Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:15]1(Br)[NH:20][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:18][CH:17]=[CH:16]1.[C:28](=[O:31])([O-])[O-].[Na+].[Na+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:23]1[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH2:9][CH3:10])[C:28]=3[OH:31])[N:20]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: O=C([O-])[O-]
Reactant: CCOc1cccc(B(O)O)c1O
Reactant: BrC1(Br)C=CC=C(c2ccccn2)N1
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCOc1cccc(-c2cccc(-c3cccc(-c4cccc(OCC)c4O)n3)n2)c1O
Yield: 48 %

Procedure:
6,6′-Bis(2-hydroxy-3-ethoxyphenyl)-2,2′-bipyridine was prepared by reaction of 2-hydroxy-3-ethoxyphenylboronic acid (836 mg, 4.60 mmol) with 6,6-dibromo-2,2′-bipyridyl (722 mg, 2.30 mmol), sodium carbonate (2N solution, 6 ml) and tetrakis(triphenylphosphine) palladium (40 mg) in ethylene glycol dimethyl ether (30 ml) at reflux under nitrogen for 4 hours. The solid was filtered from the cooled reaction and washed with ether and water and toluene, to give the desired product as a yellow solid (446 mg, 48%);δH [2H6]-DMSO 8.33,(2H, d), 8.23,(2H, t), 8.14,(2H, d), 7.68,(2H, d), 7.05,(2H, d), 6.88,(2H, t), 4.06,(4H, q), 1.35,(6H, t).
Reaction SMILES: [CH3:1][CH:2]([O:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([O:30]CC5C=CC=CC=5)=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[C:8]1=[O:38])[CH3:3].[H][H]>[Pd].C(O)(=O)C>[OH2:4].[OH:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[CH2:20][CH2:19][N:18]([C:15]3[CH:14]=[CH:13][C:12]([N:9]4[CH2:10][CH2:11][N:7]([CH2:6][CH2:5][O:4][CH:2]([CH3:1])[CH3:3])[C:8]4=[O:38])=[CH:17][CH:16]=3)[CH2:23][CH2:22]2)=[CH:25][CH:26]=1.[OH:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[CH2:20][CH2:19][N:18]([C:15]3[CH:14]=[CH:13][C:12]([N:9]4[CH2:10][CH2:11][N:7]([CH2:6][CH2:5][O:4][CH:2]([CH3:1])[CH3:3])[C:8]4=[O:38])=[CH:17][CH:16]=3)[CH2:23][CH2:22]2)=[CH:25][CH:26]=1
Reactant: CC(C)OCCN1CCN(c2ccc(N3CCN(c4ccc(OCc5ccccc5)cc4)CC3)cc2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)OCCN1CCN(c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)C1=O
Product: O
Yield: 76.8 %

