Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH2:6][CH2:5]1)C>Cl.O1CCOCC1>[CH3:2][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:6][CH2:5]1
Reactant: CC(C)N1CCC(CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCC(CC2CCNCC2)CC1
Yield: 35.1 %

Procedure:
1,1-Dimethylethyl 4-{[1-(1-methylethyl)-4-piperidinyl]methyl}-1-piperidinecarboxylate (may be prepared as described in Description 3) (3.1 g) was stirred in a solution of HCl-Dioxane (50 ml, 4M) for 2 h. The solvent was evaporated and the product was dissolved in saturated potassium carbonate (25 ml). The solution was extracted into dichloromethane (3×50 ml) and the combined organics dried (Na2SO4) and evaporated to give the title compound (D19) (0.658 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][C:3]2[N:7]=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:2]1=2.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[N:21]=[C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[C:19]=1[CH3:35].CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[F:28][C:24]1[CH:23]=[C:22]2[C:27]([C:18]([N:1]3[CH2:6][CH2:5][S:4][C:3]4[N:7]=[CH:8][C:9]([N:11]5[CH2:12][CH2:13][O:14][CH2:15][CH2:16]5)=[CH:10][C:2]3=4)=[C:19]([CH3:35])[C:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[N:21]2)=[CH:26][CH:25]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: c1nc2c(cc1N1CCOCC1)NCCS2
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CCSc2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y by using 4-(2,3-dihydro-1H-pyrido[2,3-b]-[1,4]thiazin-7-yl)morpholine (43.5 mg, 0.18 mmol), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (50 mg, 0.183 mmol), XPhos precatalyst (13.5 mg, 0.018 mmol) and sodium tert-butoxide (35.2 mg, 0.37 mmol) with heating in toluene (5 mL) for 1 h at 110° C. Purification by column chromatography (gradient of DCM to (DCM:MeOH:NH4OH, 90:9:1) from 1:0 to 9:1) gave 4-(1-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl)morpholine. Mass Spectrum (ESI) m/e=474.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[O:15]1[C:19]2[C:20]([CH2:24]O)=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][CH2:16]1>>[O:15]1[C:19]2[C:20]([CH2:24][O:1][C:2]3[N:6]([C:7]4[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=4)[N:5]=[CH:4][CH:3]=3)=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][CH2:16]1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1cccc2c1OCC2
Product: N#Cc1ccnc(-n2nccc2OCc2cccc3c2OCC3)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 2,3-dihydro-1-benzofuran-7-ylmethanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 3.27 (2H, q, J=8.8 Hz), 4.68 (2H, q, J=8.8 Hz), 5.21 (2H, s), 5.83 (1H, d, J=2.0 Hz), 6.86 (1H, q, J=7.6 Hz), 7.17 (1H, d, J=7.6 Hz), 7.22 (1H, d, J=7.2 Hz), 7.37 (1H, dd, J=1.2 Hz, 4.8 Hz), 7.58 (1H, d, J=2.0 Hz), 8.14 (1H, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C18H14N4O2, 319; Found, 319.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:40]3[S:44][C:43]([O:45][CH2:46][CH2:47][OH:48])=[N:42][CH:41]=3)=[C:13]2[C:24](=[O:39])[N:25]([CH:36]2[CH2:38][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=2[CH3:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:49][C:50]1[C:51](O)=[N:52][N:53]([CH3:59])[C:54]=1[C:55]([F:58])([F:57])[F:56]>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH:10]([CH2:11][C:12]([C:40]3[S:44][C:43]([O:45][CH2:46][CH2:47][O:48][C:51]4[C:50]([Cl:49])=[C:54]([C:55]([F:58])([F:57])[F:56])[N:53]([CH3:59])[N:52]=4)=[N:42][CH:41]=3)=[C:13]2[C:24](=[O:39])[N:25]([CH:36]2[CH2:37][CH2:38]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=2[CH3:35])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cccc(CN(C(=O)C2=C(c3cnc(OCCO)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C
Reactant: Cn1nc(O)c(Cl)c1C(F)(F)F
Product: COc1cccc(CN(C(=O)C2=C(c3cnc(OCCOc4nn(C)c(C(F)(F)F)c4Cl)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C

