours. Aqueous layer was extracted with DCM (3×50 mL). Combined organic layers were dried over sodium sulphate, filtered and evaporated. Purification was done by column chromatography on silica gel (100-200 mesh size). Compounds were eluted using 5% ethyl acetate in hexane to afford two off-white solids (2 g-non-polar spot, and 1.2 g-polar spot). 1H NMR (400 MHz, CDCl3) (Non Polar spot) δ: 1.26 (t, J=7.12 Hz, 3H), 2.80 (d, J=8.76 Hz, 2H), 2.87 (d, J=8.72 Hz, 2H), 3.47-3.49 (m, 1H), 3.67 (d, J=17.16 Hz, 1H), 4.08 (d, J=17.16 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 7.51 (d, J=8.12 Hz, 2H), 7.63 (s, 2H), 7.67 (d, J=8.16 Hz, 2H); LC-MS (m/z): 536.00 (M−H).
Reaction SMILES: [NH2:1][C@H](C(O)=O)CCC(=O)N.[NH2:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14](=O)[OH:15].N[C@H](C(O)=O)CCCCN.N[C@H](C(O)=O)CCCNC(=N)N>>[NH2:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14](=[O:15])[NH2:1]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: NCCCC[C@H](N)C(=O)O
Product: NC(=O)C[C@H](N)C(=O)O

Procedure:
Gln -0.69; Asp -0.72; Lys -1.10; Arg -1.76.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([SH:11])[S:10][C:6]=2[CH:5]=1)[CH3:2].[CH2:14]([O:16][C:17](=[O:27])[C:18](Br)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[CH3:15]>C(O)C>[CH2:14]([O:16][C:17](=[O:27])[C:18]([S:11][C:9]1[S:10][C:6]2[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=[CH:12][C:7]=2[N:8]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[CH3:15]
Reactant: CCOC(=O)C(C)(Br)c1ccccc1
Reactant: CCOc1ccc2nc(S)sc2c1
Solvent: CCO
Product: CCOC(=O)C(C)(Sc1nc2ccc(OCC)cc2s1)c1ccccc1

Procedure:
2.3 g of Na is dissolved in 80 ml of ethanol; 21.1 g of 6-ethoxy-2-mercaptobenzothiazole is added and the mixture is stirred until solution takes place. 25.7 g of 2-bromo-2-phenylpropionic acid ethyl ester is then added and the mixture is stirred overnight at 20° and worked up in the customary manner to give 2-(6-ethoxybenzothiazol-2-ylthio)-2-phenylpropionic acid ethyl ester, m.p. 92°-94°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[CH2:18][CH:19]=O>O1CCOCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[N:9]=[C:19]([CH2:18][C:12]1[C:11]([Cl:10])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:17])[NH:8]2
Reactant: O=CCc1c(Cl)cccc1Cl
Reactant: Nc1ncnc(Cl)c1N
Solvent: C1COCCO1
Product: Clc1cccc(Cl)c1Cc1nc2c(Cl)ncnc2[nH]1
Temperature: 100 °C
Reaction time: 24 h
Yield: 11.5 %

Procedure:
To a mixture of 6-chloro-pyrimidine-4,5-diamine (100 mg, 0.694 mmol), (2,6-dichloro-phenyl)-acetaldehyde (260 mg, 1.38 mmol) and 1,4-dioxane (7 mL) was added 5% FeCl3.SiO2 (150 mg). The resulting mixture was heated to 100° C. in a sealed tube. After 24 h, the mixture was cooled to rt and filtered through a pad of diatomaceous earth, washing with EtOAc (3×10 mL). The filtrate was concentrated and the residue was purified by preparative reverse-phase HPLC to afford the title compound as a white solid (25 mg, 36%). MS (ESI): mass calcd. for C12H7Cl3N4, 311.9; m/z found, 313.0 [M+H]+. 1H NMR (CDCl3): 8.65 (s, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.34-7.29 (m, 1H), 4.78 (s, 2H).
Reaction SMILES: C(O[C:5]1([CH3:14])[CH:9]=[CH:8][C:7](=[O:10])[CH:6]1[CH2:11][CH:12]=[CH2:13])(=O)C.[C:15]([O-:19])(=[O:18])[CH2:16][CH3:17].[Na+]>C(O)(=O)CC>[CH2:11]([C:6]1[C:7](=[O:10])[CH2:8][CH:9]([O:19][C:15](=[O:18])[CH2:16][CH3:17])[C:5]=1[CH3:14])[CH:12]=[CH2:13]
Reactant: C=CCC1C(=O)C=CC1(C)OC(C)=O
Reactant: CCC(=O)[O-]
Agent: [Na+]
Solvent: CCC(=O)O
Product: C=CCC1=C(C)C(OC(=O)CC)CC1=O
Reaction time: 6 h
Yield: 148.5 %

