Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:14]2[CH:5]([N:6]3[CH:11]([CH2:12][C:13]2=[O:15])[C:10]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[CH2:8][CH2:7]3)[CH2:4][CH2:3][CH2:2]1.Cl>>[CH2:1]1[CH:14]2[CH:5]([N:6]3[CH:11]([CH2:12][CH:13]2[OH:15])[C:10]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[CH2:8][CH2:7]3)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CC2c3ccccc3CCN2C2CCCCC12
Agent: Cl
Product: OC1CC2c3ccccc3CCN2C2CCCCC12

Procedure:
The following products are obtained when in Example 1 (A) appropriate amounts of the ketone derivatives listed below are substituted for 1,2,3,4,4a,6,7,11b,12,13a-decahydrodibenzo[a,f]quinolizin-13-one, the residual oil is additionally treated with excess ethereal hydrochloric acid and the precipitate is recrystallized from butanonemethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][CH2:24][C:25]#[CH:26])=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[CH2:24]([O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1)[C:25]#[CH:26]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: C#CCOc1ccc2ccc(N)nc2n1
Solvent: CCO
Solvent: O
Product: C#CCOc1ccc2ccc(NC(=O)c3ccc(OC)cc3)nc2n1
Temperature: 4 °C
Yield: 60.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (11.5 g), N,N'-carbonyldiimidazole (12 g) and 2-amino-7-propargyloxy-1,8-naphthyridine (10 g). The product produced by precipitation in water (15.3 g; m.p. 140° C.) is dissolved in boiling ethanol (190 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (3×20 cc) and dried at 50° C. under reduced pressure (0.067 kPa). N-(7-propargyloxy-1,8-naphthyridin-2-yl)-4-methoxybenzamide (10.1 g) is produced, m.p. 140° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>ClCCl>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:11]2[CH2:10][CH2:9][N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:13][CH2:12]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1cccnc1N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(S(=O)(=O)N2CCN(c3ncccc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.3 %

Procedure:
To a stirred solution of 1-(3-chloropyridin-2-yl)piperazine (316 mg, 1.6 mmol) in anhydrous dichloromethane (5 mL) was added diisopropylethylamine (0.975 mL, 5.6 mmol) then 4-tert-butylbenzene-1-sulfonyl chloride (372.4 mg, 1.6 mmol). The mixture was stirred at room temperature for 1.5 hour. Reaction was complete as determined by TLC. The reaction mixture was purified with flash column chromatography to yield 1-[(4-tert-butylphenyl)sulfonyl]-4-(3-chloropyridin-2-yl)piperazine in 59.3% yield (374 mg) as white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=[O:17])[C:5]([C:8]1[CH:9]=[CH:10][C:11]([F:16])=[C:12]([CH:15]=1)[C:13]#[N:14])([CH3:7])[CH3:6].CCN(CC)CC.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[S:34])=[CH:28][C:27]=1[O:35][CH3:36]>C(Cl)Cl>[C:13]([C:12]1[CH:15]=[C:8]([C:5]([CH3:7])([CH3:6])[C:4](=[O:17])[CH2:3][NH:2][C:33]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[C:27]([O:35][CH3:36])[CH:28]=2)=[S:34])[CH:9]=[CH:10][C:11]=1[F:16])#[N:14]
Reactant: CC(C)(C(=O)CN)c1ccc(F)c(C#N)c1
Reactant: COc1cc(N=C=S)ccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=S)NCC(=O)C(C)(C)c2ccc(F)c(C#N)c2)ccc1F
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a suspension of 5-(4-amino-2-methyl-3-oxobutan-2-yl)-2-fluorobenzonitrile hydrochloride (2.8 g, 10.9 mmol) in DCM (50 mL) were added Et3N (4.6 mL, 32.7 mmol, 3 eq) and 1-fluoro-4-isothiocyanato-2-methoxybenzene (2.2 g, 12 mmol, 1.1 eq). After stirring 2 h, the reaction mixture was partitioned in DCM and water. The organic layer was separated, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography (silica, Hex:EA=1:1) to give 1-(3-(3-cyano-4-fluorophenyl)-3-methyl-2-oxobutyl)-3-(4-fluoro-3-methoxyphenyl)thiourea (3.7 g, 84%). 1H NMR (400 MHz, CDCl3) δ 7.59 (bs, 1H), 7.53-7.49 (m, 2H), 7.26-7.18 (m, 2H), 6.89-6.79 (m, 2H), 6.70 (bs, 1H), 4.44 (d, J=4.4 Hz, 2H), 3.90 (s, 3H), 1.58 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[CH:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[N:8]=[CH:7]2
Reactant: Oc1ccccc1
Reactant: Clc1ncc2cccc(Br)c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Brc1cccc2cnc(Oc3ccccc3)nc12
Temperature: 120 °C
Yield: 71.4 %