Procedure:
This compound is prepared from compound E9 and 4-chloro-1-methyl-5-trifluoromethyl-1H-pyrazol-3-ol (Eur. Pat. Appl., 1989, EP 304409), according to the above-described procedure A. LC-MS: tR=1.23 min, ES+: 867.40.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]3=[O:20])=[CH:10][CH:9]=2)[CH:7]=1.O=S(Cl)Cl.[N-:25]=[N+:26]=[N-:27].[Na+].O>CC#N.CCOC(C)=O>[N:25]([CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]3=[O:20])=[CH:10][CH:9]=2)[CH:7]=1)=[N+:26]=[N-:27]
Reactant: O=c1ccccn1-c1ccc(-n2cnc(CO)c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: [N-]=[N+]=NCc1cn(-c2ccc(-n3ccccc3=O)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-(4-(4-(hydroxymethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one prepared above (335 mg, 1.25 mmol) in CH3CN (20 mL), SOCl2 (5.0 mL) was added. After the mixture was stirred at room temperature for 2 h, it was concentrated in vacuo. The residue was then dissolved in DMF (20 mL). To the solution, NaN3 (244 mg, 3.75 mmol) was added. After the mixture was stirred at room temperature overnight, water and EtOAc were added. The organic layer was separated, washed with 5% aq. NaHCO3, dried over Na2SO4, concentrated in vacuo to give 1-(4-(4-(azidomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one (203 mg). MS 293 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1
Reactant: CCOC(=O)C[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CCCNC1

Procedure:
290 mg (1.07 mmol) of ethyl (R)-(1-tert-butoxycarbonylpiperidin-3-yl)acetate (Example 17A) are stirred with 2 ml of dichloromethane and 2 ml of trifluoroacetic acid at RT for 1 h. The volatile components are removed on a rotary evaporator and the residue is dried under high vacuum. The resulting oil (301 mg, 99% of theory) is reacted further as it is.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[S:18])[N:10]=[CH:9]2)C=CC=CC=1.[ClH:50]>C(O)C>[ClH:50].[ClH:50].[Br:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:23]([CH2:22][CH2:21][CH2:20][NH:19][C:17]([NH:16][CH2:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][NH:8][CH:12]=2)=[S:18])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:36][CH:35]=1
Reactant: S=C(NCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NCCCN(Cc1ccc(Br)cc1)c1ccccn1
Agent: Cl
Solvent: CCO
Product: S=C(NCCCc1c[nH]cn1)NCCCN(Cc1ccc(Br)cc1)c1ccccn1
Temperature: 50 °C
Yield: 99 %

Procedure:
To a solution of the above thiourea (1.59 g, 2.215 mmol) in ethanol (50 ml), 1 N hydrochloric acid (16 ml) was added and the reaction mixture was heated to 50° C. for 10 h. The cooled reaction mixture was washed with diethyl ether (3×30 ml) and the aqueous phase evaporated in vacuo. The residue was extracted with absolute ethanol (3×20 ml) and evaporated in vacuo followed by drying in vacuo affording 1.23 g (99%) of the title compound as an amorphous powder.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH:6]([O:8][CH3:9])[O:5][CH:4]1[O:10][CH3:11].[CH2:12]([O:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1)=[O:16])[CH3:13]>>[CH3:11][O:10][CH:4]1[CH:3]([CH2:2][NH:1][C:24]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])=[CH:22][CH:21]=2)=[O:25])[CH2:7][CH:6]([O:8][CH3:9])[O:5]1
Reactant: COC1CC(CN)C(OC)O1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Product: CCOC(=O)c1ccc(NC(=O)NCC2CC(OC)OC2OC)cc1
Yield: 107.8 %

