Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].CN(C)C=O.[H-].[Na+].Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([O:1][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: ClCCCN1CCOCC1
Reactant: COc1ccc(O)c(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(OCCCN2CCOCC2)c(C=O)c1
Temperature: 70 °C

Procedure:
A stirred solution of 25 g of 2-hydroxy-5-methoxybenzaldehyde in 125 ml. of dimethylformamide is treated portionwise with 8.2 g of 50% sodium hydride (oil dispersion). The temperature is kept below 35° C. by means of an ice-water bath. When the addition is complete, the mixture is warmed to 70° C. and cooled to 25° C. This is followed by the addition of a solution of 36 g. of N-(3-chloropropyl)morpholine in 65 ml. of toluene. The mixture is stirred and heated at 100°-105° C. for 4 hours, cooled, poured into 300 ml. of ice-water and extracted with three 150 ml. portions of ether. The combined ether layers are then extracted with 40 ml. of cold 1:1 hydrochloric acid, followed by 20 ml of water. The aqueous phases are combined, layered over with 150 ml of ether, stirred and basified with 40 g. of potassium carbonate. The layers are separated and the aqueous phase is extracted with three 100 ml portions of ether. The combined ether layers are dried over magnesium sulfate. The solvent is removed on a rotary evaporator and the residue is distilled to give 34 g. of the title compound, boiling point 180°-185° C. at 0.1-0.2 mm of Hg.
Reaction SMILES: CN1C(S[CH2:8][C:9]([OH:11])=[O:10])=NN=N1.O[N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[O:19]=[C:14]1[CH2:15][CH2:16][C:17](=[O:18])[N:13]1[O:11][C:9](=[O:10])[CH3:8]
Reactant: Cn1nnnc1SCC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(=O)ON1C(=O)CCC1=O
Reaction time: 120 h

Procedure:
5.2 g (885 mmol) (1-methyl-1H-tetrazol-5-ylsulfanyl)-acetic acid (CAS Reg. No 55862-52-7; Saito, Seiki et al, Synlett (1993), 2, 139-40 ; 29) were dissolved in 100 ml dimetylformamide. Then 3.44 g (32.84 mmol) N-hydroxysuccinimide were added. Then 6.78 g N,N'-dicyclohexylcarbodiimid were added. After a few minutes white crystals were obtained. The suspension was stirred for further five days. The crystals were filtered off. Dimethylformamide was removed in vacuum. The residue was taken up in 60 ml ethyl acetate at 60° C., filtered off, washed with 30 ml ethylacetate (three times) and dried at high vacuum. 1-Methyl-1H-tetrazol-5-ylsulfanyl)-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester was obtained.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C(C)=O.[C:12](=O)([O-:14])[O-:13].[K+].[K+].[Si](=O)=O.C(=O)=O>>[NH2:1][C:5]1[CH:6]=[C:7]([C:12]([OH:14])=[O:13])[C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C=O
Agent: O=[Si]=O
Agent: [K+]
Product: Nc1ccc(O)c(C(=O)O)c1
Temperature: 170 °C
Yield: 88 %

Procedure:
p-Acetaminophenol 15 g, potassium carbonate 22.5 g, and silicon dioxide 7.5 g were added into a 500 ml autoclave, and CO2 was introduced to perform a carboxylation reaction under a reaction pressure of 1.5 MPa and heated to 170° C., maintained for 4 hours, then the reaction was terminated, cooled to 80° C., and 1500 ml distilled water was added to dissolve potassium 5-aminosalicylate. After decolorization, the aqueous phase was acidified with 20˜30% hydrochloric acid until pH=4, cooled and then filtered to obtain the product of 5-aminosalicylic acid, the content is 99.8% and the yield is 88%.
Reaction SMILES: [Na].[CH3:2][N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12]C3C=CC=CC=3)[C:7]=2[C:6](=[O:19])[NH:5][C:4]1=[O:20].[CH2:21]([CH:23]1[O:25][CH2:24]1)Cl>>[O:25]1[CH2:24][CH:23]1[CH2:21][N:5]1[C:6](=[O:19])[C:7]2[N:8]([CH3:12])[CH:9]=[N:10][C:11]=2[N:3]([CH3:2])[C:4]1=[O:20]
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: ClCC1CO1
Agent: [Na]
Product: Cn1cnc2c1c(=O)n(CC1CO1)c(=O)n2C
Reaction time: 20 h

