Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)CCN.[CH3:7][O:8][CH2:9][CH2:10][O:11][N:12]1C(=O)C2=CC=CC=C2C1=O.C(O)(=O)C.[C:27]([C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[NH:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])(=O)[CH3:28]>CCO>[Cl:36][C:34]1[CH:33]=[CH:32][C:31]([NH:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])=[C:30]([C:27](=[N:12][O:11][CH2:10][CH2:9][O:8][CH3:7])[CH3:28])[CH:35]=1
Reactant: CC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: COCCON1C(=O)c2ccccc2C1=O
Agent: CN(C)CCN
Solvent: CCO
Solvent: CC(=O)O
Product: COCCON=C(C)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.1 %

Procedure:
N,N-Dimethylethylenediamine (2.54 mL, 22.0 mmol) was added to a solution of N-(2-methoxyethoxy)phthalimide (3.32 g, 15.0 mmol) in EtOH (50 mL), and the reaction allowed to stir at RT for 15 h. Glacial acetic acid (20 mL) was then added to adjust the mixture to Ca. pH 4, followed by the addition of a solution of N-(2-acetyl-4-chlorophenyl)trifluoromethanesulfonamide 19 (3.02 g, 10.0 mmol) in EtOH (2 mL), and the mixture stirred for 65 h at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 1:1). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:9 to 1:1) afforded N-{4-chloro-2-[1-(2-methoxyethoxyimino)ethyl]phenyl}trifluoromethanesulfonamide 185 (3.0 g, 80%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) δ 11.40, br s, 1H; 7.65, d, J=8.8 Hz, 1H; 7.47, d, J=2.4 Hz, 1H; 7.33, dd, J=2.4 and 8.8 Hz, 1H; 4.37, m, 2H; 3.71, m, 2H; 3.41, s, 3H; 2.32, s, 3H. HRMS (M+) 374.0308.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14]([I:19])=[CH:13][C:12]=3[N:11]=[C:10]([C:20]3C(C)=CC(C)=CC=3C)[C:9]=2[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]>C1(C)C=CC=CC=1.C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14]([I:19])=[CH:13][C:12]=3[N:11]=[C:10]([CH3:20])[C:9]=2[CH:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCc2c(-c3c(C)cc(C)cc3C)nc3cc(I)ccc3c21
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCC(CC)n1ccc2c(C)nc3cc(I)ccc3c21
Yield: 84.6 %

Procedure:
Activated manganese dioxide (45 mg, 0.51 mmol) was added to a solution of 1-(1-ethylpropyl)-7-iodo-4-mesityl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline (39 mg, 0.10 mmol) in toluene (4.0 mL) and methylene chloride (4.0 mL), followed by heating under reflux for one day. The mixture was filtered through Celite and evaporated, to give the title compound (32 mg) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[CH2:20]O.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[CH2:20][N:27]1[C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]2[C:23]1=[O:33]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(c1ccccc1Cl)c1ccccc1-n1ccnc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(c1ccccc1Cl)c1ccccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 17, 2'-chloro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone is treated with phthalimide and triphenylphosphine and finally with diethyl azodicarboxylate to give 2'-chloro-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[N:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[F:16][C:17]([F:25])(S(F)(=O)=O)C(O)=O.C([O-])(O)=O.[Na+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:17]([F:25])[F:16])[N:3]=1
Reactant: Oc1cccc(Br)n1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: FC(F)Oc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.5 %

