Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:9][C:10]1[NH:11][N:12]([C:21]2[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][C:22]=2[Cl:29])[C:13](=[O:20])[C:14]=1[N:15]1[CH:19]=[CH:18][CH:17]=[N:16]1)(=O)C1C=CC=CC=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].[OH-].[Na+].Cl>CO>[NH2:9][C:10]1[NH:11][N:12]([C:21]2[C:22]([Cl:29])=[CH:23][C:24]([Cl:28])=[CH:25][C:26]=2[Cl:27])[C:13](=[O:20])[C:14]=1[N:15]1[CH:19]=[CH:18][CH:17]=[N:16]1
Reactant: O=C(Nc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c(=O)c1-n1cccn1)c1ccccc1
Agent: Cl
Agent: [Ba+2]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c(=O)c1-n1cccn1
Temperature: 45 °C
Yield: 70.5 %

Procedure:
194 g of 3-benzoylamino-4-(1-pyrazolyl)-1-(2,4,6-trichlorophenyl)-5-pyrazolone were mixed with 400 mL of methanol, and 30 g of barium hydroxide octahydrate and 140 g of a 25% (W/V) aqueous solution of sodium hydroxide were added to the resultant mixture. After agitation of the resultant reaction mixture for 6 hours at an internal temperature of 65° C., the residual ratio of the raw material was 0.5% or less in an HPLC analysis. After the reaction mixture was cooled to 45° C., 500 mL of concentrated hydrochloric acid were added to the reaction mixture, and precipitated insoluble substances (barium chloride and sodium chloride) were eliminated by filtration. The filtrate was extracted twice with toluene, and the aqueous phase after the extraction was neutralized by adding a 25% (W/V) aqueous solution of sodium hydroxide so that the pH value of the aqueous phase became 3.5. Precipitated crystals were separated by filtration, and the obtained crystals were washed and dried to obtain 105 g of desired 3-amino-4-(1-pyrazolyl)-1-(2,4,6-trichlorophenyl)-5-pyrazolone (yield of 70.5%) as gray-white powder. The structure of the product was confirmed by 1H-NMR. Results of physical analyses are as follows.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:18])=[C:11]([NH2:17])[C:12]([CH3:16])=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19](O)=O>>[CH2:1]([O:8][C:9]1[C:10]2[N:18]=[CH:19][NH:17][C:11]=2[C:12]([CH3:16])=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: Cc1cc(C)c(OCc2ccccc2)c(N)c1N
Product: Cc1cc(C)c2[nH]cnc2c1OCc1ccccc1
Yield: 61 %

Procedure:
A mixture of 2.50 g (10.3 mmols) of 3-benzyloxy-4,6-dimethyl-1,2-phenylenediamine [J. Med. Chem., 30, 2216 (1987)]and 20 ml of formic acid was heated under reflux for 30 minutes. The mixture was concentrated under reduced pressure, and then an aqueous saturated sodium bicarbonate solution was added to the residue followed by extraction of the solution with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/ methanol =40/1) to afford 1.59 g (yield: 61%) of 7-benzyloxy-4,6-dimethylbenzimidazole.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:27]4[CH:28]=[N:23][CH:24]=[N:25][CH:26]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Reactant: OB(O)c1cncnc1
Product: CC(C)OC(=O)N1CCC(C2Cc3cc(-c4cncnc4)ccc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidine-1-carboxylic acid isopropyl ester and pyrimidine-5-boronic acid following a procedure analogous to that described in Example 1. LC (method 5): tR=1.49 min; Mass spectrum (ESI+): m/z=368 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:20][CH:19]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=Cc1ccc(F)cc1
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccc(F)cc2)N1

