Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=1)[S:8][C:7](=[O:19])[C:6]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])=[C:5]2[OH:27]>[OH-].[Na+].[Pd]>[CH2:12]([C:10]1[CH:11]=[CH:2][CH:3]=[C:4]2[C:9]=1[S:8][C:7](=[O:19])[C:6]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])=[C:5]2[OH:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)CNC(=O)c1c(O)c2cc(Cl)cc(Cc3ccccc3)c2sc1=O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CNC(=O)c1c(O)c2cccc(Cc3ccccc3)c2sc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
[(6-Chloro-4-hydroxy-2-oxo-8-benzyl-2H-thiochromene-3-carbonyl)-amino]-acetic acid (Example 42a) (70 mg, 0.173 mmol) was dissolved in aqueous sodium hydroxide (870 uL 1M in 8 mL of water) and 10% palladium on carbon (7 mg) was added. The reaction was vacuum-purged and placed under an atmosphere of hydrogen gas and permitted to stir overnight at ambient temperature. Upon completion, the reaction was filtered through a pad of Celite® to remove the palladium catalyst. The product was precipitated with 1N HCl, isolated via filtration and dried to provide the title compound (30 mg.) MS ESI(−) m/e: 368.093 (M−1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH:4]([CH:10]1[NH:14]C(=O)N[C:11]1=[O:16])[CH2:5][C:6]([F:9])([F:8])[F:7].[OH-:19].[Na+]>>[F:1][C:2]([F:18])([F:17])[CH2:3][CH:4]([CH2:5][C:6]([F:9])([F:8])[F:7])[CH:10]([C:11]([OH:19])=[O:16])[NH2:14]
Reactant: O=C1NC(=O)C(C(CC(F)(F)F)CC(F)(F)F)N1
Reactant: [OH-]
Agent: [Na+]
Product: NC(C(=O)O)C(CC(F)(F)F)CC(F)(F)F

Procedure:
5-(3,3,3-Trifluoro-1-(2,2,2-trifluoroethyl)propyl) imidazolidine-2,4-dione (1.0 g, 3.59 mmol) was dissolved in a 10 mL solution of aqueous NaOH (0.575 g in 10 mL H2O, 14.38 mmol). The solution was divided in 2 special vessels for microwave technology. The solution was heated by microwave in sealed vessels for 1 h. Microwave conditions: 15 min at about 100% power, 150° C., 50 psi, then 5 min at rest, 0% power. The sequence was repeated until the reaction was done. Water and ammonia were removed from the reaction mixture in vacuo and the resulting crude 5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-dl-norvaline (0.92 g, 100%) and NaOH mixture was used in the next reaction without further purification. Mass Spectrum (+ESI): 254 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[H-].[Na+].[CH3:30][C:31]1[CH:32]=[N:33][NH:34][CH:35]=1>CN(C)C=O>[CH3:30][C:31]1[CH:32]=[N:33][N:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][N:13]4[CH:21]=[CH:22][CH:23]=[C:12]4[CH2:11]3)=[O:9])=[C:4]([C:24]([F:25])([F:26])[F:27])[CH:3]=2)[CH:35]=1
Reactant: Cc1cn[nH]c1
Reactant: O=C(c1ccc(F)cc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(C(F)(F)F)c2)c1
Yield: 50.4 %

Procedure:
In the manner of Example 2, employing (4-fluoro-2-trifluoromethyl-phenyl)(5H, 11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.8 g), 60% sodium hydride in oil (0.15 g), 4-methylpyrazole (0.20 g) and dimethylformamide (25 ml), the product (0.47 g) was obtained as a colorless amorphous solid, MS, m/z: 437.3 (M+H)+, 873.2 (2M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:33]=3[CH:43]=2)=[CH:7][CH:6]=1.[CH:44]1([CH:50]=O)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1.[BH4-].[Na+].[OH-].[Na+]>CO>[CH:44]1([CH2:50][NH:1][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:13][CH:12]3[O:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]4[O:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:33]=4[CH:43]=3)=[CH:9][CH:10]=2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCN)cc3)cc21
Reactant: O=CC1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCNCC4CCCCC4)cc3)cc21
Reaction time: 2 h