Procedure:
and R═R1═CH3). A suspension of 3 g (0.148 mole) of the sodium salt of 3,7-dimethylxanthine (III, 1-Na salt; R═R1═CH3) and 20 mL of epichlorhydrin is heated while stirring at 65-70° for 20 hours. After cooling, the precipitate is filtered out and washed with methylene chloride. The derived solution of IX in methylene chloride is stripped and the grease-like residue is kneaded in absolute ether, yielding 2.7 (77%) of 1-(2,3-epoxypropyl)-3,7-dimethylxanthine, melting point 115-119°, M+ 236 (J-C. Pascal et al, J. Med. Chem., 1985, No. 28, No. 5, pp. 647-652, melting point 116-117°).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([F:22])[CH:15]=2)=[CH:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH:30]([S:33](Cl)(=O)=[O:34])([CH3:32])[CH3:31]>C(Cl)Cl>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:6]2[C:7]3[C:12](=[CH:11][C:10]([NH:13][S:33]([CH:30]([CH3:32])[CH3:31])=[O:34])=[CH:9][CH:8]=3)[N:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)=[CH:15][C:16]=1[F:22])#[N:21]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(C)n1cc(-c2ccc(C#N)c(F)c2)c2ccc(N)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1cc(-c2ccc(C#N)c(F)c2)c2ccc(NS(=O)C(C)C)cc21
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
Cool a mixture of 1-Isopropyl-3-(4-cyano-3-fluoro-phenyl)-1H-indol-6-ylamine (0.442 g, 1.51 mmol) and triethylamine (0.306 g, 3.02 mmol) in methylene chloride (10 mL) in a brine/ice bath under argon and treated with a solution of isopropyl sulfonyl chloride (0.210 g, 1.66 mmol) in methylene chloride and the resulting mixture was stirred in the cooling bath for 30 min. After this time dilute the reaction with methylene chloride (40 mL); wash with a saturated aqueous sodium bicarbonate solution (50 mL), then water (50 mL), then brine (50 mL); and dry over sodium sulfate. Remove the solids by filtration; concentrate the filtrate under reduced pressure. Triturate the residue with boiling methylene chloride (×3) then boiling acetonitrile to afford the title compound (0.212 g, 37%) as a white solid: mp 173-175° C. dec;
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1B(O)O>>[CH2:17]([NH:16][C:14]([C:3]1[N:4]=[N:5][C:6]2[C:11]([C:2]=1[NH2:1])=[CH:10][CH:9]=[C:8]([F:12])[C:7]=2[C:25]1[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=1[O:27][CH3:28])=[O:15])[CH2:18][CH3:19]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: CCCNC(=O)c1nnc2c(I)c(F)ccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(F)ccc3OC)c(F)ccc2c1N

Procedure:
The title compound was prepared from 4-amino-7-fluoro-8-iodo-N-propylcinnoline-3-carboxamide (200.0 mg, 0.53 mmol) and 2-fluoro-5-methoxyphenyl boronic acid (181.7 mg, 1.07 mmol) according to Method A to afford a yellow crystalline solid (111.0 mg, 56%). 1H NMR (300.132 MHz, CDCl3) δ 8.49 (t, J=5.3 Hz, 1H), 7.91 (dd, J=9.3, 5.2 Hz, 1H), 7.52 (t, J=8.8 Hz, 1H), 7.16-7.07 (m, 2H), 6.98 (dd, J=9.1, 4.5 Hz, 1H), 3.70 (s, 3H), 3.44 (q, J=6.7 Hz, 2H), 1.64 (sextet, J=7.3 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H). MS APCI, m/z=373 (M+H). HPLC 2.66 min.
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[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:32][C:29]1[CH:30]=[CH:31][C:23]([NH:22][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:6]=3[N:7]=[C:2]([Cl:1])[N:3]=2)=[C:24]([CH:28]=1)[C:25]([NH2:27])=[O:26]
Reactant: NC(=O)c1cc(Cl)ccc1N
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc(Cl)cc4C(N)=O)nc(Cl)nc32)cc1

