Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[C:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([CH:31]=[CH:32][CH:33]=2)[C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[O:23])=[CH:13][CH:12]=1)(=[NH:10])[NH2:9].[OH-].[Na+].C(O)(C(F)(F)F)=O>CO>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[C:8]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([CH:31]=[CH:32][CH:33]=2)[C:22]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[CH:15][CH:16]=1)(=[NH:9])[NH2:10]
Reactant: COC(=O)CCNC(=O)c1cccc(COc2ccc(C(=N)N)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc(OCc2cccc(C(=O)NCCC(=O)O)c2)cc1
Yield: 88.9 %

Procedure:
XX (0.21 mmol, 100 mg) was dissolved in 2 mL methanol and 2 mL 1N NaOH and after 1 hour the solution was acidified with TFA to pH 3. Purification on reversed phase HPLC gave 85 mg (88%) product. ESI (M+H)+ : Calc. 342.2; Found 342.2.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)=[O:20]>O>[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:2]2[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:15]([O-:17])=[O:16])=[CH:24][CH:23]=1)(=[O:20])[CH3:18]
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Solvent: O
Product: CC(=O)Nc1ccc(Nc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)cc1
Temperature: 25 °C

Procedure:
The starting material is prepared as follows: The mixture of 5.6 g of 4-chloro-3-nitro-5-sulfamoylbenzoic acid, 200 ml of water and 9 g of 4-aminoacetanilide is refluxed for four hours while stirring under nitrogen. It is cooled to room temperature and the precipitate formed filtered off, to yield the 4-(4-acetamidophenylamino)-3-nitro-5-sulfamoylbenzoic acid, melting above 275°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:16]([C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([N+:29]([O-])=O)=[C:24]([F:32])[CH:23]=2)([CH3:19])([CH3:18])[CH3:17]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:29][C:25]4[CH:26]=[C:27]5[C:22](=[CH:23][C:24]=4[F:32])[N:21]([CH2:6][C@H:5]([OH:1])[CH2:4][OH:3])[C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:28]5)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)c(F)cc2n1C[C@H](O)CO

Procedure:
(S)-1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2,3-dihydroxypropyl)-6-fluoro-1H-indol-5-yl)cyclopropanecarboxamide was prepared using an experimental procedure similar to Example 72 from 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid and 2-tert-butyl-6-fluoro-5-nitro-1H-indole.
Reaction SMILES: IC1C=CC=CC=1S([O-])(=O)=O.[Na+].OOS([O-])=O.[K+].S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:26][C:27]1[CH2:32][CH:31]([C:33]([CH3:35])=[CH2:34])[CH2:30][CH:29]([OH:36])[CH:28]=1>C(OCC)(=O)C>[CH3:26][C:27]1[CH2:32][CH:31]([C:33]([CH3:35])=[CH2:34])[CH2:30][C:29](=[O:36])[CH:28]=1
Reactant: C=C(C)C1CC(C)=CC(O)C1
Agent: O=S(=O)([O-])[O-]
Agent: O=S(=O)([O-])c1ccccc1I
Agent: O=S([O-])OO
Solvent: CCOC(C)=O
Product: C=C(C)C1CC(=O)C=C(C)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
6.1 mg (0.02 mmol) of sodium 2-iodobenzenesulfonate prepared by Preparation Example 4, 0.49 g (0.8 mmol) of powdered Oxone (registered trademark), 0.5 g (3.5 mmol) of anhydrous sodium sulfate and 152 mg (1 mmol) of 3-methyl-5-(prop-1-en-2-yl)cyclohexa-2-enol were added to 5 ml of ethyl acetate, and the mixture was heated at 70° C. while being stirred under a nitrogen for eight hours. The later treatment was carried out in the same way as in Example 1, and then 3-methyl-5-(prop-1-en-2-yl)cyclohexa-2-enone was obtained. The yield of the obtained 3-methyl-5-(prop-1-en-2-yl)cyclohexa-2-enone was determined and the result is shown in Table 2. (Yield 91%)
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]3[C:13]=2[CH2:14][CH2:15][CH2:16]3)=[CH:7][C:4]=1[CH:5]=[O:6].B(Cl)(Cl)Cl.CO.Cl>ClCCl>[OH:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]3[C:13]=2[CH2:14][CH2:15][CH2:16]3)=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1C=O
Agent: Cl
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(O)c(C=O)c1)CCC2
Yield: 74.6 %