Procedure:
In the same apparatus as in Example 1, 3-acetoxy-2-allyl-3-methyl-4-cyclopentenone (19.4 g), propionic acid (70 ml) and sodium propionate (5 g) were charged and agitated at 110° to 120° C. for 6 hours. After the completion of the reaction, propionic acid was evaporated off under reduced pressure. The residue was extracted with toluene (70 ml) and water (40 ml) and treated as in Example 1 to obtain 2-allyl-4-propionyloxy-3-methyl-2-cyclopentenone (16.1 g). Yield, 83%. B.P., 115°-120° C./0.1-0.2 mmHg.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[C:18](=[O:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:5]([O:7]C)=[O:6].[OH-].[Li+].O>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[C:18](=[O:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(N2CCOCCC2=O)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)O)ccc1N1CCOCCC1=O

Procedure:
Prepared analogously to Example 39d from methyl 3-methyl-4-(5-oxo-[1,4]oxazepan-4-yl)-benzoate and lithium hydroxide in a solvent mixture of water and ethanol.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]1([N:16]2[CH2:20][CH2:19][C:18]3([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:17]2=[O:26])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)C(C)C)(C)C.C(O)(C(F)(F)F)=O>CN(C)C=O.CO>[C:1]([N:23]1[CH2:24][CH2:25][C:18]2([C:17](=[O:26])[N:16]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:20][CH2:19]2)[CH2:21][CH2:22]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1N(C2CCCCC2)CCC12CCNCC2
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(c1ccccc1)N1CCC2(CC1)CCN(C1CCCCC1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzoyl chloride (15 μL, 0.00013 mol) was added to a solution of 2-cyclohexyl-2,8-diazaspiro[4.5]decan-1-one (20.0 mg, 0.0000846 mol) and N,N-diisopropylethylamine (44 μL, 0.00025 mol) in N,N-dimethylformamide (1.0 mL). The mixture was stirred at room temperature for 30 min, then adjusted to be acidic (pH to −2.0) with TFA, and diluted with methanol (0.8 mL). The resulting solution was purified by Prep-HPLC to give 8-benzoyl-2-cyclohexyl-2,8-diazaspiro[4.5]decan-1-one. LCMS: (M+H)+=341.20.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:28])[C:10]=1[C:11](=[O:27])[NH:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([N:19]=[C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:21]=2)[CH:18]=1)=[O:5])C.CN1C(C(=O)NC2C=CC3N(N=C(N4CCOCC4)N=3)C=2)=C(C(O)=O)C=N1>>[CH2:25]([N:22]([CH2:23][CH3:24])[C:20]1[N:21]=[C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:11]([C:10]3[N:9]([CH3:28])[N:8]=[CH:7][C:6]=3[C:4]([OH:5])=[O:3])=[O:27])=[CH:18][N:17]2[N:19]=1)[CH3:26]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(N(CC)CC)nn2c1
Agent: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Product: CCN(CC)c1nc2ccc(NC(=O)c3c(C(=O)O)cnn3C)cn2n1

