Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[CH2:8][N:9]1[C@@H:17]2[C@H:12]([C@H:13]([CH2:20][C:21]3[CH:26]=[C:25]([F:27])[C:24]([NH:28][C:29](=[O:32])[CH2:30][Cl:31])=[C:23]([CH2:33][CH3:34])[CH:22]=3)[CH2:14][S:15](=[O:19])(=[O:18])[CH2:16]2)[O:11]C1=O)([CH3:4])([CH3:3])[CH3:2].[CH3:39][O:40]CC(Cl)=O>>[ClH:31].[C:1]([C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[CH2:8][NH:9][C@H:17]1[CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][C@@H:13]([CH2:20][C:21]2[CH:26]=[C:25]([F:27])[C:24]([NH:28][C:29](=[O:32])[CH2:30][O:40][CH3:39])=[C:23]([CH2:33][CH3:34])[CH:22]=2)[C@@H:12]1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC(=O)Cl
Reactant: CCc1cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc(F)c1NC(=O)CCl
Product: CCc1cc(C[C@@H]2CS(=O)(=O)C[C@H](NCc3cccc(C(C)(C)C)c3)[C@H]2O)cc(F)c1NC(=O)COC
Product: Cl

Procedure:
The title compound was prepared in analogous manner as described for example 8q and 8r from N-{4-[(3aR,7S,7aS)-3-(3-tert-butyl-benzyl)-2,5,5-trioxo-octahydro-1-oxa-5lambda*6*-thia-3-aza-inden-7-ylmethyl]-2-ethyl-6-fluoro-phenyl}-2-chloro-acetamide and methoxy-acetyl chloride to yield after preparative HPLC purification (Sunfire C18 OBD 5 μm, 100×30, 5-100% ACN in water+0.1% TFA gradient, 25 min) the title compound as a light yellow amorphous solid: TLC (EtOAc-MeOH 9:1) Rf=0.56; UPLC RtD=1.298 min; ESIMS [M+H]+=535; 1H NMR (600 MHz, DMSO-d6): δ 9.99 (s, 1H), 9.31 (s, 1H), 9.08 (s, 1H), 7.68 (s, 1H), 7.44 (dd, 1H), 7.39 (m, 3H), 6.96 (d, 1H), 6.92 (s, 1H), 6.23 (s, 1H), 4.23 (m, 4H), 4.01 (s, 2H), 3.91 (d, 1H), 3.66 (m, 2H), 3.38 (s, 3H), 3.26 (dd, 1H), 3.17 (m, 2H), 2.76 (dd, 1H), 2.52 (m, 3H), 2.10 (m, 1H), 1.29 (s, 9H), 1.08 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:34])[C@@H:16]([NH:23][C:24]([C@H:26]3[O:28][C@@H:27]3[C:29]([O:31]CC)=[O:30])=[O:25])[CH2:17][C:18]3[N:19]=[CH:20][S:21][CH:22]=3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[CH:2].[Li+].[OH-]>C1COCC1.CO.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:34])[C@@H:16]([NH:23][C:24]([C@H:26]3[O:28][C@@H:27]3[C:29]([OH:31])=[O:30])=[O:25])[CH2:17][C:18]3[N:19]=[CH:20][S:21][CH:22]=3)[S:12][CH:13]=2)=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1ccc(-c2csc(NC(=O)[C@H](Cc3cscn3)NC(=O)[C@H]3O[C@@H]3C(=O)OCC)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C#Cc1ccc(-c2csc(NC(=O)[C@H](Cc3cscn3)NC(=O)[C@H]3O[C@@H]3C(=O)O)n2)cc1
Yield: 44.5 %