Procedure:
To a solution of 2-bromo-6-hydroxypyridine (535 mg, 3.07 mmol) in anhydrous acetonitrile (10 mL) was added sodium sulphate (44 mg, 0.31 mmol) and a solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (0.35 mL, 3.38 mmol) in acetonitrile (2 mL). The reaction was stirred at room temperature for 18 hours. Saturated aqueous NaHCO3 solution (10 mL) was added and the solution was concentrated in vacuo. The residue was dissolved in diethyl ether (30 mL), washed with water (20 mL), brine (20 mL), saturated aqueous NaHCO3 solution (20 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 70-100% DCM in heptanes to afford the title compound (347 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:17])[C:14]=1[S:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].Cl.CN(C)CCCN=C=NCC.O>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:17][C:21](=[O:22])[C:20]3[CH:24]=[CH:25][CH:26]=[N:27][C:19]=3[CH3:18])[C:14]=1[S:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: Cc1ncccc1C(=O)O
Reactant: CSc1c(Cl)cc2c([nH]c3cnccc32)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: CSc1c(Cl)cc2c([nH]c3cnccc32)c1NC(=O)c1cccnc1C
Temperature: 100 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
A 250 ml round-bottom flask with magnetic stirrer was charged with 6-chloro-7-methylsulfanyl-9H-β-carbolin-8-ylamine (Intermediate 28, 2.336 g, 8.86 mmol) and 2-methylnicotinic acid (3.219 g, 23.4 mmol) in 80 ml anhydrous pyridine. To the resulting reaction mixture at RT was added solid 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.080 g, 36.9 mmol) and the reaction mixture was heated to 100° C. (oil bath) for 2 days. The resulting mixture was cooled to RT and concentrated (rotavap) to afford a brown residue. The residue was redissolved in MeOH (50 ml), slowly added to a stirring mixture of 5:1 H2O/saturated aqueous sodium bicarbonate (600 mlL) and stirred at RT for ˜18 hr. The precipitated solid was collected via suction filtration, washed with Et2O (2×150 ml), and air-dried to afford 3.036 g of crude N-(6-chloro-7-methylsulfanyl-9H-β-carbolin-8-yl)-2-methyl-nicotinamide as a brown solid. The crude material was purified via HPLC (yields=˜40-60%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[F:39])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[F:39])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(F)c2F)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 26.4 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (640 mg, 0.003 mol) in N,N-dimethylformamide (7 mL) was added N,N-diisopropylethylamine (2.00 g, 0.015 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2,3-difluoro-phenoxy)-but-2-enoic acid ethyl ester (1.00 g, 0.003 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2,3-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (300 mg, 23%) as yellow oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[C:10]1([CH:16]2[C:19]3([CH2:21][O:20]3)[O:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[N:1]1[N:2]([C:19]2([CH2:21][OH:20])[CH:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:17][O:18]2)[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: c1ccc2[nH]nnc2c1
Reactant: c1ccc(C2COC23CO3)cc1
Solvent: ClCCl
Product: OCC1(n2nc3ccccc3n2)OCC1c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
Benzotriazole (0.15 g, 1.3 mmol) in dry CH2Cl2 (4 mL) at 0° C. was added to a stirred solution under N2 of 3-phenyl-1,5-dioxaspiro[3.2]hexane (0.21 g, 1.3 mmol) in dry CH2Cl2 (4 mL) at 0° C. The reaction mixture was left to stir for 3 hours at 0° C. It was then concentrated to provide a light brown oil. The residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc 80:20) to give 2-(benzotriazol-2-yl)-2-(hydroxymethyl)-3-phenyloxetane as a white solid (0.15 g, 41%): mp 119-123° C.; IR (film) 3437 (br), 3094, 3064, 2941, 1560, 1499 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J=8.1 Hz, 2H), 7.35 (m, 7H), 5.42 (dd, J=8.7, 7.0 Hz, 1H), 5.20 (dd, J=8.7, 6.0 Hz, 1H), 5.09 (dd, J=6.8, 6.0 Hz, 1H), 4.25 (dd, J 13.0, 7.7 Hz, 1H), 4.20 (dd, J=13.0, 7.0 Hz, 1H), 2.6 (dd, J=7.3, 7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 144.8, 134.3, 129.3, 128.6, 128.5, 127.8, 119.1, 102.2, 69.8, 63.8, 48.8; MS (EI) m/z 281 (M+), 251, 162, 104 (100), 91; HRMS (FAB) calculated for C16H16N3O2 (M++H) m/z 282.1242. Found: 282.1248; Anal. calculated for C16H15N3O2: C, 68.31; H, 5.37; N, 14.94. Found: C, 68.13; H, 5.40; N, 14.97.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[C:6](Cl)[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1.[CH3:24][C:25]1([CH3:32])[O:29][CH:28]([CH2:30][NH2:31])[CH2:27][O:26]1>C(O)C>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:7]1[C:6]([NH:31][CH2:30][CH:28]2[CH2:27][O:26][C:25]([CH3:32])([CH3:24])[O:29]2)=[N:5][C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:3][C:2]=1[Cl:1]
Reactant: CC1(C)OCC(CN)O1
Reactant: Clc1nc(N2CCOCC2)nc(Cl)c1-c1nc2ccccc2s1
Solvent: CCO
Product: CC1(C)OCC(CNc2nc(N3CCOCC3)nc(Cl)c2-c2nc3ccccc3s2)O1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
Into a solution of 2-[4,6-dichloro-2-(morpholin-4-yl)pyrimidin-5-yl]-1,3-benzothiazole (200 mg, 0.54 mmol, 1.00 equiv) in ethanol (3 mL) was added (2,2-dimethyl-1,3-dioxolan-4-yl)methylamine (142.9 mg, 1.09 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 85° C. Removal of the solvent under reducing pressure gave 0.35 g (crude) of the title compound as a yellow solid, which was used for next step without further purification. MS m/z [M+H]+ (ESI): 462.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([C:22]4[C:23]([O:32]C)=[N:24][C:25]([NH:28][CH:29]([CH3:31])[CH3:30])=[N:26][CH:27]=4)=[N:19][C:20]=3[CH3:21])[CH:11]=[CH:10][N:9]=2)[CH:5]=[N:4]1)[CH3:2].Br>CC(O)=O>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([C:22]4[C:23](=[O:32])[NH:24][C:25]([NH:28][CH:29]([CH3:31])[CH3:30])=[N:26][CH:27]=4)=[N:19][C:20]=3[CH3:21])[CH:11]=[CH:10][N:9]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2cc(Oc3ccc(-c4cnc(NC(C)C)nc4OC)nc3C)ccn2)cn1
Agent: Br
Solvent: CC(=O)O
Product: CCn1cc(-c2cc(Oc3ccc(-c4cnc(NC(C)C)[nH]c4=O)nc3C)ccn2)cn1
Temperature: 90 °C
Yield: 76.6 %