Procedure:
2-Methoxy-5-(5-methyl-7-nitroindan-4-yloxy) benzaldehyde (2.03 g) was dissolved in dichloromethane (80 mL). To the solution was added dropwise a 1 mol/L solution of boron trichloride in dichloromethane (20 mL) under ice-cooling with stirring. The reaction mixture was stirred at room temperature for 24 hours. To the reaction mixture was added dropwise methanol (10 mL) under ice-cooling with stirring. After adding diluted hydrochloric acid, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (1.45 g).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[N:4]=1)[NH2:2].C(O[CH:24]=[C:25]([C:31](=O)[C:32]([F:35])([F:34])[F:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])C>>[CH3:20][O:19][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[C:5]1[N:4]=[C:3]([N:1]2[C:31]([C:32]([F:33])([F:34])[F:35])=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:24]=[N:2]2)[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: COc1ccc(C)cc1-c1cc([N+](=O)[O-])cc(NN)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Product: CCOC(=O)c1cnn(-c2cc([N+](=O)[O-])cc(-c3cc(C)ccc3OC)n2)c1C(F)(F)F

Procedure:
Reaction of the title compound from Example 19 Step C with ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate, according to chemistry described in Example 1 Step A, provided the title compound: LCMS m/z 451.6 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH:8]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[CH2:7][S:6][CH:5]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[CH2:4][NH:3]1.Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>>[O:1]=[C:2]1[CH:8]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[CH2:7][S:6][CH:5]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[CH2:4][N:3]1[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: O=C1NCC(c2cccs2)SCC1N1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)CN1CC(c2cccs2)SCC(N2C(=O)c3ccccc3C2=O)C1=O