Procedure:
The same method as employed in the preparation of intermediate 1 and 2 but starting from racemic tryptophan methyl ester and 4-fluorobenzaldehyde gave the cis isomer as white crystals m.p.:92° C. and the trans isomer as pale yellow crystals m.p.:183° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10](Cl)=[CH:11][CH:12]=2)[N:7]([CH:15]([CH3:17])[CH3:16])[C:6]=1[CH3:18])=[O:4].[CH3:19][C:20]1[CH:21]=[C:22]([OH:35])[CH:23]=[CH:24][C:25]=1B1OC(C)(C)C(C)(C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl>O.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].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:25]3[CH:24]=[CH:23][C:22]([OH:35])=[CH:21][C:20]=3[CH3:19])=[CH:11][CH:12]=2)[N:7]([CH:15]([CH3:17])[CH3:16])[C:6]=1[CH3:18])=[O:4]
Reactant: Cc1cc(O)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1c(C)n(C(C)C)c2cc(Cl)ccc12
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1c(C)n(C(C)C)c2cc(-c3ccc(O)cc3C)ccc12
Temperature: 120 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
A mixture of 6-chloro-1-isopropyl-2-methyl-1H-indole-3-carboxylic acid methyl ester (200 mg, 0.75 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (351 mg, 1.50 mmol), dioxane (2.5 mL), potassium phosphate tribasic, N-hydrate (2.59 g, 1.28 mmol), tris(dibenzylideneacetone)dipalladium(0) (12 mg, 0.013 mmol) and tricyclohexylphosphine (9 mg, 0.03 mmol) is stirred under nitrogen at 120° C. for 16 h. The mixture is acidified with 1N HCl, diluted with water, and extracted with ether. The combined ether layers are washed with brine and dried over MgSO4. The crude product is purified via flash chromatography (40 g SiO2) cluting with 30% THF-heptane to yield the title compound (223 mg, 88%) as a white solid. ES/MS ma/c 338.0 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:29][C:30]([F:42])([F:41])[O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH:18]([N:13]1[C:12]([C:35]2[CH:34]=[CH:33][C:32]([O:31][C:30]([F:29])([F:41])[F:42])=[CH:37][CH:36]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)n1nc2c(c1-c1ccc(OC(F)(F)F)cc1)CCNCC2
Yield: 88.8 %

Procedure:
The title compound (196 mg) was prepared according to Example 189 using 278 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 402 mg of 4-trifluoromethoxyphenylboronic acid. MS (ESI): exact mass calculated for C17H20F3N3O, 339.36; found, m/z 340.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.53-7.45 (m, 4H), 4.66 (br s, 1H), 4.40 (J=6.68 Hz, 1H), 3.45-3.43 (m, 1H), 3.23-3.21 (m, 1H), 2.88-2.79 (m, 2H), 1.42 (d, J=6.7 Hz, 6H).
Reaction SMILES: [OH:1][CH:2]1[CH:6]([OH:7])[CH2:5][NH:4][CH:3]1[CH2:8][OH:9].[C:10]([C@H:13]([C@@H:15]([C:17]([O-:19])=[O:18])[OH:16])[OH:14])([O-:12])=[O:11].C(O[C@H]1[C@H](OCC2C=CC=CC=2)[C@@H](COCC2C=CC=CC=2)NC1)C1C=CC=CC=1>C(O)(=O)C.CO.[Pd]>[OH:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][NH:4][C@@H:3]1[CH2:8][OH:9].[C:10]([C@H:13]([C@@H:15]([C:17]([O-:19])=[O:18])[OH:16])[OH:14])([O-:12])=[O:11]
Reactant: OCC1NCC(O)C1O
Agent: [Pd]
Agent: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Agent: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CO
Product: OC[C@H]1NC[C@@H](O)[C@@H]1O

Procedure:
A more direct way to synthesise 3,4-dihydroxy-2-hydroxymethylpyrrolidine, D-tartrate is by reduring 2,3,5-Tri-O-benzyl-1,4-dideoxy-1,4-imino-D-arabinitol with Pd/C in glacial acetic acid. The formed, oily (2R,3R,4R)-3,4-dihydroxy-2-hydroxymethyl-pyrrolidine,acetate is dissolved in methanol and added to a solution containing D-tartraric acid at reflux and (2R,3R,4R)-3,4-dihydroxy-2-hydroxymethylpyrrolidine, D-tartrate is formed and can be isolated by filtration. Ion exchange chromatography is thereby avoided.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH2:31][N:32]=[C:33]=[S:34]>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:33]([NH:32][CH2:31][C:27]4[O:26][CH:30]=[CH:29][CH:28]=4)=[S:34])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: S=C=NCc1ccco1
Solvent: CC#N
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=S)NCc5ccco5)c4c(c23)C1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
200 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.60 mmole) were dissolved in 15 ml of acetonitrile. 120 μl (2 molar equivalents) of 2-furylmethyl isothiocyanate was added and the reaction was maintained at room temperature overnight then for 5 hours at 55° C. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 212 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=75%) which was characterized as follows:
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[CH2:9][C:10]1[CH:25]=[CH:24][C:13]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:12][CH:11]=1.CCN(CC)CC.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[O:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:3]2[CH2:4][C@@H:5]3[CH2:8][C@H:2]2[CH2:7][N:6]3[C:36](=[O:37])[CH2:35][O:34][CH3:33])=[CH:25][CH:24]=1
Reactant: COCC(=O)Cl
Reactant: c1ccc2sc(Oc3ccc(CN4C[C@@H]5C[C@H]4CN5)cc3)nc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Oc2nc3ccccc3s2)cc1
Reaction time: 18 h