Procedure:
Synthesized following general saponification procedure using the following quantities: 19c (115 mg, 0.23 mmol); LiOH (6.7 mg, 0.28 mmol); THF/MeOH/H2O (4.5 ml: 1.5 ml: 1.5 ml); yielded 34 as a white solid (48 mg, 44.2%). 1H NMR (DMSO-d6, 400 MHz): δ 12.57 (s, 1H); 9.06-9.05 (d, 1H, J=1.92 Hz); 8.81-8.79 (d, 1H, J=7.8 Hz); 7.93-7.91 (d, 2H, J=8.4 Hz); 7.76 (s, 1H); 7.55-7.53 (d, 2H, J=8.4 Hz); 7.45-7.44 (d, 1H, 1.8 Hz); 4.98-4.93 (q, 1H); 4.25 (s, 1H): 3.66-3.65 (d, 1H, J=1.8 Hz); 3.42-3.41 (d, 1H, J=1.8 Hz): 3.35-3.22 (m, 2H). 13C NMR (DMSO-d6, 100 MHz): 170.08, 169.03, 165.98, 158.25, 154.33, 152.54, 148.47, 134.95, 132.61, 126.26, 121.32, 116.75, 110.20, 83.87, 81.99, 53.15, 53.08, 51.88, 33.05. ESI-HRMS (m/z): [M+H+] calcd. for C21H16N4O5S2: 469.0635; observed, 469.0627; HPLC method 1: Rt=12.5 min, Purity=95.7%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[CH:5]=1)([O-])=O.[Cl-].[NH4+].O.C(O)C>O1CCCC1.[Fe]>[Br:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][CH2:10][C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(COc2cccc(Br)c2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc(COc2cccc(Br)c2)c1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
To a solution of the product from Example 104A (1.64 g, 5.32 mmol), iron powder (1.49 g, 26.62 mmol) and ammonium chloride (430 mg, 7.98 mmol) in a mixture of tetrahydrofuran (20 mL), water (6 mL) and ethanol (20 mL) was heated to reflux for 3 hours. The mixture was cooled to room temperature, filtered through a pad of celite, which was washed with ethanol and the resultant filtrate concentrated under vacuum. The material was then dissolved in water (50 mL) and extracted with ethyl acetate (50 mL), the organic layer dried and concentrated under vacuum to provide the title compound as a yellow oil (1.43 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O=[C:11]([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[C:11]([CH3:18])[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: N#Cc1ccccc1N
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2ccccc2c1N

Procedure:
Prepared as in Example 2a from 2-aminobenzonitrile and ethyl 3-oxobutanoate as a yellow solid (32%). 1H NR (400 MHz, DMSO-d6) δ 1.33 (t, J=8.0 Hz, 3H), 2.61 (s, 3H), 4.34 (q, J=8.0 Hz, 2H), 7.41 (m, 1H), 7.66 (m, 2H), 7.74 (bs, 2H), 8.27 (d, J=8.0 Hz, 1H). MS 231 (MH+).
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:16][S:17][N:18]=1)[CH2:4][CH2:5][CH3:6]>CC(C)=O>[I-:2].[CH2:3]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([C:19]2[CH:20]=[N+:21]([CH3:1])[CH:22]=[CH:23][CH:24]=2)=[N:16][S:17][N:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOCCOCCOc1nsnc1-c1cccnc1
Reactant: CI
Solvent: CC(C)=O
Product: CCCCOCCOCCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.5 ml, 9 mmol) and 3-(4-(2-(2-butoxyethoxy)ethoxy)-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration.
Reaction SMILES: [C:1]([OH:16])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].[CH2:23]([C@H:25]1[CH2:30][C@H:29]2[C@H:31]3[C@H:40]([CH2:41][CH2:42][C@:27]2([CH3:28])[C@H:26]1[O:44][C:45](=[O:48])[CH2:46]Br)[C@@H:39]1[C:34](=[CH:35][C:36](=[O:43])[CH2:37][CH2:38]1)[CH2:33][CH2:32]3)[CH3:24]>CC(C)=O>[CH2:23]([C@H:25]1[CH2:30][C@H:29]2[C@H:31]3[C@H:40]([CH2:41][CH2:42][C@:27]2([CH3:28])[C@H:26]1[O:44][C:45](=[O:48])[CH2:46][O:15][C:1](=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C@@H:39]1[C:34](=[CH:35][C:36](=[O:43])[CH2:37][CH2:38]1)[CH2:33][CH2:32]3)[CH3:24]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: CCCCCCCCCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCC(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Yield: 63.9 %

Procedure:
To 100 ml of 30% aqueous acetone are added 1.0 g of myristic acid and 0.8 g of potassium carbonate, followed by addition of 1.16 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one. The mixture is refluxed for 5 hours. After cooling, the reaction mixture is extracted with 150 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography, elution being carried out with 600 ml of toluene-diisopropyl ether (19:1). The eluate is evaporated under reduced pressure to remove the solvent, giving a light-yellow viscous oil. This product is allowed to stand at room temperature (15°-25° C.) to give 1.0 g of the above-identified compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:22]=[C:21]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:34]=3[N:33]=[C:32]2[CH:42]([F:44])[F:43])[N:20]=1>C1COCC1.C(O)(=O)C.O>[F:44][CH:42]([F:43])[C:32]1[N:31]([C:21]2[N:22]=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:24]=[C:19]([NH:1][C:2]3[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=3)[N:20]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:34]=2[N:33]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: COc1ccc(N)cn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Nc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)cn1
Reaction time: 0.33 h
Yield: 3.4 %