Procedure:
5-(5-((2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)-N-isopropyl-4-methoxypyrimidin-2-amine (0.25 g, 0.56 mmol) was dissolved in AcOH (5 mL) and 48% hydrobromic acid (0.25 mL, 2.24 mmol) was added. The mixture was heated at 90° C. for 5 hours. The mixture was evaporated under high vacuum. The residue was treated with NaHCO3 solution and the solution was extracted with EtOAc (3×). The organic was dried over Na2SO4, filtered, and concentrated. The residue was treated with hot MeCN. The solid was filtered, and dried under vacuum to obtain 5-(5-((2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)-2-(isopropylamino)pyrimidin-4(3H)-one (185 mg, 73.1% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.81 (s, 1H), 8.68 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.31 (s, 1H), 8.26 (d, J=8.6 Hz, 1H), 7.98 (s, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 6.60 (dd, J=5.7, 2.4 Hz, 1H), 4.14 (q, J=7.3 Hz, 2H), 4.07 (m, 1H), 2.34 (s, 3H), 1.37 (t, J=7.3 Hz, 3H), 1.17 (d, J=6.5 Hz, 6H); MS (ESI) m/z: 432.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: ClCCCCc1ccc(Cl)cc1
Solvent: CCO
Product: Clc1ccc(CCCCN2CCNCC2)cc1
Yield: 46.3 %

Procedure:
A mixture of 26.4 g of 4-(4-chlorophenyl)butyl chloride, 86.1 g of anhydrous piperazine and 250 ml of reagent ethanol was refluxed overnight. Solvent was evaporated from the product and the residue was chromatographed twice on silica with the eluant being CH2Cl2 /CH3OH/ammonium hydroxide (45:5:1). The first chromatography removed the bulk of the excess piperazine, the second provided 15.2 g of 1-[4-(4-chlorophenyl)butyl]piperazine as a colorless oil which solidified on standing (m.p. 139°-145° C.).
Reaction SMILES: [C:1]([C:4]1[C:5]([N:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].[CH2:24](I)[CH2:25][CH3:26]>>[C:1]([C:4]1[C:5]([N:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:24][CH2:25][CH3:26])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CCCI
Reactant: CC(=O)c1c(C)[nH]c(-c2ccccc2)c1N=Cc1ccccc1
Product: CCCn1c(C)c(C(C)=O)c(N=Cc2ccccc2)c1-c1ccccc1

Procedure:
Starting from the compound of Example 46 and propyl iodide, and using procedure (a) of Example 49, 4-acetyl-3-benzylideneamino-5-methyl-2-phenyl-1-propylpyrrole is obtained as an oily substance. This compound is hydrolyzed as in procedure (b) of Example 49. Yield of the title compound: 50%, m.p. 113°-15° C. (from ethanol).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[OH:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](=[O:27])[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:16]([CH3:20])[O:17]2)=[CH:12][CH:11]=1.O>CN(C=O)C>[Br:1][C:19]1[C:10]([OH:9])=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][C:16]([CH3:20])=[C:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14]2=[O:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1oc2cc(O)ccc2c(=O)c1-c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc2c(Br)c(O)ccc2c(=O)c1-c1ccccc1
Reaction time: 24 h
Yield: 58.9 %

