Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: NCCCCC(=O)O
Product: O=C(O)CCCCN1C(=O)c2ccc(C(=O)O)cc2C1=O
Yield: 99.7 %

Procedure:
4-carboxyphthalic anhydride (1.0 g, 0.0052 mol) and 5-aminopentanoic acid (0.61 g, 0.0052 mol) were refluxed as above overnight. Crystallisation of the product from EtOH yielded 1.51 g (72%) of 103 as a white solid: mp=223° C.; Rf0.79 (A): Rf0.92 (C): Rf0.36 (D): IR (cm−1): 2750-3375 (OH), 3084 (C═CH), 2665 (C—H), 1767 (C═O), 1705 (bs, C═O), 1620 (C═C), 1486 (C═C), 1402 (CH2), 1382 (C—O), 1302 (C—O), 732 (C═CH); MS m/z (rel intensity) 291 (15), 290 (100).
Reaction SMILES: C([NH:5][S:6]([C:9]1([CH2:12][F:13])[CH2:11][CH2:10]1)(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[F:13][CH2:12][C:9]1([S:6]([NH2:5])(=[O:8])=[O:7])[CH2:11][CH2:10]1
Reactant: CC(C)(C)NS(=O)(=O)C1(CF)CC1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)C1(CF)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a round-bottom flask equipped with a stir bar was added N-(tert-butyl)-1-(fluoromethyl)cyclopropane-1-sulfonamide (5.66 g, 27.0 mmol) and trifluoroacetic acid (20 mL). The solution was stirred at room temperature for 18 h. The solution was concentrated in vacuo to afford a dark orange oil. The oil was treated with hexanes:EtOAc (4:1) upon which a solid crystallized. The crystals were collected via filtrated and residual solvent was removed in vacuo to afford 1-(fluoromethyl)cyclopropane-1-sulfonamide as a colorless, crystalline solid (3.5 g, 84%). 1H NMR (400 MHz, CDCl3) δ 4.79 (s, 1H), 4.67 (s, 1H), 3.28 (br. s., 2H), 1.63-1.56 (m, 2H), 1.16-1.10 (m, 2H).
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH2:6][CH2:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12.[BH4-].[Na+].C(O)C.C(OCC)(=O)C>C(O)C>[OH:21][CH:1]1[C:2]2[C:3](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:4](=[O:16])[N:5]1[CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCSc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(O)N1CCCSc1ccncc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.4 %

Procedure:
To a solution of 5.97 g (20.0 mmol) of 4-(3-phthalimidopropylthio)pyridine in 300 ml of ethanol, 1.51 g (40 mmol) of sodium borohydride was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off and saturated saline was added to the residue. The mixture was extracted with chloroform and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethanol/ethyl acetate =1:10 to give 3.27 g of the desired compound (54.4% yield, colorless crystals), mp. 132°-134° C. NMR (200 MHz, CDCl3) δ: 2.11 (2H, m), 2.97 (2H, m), 3.72 (2H, m), 5.83 (1H, s), 6.98 (2H, d, J=5.4 Hz), 7.47-7.67 (3H, m), 7.77 (1H, dd, J=7.6, 1.2 Hz), 8.02 (2H, m).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:13](=[O:15])[N:11]([CH3:12])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[CH:6]1.[C:18]1([S:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>>[C:18]1([S:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][N:5]3[C:14]4[C:13](=[O:15])[N:11]([CH3:12])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=4[N:7]=[CH:6]3)[CH2:30][CH2:29]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(SCCCN2CCNCC2)cc1
Reactant: Cn1c(=O)c2c(ncn2CCCCl)n(C)c1=O
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(=O)c2c(ncn2CCCN2CCN(CCCSc3ccccc3)CC2)n(C)c1=O