Procedure:
Following the procedure described in Example 42(f), 1.6 g of 5-oxo-6-phthalimido-2-(2-thienyl)perhydro-1,4-thiazepine [prepared as described in step (e) above] was treated with t-butyl bromoacetate to give 1.15 g of the title compound as crystals, melting at 183°-184° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([CH:40]([CH3:43])[C:41]#[N:42])[CH:37]=[N:38][CH:39]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[C:20]1([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:11][C:2]([C:34]2[CH:35]=[C:36]([CH:40]([CH3:43])[C:41]#[N:42])[CH:37]=[N:38][CH:39]=2)=[N:3]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Reactant: CC(C#N)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C#N)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 95 °C
Reaction time: 16 h
Yield: 53.7 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (from example 1, step 4, 0.12 g, 0.5 mmol) in 1,4-dioxane (8 mL) and H2O (0.55 mL) under nitrogen was added 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)propanenitrile (0.120 g, 0.4 mmol) and potassium carbonate (0.14 g, 1 mmol). The resulting mixture was degassed with nitrogen for 15 min. After this time, (1,1′-bis(diphenylphosphino)ferrocene)palladium (II) chloride dichloromethane complex (0.26 mg, 0.036 mmol) was added and the reaction mixture was again degassed with nitrogen for 10 min. At the conclusion of this period, the reaction mixture was stirred at 95° C. for 16 h. The reaction mixture was then allowed to cool to room temperature. Once at the prescribed temperature, the reaction mixture was quenched by the addition of water and then transferred to a separation funnel. The aqueous layer was extracted with ethyl acetate. The combined organic portions were washed with water and saturated NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting concentrate was purified by silica gel column chromatography using 1% methanol in DCM to afford racemic 2-(5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)pyridin-3-yl)propanenitrile (95 mg, 63% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.60 (s, 1H), 8.80 (d, 1H, J=2 Hz); 8.77 (s, 1H); 8.26 (d, 1H, J=6 Hz); 7.92 (dd, 1H, J=1.2, 6.8 Hz); 7.85 (t, 1H, J=6.8 Hz); 7.73 (dt, 1H, J=1.6, 7.6 Hz); 7.58-7.52 (m, 5H); 7.34-7.32 (m, 2H); 7.24 (t, 1H, 7.2 Hz); 6.86 (t, 1H, J=4 Hz); 4.76 (d, 2H, J=4.4 Hz); 4.59 (q, 1H, J=7.2 Hz); 1.68 (d, 3H, 7.2 Hz). LCMS Method Y: retention time 1.68 min, [M+1]=443.2.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:19]([O:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[C:9]([F:10])=[C:8]([C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])=[CH:32][CH:31]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Reactant: N#Cc1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)c(F)c2F)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A solution of 2,3-difluoro-4-trifluoromethylsulfonyloxybenzonitrile in 60 mL of dioxane is admixed under an argon atmosphere with 1.24 g of 4-(tert-butyloxycarbonylamino)phenylboronic acid. A solution of 1.03 g of sodium carbonate in 15 mL of water is added, followed by 0.48 g of tetrakistriphenylphosphinepalladium. The reaction mixture is stirred at 90° C. for 3 hours and then poured into 80 mL of distilled water. Following extraction with ethyl acetate and then washing with saturated sodium chloride solution, the organic phase is concentrated under reduced pressure, to give 0.8 g of 2,3-difluoro-4-(4-tert-butoxycarbonylaminophenyl)benzonitrile, whose characteristics are as follows:
Reaction SMILES: C[N:2]1[C:6]([CH3:7])=[N:5][C:4]([C:8]2[CH:13]=[CH:12][N:11]3[CH:14]=[C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])[N:16]=[C:10]3[CH:9]=2)=[N:3]1.N1C=C(B(O)O)C=NC=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C(COC)OC.O.C(O)C.C(O)(=O)C>[CH2:21]([NH:20][C:18]([NH:17][C:15]1[N:16]=[C:10]2[CH:9]=[C:8]([C:4]3[NH:3][N:2]=[C:6]([CH3:7])[N:5]=3)[CH:13]=[CH:12][N:11]2[CH:14]=1)=[O:19])[CH3:22]
Reactant: CCNC(=O)Nc1cn2ccc(-c3nc(C)n(C)n3)cc2n1
Agent: O=C([O-])[O-]
Agent: OB(O)c1cncnc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CCNC(=O)Nc1cn2ccc(-c3nc(C)n[nH]3)cc2n1
Temperature: 80 °C

Procedure:
A suspension of 5 (0.76 mmol), pyrimidine-5-boronic acid (0.105 g, 0.85 mmol), sodium carbonate (0.292 g, 2.75 mmol), and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.007 g, 8.6 μmol) in 6 mL of 7:3:2 dimethoxyethane/water/ethanol was heated for 30 minutes at 80° C. in a CEM microwave reactor. The reaction was acidified with 2 mL glacial acetic acid and evaporated in vacuo. The residue was purified by silica gel chromatography (gradient elution 0-50% isopropanol in dichloromethane) to give the target compound (4). MS (APCI)=295.1 [M+H].
Reaction SMILES: [Mg].[CH3:2]I.[CH2:4]1[CH2:23][O:22][CH:21]2[CH:6]([C@@H:7]([C@@H:19]([CH2:24][CH2:25][C:26](=[O:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:20]2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:5]1.[Cl-].[NH4+]>CCOCC.O>[CH2:4]1[CH2:23][O:22][CH:21]2[CH:6]([C@@H:7]([C@@H:19]([CH2:24][CH2:25][C:26]([OH:32])([CH3:2])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:20]2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:5]1
Reactant: CCCCCC(=O)CC[C@H]1CC2OCCOC2[C@@H]1CCCCCCC(=O)OCC
Reactant: CI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CCCCCC(C)(O)CC[C@H]1CC2OCCOC2[C@@H]1CCCCCCC(=O)OCC

