Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[S:12][C:11]([S:13]([NH:16][CH:17]([CH:22]2[CH2:27][CH:26]3[CH:24]([C:25]3([F:29])[F:28])[CH2:23]2)[C:18](OC)=[O:19])(=[O:15])=[O:14])=[CH:10][CH:9]=1>C1COCC1>[Cl:7][C:8]1[S:12][C:11]([S:13]([NH:16][CH:17]([CH:22]2[CH2:27][CH:26]3[CH:24]([C:25]3([F:29])[F:28])[CH2:23]2)[CH2:18][OH:19])(=[O:14])=[O:15])=[CH:10][CH:9]=1
Reactant: COC(=O)C(NS(=O)(=O)c1ccc(Cl)s1)C1CC2C(C1)C2(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(NC(CO)C1CC2C(C1)C2(F)F)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
To a slurry of LAH (0.030 g, 0.78 mmol) in THF (5 mL) was added methyl {[(5-chlorothien-2-yl)sulfonyl]amino}(6,6-difluorobicyclo [3.1.0]hex-3-yl)acetate (0.154 g, 0.38 mmol) dropwise at 0° C. over 20 min. The slurry (gray) was allowed to warm to 25° C. over 19 h. The reaction slurry was cooled to 0° C. and the reaction was quenched with H2O (0.5 mL), 1N NaOH (1.5 mL) and H2O (0.5 mL). The reaction was stirred 4 h to obtain a white slurry. The slurry was filtered and the mother liquor was further dried over MgSO4, filtered, and concentrated in vacuo to obtain a crude yellow oil (0.162 g). The crude product was purified by the Biotage Flash™ 40 chromatography system, eluent: 1:4 EtOAc-hexanes, to afford 5-chloro-N-[1-(6,6-difluorobicyclo[3.1.0]hex-3-yl)-2-hydroxyethyl]thiophene-2-sulfonamide as a colorless oil (0.105 g, 77.77%).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14](B(O)O)=[CH:15][CH:16]=2)[C:11]([CH3:21])=[CH:10][C:9]1([CH3:23])[CH3:22])=O)(C)(C)C.BrC1C=C(C#N)SC=1>>[CH3:22][C:9]1([CH3:23])[CH:10]=[C:11]([CH3:21])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:8]1
Reactant: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(B(O)O)cc21
Agent: N#Cc1cc(Br)cs1
Product: CC1=CC(C)(C)Nc2ccccc21
Yield: 146.6 %

Procedure:
This compound was prepared by General Method 2 from compound 9 (200 mg, 0.63 mmol) and 4-bromo-2-cyanothiophene (0.50 g, 2.65 mmol). The crude product was purified by prep. TLC (20×20 cm, 1000 μm, 25% ETOAc:Hexane) to afford 160 mg (91%) of Compound 452 as a yellow oil. Data for Compound 452: Rf 0.50 (silica gel, 25% EtOAc:hex); 1H NMR(400 MHz, CDCl3) 7.79 (s, 1H), 7.46 (s, 1H), 7.20 (s, 1H), 7.16 (d, J=8.3, 1H), 6.46 (d, J=8.3, 1H), 2.03 (s, 3H), 1.31 (s, 6H); IR (film, NaCl) 1159, 1381, 1402, 1449, 1476, 1499, 1609, 1653, 2216, 2915, 3294, 3584.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([OH:14])(=O)[CH3:12].N1C2C=CC=CC=2NC=1.[NH2:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28]>C1COCC1>[NH2:28][C:27]1[C:26]2[C:25](=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH:24][C:11](=[O:14])[CH:12]=1
Reactant: N#Cc1ccccc1N
Reactant: CC(=O)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: c1ccc2[nH]cnc2c1
Solvent: C1CCOC1
Product: Nc1cc(=O)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
LiHMDS (3-4 eq) was added to the benzimidazole acetate (1.0 eq) in THF (at a constant temperature ranging from −78° C. to 0° C). After 20 minutes, a solution of the 2-aminobenzonitrile (1.1 eq) in THF was then added. The resulting mixture was allowed to warm to room temperature, stirred for 1-3 hours and was then heated to approx. 40° C. −65° C. (1 hour to 12 hours). The mixture was cooled to 0° C. and quenched with NH4Cl (aq, saturated). The aqueous phase was extracted with CH2Cl2 or EtOAc, and the organic extracts were collected, dried (Na2SO4), and filtered. Evaporation of the solvent under reduced pressure and purification of the residue by silica gel chromatography or HPLC provided the 4-amino quinolinone products.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([N:22]=O)[CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>CO.O.[Cl-].[Ti+3].[Cl-].[Cl-]>[C:17]([O:16][C:15]([NH:14][CH2:13][CH2:12][N:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[NH2:22])=[O:21])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCN(CCNC(=O)OC(C)(C)C)N=O
Agent: [Ti+3]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCN(N)CCNC(=O)OC(C)(C)C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl N-{2-[(2-{[(tert-butoxy)carbonyl]amino}ethyl)(nitroso)amino]ethyl}carbamate LIV (2 g; 6.02 mmol) in methanol (15 mL) was added a solution of titanium (III) chloride (3.7 g; 24.07 mmol) in water (20 mL). The mixture was stirred for 1.5 h and then cooled in a ice/water bath before adding KOH (12 g) in portions for 40 min. Stirring was continued for an additional 1 h at r.t. The reaction was filtered, solvent evaporated and purified on a silica gel column (1:1 chloroform/methanol) to obtain crude tert-butyl N-{2-[1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)hydrazin-1-yl]ethyl}carbamate LV (0.85 g) used directly for step 5. ESIMS found for C15H32N3O4 m/z 319.4 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([S:19][C:20]3[CH:21]=[C:22]([C:26]4([C:32]#[N:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:23]=[CH:24][CH:25]=3)=[CH:7][CH:8]=2)[N:3]=1.CCN(C(C)C)C(C)C.Cl[CH2:44][C:45](Cl)=[O:46]>C(Cl)Cl.O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([S:19][C:20]4[CH:21]=[C:22]([C:26]5([C:32]#[N:33])[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)[CH:23]=[CH:24][CH:25]=4)=[CH:7][CH:8]=3)[N:3]3[CH2:44][C:45](=[O:46])[N:1]=[C:2]3[CH:11]=2)=[CH:13][CH:14]=1
Reactant: O=C(Cl)CCl
Reactant: N#CC1(c2cccc(Sc3ccc4c(-c5ccc(F)cc5)cc(N)nc4c3)c2)CCOCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#CC1(c2cccc(Sc3ccc4c(c3)N3CC(=O)N=C3C=C4c3ccc(F)cc3)c2)CCOCC1
Temperature: 25 °C