Procedure:
To a solution of 0.310 g (2.50 mmol) of 5-amino-2-methoxypyridine in THF (3 mL) at 0° C. was added 1.35 mL of lithium diisopropylamide (2 M solution in benzene/heptanes/THF), and the mixture was stirred for 20 min. A solution of 0.240 g (0.61 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole in THF (5 mL) was added, and the resulting mixture was stirred for 1 hr at RT. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed sequentially with water and aq. NH3, dried, and concentrated. Chromatography on alumina, eluting first with hexanes/EtOAc (1:1) and then with CH2Cl2/EtOAc (1:3) gave a reddish powder. Recrystallization from ethanol/CH2Cl2 gave 0.010 g (4% yield) of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-(6-methoxy-3-pyridinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 201-202° C.; 1H NMR (CDCl3) δ8.33 (br s, 1H), 7.93 (br s, 1H), 7.79 (dd, J=8.8, 2.7 Hz, 1H), 7.32-7.31 (m, 2H), 6.88-6.79 (m, 3H), 4.04 (s, 3H), 3.97 (s, 3H), 3.90 (s, 4H), 3.79 (s, 4H); Anal. Calcd. for C22H22F2N8O3: C, 54.5; H, 4.6; N, 23.1. Found: C, 54.6; H, 4.5; N, 22.9%.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:13])[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([OH:23])[CH:21]=[CH2:22]>>[CH2:20]([O:23][C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[CH:21]=[CH2:22]
Reactant: CC(C(=O)N=C=O)(c1ccccc1)c1ccccc1
Reactant: C=CCO
Product: C=CCOC(=O)NC(=O)C(C)(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p.=89° C. and MS: m/e=309.4 (M+H+) was prepared in accordance with the general method of example 1 from 2,2-diphenylpropionyl isocyanate and prop-2-en-1-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][CH:50]([S:53]([C:56]2[CH:61]=[CH:60][C:59]([NH:62][C:63]3[N:68]=[CH:67][C:66]([NH2:69])=[CH:65][N:64]=3)=[CH:58][CH:57]=2)(=[O:55])=[O:54])[CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]>C(Cl)Cl>[C:40]([O:44][C:45]([N:47]1[CH2:48][CH2:49][CH:50]([S:53]([C:56]2[CH:57]=[CH:58][C:59]([NH:62][C:63]3[N:68]=[CH:67][C:66]([NH:69][C:4](=[O:6])[C:3]4[CH:7]=[C:8]([NH:11][C:12](=[O:21])[C:13]5[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=5)[CH:9]=[CH:10][C:2]=4[Cl:1])=[CH:65][N:64]=3)=[CH:60][CH:61]=2)(=[O:54])=[O:55])[CH2:51][CH2:52]1)=[O:46])([CH3:43])([CH3:41])[CH3:42]
Reactant: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(C(=O)O)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(N)cn3)cc2)CC1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(NC(=O)c4cc(NC(=O)c5ccc(C#N)cc5)ccc4Cl)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
Intermediate 16 (Example 24) (0.132 g, 0.439 mmol) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.093 g, 0.53 mmol) and diluted with DCM (4 mL). This was immediately treated with 4-methyl morpholine (0.10 mL, 0.88 mmol) and allowed to stir at ambient temperature for 1 h. Intermediate 13 (Example 20) (0.20 g, 0.462 mmol) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids purified via HPLC to afford the title compound as a white solid (0.12 g, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][N:3]=1.Br[CH2:14][CH2:15]Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([S:9]([CH3:12])(=[O:11])=[O:10])[CH2:15][CH2:14]2)=[CH:4][N:3]=1
Reactant: BrCCBr
Reactant: CS(=O)(=O)Cc1ccc(Cl)nc1
Product: CS(=O)(=O)C1(c2ccc(Cl)nc2)CC1
Yield: 52 %

