Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:22][F:23])([CH2:20][F:21])[CH:7]=1)=[O:5])C.[OH-].[K+].Cl>C(O)C>[F:23][CH2:22][C:8]1([CH2:20][F:21])[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:11]2[CH:12]=[C:13]([C:16]([F:19])([F:17])[F:18])[CH:14]=[CH:15][C:10]=2[O:9]1
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of 0.51 g of 2,2-bisfluoromethyl-6-trifluoromethyl-2H-1-benzopyran-4-carboxylic acid ethyl ester, 0.13 g of potassium hydroxide and 10 ml of ethyl alcohol was stirred at room temperature for 2 hours. The reaction mixture was combined with ice water and hydrochloric acid, and the precipitated crystals were filtered off to give 0.43 g of 2,2-bisfluoromethyl-6-trifluoromethyl-2H-1-benzopyran-4-carboxylic acid; m.p. 162-163° C.;
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([SH:14])[C:11]([CH:15]([CH3:17])[CH3:16])=[CH:10][C:9]=1[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH3:4])([CH3:3])[CH3:2].[S:27](Br)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28].N1C=CC=CC=1>CCOC(C)=O>[C:22]([O:21][C:19]([NH:18][C:9]1[C:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:26])=[CH:13][C:12]([S:14][S:27]([C:30]2[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=2)(=[O:29])=[O:28])=[C:11]([CH:15]([CH3:16])[CH3:17])[CH:10]=1)=[O:20])([CH3:24])([CH3:23])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Reactant: CC(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)cc1S
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Sc2cc(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)cc2C(C)C)cc1

Procedure:
The title compound was prepared according to the General Method 15 using (2-tert-butyoxycarbonylamino-4-isopropyl-5-mercapto-phenyl)-carbamic acid tert-butyl ester (prepared in Example TT-1; 22.1 mmol), tosyl bromide (5.2 g, 22 mmol), pyridine (5 mL), and EtOAc (50 mL). The crude product was purified by flash chromatography (5%-60% EtOAc in hexanes as eluents). 1H-NMR (CDCl3): δ0.97 (s, 6 H), 1.53 (s, 18 H), 2.4 (s, 3 H), 3.2 (m, 1 H), 7.11 (br s, 1 H), 7.22 (d, 2 H), 7.28 (s, 1 H), 7.36 (s, 1 H), 7.5 (d, 2 H), 7.75 (br s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[N:11]=[C:10]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(Nc2nc(Cl)nc3ccccc23)cc1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and 4-methoxyaniline (45 mg, 0.326 mmol) by a procedure similar to example 1b and was isolated as off white powder (55 mg, 77%). 1H NMR (CDCl3): 10.25 (s, 1H), 8.58 (d, J=8.4 Hz, 1H), 7.88 (t, J=7.2 Hz, 1H), 7.71-7.63 (m, 4H), 7.03-6.99 (m, 2H), 3.79 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.[C:19]([CH:21]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)[CH2:22][C:23]([O:25][CH3:26])=[O:24])#[N:20].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[C:19]([CH:21]([C:27]1[CH:32]=[CH:31][C:30]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9](=[O:10])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:17][CH:18]=2)=[CH:29][CH:28]=1)[CH2:22][C:23]([O:25][CH3:26])=[O:24])#[N:20]
Reactant: O=C(COc1ccc(CO)cc1)c1ccccc1
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)CC(C#N)c1ccc(OCc2ccc(OCC(=O)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.1 %