Procedure:
To 3e (120 mg, 0.26 mmol) in CH2Cl2 (3 mL) was added iPr2NEt (0.12 mL, 0.66 mmol), followed by chloroacetyl chloride (0.03 mL, 0.40 mmol), and the reaction was stirred at room temperature. Once complete, the reaction was diluted with water, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was dissolved in C2H4Cl2. iPr2NEt (0.12 mL, 0.66 mol) was added, and the reaction was sealed and heated to 80° C. overnight. After cooling to room temperature, the reaction was concentrated and purified by preparative HPLC to give the desired product.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[C:9]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:8][N:7]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39]>C(#N)C.[Cu]I.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>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([C:42]#[C:41][Si:38]([CH3:40])([CH3:39])[CH3:37])[C:9]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:8][N:7]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(COc2cnc(COC(C)=O)cc2OS(=O)(=O)C(F)(F)F)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(COc2cnc(COC(C)=O)cc2C#C[Si](C)(C)C)cc1
Temperature: 45 °C
Yield: 95.8 %

Procedure:
(5-({[4-(Methyloxy)phenyl]methyl}oxy)-4-{[(trifluoromethyl)sulfonyl]oxy}-2-pyridinyl)methyl acetate (10 g, 23 mmol) (for a synthesis see WO2004058144, Example 60(d)) was dissolved in acetonitrile (400 ml) and triethylamine (65 ml) and treated with trimethylsilyl acetylene (10 ml, 69 mmol). The mixture was then degassed several times and put under an atmosphere of argon. Copper(I) iodide (0.44 g, 2,3 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.645 g, 0.9 mmol) was added and the mixture heated at 45° C. for 18 h. The mixture was allowed to cool and filtered. The filtrate was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was dried then evaporated to dryness. Chromatography on silica gel eluting with 40-60 petrol and ethyl acetate gradient provided the desired compound (8.45 g, 96%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[N:7][C:6]([CH3:9])=[CH:5][N:4]=1.C([N:18]=[C:19]=[S:20])(=O)C1C=CC=CC=1.N>CO>[CH3:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][NH:1][C:19]([NH2:18])=[S:20])=[N:4][CH:5]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1cnc(CN)cn1
Agent: N
Solvent: CO
Product: Cc1cnc(CNC(N)=S)cn1
Yield: 91 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 12(a) by using 2-(aminomethyl)-5-methylpyrazine (1.00 g, 7.89 mmol), benzoyl isothiocyanate (1.20 mL, 8.90 mmol) and ammonia in methanol (7 N, 27 mL) with the exception that the crude product isolated by filtration (1.30 g, 91% yield) was used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:2]=1.[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=O)[NH:33][C:32]=2[CH3:39])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=[C:14]3[C:13]4[C:17](=[CH:18][CH:19]=[C:11]([S:8](=[O:10])(=[O:9])[NH:7][C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)[CH:12]=4)[NH:16][C:15]3=[O:20])[NH:33][C:32]=2[CH3:39])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1Cc2cc(S(=O)(=O)Nc3cccnc3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(S(=O)(=O)Nc4cccnc4)cc32)c(C)c1C(=O)NCCN1CCCC1
Yield: 73.9 %

