Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1cccnc1
Product: Cc1c2n(c3c(-c4cccnc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (60 mg, 77%), MS (ISP) m/z=312.5 [(M+H)+], mp 252.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available pyridin-3-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]2[C:8](=[O:17])[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH:11]=[CH:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.C1C=CC=CC=1.C(N(CC)CC)C.[CH3:39][CH2:40][O:41]CC>O.C(#N)C.C(O)CO>[CH2:39]1[CH2:40][O:41][C:8]2([C:7]3[CH:18]=[CH:19][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][C:6]=3[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]2=3)[O:17]1
Reactant: CCOCC
Reactant: CC(=O)c1ccc2c(=O)c3ccccc3ccc2c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: OCCO
Product: CC(=O)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Reaction time: 20 h

Procedure:
0.50 Gm. of 2-acetyl-5H-dibenzo[a,d]cycloheptene-5-one and 0.45 gm. of phosphorus pentachloride are stirred in 50 ml. of dry benzene for one hour, and then the solution is added to a mixture of 1.01 gm. of triethylamine, 1.35 gm. of ethylene glycol and 100 ml. of acetonitrile. The mixture is stirred for 20 hours then added to water and ether. The ethereal layer is washed with water, dried and evaporated to give a nearly quantitative yield of 5,5-ethylenedioxy-2-acetyl-5H-dibenzo[a,d]cycloheptene.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([C@H:22]2[C@H:27]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@@H:26]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@H:25]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@@H:24]([CH2:52][O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[O:23]2)=[CH:18][C:3]=1[CH2:4][C:5]1[N:10]=[N:9][C:8]([C:11]([NH:13][CH2:14][C:15](=O)[CH3:16])=[O:12])=[CH:7][CH:6]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([C@H:22]2[C@H:27]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C@@H:26]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@H:25]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@@H:24]([CH2:52][O:53][CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[O:23]2)=[CH:18][C:3]=1[CH2:4][C:5]1[N:10]=[N:9][C:8]([C:11]2[O:12][C:15]([CH3:16])=[CH:14][N:13]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)CNC(=O)c1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)nn1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cnc(-c2ccc(Cc3cc([C@@H]4O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)ccc3Cl)nn2)o1
Temperature: 25 °C

Procedure:
To a solution of 6-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)benzyl)-N-(2-oxopropyl)pyridazine-3-carboxamide (1.2 mmol) form Step 1 in tetrahydrofuran (30 mL) was added Burgess reagent (343 mg, 1.4 mmol). The reaction mixture was refluxed overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered through a plug of silica gel and concentrated in vacuo. The resulting crude residue was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]2=[O:15])=[CH:5][CH:4]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([N:10]1[C:11]([CH3:14])([CH3:13])[CH2:12][N:8]([CH2:7][C:6]2[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:15])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(CN2CC(C)(C)NC2=O)cc1
Reactant: O=C(Cl)c1ccccc1
Product: COc1ccc(CN2CC(C)(C)N(C(=O)c3ccccc3)C2=O)cc1

Procedure:
Using 1-(4-methoxybenzyl)-4,4-dimethylimidazolidin-2-one (500 mg) described in Preparation Example 54 and benzoyl chloride (0.28 mL) and by the reaction and treatment in the same manner as in Preparation Example 55, the title compound (500 mg) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[C:18]([NH2:22])(=[O:21])[CH2:19][CH3:20].C([O-])([O-])=O.[Cs+].[Cs+]>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.[Fe+2].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]>[N+:15]([C:12]1[N:11]=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:22][C:18](=[O:21])[CH2:19][CH3:20])[CH:7]=2)=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: CCC(N)=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccn1
Temperature: 95 °C
Yield: 44.8 %