Procedure:
7-(3-Chloropropyl)-theophylline (1 mole) and 1-(3-phenylthiopropyl)-piperazine are refluxed for 24 hours in a 50% aqueous-alcoholic solution. On completion of the reaction, sodium hydroxide (1 mole) is then added. The mixture is extracted with methylene chloride and washed with water, after which the solvent is evaporated off and the residue is recrystallized from ethanol.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]([C:15]1[C:16]2[CH:17]=[CH:18][NH:19][C:20]=2[CH:21]=[CH:22][CH:23]=1)=[O:14].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>C(O)C>[CH3:25][C:24]([NH:28][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]([C:15]1[C:16]2[CH:17]=[CH:18][NH:19][C:20]=2[CH:21]=[CH:22][CH:23]=1)=[O:14])([CH3:27])[CH3:26]
Reactant: O=C(Nc1ccccc1OCC1CO1)c1cccc2[nH]ccc12
Reactant: CC(C)(C)N
Solvent: CCO
Product: CC(C)(C)NCC(O)COc1ccccc1NC(=O)c1cccc2[nH]ccc12

Procedure:
A solution of 2.8 g of the product from Step C for 1 hour in 40 ml of ethanol and 7.6 ml of tert-butylamine was heated at 80° C. under an inert atmosphere with stirring and after purification by chromatography over silica (eluent:ethyl acetate--triethylamine, 9-1, then chloroform-methanol 5-5), 3.05 g of N-[2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]phenyl]-1H-indol-4-carboxamide were obtained (amorphous beige--colored powder).
Reaction SMILES: [CH:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:18][CH2:17][C:14]3([O:16][CH2:15]3)[CH:13]([C:19]3([CH3:27])[CH:21]([CH2:22][CH:23]=C(C)C)[O:20]3)[CH:12]2[O:28][CH3:29])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:30]=[O+][O-]>CO.ClCCl>[CH:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:18][CH2:17][C:14]3([O:16][CH2:15]3)[CH:13]([C:19]3([CH3:27])[CH:21]([CH2:22][CH:23]=[O:30])[O:20]3)[CH:12]2[O:28][CH3:29])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[O+][O-]
Reactant: COC1C(OC(=O)NC2CCCCC2)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Solvent: CO
Solvent: ClCCl
Product: COC1C(OC(=O)NC2CCCCC2)CCC2(CO2)C1C1(C)OC1CC=O

Procedure:
To a solution of 6-cyclohexylcarbamoyloxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (70 mg) in a mixture of methanol (0.1 ml) and dichloromethane (5 ml) was passed through ozone for 13 minutes at -78° C. to give 6-cyclohexylcarbamoyloxy-5-methoxy-4-[2-methyl-3-formylmethyloxiranyl)-1-oxaspiro[2,5]octane in the reacting mixture. After babbling of nitrogen, methyl sulfide (0.2 ml) was added to the mixture at the same temperature. The mixture was stirred at -78° C. for 15 minutes and allowed to warm to 0° C. followed by the addition of carboethoxymethylene-triphenylphosphorane (150 mg). The mixture was stirred at ambient temperature for 18 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluted with a mixture of diethyl ether and n-hexane (1:1) to yield 6-cyclohexylcarbamoyloxy-4-[3-(3-ethoxycarbonyl-2-propenyl)-2-methyloxiranyl]-5-methoxy-1-oxaspiro[2,5]-octane (53 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12]O)[C:3]1=[O:14].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:28]1[C:40]2[NH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]=2[CH2:31][CH2:30][NH:29]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C(O)(=O)/C=C\C(O)=O>ClCCl.C(OCC)(=O)C>[CH2:28]1[C:40]2[NH:39][C:38]3[C:33]([C:32]=2[CH2:31][CH2:30][N:29]1[CH2:12][CH2:11][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:15])([CH3:1])[C:3]1=[O:14])=[CH:34][CH:35]=[CH:36][CH:37]=3
Reactant: CC1(C)C(=O)N(CCO)c2ccccc21
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Agent: CS(=O)(=O)Cl
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)C(=O)N(CCN2CCc3c([nH]c4ccccc34)C2)c2ccccc21
Temperature: 0 °C
Reaction time: 12 h