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 7.3 mmol) and 2-amino-5-chlorobenzamide (3.73 g, 22 mmol), 5-chloro-2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide was isolated as a yellow solid (2.0 g, 57% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3 H), 6.70 (d, J=4.03 Hz, 1 H), 7.47 (d, J=8.23 Hz, 2 H), 7.64 (dd, J=8.87, 2.47 Hz, 1 H), 7.76 (d, J=3.84 Hz, 1 H), 7.88 (d, J=2.38 Hz, 2 H), 7.98 (d, J=8.60 Hz, 2 H), 8.38 (s, 1 H), 8.41 (d, J=8.97 Hz, 1 H), 12.14 (s, 1 H).
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][C:13](=[O:20])[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]3=[N:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH3:28][N:29]1[C:33]([CH2:34]Cl)=[N:32][CH:31]=[N:30]1>CN(C=O)C.O>[CH3:28][N:29]1[C:33]([CH2:34][O:20][C:13]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]3[N:9]=[N:8][N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]=3[N:12]=2)=[N:32][CH:31]=[N:30]1
Reactant: O=c1nc2n(-c3ccccc3)[nH]nc-2c2ccccc12
Reactant: Cn1ncnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncnc1COc1nc2c(nnn2-c2ccccc2)c2ccccc12
Temperature: 60 °C
Reaction time: 5 h
Yield: 68.5 %

Procedure:
A mixture of 3-phenyl-1,2,3-triazolo[4,5-c]isoquinolin-5-one (0.10 g, 0.38 mmol), cesium carbonate (0.33 g, 1.0 mmol) and 2-methyl-3-chloromethyl-1,2,4-triazole hydrochloride (0.08 g, 0.48 mmol) in dry DMF (2 ml) was stirred at 60° C. for 5 h. The mixture was diluted with water (20 ml) and the white solid was collected, washing with water (10 ml) and diethyl ether (10 ml). The solid was dried to give 5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,3-triazolo[4,5-c]isoquinoline (0.093 g, 68%), m.p. 188-190° C. Found: C, 63.48; H, 4.19; N, 27.14. C19H15N7O.0.1(H2O) requires C, 63.54; H, 4.27; N, 27.30. δH (360 MHz; CDCl3) 3.99 (3H, s), 5.83 (2H, s), 7.48-7.53 (1H, m), 7.61-7.70 (3H, m), 7.94-7.98 (2H, m), 8.20-8.22 (2H, m), 8.37 (1H, d, J=8) and 8.69 (1H, d, J=8); m/z (ES+) 358 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:41]=[CH:40][C:29]([O:30][CH2:31][C:32]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[O:33])=[CH:28][CH:27]=1>O1CCOCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([O:30][CH2:31][C:32]([N:34]2[CH2:39][CH2:38][N:37]([C:2]3[C:3]4[CH:10]=[C:9]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=5)[S:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH2:36][CH2:35]2)=[O:33])=[CH:40][CH:41]=1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCNCC1
Reactant: Fc1ccc(-c2cc3c(Cl)ncnc3s2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(COc1ccc(Cl)cc1)N1CCN(c2ncnc3sc(-c4ccc(F)cc4)cc23)CC1
Temperature: 60 °C
Yield: 69.9 %