Procedure:
A mixture of 9.7 parts of 1-[2-(1-methylethoxy)ethyl]-3-[4-[4-[4-(phenylmethoxy)phenyl]-1-piperazinyl]phenyl]-2-imidazolidinone and 250 parts of acetic acid was hydrogenated at normal pressure and at 50° C. 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 dissolved in a mixture of methanol and water and the whole was neutralised with a sodium hydrogen carbonate solution. The precipitated product was filtered off and crystallized from 4-methyl-2-pentanone. The product was filtered off and dried at 100° C., yielding 6.3 parts (76.8%) of 1-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3-[2-(1-methylethoxy)ethyl]-2-imidazolidinone hemihydrate; mp. 178.3° C. (intermediate 28).
Reaction SMILES: Br[CH:2]([CH2:15][CH3:16])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)=[O:4].[CH3:17][NH:18][CH3:19].CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl.CO>[CH3:17][N:18]([CH3:19])[CH:2]([CH2:15][CH3:16])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)=[O:4]
Reactant: CCC(Br)C(=O)c1ccc(NC(C)=O)cc1
Reactant: CNC
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C(=O)c1ccc(NC(C)=O)cc1)N(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of N-(4-(2-bromobutanoyl)phenyl)acetamide (4.80 g, 16.9 mmol) in 30 mL CHCl3 and 30 mL MeOH was treated with 16.9 mL dimethylamine in MeOH (2M, 33.8 mmol) and DIPEA (2.90 mL, 16.9 mmol). After stirring at rt for 48 hr, the mixture was concentrated in vacuo and the residue partitioned between DCM and saturated NaHCO3. The aqueous phase was extracted with DCM three times. The combined organic extracts were dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with 6% MeOH (2N NH3)/DCM to provide N-(4-(2-(dimethylamino)butanoyl)phenyl)acetamide as a light brown oil. MS ESI: m/z 249.19 [M+1+].
Reaction SMILES: NC1C=CC(N2CC[C@H](N)[C@H](F)C2)=CC=1OC.[NH2:18][C@@H:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]3[N:37]=[C:36]([C:38]4[C:46]5[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=5)[NH:40][CH:39]=4)[C:35]([Cl:47])=[CH:34][N:33]=3)=[C:27]([O:48][CH3:49])[CH:26]=2)[CH2:21][C@H:20]1[F:50]>>[NH2:18][C@H:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]3[N:37]=[C:36]([C:38]4[C:46]5[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=5)[NH:40][CH:39]=4)[C:35]([Cl:47])=[CH:34][N:33]=3)=[C:27]([O:48][CH3:49])[CH:26]=2)[CH2:21][C@H:20]1[F:50]
Reactant: COc1cc(N2CC[C@@H](N)[C@H](F)C2)ccc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Agent: COc1cc(N2CC[C@H](N)[C@H](F)C2)ccc1N
Product: COc1cc(N2CC[C@H](N)[C@H](F)C2)ccc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting material: (cis)-(±)-1-(4-amino-3-methoxyphenyl)-3-fluoropiperidin-4-amine (INTERMEDIATE 65) and 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2). The NMR spectra of the title compound was identical to Example 33.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(COC)OC.C([O-])(O)=O.[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH3:10])[N:5]=[C:4]([NH2:9])[N:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1-c1cc(Cl)nc(N)n1
Yield: 63.2 %

Procedure:
4,6-dichloropyrimidin-2-ylamine (1.0 g, 6.13 mmol) and 2-methoxyphenylboronic acid (0.775 g, 5.1 mmol) were added to a solution of dimethoxyethane (20 mL) and water (3 mL), followed by the addition of NaHCO3 (1.03 g, 12.26 mmol) and (PPh3)2PdCl2 (0.2 g) to this and the reaction mixture was allowed to reflux for 4 h, and then the solvent removed under reduced pressure. The residue was taken up in ethyl acetate (50 mL), and the resulting solution washed with water, dried over anhydrous K2CO3, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chropatography on silica gel (eluent CH2Cl2) and recrystallized from hexanes yielding 4-chloro-6-(2-methoxyphenyl)-pyrimidin-2-ylamine (0.76 g; 63%) as light yellow powder.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH:13][C:14]2[NH:15][C:16]3[C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[O:12])[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:59]([O:63][C:64]([N:66]1[CH2:71][CH2:70][C:69]2[N:72]=[C:73]([NH2:75])[S:74][C:68]=2[CH2:67]1)=[O:65])([CH3:62])([CH3:61])[CH3:60]>CN(C=O)C>[C:59]([O:63][C:64]([N:66]1[CH2:71][CH2:70][C:69]2[N:72]=[C:73]([NH:75][C:23]([C:22]3[C:16]4[NH:15][C:14]([NH:13][C:11]([C:3]5[N:2]=[CH:1][C:10]6[C:5]([CH:4]=5)=[CH:6][CH:7]=[CH:8][CH:9]=6)=[O:12])=[N:18][C:17]=4[CH:19]=[CH:20][CH:21]=3)=[O:24])[S:74][C:68]=2[CH2:67]1)=[O:65])([CH3:62])([CH3:60])[CH3:61]
Reactant: O=C(Nc1nc2cccc(C(=O)O)c2[nH]1)c1cc2ccccc2cn1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)sc2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)c3cccc4nc(NC(=O)c5cc6ccccc6cn5)[nH]c34)sc2C1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 49.8 %