Procedure:
2-((3,3-Dimethyl)oxindolyl)ethanol and triethylamine (1.1 equivalent) were dissolved in dichloromethane, cooled to 0° C. under nitrogen with stirring and methanesulfonyl chloride (1 equivalent) was added. The mixture was stirred for 30 minutes, washed with cold dilute hydrochloric acid, dried (MgSO4), filtered and concentrated to dryness. The resulting oil was dissolved in acetonitrile and added to a solution of tetrahydro-β-carboline (1 equivalent) containing potassium carbonate (2.5 equivalent) and potassium iodide (0.1 equivalent). The reaction mixture was heated under reflux for three days under nitrogen. The solvent was removed under reduced pressure and the residue taken up in ethyl acetate. This solution was washed (×2) with water, dried (MgSO4), filtered and concentrated to dry under reduced pressure. Chromatography on silica gel (eluent ethyl acetate/methanol) gave an oil which was taken up in ethyl acetate. Maleic acid (1 equivalent) was added. The solution was refrigerated for 12 hours and the white crystals collected to given 1-(2-(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2-yl)-1-ethyl)-1,3-dihydro-3,3-dimethyl-2H-indol-2-one as its monomaleate salt, melting point 156°-158° C.
Reaction SMILES: [C:1]1(=[O:14])[C:6]2=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Br[C:16]1[CH:23]=[N:22][CH:21]=[C:20]([Br:24])[C:17]=1[CH:18]=[O:19].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:24][C:20]1[CH:21]=[N:22][CH:23]=[C:16]([N:2]2[CH2:3][CH2:4][N:5]3[C:13]4[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=4[CH:7]=[C:6]3[C:1]2=[O:14])[C:17]=1[CH:18]=[O:19]
Reactant: O=C1NCCn2c1cc1c2CCCC1
Reactant: O=Cc1c(Br)cncc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=Cc1c(Br)cncc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 100 °C
Yield: 59.6 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 101e (300 mg, 1.57 mmol), 3,5-dibromoisonicotinaldehyde (2) (517 mg, 1.96 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos, 120 mg, 0.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (180 mg, 0.2 mmol), Cs2CO3 (650 mg, 2 mmol), and 1,4-dioxane (8 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 6 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with DCM/MeOH (from 40:1 to 20:1) to afford 101f as a pale yellow solid (350 mg, 40%). MS: [M+H]+ 374.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][C:3]=1[C:21]#[C:22][CH2:23][CH2:24][CH2:25]O.[CH2:27]([NH:29][CH2:30][CH2:31][OH:32])[CH3:28]>>[CH2:27]([N:29]([CH2:25][CH2:24][CH2:23][C:22]#[C:21][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[F:1])[N:8]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:7][CH2:6]2)[CH2:30][CH2:31][OH:32])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)N2CCc3cc(C#CCCCO)c(F)cc32)cc1
Reactant: CCNCCO
Product: CCN(CCO)CCCC#Cc1cc2c(cc1F)N(S(=O)(=O)c1ccc(C)cc1)CC2

Procedure:
In analogy to example 16.13, 5-[6-Fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pent-4-yn-1-ol and 2-(ethylamino)ethanol instead of 2-(methylamino)ethanol were converted to yield 2-(Ethyl-{5-[6-fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pent-4-ynyl}-amino)-ethanol as a light yellow oil, MS: 445 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[C:9]2[C:10]([C:25]#[N:26])=[CH:11][C:12]([O:14][Si](C(C)C)(C(C)C)C(C)C)=[CH:13][C:8]=2[S:7][CH:6]=1.O.O.[F-].[K+]>CCO>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[C:9]2[C:10]([C:25]#[N:26])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: COC(=O)Cc1csc2cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C#N)c12
Agent: [F-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COC(=O)Cc1csc2cc(O)cc(C#N)c12
Yield: 79.5 %

Procedure:
To a mixture of methyl(4-cyano-6-((triisopropylsilyl)oxy)-1-benzothiophen-3-yl)acetate (1.92 g) and EtOH (30 mL) was added potassium fluoride dihydrate (0.448 g) at room temperature, and the mixture was refluxed for 30 min. The mixture was concentrated under reduced pressure. The residue was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with 0.1N HCl and brine, dried over MgSO4 and concentrated in vacuo. The residue was crystallized from EtOAc-hexane to give the title compound (0.935 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[N+](=[CH2:15])=[N-].CO>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([O:9][CH3:15])=[O:8])([O-:3])=[O:2]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-Nitrobenzoic acid (Aldrich)(1 g; 5.98 mmol; 1 eq.) is dissolved in toluene (15 ml). Timethylsilyl diazomethane in toluene and MeOH (1/1)(9.0 ml; 2 M; 17.95 mmol; 3 eq.) is added dropwise. The solution is stirred at rt for 1.5 h. Solvents are removed affording methyl 3-nitrobenzoate as a yellow powder (940.7 mg; 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[CH:34]1([NH2:37])[CH2:36][CH2:35]1>>[CH:34]1([NH:37][C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:31])[CH2:36][CH2:35]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: NC1CC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NC1CC1