Procedure:
To a solution of 4-chloro-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine (20 mg, 0.08 mmol) and triethylamine (42 μl, 0.3 mmol) in dioxane (1 ml) was added 2-(4-chlorophenoxy)-1-(piperazin-1-yl)ethanone (25 mg, 0.1 mmol). The mixture was heated at 60° C. for 2 hours. After cooling down to room temperature, the solvents were removed under reduced pressure. The crude residue was purified by silica gel chromatography (CH2Cl2/MeOH 50:1) to yield the title compound as a white solid (27 mg, 75%).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]([F:43])([F:42])[O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:38][C:37]3[CH:40]=[CH:41][C:34]([O:33][C:32]([F:43])([F:42])[F:31])=[CH:35][CH:36]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: Cc1nc2c(ccn2Cc2ccc(OC(F)(F)F)cc2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 4-(trifluoromethoxy)benzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.51-7.43 (m, 1 H), 7.33-7.28 (m, 2 H), 7.26-7.15 (m, 3 H), 7.06 (t, J=3.3 Hz, 1 H), 6.94 (dd, J=5.3, 8.4 Hz, 1 H), 6.29 (dd, J=3.5, 11.7 Hz, 1 H), 5.65-5.55 (m, 2 H), 5.53-5.43 (m, 1 H), 4.32-4.26 (m, 2 H), 2.95-2.81 (m, 2 H), 2.78-2.73 (m, 3 H), 2.14-2.05 (m, 2 H), 0.97 (s, 9 H); LC/MS (m/z) ES+=569.19 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]1>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Reactant: CC(C)(O)C1CCNCC1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1

Procedure:
Following General Procedure B, 4-(6-(bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 and 2-(piperidin-4-yl)propan-2-ol were reacted to give 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[C:13](O)(=O)[CH3:14].Cl.[OH-].[NH4+]>O>[CH3:13][C:14]1[NH:1][C:2]2[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: CC(=O)O
Reactant: Cc1c([N+](=O)[O-])ccc(N)c1N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2ccc([N+](=O)[O-])c(C)c2[nH]1
Temperature: 25 °C

Procedure:
A mixture of 668 mg of 2,3-diamino-6-nitrotoluene, 20 mL of glacial acetic acid and 2 mL of 12N hydrochloric acid is heated to reflux for 3 hours. The resulting mixture is cooled to room temperature and rotary evaporated. The residue is diluted with 20 mL of water, and basified with ammonium hydroxide (28-30%). The resulting suspension is extracted with ethyl acetate and the extracts are dried over magnesium sulfate, filtered and rotary evaporated to provide 720 mg of 2,4-dimethyl-5-nitrobenzimidazole as a tan solid.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([CH:29]([CH3:31])[CH3:30])[NH:5][C:6](=[O:28])[C@H:7]([CH:25]([CH3:27])[CH3:26])[NH:8][C:9](=[O:24])[C@H:10]([CH2:19][O:20][CH2:21][CH:22]=[CH2:23])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C([O-])(O)=O.[Na+]>C1COCC1.O>[C:15]([O:14][C:12]([NH:11][C@H:10]([C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:32])=[O:2])[CH:29]([CH3:30])[CH3:31])=[O:28])[CH:25]([CH3:27])[CH3:26])=[O:24])[CH2:19][O:20][CH2:21][CH:22]=[CH2:23])=[O:13])([CH3:16])([CH3:18])[CH3:17]
Reactant: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C(=O)OC)C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C(=O)O)C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 70.7 %

