Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=1.[C:13]1([C:19]#[CH:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([C:19]#[C:20][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[CH:9][C:10]=3[C:11]#[N:12])[CH:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1cnn2cc(Br)cnc12
Reactant: C#Cc1ccccc1
Product: N#Cc1cnn2cc(C#Cc3ccccc3)cnc12

Procedure:
The title compound, yellow solid, MS: m/e=245.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-pyrazolo(1,5-A)pyrimidine-3-carbonitrile and phenylacetylene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C@H:10]([C:22]([OH:24])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[F:65][C:66]1[CH:78]=[CH:77][C:69]([CH2:70][C@@H:71]2[CH2:76][CH2:75][CH2:74][NH:73][CH2:72]2)=[CH:68][CH:67]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C@H:10]([C:22]([N:73]2[CH2:74][CH2:75][CH2:76][C@@H:71]([CH2:70][C:69]3[CH:68]=[CH:67][C:66]([F:65])=[CH:78][CH:77]=3)[CH2:72]2)=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(C[C@@H]2CCCNC2)cc1
Reactant: C[C@@H](N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Reaction time: 0.08 h
Yield: 82 %

Procedure:
A cloudy solution of (3R,4S)-4-[(R)-1-phenyl-ethylamino]-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (80 mg, 240 μmol) in methylene chloride (5 mL) was treated with benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (151 mg, 290 μmol) and triethylamine (77 μL, 550 μmol) and stirred for 5 minutes. A solution of the (S)-3-(4-flourobenzyl)-piperdine prepared above in methylene chloride (5 mL) was added and the mixture was stirred at room temperature. After 18 h, the mixture was washed with water and saturated NaHCO3, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (50% ethyl acetate/hexanes) to provide the product as a gum (100 mg, 82%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:11]=[C:12]([CH:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=2)[C:21]#[N:22])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1.C(Cl)Cl>[F:9][C:10]1[CH:11]=[C:12]([C:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=2)([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21]#[N:22])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1
Reactant: N#CC(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)cn1
Reactant: BrCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#CC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a solution of LDA (2.0 M in THF, 3.7 mL) in THF (20 mL) at −78° C. under argon was added dropwise a solution of 2-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(5-fluoropyridin-2-yl)acetonitrile (1.7 g, 5.7 mmol), prepared as described in Procedure 3, in THF (4 mL). The resulting solution was stirred at −78° C. for 1 h. Benzylbromide (0.88 mL, 7.4 mmol) was added to the reaction mixture and allowed to warm to room temperature. The reaction mixture was stirred at rt for 1 h, concentrated under reduced pressure and diluted with EtOAc (approx 100 mL). The resulting solution was washed with water (30 mL) and sat. NaCl (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a yellow oil. The yellow oil was dissolved in CH2Cl2 and loaded directly onto a silica gel ISCO cartridge (40 g) with elution at 35 mL/min gradient 0 to 30% EtOAc in hexane over 35 min (RT=27-32 min). 2-(3-Fluoro-5-(trifluoromethyl)phenyl)-2-(5-fluoropyridin-2-yl)-3-phenylpropanenitrile (1.6 g, 72% yield) was isolated as a pale yellow oil. LCMS: RT=2.17 min [M+H] 389.0 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=4.24 min (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) ppm 3.59 (d, J=13.18 Hz, 1 H), 3.90 (d, J=13.62 Hz, 1 H), 6.89 (d, J=6.59 Hz, 2 H), 7.09-7.15 (m, 3 H), 7.20 (d, J=7.91 Hz, 1 H), 7.32 (td, J=8.35, 3.08 Hz, 1H), 7.37 (d, J=9.23 Hz, 1 H), 7.45-7.48 (m, 1 H), 7.49 (s, 1 H), 8.50 (d, J=2.64 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:19]#[N:20])=[CH:11][C:12]([N+:16]([O-])=O)=[C:13]([CH3:15])[CH:14]=2)=[CH:5][CH:4]=1.[CH3:21]N(C(N(C)C)N(C)C)C.Cl>C1(C)C=CC=CC=1.O.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]3[C:12](=[CH:11][C:10]=2[C:19]#[N:20])[NH:16][CH:21]=[CH:15]3)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(C)c([N+](=O)[O-])cc2C#N)cc1
Reactant: CN(C)C(N(C)C)N(C)C
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc3cc[nH]c3cc2C#N)cc1
Yield: 32 %