Procedure:
A mixture of 8-bromo-2-chloroquinazoline (Ark Pharm Inc, Libertyville Ill.; 0.550 g, 2.259 mmol), cesium carbonate (0.883 g, 2.71 mmol), and phenol (0.234 g, 2.485 mmol) in 3 mL DMSO was sealed and heated to 120° C. for 2 h. The reaction was then partitioned between water and EtOAc. The organic layer was sequentially washed with water (2×), and saturated aq. NaCl (1×), then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography using 0-20% EtOAc/hexane. The material-containing fractions were concentrated to afford 8-bromo-2-phenoxyquinazoline (0.486 g, 1.614 mmol, 71% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 9.25 (1H, s), 8.15 (1H, dd, J=7.6, 1.4 Hz), 7.87 (1H, dd, J=8.0, 1.4 Hz), 7.34-7.50 (5H, m), 7.26-7.31 (1H, m). m/z (ESI, +ve) 302.9 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:17])[N:8]([C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:27])[Cl:26])=[O:22]>CCOC(C)=O>[Cl:26][C:25]([Cl:28])([Cl:27])[CH2:24][O:23][C:21](=[O:22])[NH:17][C:7]1[N:8]([C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cn1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a mixture of 5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylamine (for reference procedure see for example WO2003072569, which is incorporated herein by reference in its entirety; 833 mg, 3.62 mmol) in NaOH (1M in water, 5.4 mL, 4.4 mmol) and EtOAc (5 mL) was added 2,2,2-trichloroethyl chloroformate (548 μL, 3.98 mmol) and the reaction mixture was stirred at RT for 1 h. Additional NaOH (1M in water, 5.4 mL) and 2,2,2-trichloroethyl chloroformate (548 μL) were added and stirring at RT was continued for 1 h. Additional NaOH (1M in water, 5.4 mL) and 2,2,2-trichloroethyl chloroformate (548 μL) were added and stirring at RT was continued for 2 h. Additional NaOH (1M in water, 10.8 mL) and 2,2,2-trichloroethyl chloroformate (1.10 mL) were added and stirring at RT was continued for 24 h. The aqueous layer was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 10-50% EtOAc in cyclohexane, to afford the title compound (550 mg, 37%) as a white foam. LCMS (Method 3): Rt 3.87 min, m/z 405 [MH+].
Reaction SMILES: C1(C[N:8]([CH2:22][CH:23]([CH:25]2[CH2:30][CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[O:26]2)[OH:24])[CH2:9][CH:10]([CH:12]2[CH2:17][CH2:16][C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[O:13]2)[OH:11])C=CC=CC=1.[H][H]>[Pd].CO>[NH:8]([CH2:9][CH:10]([CH:12]1[CH2:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[O:13]1)[OH:11])[CH2:22][CH:23]([CH:25]1[CH2:30][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[O:26]1)[OH:24]
Reactant: [H][H]
Reactant: OC(CN(Cc1ccccc1)CC(O)C1CCc2ccccc2O1)C1CCc2ccccc2O1
Agent: [Pd]
Solvent: CO
Product: OC(CNCC(O)C1CCc2ccccc2O1)C1CCc2ccccc2O1