Procedure:
The title compound was prepared from 2-chloro-5-methanesulfonylmethyl-pyridine and 1,2-dibromoethane following a procedure analogous to that described in Step 3 for Intermediate 4. Yield: 52% of theory; Mass spectrum (ESI+): m/z=232/234 (Cl) [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17]O)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].S(Cl)([Cl:21])=O>ClCCl>[Cl:21][CH2:17][CH2:16][CH2:15][NH:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCCO
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 3-[(3-nitroquinolin-4-yl)amino]propan-1-ol (20.75 g, 83.93 mmol), thionyl chloride (15.0 g, 125.89 mmol), and dichloromethane (420 mL). The bright yellow, homogeneous solution was stirred at ambient temperature for 2 hours at which time the starting material was completely consumed. The volatiles were removed under reduced pressure and the resulting solid stirred in water (400 mL) made basic (pH 10) with solid sodium carbonate. A bright yellow solid was collected by filtration to afford N-(3-chloropropyl)-3-nitroquinolin-4-amine (21.63 g, 81.41 mmol) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:14]([O-])=O>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[NH2:14]
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCOCC2)cc1F
Reaction time: 2.5 h
Yield: 96.7 %

Procedure:
2-Fluoro-4-morpholinonitrobenzene (1.80 g) was dissolved in methanol (100 mL) and 10% Pd/C (94 mg) was added. The mixture was placed in a hydrogenator (45 psi) for 2.5 h. The reaction mixture was filtered through celite and washed with methanol. The filtrate was concentrated to give 1.51 g solid. 1H NMR (CDCl3) δ6.76-6.54 (m, 3H), 3.84 (t, 4H), 3.45 (bs, 2H), 3.02 (t, 4H) ppm. ESI mass spectrum z (rel. intensity) 197.1 (M+H, 100).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccccn2)CC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 130.8 %

Procedure:
To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1 g, 3.23 mmol) in dioxane (35 ml) and water (2.0 ml) was added 2-bromopyridine (2.9 g, 18.35 mmol), K3PO4 (3.8 g, 17.90 mmol) and Pd(PPh3)4 (350 mg, 0.30 mmol), and the resulting mixture was allowed to react with stirring for 3 hours at 90° C. The reaction mixture was diluted with water (180 ml) and extracted with ethyl acetate (3×50 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford tert-butyl 4-(pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate as pink oil (1.1 g, 70%).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][Si](C(C)(C)C)(C)C.C1COCC1.C[N+](C)(C)C.[F-]>>[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH:26][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NCCCCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 100 mg (0.16 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrochloride and 90 μl (0.32 mmol) of (6-bromohexyloxy)tert-butyldimethylsilane. The protecting group was cleaved off in THF using 7 equivalent of TMAF. The product was purified by means of preparative HPLC. The product is in the form of the hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].[CH3:12][C:13]([CH3:21])([CH3:20])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18]Br.C(OCC)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:9])[CH:4](/[CH:18]=[CH:17]/[CH2:16][C:15]#[C:14][C:13]([CH3:21])([CH3:20])[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)(C)C#C/C=C/CBr
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)C(/C=C/CC#CC(C)(C)C)C(=O)OC
Reaction time: 1 h

Procedure:
4.05 ml of malonic acid dimethyl ester is dissolved in 40 ml of dimethylformamide, 1.29 g of 60% oily sodium hydride and 6.5 g of (E)-6,6-dimethyl-2-hepten-4-ynyl bromide (containing about 5% Z-form) are added gradually, and the mixture is stirred at that temperature for 1 hour. Saturated saline and ethyl ether are added to the reaction solution to form two liquid phases, the ether layer is taken, washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography [Wako gel C-200, 400 g; hexane/ethyl acetate=19/1→9/1] to obtain 6.26 g of (E)-6,6-dimethyl-2-hepten-4-ynylmalonic acid dimethyl ester as colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH2:12][C:13]([CH3:16])([CH3:15])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1C[O:20][CH2:19]C1.C([Li])CCC.CN(C=O)C>O.CCCCCC>[CH3:15][C:13]1([CH3:16])[CH2:12][O:11][C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([CH:3]=2)[CH:19]=[O:20])=[N:14]1
Reactant: C1CCOC1
Reactant: COc1ccc(C2=NC(C)(C)CO2)cc1Br
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: COc1ccc(C2=NC(C)(C)CO2)cc1C=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
2-(3-Bromo-4-methoxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (2.1 g, 7.4 mmol) and THF (15 ml) were mixed, and this solution was cooled to -78° C. A hexane solution (1.6M, 4.75 ml) of n-butyllithium (7.6 mmol) was added, and the mixture was stirred for 2 hours. DMF (1.16 ml, 15 mmol) was added and the mixture was stirred for 20 minutes. Water (20 ml) was added to stop the reaction. The aqueous layer was extracted twice with ethyl acetate (20 ml). The organic layers were combined, and washed with saturated brine (30 ml). This solution was dried over anhydrous magnesium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane/ethyl acetate=3/1-1/3) to give 5-(4,4-dimethyl-4,5-dihydrooxazole-2-yl)-2-methoxybenzaldehyde (0.71 g, 41%) as colorless transparent crystals.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[C:13]3=[C:14]([F:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][CH2:3]1.C(OC(=O)NC1CCNCC1O)(C)(C)C.[O:38]=[C:39]1[CH2:44][S:43][C:42]2[N:45]=[CH:46][C:47]([CH:49]=O)=[CH:48][C:41]=2[NH:40]1.C([BH3-])#N.[Na+].C(Cl)(Cl)[Cl:56]>CO>[ClH:56].[F:22][C:14]1[CH:15]=[N:16][C:17]2[CH:18]=[CH:19][C:20](=[O:21])[N:11]3[CH2:10][C@@H:9]([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][CH2:49][C:47]5[CH:46]=[N:45][C:42]6[S:43][CH2:44][C:39](=[O:38])[NH:40][C:41]=6[CH:48]=5)[CH2:3][CH2:4]4)[C:13]=1[C:12]=23
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ncc(F)c2c43)CC1
Reactant: ClC(Cl)Cl
Reactant: O=Cc1cnc2c(c1)NC(=O)CS2
Agent: CC(C)(C)OC(=O)NC1CCNCC1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cl
Product: O=C1CSc2ncc(CNC3CCN(C[C@@H]4Cn5c(=O)ccc6ncc(F)c4c65)CC3)cc2N1
Reaction time: 18 h
Yield: 39 %