Procedure:
A solution of Example A1 (1.0 g, 3.97 mmol) in dioxane (20 mL) was sparged with Ar, treated with propionamide (0.581 g, 7.95 mmol) and Cs2CO3 (1.942 g, 5.96 mmol), sparged with, treated with dppf (12.38 g, 22.33 mmol) and Pd2(dba)3 (0.182 g, 0.199 mmol), sparged once again with Ar and heated at 95° C. overnight. Pd(dppf)2Cl2.DCM (50 mg) was added and the mixture heated at 95° C. for 4 h. The mixture was cooled to RT, treated with EtOAc and the solids removed via filtration through silica gel. The filtrate was concentrated to dryness and purified twice via silica gel chromatography (MeOH/DCM) to afford N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)propionamide (513 mg, 45%). MS (ESI) m/z: 289.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]2[CH:17]=[C:16]([N:18]3[C@@H:22]([CH3:23])[C@@H:21]([CH2:24][CH2:25][O:26][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[O:20][C:19]3=[O:44])[N:15]=[C:14]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[N:13]=2)=[CH:4][N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]2[CH:17]=[C:16]([N:18]3[C@@H:22]([CH3:23])[C@@H:21]([CH2:24][CH2:25][OH:26])[O:20][C:19]3=[O:44])[N:15]=[C:14]([N:45]3[CH2:46][CH2:47][O:48][CH2:49][CH2:50]3)[N:13]=2)=[CH:4][N:3]=1
Reactant: C[C@H]1[C@@H](CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)OC(=O)N1c1cc(-c2cnc(N)nc2C(F)(F)F)nc(N2CCOCC2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](CCO)OC(=O)N1c1cc(-c2cnc(N)nc2C(F)(F)F)nc(N2CCOCC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a solution of (4S,5R)-3-(2′-amino-2-morpholino-4′-(trifluoromethyl)-[4,5′-bipyrimidin]-6-yl)-5-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-methyloxazolidin-2-one (2.1 g, 3 mmol) in THF (20 mL), was added dropwise 1M TBAF in THF (3 mL, 3 mmol) at 0° C. The reaction mixture was stirred for 1 h at 0° C. before evaporation. The residue was purified by flash chromatography (hexane/EtOAc/MeOH 90:10:1→0:100:10). The purified product was re-crystallized from MeOH to afford the title compound as a white solid (1.17 g, 83%): tR=0.80 min (UPLC 1), tR=0.82 min (LC-MS 3); ESI-MS: 470 [M+H]+ (LC-MS 3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]([CH2:15][C:16](=O)[CH3:17])[C:12]([CH3:14])=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:17][C:16]1[N:1]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[C:12]([CH3:14])=[CH:11][CH:15]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CC(=O)CCC(C)=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 250 mL argon purged round bottom flask containing a magnetic stirbar and a solution of 5-aminoindole (91) (15.00 g, 113 mmol) in anhydrous toluene (50 mL) was added acetonylacetone (25.4 mL, 216 mmol, 1.9 eq). The flask was fitted with a Dean-Stark trap with a 10 mL reservoir filled with toluene. The uppermost portion of the flask and the condensing arm of the trap were wrapped with foil and the reaction vessel placed into an oil bath preheated to a temperature of 125° C. The dark brown solution was allowed to stir under a continuous flow of argon at this temperature for 45 minutes, followed by draining of the trap solvent reservoir. After a total of 4 hours, TLC (5% ethyl acetate, 95% hexanes) revealed the reaction was complete. The reaction was cooled gradually to room temperature overnight. The reaction was poured onto a plug of silica gel and the solvent pulled through by vacuum filtration. The silica was washed with hexanes (200 mL). A white precipitate started to form almost immediately in the filtrate. The silica was washed again with a solution of 6% diethyl ether, 94% hexanes (800 mL). Crystals were collected from both washes, and the filtrates combined. The plug was washed with ether (150 mL) and the filtrate combined with the washes. The combined filtrates were concentrate to afford a brown oil. The oil was purified on the Biotage SP-1 (0-8% ether in hexanes). TLC revealed that all products were identical (white solids) and all products were combined. (Yield: 17.10 g of white solid, compound 92 (72%). 