Procedure:
To a 100 mL of two neck RB flask was charged with 2-[4-(hydroxy methyl)phenoxy]-1-phenylethanone (2.5 g, 10.3 mmol) and methyl 3-cyano-3-(4-hydroxyphenyl)propanoate (2.5 g, 12.4 mmol) in 50 mL of toluene. To this added tributylphosphine (3.33 g, 16.5 mmol) at 0° C. and added 1,1′-(Azodicarbonyl)dipiperidine (4.165 g, 16.5 mmol) portion wise over a period of 15 min at 0° C. After 12 h of stirring at RT, the mixture was diluted with n-hexane and stirred for 10 min. Solid formed was filtered off and the filtrate was concentrated to afford crude product which on trituration with ethyl acetate and pet ether gave pure product. (2.5 g yield: 56.1%); 1H NMR (300 MHz, DMSO-d6): δ 8.01-8.03 (d, 2H), 7.67-7.72 (t, 1H), 7.55-7.60 (t, 2H), 7.34-7.37 (d, 4H), 6.96-7.02 (t, 4H), 5.59 (s, 2H), 5.01 (s, 2H), 4.37-4.46 (m, 1H), 3.61 (s, 3H), 3.07-3.16 (m, 1H), 2.90-2.97 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[C:24]([C:33]([NH2:35])=[O:34])=[CH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[C:24]([C:33]([NH2:35])=[O:34])=[CH:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: NC(=O)c1cc2ccccc2cc1N
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cc5ccccc5cc4C(N)=O)nc(Cl)nc32)cc1

Procedure:
Using General Protocol II (but using methanol in place of dimethylether) and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 13.2 mmol) and 3-amino-2-naphthalenecarboxamide (3.00 g, 8.8 mmol), 3-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2-naphthalenecarboxamide was isolated as a white solid (2.56 g, 59% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.35 (s, 3 H), 6.69 (d, J=4.03 Hz, 1 H), 7.42-7.51 (m, 3 H), 7.58 (t, J=7.51 Hz, 1 H), 7.72 (d, J=4.03 Hz, 1 H), 7.78-7.85 (m, 2 H), 7.90 (d, J=8.06 Hz, 1 H), 7.97 (d, J=8.42 Hz, 2 H), 8.40 (s, 2 H), 8.69 (s, 1 H), 11.90 (s, 1 H).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH2:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19]>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:20][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: CCCCCO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CCCCCOc1cccc([N+](=O)[O-])c1C#N

Procedure:
Prepared as in Example 111c from 2,6-dinitrobenzonitrile and pentanol to provide 2-nitro-6-(pentyloxy)benzonitrile.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH2:16])=[C:11]([CH3:17])[CH:10]=1>>[Br:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH:16][C:5](=[O:7])[CH3:6])=[C:11]([CH3:17])[CH:10]=1
Reactant: Cc1cc(Br)c(F)cc1N
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(F)c(Br)cc1C
Reaction time: 0.17 h

Procedure:
73.6 mL of acetic anhydride was added with 80.0 g of 4-bromo-5-fluoro-2-methylphenylamine at room temperature, and stirred at this temperature for 10 minutes. Excess acetic anhydride was distilled off under reduced pressure, and the precipitated crystals were washed with water, to afford 77.6 g of the title compound as colorless crystal.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Br.[H-].[Na+]>CN(C)C=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH:15]2[CH2:16][O:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCC1CO1
Reactant: OCCCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CCCCCOCC2CO2)cc1

Procedure:
A procedure similar to that described in Preparation 46 was repeated, except that 5 g of 5-phenyl-1-pentanol, 4.99 ml of epibromohydrin, 1.31 g of sodium hydride (as a 55% by weight dispersion in mineral oil) and 80 ml of anhydrous dimethylformamide were used. The resulting crude product was purified by silica gel column chromatography, using a 1:6 by volume mixture of ethyl acetate and hexane as the eluent, to give 4.2 g of the title compound as a colorless oil having an Rf value of 0.49 (on silica gel thin layer chromatography, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]([NH:22][C:23]#[N:24])=[N:18][CH2:19][CH2:20][NH2:21])[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39]>CO.CCOCC>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39].[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]([NH:22][C:23]#[N:24])=[N:18][CH2:19][CH2:20][NH:21][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[Cl:25])[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N#CNC(=NCCN)NC1CCCC(c2csc(NC(=N)N)n2)C1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCOCC
Solvent: CO
Product: N#CNC(=NCCNC(=O)c1ccccc1Cl)NC1CCCC(c2csc(NC(=N)N)n2)C1
Reaction time: 16 h