Procedure:
A solution of 0.346 g of benzyl 4-[4-(2-aminoethoxy)phenyl]-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 184b) and 0.068 ml of cyclohexanecarbaldehyde in 2 ml of methanol is stirred at room temperature over 3.5 hours, admixed in portions with 0.037 g of sodium borohydride and subsequently stirred for a further 2 hours. The reaction mixture is admixed with 2 ml of 1N NaOH, stirred for 30 minutes and then partitioned between ethyl acetate and water. The organic phase is washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.48 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=4.97.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[C:26]([C:27]2[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([CH3:34])[CH:28]=2)=[CH:25][NH:24][N:23]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([CH3:34])[CH:28]=4)=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1C(F)(F)F
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(C)c4)nc23)cc(C)n1
Yield: 47.5 %

Procedure:
Reaction of 1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (149 mg, 0.5 mmol), prepared from 3-methyl-4-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (107 mg, 48%). MS (ISP) 451.5 [(M+H)+]; mp 253° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH:3]=1.B([C:27]1[CH:38]=[CH:37][C:30]([CH2:31][C@@H:32]([C:34]([OH:36])=[O:35])[NH2:33])=[CH:29][CH:28]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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(#N)C>[NH2:33][CH:32]([CH2:31][C:30]1[CH:37]=[CH:38][C:27]([C:2]2[CH:3]=[C:4]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH:11]=3)[N:5]=[CH:6][N:7]=2)=[CH:28][CH:29]=1)[C:34]([OH:36])=[O:35]
Reactant: COc1ccc(CNc2cc(Cl)ncn2)cc1OC1CCCC1
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CNc2cc(-c3ccc(CC(N)C(=O)O)cc3)ncn2)cc1OC1CCCC1
Temperature: 150 °C
Yield: 6 %