Procedure:
A mixture of 4′-methoxy-5-methyl-4-nitro-biphenyl-2-carbonitrile (118.0 mg, 0.44 mmol) and tris(dimethylamino) methane (128.0 mg, 0.88 mmol) in toluene (15 mL) was heated to reflux for 2 hours. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in EtOH (1 mL) and water (0.10 mL), and treated with iron powder (64.0 mg, 1.15 mmol), followed by concentrated HCl (28.0 mg, 0.29 mmol). The reaction mixture was heated to reflux for an additional 16 hours, and quenched with 1N aqueous NaOH (0.288 mL). The solution was filtered through celite and rinsed with EtOH (10 mL). The filtrate was concentrated in vacuo to give the title compound (35 mg, 49% yield). MS (ES−) 247.1 (M−1)−. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.68 (d, J=2.73 Hz, 1H), 7.66 (s, 1H), 7.48 (d, J=8.59 Hz, 2H), 7.05 (d, J=8.59 Hz, 2H), 6.58 (d, J=2.73 Hz, 1H), 3.82 (s, 3H).
Reaction SMILES: [CH:1]1[N:9]2[C:5](=[N:6][C:7]3[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[C:8]=32)[CH:4]=[CH:3][CH:2]=1.[BrH:15].[Br:16]C1C(=O)C2N3N=CN=C3SC=2CC1>>[BrH:16].[Br:15][CH:11]1[C:10](=[O:14])[C:8]2[N:9]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]3=[N:6][C:7]=2[CH2:13][CH2:12]1
Reactant: O=C1c2c(sc3ncnn23)CCC1Br
Reactant: O=C1CCCc2nc3ccccn3c21
Agent: Br
Product: O=C1c2c(nc3ccccn23)CCC1Br

Procedure:
6,7-Dihydropyrido[1,2-a]benzimidazole-9 (8H)-one prepared in the above (A) was subjected to bromination in the similar manner to that of Example 1, Route 1(C) to give 8-bromo-6,7-dihydropyrido[1,2-a]benzimidazole-9(8H)-one hydrobromide. The resulting compound (17.4 g) and thiourea (6.0 g) were dissolved into absolute ethanol (200 ml), and the solution was heated to reflux for 4 hours. After completion of the reaction, the reaction mixture was cooled and filtered to give solids (10.6 g), which are dihydrobromide of the desired compound. The dihydrobromide was neutralized with 2N-potassium hydroxide in an aqueous system and recrystallized with a mixture of DMF and ethanol to give the titled compound (7.1 g, 56%).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH:4]=[CH2:5].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.C(=O)(O)[O-].[Na+]>CO>[CH2:1]([N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCCBr
Reactant: c1c[nH]cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C=CCCCn1ccnc1
Reaction time: 50 h

Procedure:
Pent-4-enyl bromide (10 g, 0.067 mole) was added dropwise to a stirred refluxing mixture of imidazole (9 g; 0.132 mole) and sodium bicarbonate (11 g; 0.13 mole) in methanol (50 ml). After addition the mixture was stirred for a further 50 hours under reflux. The reaction mixture was filtered to remove the insoluble matter and the filtrate evaporated to a yellow oil. This oil was taken up in 2M HCl (150 ml) and washed with ether (50 ml). The acid solution was then basified with 10M NaOH (about 30 ml) and extracted with chloroform (3×50 ml). The combined extracts were dried over anhydrous MgSO4 and the solvent removed under vacuum to leave a yellow oil as crude product, which was purified on silica gel column using 10% MeOH/EtOAc as eluent. 1.0 g distilled in vacuo b.p. 132°/12 mm, yield 0.9 g. Micro analysis: C8H12N2 requires C,70.59, H,8.82, N,20.59. Found: C,69.24, H,8.56, N,20.11.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:7]([CH2:8][OH:9])=[CH:6][NH:5][N:4]=1>C1(C)C=CC=CC=1.O=[Mn]=O>[F:11][C:2]([F:1])([F:10])[C:3]1[C:7]([CH:8]=[O:9])=[CH:6][NH:5][N:4]=1
Reactant: OCc1c[nH]nc1C(F)(F)F
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: O=Cc1c[nH]nc1C(F)(F)F
Yield: 101.2 %