Procedure:
To a stirred solution of (S,S)-2-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazole hydrochloride (144 mg, 0.35 mmol) and Et3N (200 μL, 1.4 mmol) in CH2Cl2 (15 mL) at rt was added methoxyacetyl chloride (50 μL, 0.53 mmol). After 18 h at rt, the reaction mixture was partitioned between CH2Cl2 (150 mL) and satd. aq. NaHCO3 (50 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated. Purification by silica gel flash chromatography (0% to 5% CH3OH in CH2Cl2) afforded the title compound as a viscous, colorless oil (127 mg, 89%). MS (ESI): mass calcd. for C22H23N3O3S, 409.15; m/z found, 410.2 [M+H]+. 1H NMR (500 MHz, CDCl3, mixture of rotamers): 7.74 (d, J=7.5 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.40 (m, 3H), 7.30 (m, 3H), 4.83 (br m, 0.5H), 4.46 (br m, 0.5H), 4.06 (m, 1H), 4.01 (s, 1H), 3.76 (m, 2.5H), 3.63 (br d, J=9.3 Hz, 0.5H), 3.58 (br s, 1H), 3.45 (s, 1.5H), 3.43 (s, 1.5H), 3.35 (br d, J=2.1 Hz, 0.5H), 3.33 (m, 0.5H), 3.01 (dd, J=9.9, 2.3 Hz, 0.5H), 2.87 (dd, J=9.8, 2.2 Hz, 0.5H), 2.78 (br d, J=9.9 Hz, 0.5H), 2.58 (d, J=9.5 Hz, 0.5H), 1.99 (br d, J=9.3 Hz, 0.5H), 1.96 (br d, J=9.8 Hz, 0.5H), 1.76 (br d, J=10.0 Hz, 0.5H), 1.66 (br d, J=10.0 Hz, 0.5H).
Reaction SMILES: [Br:1][C:2]1[C:15]([F:16])=[CH:14][C:13]2[CH:12]3[CH2:17][CH:10]([CH2:11]3)[N:9]3[C:5](=[N:6][C:7]([C:20]([O:22]C)=[O:21])=[C:8]3[CH:18]=[O:19])[C:4]=2[CH:3]=1.[Li+].[OH-]>O.CO>[Br:1][C:2]1[C:15]([F:16])=[CH:14][C:13]2[CH:12]3[CH2:11][CH:10]([CH2:17]3)[N:9]3[C:5](=[N:6][C:7]([C:20]([OH:22])=[O:21])=[C:8]3[CH:18]=[O:19])[C:4]=2[CH:3]=1
Reactant: COC(=O)c1nc2n(c1C=O)C1CC(C1)c1cc(F)c(Br)cc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=Cc1c(C(=O)O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Yield: 74.8 %

Procedure:
Methyl 9-bromo-10-fluoro-3-formyl-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7(12),8,10-pentaene-4-carboxylate (125 mg) was saponified with LiOH in H2O/MeOH to give 90 mg of 9-bromo-10-fluoro-3-formyl-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7(12),8,10-pentaene-4-carboxylic acid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([Si](CC)(CC)CC)=[C:6]2[CH2:19][CH2:20][NH:21][C:22]([C:24]1[CH:28]=[C:27]([CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[F:37])[O:26][N:25]=1)=[O:23])#[N:2]>FC(F)(F)C(O)=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:19][CH2:20][NH:21][C:22]([C:24]1[CH:28]=[C:27]([CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[F:37])[O:26][N:25]=1)=[O:23])#[N:2]
Reactant: CC[Si](CC)(CC)c1[nH]c2ccc(C#N)cc2c1CCNC(=O)c1cc(Cc2cc(F)ccc2F)on1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2[nH]cc(CCNC(=O)c3cc(Cc4cc(F)ccc4F)on3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
N-(2-(5-cyano-2-(triethylsilyl)-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide (0.036 g; 0.069 mmol) was dissolved in trifluoroacetic acid (2 mL) and the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure with toluene. The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.012 g (47%) of N-(2-(5-cyano-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a white solid.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:31]=2)[CH:26]=[N:25]1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:29]3[CH:28]=[C:27]4[C:32](=[CH:31][CH:30]=3)[N:24]([CH3:23])[N:25]=[CH:26]4)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: Cn1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc5c(cnn5C)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (from Combi-Blocks). LCMS calculated for C24H24N5O2(M+H)+: m/z=414.2. Found 414.2.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]#[N:14])=[N:4][NH:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16]>N1C=CC=CC=1>[SH:16][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]#[N:14])=[N:4][N:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: N#CCc1n[nH]c(=O)c2ccccc12
Solvent: c1ccncc1
Product: N#CCc1nnc(S)c2ccccc12
Reaction time: 2 h
Yield: 105.6 %

Procedure:
3,4-dihydro-4-oxo-1-phthalazin-acetonitrile (126 g) is suspended in anhydrous pyridine (1300 ml) under anhydrous conditions. P2S5 (230 g) is added portionwise to this suspension at room temperature and with stirring, then the mixture is slowly heated to reflux temperature and kept at this temperature for about 2 h. Pyridine is then evaporated under reduced pressure and the residue is poured into water (3 l). The solid which separates is recovered by filtration, thoroughly wshed first with water and then with cold dilutes aqueous ammonia. The recovered solid is oven-dried, yielding 4-mercapto-phthalazin-acetonitrile (110 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15](Cl)=[O:16])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:18]1([NH2:27])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]=[CH:19]1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[N:18]1([NH:27][C:15]([C:11]2[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:16])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]=[CH:19]1
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Cl
Reactant: Nn1ccc2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid chloride (1 mmol) in EtOAc (10 mL) is added to a stirred solution of pyrrolo[2,3-b]pyridin-1-ylamine (1 mmol) and K2CO3 (1 mmol) in EtOAc (20 mL) and H2O (20 mL) at rt, then stirred at rt overnight. EtOAc is evaporated in vacuo, and the resulting solid is collected by filtration. The solid is purified by silica gel chromatography eluting with 20-80% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid pyrrolo[2,3-b]pyridin-1-ylamide (162 mg, 47%) as a solid. MS: 348 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.78 (s, 3H), 6.59 (m, H) 7.09-7.58 (m, 4H), 7.96 (m, H), 8.22 (m, H), 8.31 (d, 2H), 9.14 (s, 2H). IC50=12 nM.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:9]=[C:10](I)[C:3]=12.[CH2:30]([OH:33])[C:31]#[CH:32].ClCCl>C1COCC1.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:9]=[C:10]([C:32]#[C:31][CH2:30][OH:33])[C:3]=12
Reactant: Nc1ncnc2c1c(I)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Reactant: C#CCO
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1ncnc2c1c(C#CCO)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Yield: 76.8 %

Procedure:
To a solution of Example 57a (0.180 g, 0.363 mmoles) in THF (5 ml), propargyl alcohol (0.051 g, 0.436 mmoles) diisopropylamine (0.31 ml, 1.81 mmoles), copper(I) iodide (7 mg, 0.036 mmoles) and) Tetrakis triphenylphosphine Palladium (0.042 g, 0.0363 mmoles) were added and the system is degassed for 30 min. and heated to reflux for 4 h. The reaction mixture filtered through celite pad and washed with ethyl acetate. The filtrate was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as brown solid (0.118 g, 77% yield). MP: 171-173° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.21(s, 1H), 8.06(dd, J=7.9, 1.6 Hz, 1H), 7.77(m, 1H), 7.50(dt, J=8.0, 0.9 Hz, 1H), 7.40-7.33(m, 6H), 5.43(s, 2H), 4.33(d, J=6.1 z, 2H). Mass: 423.88(M+).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[N+]([C:13]1[CH:18]=CC=C[CH:14]=1)([O-])=O.S(=O)(=O)(O)O>OCC(CO)O>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[C:4]([CH3:9])[CH:3]=1)[N:6]=[CH:18][CH:13]=[CH:14]2
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Cc1cc(Br)ccc1N
Agent: O=S(=O)(O)O
Solvent: OCC(O)CO
Product: Cc1cc(Br)cc2cccnc12
Reaction time: 3 h

Procedure:
A mixture of 10 g of 4-bromo-2-methylaniline, 3.3 g of ferrous sulfate, 20.4 g of glycerol, 4.06 g of nitrobenzene and 11.5 ml of concentrated sulfuric acid was heated gently. After the first vigorous reaction, the mixture was boiled for 3 h under reflux and then evaporated to remove t nitrobenzene. The solution was added std. aq.NaHCO3 and extracted with dichloromethane, dried with Na2SO4 and concentrated to give solid. The solid was purified with flash column chromatography to return the title compound (9.5 g, 80%). 1H NMR (CDCl3, 300 MHz) δ 8.92 (m, 1H), 8.01 (m, 1H), 7.81 (d, 1H), 7.66 (m, 1H), 7.43 (m, 1H), 2.79 (s, 3H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][CH:16]=2)(=O)=O)=CC=1.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C>[N:23]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][CH:16]=1)=[N+:24]=[N-:25]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(C=O)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOc1ccc(C=O)cc1

Procedure:
A solution of 5.0 g (15.61 mmol) of the compound from Example 35A and 2.03 g (31.22 mmol) of sodium azide in 100 ml of dry DMF is stirred at RT for 12 h. The reaction mixture is concentrated using a rotary evaporator, and the residue is suspended in about 20 ml of water. After three extractions with in each case 30 ml of diethyl ether, the combined organic phases are washed twice with in each case 10 ml of water and once with 10 ml of saturated sodium chloride solution. After drying over sodium sulphate, the solvent is removed on a rotary evaporator.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13](SCC)[N:12]2[CH:18]=[C:19]([CH2:21][N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[N:20]=[C:11]2[CH:10]=1.[OH-:29].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([OH:29])[N:12]2[CH:18]=[C:19]([CH2:21][N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[N:20]=[C:11]2[CH:10]=1
Reactant: [OH-]
Reactant: CCSc1nc(-c2ccc(Cl)cc2Cl)cc2nc(CN3CCN(C)CC3)cn12
Agent: [K+]
Product: CN1CCN(Cc2cn3c(O)nc(-c4ccc(Cl)cc4Cl)cc3n2)CC1

Procedure:
In analogy to Example 10A, 500 mg (97% of theory) of the product are obtained from 675 mg (1.31 mmol) of 7-(2,4-dichlorophenyl)-5-(ethylsulphanyl)-2-[(4-methylpiperazin-1-yl)methyl]-imidazo[1,2-c]pyrimidine (Example 93A) by heating in methanolic potassium hydroxide solution.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].[CH3:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=2[Cl:27])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].Cl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCOC(C)=O>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([C:2]3[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=3[OH:12])[CH:24]=[CH:25][C:26]=2[Cl:27])=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccc(O)c(Br)n1
Reactant: COc1ccc(COc2cc(B(O)O)ccc2Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(O)c(-c2ccc(Cl)c(OCc3ccc(OC)cc3)c2)n1
Temperature: 95 °C
Reaction time: 10 h
Yield: 76.1 %

Procedure:
A solution of 80 g (345 mmol) of methyl 6-bromo-5-hydroxy-2-pyridinecarboxylate and 146 g (499 mmol) of [3-[(4-methoxybenzyl)oxy]-4-chlorophenyl]boronic acid in 1600 mL of anhydrous dioxane is stirred for 15 minutes while sparging with argon, followed by addition of 143 g (1034 mmol) of anhydrous K2CO3 and 14 g (17.2 mmol) of PdCl2(dppf). The reaction medium is stirred for 10 hours at 95° C. under argon, cooled to room temperature and then poured at room temperature into 2 L of EtOAc and 350 mL of aqueous 1N HCl solution. The organic phase is washed with 300 mL of aqueous 1N HCl solution and 600 mL of water. After drying over Na2SO4 and concentrating under reduced pressure, the precipitate is taken up in 500 mL of a 7/3 pentane/DCM mixture, filtered and washed with 200 mL of pentane. 105 g of methyl 6-[3-[(4-methoxybenzyl)oxy]-4-chlorophenyl]-5-hydroxypyridine-2-carboxylate are thus obtained in the form of a brown powder, which is used without further purification in the following step.