Procedure:
Using 5-(2-diethylamino-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester, this compound was prepared following the same method as for the synthesis of 1-Methyl-5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid. Off white solid (500 mg, 54%). MS: m/z=358 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[CH:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:25]1[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[C:23][C:25]4[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: NS(=O)(=O)c1cccc(Br)c1
Product: NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.9) (89 mg, 0.25 mmol) and 3-bromo-benzenesulfonamide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (13 mg, 10%). MS (ISP) 511.5 [(M+H)+]; mp 230-231° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH:15]=[CH:14][N:13]([CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[C:12]1=[S:24].FC(F)(F)C(O)=O>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH:15]=[CH:14][N:13]([CH2:16][C:17]([OH:19])=[O:18])[C:12]1=[S:24]
Reactant: CC(C)(C)OC(=O)Cn1ccn(C2CCc3ccccc3C2)c1=S
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1ccn(C2CCc3ccccc3C2)c1=S

Procedure:
substituting tert-butyl 3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-1-ylacetate and trifluoroacetic acid gave 3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-1-yl-acetic acid, m.p. 228°-230° C.;
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[C:6]([C:7]1[CH:8]=[CH:9][C:10]([CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)=[CH:11][CH:12]=1)#[CH:5]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.4 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 4-(4-((trimethylsilyl)ethynyl)phenyl)piperidine-1-carboxylate (compound 76.2, 1.34 g, 3.75 mmol) in tetrahydrofuran (20 mL). Tetrabutylammonium fluoride (1.95 g, 7.47 mmol) was added and the resulting solution was stirred for 10 min at room temperature. The mixture was diluted with water (30 mL) and extracted with EtOAc (3×20 mL). The organic layers were combined, dried (Na2SO4), filtered and concentrated under reduced pressure to yield the title compound as a brown oil (1.0 g, crude).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19]C(=O)C)[CH:12]=2)[CH:6]=[C:5]([O:23][CH3:24])[CH:4]=1.C[O-].[Na+].Cl>CO>[CH3:24][O:23][C:5]1[CH:6]=[C:7](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([OH:19])[CH:12]=2)[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(/C=C/c2ccc(OC)c(OC(C)=O)c2)cc(OC)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(/C=C/c2ccc(OC)c(O)c2)cc(OC)c1
Temperature: 0 °C
Yield: 86.1 %

Procedure:
Dissolve compound 21c (5.0 g, 0.015 mol) in anhydrous methanol (50 ml), add in sodium methoxide (1.41 g, 0.024 mol), reflux to react for 3h, after completion of the reaction, pour the reaction solution into ice water, adjust pH to less than 2 with dilute hydrochloric acid, extract three times with ethyl acetate, pool the organic layer, dry the solution over anhydrous magnesium sulfate. Filter, and evaporate the solvent in the solution, redissolve the residue with petroleum ether/ethyl acetate, recrystallize to obtained a white solid (3.70 g, 85%). 1H NMR (400 MHz, DMSO-d6): 3.75 (s, 3H), 3.81 (s, 6H), 6.24 (s, 1H), 6.86 (s, 2H), 6.93 (d, J=16.0 Hz, 1H), 7.01 (d, J=16.0 Hz, 1H), 7.08 (d, J=7.6 Hz, 1H), 7.13 (d, J=7.6 Hz, 1H), 7.15 (s, 1H), 9.89 (s, 1H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:26]=[C:25]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][C:12]=1[C:13]([O:15]CC1C=CC=CC=1)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>O1CCOCC1.CO.C(OCC)(=O)C>[CH2:3]([O:10][C:11]1[CH:26]=[C:25]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][C:12]=1[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OCc1ccccc1)c1ccc(-c2cccnc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2cccnc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (1.3 mL) was added to a solution mixture of the obtained benzyl 2-(benzyloxy)-4-(pyridin-3-yl)benzoate (0.35 g) in dioxane (1.8 mL) and methanol (1.8 mL), followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture. After adjusting the pH to 4.5 with 6 mol/L hydrochloric acid, ethyl acetate was added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.20 g of 2-(benzyloxy)-4-(pyridin-3-yl)benzoic acid as a light yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[Cl:25])[O:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C.[Cl:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39](Cl)=[O:40].Cl>CN(C=O)C.CCOCC.C(OCC)(=O)C.O>[ClH:8].[Cl:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39]([NH:21][CH2:20][CH2:19][N:16]1[CH2:15][CH2:14][CH:13]([O:12][C:11]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:9]([Cl:8])[CH:10]=2)[CH2:18][CH2:17]1)=[O:40]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: NCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(NCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)c1cccc(Cl)c1
Reaction time: 2 h