Procedure:
25.0 g (0.15 Mol) of 3-aminomethyl-2,5-dimethoxytetrahydrofuran and 30 g (0.15 mol) of 4-ethoxycarbonylphenyl isocyanate were reacted by method 48a. 57 g of the crude product were obtained and were reacted without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([F:16])([F:15])[C:10](OCC)=[O:11])=[C:4]([CH3:17])[CH:3]=1.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+]>CCO.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([CH3:17])[C:5]([C:9]([F:15])([F:16])[CH2:10][OH:11])=[C:6]([CH3:8])[CH:7]=1
Reactant: CCOC(=O)C(F)(F)c1c(C)cc(Br)cc1C
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc(C)c1C(F)(F)CO
Temperature: -10 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of Intermediate 7A (3.1 g, 10.09 mmol) in EtOH (30 ml) was added calcium chloride (0.336 g, 3.03 mmol). The resulting mixture was cooled to −10° C. and sodium borohydride (0.955 g, 25.2 mmol) was added. The mixture was then allowed to warm to rt and stand at rt. for 1 h. The reaction mixture was diluted with EtOAc and Sat. NaHCO3, extracted with EtOAc (×3). The combined organic layer was dried (MgSO4), concentrated to yield Intermediate 7B (2.68 g, 10.11 mmol, 100% yield) as a white solid. 19F NMR (376 MHz, methanol-d3) δ ppm −98.12 (br. s., 2F). 1H NMR (400 MHz, methanol-d3) δ ppm 2.42 (t, J=4.39 Hz, 6H) 3.92 (t, J=14.06 Hz, 2H) 7.26 (s, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:11]1([CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: BrCCCCCCOCCc1ccccc1
Agent: Cl
Product: c1ccc(CCOCCCCCCNCc2ccccc2)cc1

Procedure:
[2-[(6-Bromohexyl)oxy]ethyl]benzene (4.0 g) was added dropwise to benzylamine (20 ml) at 110°. The solution was heated at 110°-120° for 90 min, cooled, and treated with hydrochloric acid (2M; 125 ml). The mixture was extracted with EA (2×100 ml) and the extract was washed with aqueous sodium carbonate (100 ml) and brine (100 ml), dried and evaporated. Distillation of the residue gave the title compound as a colourless oil (3.2 g) b.p. 180°-190°/0.1 mmHg. T.l.c. (CX-ER 1:1) Rf 0.25.
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=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Product: N#Cc1cc(-c2ccc([N+](=O)[O-])cc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, yellow solid (16 mg, 19%), MS (ISN) m/z=333.4 [(M+H)+], mp 369.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-nitro-phenylboronic acid (54.3 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:22]([C:23]3[C:24](=O)[NH:25][C:26](=[O:30])[N:27]([CH3:29])[CH:28]=3)[C:10]3[N:11]=[C:12]([CH3:21])[N:13]([CH2:14][CH2:15][C:16]4[N:17]=[CH:18][NH:19][CH:20]=4)[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:32]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:22]([C:23]3[C:24](=[S:42])[NH:25][C:26](=[O:30])[N:27]([CH3:29])[CH:28]=3)[C:10]3[N:11]=[C:12]([CH3:21])[N:13]([CH2:14][CH2:15][C:16]4[N:17]=[CH:18][NH:19][CH:20]=4)[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:32]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1nc2c(n1CCc1c[nH]cn1)C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=O
Product: Cc1nc2c(n1CCc1c[nH]cn1)C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=S

Procedure:
The title compound was prepared from the product of step (iii) (0.2 g) and Lawesson's reagent (0.9 g) according to the method of example 34 step (iv). Purification was by biotage chromatography on silica eluting with 5% methanol in dichloromethane with 1% 0.880 ammonia present to give a yellow glass.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Br>CC(C)=O>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:26][CH:28]3[O:30][CH2:29]3)[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCC1CO1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc(C(c2ccccc2)N2CCN(CC3CO3)CC2)cc1

Procedure:
In acetone, 1-(diphenylmethyl)piperazine (6.0 g) was dissolved (20 v/w), and potassium carbonate (1.5 eq.) and epibromohydrin (2.0 eq.) were added thereto, and the obtained mixture was heated to reflux for 3.5 hours. The salt produced by the reaction was separated by filtration, and the filtrate was then concentrated in vacuo to obtain a crude product of 1-(diphenylmethyl)-4-(1-(2,3-epoxy)propyl)piperazine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)[C:14](Cl)=[O:15])([O-:10])=[O:9].Cl>O>[N+:8]([C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)[C:14]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])([O-:10])=[O:9]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: O
Product: O=C(Nc1ccccc1)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Yield: 84.9 %