Procedure:
To a Grignard solution prepared from 207 mg. of magnesium and 1.3 g. of methyl iodide in 10 ml. of ether under nitrogen atmosphere is added a solution of 1.77 g. of ethyl 9-ethylenedioxy-15-oxo-prostanoate (Example 56) in 10 ml. of ether and the resulting mixture is stirred at room temperature for 18 hours. Saturated ammonium chloride (20 ml.) is added followed by 10 ml. of water and 50 ml. of ether. The ethereal solution is washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 1.77 g. (94%) of viscous oil; λ max. 2.94 (hydroxyl group) and 5.77 μ (carbonyl group).
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:13][NH:14][NH2:15]>C1(C)C=CC=CC=1>[CH2:10]([C:9]1[CH:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:14]([CH3:13])[N:15]=1)[CH3:11]
Reactant: CCOC(=O)C(=O)CC(=O)CC
Reactant: CNN
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(CC)nn1C
Temperature: -20 °C

Procedure:
To a solution of compound 2 (3.8 g, 22 mmol) in toluene (20 mL) was added methylhydrazine (1.8 g, 0.039 mol) cooled to −20° C. After completion of the reaction, the reaction liquid was washed with water and the solvent was removed by evaporation to obtain crude product, the crude product was purified by silica gel column chromatography (PE:EA=5:1) to give the desired product as a white oil.
Reaction SMILES: C1(C)C=CC=CC=1.N1CCCCC1.[C:14]12([C:24]3[CH:25]=[C:26]([C:33]4[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=4)[CH:27]=[C:28]4[O:32][CH2:31][O:30][C:29]=34)[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.[S:41]1[CH2:45][C:44](=[O:46])[NH:43][C:42]1=[O:47]>C(O)(=O)C>[C:14]12([C:24]3[CH:25]=[C:26]([C:33]4[CH:40]=[CH:39][C:36]([CH:37]=[C:45]5[S:41][C:42](=[O:47])[NH:43][C:44]5=[O:46])=[CH:35][CH:34]=4)[CH:27]=[C:28]4[O:32][CH2:31][O:30][C:29]=34)[CH2:23][CH:18]3[CH2:17][CH:16]([CH2:22][CH:20]([CH2:19]3)[CH2:21]1)[CH2:15]2
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(-c2cc3c(c(C45CC6CC(CC(C6)C4)C5)c2)OCO3)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1NC(=O)C(=Cc2ccc(-c3cc4c(c(C56CC7CC(CC(C7)C5)C6)c3)OCO4)cc2)S1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
A solution of toluene (10 mL), piperidine (10 μL), acetic acid (10 μL), 4-[3-(1-adamantyl)-4,5-methylenedioxyphenyl]-benzaldehyde (0.400 g, 1.11 mmol) and 2,4-thiazolidinedione (0.130 g, 1.11 mmol) was heated at reflux overnight under an argon atmosphere. The reaction mixture was cooled to room temperature, and the resulting crystalline compound was filtered, washed with toluene and ethanol. The yellow solid was dried under high vacuum to afford 0.390 g (76%) of 4-[3-(1-adamantyl)-4,5-methylenedioxyphenyl]-benzylidene-2,4-thiazolidinedione, mp 308° (dec). 1H NMR (500 MHz; DMSO-d6): 1.74 (s, 6H), 2.04 (s, 9H), 6.05 (s, 2H), 7.06 (d, J=1.5 Hz, 1H), 7.20 (d, J=1.5 Hz, 1H), 7.63 (d, J=8.0 Hz, 2H), 7.78 (d, J=8.0 Hz, 2H), 7.81 (s, 1H), 12.5–12.7 (brs, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=3)[O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:10]=[C:4]2[CH:3]=1.[CH2:23]([N:25]([CH3:37])[C:26]([C:28]1[CH:29]=[N:30][N:31]([CH3:36])[C:32]=1[C:33](O)=[O:34])=[O:27])[CH3:24]>>[CH3:19][O:18][C:16](=[O:17])[CH2:15][O:14][C:13]1[CH:20]=[CH:21][CH:22]=[C:11]([C:9]2[N:10]=[C:6]3[N:7]=[C:2]([NH:1][C:33]([C:32]4[N:31]([CH3:36])[N:30]=[CH:29][C:28]=4[C:26](=[O:27])[N:25]([CH2:23][CH3:24])[CH3:37])=[O:34])[CH:3]=[CH:4][N:5]3[CH:8]=2)[CH:12]=1
Reactant: COC(=O)COc1cccc(-c2cn3cnc(N)cc3n2)c1
Reactant: CCN(C)C(=O)c1cnn(C)c1C(=O)O
Product: CCN(C)C(=O)c1cnn(C)c1C(=O)Nc1ccn2cc(-c3cccc(OCC(=O)OC)c3)nc2n1