Procedure:
An Emrys process vial (2-5 ml) for microwave was charged with (6-chloro-pyrimidin-4-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine (64 mg, 0.19 mmol), 4-borono-L-phenylalanine (40 mg, 0.19 mmol) and 2 ml of acetonitrile. Aqueous sodium carbonate (2 ml, 1M) was added to above solution followed by 5 mol percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol and purified with Prep-LC to give 5.3 mg of 2-amino-3-{4-[6-(3-cyclopentyloxy-4-methoxy-benzylamino)-pyrimidin-4-yl]-phenyl}-propionic acid, yield 6%. 1H-NMR (400 MHz, DMSO-d6): δ 1.46 (m, 2H), 1.62 (m, 4H), 3.01 (m, 2H), 3.08 (m, 2H), 3.65 (s, 3H), 4.20 (m, 1H), 4.46 (d, 2H), 4.68 (m, 1H), 6.82 (t, 2H), 6.87 (d, 2H), 7.40 (d, 2H), 7.90 (s, 2H), 8.25 (s, 2H), 8.6 (s, 1H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:11](O)=[O:12])[CH2:8]2.S(Cl)(Cl)=O.[NH2:18][N:19]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C>>[O:29]=[C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:19]1[NH:18][C:11]([CH:2]1[CH:1]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]1[CH2:4]3)[CH2:8]2)=[O:12]
Reactant: O=C(O)C1C2CC3CC(C2)CC1C3
Reactant: Nn1c(-c2ccccc2)nc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: O=C(Nn1c(-c2ccccc2)nc2ccccc2c1=O)C1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
A solution of adamantane-2-carboxylic acid (110 mg, 0.61 mmol, prepared as described in J. Med. Chem, (2007), 50(1), 149-164) in thionyl chloride (1.5 mL, 20.6 mmol) was heated at 80° C. for 90 minutes and then cooled to room temperature and concentrated under vacuum. The residue was dissolved in CH2Cl2 (3 mL) and 3-amino-2-phenylquinazolin-4(3H)-one (145 mg, 0.61 mmol, Aldrich) and diisopropylethylamine (0.2 mL, 1.14 mmol) were added. The mixture was stirred at room temperature for 2 hours and concentrated under vacuum. The residue was purified by flash chromatography (SiO2, eluted with hexanes-EtOAc, 90:10-70:30), then by preparative HPLC on a Waters Nova-Pak® HR C18 6 μm 60 {acute over (Å)} Prep-Pak® cartridge column (40 mm×100 mm) using a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 mL/min to provide the title compound as a white powder (56 mg, 23%): 1 H NMR (300 MHz, CD3OD) δ ppm 1.21 (br. d, J=12.9 Hz, 1 H), 1.31 (br. d, J=12.9 Hz, 1 H), 1.51 (br. d, J=12.7 Hz, 1 H), 1.58-1.72 (m, 3 H), 1.73-1.91 (m, 5 H), 1.90-2.01 (m, 2 H), 2.21 (br. s, 1 H), 2.61 (br. s, 1 H), 7.44-7.56 (m, 3 H), 7.56-7.65 (m, 3 H), 7.76 (d, J=8.3 Hz, 1 H), 7.89 (ddd, J=8.4, 7.0, 1.6 Hz, 1 H), 8.27 (dd, J=7.9, 1.6 Hz, 1 H); MS (DCI) m/z 400 (M+H); Elemental analysis calculated for C25 H25N3O2.0.7 H2O: C, 72.86; H, 6.46; N, 10.20. Found: C, 72.72; H, 6.30; N, 10.06.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2].[F:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21](=[CH:27]O)[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1>>[CH2:14]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][CH:27]=[C:21]2[C:20]3[C:24](=[CH:25][C:17]([F:16])=[CH:18][CH:19]=3)[NH:23][C:22]2=[O:26])=[CH:11][CH:12]=1)[CH3:15]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: O=C1Nc2cc(F)ccc2C1=CO
Product: CCN(CC)CCOc1ccc(NC=C2C(=O)Nc3cc(F)ccc32)cc1
Yield: 38.7 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-Diethylamino-ethoxy)-phenylamine (697 mg, 1.2 equiv.) and 6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.79 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (399 mg, 39%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:13]([Cl:12])(=[O:15])=[O:14])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: Clc1nccc2ccccc12
Product: O=S(=O)(Cl)c1cccc2c(Cl)nccc12
Temperature: 25 °C
Yield: 86 %

Procedure:
Chlorosulfonic acid (40 mL) is added slowly to 1-chloro-isoquinoline (9.92 g, 60.6 mmol) at 0° C. with stirring under nitrogen. The resultant mixture is heated at 155° C. for 24 hours. Then the mixture is cooled to ambient temperature before it is poured very slowly into ice (200 g). While cold, the mixture is extracted with dichloromethane (300 mL). The organic layer is dried over Na2SO4, filtered and concentrated in vacuo to give 13.6 g (51.9 mmol, yield 86%) of 1-chloro-isoquinoline-5-sulfonyl chloride as a white powder. 1H NMR (CDCl3): δ7.87(t, J=7.5 Hz, 1H), 8.52 (d, J=6.2 Hz, 1H), 8.59 (d, J=6.2 Hz, 1H), 8.62 (d, J=7.5 Hz, 1H), 8.82 (d, J=7.5 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19](O)=[O:20])[CH2:15][CH2:14]2)[C:10](=[O:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)=[O:60])([CH3:57])([CH3:56])[CH3:55]>CC(N(C)C)=O>[C:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][N:64]([C:19]([C@H:16]2[CH2:15][CH2:14][C@H:13]([CH2:12][N:11]3[C:10](=[O:22])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[NH:3][C:2]3=[O:1])[CH2:18][CH2:17]2)=[O:20])[CH2:63][CH2:62]1)=[O:60])([CH3:57])([CH3:55])[CH3:56]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=c1[nH]c2ccccc2c(=O)n1C[C@H]1CC[C@H](C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)[C@H]2CC[C@H](Cn3c(=O)[nH]c4ccccc4c3=O)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-4-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-cyclohexanecarboxylic acid (1.5 g, 4.96 mmol) in dimethylacetamide (10 mL), HATU (1.88 g, 4.96 mmol) and triethylamine (0.76 mL, 5.45 mmol) were added and the mixture left stirring at room temperature for 1 hour. Then tert-butyl-1-piperazinecarboxylate (0.92 g, 4.96 mmol) was added and the reaction left stirring for 18 h at room temperature. The solvent was removed under reduced pressure and the residue was washed with a 0.4M Na2CO3 solution. The titled compound was obtained as a white solid (2.3 g, quantitative yield).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C(#N)C.[N:26]1([C:32]2[CH:33]=[C:34](/[CH:38]=[CH:39]/[C:40]#[N:41])[CH:35]=[N:36][CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C1CCN2C(=NCCC2)CC1>>[N:26]1([C:32]2[CH:33]=[C:34]([CH:38]([N:1]3[CH:5]=[C:4]([C:6]4[C:7]5[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=5[N:9]=[CH:10][N:11]=4)[CH:3]=[N:2]3)[CH2:39][C:40]#[N:41])[CH:35]=[N:36][CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#C/C=C/c1cncc(N2CCOCC2)c1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(N5CCOCC5)c4)c3)ncnc21
Reaction time: 8 h
Yield: 125.6 %