1H NMR (CDCl3) δ: 8.26 (bs, NH), 7.48-7.48 (d, 1H, J=1.2 Hz), 7.46-7.43 (d, 1H, J=8.7 Hz), 7.31-7.29 (t, 1H, J=2.7), 7.04-7.00 (dd, 1H, J=2.1, 8.4), 6.61 (s, 1H), 5.92 (s, 2H), 2.05 (s, 6H). MS-ESI m/z (%): 211 (M+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[O:10]1.CC(C)([O-])C.[K+].Cl[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH3:35])=[CH:29][C:28]=1[N+:36]([O-:38])=[O:37].Cl>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH3:35])=[CH:29][C:28]=3[N+:36]([O-:38])=[O:37])[CH:15]=2)[O:10]1
Reactant: Oc1ccc2c(c1)CCC(c1cc(F)ccc1F)O2
Reactant: CCOc1ccc(Cl)c([N+](=O)[O-])c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(Oc2ccc3c(c2)CCC(c2cc(F)ccc2F)O3)c([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
320 mg of 2-(2,5-Difluorophenyl)chroman-6-ol (Example 14(c)) was dissolved in dry DMF and potassium tert-butoxide (150 mg) was added. The resulting mixture was stirred for 30 minutes and 1-chloro-4-ethoxy-2-nitrobenzene (250 mg) was added. The reaction mixture was refluxed for 8 hours. After cooling to room temperature 1 M HCl-solution was added into the reaction mixture and it was extracted with ethyl acetate. The combined organic extracts were washed with water and saturated NaCl-solution. The product was purified by column chromatography using heptane-ethyl acetate (3:1) as an eluant. 1H NMR (300 MHz, CDCl3) δ: 7.43 (d, 1H, J 2.9Hz), 7.25 (m, 1H), 7.08-6.97 (m, 4H), 6.89-6.75 (m, 3H), 5.31 (d, 1H, J 9.1 Hz), 4.06 (q, 2H, J 7.0 Hz), 2.97 (m, 1H), 2.74 (m, 1H), 2.26 (m, 1H), 1.98 (m, 1H), 1.44 (t, 3H, 7.0 Hz).
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=O)=O)=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:22]([CH2:24][C:25]([NH2:27])=[S:26])#[N:23]>C(O)C>[C:22]([CH2:24][C:25]1[S:26][C:2]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:21])=[CH:14][CH:13]=2)=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[N:27]=1)#[N:23]
Reactant: N#CCC(N)=S
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CCO
Product: CSc1ccc(-c2sc(CC#N)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (Example 26, Step 2) (0.249 g, 0.734 mmol) in ethanol (9 mL) in a 25 mL round bottom flask was added 2-cyanothioacetamide (0.077 g, 0.771 mmol) and the solution heated to reflux for 14 hours. The reaction was cooled to room temperature, was was concentrated in vacuo and the residue dissolved in ethyl acetate. This solution was washed successively with Na2CO3 (10% solution) and brine, dried over Na2SO4, filtered and reconcentrated in vacuo yielding an orange crystalline solid. This solid was purified by flash chromatography (4:1 hexane:ethyl acetate ) yielding 2-(cyanomethyl)-4-(4-fluorophenyl)-5-(4-methylthiophenyl)thiazole as very fine pink crystals (0.090 g, 36%): mp 118°-119° C. 1H NMR (CDCl3) 400 mHz δ7.50 (d, J=5.38, 2H), 7.47 (d, J=5.38, 2H), 7.24-7.18 (m, 4H), 7.00 (t, J=8.80, 2H), 4.16 (s, 2H), 2.50 (s, 3H). MS (EI): m/z 340 (M+). HRMS Δ=2.7 mmu.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][C:6]1[S:7][C:8]([Cl:17])=[C:9]([Cl:16])[C:10]=1[CH2:11][C:12]([O:14]C)=[O:13])C.[OH-].[Na+]>CO>[C:12]([CH2:11][C:10]1[C:9]([Cl:16])=[C:8]([Cl:17])[S:7][C:6]=1[CH2:5][C:4]([OH:18])=[O:3])([OH:14])=[O:13]
Reactant: CCOC(=O)Cc1sc(Cl)c(Cl)c1CC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1sc(Cl)c(Cl)c1CC(=O)O
Temperature: 22 °C
Reaction time: 8 h
Yield: 279.2 %