Procedure:
The title compound was prepared in analogy to example 82 from methyl 2-(3-(7-aminoimidazo[1,2-c]pyrimidin-2-yl)phenoxy)acetate (105 mg, 352 μmol) and 4-(ethyl(methyl)carbamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid (74.3 mg, 352 μmol). Light yellow solid (30 mg, 16%). MS (m/z)=492.2 [M+H+].
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:15]2[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH:17]=[N:18][C:14]=2[CH:13]=[C:12]([Cl:30])[N:11]=1>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:17]1[N:16]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[C:15]2[C:10]([Cl:9])=[N:11][C:12]([Cl:30])=[CH:13][C:14]=2[N:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: FC(F)(F)c1ccc(Cn2cnc3cc(Cl)nc(Cl)c32)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Cn2c(Br)nc3cc(Cl)nc(Cl)c32)cc1
Temperature: 25 °C

Procedure:
N-bromosuccinimide (352 mg, 1.98 mmol) was added to a solution of 4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine (200 mg, 0.99 mmol) stirring in degassed chloroform (20 mL) at room temperature. The reaction was heated to reflux for 1 hour. The mixture was cooled to room temperature, diluted with dichloromethane, and washed with saturated aqueous sodium thiosulfate and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 2-bromo-4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine. MS APCl calc'd. for C14H7BrCl2F3N3 [M+H]+ 426. found 426.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)COCC4C=CC=CC=4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1.Cl[C:58]1[N:66]=[C:65]2[C:61]([N:62]=[CH:63][N:64]2[C@@H:67]2[CH2:71][C@H:70]([NH:72][C:73]([CH:75]3[CH2:78][CH2:77][CH2:76]3)=[O:74])[C@@H:69]([OH:79])[C@H:68]2[OH:80])=[C:60]([NH:81][CH2:82][CH:83]([C:90]2[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=2)[C:84]2[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=2)[N:59]=1.[CH2:96]([N:103]1[CH2:107][CH2:106][C@@H:105]([NH2:108])[CH2:104]1)[C:97]1[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:96]([N:103]1[CH2:107][CH2:106][C@@H:105]([NH:108][C:58]2[N:66]=[C:65]3[C:61]([N:62]=[CH:63][N:64]3[C@@H:67]3[CH2:71][C@H:70]([NH:72][C:73]([CH:75]4[CH2:78][CH2:77][CH2:76]4)=[O:74])[C@@H:69]([OH:79])[C@H:68]3[OH:80])=[C:60]([NH:81][CH2:82][CH:83]([C:84]3[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=3)[C:90]3[CH:91]=[CH:92][CH:93]=[CH:94][CH:95]=3)[N:59]=2)[CH2:104]1)[C:97]1[CH:98]=[CH:99][CH:100]=[CH:101][CH:102]=1
Reactant: O=C(N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O)C1CCC1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Agent: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)COCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N[C@@H]4CCN(Cc5ccccc5)C4)nc32)[C@H](O)[C@@H]1O)C1CCC1