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid pyridin-3-ylamide (110 mg, 0.38 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (100 mg) to give 150 mg (74%) of the title compound as an orange solid.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][CH3:20])[CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:21].N(C(C)C)(C(C)C)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33].O>C(Cl)Cl.N1C=CC=CC=1.C(OCC)(=O)C>[CH3:20][N:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:21])[N:3]([CH3:2])[CH:12]=2)[CH:14]=1)[S:32]([CH3:31])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CNc1cccc(-c2cn(C)c(=O)c3ccccc23)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1cccc(-c2cn(C)c(=O)c3ccccc23)c1)S(C)(=O)=O
Reaction time: 0.75 h
Yield: 50 %

Procedure:
To the title compound of Example 32 (35 mg, 0.12 mmol) in anhydrous CH2Cl2 (0.3 mL), pyridine (0.1 mL) and NEtiPr2 (0.021 mL, 0.12 mmol) was added methanesulfonyl chloride (0.011 mL, 0.14 mmol). After 0.5-1 h, ice was added to the mixture followed by water and ethyl acetate. Extractive work up, washing with H2O, a 1:1 aqueous saturated KHSO4:H2O, and brine, and purification on silica gel eluting with 35-80% EA in hexane over 6 min and continuing 80% isocratic EA gave the title compound (22 mg, 0.06 mmol) as a cream solid in 54% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.00 (s, 3H), 3.30 (s, 3H), 3.58 (s, 3H), 7.40 (d, J=7.58 Hz, 1H), 7.45-7.61 (m, 6H), 7.71 (td, J=7.58, 1.26 Hz, 1H), 8.34 (dd, J=8.21, 1.14 Hz, 1H). LCMS (M+H)+ 343.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C.C(OC(=O)C)(=O)C>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.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCC(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)OC(C)=O
Product: C=CCCCCCCC
Temperature: 255 °C
Yield: 867.3 %

Procedure:
A mixture of decanoic acid (100 g, 0.580 mol), acetic anhydride (59.2 g, 0.580 mol), dichlorobis(triphenylphosphine)palladium (0.0407 g, 5.8×10-5 mol), and triphenylphosphine (1.52 g, 5.9×10-3 mol) was heated under a slow stream of nitrogen using an oil bath maintained at 255° C. Upon reaching a reaction temperature of ca. 130° C., the acetic acid and/or acetic anhydride distilled out of the reactor into a receiver. When the reaction temperature reached 180°-190° C. decarbonylation initiated, as evidenced by the rapid liberation of gas, and 1-nonene product was distilled from the reactor. The olefin product was removed as rapidly as possible from the reactor. As material distilled from the reactor, it was continuously replaced with an equimolar mixture of decanoic acid and acetic anhydride in a rate that maintained the initial level of the reactor contents throughout the course of the entire reaction. The decarbonylation reaction proceeded rapidly until the reaction temperature reached ca. 245° C. (ca. 40 minutes reaction time), at which point the generation of gas from the reaction had ceased. The reactor was cooled and recharged with another equal portion of Pd-catalyst, heated to 255° C., and the 1-nonene product collected as before. A total of 11 consecutive runs were carried out in this fashion (occasionally adding additional triphenylphosphine as well), using a total of 0.448 g of dichlorobis(triphenylphosphine)palladium and 2.28 g of triphenylphosphine. The combined product was washed sequentially with water, 3N sodium hydroxide, and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. Distillation afforded 635 g of 1-nonene (bp 144°-145° C./760 torr), which GC analysis showed to be 97.1% of the α-olefin. TON=7885.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:42])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:41])[CH2:27][CH:28]=[C:29]([F:40])[C:30]([F:39])([F:38])[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33].[BH4-].[Na+]>CO>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:42])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:41])[CH2:27][CH:28]=[C:29]([F:40])[C:30]([F:38])([F:39])[C:31]([F:36])([F:37])[C:32]([F:33])([F:34])[F:35]
Reactant: CN(CC=C(F)C(F)(F)C(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(CC=C(F)C(F)(F)C(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 4.9 %