Procedure:
A mixture of 3 parts of (A+A+)-α,α'-[[(phenylmethyl)imino]bis(methylene)]bis[3,4-dihydro-2H-1-benzopyran-2-methanol] and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in dichloromethane. The organic phase was washed with a 10% sodium hydroxide solution and with water, dried, filtered and evaporated. The residue was dried in vacuo at 80° C., yielding 1.2 parts (19%) of (A+A+)-α,α'-[iminobis(methylene)]bis[3,4-dihydro-2H-1-benzopyran-2-methanol]; mp. 130.8° C.; [α]589 =+121.50° (c=1% CH3OH) (compound 74).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([CH:12]([F:14])[F:13])=[C:7]([CH:11]=1)[C:8](O)=[O:9])#[N:2].C[N:16](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[N:5][C:6]([CH:12]([F:14])[F:13])=[C:7]([CH:11]=1)[C:8]([NH2:16])=[O:9])#[N:2]
Reactant: N#Cc1cnc(C(F)F)c(C(=O)O)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cnc(C(F)F)c(C(N)=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of 5-cyano-2-(difluoromethyl)nicotinic acid (0.600 g, 3.0 mmol) in dry DMF (20 mL), TBTU (10.0 g, 3.33 mmol) was added at 0° C. followed by slow addition of DIPEA (0.7 mL, 3.93 mmol). The reaction mass was stirred at 0° C. for 1 h and ammonium chloride (3.33 g, 60.7 mmol) was added. The reaction mass was stirred at RT for 30-48 h. After completion of reaction quenched the reaction mass with DCM, filtered off solid to afford 0.500 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 8.16 (m, 1H), 8.63 (s, 1H), 9.22 (s, 1H).
Reaction SMILES: Cl[CH:2]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=2[C:7]=1[CH3:8].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=1>>[CH:15]1([CH:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=2)[C:3]2[O:4][C:5]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=3[C:7]=2[CH3:8])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccc2oc(C(Cl)C3CCCCC3)c(C)c2c1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: COc1ccc2oc(C(Nc3ccc(C(=O)NCCC(=O)O)cc3)C3CCCCC3)c(C)c2c1
Yield: 65.9 %

Procedure:
Using 2-[chloro(cyclohexyl)methyl]-5-methoxy-3-methyl-1-benzofuran (395 mg) synthesized in Example A27(4) and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (319 mg) synthesized in Example 1(2) and in the same manner as in Example A22(4), the title object compound (413 mg, 66%) was obtained as a white solid.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]1[CH2:13][CH:12]([CH3:14])[CH:11]([C:15]2[N:19]3[C:20]4[CH:26]=[CH:25][NH:24][C:21]=4[N:22]=[CH:23][C:18]3=[N:17][CH:16]=2)[CH2:10]1)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[CH:26]1[C:20]2[N:19]3[C:15]([CH:11]4[CH:12]([CH3:14])[CH2:13][CH:9]([NH2:8])[CH2:10]4)=[CH:16][N:17]=[C:18]3[CH:23]=[N:22][C:21]=2[NH:24][CH:25]=1
Reactant: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CC1c1cnc2cnc3[nH]ccc3n12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC1CC(N)CC1c1cnc2cnc3[nH]ccc3n12
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a mixture of N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclo-pentanamine (1.84 g, 4.22 mmol, Preparation #52) in EtOH (50 mL) was added 20 wt % Pd(OH)2 on C (0.43 g, 0.61 mmol) and the resulting mixture was shaken under hydrogen pressure of about 50 psi on a Parr shaker at about 50° C. for about 2 h. The catalyst was filtered off using a pad of Celite®, 20 wt % Pd(OH)2 on C (0.43 g, 0.61 mmol) was added, and the mixture was shaken under hydrogen pressure of about 50 psi on a Parr shaker at about 50° C. for about 16 h. The catalyst was filtered off using a pad of Celite®, 20 wt % Pd(OH)2 on C (0.43 g, 0.61 mmol) was added, and the mixture was shaken under hydrogen pressure of about 50 psi on a Parr shaker at about 50° C. for about 4 h. The catalyst was filtered off using a pad of Celite® and the filtrate was concd under reduced pressure to yield 3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine (0.88 g, 82%) as an off-white amorphous solid: LC/MS (Table 1, Method a) Rt=0.75 min and 0.87 min; MS m/z 256 (M+H)+.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[C:37](=[N:39]O)[NH2:38]>>[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[C:37]1[N:39]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:28][N:38]=1
Reactant: NC(=NO)c1ccc(F)cc1F
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccc(F)cc3F)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 38 mg (0.22 mmol, 1.1 eq.) of 2,4-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 52 mg (48% of theory)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]2=[N:5][N:4]=1>CO.[Pd]>[F:12][C:2]([F:1])([F:13])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[N:5][N:4]=1
Reactant: FC(F)(F)c1nnc2cnccn12
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)c1nnc2n1CCNC2
Reaction time: 5 h