Procedure:
To 71 g of aniline was added 22.3 g of powdery 3,5-dinitrobenzoyl chloride with stirring. Generation of heat was observed until the temperature reached 50° C. A yellowish orange paste was obtained. The paste was stirred for 10 minutes and, then, when the liquid reaction mixture was poured into 1 l of water and the mixture was rendered acidic by concentrated hydrochloric acid (35%), a white precipitate was formed. The precipitate was recovered by filtration and dried to obtain 23.58 g of 3,5-dinitrobenzanilide (the yield was 84.6%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:15])[CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].B(Cl)([C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1)[C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1>O1CCCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C@H:11]([OH:15])[CH2:12][CH2:13][CH3:14])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCC(=O)c1ccc(CC(C)C)cc1
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@H]2C[C@@H]1C2(C)C
Solvent: C1CCOC1
Product: CCC[C@@H](O)c1ccc(CC(C)C)cc1
Reaction time: 5 h
Yield: 77.3 %

Procedure:
4'-Isobutylbutanophenone (1.2 g) was added to a solution of (+)-B-chlorodiisopinocampheylborane (2.10 g) in tetrahydrofuran (4 ml) at 25° C. After 5 hours, the solvent was removed and the residue was dissolved in ethyl ether (20 ml). Diethanolamine (1.4 ml) was added to the mixture and the mixture was stirred for 2 hours. The solid was filtered off and washed with ethyl ether. The combined filtrates were concentrated and the residue was chromatographed on silica gel (eluent:hexane:CH2Cl2 =1:2) to give (R)-1-(4-isobutylphenyl)butan-1-ol (937 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:15]=[CH:14][O:13][CH:12]=3)=[C:9]([Si](C)(C)C)[NH:8][C:5]2=[N:6][CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:15]=[CH:14][O:13][CH:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)c1[nH]c2ncc(Br)cc2c1-c1ccoc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Brc1cnc2[nH]cc(-c3ccoc3)c2c1
Yield: 60.8 %

Procedure:
To a stirred solution of azaindole 13 (20.9 mg, 0.06 mmol) in THF (3 mL) was added a 1M solution of TBAF in THF (0.12 mL, 0.12 mmol). After 1.5 h the mixture was concentrated and purified by PTLC with AcOEt as eluent to give azaindole 14 (9.6 mg, 58%) as a white solid. 1H NMR (400 MHz; CDCl3) δ 6.67 (m, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.53 (m, 1H), 7.76 (m, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.39 (m, 1H), 9.33 (brs, NH).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH:18]1(O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:18]1([O:1][C:2]2[CH:3]=[C:4]([C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH:5]=[CH:6][CH:7]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: OC1CCCCC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1cccc(OC2CCCCC2)c1
Reaction time: 16 h
Yield: 55.1 %

Procedure:
To a solution of (S)-tert-butyl 1-(3-hydroxyphenyl)ethylcarbamate (100 mg, 0.421 mmol), cyclohexanol (0.180 ml, 1.686 mmol) and PPh3 (221 mg, 0.843 mmol) in THF (2 ml), was added DEAD (0.133 ml, 0.843 mmol) dropwise, under N2, at room temperature. The resulting yellow solution was stirred for 3 hours, at which point another batch of cyclohexanol (0.180 ml, 1.686 mmol), PPh3 (221 mg, 0.843 mmol), and 10 min later DEAD (0.133 ml, 0.843 mmol), was added at room temperature. The reaction mixture was stirred for 16 hours and then concentrated. The crude clear oil was re-dissolved in DMSO and purified by reverse phase HPLC. The combined product fractions were desalted by addition of equal amount of EtOAc and about 250 mg Na2CO3 in a separatory funnel. The phases were separated and the organic washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield (S)-tert-butyl 1-(3-(cyclohexyloxy)phenyl)ethylcarbamate (74.1 mg, 0.232 mmol, 55.0% yield) as a clear colourless film. LCMS m/z 305.0/264.0 (the parent not observed, just the Boc fragments) (M+H)+, Rt 1.12 min.
Reaction SMILES: C(N[C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][N:18]3[C:22](=[O:32])[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:25]=[C:17]23)[CH:13]=[CH:12][N:11]=1)CC1C=CC=CC=1.[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=1[CH2:41][CH2:42][NH2:43]>>[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=1[CH2:41][CH2:42][NH:43][C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][N:18]3[C:22](=[O:32])[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:25]=[C:17]23)[CH:13]=[CH:12][N:11]=1
Reactant: O=c1cc(-c2ccccc2)cc2n1CCCN2c1ccnc(NCCc2ccccc2)n1
Reactant: NCCc1c(Cl)cccc1Cl
Product: O=c1cc(-c2ccccc2)cc2n1CCCN2c1ccnc(NCCc2c(Cl)cccc2Cl)n1