Procedure:
1.7 g of 11β-fluoro-3-hydroxy-7α-{5-[methyl-(3,4,4,5,5,6,6,6-octafluoro-hex-2-enyl)-amino]-pentyl}-estra-1,3,5(10)-trien-17-one is dissolved in 15 ml of methanol and carefully mixed with 222 mg of sodium borohydride. After 15 minutes of stirring at room temperature, the batch is added to saturated common salt solution, extracted with methylene chloride, dried on magnesium sulfate and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with ethyl acetate as an eluent, 84 mg of 11β-fluoro-7α-{5-[methyl-(3,4,4,5,5,6,6,6-octafluoro-hex-2-enyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol with a melting point of 130° C. is obtained.
Reaction SMILES: C(CC[C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[S:19][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)(O)=O.[C:24]([CH2:27]CCC1C=CC(S(C2SC(S(N)(=O)=O)=CC=2)(=O)=O)=CC=1)([OH:26])=[O:25]>>[C:24]([CH2:27][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[S:19][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:17][CH:16]=2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)([OH:26])=[O:25]
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)c2ccc(CCC(=O)O)cc2)s1
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)c2ccc(CCCC(=O)O)cc2)s1
Product: NS(=O)(=O)c1ccc(S(=O)(=O)c2ccc(CC(=O)O)cc2)s1

Procedure:
In a similar manner 5-[4-(2-carboxyethyl)phenylsulfonyl]thiophene-2-sulfonamide (m.p. 195°-197° C.) and 5-[4-(3-carboxypropyl)phenylsulfonyl]thiophene-2-sulfonamide (m.p. 124°-126° C.) were synthesized.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][C:12](=[O:15])[CH:13]=[CH2:14])[CH:5]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([O:23][C:24](=[O:38])[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:19][CH2:18]1>CCO>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][C:12](=[O:15])[CH2:13][CH2:14][N:17]2[CH2:18][CH2:19][CH:20]([O:23][C:24](=[O:38])[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:21][CH2:22]2)[CH:5]=1
Reactant: C=CC(=O)CNc1cccc(C(=O)OC)c1
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Solvent: CCO
Product: COC(=O)c1cccc(NCC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c1
Yield: 45 %

Procedure:
A stirred solution of 3-(acryloylmethylamino)benzoic acid methyl ester (estimated ˜56 mmol) and biphenyl-2-ylcarbamic acid piperidin-4-yl ester (16.6 g, 56.0 mmol) in EtOH (20.0 mL) was heated at 90° C. overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel flash chromatography (0-10% MeOH in DCM) to give the title compound (13.0 g, 45% yield) as an off-white solid.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([CH2:25][CH:26]([CH3:28])[CH3:27])=[N:15][N:16]4[C:21](S(C)=O)=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C1(N)CCCC1>[CH:1]1([NH:6][C:21]2[N:16]3[N:15]=[C:14]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:13]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[N:12]=4)=[C:17]3[CH:18]=[CH:19][CH:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)Cc1nn2c(S(C)=O)cccc2c1-c1ccnc(NC2CCCC2)n1
Agent: NC1CCCC1
Product: CC(C)Cc1nn2c(NC3CCCC3)cccc2c1-c1ccnc(NC2CCCC2)n1
Temperature: 25 °C
Yield: 158.7 %

Procedure:
A solution of N-cyclopentyl-4-[2-isobutyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-amine (110 mg, 0.28 mmol) in cyclopentylamine (5 mL) was heated at 130° C. for 72 h. The mixture was cooled to room temperature and concentrated in vacuo and the residue was purified by flash chromatography on silica gel (hexane-ethyl acetate) to give N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-isobutylpyrazolo[1,5-a]pyridin-7-amine (93 mg, 81%) as a White solid. 1H NMR (CDCl3) δ 8.20 (d, 1H), 7.50 (d, 1H), 7.21 (t, 1H), 6.74 (d, 1H), 5.97–5.92 (m, 2H), 5.09 (d, 1H), 4.38 (m, 1H), 3.96 (m, 1H), 3.01 (d, 2H), 2.27–2.04 (m, 5H), 1.81–1.50 (m, 12H), 0.97 (d, 6H); MS m/z 419 (M+1).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[N:15]=[C:14]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:5])C.[OH-].[Na+]>>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[N:15]=[C:14]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCCCCCCn1c(-c2ccccc2)nc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2nc(-c3ccccc3)n(CCCCCCCC(=O)O)c2-c2ccc(OC)cc2)cc1
Yield: 21.2 %