Procedure:
To a solution of 0.25 g (0.75 mmol) of 2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid in DMF (4 mL) was added 0.4 g (1.05 mmol) of HBTU and DIEA (1 mL). The mixture was stirred for 5 min and then 0.18 g (0.7 μmmol) of 2-amino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester was added. The resulting reaction mixture was heated at 80° C. for 2 h. After usual workup, the residue was purified by column chromatography to afford the 0.2 g (55%) of 2-({2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carbonyl}-amino)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester. LCMS: 570 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 9.56 (s, 1H), 8.84 (s, 1H), 8.35 (m, 2H), 7.96 (m, 4H), 7.84 (d, 1H), 7.35 (t, 1H), 4.58 (bs, 2H), 3.70 (t, 2H), 2.73 (t, 2H), 1.44 (s, 9H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10](=[O:12])[CH3:11].C[O:14][C:15]1C=CC=C[C:16]=1C1CC(=O)CC(=O)C1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15](=[O:14])[CH2:11][C:10](=[O:12])[CH2:9]1
Reactant: COc1ccccc1C1CC(=O)CC(=O)C1
Reactant: CC(=O)C=Cc1ccccc1Br
Product: O=C1CC(=O)CC(c2ccccc2Br)C1

Procedure:
The title compound was prepared from 4-(2-bromo-phenyl)-but-3-en-2-one (1.2 g, 4.44 mmol), stage 1, following the procedure describing the synthesis of 5-(2-methoxy-phenyl)-cyclohexane-1,3-dione (example 1/a stage 2).
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Cl[CH2:39][C:40]([N:42]([CH3:44])[CH3:43])=O>>[CH3:43][N:42]([CH3:44])[CH2:40][CH2:39][O:10][C:8]1[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN(C)C)cc2)c1
Yield: 72.9 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N,N-dimethylacetamide (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.9 mg) was obtained.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH:12]1[C:24]2[CH:23]([CH2:25][O:26][C:27]([NH:29][C@@H:30]([CH2:34][CH2:35][NH2:36])[C:31]([OH:33])=[O:32])=[O:28])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH:21]1[C:22]2[CH:23]([CH2:25][O:26][C:27]([NH:29][C@@H:30]([CH2:34][CH2:35][NH:36][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:31]([OH:33])=[O:32])=[O:28])[C:24]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](CCNC(=O)c1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzoyl chloride (83 mg, 0.588 mmol) and NaOH (0.705 mL, 0.705 mmol) were dropped at the same time to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-aminobutanoic acid (200 mg, 0.588 mmol) in THF (1.5 mL) and of NaOH (1N, 0.7 mL) at 0° C. The reaction mixture was allowed to stir at rt for 1 h at which time LC-MS showed desired product peak. The reaction solution was acidified with 1N HCl and extracted with EtOAc (60 mL×1). The crude was purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to provide the title compound (160 mg, 57%).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].C([O-])(O)=O.[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1.CO>C(O)C.C(Cl)Cl>[OH2:5].[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][N:29]1[CH2:28][CH2:27][N:26]([CH:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:15]2[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=2)[CH2:31][CH2:30]1
Reactant: ClCC1CO1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: O
Product: OC(CCl)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 100.8 %

