Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10](=[O:19])[NH:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:28][C:29](=[O:35])[NH:30][CH2:31][CH2:32][C:33]#[CH:34])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[CH2:21]([O:28][C:29](=[O:35])[NH:30][CH2:31][CH2:32][C:33]#[C:34][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:10](=[O:19])[CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:20])=[CH:13][CH:14]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc(I)cc1
Reactant: C#CCCNC(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc(C#CCCNC(=O)OCc2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
To a solution of [2-(4-iodophenylcarbamoyl)ethyl]carbamic acid tert-butyl ester 310 (1.5 g, 3.84 mmol), and triethylamine (40 mL) was added trans-dichlorobis-(triphenylphosphine)palladium (II) (Ph3P, PdCl2, 0.27 g, 0.38 mmol). The reaction mixture was stirred for 20 minutes when it became a clear solution. But-3-ynyl-carbamic acid benzyl ester (0.94 g, 4.6 mmol) and copper iodide (0.14 g, 0.768 mmol) were then added and the reaction was further stirred at room temperature for 18 hours. The solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (100 mL) and washed with water (3×150 mL). The organic layer was dried over sodium sulfate and then concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 1:1, v/v hexanes/ethyl acetate) to provide 320 (1.91 g, still a mixture, but used as it was without further purification). 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 2.60 (m, 4H), 3.47 (m, 4H), 5.12 (s, 2H), 7.37 (m, 7H), 7.49 (d, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(-c2coc3cc(O)ccc3c2=O)c1
Solvent: c1ccncc1
Product: COc1cccc(-c2coc3cc(OC(C)=O)ccc3c2=O)c1

Procedure:
7-Acetoxy-3′-methoxyisoflavone was prepared from 7-hydroxy-3′-methoxyisoflavone (1.7 g, 6.3 mmol), acetic anhydride (6 ml) and pyridine (1.0 ml) as described for 4′,7-diacetoxydaidzein. Yield: (1.6 g, 81%) m.p. 118° C. 1H NMR (CDCl3): δ 2.36 (s, 3H, OCOCH3), 3.85 (s, 3H, OMe), 6.95 (dd, 1H, J 2.0 Hz 8.3 Hz, H6), 6.70-7.40 (m, 5H, ArH), 8.01 (s, 1H, H2), 8.32 (d, 1H, J 8.7 Hz, H5).
Reaction SMILES: [I:1][C:2]1[C:10](C)=CC=C[C:3]=1[C:4](O)=O.B.[O:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[I:1][C:2]1[CH:10]=[C:16]([CH2:17][OH:13])[CH:15]=[CH:14][C:3]=1[CH3:4]
Reactant: C1CCOC1
Reactant: Cc1cccc(C(=O)O)c1I
Agent: B
Product: Cc1ccc(CO)cc1I