Procedure:
(3-(Trifluoromethyl)-1H-pyrazol-4-yl)methanol (54.00 g, 0.325 mol) was suspended in toluene (2 L). MnO2 (113.00 g, 1.30 mol) and 4 Å molecular sieve powder (54.00 g) were added. The reaction mixture was stirred at reflux under nitrogen with a Dean-Stark trap for 5.5 h. The resulting mixture was filtered hot and the cake allowed to cool before washing with 1:1 DCM:MeOH solution (3×500 mL). The combined filtrates were concentrated in vacuo to give the desired product (54.00 g, 0.329 mol, 100%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[NH3:14]>C(O)C>[NH2:14][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: N
Solvent: CCO
Product: Nc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a solution of 25 g 2-Chloro-3,5-dinitropyridine in 190 ml ethanol were added dropwise 75 ml concentrated ammonia at room temperature. After stirring for 1 hour (hr), the mixture was cooled in an ice bath. The product was isolated by filtration and washed with cold water.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:12]([NH:15][CH3:16])(=[O:14])=[O:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[C:32]([Sn](C)(C)C)[N:31]=[C:30]([C:38]#[N:39])[N:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.C(OCC)(=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>[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([S:12](=[O:14])(=[O:13])[NH:15][CH3:16])[CH:3]=2)[N:31]=[C:30]([C:38]#[N:39])[N:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[Sn](C)(C)c1cc(CCCOCc2ccccc2)nc(C#N)n1
Reactant: CNS(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1cc(-c2cc(CCCOCc3ccccc3)nc(C#N)n2)cc(C(F)(F)F)c1
Yield: 35 %

Procedure:
3-Bromo-N-methyl-5-trifluoromethyl-benzenesulphonamide (37 mg), 4-(3-benzyloxy-propyl)-6-trimethylstannanyl-pyrimidine-2-carbonitrile (40 mg) and dichlorobis(triphenylphosphine)palladium(II) (7 mg) in DMF (1 mL) were heated in a microwave to 180° C. for five minutes. The mixture was diluted with ethyl acetate (20 mL) and washed with water (3×20 mL). Organics were separated, dried over sodium sulphate, filtered, and solvent was removed under reduced pressure to yield crude product. Purification by preparative-HPLC afforded 4-(3-benzyloxy-propyl)-6-(3-methylsulphamoyl-5-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile (16.5 mg).
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][CH:8]=O)[C:4](=[O:10])O1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl>[OH:6][C@@H:5]1[CH2:7][CH2:8][N:12]([CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)[C:4]1=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC1(C)OC(=O)[C@@H](CC=O)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](O)C2=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
(R)-2-(2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (16 g, 101 mmol) was dissolved in ClCH2CH2Cl (500 mL) and tert-butyl 4-aminopiperidine-1-carboxylate (40.5 g, 202 mmol) and acetic acid (6.94 mL, 121 mmol) were added and stirred at ambient temperature for 15 minutes. NaBH(OAc)3 (64.3 g, 304 mmol) was added in 3 portions and the reaction stirred at ambient temperature overnight. The reaction was carefully quenched with saturated aqueous NaHCO3. The reaction was partitioned between aqueous NaHCO3 and CH2Cl2, extracted, washed with 10% citric acid, brine, dried over Na2SO4, filtered and concentrated. The solids were purified over silica gel (5 to 10% methanol in EtOAc) to afford (R)-tert-butyl 4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (20.5 g, 72.1 mmol, 71.3% yield) as a white solid.
Reaction SMILES: [CH:1]#[C:2][CH2:3][NH:4][C:5]([NH2:7])=[O:6].[F:8][C:9]1[C:10](I)=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])/[C:12]/2=[CH:19]\[C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH3:25]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:8][C:9]1[C:10]([C:1]#[C:2][CH2:3][NH:4][C:5]([NH2:7])=[O:6])=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])/[C:12]/2=[CH:19]\[C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH3:25]
Reactant: C#CCNC(N)=O
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCNC(N)=O)c21

Procedure:
Using Method C above, 2-propynylurea (50 mg, 0.51 mmol) (see below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (75 mg, 0.203 mmol) using (Ph3P)4Pd (23.5 mg) and CuI (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 18 h to give (Z)-[3-[5-fluoro-2,3-dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2-oxo-1H-indol-4-yl]-2-propynyl]urea. (Yield 11 mg, 16%).
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][NH2:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[O-:20][C:21]#[N:22].[K+].O.C(OCC)C>Cl>[CH2:17]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][NH:16][C:21]([NH2:22])=[O:20])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:18][CH3:19]
Reactant: N#C[O-]
Reactant: CCCN(CCC)C1CCc2cccc(CN)c2C1
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCCN(CCC)C1CCc2cccc(CNC(N)=O)c2C1