Procedure:
To a solution of 3-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyrazine (1.60 g) in methanol (20 mL) was added a catalytic amount of Pd/C. The suspension was stirred under H2 for 5 h, and then filtered. The filtrate was concentrated in vacuo to give a residue, which was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>C1COCC1>[Cl:1][C:2]1[C:7]([CH:21]([C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[Cl:18])[OH:22])=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1
Reactant: O=Cc1ccccc1Cl
Reactant: CSc1nccc(Cl)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ncc(C(O)c2ccccc2Cl)c(Cl)n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-chloro-2-(methylthio)pyrimidine (Aldrich) (20 g, 124.51 mmol) in dry THF (300 mL) at −78° C. under argon was slowly added a solution of 2.0 M lithium diisopropyl amide, i.e., LDA, (109 mL, 1.75 eq) in THF via a cannula. After addition was complete, the resulting mixture was stirred at −78° C. for an additional 15 minutes, after which 2-chlorobenzaldehyde (Aldrich) (29.5 mL, 2.1 eq) was added dropwise via syringe. The reaction mixture was stirred for an additional 30 minutes at −78° C. and then quenched with saturated ammonium chloride solution. Ethyl acetate was added, the mixture was allowed to warm to room temperature, and the layers were partitioned and separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine solution. The ethyl acetate layers were combined, dried over magnesium sulfate, filtered and concentrated to give the crude product as an oil. Purification using Flash Column Chromatography on Silica Gel, eluting with a gradient of 5%-20% ethyl acetate in hexanes gave the title compound (10.8 g, (M+H)+=301) as an orange-yellow semi-solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:20]#[C:21][CH3:22])[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=1.[I-].[NH2:24][N+:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>>[Br:1][C:2]1[N:3]=[C:4]([C:20]2[C:21]([CH3:22])=[N:24][N:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=23)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=1
Reactant: N[n+]1ccccc1
Reactant: CC#Cc1nc(Br)c(-c2ncn(COCC[Si](C)(C)C)n2)s1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn2ccccc2c1-c1nc(Br)c(-c2ncn(COCC[Si](C)(C)C)n2)s1
Temperature: 25 °C
Reaction time: 29 h
Yield: 64.8 %

Procedure:
A mixture of 3-(4-bromo-2-prop-1-yn-1-yl-1,3-thiazol-5-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazole (0.514 g, 1.29 mmol), 1-aminopyridinium iodide (0.343 g, 1.54 mmol) and potassium carbonate (0.231 g, 1.67 mmol) in N,N-dimethylformamide (8.0 mL, 1.0E2 mmol) was stirred at rt for 29 hours. The mixture was quenched with ice water (80 mL) then extracted with EtOAc 3 times. The combined EtOAc solution was washed with water, brine, dried over Na2SO4, filtered and purified by column chromatography (SiO2, elution with 0-100% EtOAc in hexane) to afford a solid product. (0.410 g, 64.8% yield). LCMS: (FA) ES+ 491, 493. 1H NMR (400 MHz, CDCl3) δ: 8.43-8.46 (m, 2H), 8.32 (s, 1H), 7.39-7.42 (m, 1H), 6.90-6.93 (m, 1H), 5.57 (m, 2H), 3.72-3.76 (m, 2H), 2.76 (s, 3H), 0.96-1.00 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]3[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([N:23]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.Cl[C:49]1[N:54]=[CH:53][C:52]([N:55]2[C:59]3N=C(N4CCOCC4)N=C(C4C=NC(N(CC5C=CC(OC)=CC=5)CC5C=CC(OC)=CC=5)=NC=4)C=3C[CH2:56]2)=CC=1.CN(C)CCNC>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:20]2[N:19]=[CH:18][C:17]([C:16]3[C:11]4[CH2:10][CH2:9][N:8]([C:6]5[CH:5]=[CH:4][N:3]=[C:2]([N:54]([CH3:49])[CH2:53][CH2:52][N:55]([CH3:59])[CH3:56])[CH:7]=5)[C:12]=4[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=3)=[CH:22][N:21]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(Cl)c3)cn2)cc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(Cl)nc3)cn2)cc1
Agent: CNCCN(C)C
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(N(C)CCN(C)C)c3)cn2)cc1