Procedure:
5-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid was coupled with cyclopropylamine to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:40]#[N:41])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C@@H:34]3[CH2:38][CH2:37][CH2:36][O:35]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:39])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:40]#[N:41])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C@@H:34]3[CH2:38][CH2:37][CH2:36][O:35]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:39])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C[C@@H]2CCCO2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(C[C@@H]2CCCO2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
1612 mg (2.78 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydrofuran-2-yl]propanoyl}amino)benzoate (mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysed with TFA according to General Method 2. Yield: 1270 mg (purity 90%, 79% of theory)
Reaction SMILES: [CH3:1][Si:2]([CH3:55])([O:7][C@@H:8]1[C@H:12]([O:13][Si:14]([CH3:20])([CH3:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C@@H:11]([CH2:21][O:22][Si:23]([CH3:29])([CH3:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[O:10][C@H:9]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][C:33]([N:45]1[CH:49]=[C:48]([C:50]([O:52]CC)=[O:51])[CH:47]=[N:46]1)=[N:34][C:35]=2[NH:39][CH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)[C:3]([CH3:6])([CH3:5])[CH3:4].[OH-].[K+]>C(O)C>[CH3:55][Si:2]([CH3:1])([O:7][C@@H:8]1[C@H:12]([O:13][Si:14]([CH3:20])([CH3:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[C@@H:11]([CH2:21][O:22][Si:23]([CH3:28])([CH3:29])[C:24]([CH3:27])([CH3:26])[CH3:25])[O:10][C@H:9]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][C:33]([N:45]1[CH:49]=[C:48]([C:50]([OH:52])=[O:51])[CH:47]=[N:46]1)=[N:34][C:35]=2[NH:39][CH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)[C:3]([CH3:4])([CH3:5])[CH3:6]
Reactant: CCOC(=O)c1cnn(-c2nc(NC3CCCC3)c3ncn([C@@H]4O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]4O[Si](C)(C)C(C)(C)C)c3n2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)nc(-n4cc(C(=O)O)cn4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
2.75 g of ethyl 1-(9-{(2R,3R,4R,5R)-3,4-bis(1,1,2,2-tetramethyl-1-silapropoxy)-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]oxolan-2-yl}-6-(cyclopentylamino)purin-2-yl)pyrazole-4-carboxylate prepared as described in Example 11A and 0.5 g KOH were stirred in 50 mL of ethanol at room temperature overnight. In the morning the mixture was refluxed for 1.5 hours. After reflux, the product was concentrated and the residue dissolved in 30 mL of water and acidified to a pH of 2.0 using a 2N aqueous HCl solution. The product was then extracted with ethyl acetate and the combined organic layers were dried over Na2SO4. The solvent was removed by evaporation and the product purified using a graduated, 2:3 to 3:2 ethyl acetate/hexane column to provide 1-(9-{(2R,3R,4R,5R)-3,4-bis(1,1,2,2-tetramethyl-1-silapropoxy)-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]oxolan-2-yl}-6-(cyclopentylamino)purin-2-yl)pyrazole-4-carboxylic acid.
Reaction SMILES: Br.Cl[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1.[O-:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+].O>CN1C(=O)CCC1>[O:13]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1nnc2ccc(Cl)nn12
Reactant: [O-]c1ccccc1
Agent: Br
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1nnc2ccc(Oc3ccccc3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.001; 200 mg) were initially charged dissolved in NMP (4 ml). Thereafter, sodium phenoxide (185 mg) was introduced at RT. After stirring at RT for one hour, the reaction was completed by heating to 55° C. for 2 h. Subsequently, the mixture was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. The crude product was purified using silica gel with a dichloromethane/methanol gradient. 38 mg of the title compound were obtained in solid form. LC-MS rt: 0.80 min [M+H]+: 228.1 (met. a)
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]=O)[CH:4]=[N:3]1.[CH2:10]([NH2:12])[CH3:11]>C1COCC1>[CH2:10]([NH:12][CH2:8][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[CH3:7])[CH3:11]
Reactant: Cc1c(C=O)cnn1C
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1cnn(C)c1C