Procedure:
To a solution of 2-guanidino-4-{3-[3-cyano-2-(2-aminoethyl)guanidino]cyclohexyl}thiazole (0.5 g.) in methanol (30 ml.) was added o-chlorobenzoyl chloride (0.4 g.) and the mixture allowed to stand at room temperature for 16 hours. The residue obtained by evaporation of the solvent was partitioned between ethyl acetate (100 ml.) and water (20 ml.) The organic layer was isolated, washed with water (20 ml), dried (magnesium sulphate) and evaporated. The residue was subjected to preparative thin layer chromatography on Merck 60 F-254 plates using chloroform/methanol/aqueous ammonia (s.g. 0.88) 80:20:0.1 v/v/v for development. The appropriate zone of the chromatogram was isolated and extracted with hot ethanol/chloroform 50:50 v/v (200 ml.) and the residue obtained on evaporation of the solvents was dissolved in methanol. To this solution was added an excess of maleic acid in ether followed by a further amount of ether until precipitation began. The white powder precipitate (0.2 g.) was washed with ether to give 2-guanidino-4-{ 3-[3-cyano-2-(2-(2-chlorobenzoylamino)ethyl)guanidino]cyclohexyl}thiazole hydrogen maleate, m.p. 158°-165° (decomp.).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:3]=1[C:4]([N:6]1[CH:11]=[CH:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5].C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[CH3:17][C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[CH:7]1[CH2:8][C:9](=[O:12])[CH2:10][CH2:11][N:6]1[C:4]2=[O:5]
Reactant: Cc1ccc(Br)c(C(=O)N2C=CC(=O)CC2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)C(=O)N1CCC(=O)CC21
Temperature: 95 °C
Yield: 31.8 %

Procedure:
A mixture of 1-(2-bromo-5-methylbenzoyl)-2,3-dihydro-4-pyridinone (1.19 g, 4.03 mmol), tri-n-butyltin hydride (1.14 ml, 4.24 mmol) and azobis(isobutyronitrile) (AIBN, 66 mg, 10 mol %) in toluene (40 ml) was heated at 95° C. for 2 h, cooled, evaporated and purified by flash column chromatography on silica eluting with 30% ethyl acetate in hexane to yield the title compound as a pale yellow oil (276 mg), MS (+EI) m /z 215 [M+ ].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][CH2:10][C:11]#[N:12])=[C:4]([CH3:13])[N:3]=1.[CH2:14]([NH2:19])[CH2:15][CH2:16][CH2:17][CH3:18]>O1CCOCC1>[NH2:1][C:2]1[N:3]=[C:4]([CH3:13])[C:5]([CH2:9][CH2:10][C:11]#[N:12])=[C:6]([NH:19][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:7]=1
Reactant: Cc1nc(N)nc(Cl)c1CCC#N
Reactant: CCCCCN
Solvent: C1COCCO1
Product: CCCCCNc1nc(N)nc(C)c1CCC#N
Reaction time: 8.5 h
Yield: 55 %

Procedure:
A mixture of 3-(2-amino-4-chloro-6-methylpyrimidine-5-yl)propanenitrile (500 mg, 2.54 mmol), amylamine (2.94 ml) and dioxane (5 ml) was kept at 90° C. for 8.5 hours. The procedure according to pro-treatment of Example 23 was carried out to give the object compound (346 mg, 55.0%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[N+:18]=[N-:19].C[O-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[C:20]([N:17]=[N+:18]=[N-:19])[C:21]([O:23][CH3:24])=[O:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)CN=[N+]=[N-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=Cc1ccc(OCc2ccccc2)cc1)N=[N+]=[N-]
Reaction time: 2 h