Procedure:
N-Bromosuccinimide (2.0 g, 11.2 mmol) was added to a solution of 7-hydroxy-2-methyl-3-phenyl-chromen-4-one (2.5 g, 10 mmol) in DMF (20 ml) and the solution stirred for ˜24 hrs. to give an orange suspension. The suspension was poured into water (200 ml) to give a pale pink precipitate, solids were removed by filtation and washed with water. Solids were recrystallised from ethanol, to give the 8-bromo-7-hydroxy-2-methyl-3-phenyl-chromen-4-one as an off-white solid (1.95 g)
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:18]4[O:20][CH2:21][CH2:22][O:23][C:17]=4[CH:16]=[CH:15][C:14]=3[CH:13]=[CH:12][C:11]2=[O:24])[CH2:4][CH2:3]1.[O:25]1[C:34]2[CH:33]=[C:32]([CH:35]=O)[N:31]=[CH:30][C:29]=2[O:28][CH2:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)(Cl)[Cl:52]>CO>[ClH:52].[O:25]1[C:34]2[CH:33]=[C:32]([CH2:35][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:18]6[O:20][CH2:21][CH2:22][O:23][C:17]=6[CH:16]=[CH:15][C:14]=5[CH:13]=[CH:12][C:11]4=[O:24])[CH2:6][CH2:7]3)[N:31]=[CH:30][C:29]=2[O:28][CH2:27][CH2:26]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: ClC(Cl)Cl
Reactant: NC1CCN(CCn2c(=O)ccc3ccc4c(c32)OCCO4)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: Cl
Product: O=c1ccc2ccc3c(c2n1CCN1CCC(NCc2cc4c(cn2)OCCO4)CC1)OCCO3
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
10-[2-(4-amino-1-piperidinyl)ethyl]-2,3-dihydro[1,4]dioxino[2,3-h]quinolin-9(10H)-one (100 mg; 0.304 mmol) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (50 mg; 0.304 mmol) were dissolved in a 5:1 mixture of chloroform and MeOH (5 ml:1 ml) and stirred at rt for 2.5 h. More 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (10 mg; 0.031 mmol) was added to the reaction and stirred for 20 mins. This was then treated with NaBH(OAc)3 (20 mg; 0.092 mmol) and stirred for 30 mins. More 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (10 mg; 0.031 mmol) was added to the reaction and stirred for 15 mins. This was then treated with NaBH(OAc)3 (20 mg; 0.092 mmol) and stirred for 15 mins. The solvents were then removed and the crude residues purified by column chromatography on silica gel using a 0-20% 2M NH3:MeOH/DCM gradient. Fractions containing the desired were concentrated to afford the free base of the title compound. (140 mg; 96%). δH CDCl3, (400 MHz) 1.49 (m, 2H), 1.8-2.6 (m, 8H), 2.76 (m, 2H), 3.04 (d, 2H), 3.81 (s, 2H), 4.2-4.4 (m, 8H), 4.71 (m, 2H), 6.51 (d, 1H), 6.78 (d, 1H), 6.83 (s, 1H), 7.01 (d, 1H), 7.49 (d, 1H), 8.1 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=O)[O:11][CH:12]=2)=[C:6]([CH3:16])[CH:5]=[N:4]1)[CH3:2].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][C@@H:51]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([F:71])[CH:66]=1)[CH2:52][N:53]1[C:61](=[O:62])[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]1=[O:63]>C(Cl)Cl>[O:63]=[C:54]1[C:55]2[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:61](=[O:62])[N:53]1[CH2:52][C@@H:51]([NH:50][C:13]([C:10]1[O:11][CH:12]=[C:8]([C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=2[CH3:16])[CH:9]=1)=[O:15])[CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([F:71])[CH:66]=1
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: CCn1ncc(C)c1-c1coc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc(C)c1-c1coc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)c1
Reaction time: 0.17 h
Yield: 54 %