Procedure:
The product of Example 1 step (iv) (0.15 g) was dissolved in DMF (3 ml), N,N-di-isopropylethylamine (0.3 ml) and 3-chlorobenzoyl chloride (0.054 ml) were added. After 2 hours at room temperature, water and ethyl acetate were added, the organic phase separated dried and concentrated. The residue was purified by chromatography (dichloromethane:methanol, 95:5) to give an oil which was dissolved in ether and 1.0 M ethereal hydrogen chloride solution added to give the titled product as a solid (0.12 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[C:13]2[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=2[N:15]=[CH:16][CH:17]=1>C(O)C.C1COCC1.[Pt](=O)=O>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][C:13]=12
Reactant: C[Si](C)(C)CCOCn1ccc2c(Nc3ccc([N+](=O)[O-])cc3F)ccnc21
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1ccc2c(Nc3ccc(N)cc3F)ccnc21
Reaction time: 8 h

Procedure:
115 mg (0.29 mmol) of N-(2-fluoro-4-nitrophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-4-amine are dissolved in 10 ml of a mixture of ethanol/THF (1:1). 13 mg (0.06 mmol) of platinum(IV) oxide are added, and the mixture is stirred under an atmosphere of hydrogen under atmospheric pressure overnight. The suspension is then filtered through Celite and the solvent is removed under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:5]=1[Cl:11].Cl.[CH3:14][NH:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([N:15]([CH3:16])[CH3:14])[CH:7]=[CH:6][C:5]=1[Cl:11]
Reactant: CNC
Reactant: COC(=O)c1cc(F)ccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(N(C)C)ccc1Cl
Yield: 99 %

Procedure:
To a stirred solution of 4.00 g (20.6 mmol) 2-Chloro-5-fluoro-benzoic acid methyl ester (Rarechem) and 60 ml dimethylsulphoxid were added 2.03 g (24.7 mmol) dimethylamine hydrochloride and 5.97 g (43.2 mmol) potassium carbonate. The reaction mixture was stirred over night and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude product 18a was obtained in 99% yield (4.46 g, 20.9 mmol) and was used for the next step without purification.
Reaction SMILES: C[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1.I[CH2:27]CC>C1COCC1.C(#N)C>[CH3:27][C:6]1[N:5]([CH2:7][CH2:20][CH3:25])[CH:4]=[N:3][CH:2]=1
Reactant: CCCI
Reactant: Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: C1CCOC1
Solvent: CC#N
Product: CCCn1cncc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To a solution of 4-methyl-1-triphenylmethylimidazole (20.0 g) in THF (300 ml) and acetonitrile (300 ml) was added 1-iodopropane (26.2 g) and the mixture was stirred overnight under nitrogen atmosphere at 80° C. The solvent was distilled off under reduced pressure and the residue was dissolved in acetic acid (200 ml), and the mixture was stirred for 3 hours under nitrogen atmosphere at 60° C. The mixture was allowed to be at room temperature, water was added to the mixture, and the insolubles were filtered off. Potassium carbonate was added to the filtrate to make it basic and the mixture was extracted with chloroform three times, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained oil was distilled off under reduced pressure (1.5 mmHg, 72° C. to 73° C.), to give 5-methyl-1-propylimidazole (1.9 g) as colorless oil.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[N:10]=[C:11]([O:21][CH:22]3[CH2:39][CH:38]4[N:24]([C:25](=[O:45])[N:26]([CH3:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]5[C:35]([C:41]([OH:43])=O)([NH:36][C:37]4=[O:40])[CH2:34]5)[CH2:23]3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=3)[S:7][CH:8]=1)([CH3:3])[CH3:2].ClC1N=C(OC2CC3N(C(=O)N(C)CCCCC=CC4C(C([NH:81][S:82]([CH:85]5[CH2:87][CH2:86]5)(=[O:84])=[O:83])=O)(NC3=O)C4)C2)C2C(C=1)=CC(OC)=CC=2>>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[N:10]=[C:11]([O:21][CH:22]3[CH2:39][CH:38]4[N:24]([C:25](=[O:45])[N:26]([CH3:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]5[C:35]([C:41]([NH:81][S:82]([CH:85]6[CH2:87][CH2:86]6)(=[O:84])=[O:83])=[O:43])([NH:36][C:37]4=[O:40])[CH2:34]5)[CH2:23]3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=3)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3nc(C(C)C)cs3)cc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3nc(C(C)C)cs3)cc2c1