Procedure:
Followed the same procedure described for the synthesis of 1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro -pyrido[1,2-a]pyrimidin-6-one, the sulfoxide (0.1 g, 0.27 mmol) was displaced with 2-(2,6-dichlorophenyl)ethylamine (0.16 g, 0.82 mmol) to give the title compound as a yellow solid. MS m/e 492 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.O[C:49]1[C:54]([CH3:55])=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:56][CH2:57][NH:58][C:59](=[O:61])[CH3:60]>>[C:59]([NH:58][CH2:57][CH2:56][C:50]1[CH:51]=[CH:52][CH:53]=[C:54]([CH3:55])[C:49]=1[O:33][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1)(=[O:61])[CH3:60]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(=O)NCCc1cccc(C)c1O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2c(C)cccc2CCNC(C)=O)cc1

Procedure:
Analogously to Method G, 0.36 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.21 g of N-[2-(2-hydroxy-3-methylphenyl)ethyl]acetamide are reacted. The title compound is obtained as a yellow oil. Rf=0.47 (EtOAc); Rt=5.75.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]([OH:26])([CH3:25])[CH3:24])[N:18]=3)[CH:11]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([CH3:37])[C:31]=1[F:38].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CCCCCCC>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]([OH:26])([CH3:24])[CH3:25])[N:18]=3)[CH:11]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([CH3:37])[C:31]=1[F:38]
Reactant: Cc1cnc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)cc(O)c(Cl)c1=O
Reactant: Cc1c(F)ccc(CBr)c1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1cnc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)cc(OCc2ccc(F)c(C)c2F)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.5 %

Procedure:
To a solution of 3-chloro-4-hydroxy-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one (386 mg, 1.0 mmol) in N,N-dimethylformamide (1.7 mL) was added 1-(bromomethyl)-2,4-difluoro-3-methylbenzene (243 mg, 1.1 mmol), potassium carbonate (0.35 g, 2.52 mmol) and 18-crown-6 (7 mg). The slurry was stirred at ambient temperature for 18 hours. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The solution was concentrated in vacuo to provide a brown oil. Normal phase chromatography (ethyl acetate/heptane) provided 319 mg of the alkylated product: MS (M+H) 528.
Reaction SMILES: Cl[C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.C(Cl)(Cl)Cl.[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>>[F:33][C:19]([F:18])([F:32])[C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([C:2]3[N:12]4[C:13]5[C:8]([CH2:9][CH2:10][CH2:11]4)=[CH:7][CH:6]=[CH:5][C:4]=5[N:3]=3)[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: Clc1nc2cccc3c2n1CCC3
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1cccc(N2CCN(c3nc4cccc5c4n3CCC5)CC2)c1
Reaction time: 4 h
Yield: 50 %

Procedure:
A solution of 2-chloro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline (3.00 g) in 1-[3-(trifluoromethyl)phenyl]piperazine (5 ml) was stirred at 110° C., under nitrogen. After four hrs, chloroform (50 ml) was added, and the solution was stirred under reflux overnight. The reaction mixture was quenched with dilute sodium bicarbonate solution (200 ml) and extracted with chloroform. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was purified by high performance liquid chromatography (silica gel; 8:1 dichloromethane-ethyl acetate). The appropriate fractions were collected and evaporated. The residue was recrystallized from ethyl acetate to give 3.0 g (50%) of product, mp 158°-159° C.