Procedure:
To a solution of 5.0 g (19.1 mmol) of 2-iodo-3-methyl benzoic acid in 50 mL of anhydrous tetrahydrofuran, was slowly added 22 mL of a 1M borane solution in tetrahydrofuran. The resultant reaction mixture was reacted for approximately ninety minutes and then was quenched with ethanol resulting in the evolution of hydrogen gas. The mixture was diluted with ethyl acetate. The resulting layers were separated and the organic layer was washed sequentially with sodium bicarbonate and brine, dried over sodium sulfate, filtered and crystallized from a hexane/ethyl acetate mixture to provide 120 mg of the desired subtitled compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH:10](O)[CH2:11][S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:23][N:22]=2)[CH2:17][CH2:16]1)(=[O:14])=[O:13].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]/[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:22]=[CH:23][C:24]([O:27][CH2:28][C:29]([F:30])([F:31])[F:32])=[CH:25][N:26]=2)[CH2:17][CH2:16]1)(=[O:14])=[O:13]
Reactant: O=S(=O)(CC(O)CCCc1ncccn1)N1CCN(c2ncc(OCC(F)(F)F)cn2)CC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(/C=C/CCCc1ncccn1)N1CCN(c2ncc(OCC(F)(F)F)cn2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a stirred solution of the 5-pyrimidin-2-yl-1-({4-[5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl]piperazin-1-yl}sulfonyl)pentan-2-ol (9.10 g, 18.6 mmol), triethylamine (13 mL, 93.0 mmol) in DCM (200 mL) at 0° C. was added methanesulfonyl chloride (2.16 mL, 27.9 mmol). The reaction was stirred at 0° C. for 15 minutes, warmed to room temperature and stirred for 16 hours. The reaction mixture was then washed with water (200 mL) and the aqueous back extracted with DCM (200 mL). The combined DCM extracts were washed with brine (250 mL), dried (MgSO4), filtered and concentrated in vacuo to give 2-(4-{[(1E)-5-pyrimidin-2-ylpent-1-en-1-yl]sulfonyl}piperazin-1-yl)-5-(2,2,2-trifluoroethoxy)pyrimidine as an orange solid (8.79 g, 18.6 mmol, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].Cl[C:27]1[S:28][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:30][N:31]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[S:28][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:30][N:31]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:10]=1
Reactant: NS(=O)(=O)c1cnc(Cl)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Product: NS(=O)(=O)c1cnc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (355 mg, 1.0 mmol) and 2-chloro-thiazole-5-sulfonamide (199 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (270 mg, 52%). MS (ISN) 516.1 [(M−H)−]; mp 251° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2=[N:8][NH:9][C:10]([CH:11]3[CH2:14][CH:13]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[C:18]#N)[CH2:12]3)=[C:5]2[CH:4]([C:23]2[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=2[F:31])[CH2:3]1.CC(C)=[O:34].C(=O)=O.CC(C[AlH]CC(C)C)C>C(Cl)(Cl)Cl>[O:1]=[C:2]1[NH:7][C:6]2=[N:8][NH:9][C:10]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[CH:18]=[O:34])[CH2:14]3)=[C:5]2[CH:4]([C:23]2[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=2[F:31])[CH2:3]1
Reactant: CC(C)=O
Reactant: N#Cc1cccc(C2CC(c3[nH]nc4c3C(c3cc(F)c(F)cc3F)CC(=O)N4)C2)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Solvent: ClC(Cl)Cl
Product: O=Cc1cccc(C2CC(c3[nH]nc4c3C(c3cc(F)c(F)cc3F)CC(=O)N4)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3-{3-[6-oxo-4-(2,4,5-trifluoro-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-cyclobutyl}-benzonitrile (0.16 g, 0.34 mmol) in CHCl3 (5 mL) at −78° C. (acetone/CO2 bath) was added a solution of DIBAL-H (1.8 mL, 1M in CH2Cl2). After 30 min, the reaction was quenched cold with MeOH (1 mL), followed by a saturated aqueous solution of sodium and potassium tartrates. The reaction mixture was allowed to warm to room temperature and stirred for one hr. The reaction mixture was extracted with CHCl3, and the combined organic layers were dried over MgSO4. The organic layer was filtered, and concentrated under reduced pressure. Purification of this material was accomplished by MPLC using a 10 g ISCO column, eluting with 4% MeOH/CHCl3. The product-containing fractions were collected and concentrated to give the title compound. LRMS m/z (APCI+) 426 (M+1)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=3)[C:16]([OH:18])=O)[CH:12]=[C:6]2[C:5]=1[NH:22][C@@H:23]([CH:25]1[CH2:27][CH2:26]1)[CH3:24])(=[O:3])[NH2:2].[CH3:28][NH:29][CH3:30].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH:25]1([C@H:23]([NH:22][C:5]2[C:6]3[N:7]([CH:10]=[C:11]([C:13]4[CH:21]=[CH:20][CH:19]=[C:15]([C:16](=[O:18])[N:29]([CH3:30])[CH3:28])[CH:14]=4)[CH:12]=3)[N:8]=[CH:9][C:4]=2[C:1]([NH2:2])=[O:3])[CH3:24])[CH2:26][CH2:27]1
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3cccc(C(=O)O)c3)cc12)C1CC1
Reactant: CNC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3cccc(C(=O)N(C)C)c3)cc12)C1CC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
To a solution of (R)-3-(3-carbamoyl-4-(1-cyclopropylethylamino) pyrrolo[1,2-b]pyridazin-6-yl)benzoic acid (Example 85, 15 mg, 0.041 mmol), dimethylamine (0.021 mL, 0.041 mmol) and triethylamine (8.61 μl, 0.062 mmol) in DMF (0.5 mL) was added BOP (18.21 mg, 0.041 mmol) which was stirred at 23° C. for 30 minutes. The reaction mixture was purified by reverse-phase preparative HPLC (condition C) to yield the title compound (5.7 mg, 35%). HPLC (condition H): retention time=1.47 minutes. LC/MS (M+H)+=392.3. 1H NMR (500 MHz, MeOD) δ ppm 8.06 (1 H, s), 7.86 (1 H, d, J=1.9 Hz), 7.67-7.71 (1 H, m), 7.64 (1 H, t, J=1.4 Hz), 7.45 (1 H, t, J=7.6 Hz), 7.24-7.27 (1 H, m), 7.09 (1 H, d, J=1.7 Hz), 4.01-4.09 (1H, m), 3.13 (3 H, s), 3.04 (3 H, s), 1.44 (3 H, d, J=6.4 Hz), 1.09-1.18 (1 H, m), 0.57 (2H, dd, J=13.5, 8.7 Hz), 0.34-0.41 (2 H, m).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6](=[N:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)SC)(=[O:4])=[O:3].S(Cl)([Cl:21])(=O)=O>C(OCC)(=O)C>[CH3:1][S:2]([NH:5][C:6]([Cl:21])=[N:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(Cl)Cl
Reactant: CSC(=Nc1ccc(Cl)c(Cl)c1)NS(C)(=O)=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC(Cl)=Nc1ccc(Cl)c(Cl)c1