Procedure:
The title product 70 was prepared from 17-[3-(4-isopropylthiazol-2-yl)-6-methoxyisoquinolin-1-yloxy]-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (69) following the same procedures described for the preparation of N-[17-(3-chloro-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (43, Example 11): m/z=737 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[C:14]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(Cl)c(Cl)cc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(Cl)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4,5-dichloro-2-methoxybenzoic acid (8.2 g, 37 mmol) and K2CO3 (11.8 g, 111 mmol) in DMF (100 mL), CH3I (6.3 g, 44 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 16 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=10:1) to afford the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:15]3[C:11]([S:12][C:13]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=4)=[N:14]3)=[N:10][C:9]=2[CH3:25])=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].Cl[CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:15]3[C:11]([S:12][C:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33])=[C:18]([O:23][CH3:24])[CH:17]=4)=[N:14]3)=[N:10][C:9]=2[CH3:25])=[CH:4][C:3]=1[C:26]([F:28])([F:27])[F:29]
Reactant: COc1cc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)c(C)nc3s2)ccc1O
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)c(C)nc3s2)ccc1OCC(=O)N(C)C
Temperature: 105 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-(6-amino-5-(trifluoromethyl)pyridin-3-yl) -6-methylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-methoxyphenol (0.042 g, 0.1 mmol, 1 eq) in dry DMF (1 mL), 2-chloro-N,N-dimethylacetamide (0.016 g, 0.13 mmol, 1.25 eq) and K2CO3 (0.018 g, 0.13 mmol, 1.25 eq) were added. The mixture was stirred at 105° C. for 1 h and cooled to RT. The solvent was evaporated, and the dry residue was taken up in DCM, washed with water (2×1 mL), dried (MgSO4), filtered and concentrated to dryness. Purification by preparative HPLC (RP-C18, ACN/water) and trituration with Et2O gave the desired product. HPLC-MS: (5-100% B in 8 min, 0.8 mL/min): tR=4.68 min, [M+H]+ m/z 507.1; 1H NMR (300 MHz, CDCl3) δ 8.41 (d, J=1.7, 1H), 7.95 (d, J=1.8, 1H), 7.49 (s, 1H), 7.42 (d, J=2.1, 1H), 7.29 (d, J=2.1, 1H), 5.12-5.01 (m, 2H), 4.57 (d, J=9.2, 2H), 4.03-3.90 (m, 3H), 3.47 (s, 2H), 2.92 (s, 3H), 2.82 (s, 3H), 2.37 (d, J=0.6, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:23]=[C:22]([CH3:24])[C:21]([CH3:25])=[CH:20][C:16]=1[C:17](O)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][C:22]([CH3:24])=[C:21]([CH3:25])[CH:20]=3)[NH:14][C:12]2=[O:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Cc1cc(N)c(C(=O)O)cc1C
Product: Cc1cc2[nH]c(=O)n(S(=O)(=O)c3ccc(Cl)cc3)c(=O)c2cc1C
Yield: 15.7 %

Procedure:
365 mg (1.68 mmol) of 4-chlorobenzenesulfonylisocyanate and 230 mg (1.40 mmol) of 2-amino-4,5-dimethylbenzoic acid were treated in the same way as in Example 1 to obtain 80 mg of the above-identified compound (yield 15.7%). Properties: colorless crystal, Melting point: 221°-222° C., PMR (δppm, DMSO-d6): 2.23 (3H,s), 2.27 (3H,s), 6.89 (1H,s), 7.60 (1H,s), 7.75 (2H,d), 8.15 (2H,d), 11.40 (1H,br).