Procedure:
To a mixture of epichlorohydrin (3.5 mL, 0.05 mol) in ethanol (12 mL) at 0° C. (ice bath) and anhydrous NaHCO3 (4.2 g, 0.05 mol), [bis(4-fluorophenyl)methyl]piperazine (14.4 g, 0.05 mol) in ethanol (200 mL) was added dropwise over 45 min under N2. The ice bath was removed and the mixture was allowed to come to room temperature. After 18 h the NaHCO3 was removed by filtration via a sintered glass funnel and the ethanol in the filtrate was removed in vacuo to give the crude product (21.3 g). Silica gel flash chromatography using 2.0% MeOH:CH2Cl2 gave pure product (10.05 g, 52.9%) as an amber oil. DCI/MS (M+1) 381. 400 MHz 1H NMR (CDCl3) δ: 7.3 (m, 4H), 6.95 (m, 4H), 4.2 (s, 1H), 3.95 (m, 1H), 3.55 (m, 2H), 2.7 (m, 2H), 2.5 (m, 4H), 2.4 (m, 4H).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[CH:5]1([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH2:16]=O>C(O)C.O>[CH:5]1([N:11]2[CH:15]=[CH:14][CH:13]=[C:12]2[CH2:2][N:3]([CH3:16])[CH3:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CNC
Reactant: c1ccn(C2CCCCC2)c1
Reactant: C=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN(C)Cc1cccn1C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of dimethylamine hydrochloride (3.76 g) in 40% aqueous formaldehyde (3.5 ml) was added over 30 minutes to a stirred solution of 1-cyclohexylpyrrole in ethanol (25 ml) and the resulting solution was stirred at room temperature for 18 hours. Evaporation of the solution gave a solid which was dissolved in water. The solution was extracted with ether and then basified to pH 9-10 with 1 N sodium hydroxide solution. The resulting oil was extracted with ether (3×50 ml) and the combined ethereal extracts were washed with water and dried (MgSO4). Evaporation of the ether gave an oil which was chromatographed on silica gel. Elution with chloroform gave 1-cyclohexyl-2-(dimethylaminomethyl)pyrrole (5.0 g) as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][C:46]([O:49][Si:50]([CH:57]([CH3:59])[CH3:58])([CH:54]([CH3:56])[CH3:55])[CH:51]([CH3:53])[CH3:52])=[C:45]([Cl:60])[CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C@@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][C:46]([O:49][Si:50]([CH:54]([CH3:56])[CH3:55])([CH:57]([CH3:58])[CH3:59])[CH:51]([CH3:53])[CH3:52])=[C:45]([Cl:60])[CH:44]=2)[N:36]=1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1Cl)(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@@H]5CCCN5C)n4c3)c3ccccc32)cc1Cl)(C(C)C)C(C)C
Yield: 89 %

Procedure:
A mixture of Intermediate E (145 mg, 0.40 mmol) and [5-tert-butyl-2-(3-chloro-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (WO2011/154734A1, which is incorporated herein by reference, 251 mg, 0.420 mmol) in 1,4-dioxane (4 mL) and DIPEA (110 μL, 0.63 mmol) was stirred at 90° C. for 5.5 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-12% MeOH in DCM, to give the title compound (288 mg, 89%). LCMS (Method 3): Rt 3.85 min, m/z 811 [MH+].
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](=[O:27])[NH2:26])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(Cl)[Cl:35]>>[ClH:35].[NH2:7][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25](=[O:27])[NH2:26])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)[C:28]([N:29]([CH3:31])[CH3:30])=[O:32]
Reactant: ClCCl
Reactant: CN(C)C(=O)C(Cc1ccc(Oc2ccc(CCC(N)=O)cc2)cc1)NC(=O)OC(C)(C)C
Product: CN(C)C(=O)C(N)Cc1ccc(Oc2ccc(CCC(N)=O)cc2)cc1
Product: Cl
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
The amide compound 11 (1.5 g) was dissolved in CH2Cl2 (30 mL) and cooled to 0-5° C. Hydrogen chloride gas was bubbled through this solution for 20 min. The bubbling was discontinued and the reaction mixture was stirred at room temperature for 1 h. The excess HCl was degassed and the CH2Cl2 was removed. The residual solid was triturated with EtOAc (2×50 mL), decanted, and dried to yield the desired compound 12 as a white amorphous solid that was extremely hygroscopic (1.0 g, 77%). 1H NMR (DMSO-d6): 7.29 (br, 1H), 7.20 (overlapped d, J=8.8 Hz, 2H), 7.19 (overlapped d, J=8.8 Hz, 2H), 6.88 (overlapped d, J=8.4 Hz, 2H), 6.87 (overlapped d, J=8.4 Hz, 2H), 6.87 (overlapped d, J=8.8 Hz, 2H), 6.76 (br, 1H), 4.63 (m, 1H), 2.83 (s, 3H), 2.54-2.78 (m, 7H), 2.34 (t, J=8.4 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[CH2:11][C:12]([O-:14])=[O:13].[Na+].C(=O)(O)[O-].[Na+]>O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][CH2:11][C:12]([OH:14])=[O:13])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C([O-])CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(NCC(=O)O)cc1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
54.0 g (0.46 mol) of 4-aminobenzonitrile and 106.5 g (0.92 mol) of sodium chloroacetate were suspended in 750 mL of water, and the resulting mixture was stirred at reflux temperature for 4 hours. After cooling to room temperature, pH was adjusted to 8-9 with sodium bicarbonate. The resulting solution was washed with 2×200 mL of ethyl acetate, and 5M hydrochloric acid was added to the aqueous phase until pH=3. The precipitated solid was isolated by filtration, washed with 100 mL of water and dried to yield 57.1 g of 2-(4-cyanophenylamino)acetic acid as an off-white solid. Yield: 70.9%. Purity (HPLC, method 3): 88.4%.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6]2=[N:7][CH:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:10]=[C:5]2[NH:4][CH2:3]1.Cl[C:19]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[C:21]([C:29]2[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=2)[C:20]=1[CH3:36].CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:17])[C:6]2=[N:7][CH:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:10]=[C:5]2[N:4]([C:19]2[C:28]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([C:29]3[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=3)[C:20]=2[CH3:36])[CH2:3]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Reactant: Cc1ccnc(-c2nc3ncccc3c(Cl)c2C)c1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2nc3ncccc3c(N3CC(C)(C)c4ncc(N5CCOCC5)cc43)c2C)c1