Procedure:
A solution of the product from step (c) (1.14 g, 3.66 mmol) in MeOH (7 ml) at 0° C. was treated dropwise with 2M NaOH (3.8 ml). The reaction was warmed to 22° C. and stirred overnight. The solvent was evaporated and the residue was dissolved in 2 M NaOH (50 ml) and extracted with ether (2×50 ml). The basic layer was cooled to 0° C. and acidified to pH 1 with 6 M HCl. The acidic layer was back extracted EtOAc (4×100 ml) and the organic layer was dried (MgSO4) and concentrated. The crude solid was triturated with hexanes and filtered providing 2.75 g (73%) of the subtitle compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH3:21])[CH:7]=[C:8]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH2:20])[CH:9]=2)[N:4]=1.[C:22](C1NC=CN=1)(C1NC=CN=1)=[O:23]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH3:21])[CH:7]=[C:8]([N:13]3[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[NH:20][C:22]3=[O:23])[CH:9]=2)[N:4]=1
Reactant: COc1ccc2cc(Nc3ccccc3N)cc(C)c2n1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Product: COc1ccc2cc(-n3c(=O)[nH]c4ccccc43)cc(C)c2n1

Procedure:
This compound, m.p. 280°, was prepared similarly to Example 16 using 2-methoxy-6-[(N-2-aminophenyl)-amino]-8-methylquinoline, and carbonyl diimidazole as starting materials. The product was characterised spectroscopically and used directly in Example 3 without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[OH-].[K+].[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.O>CO>[CH3:14][N:15]1[CH2:16][CH:17]=[C:18]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)[NH:8][CH:7]=2)[CH2:19][CH2:20]1
Reactant: CN1CCC(=O)CC1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CC=C(c2c[nH]c3ccc(C#N)cc23)CC1
Yield: 97.6 %

Procedure:
5-Cyanoindole (Aldrich, 20.0 g) was added to a solution of KOH (22.4 g) in methanol (200 ml). N-Methyl-4-piperidone (Aldrich, 40.4 g) was then added dropwise and the resulting mixture refluxed for 4 hours, then cooled and poured into water. The resulting precipitate was filtered off and dried to give the desired product as a pale pink crystalline solid (32.6 g).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[O:22])=[CH:20][C:13]=3[N:12]=2)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(N(C(C)C)C(C)C)C.Cl[C:40]([O:42][CH3:43])=[O:41]>C(Cl)Cl>[CH3:43][O:42][C:40]([NH:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[O:22])=[CH:20][C:13]=3[N:12]=2)=[CH:7][CH:6]=1)=[NH:3])=[O:41]
Reactant: COC(=O)Cl
Reactant: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C(=N)N)cc1)n2C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C(=N)NC(=O)OC)cc1)n2C
Reaction time: 0.5 h