Procedure:
The N-methylsulphonyl-N'-(3,4-dichlorophenyl)-S-methylisothiourea (150 g) obtained in the manner described was suspended in 250 ml of ethyl acetate, and 45 ml of sulphonyl chloride (0.55 mole) was added dropwise to the suspension at a temperature of 50° C. The solvent as well as the formed methanesulphonyl chloride and unreacted sulphonyl chloride was distilled off in the Rotovap, and the crystallising residue was taken up in hexane. After filtration with suction, the resulting N-methylsulphonyl-N'-(3,4-dichlorophenyl)-chloroformamidine had a melting oint of 154° - 156° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][N:9]=1.[OH-].[Na+].C(O)(=O)C>O1CCOCC1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1
Reactant: COC(=O)c1ccc(-c2ccccc2O)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2ccccc2O)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
Methyl 6-(2-hydroxyphenyl)nicotinate (1.13 g, 4.9 mmol) was dissolved in 1,4-dioxane (10.0 ml) and 1N aqueous NaOH (12.0 ml) added. The resulting solution was stirred at r.t. for 16 h. This solution was then acidified to pH 4-5 with glacial acetic acid and concentrated under reduced pressure to 5 ml volume. This solution was diluted with water (30 ml) and the resulting precipitate filtered, washed with water (10 ml) and dried to give the title compound as a yellow solid (0.77 g) (72%). 1H NMR (400 MHz, DMSO-d6) □ ppm 9.07 (1H, s), 8.39-8.34 (1H, m), 8.30-8.25 (1H, m), 8.06-7.99 (1H, m), 7.36-7.29 (1H, m), 6.96-6.89 (2H, m). LRMS: ES m/z 216 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([OH:24])=[CH:11][CH:10]=3)[CH3:2].CS(C)=O.[OH-].[K+].Br[CH:32]([CH3:38])[C:33]([O:35]CC)=[O:34]>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([O:24][CH:32]([C:33]([OH:35])=[O:34])[CH3:38])=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(NCC3CCCCC3)c3cc(O)ccc3nc21
Reactant: CCOC(=O)C(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(OC(C)C(=O)O)ccc3nc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 1-ethyl-6-hydroxy-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine (0.5 g, 1.5 mmol), DMSO (5 ml) and KOH (0.5 g) is stirred at room temperature for 20 minutes, then ethyl 2-bromopropionate (0.2 ml) is added, and the mixture is stirred overnight. The reaction mixture is poured into 10 volumes of water, extracted with CH2Cl2 (2×10 ml), and the aqueous layer is acidified with acetic acid. A precipitate forms which is collected by filtration, dissolved in methanol and filtered. The filtrate is allowed to stand, and the product that precipitates is collected by filtration and dried to afford 180 mg of 1-ethyl-6-(1-carboxyethoxy)-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine. 1/4 Hydrate, m.p. 280° C. (dec.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=O)[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:16][CH3:17].CN(C=O)C.S(Cl)([Cl:25])=O>>[Cl:25][C:9]1[C:8]2[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][Cl:1])=[C:6]([O:16][CH3:17])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCl
Temperature: 80 °C
Yield: 59 %