Procedure:
Using {5-[7-(2-chloro-pyridin-4-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (100 mg, 0.154 mmol) obtained in Step A in Example 1-D-69 instead of {5-[7-(6-chloro-pyridin-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine, and N,N,N′-trimethyl ethylenediamine (30 μl, 0.23 mmol), in the same manner as Example 1-D-48, amination was carried out, to obtain a crude product of N-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-N,N′,N′-trimethyl-ethane-1,2-diamine as a dark brown solid (55 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-74) as a yellow powder (25 mg, 68%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:11][C:12]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:13]=1[CH2:14]Br>>[F:21][C:17]1[CH:16]=[C:13]([CH2:14][O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:12]([F:11])=[CH:19][C:18]=1[F:20]
Reactant: Fc1cc(F)c(CBr)cc1F
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: O=[N+]([O-])c1ccc(OCc2cc(F)c(F)cc2F)cc1
Yield: 92 %

Procedure:
Prepared in analogy to example 8 from 4-nitrophenol and 2,4,5-trifluoro-benzylbromide. Colorless solid. Yield=92%. MS: m/e=283.0 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH2:12][C:9]([NH:14][CH2:15][C:16]([N:18]3[CH2:22][C@@H:21]([F:23])[CH2:20][C@H:19]3[C:24]([NH2:26])=O)=[O:17])([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)=[O:5])[CH3:2].ClC(Cl)(Cl)C(OC(=O)C(Cl)(Cl)Cl)=O.FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH2:12][C:9]([NH:14][CH2:15][C:16]([N:18]3[CH2:22][C@@H:21]([F:23])[CH2:20][C@H:19]3[C:24]#[N:26])=[O:17])([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C(N)=O)(CC1)CC2
Agent: O=C(OC(=O)C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 81 %

Procedure:
Using (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide (3.70 g), trichloroacetic anhydride (1.9 mL) as a dehydrating agent and trifluoroacetic acid (0.78 mL) as an acid, a white powder of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile was obtained (obtained amount: 2.86 g, yield: 81%) by the same method of Example 1.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[N:16]=[C:17]([CH3:21])[C:18]=2[O:19][CH3:20])[CH:5]=1.C([O-])(O)=O.[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[CH3:20][O:19][C:18]1[C:17]([CH3:21])=[N:16][N:15]([CH3:22])[C:14](=[O:23])[C:13]=1[N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([Cl:3])=[C:5]1[Br:1]
Reactant: BrBr
Reactant: COc1c(C)nn(C)c(=O)c1-n1cc(Cl)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(C)nn(C)c(=O)c1-n1c(Br)c(Cl)c2ccccc21
Yield: 49.7 %

Procedure:
Part of a solution of bromine (200 mg, 1.25 mmol) in DCM (4 mL) is added dropwise, slowly, to a solution of 4-(3-chloroindol-1-yl)-5-methoxy-2,6-dimethyl-pyridazin-3-one (184 mg, 0.606 mmol) in DCM (2 mL) at 0° C. The bromine decolourised as it was added and addition was continued cautiously until an orange colour just persisted. NaHCO3 (0.5 g saturated solution in water) is added cautiously, followed by sufficient sodium metabisulphite to decolorise the excess bromine. The resulting reaction mixture was extracted with DCM (3×60 mL) and the combined DCM layers were filtered through MgSO4 and concentrated in vacuo. The resulting yellow gum was purified by flash chromatography (combiflash, 0 to 30% DCM/EtOAc) to yield the desired pro duct 5-methoxy-2,6-dimethyl-4-(2-bromo-3-chloroindol-1-yl)pyridazin-3-one (115 mg, 0.301 mmol, 50% Yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N+:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]>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>[CH3:8][O:7][C:5]([C:4]1[CH:3]=[C:2]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=2)[CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: COC(=O)c1cccc(Br)c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1cccc(-c2cccc([N+](=O)[O-])c2)c1

Procedure:
n.m.r. δ values include 3.96 (s, 3 H), 7.57 (t, 1 H), 7.64 (t, 1 H), 7.81 (d, 1 H), 7.94 (d,1 H), 8.09 (d, 1 H), 8.23 (dd, 1 H), 8.30 (s, 1 H), 8.48 (t, 1 H), m.p., 88-90° C.; from methyl 3-bromobenzoate (2.0 g), tetrakis(triphenylphosphine)palladium(0) (348mg) and 3-nitrophenylboronic acid (1.9 g).