Procedure:
This compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-acetamide trifluoroacetate Example 1 (Step 2) by replacing 2-benzyloxy-N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-acetamide with cyclobutanecarboxylic acid {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-amide (Intermediate K) and by replacing (3R)-3-aminopyrrolidine with (R)-1-benzyl-pyrrolidin-3-ylamine. (MH+ 687.5)
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:13]#[N:14])=[C:10]([NH2:12])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.[SH2:20]>C(N(CC)CC)C>[C:1]1([C:7]2[S:8][C:9]([C:13](=[S:20])[NH2:14])=[C:10]([NH2:12])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1sc(-c2ccccc2)nc1N
Reactant: S
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=S)c1sc(-c2ccccc2)nc1N
Yield: 89 %

Procedure:
75 parts of 2-phenyl-4-amino-5-cyanothiazole in 300 parts of dimethylformamide and 15 parts of triethylamine are reacted with 13 parts of hydrogen sulfide as described in Example 1(a). 77 parts of 2-phenyl-4-amino-5-thiocarbamoylthiazole (89% of theory) of melting point 164°-167° C. are obtained.
Reaction SMILES: FS(O)(=O)=O.C(=O)=O.CC(C)=O.[CH2:13]=[CH:14][CH2:15][CH2:16][CH3:17].[N+:18]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24])([O-:20])=[O:19].[OH-].[Na+]>C(Cl)Cl>[N+:18]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](=[NH:25])[O:24][CH:14]([CH3:13])[CH2:15][CH2:16][CH3:17])([O-:20])=[O:19]
Reactant: NC(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCCC
Agent: O=C=O
Agent: O=S(=O)(O)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCCC(C)OC(=N)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
9 g of fluorosulfonic acid was cooled to -78° C. with dry ice-acetone, 30 ml of 1-pentene was gradually dropwise added thereto under stirring. After completion of the dropwise addition, the stirring was continued at the same temperature for 15 minutes. 100 ml of methylene chloride which was previously cooled to -78° C., was added thereto, and then 15 g of 2-nitrobenzamide was added thereto at once. Then, the reaction was conducted for 12 hours under stirring while the temperature of the solution was returned to room temperature. After completion of the reaction, the reaction solution was poured into a mixture of 250 ml of a 1N sodium hydroxide aqueous solution and 100 ml of methylene chloride, which was cooled to 0° C., and then the mixture was vigorously stirred for 10 minutes. The reaction solution was extracted, and the extract was washed with water and then dried over Glauber's salt. After distillation of the solvent, the residue was purified by silica gel column chromatography to obtain 0.3 g of oily 1-methylbutyl 2-nitrobenzimidate (Intermediate Compound No. 63).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]([NH2:11])=[S:10])=[CH:3][CH:2]=1.[C:12]([CH2:14][C:15](OCC)=[O:16])#[N:13]>C(O)(=O)C>[NH2:13][C:12]1[N:8]([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[C:9](=[S:10])[NH:11][C:15](=[O:16])[CH:14]=1
Reactant: CCOC(=O)CC#N
Reactant: NC(=S)NCc1ccncc1
Solvent: CC(=O)O
Product: Nc1cc(=O)[nH]c(=S)n1Cc1ccncc1

Procedure:
The title compound was prepared in accordance with the general method described in Example 11(b), using N-(pyridin-4-ylmethyl)thiourea (1.0 g, 5.98 mmol) and ethyl cyanoacetate (0.64 mL, 5.98), with the exception that a 4 h reaction time was used, and the solution was neutralized with acetic acid. The crude title compound was obtained (1.07 g, 76%) as a solid.