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (120 mg, 0.00038 mol) in ACN (10 mL, 0.2 mol) and (2E)-3-(5-morpholin-4-ylpyridin-3-yl)acrylonitrile (70 mg, 0.0003 mol) (mixture of isomers), DBU (50 μL, 0.0003 mol) was added and the resulting mixture was stirred overnight. The mixture was partitioned between water and ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-(5-morpholin-4-ylpyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (200 mg, 100%) as a crude product; L/MS=531 (M+1).
Reaction SMILES: Cl[C:2]1N=C2C(=C[C:14]=1OCC)C=C1N2C(C)CNC1.[C:19]([O:23][C:24]([N:26]1[CH2:38][C@@H:37]([CH3:39])[N:36]2[C@H:28]([CH2:29][C:30]3[C:35]2=[N:34][C:33]([CH2:40][O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)=[C:32]([CH2:46][OH:47])[CH:31]=3)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].[H-].[Na+].C(Br)C>>[C:19]([O:23][C:24]([N:26]1[CH2:38][C@@H:37]([CH3:39])[N:36]2[C@H:28]([CH2:29][C:30]3[C:35]2=[N:34][C:33]([CH2:40][O:41][CH2:42][CH:43]2[CH2:44][CH2:45]2)=[C:32]([CH2:46][O:47][CH2:2][CH3:14])[CH:31]=3)[CH2:27]1)=[O:25])([CH3:20])([CH3:21])[CH3:22]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(CO)c(COCC4CC4)nc3N21
Reactant: CCOc1cc2cc3n(c2nc1Cl)C(C)CNC3
Agent: [H-]
Agent: [Na+]
Solvent: CCBr
Product: CCOCc1cc2c(nc1COCC1CC1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to example 1, intermediate d) from (4R,9aR)-6-cyclopropylmethoxymethyl-7-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and ethyl bromide.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(CN)cc1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: COc1ccc(CNc2nccc(-n3cnc4ccccc43)n2)cc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 4-methoxybenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 332.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.61 (s, 1H); 8.42 (br s, 1H); 8.12 (br s, 1H); 7.86 (m, 1H); 7.36 (m, 4H); 6.92 (m, 2H); 6.83 (d, J=5.5 Hz, 1H); 5.76 (br s, 1H); 4.68 (d, J=5.7 Hz, 2H); 3.83 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=O)[C:4](=[CH:8][C:9]2[CH:10]=[C:11]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH:12]=[CH:13][C:14]=2[N+:15]([O-])=O)[NH:3]1>CN(C=O)C.[Pd]>[O:1]=[C:2]1[NH:6][C:5]2=[N:15][C:14]3[CH:13]=[CH:12][C:11]([N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]4)=[CH:10][C:9]=3[CH:8]=[C:4]2[NH:3]1
Reactant: CCOC(=O)N1CCN(c2ccc([N+](=O)[O-])c(C=C3NC(=O)NC3=O)c2)CC1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(c2ccc3nc4[nH]c(=O)[nH]c4cc3c2)CC1
Reaction time: 17 h