Procedure:
(4R)-4-[(4-amino-1-piperidinyl)methyl]-3-fluoro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one Enantiomer 1 (50 mg, 0.166 mmol) and 2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxaldehyde (for a synthesis see WO2004058144 Example 48(e)) (32 mg, 0.166 mol) were stirred in chloroform (1 mL) and methanol (1 mL) for 2 h at room temperature. Sodium cyanoborohydride (40 g) was added and the mixture was stirred for 18 h. The mixture was filtered and evaporated. Chromatography on silica, eluting with 0-20% methanol/dichloromethane, gave the free base of the title compound (31 mg, 39%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:9]2[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]([OH:29])[CH2:18][S:19][C:20]3[N:28]=[CH:27][N:26]=[C:25]4[C:21]=3[NH:22][CH:23]=[N:24]4)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38].CCN(CC)CC>C(Cl)Cl>[OH2:29].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[N:9]2[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]([O:29][C:37](=[O:39])[CH3:38])[CH2:18][S:19][C:20]3[N:28]=[CH:27][N:26]=[C:25]4[C:21]=3[NH:22][CH:23]=[N:24]4)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:9]2[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]([O:29][C:37](=[O:39])[CH3:38])[CH2:18][S:19][C:20]3[N:28]=[CH:27][N:26]=[C:25]4[C:21]=3[NH:22][CH:23]=[N:24]4)[CH2:11][CH2:10]2)[C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)=[CH:4][CH:3]=1
Reactant: OC(CSc1ncnc2nc[nH]c12)CN1CCCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC(CSc1ncnc2nc[nH]c12)CN1CCCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Product: O
Reaction time: 72 h
Yield: 204.2 %

Procedure:
To 6-[1-[1-[bis(4-fluorophenyl)methyl]homopiperazin-4-yl]-2-hydroxy-3-propanylthio]purine (0.26 g, 0.51 mmol) (the filtrate from above) in methylene chloride (2 mL) was added acetic anhydride (0.05 mL, 0.51 mmol) in Et3N (0.07 mL, 0.51 mmol) at room temperature under a nitrogen atmosphere. After three days, the solution was filtered and the filtrate extracted with aqueous saturated sodium bicarbonate (2×50 mL), water (1×50 mL) and saturated brine (1×50 mL), and dried over Na2SO4. Evaporation of the solvent gave a white solid (390 mg). After several washings with pentane, the solid was dried in a vacuum oven for 4 days to give pure product (0.160 g, 56.8%) as a white solid, mp 88°-90° C. (dec). DCI/MS (M+1) 553; 300 MHZ1H NMR (CDCl3) δ: 8.7 (s, 1H), 8.1 (s, 1H), 7.3 (m, 4H), 6.95 (m, 4H), 5.3 (m, 1H), 4.1 and 3.45 (q of q, 2H), 2.6-2.8 (m, 10H), 2.0 (s, 3H), 1.75 (m, 2H).