Procedure:
0.26 g of 2-(4-amidino-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-1-methyl-benzimidazole-hydrochloride are suspended in 50 ml of methylene chloride and, whilst cooling with ice, 0.5 ml of N-ethyl-diisopropylamine and 0,067 ml of methyl chloroformate are added. The mixture is stirred at ambient temperature, after half an hour a further 0.5 ml of N-ethyl-diisopropylamine and 0.03 ml of methyl chloroformate are added and, after another half hour, a further 0.1 ml of N-ethyl-diisopropylamine and 0.03 ml of methyl chloroformate. The mixture is stirred for a further half hour, evaporated down in vacuo and purified by column chromatography (silica gel; eluant:ethyl acetate/ethanol=100:2.5 to 100:12.5). Yield: 0.12 g (40% of theory), Rf value: 0.41 (silica gel; ethyl acetate/ethanol=8:2)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][C:43]=1[F:51].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>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].O.CN(C)C=O>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][C:43]=5[F:51])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A dimethylformamide solution (15 ml) of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (700 mg, 1.30 mmol), 4-bromo-3-fluorobenzoic acid (341 mg, 1.56 mmol), tris(dibenzylideneacetone)dipalladium (29.7 mg, 0.0324 mmol), X-Phos (61.8 mg, 0.130 mmol) and potassium phosphate (881 mg, 4.15 mmol) was degassed under ultrasonic irradiation, followed by stirring at 100° C. for 24 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, 6M hydrochloric acid (2 ml) and water (15 ml) were added, followed by stirring at room temperature for 1 hour. The precipitated solid was filtered, and ethyl acetate (15 ml) was added, followed by irradiation of ultrasonic wave. The solid was filtered, and washed with ethyl acetate, whereby 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)-3-fluoro-benzoic acid was obtained as a yellow solid (679 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([NH:15][S:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=3)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:29])=[CH:4][N:3]=1>O.CO.C(O)(=O)C.[Fe]>[NH2:26][C:22]1[CH:21]=[C:20]([CH2:19][S:16]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6]3[C:5]([Cl:29])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:10]=2)(=[O:17])=[O:18])[CH:25]=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)Nc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: [Fe]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cccc(CS(=O)(=O)Nc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}-1-(3-nitrophenyl)methanesulfonamide (0.060 g, 0.13 mmol) in water (0.1 mL), methanol (0.5 mL) and acetic acid (0.20 mL) was added iron (0.030 g, 0.53 mmol) powder in one batch. The mixture was stirred at 0° C. for 0.5 h. The reaction was mixed with celite, filtered, and the cake was washed with EtOAc. The brown filtrate was concentrated and EtOAc and NaHCO3/water added. Water phase was extracted with EtOAc twice. The organics were combined, dried over Na2SO4 and concentrated to give the desired product as a yellow powder (0.050 g, 89%. LCMS for C17H15Cl2N5O2S (M+H)+: m/z=423.9, 426.0.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C@@H:8]3[C@@H:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@@H:7]3[C:6]=2[CH:16]=1.F[C:18]1[CH:27]=[CH:26][N:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][C:22](=[O:28])[NH:23]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[O:28]=[C:22]1[NH:23][C:24]2[N:25]=[CH:26][CH:27]=[C:18]([O:1][C:2]3[CH:3]=[CH:4][C:5]4[O:9][C@@H:8]5[C@@H:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@@H:7]5[C:6]=4[CH:16]=3)[C:19]=2[CH2:20][CH2:21]1
Reactant: O=C1CCc2c(F)ccnc2N1
Reactant: CCOC(=O)[C@@H]1[C@H]2Oc3ccc(O)cc3[C@H]21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@@H]1[C@H]2Oc3ccc(Oc4ccnc5c4CCC(=O)N5)cc3[C@H]21
Temperature: 120 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
The mixture of Intermediate III (400 mg, 1.8 mmol), 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one (250 mg, 1.5 mmol) and cesium carbonate (801 mg, 2.3 mol) in DMF (20 mL) was stirred at 120° C. for 2 hrs. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE=3:1) to obtain the title compound (360 mg, 54.6%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[CH:9]1([NH2:12])[CH2:11][CH2:10]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][CH:9]2[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: NC1CC1
Product: Brc1ccc(NC2CC2)nc1
Temperature: 80 °C
Yield: 74.7 %

Procedure:
To a sealed tube was added 5-bromo-2-fluoropyridine (1.25 g, 7.10 mmol) and cyclopropylamine (5.0 mL, 72 mmol). Upon heating at 80° C. for 48 hours the reaction was complete. The contents of the tube were transferred to a round bottom flask and concentrated in vacuo. The remaining residue was dissolved in dichloromethane and washed twice with saturated sodium bicarbonate and twice with brine. The organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (1.13 g, 75%) as a tan solid.