Procedure:
Prepared according to procedure Y using 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (18 mg, 0.077 mmol), 4-chloro-3-methyl-2-(4-methylpyridin-2-yl)-1,8-naphthyridine (20.81 mg, 0.077 mmol), sodium tert-butoxide (14.86 mg, 0.154 mmol) and XPhos (7.72 mmol, 7.72 mol) in toluene (4 mL) for 2 hours at 110° C. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-methyl-2-(4-methyl-2-pyridinyl)-1,8-naphthyridine. 1H NMR (400 MHz, chloroform-d) δ ppm 9.12 (1H, dd, J=4.3, 2.0 Hz), 8.57 (1H, d, J=5.1 Hz), 8.17 (1H, dd, J=8.2, 2.0 Hz), 8.00-8.03 (1H, m), 7.61 (1H, d, J=2.3 Hz), 7.44 (1H, dd, J=8.3, 4.2 Hz), 7.22 (1H, ddd, J=5.1, 1.8, 0.8 Hz), 5.81 (1H, d, J=2.3 Hz), 3.86-3.90 (1H, m), 3.77-3.82 (1H, m), 3.72-3.77 (4H, m), 2.93-3.04 (4H, m), 2.50 (3H, s), 2.49 (3H, s), 1.58 (3H, s), 1.53 (3H, s). Mass Spectrum (ESI) m/e=467.2 (M+1).
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)C=CC=CC=1.C([Li])CCC.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([CH:48]=[CH:49][C:50]=1[O:51][CH3:52])[CH:46]=O>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH3:41][O:42][C:43]1[CH:44]=[C:45]([CH2:46][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[CH:48]=[CH:49][C:50]=1[O:51][CH3:52]
Reactant: COc1ccc(C=O)cc1OC
Reactant: COc1cc(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1OC
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(CCCCc2cc(OC)c(OC)c(OC)c2)cc1OC
Reaction time: 1 h
Yield: 50.8 %

Procedure:
Suspended in 15 ml of THF were 1.23 g (2.2 mmol) of triphenyl[3-(3,4,5-trimethoxyphenyl)propyl]phosphonium bromide. The suspension was added with 1.4 ml (1.57M, 2.2 mmol) of butyl lithium in hexane under ice cooling, followed by stirring for one hour. The reaction mixture was further added with 365 mg (2.2 mmol) of 3,4-dimethoxybenzaldehyde, followed by stirring at room temperature for 21 hours. After the reaction mixture was dissolved in 30 ml of ethyl acetate, the resulting solution was washed with water and then with saturated NaCl. The organic layer was then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The oil thus obtained (1.31 g) was purified by column chromatography (silica gel: "MERCK #9385", 30 g, eluent: 1:4 mixed solvent of ethyl acetate and hexane), whereby 403 mg of the title compound were obtained as colorless oil. The oil was immediately dissolved in 10 ml of ethyl acetate, followed by the addition of 10 mg of a 10% palladium-carbon catalyst. The resulting suspension was stirred at room temperature for 35 hours under a hydrogen atmosphere of 1 atm. Insoluble matter was removed by filtration and the filtrate was concentrated. The concentrate was purified by column chromatography (silica gel: "MERCK #9385", 10 g, eluent: 1:4 mixed solvent of ethyl acetate and hexane), whereby 198 mq of the title compound were obtained as a colorless solid (25%)