Procedure:
A solution of ethyl 4-[3-[(2,4-dioxoimidazolin-5-ylidene)methyl]-4-nitrophenyl]-1-piperazinecarboxylate (4.25 g, 10.9 mmol) in DMF (200 mL) was hydrogenated over 10% Pd/C (0.7 g) at 60 p.s.i. After 17 hours, the mixture was filtered through kieselguhr and the solvent removed in vacuo. Evaporation was repeated with two portions (200 mL each) of methanol. Residual solid was suspended in absolute ethanol (200 mL) and glacial acetic acid (8 mL) and stirred at reflux for one hour. The mixture was concentrated in vacuo, the residue suspended in DMF (200 mL) and warmed to solution on a steam bath. Palladium on carbon (0.5 g) was added and heating continued for two hours. The mixture was filtered through kieselguhr, the filtrate concentrated to a slurry and diluted with methanol. The precipitate was collected and crystallized from DMF to afford ethyl 4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)-1-piperazinecarboxylate, a yellow solid (0.74 g) of analytical purity, m.p. >300° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)[C:20](=[O:32])[N:19]2CC2C=CC(OC)=CC=2)=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]>FC(F)(F)C(O)=O.O>[CH2:1]([O:3][C:4](=[O:42])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)[C:20](=[O:32])[NH:19]2)=[CH:13][CH:14]=1)([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CN(Cc3ccc(C)c(C)c3)C(=O)N2Cc2ccc(OC)cc2)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CN(Cc3ccc(C)c(C)c3)C(=O)N2)cc1
Yield: 60.5 %

Procedure:
A solution of 2-(4-{2-[1-(3,4-dimethyl-benzyl)-3-(4-methoxy-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester (2.51 g, 4.36 mmol) in trifluoroacetic acid (70 mL) was stirred at room temperature under N2 for 1 h. The reaction was diluted with water, and extracted with Et2O. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 98:2 CH2Cl2:MeOH to afford 1.20 g (60%) 2-(4-{2-[1-(3,4-dimethyl-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester. MS (ES+) Calc'd for C26H35N2O5 (M+1) 455. Found m/z 455 (100%). 1H NMR.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:42][CH2:43]OS(C)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:49]=[N+:50]=[N-:51].[Na+].CN(C=O)C>O>[N:49]([CH2:43][CH2:42][C:15]1[N:14]([CH:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:22]2[C:17]([C:16]=1[CH2:24][CH2:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)=[N+:50]=[N-:51]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CCc1ccc(S(=O)(=O)CCc2c(CCOS(C)(=O)=O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc(S(=O)(=O)CCc2c(CCN=[N+]=[N-])n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 60 °C
Yield: 96 %

Procedure:
Ethyl 3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)propanoate (1 eq), sodium azide (5 eq), and DMF (0.05M) were placed together under N2 and heated to 60° C. After 1 hour the reaction was cooled and water was added. Extracted with EtOAc/Et2O mix and washed with water and brine and dried over sodium sulfate. Removed solvent to obtain ethyl 3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (light-brown solid) in 96% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([NH:18][NH2:19])[CH:9]=1.[C:20](OCC)(OCC)(OCC)[CH3:21]>C1(C)C(C)=CC=CC=1>[CH3:20][C:21]1[N:11]2[C:12]3[C:17]([C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[CH:9][C:10]2=[N:18][N:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CCOC(C)(OCC)OCC
Reactant: NNc1cc(-c2ccccc2Cl)c2ccccc2n1
Solvent: Cc1ccccc1C
Product: Cc1nnc2cc(-c3ccccc3Cl)c3ccccc3n12

Procedure:
In the manner given in Example 2, 4-(o-chlorophenyl)-2-hydrazinoquinoline and triethyl orthoacetate are refluxed in xylene to give 1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline.