Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][CH:9]=[C:8]2[O:17][C:18]1[C:19]([F:29])=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([NH2:28])[CH:22]=[CH:21]2.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35](O)=[O:36].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][CH:9]=[C:8]2[O:17][C:18]1[C:19]([F:29])=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([NH:28][C:35]([C:31]1[S:30][CH:34]=[CH:33][CH:32]=1)=[O:36])[CH:22]=[CH:21]2
Reactant: O=C(O)c1cccs1
Reactant: COc1cc2nccc(Oc3ccc4cc(N)ccc4c3F)c2cc1OC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc4cc(NC(=O)c5cccs5)ccc4c3F)c2cc1OC
Reaction time: 16 h

Procedure:
To a solution of 6-(6,7-dimethoxy-4-quinolyloxy)-5-fluoro-2-naphthylamine 2HCl (Step c, 200 mg, 0.46 mmol), thiophene-2-carboxylic acid (120 mg, 0.91 mmol, Aldrich) and DIEA (353 mg, 2.74 mmol, Aldrich) in dry DMF was added PyBOP (476 mg, 0.91 mmol, Fluka) at RT. The reaction was stirred for 16 h. It was diluted with 40 mL of EtOAc and washed with saturated aqueous NaHCO3, followed by brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc) to give the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 475.0 (M+1). Mass Calc'd for C26H19FN2O4S: 474.10.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=O)[C:5]([CH:7]1[CH2:9][CH2:8]1)=O.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([NH:27][NH2:28])[CH:24]=[CH:25][CH:26]=1>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:28][N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:19])([F:30])[F:29])[CH:22]=2)[C:5]=1[CH:7]1[CH2:9][CH2:8]1)=[O:18]
Reactant: NNc1cccc(C(F)(F)F)c1
Reactant: COC(=O)C(C(=O)c1cccnc1)C(=O)C1CC1
Solvent: CC(=O)O
Product: COC(=O)c1c(-c2cccnc2)nn(-c2cccc(C(F)(F)F)c2)c1C1CC1
Yield: 8.5 %

Procedure:
A solution of gave 3-cyclopropyl-3-oxo-2-(pyridine-3-carbonyl)-propionic acid methyl ester (326 mg, 1.25 mmol) and 3-(trifluoromethyl)phenylhydrazine (220 mg, 1.12 mmol) in 2 ml acetic acid was stirred 20 h at room temperature. The reaction mixture was evaporated, the residue treated with EtOAc:n-heptane 1:1 and filtered off. The filtrate was concentrated in vacuo and chromatographed (amino-phase silica gel, EtOAc:n-heptane 1:1) to yield the title compound as a light yellow gum (37 mg, 8%). MS: 388.3 (MH+).
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][N:14]2[C:19](=[O:20])[CH:18]=[CH:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([NH:27]C(=O)OC(C)(C)C)=[CH:23][CH:22]=3)=[CH:15]2)=[C:11]([F:37])[CH:10]=1>CO>[ClH:8].[Cl:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][N:14]2[CH:15]=[C:16]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[CH:17]=[CH:18][C:19]2=[O:20])=[C:11]([F:37])[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 178 %

Procedure:
According to Scheme 19 Step 2: HCl/dioxane (10 eq, 4M, 5.00 mL) was added to a solution of tert-butyl 4-(1-(4-chloro-2-fluorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)phenylcarbamate (1 eq, 2.00 mmol, 1.00 g) in MeOH (20 mL) at 0° C. The reaction was stirred for 2 days at 80° C., then the solvent was concentrated and Et2O was added. The solid was filtered and dried to yield 1-(4-chloro-2-fluorobenzyl)-5-(4-aminophenyl)pyridin-2(1H)-one hydrochloride (1.78 mmol, 0.76 g, 89%) as a beige solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[NH2:13][C:14]1[N:19]=[CH:18][N:17]=[C:16](Cl)[CH:15]=1>CS(C)=O>[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([O:3][C:16]3[N:17]=[CH:18][N:19]=[C:14]([NH2:13])[CH:15]=3)[CH:12]=2)[CH:8]=[CH:9]1
Reactant: Nc1cc(Cl)ncn1
Reactant: Oc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccc3cc[nH]c3c2)ncn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.5 %

Procedure:
Sodium hydride (200 mg, 5.00 mmol) was suspended in dimethyl sulfoxide (8 ml); while stirring at room temperature, 6-hydroxyindole (666 mg, 5.00 mmol) and 6-amino-4-chloropyrimidine (518 mg, 4.00 mmol) were added thereto one by one; and the reaction mixture was stirred at 60° C. for 2 hours, at 80° C. for 1 hour, and at 100° C. for 1.5 hours. After cooled down to room temperature, the reaction mixture was partitioned between ethyl acetate and water; and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300, hexane:ethyl acetate=1:1, ethyl acetate, then ethyl acetate:methanol=98:2); the obtained crystals were suspended in ethyl acetate (50 ml) and stirred at room temperature overnight, filtered off, washed with diethyl ether, and dried to yield the title compound (322 mg, 1.42 mmol, 35.6%) as pale yellow crystals.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:22][O:23][CH3:24])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:25])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[C:33]=1[CH:34]=[O:35]>C1COCC1>[Cl:25][C:5]1[CH:6]=[C:7]([N:8]([CH2:22][O:23][CH3:24])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)(=[O:11])=[O:10])[C:2]([CH:34]([C:33]2[C:36]([O:40][CH3:41])=[CH:37][CH:38]=[CH:39][C:32]=2[F:31])[OH:35])=[N:3][CH:4]=1
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: COc1cccc(F)c1C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(O)c1c(F)cccc1OC)S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-(2-Bromo-5-chloro-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (459 mg, 1.00 mmol) in anhydrous THF (5 mL) at −10° C. was added 2 M isopropylmagnesium chloride in THF (1.1 mL, 2.2 mmol) and stirred at the same temperature for 30 min. 2-Fluoro-6-methoxy-benzaldehyde (308 mg, 2.00 mmol) was subsequently added in one portion, and the reaction mixture was warmed to room temperature and stirred overnight (18 h). It was then quenched with saturated aqueous NH4Cl (10 mL), and extracted with EtOAc (3×75 mL). The combined extracts were washed with aqueous NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate-hexane to provide N-{5-chloro-2-[(2-fluoro-6-methoxy-phenyl)-hydroxy-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide. MS m/z 535.4 (M+H).
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[C:15]([OH:17])=O.[CH2:18]([C@@H:25]1[CH2:30][C@@H:29]([N:31]([CH2:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]=[CH:41][CH:40]=2)[C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH2:28][CH2:27][NH:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:18]([C@@H:25]1[CH2:30][C@@H:29]([N:31]([CH2:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]=[CH:41][CH:40]=2)[C:32](=[O:37])[C:33]([F:35])([F:36])[F:34])[CH2:28][CH2:27][N:26]1[C:15]([C:6]1[CH:7]=[CH:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=1)=[O:17])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(O)c1ccc2ccccc2c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(c1ccc2ccccc2c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Reaction time: 2 h

Procedure:
A solution of 58 μl (0.795 mmol) of thionyl chloride in 0.2 ml of toluene is added dropwise to a solution of 97 mg (0.56 mmol) of 2-naphthoic acid in 1 ml of toluene over the course of 10 minutes at 50° under argon, and the reaction mixture is stirred at 80° for 2 hours. It is then concentrated in a rotary evaporator, and 1 ml of toluene is added, and evaporation is repeated, twice each. The brown oil is dissolved in 1 ml of methylene chloride and added under argon to a solution of 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine at 0° and stirred at 0° for 2 hours. Water is subsequently added to the reaction mixture, and extraction with methylene chloride is carried out. The organic phases are washed with brine, dried over magnesium sulfate and evaporated to dryness. The yellow oil is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (1000:50:1). The title compound is obtained as yellow oil. TLC: methylene chloride/methanol/conc. ammonia (2000:50:1) Rf =0.36, FD-MS: M+ =581.
Reaction SMILES: Cl.C(OC(=O)[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH:21]([CH3:22])[CH2:20][CH2:19][CH2:18][CH:17]2[CH3:23])[N:10]=1)(C)(C)C.[OH-].[Na+]>CO>[CH3:23][CH:17]1[CH2:18][CH2:19][CH2:20][CH:21]([CH3:22])[N:16]1[CH2:15][C:11]1[N:10]=[C:9]([NH2:8])[CH:14]=[CH:13][CH:12]=1
Reactant: CC1CCCC(C)N1Cc1cccc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CCCC(C)N1Cc1cccc(N)n1
Temperature: 40 °C

Procedure:
HCl (1.25 mL, 1.25 mmol) in MeOH (15 mL) was added to [6-(2,6-dimethyl-piperidin-1-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (200 mg, 0.63 mmol) followed by heating at 40° C. for 18 h. The resulting mixture was cooled to RT and basified to pH 9 with 2 N NaOH. The mixture was extracted with CHCl3 (3×20 mL). The combined organic layers was dried over MgSO4 and concentrated in vacuo to give a yellow oil. MS m/z: 220.2 (M+H). Calc'd. for C13H21N3-219.17.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[NH2:46]>>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:46][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[Br:39])=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Reactant: Nc1ccccc1Br
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccccc4Br)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1

Procedure:
A solution of the product from Example 43D and 2-Bromo-phenylamine was reacted to provide 4-(4-Benzyloxy-phenoxy)-N-(2-bromo-phenyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzamide using the procedure from Example 43E. The material was then deprotected using the procedure from Example 43F to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (8 mg, 14%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H) 3.28 (m, 1 H) 6.77 (m, 2 H) 6.94 (m, 3 H) 7.24 (m, 1 H) 7.44 (m, 1 H) 7.54 (dd, J=7.74, 1.84 Hz, 1 H) 7.73 (dd, J=8.09, 1.50 Hz, 1 H) 7.86 (d, J=8.46 Hz, 1 H) 8.01 (dd, J=8.64, 2.02 Hz, 1 H) 8.15 (d, J=2.21 Hz, 1 H) 8.89 (s, 1 H) 8.98 (d, J=8.46 Hz, 1 H) 9.46 (s, 1 H) 10.06 (s, 1 H) 11.37 (s, 1 H); MS (ESI+) m/z 570, 572 (M+H)+.
Reaction SMILES: [C:1]1(=[O:19])[N:5]([C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=2)[C:9]([OH:11])=[O:10])[C:4](=[O:18])[CH2:3][CH2:2]1.[OH-:20].[Na+]>>[C:9]([C:8]1[CH:7]=[C:6]([CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=1)[NH:5][C:4](=[O:18])[CH2:3][CH2:2][C:1]([OH:19])=[O:20])([OH:11])=[O:10]
Reactant: O=C(O)c1cc(N2C(=O)CCC2=O)cc([N+](=O)[O-])c1
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)CCC(=O)Nc1cc(C(=O)O)cc([N+](=O)[O-])c1

Procedure:
3'-Carboxy-5'-nitrosuccinanilic Acid [F; Y is CH2CH2, Z is OH] was prepared by treating 3-succinimido-5-nitrobenzoic acid with warm dilute aqueous sodium hydroxide, and had the m.p. 220°-221° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[CH:24][C:25]([N+:37]([O-])=O)=[C:26]([N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[Pd].CCCCCC.C(OCC)(=O)C>[NH2:37][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)=[CH:16][CH:17]=2)=[CH:27][C:26]=1[N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3ccc(OCc4ccccc4)cc3)cc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3ccc(O)cc3)cc2)ccc1N
Yield: 89.6 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[5-(4′-benzyloxybiphenyl-4-yloxy)-2-nitrophenyl]-N-methylcarbamate (14.75 g), palladium on carbon (10%, 0.86 g) and toluene/ethyl acetate=1/1 (140 ml) and the reaction mixture was purified to give the title compound (10.2 g).
Reaction SMILES: [CH3:1][S-:2].[Na+].F[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[C:7]([O:14][CH3:15])[CH:6]=1.Cl>CN(C=O)C>[CH3:15][O:14][C:7]1[CH:6]=[C:5]([S:2][CH3:1])[CH:10]=[CH:9][C:8]=1[C:11](=[O:13])[CH3:12]
Reactant: COc1cc(F)ccc1C(C)=O
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(SC)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.5 %

Procedure:
Sodium thiomethoxide (1.3 g, 18.5 mmol) in DMF (15 ml) was added to 1-(4-fluoro-2-methoxyphenyl)ethanone (2.85 g, 16.9 mmol) in DMF (5 ml). The mixture was stirred for overnight at room temperature. HCl (1%) was added, the water phase was extracted with EtOAc, the combined organic phases were washed with LiCl (5%), brine and were concentrated to give the title compound (3.6 g) MS m/z (rel. intensity, 70 eV) 196 (M+, 35), 182 (11), 181 (bp), 166 (8), 136 (10).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:22]1>CCCCO>[Br:1][C:2]1[C:3]([N:21]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: c1ccc(C2CCNC2)nc1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Solvent: CCCCO
Product: O=C(Nc1c[nH]c2ncc(Br)c(N3CCC(c4ccccn4)C3)c12)c1cccnc1
Yield: 20.9 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (100 mg, 0.3 mmol, Example 1, Step I) in n-BuOH (3 mL) and 2-(pyrrolidin-3-yl)pyridine (133 mg, 0.9 mmol) were heated to 160° C. in a sealed tube for 48 hours. After cooling down, the reaction was concentrated to dryness, and the residue purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-90% CH3CN/water gradient; 30 CV) to yield N-(5-bromo-4-(3-(pyridin-2-yl)pyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (29 mg) as a solid. This solid was dissolved in MeOH (1 mL), and then the solution was added dropwise to a 4N HCl solution in dioxane. The resulting solid was collected and dried to yield N-(5-bromo-4-(3-(pyridin-2-yl)pyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (35 mg, 25% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.07 (d, 1H), 10.52 (s, 1H), 9.30 (d, 1H), 8.94-8.91 (m, 1H), 8.72-8.66 (m, 2H), 8.39-8.33 (m, 2H), 7.92-7.76 (m, 3H), 7.71 (d, 1H), 7.20 (br s, 2H), 4.06-3.95 (m, 2H), 3.80-3.67 (m, 3H), 2.48-2.40 (m, 1H), 2.23-2.11 (m, 1H). LCMS (APCI+) m/z 463, 465 (M+H)+, Retention time=2.78 minutes (Method 1).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.Br[C:27]1[C:32]2=[CH:33][CH:34]=[C:35]3[C:44](C=C4[C:37](C=CC=C4)=[CH:36]3)=[C:31]2[CH:30]=[CH:29][CH:28]=1>>[CH:13]1[C:12]2=[C:25]3[C:16](=[CH:9][CH:10]=[C:11]2[C:2]([C:3]2[C:8]4=[CH:37][CH:36]=[C:35]5[C:34]([CH:33]=[C:32]6[C:31]([CH:30]=[CH:29][CH:28]=[CH:27]6)=[CH:44]5)=[C:7]4[CH:6]=[CH:5][CH:4]=2)=[CH:15][CH:14]=1)[CH:17]=[C:18]1[C:23]([CH:22]=[CH:21][CH:20]=[CH:19]1)=[CH:24]3
Reactant: Brc1c2ccccc2c(-c2ccc3ccccc3c2)c2ccccc12
Reactant: Brc1cccc2c1ccc1cc3ccccc3cc12
Product: c1ccc2cc3c(ccc4c(-c5cccc6c5ccc5cc7ccccc7cc56)cccc43)cc2c1

Procedure:
Preparation analogous to Example 7. 9-Bromo-10-(2-naphthyl)anthracene is replaced by 15.4 g (50 mmol) of 4-bromobenz[a]anthracene. Recrystallisation four times from o-dichlorobenzene (about 15 ml/g); sublimation (p=5×10−5 mbar, T=320° C.). Yield: 16.8 g (37 mmol), 74.0%, purity 99.9% (HPLC), Tg=130.3° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][N:5]1[CH2:10][CH2:9][C:8]([F:12])([F:11])[CH2:7][CH2:6]1.[CH:14]([N-:17]C(C)C)(C)[CH3:15].[Li+].CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.BrCC#N.[NH4+].[Cl-]>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[CH:4]([N:5]1[CH2:6][CH2:7][C:8]([F:11])([F:12])[CH2:9][CH2:10]1)[CH2:15][C:14]#[N:17]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)CN1CCC(F)(F)CC1
Agent: N#CCBr
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Product: COC(=O)C(CC#N)N1CCC(F)(F)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 22 %

Procedure:
Treat a −78° C. solution of (4,4-difluoro-piperidin-1-yl)-acetic acid methyl ester (14.21 g, 73.6 mmol) (Preparation 33) in THF (150 mL) with a 2M solution of lithium diisopropylamide in heptane/THF/ethylbenzene (44.2 mL, 88.4 mmol) and stir at −78° C. for 20 minutes under N2. Treat the reaction with bromoacetonitrile (13.25 g, 110.5 mmol) and stir at −78° C. for 15 minutes. Warm the reaction to room temperature and stir 4 hours. Pour the reaction into saturated NH4Cl. Dilute the reaction with ethyl acetate and wash with water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Then, purify on silica with a 0 to 100% ethyl acetate in hexanes gradient to afford 3.74 g (22%) of the titled product. Rf=0.50 (1/1 hexanes/ethyl acetate). ES MS (m/z): 233 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[N+:10]([O-])([O-:12])=[O:11].[Na+].Cl.C(OCC)(=O)C>O.CCOCC>[CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1cc(C)cc(O)c1
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 30 %

Procedure:
Under a nitrogen atmosphere, 3,5-dimethylphenol (40.9 mmoles) was dissolved in 40 mL water and 40 mL ether. To this was added 1.5 equivalents (61.4 mmoles) of sodium nitrate (NaNO3). The reaction was cooled in an ice bath and 50 mL concentrated HCl was slowly added to the reaction. The reaction was warmed to room temperature and followed by TLC (ethyl acetate:hexanes, 1:1) until the reaction was complete (0.5 hour). The reaction was extracted into ether (×3), washed with saturated NaHCO3, saturated NaCl, dried over MgSO4, filtered, rinsed with ether, and concentrated. The product was purified using silica-gel chromatography, yielding 3,5-dimethyl-4-nitro-phenol as a yellow solid (2.05 grams; 30% yield). The product was characterized by NMR (DMSO).
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C@@H:8]([CH3:30])[CH2:9][O:10]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:4]1>C(O)=O.C(OCC)C>[F:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C@@H:8]([CH3:30])[CH2:9][OH:10])[CH2:4]1
Reactant: C[C@@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)N1CC[C@@H](CF)C1
Solvent: CCOCC
Solvent: O=CO
Product: C[C@@H](CO)N1CC[C@@H](CF)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
A mixture of (R)-3-(fluoromethyl)-1-((S)-1-(trityloxy)propan-2-yl)pyrrolidine (19.0 g, 47.1 mmol) and formic acid/diethyl ether (4:1, 189 mL) was stirred at room temperature for 8 h. This reaction mixture was concentrated on a rotary evaporator. The residue was dissolved in DCM, washed with sat'd aqueous K2CO3, and washed with brine. Organic layer was dried over Na2SO4, filtered, and concentrated to give the crude product that was purified by silica gel chromatography (10:7 ethyl acetate/hexanes to 10:7:2:1 ethyl acetate/hexane/methanol/triethylamine) to afford (S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propan-1-ol (3.9 g) as a dark orange oil. 1H NMR (400 MHz, DMSO-d6) δ 4.38-4.32 (m, 2H), 4.22-4.20 (m, 1H), 3.49-3.44 (m, 1H), 3.21-3.16 (m, 1H), 2.65-2.61 (m, 1H), 2.58-2.53 (m, 1H), 2.52-2.47 (m, 1H), 2.45-2.35 (m, 1H), 2.34-2.30 (m, 1H), 2.29-2.24 (m, 1H), 1.83-1.75 (m, 1H), 1.38-1.30 (m, 1H), 0.98 (d, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:11])=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2].[C:12]1([N:18]2[C:22](=[O:23])[CH:21]=[C:20]([CH2:24]S(O)(=O)=O)[NH:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Cr].O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:11])=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2].[C:12]1([N:18]2[C:22](=[O:23])[CH:21]=[C:20]([CH3:24])[NH:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=c1cc(CS(=O)(=O)O)[nH]n1-c1ccccc1
Agent: [Cr]
Agent: Nc1ccc([N+](=O)[O-])cc1O
Solvent: O
Product: Cc1cc(=O)n(-c2ccccc2)[nH]1

Procedure:
44.0 Parts of the 1:1 chromium complex (obtained by the known process and containing 1 atom of chromium for each molecule of monoazo dyestuff) of the azo dyestuff from diazotised 5-nitro-2-amino-1-hydroxybenzene and 1-phenyl-3-sulphomethyl-5-pyrazolone are stirred together in 1000 parts of hot water with 33.9 parts of the monoazo dyestuff obtained by the known process from diazotised 5-nitro-2-amino-1-hydroxybenzene and 1-phenyl-3-methyl-5-pyrazolone. The suspension is adjusted to a pH of 7 to 8 by addition of 20 parts by volume of concentrated sodium hydroxide solution and subsequently stirred at 90°-95° C. until both starting dyestuffs can no longer be detected. The unitary chromium mixed complex present in the clear solution is precipitated by addition of sodium chloride, isolated by filtration, washed with sodium chloride solution, and then dried in vacuo. After it has been ground, the dyestuff is in the form of a red, readily water-soluble powder and from a bath containing ammonium sulphate dyes wool or polyamide fibres in full red shades with good fastness properties. It has the following constitution: ##STR12##