Procedure:
1-(7-Ethoxycarbonylheptyl)-4,5-bis(4-methoxyphenyl)-2-phenylimidazole (10 g) was reacted with 2N sodium hydroxide in a method similar to Example 10. The aqueous reaction mixture was evaporated to dryness in vacuo and the residue was mixed with ethanol (150 ml) and insoluble material was filtered off. The filtrate was evaporated to dryness and the residue was purified by column chromatography on silica gel eluted with a dichloromethane:methanol gradient. Further purification on Amberlite resin IRA-400 eluted with a methanol:water to methanol:2N HCl gradient and recrystallisation from ethanol gave 1-(7-carboxyheptyl)-4,5-bis(4-methoxy-phenyl)-2-phenylimidazole (2.01 g, 21%) as a white solid, m.p. 149°-150°. Found: C, 74.50; H, 6.75; N, 5.69%; C31H34N2O4 0.5% w/w C2H5OH requires: C, 74.56; H, 6.90; N, 5.59%.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1([CH3:22])[CH2:16][C:15](=[O:17])[C:14]2[C:9](=[C:10]([CH3:21])[C:11]([CH3:20])=[C:12]([OH:19])[C:13]=2[CH3:18])[O:8]1)([CH3:4])([CH3:3])[CH3:2].[CH:23]1[CH:24]=[CH:25][C:26]2OCC[C:29](=O)[C:27]=2[CH:28]=1.C(Br)C1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH2:29]([O:19][C:12]1[C:13]([CH3:18])=[C:14]2[C:9](=[C:10]([CH3:21])[C:11]=1[CH3:20])[O:8][C:7]([CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:22])[CH2:16][C:15]2=[O:17])[C:27]1[CH:28]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC(C)(COC(C)(C)C)O2
Reactant: O=C1CCOc2ccccc21
Agent: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)C(=O)CC(C)(COC(C)(C)C)O2

Procedure:
3.5 g of the crude product from Example 4 were converted to the above chromanone, using 7 g of benzyl bromide, 3 of Na2CO3 and 15 ml of dimethylformamide, by a method similar to that of Example 9. Yield (after purification three times by chromatography): 20%; melting point: 51°-62° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=3)[CH:13]=[O:14])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([CH2:13][OH:14])[CH:15]=[CH:16][CH:17]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1cccc(-c2ccc3sccc3c2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: OCc1cccc(-c2ccc3sccc3c2)c1
Yield: 99 %

Procedure:
3-(1-Benzothien-5-yl)benzaldehyde (3.9 g, 16.4 mmol) was dissolved in ethanol (80 mL) and tetrahydrofuran (20 mL), and the mixture was ice-cooled. Sodium borohydride (0.62 g, 16.4 mmol) was added to this solution, and the mixture was stirred under ice-cooling for 3 hr. Aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The obtained oil was crystallized from ethyl acetate-hexane to give the title compound (3.9 g, yield 99%) as colorless prism crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH:17]1[C:22]([CH:23]=O)=[CH:21][C:20]2[O:25][CH2:26][O:27][C:19]=2[CH:18]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:23][C:22]3[CH:17]=[CH:18][C:19]4[O:27][CH2:26][O:25][C:20]=4[CH:21]=3)[CH2:15][CH2:16]2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(F)cc1)N1CCNCC1
Reactant: O=Cc1ccc2c(c1)OCO2
Product: O=C(Nc1ccc(F)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid (4-fluoro-phenyl)-amide and piperonal. 1H NMR (400 MHz, CDCl3): 7.29-7.24 (m, 2H), 6.98-6.92 (m, 2H), 6.85 (s, 1H), 6.77-6.71 (m, 2H), 6.56 (s, 1H), 5.95 (s, 2H), 3.50-3.45 (m, 6H), 2.45 (t, J=5.1 Hz, 4H).
Reaction SMILES: [N:1]([CH:4]([C:11]1[CH:15]=[CH:14][O:13][CH:12]=1)[C:5]1[S:9][CH:8]=[N:7][C:6]=1[CH3:10])=[N+]=[N-]>C(O)C.[Pd]>[O:13]1[CH:14]=[CH:15][C:11]([CH:4]([NH2:1])[C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH3:10])=[CH:12]1
Reactant: Cc1ncsc1C(N=[N+]=[N-])c1ccoc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ncsc1C(N)c1ccoc1

Procedure:
The product from Example 53 in ethanol was shaken with 10% palladium-on-charcoal under an atmosphere of hydrogen for 3 hours. The catalyst was filtered off and the filtrate was evaporated to dryness. Flash chromatography of the residue thus obtained gave the title compound.