Procedure:
prepared by reaction of the commercially available 1,5-dimethyl-1H-pyrazole-4-carbaldehyde with 2M ethylamine in THF.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[S:17](Cl)(=[O:19])=[O:18]>>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[S:17]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:18])=[O:19]
Reactant: Cc1ccc(C)c(S(=O)(=O)Cl)c1
Reactant: Cc1noc(N)c1Br
Product: Cc1ccc(C)c(S(=O)(=O)Nc2onc(C)c2Br)c1
Yield: 81 %

Procedure:
2,5-Dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,5-di-methylbenzenesulfonyl chloride according to the procedures described in Example 25b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give off-white crystals, m.p. 102-104° C., yield 81%.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[F:36][C:37]([F:48])([F:47])[C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([C:41]3[CH:42]=[CH:43][C:38]([C:37]([F:48])([F:47])[F:36])=[CH:39][CH:40]=3)=[CH:3][CH:4]=2)[N:8]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)=[CH:24][CH:25]=2)[CH:9]=1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C(F)(F)F)cc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{-4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (100 mg, 0.17 mmol) was treated as described in general procedure G using 4-trifluoromethylphenylboronic acid to provide 5-{4-[4-(2,4-dichloro-phenyl)-2-(4′-trifluoromethyl-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[S:4].[C:14]([C:19]([OH:21])=[O:20])#[C:15][C:16](O)=[O:17]>>[Cl:13][C:8]1[CH:7]=[C:6]([N:5]=[C:3]2[N:2]([CH3:1])[C:16](=[O:17])[C:15](=[CH:14][C:19]([OH:21])=[O:20])[S:4]2)[CH:11]=[CH:10][C:9]=1[Cl:12]
Reactant: CNC(=S)Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)C#CC(=O)O
Product: CN1C(=O)C(=CC(=O)O)SC1=Nc1ccc(Cl)c(Cl)c1
Yield: 64.7 %

Procedure:
Prepared by the method described in Example 1 from N-methyl-N'-(3,4-dichlorophenyl)thiourea (4.9 g, 21 mmoles) and acetylenedicarboxylic acid (2.6 g, 22 mmoles). Recrystallization from ethyl acetate gave the product (4.5 g), mp 225°-226° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[CH:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[NH:9][C:6]2=[N:7][CH:8]=1>[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([CH:12]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=3)[CH2:13][CH:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[NH:9][C:6]2=[N:7][CH:8]=1
Reactant: COc1cnc2[nH]c(C(=CC3CCOCC3)c3ccc(C(F)(F)F)cc3)cc2c1
Agent: [Pd]
Solvent: CO
Product: COc1cnc2[nH]c(C(CC3CCOCC3)c3ccc(C(F)(F)F)cc3)cc2c1
Temperature: 50 °C
Yield: 65.9 %

Procedure:
A mixture of 5-methoxy-2-[2-(tetrahydro-pyran-4-yl)-1-(4-trifluoromethyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (180 mg, 0.45 mmol) and 10% palladium on activated carbon (50 mg) in methanol (200 mL) was heated at 50° C. under hydrogen (50 psi) for 6 h. The mixture was cooled to room temperature. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 5-methoxy-2-[2-(tetrahydro-pyran-4-yl)-1-(4-trifluoromethyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (120 mg, 66.7%) as a white solid: LC/MS m/e calcd for C22H23F3N2O2 [M+H]+ 405.44, observed 405.2; 1H NMR (400 MHz, CD3OD) δ ppm 7.84 (d, J=2.5 Hz, 1H), 7.59 (d, J=8.3 Hz, 2H), 7.51 (d, J=8.3 Hz, 2H), 7.48 (d, J=2.5 Hz, 1H), 6.30 (s, 1H), 4.36 (t, J=8.1 Hz, 1H), 3.86-3.95 (m, 2H), 3.20-3.30 (m, 2H), 2.16-2.27 (m, 1H), 1.98 (ddd, J=13.9, 7.3, 7.1 Hz, 1H), 1.70 (t, J=14.5 Hz, 2H), 1.48 (dddd, J=14.5, 10.8, 7.2, 3.7 Hz, 1H), 1.26-1.42 (m, 2H).