Procedure:
2.6 g (10 mmol) of 2-dipropylamino-8-aminomethyl-1,2,3,4-tetrahydronaphthalene were dissolved in 22 ml of 1 N hydrochloric acid under nitrogen. A solution of 0.81 g (10 mmol) of potassium cyanate and 6 ml of water was subsequently added dropwise at a maximum of +25° C., and the batch was allowed to react for 4 h at room temperature. 20 ml of diethyl ether were then added. The aqueous phase was separated off and adjusted to pH 9 using 1 N sodium hydroxide solution. The precipitated reaction product was filtered off under suction and dried at +40° C. in vacuo. The product was purified by recrystallization from methanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[NH:15][N:14]=[C:13]([CH3:16])[C:8]=2[C:9](O)=[N:10][CH:11]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:19])=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[NH:15][N:14]=[C:13]([CH3:16])[C:8]=2[C:9]([Cl:19])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(O)c2c(C)n[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc(Cl)c2c(C)n[nH]c12

Procedure:
22.1 g. of 4-hydroxy-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid ethyl ester (0.1 mol.) and 100 ml. of phosphorus oxychloride are refluxed for 10 hours. After this time, the excess phosphorus oxychloride is removed by distillation. The oily residue is poured into 50 ml. of ice water. On neutralization with aqueous ammonia, 4-chloro-3-methyl-1H-pyrazolo[4,3-c]-pyridine-7-carboxylic acid ethyl ester crystallizes and is filtered. Recrystallization yields 12 g. (50%), m.p. 180°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:32])[NH:12]3)[CH2:10][CH:9]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C2(CC(c3cccs3)Oc3ccc(Br)cc32)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CC(c1cccs1)Oc1ccc(Br)cc12
Yield: 70.9 %

Procedure:
A suspension of 6-bromo-2-(thiophen-2-yl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (135 mg, 0.357 mmol) and Lawesson's Reagent (144.3 mg, 0.357 mmol) in anhydrous 1,4-dioxane (4 mL) was heated under reflux for 24 h. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(thiophen-2-yl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (100 mg, 80%). 1H-NMR (CDCl3): 2.41 (m, 1H), 2.55 (dd, 1H), 6.04 (dd, 1H), 6.80 (d, 1H), 6.94 (t, 1H), 7.12 (d, 1H), 7.33 (m, 3H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]=[N:11][CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][CH:26]=1.O>O1CCCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)[C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:30])([F:29])[F:19])[CH:26]=1
Reactant: FC(F)(F)c1cccc([Mg]Br)c1
Reactant: CN1CCC(N=Cc2nc3ccccc3[nH]2)CC1
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(NC(c2cccc(C(F)(F)F)c2)c2nc3ccccc3[nH]2)CC1

Procedure:
To a solution of (1H-benzimidazol-2-ylmethylene)(1-methylpiperidin-4-yl)amine (70 mg) in tetrahydrofurane (3 mL) is added a 1.5M solution of 3-trifluoromethylphenylmagnesium bromide in tetrahydrofurane (0.77 mL) at room temperature. The mixture is then stirred at 40° C. for 1 h, hydrolyzed with water and extracted with ethyl acetate. The pooled organic extracts are washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography (gradient dichloromethane/methanol/ammonia from 95/5/0.5 to 90/10/0.5) to give [(1H-benzimidazol-2-yl)(3-trifluoromethylphenyl)methyl](1-methylpiperidin-4-yl)amine as a yellow solid melting at 90° C.
Reaction SMILES: [CH:1]1([N:4]([CH:30]2[CH2:32][CH2:31]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19]/[C:20](/SC)=[CH:21]/[C:22](=O)[CH3:23])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:33]([N:35](C(OC(C)(C)C)=O)[NH2:36])[CH3:34].C(O)=O>C(O)(=O)C>[CH:1]1([N:4]([CH:30]2[CH2:32][CH2:31]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:21]=[C:22]([CH3:23])[N:35]([CH2:33][CH3:34])[N:36]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCN(N)C(=O)OC(C)(C)C
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N/C(=C/C(C)=O)SC)nc21
Solvent: CC(=O)O
Solvent: O=CO
Product: CCn1nc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)cc1C
Temperature: 35 °C
Reaction time: 4 h
Yield: 54.9 %