Procedure:
7-(2-Chloroethoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (5 g, 19 mmol) was suspended in thionyl chloride (28 mL) and DMF (0.7 mL) was added. The mixture was heated at 80° C. for 1.5 hours under anhydrous conditions. The excess thionyl chloride was evaporated off and toluene was added to remove the last traces by azeotropic distillation (repeated twice). The solid was suspended in ice-water and the pH adjusted to 7.5 with sodium hydroxide 2N first then with a saturated sodium hydrogen carbonate solution. The solid was collected by filtration, washed with water, ether and dried over P2O5 under vacuum. The crude product was purified by flash chromatography using dichloromethane/acetonitrile (95/5 up to 90/10). Evaporation of the solvent gave 4-chloro-7-(2-chloroethoxy)-6-methoxyquinazoline (3.06 g, 59%).
Reaction SMILES: O=[C:2]1[CH:8]([CH2:9][C:10](O)=[O:11])[CH2:7][CH2:6][S:5][C:4]2[S:13][CH:14]=[CH:15][C:3]1=2.O.[NH2:17][NH2:18]>C(O)C>[N:17]1[NH:18][C:10](=[O:11])[CH2:9][CH:8]2[CH2:7][CH2:6][S:5][C:4]3[S:13][CH:14]=[CH:15][C:3]=3[C:2]=12
Reactant: O=C(O)CC1CCSc2sccc2C1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1CC2CCSc3sccc3C2=NN1
Yield: 71.2 %

Procedure:
A suspension of 2.0 g of 4-oxo-4,5,6,7-tetrahydrothieno[2,3-b]thiepin-5-acetic acid and 0.6 g of hydrazine hydrate in 20 ml of ethanol is refluxed under heating for 5 hours. After cooling, the precipitated crystals are collected by filtration and recrystallized from a mixed solvent of chloroform and ethanol to give 1.4 g of 4,4a,5,6-tetrahydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as white crystals, melting at 215°-217° C.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[C:24]3[C:25]([CH3:30])=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=3[S:22][N:21]=2)[C:11]1=[O:31])[CH2:7][CH2:8][CH3:9])C.O.[Li+].[OH-]>O1CCOCC1>[CH3:30][C:25]1[C:24]2[C:20]([CH2:19][N:12]3[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:32])=[O:3])[C:11]3=[O:31])=[N:21][S:22][C:23]=2[CH:28]=[C:27]([CH3:29])[CH:26]=1
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2nsc3cc(C)cc(C)c23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2nsc3cc(C)cc(C)c23)c2ccccc21
Reaction time: 4 h

Procedure:
To a solution of product 3-[3-(4,6-Dimethyl-1,2-benzisothiazol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (23 mg, 0.051 mmol)) in 1,4-dioxane (5 mL) and water (1 mL) was added LiOH (2.4 mg, 0.1 mmol) at room temperature. The solution was stirred at the same temperature for 4 hours. The solution was concentrated and water was added to the residue. The solution was acidified by 12N HCl in an ice-bath. The solid that preciptate out from the solution was collected by filtration. The solid was dried under vacuum and was confirmed to be the desirable product (10 mg, 46%). LCMS (ESMS): m/z 424.18 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C@@H:4]([NH:18][CH2:19][CH2:20][N:21]([CH2:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([Cl:32])[CH:23]=1)[CH2:5][CH2:6][C:7]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C@H:11]([OH:17])[CH2:10]1)=[O:8].[ClH:43]>O1CCOCC1.O>[ClH:32].[ClH:43].[CH3:1][O:2][C:3](=[O:42])[C@@H:4]([NH:18][CH2:19][CH2:20][N:21]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[C:24]([Cl:32])[CH:23]=1)[CH2:5][CH2:6][C:7]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:13][CH2:14]2)[C@H:11]([OH:17])[CH2:10]1)=[O:8]
Reactant: COC(=O)[C@H](CCC(=O)N1CCC2(CC2)[C@H](O)C1)NCCN(CCC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)[C@H](CCC(=O)N1CCC2(CC2)[C@H](O)C1)NCCN(CCC(=O)O)c1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 184.5 %

Procedure:
A solution of 0.47 g (0.8 mmol) of (S)-2-{2-[(2-tert-butoxycarbonyl-ethyl)-(3-chloro-4-trifluoromethyl-phenyl)-amino]-ethylamino}-5-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-5-oxo-pentanoic acid methyl ester in 2.2 ml of dioxan was cooled (10° C.), treated with 1.9 ml (7.6 mmol) of HCl solution (4 M in dioxane), 2 drops of water and stirred at RT for 22 h. The solution was evaporated, suspended in acetonitrile and evaporated (3×) to yield 0.47 g (92%) of the title compound as light yellow foam. MS (LC/MS): 564 (MH+, Cl).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][C:21]=1Br>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:21]1[CH:22]=[C:23]([S:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])[CH:24]=[CH:25][C:20]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)N2CCOCC2)cc1Br
Product: Cc1ccc(S(=O)(=O)N2CCOCC2)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Yield: 81 %