Procedure:
N-tert-butoxycarbonyl O-allyl L-seryl L-valyl L-valine methyl ester (8) (10.21 g, 22.31 mmol) was dissolved in THF (170 mL). The solution was cooled to 0° C. (icebath). LiOH monohydrate (1.03 g, 24.6 mmol) was dissolved in de-ionized water (85 mL) and the solution cooled to 0° C. The solution was then added dropwise to the solution of 8 over 20 min. The reaction mixture was stirred for an additional 2 h 40 min at 0° C. Solid NaHCO3 (3.75 g, 44.6 mmol) was added and the mixture stirred for 5 min before the THF was evaporated. The solution was diluted with water (170 mL), washed with Et2O (2×170 mL), acidified to pH 2 by addition of 2 M aqueous H2SO4 and extracted with EtOAc (3×250 mL). The combined organic fractions were dried with anhydrous MgSO4 and the solvent evaporated affording the title compound as a white solid (7.00 g, 71%); δH (300 MHz; d6-DMSO) 12.53 (1H, br s, COOH), 8.00 (1H, d, J 8, NH (Valx)), 7.62 (1H, d, J 9, NH(Valy)), 7.02 (1H, d, J 8, NH (Ser(All))), 5.84 (1H, ddt, J 5, 10 and 17, CH═CH2), 5.23 (1H, ddt, J 1, 3 and 17, CH═CHH)), 5.12 (1H, ddt, J 1, 3 and 10, CH═CHH), 4.34 (1H, dd, J 7 and 9, CαH(Valy)), 4.21-4.15 (1H, m, CαH(Ser(All))), 4.10 (1H, dd, J 6 and 8, CαH(Valx)), 3.92 (2H, dt, J 1 and 5, CH2CH═CH2), 3.59-3.45 (2H, m, CH2), 2.06-1.91 (2H, m, CH(CH3)2), 1.38 (9H, s, (CH3)3), 0.90-0.80 (12H, m, CH3); δC (75 MHz; d6-DMSO) 172.6, 170.9, 169.5, 155.1, 134.9, 116.3, 78.2, 71.0, 69.5, 57.2, 56.9, 54.6, 31.1, 29.6, 28.1, 19.0, 19.0, 17.9, 17.7; m/z (ESI) 466.2518 ([M+Na]+; C21H37N3O7Na requires 466.2529)
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.CC1CCCN1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:24][CH:23]2[CH3:28])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC1CCCN1
Product: CC1CCCN1c1nc(C(C)(C)C)nc2c1nnn2Cc1ccccc1Cl

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-methylpyrrolidine and isolated as white solid (13.0 mg, 70%). MS (m/e): 385.4 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[O:27][C:26]([C:28]([F:31])([F:30])[F:29])=[C:25]([C:32]([O:34]CC)=[O:33])[CH:24]=1.[OH-].[Na+]>C(O)C.O>[O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[O:27][C:26]([C:28]([F:31])([F:30])[F:29])=[C:25]([C:32]([OH:34])=[O:33])[CH:24]=1
Reactant: CCOC(=O)c1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)oc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)oc1C(F)(F)F
Yield: 84 %

Procedure:
To a solution of ethyl 5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxylate (1.30 g, 2.59 mmol) in ethanol (8 mL) and water (1.7 mL) was added sodium hydroxide (0.12 g, 3.00 mmol). The reaction mixture was heated at reflux for 45 min, concentrated in vacuo to remove ethanol. To the residue was added water (15 mL) and the mixture was acidified to pH˜3 by 10% hydrochloric acid at 0° C. The resulting mixture was extracted with ethyl acetate (3×50 mL). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give 5-((2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1′-yl)methyl)-2-(trifluoromethyl)furan-3-carboxylic acid (1.03 g, 84%): mp 195-197° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.13-7.26 (m, 1H), 7.17-7.15 (m, 2H), 7.05-7.00 (m, 2H), 6.67 (s, 1H), 6.09 (s, 1H), 5.90-5.88 (m, 2H), 5.11-4.96 (m, 2H), 4.80-4.66 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 177.0, 161.9, 155.8, 152.3, 148.9, 142.2, 141.9, 141.5, 132.1, 129.3, 124.1, 123.8, 122.2, 120.6, 120.1, 117.0, 111.8, 109.7, 103.1, 101.9, 93.8, 80.1, 57.9, 36.7; MS (ES−) m/z 472.0 (M−1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14]([Br:19])=[CH:13][C:12]=3[N:11]=[C:10]([NH2:20])[C:9]=2[N:8]=[C:7]1[CH2:21][CH2:22][CH3:23].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)(Cl)Cl>[NH2:20][C:10]1[C:9]2[N:8]=[C:7]([CH2:21][CH2:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[C:18]=2[C:17]2[CH:16]=[CH:15][C:14]([Br:19])=[CH:13][C:12]=2[N:11]=1
Reactant: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCN
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCNS(C)(=O)=O
Temperature: 0 °C
Yield: 37.4 %

Procedure:
A suspension of 1-(4-aminobutyl)-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (3.27 g, 8.7 mmol) and triethylamine (3.82 mL, 11.3 mmol) in chloroform (165 mL) was cooled to 0° C. A cold solution of methanesulfonyl chloride (1.37 mL, 9.6 mmol) in chloroform (10 mL) was slowly added. The reaction was allowed to warm to ambient temperature after 15 minutes. Additional triethylamine (3.74 mL) and methanesulfonyl chloride (2.12 mL) were added over the course of several days to drive the reaction to completion. The reaction was concentrated under reduced pressure, and the residue was partitioned between 1% aqueous sodium carbonate and chloroform. The aqueous layer was adjusted to pH 13 with the addition of saturated aqueous sodium bicarbonate and 50% aqueous sodium hydroxide. The precipitate was isolated by filtration, air-dried, and combined with material from another run. The crude product was recrystallized from isopropanol:water (15 mL/g:1.5 mL/g) and dried in a drying oven for several days to provide 1.48 g of N-{4-[4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide as a white solid.
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][N:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](Cl)=[S:6]>CCOCC>[CH3:3][N:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([NH:1][NH2:2])=[S:6]
Reactant: NN
Reactant: CN(C(=S)Cl)c1ccccc1
Solvent: CCOCC
Product: CN(C(=S)NN)c1ccccc1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
To a solution of 7.7 g (0.24 m) anhydrous hydrazine in 200 ml of dry ether, N-methyl-N-phenylthiocarbamyl chloride 20.4 g (0.11 m) was added below 5° C. with stirring. The mixture was stirred and allowed to warm to room temperature. The mixture was filtered and the residue resuspended in ~100 ml water and stirred. Filtration gave 8.8 g of the desired product as whitish powder, m.p. 121°-22°.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH2:22]([NH:26][C:27](=[O:55])[C@H:28]([CH2:51][CH:52]=[CH:53][CH3:54])[CH2:29][C@@H:30]1[O:34][C:33]([CH3:36])([CH3:35])[N:32]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:31]1[CH2:44][C:45]([CH3:50])([CH3:49])[CH2:46][CH2:47][OH:48])[CH2:23][CH2:24][CH3:25].[OH2:56]>CN(C)C=O>[CH2:22]([NH:26][C:27](=[O:55])[C@H:28]([CH2:51][CH:52]=[CH:53][CH3:54])[CH2:29][C@@H:30]1[O:34][C:33]([CH3:36])([CH3:35])[N:32]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[C@H:31]1[CH2:44][C:45]([CH3:50])([CH3:49])[CH2:46][C:47]([OH:56])=[O:48])[CH2:23][CH2:24][CH3:25]
Reactant: O
Reactant: CC=CC[C@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CCO)C(=O)NCCCC
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CC=CC[C@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CC(=O)O)C(=O)NCCCC
Reaction time: 23 h

Procedure:
A solution of 809 mg of pyridinium dichromate in 2 ml of N,N-dimethylformamide is added dropwise via a cannula to a solution of 290 mg of 3-[N-tert-butoxycarbonyl-4(S)-(4-hydroxy-2,2-dimethylbutyl)-2,2-dimethyl-1,3-oxazolidin-5(S)-yl]-2(R)-but-2-enyl-propionic acid (N-butyl)amide in 2 ml of N,N-dimethylformamide at room temperature under argon. After 23 h, a further 238 mg of pyridinium dichromate are added. After a total of 29 h, the reaction mixture is poured into water, extracted with diethyl ether (3 times), dried (Na2SO4) and concentrated. Purification over silica gel (mobile phase P) gives the title compound: Rf (P)=0.48; FAB-MS: (M+H)+ =497.