Procedure:
A mixture of (Z)-N,N-dicyclopropyl-6-ethyl-1-methyl-4-(1-(methylthio)-3-oxobut-1-enylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 74B, 70 mg, 0.155 mmol) and tert-butyl 1-ethylhydrazinecarboxylate (49.6 mg, 0.309 mmol) in acetic acid (1 mL) wan stirred at 35° C. for 4 h (monitored by LC/MS until no starting material left). Formic acid (1 mL) was added and the reaction mixture stirred at 60° C. for 6 h. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 2-10% methanol/dichloromethane). The material was further purified by preparative HPLC to afford N,N-dicyclopropyl-6-ethyl-4-(1-ethyl-5-methyl-1H-pyrazol-3-ylamino)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (38 mg, 53.4% yield) as an off-white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([NH:15][NH2:16])[N:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:8]2=[O:24])(=[O:3])[CH3:2].[CH:25]1(C(Cl)=O)CCC[CH2:26]1>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]1[C:25]([CH3:26])=[N:16][N:15]=[C:10]1[N:9]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:8]2=[O:24])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2nc(NN)n(Cc3ccccc3)c(=O)c2c1
Reactant: O=C(Cl)C1CCCC1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(c1)c(=O)n(Cc1ccccc1)c1nnc(C)n21

Procedure:
7.0 g (21.6 mmol) of 6-acetamido-3-benzyl-2-hydrazino-3,4-dihydro-quinazolin-4-one (synthesized according to a process described in patent application WO 00/66584) dissolved in glacial acetic acid are placed in a round-bottomed flask equipped with a stirrer and a condenser. Then, 3.15 g (23.8 mmol) of cyclopentylformyl chloride are added in a portionwise manner with stirring. The solution obtained is heated to reflux for 20 min. The solvent is evaporated off under vacuum and the residue is taken up in water.
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([CH2:9][C:10](O)=[O:11])[CH2:7][C:6]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][C:20]3[N:21]=[C:22]4[N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][CH2:24][N:23]4[CH:35]=3)=[CH:16][C:5]=2[CH2:4][N:3]1[CH2:36][C:37]([F:40])([F:39])[F:38].[CH2:41]([OH:52])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51].[ClH:53].O1CCOCC1>>[ClH:53].[O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([O:52][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:11])[CH2:7][C:6]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][C:20]3[N:21]=[C:22]4[NH:27][CH2:26][CH2:25][CH2:24][N:23]4[CH:35]=3)=[CH:16][C:5]=2[CH2:4][N:3]1[CH2:36][C:37]([F:38])([F:40])[F:39]
Reactant: CCCCCCCCCCCO
Reactant: CC(C)(C)OC(=O)N1CCCn2cc(CCOc3ccc4c(c3)CN(CC(F)(F)F)C(=O)[C@H](CC(=O)O)C4)nc21
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCCCCCCCOC(=O)C[C@@H]1Cc2ccc(OCCc3cn4c(n3)NCCC4)cc2CN(CC(F)(F)F)C1=O
Temperature: 45 °C
Reaction time: 4 h

Procedure:
704 mg (1.24 mmol) of (4S)-3-oxo-8-[2-(8-tert-butoxycarbonyl-5,6,7,8-tetra-hydroimidazo[1,2-a]pyrimidin-2-yl)ethoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetic acid obtained in Example 5-(a) and 1.30 mL (6.26 mmol) of 1-undecyl alcohol were mixed, 12.4 mL (49.6 mmol) of 4N hydrogen chloride/1,4-dioxane solution was added to the mixture, and the resulting mixture was stirred under nitrogen gas atmosphere at 45° C. for 4 hours.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH:17]1([C:20]2[C:25]([CH2:26][CH2:27]O)=[CH:24][N:23]=[C:22]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[N:21]=2)[CH2:19][CH2:18]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:27][CH2:26][C:25]3[C:20]([CH:17]4[CH2:19][CH2:18]4)=[N:21][C:22]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][CH:30]=4)=[N:23][CH:24]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: OCCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc2ccc(OCCc3cnc(-c4ccc(C(F)(F)F)cc4)nc3C3CC3)cc21

Procedure:
In analogy to the procedure described in example 5 f], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 6 b]) was reacted with 2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethanol in the presence of di-tert-butyl azodicarboxylate and triphenylphosphine in tetrahydrofuran to yield the title compound as colorless liquid.