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 1-(3-bromo-4-methylphenylsulfonyl)morpholine (Combiblocks), the title compound was obtained as a yellow sticky solid in 81% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[S:9][C:8]([CH3:16])([CH3:15])[CH2:7][C:6]2=[O:17])#[CH:2].I[C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1>CCN(CC)CC.C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:16][C:8]1([CH3:15])[CH2:7][C:6](=[O:17])[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([C:1]#[C:2][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)[CH:4]=2)[S:9]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1cc2c(cc1OC)SC(C)(C)CC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2cc3c(cc2OC)SC(C)(C)CC3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A solution of 6-ethynyl-7-methoxy-2,2-dimethylthiochroman-4-one (Compound 208, 217.0 mg, 0.88 mmol) and ethyl 4-iodobenzoate (245.0 mg, 0.89 mmol) in 10.0 mL Et3N and 2 mL THF was purged with argon for 15 minutes. To this solution was added bis(triphenylphosphine)-palladium(II) chloride (154.0 mg, 0.22 mmol) and copper(I) iodide (42.0 mg, 0.22 mmol). After sparging for an additional 10 minutes with argon, the solution was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and filtered through a pad of Celite using an EtOAc wash. Concentration of the filtrate under reduced pressure, followed by column chromatography (5 to 10% EtOAc/hexanes) of the residual solid afforded 320.0 mg (92%) of the title compound as an orange solid. 1H NMR (300 MHz, CDCQ3)δ: 8.29 (1H, s), 8.03 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=8.4 Hz), 6.70 (1H, s), 4.40 (2H, q, J=7.1 Hz), 3.96 (3H, s), 2.86 (2H, s), 1.50 (6H, s), 1.41 (3H, t, J=7.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH:28]1[O:32][CH2:31][CH2:30][O:29]1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH:28]2[O:32][CH2:31][CH2:30][O:29]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: BrCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCC2OCCO2)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.8 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (200 mg, 0.73 mmol) was suspended in dimethylformamide (80 ml). To the suspension were added potassium carbonate (150 mg, 1.1 mmol) and 2-bromomethyl-1,3-dioxolane (0.11 ml, 1.1 mmol) in order. The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (73 mg, yield 28%).
Reaction SMILES: NC(N)=O.[CH2:5]([NH:8][S:9]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=1[OH:20])(=[O:11])=[O:10])[CH2:6][CH3:7].[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>>[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29]([NH:19][C:14]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([S:9]([NH:8][CH2:5][CH2:6][CH3:7])(=[O:11])=[O:10])[C:13]=1[OH:20])=[O:30]
Reactant: CCCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: O=C=Nc1ccccc1Br
Agent: NC(N)=O
Product: CCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Br)c1O
Yield: 45.4 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-propyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (186 mg, 0.71 mmol) and 2-bromophenylisocyanate (140 mg, 0.71 mmol) were coupled to form the desired urea (149 mg, 46%). LC-MS (m/z) 464.0 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C:18]3([CH2:21][CH2:22]Br)[CH2:20][CH2:19]3)=[C:8]2[CH3:24])=[CH:4][CH:3]=1.[C-:27]#[N:28].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C:18]3([CH2:21][CH2:22][C:27]#[N:28])[CH2:19][CH2:20]3)=[C:8]2[CH3:24])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(C1(CCBr)CC1)c(C)n2Cc1ccc(Br)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(C1(CCC#N)CC1)c(C)n2Cc1ccc(Br)cc1
Temperature: 75 °C
Yield: 97.2 %

Procedure:
To a r.t. solution of bromide from Step 9 (166 mg, 0.35 mmol) in 4 mL DMF was added NaH2PO4H2O (138 mg, 1 mmol) followed by NaCN (49 mg, 1 mmol) and the resulting mixture was warmed to 75° C. for 2 h. After diluting with excess H2O, the mixture was extracted with Et2O. The organic layer was washed with brine, dried over MgSO4 and evaporated to provide 144 mg of the title compound.