Procedure:
4-Benzyloxybenzaldehyde (10.0 g) and methyl azidoacetate (21.7 g) are dissolved in 157 ml of methanol and cooled to -10° (ice-acetone bath). Then sodium methoxide (43.1 ml, 25% in methanol) is added dropwise such that the reaction temperature does not rise above -5°. After 2 hr, the cooling bath is removed and the reaction is warmed to 20°-25°. When no starting material remains by TLC, the reaction is diluted with ether and washed with saturated aqueous ammonium chloride. The organic layer is washed with water, saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography (hexane to 5% ethyl acetate/hexane) gives the title compound.
Reaction SMILES: F[C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[F:13].[C:21]([NH:28][C:29]1[CH:30]=[C:31]([OH:35])[CH:32]=[CH:33][CH:34]=1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:24]([O:23][C:21](=[O:22])[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:2]2[CH:16]=[C:15]([F:17])[CH:14]=[C:4]([NH:5][C:6]3[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=3[F:13])[C:3]=2[N+:18]([O-:20])=[O:19])[CH:30]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1Nc1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
3.0 g of 3,5-difluoro-N-(2-fluoro-4-iodophenyl)-2-nitroaniline (Intermediate 1A; 70% pure, 5.3 mmol, 1 eq.), 1.1 g N-Boc-3-amino-phenol (5.3 mmol, 1 eq.) and 3.4 g caesium carbonate (10.7 mmol, 1.5 eq.) were suspended in 30 mL DMF and stirred at rt for 16 h. LCMS analysis showed complete turnover. The reaction mixture was partitioned between water and ethyl acetate, the layers were separated and the aqueous layer was reextracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (n-hexane/ethyl acetate gradient) providing 1.35 of the desired product (44% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:42])[O:14][CH2:15][C@@H:16]([N:28]([CH3:41])[C:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=1[Cl:40])=[O:30])[CH2:17][CH:18]([OH:27])[CH2:19][O:20][P:21]([O:25]C)([O:23]C)=[O:22])=[CH:5]2.[Si](I)(C)(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:42])[O:14][CH2:15][C@@H:16]([N:28]([CH3:41])[C:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=1[Cl:40])=[O:30])[CH2:17][CH:18]([OH:27])[CH2:19][O:20][P:21]([OH:23])([OH:25])=[O:22])=[CH:5]2
Reactant: COP(=O)(OC)OCC(O)C[C@@H](COC(=O)Nc1cc2cc(F)ccc2cn1)N(C)C(=O)NCc1cccc(F)c1Cl
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2cc(F)ccc2cn1)CC(O)COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (2S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(dimethoxyphosphoryloxy)-4-hydroxypentyl 6-fluoroisoquinolin-3-ylcarbamate (0.15 g, 0.238 mmol, 1.0 equiv.) in acetonitrile (2 mL) was added TMSI (0.162 mL, 1.19 mmol, 5.0 equiv.) at RT After stirred at RT for 10 min, the reaction was quenched with MeOH. The solvent was removed, and the resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O (0.1% TFA buffer) to give the desired product. The product was dissolved in a mixture of methanol and water (2:1), and HCl (4 M in 1,4-dioxane, 2 mL) was added. The solvent was removed. This procedure was repeated to give (2S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4-hydroxy-5-(phosphonooxy)pentyl 6-fluoroisoquinolin-3-ylcarbamate (98 mg, 64%) as a HCl salt. LRMS (M+H+) m/z 603.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[CH:37][CH:36]=1)[C:9]1[N:14]2[N:15]=[CH:16][CH:17]=[C:13]2[N:12]=[C:11]([NH:18][C@H:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]2)[C:10]=1[CH2:32][CH2:33][OH:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53].Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:35]1[CH:36]=[CH:37][C:38]([O:41][CH2:42][CH3:43])=[CH:39][CH:40]=1)[C:9]1[N:14]2[N:15]=[CH:16][CH:17]=[C:13]2[N:12]=[C:11]([NH:18][C@H:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:20]2)[C:10]=1[CH2:32][CH2:33][O:34][S:52]([CH3:51])(=[O:54])=[O:53])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCO)c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)nc3ccnn23)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCOS(C)(=O)=O)c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)nc3ccnn23)cc1
Reaction time: 0.5 h

Procedure:
To a methylene chloride (2 mL) solution containing tert-butyl (S)-3-[7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate (0.693 mmol), triethylamine (290 μL, 2.08 mmol) and methanesulfonyl chloride (80 μL, 1.04 mmol) were added with ice-cooling, and the mixture was stirred for 30 min. After the reaction, 1 mol/L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain the title compound.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH:8]=[N:7][CH:6]=[N:5]1)[CH3:3].C([Li])CCC.[C:14](=[O:16])=[O:15]>C1COCC1.CCCCCC>[CH3:1][CH:2]([N:4]1[C:8]([C:14]([OH:16])=[O:15])=[N:7][CH:6]=[N:5]1)[CH3:3]
Reactant: O=C=O
Reactant: CC(C)n1cncn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)n1ncnc1C(=O)O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
1-(1-Methylethyl)-1H-1,2,4-triazole (1 g) was dissolved in THF (15 ml) and cooled to −78° C. under nitrogen. A 1.6 M solution of butyllithium in hexane (5.9 ml) was added dropwise. The solution was stirred for 1.5 h at −78° C., then the solution was treated with solid carbon dioxide (2 g). After 30 min at −78° C. the solution was allowed to warm to RT and stirred overnight. The reaction was quenched with water (1 ml), concentrated in vacuo and dried in a vacuum oven for 1 day at 50° C. to give the title compound (1.29 g) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:16]1([C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C2CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C1CC1)N1CCNCC1
Temperature: 25 °C

Procedure:
1-Tertbutoxycarbonyl-4-(cyclopropanecarbonyl) piperazine (254 mg, 1 mmol) was dissolved in dichloromethane, and then trifluoroacetic acid (1.5 mL) was added. The reaction mixture was stirred at room temperature until completed, and then washed with saturated sodium bicarbonate solution for three times. The organic phases were concentrated. N-(cyclopropanecarbonyl) piperazine was obtained for use.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[S:29](Cl)(=[O:31])=[O:30]>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[S:29]([N:8]1[C:9]2[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)(=[O:31])=[O:30]
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2c(F)cccc2F)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22.5 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 2,6-difluorobenzenesulphonyl chloride (23 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (6 mg, 24%) as a white solid. MS (ESI+) for C18H18F2N2O3S m/z 381 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[C:13]=2[Br:19])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([C:9](=[S:31])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[C:13]=2[Br:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2cccc(Br)c2Br)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(=S)Nc2cccc(Br)c2Br)cc1

Procedure:
The thioamide was prepared according to Example 19 using the 4-tert-butyl-N-(2,3-dibromophenyl)benzamide of Example 22, and Lawesson's reagent in toluene. MS (ESI) m/z 426; HPLC Method B, purity 96.3% at 210-370 nm, 11.4 min.; 98.3% at 262 nm, 11.4 min.; HRMS: calcd for C17H17Br2NS+H+, 425.95212; found (ESI, [M+H]+), 425.9527.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[Br-:50].[NH2:51][CH2:52][CH2:53][CH2:54][CH2:55][N+:56]([CH2:59][CH2:60][NH:61][C:62]([C:64]1[C:69]([NH2:70])=[N:68][C:67]([NH2:71])=[C:66]([Cl:72])[N:65]=1)=[O:63])([CH3:58])[CH3:57]>CN(C=O)C>[Br-:50].[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH:51][CH2:52][CH2:53][CH2:54][CH2:55][N+:56]([CH2:59][CH2:60][NH:61][C:62]([C:64]2[C:69]([NH2:70])=[N:68][C:67]([NH2:71])=[C:66]([Cl:72])[N:65]=2)=[O:63])([CH3:58])[CH3:57])=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: C[N+](C)(CCCCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Br-]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[N+](C)(CCCCNC(=O)Cc1ccc(OCc2ccccc2)cc1)CCNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-Benzyloxyphenyl acetic acid (0.013 g, 0.30 mmol) in DMF (1.5 mL) is added HATU (0.12 g, 0.3 mmol), N-methylmorpholine (0.13 mL, 1.2 mmol) and (4-amino-butyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate N) (0.1 g, 0.30 mmol). The solution is stirred at RT for 2 h. The solvent is removed in vacuo and the residue is purified by reverse phase chromatography (Isolute™ C18, 0-100% acetonitrile in water with 0.1% TFA) to yield the title compound. M+ 535. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (1H, t), 8.05 (1H, t), 7.25 (2H, br), 7.42-7.32 (5H, m), 7.17 (2H, d), 7.09 (2H, br), 6.92 (2H, d), 5.06 (2H, s), 3.61-3.53 (2H, m), 3.39-3.33 (4H, m), 3.32 (2H, s), 3.10-3.03 (2H, m), 3.02 (6H, s), 1.61-1.49 (2H, m), 1.44-1.33 (2H, m).