Procedure:
To the crude 4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid in DCM (5 mL) at 25° C. was added PyBrOP (370 mg, 0.79 mmol) in one portion, followed by the addition of DIPEA (0.8 mL, 4.58 mmol). After 10 min, 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (220 mg, 0.74 mmol) was added to the reaction solution. After 2 h, the reaction mixture was concentrated and purified via column chromatography (silica, 20-50% EtOAc/Hexane) affording the title compound (164 mg, 54%) as a white solid: LC-MS (ES) m/z 501 (M+H)+.
Reaction SMILES: C(OCC)(=O)C.[CH3:7][O:8][C:9](=[O:42])[CH:10]=[CH:11][CH:12]([C:35]1[CH:36]=[C:37]([CH3:41])[CH:38]=[CH:39][CH:40]=1)[CH2:13][C:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[N:16]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[N:15]=1>[Ni].C(O)C>[CH3:7][O:8][C:9](=[O:42])[CH2:10][CH2:11][CH:12]([C:35]1[CH:36]=[C:37]([CH3:41])[CH:38]=[CH:39][CH:40]=1)[CH2:13][C:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[N:16]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[N:15]=1
Reactant: COC(=O)C=CC(Cc1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(OC)cc2)n1)c1cccc(C)c1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)CCC(Cc1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(OC)cc2)n1)c1cccc(C)c1
Reaction time: 2 h
Yield: 91 %

Procedure:
To a flask containing ethyl acetate (1.0 mL), ethanol (1.0 mL) and a catalytic amount of Raney nickel was added 5-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-4-m-tolyl-pent-2-enoic acid methyl ester (92 mg, 0.17 mmol). The reaction mixture was stirred under H2 (˜1 atm) for 2 h and then filtered through a CELITE® pad. The filtrate was concentrated under reduced pressure, and the crude residue was purified by reversed-phase HPLC giving the desired ester (81 mg, 91%). HPLC: Rt=3.68 (Method B). MS (ESI): mass calculated for C29H28Cl2N3O3, 522.15; m/z found, 523.3 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:15][CH2:14][CH2:13][CH:12]([CH:16]=[O:17])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:18][Mg]Br.CO>C1COCC1>[CH2:2]([N:9]1[CH2:15][CH2:14][CH2:13][CH:12]([CH:16]([OH:17])[CH3:18])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=CC1CCCN(Cc2ccccc2)CC1
Reactant: C[Mg]Br
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)C1CCCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
To an ice-cooled suspension of 1-benzylazepane-4-carbaldehyde hydrochloride (1.0 g, 3.95 mmol) in THF (15 mL) was added methylmagnesium bromide (3M in diethyl ether, 4 mL) dropwise. The mixture was slowly warmed to RT and then stirred for 18 h at RT. MeOH was then added and volatiles were removed in vacuo. The resulting residue was dissolved in DMF and filtered thought a pad of silica eluting with 10% 2M NH3/MeOH in DCM. The residue was further purified by column chromatography (Si-PCC, gradient 0-10% 2M NH3/MeOH in DCM) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording 1-(1-Benzylazepan-4-yl)ethanol (600 mg, 65%). 1H NMR (CDCl3, 400 MHz): δ 7.38-7.19 (5H, m), 3.99-3.47 (5H, m), 2.92-2.38 (4H, m), 2.01-1.51 (6H, m), 1.19 (3H, m)
Reaction SMILES: [C:1]1([C:7]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([NH:33]C(=O)OC(C)(C)C)[CH2:32][CH2:31][CH2:30]4)=[CH:25][CH:24]=3)=[N:21][C:10]3[O:11][CH2:12][C:13]4[N:14]([C:15]([CH2:18][CH2:19][CH3:20])=[N:16][N:17]=4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O>[C:1]1([C:7]2[C:22]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4([NH2:33])[CH2:32][CH2:31][CH2:30]4)=[CH:27][CH:28]=3)=[N:21][C:10]3[O:11][CH2:12][C:13]4[N:14]([C:15]([CH2:18][CH2:19][CH3:20])=[N:16][N:17]=4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCc1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1OC2
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc1OC2
Reaction time: 0.01 h
Yield: 31.3 %

Procedure:
Tert-butyl (1-(4-(8-phenyl-1-propyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (39 mg, 0.073 mmol) was dissolved in TFA (1 ml) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 ml) and concentrated to dryness under reduced pressure three times. The residue was then slurred in diethyl ether (2 ml) and after settling the supernatant solvent removed by pipette. This was repeated three times. The residue was then slurred in n-hexane (2 ml) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and the residue was dried to give the desired product as an off-white solid (10 mg, 30% yield). LCMS (Method A): RT=3.85 min, M+1=439. 1H-NMR (500 MHz, CD3OD) δ 8.09 (1H, s), 7.50 (2H, d), 7.43 (2H, d), 7.37-7.34 (3H, m), 7.31-7.27 (2H, m), 5.66 (2H, s), 3.2 (2H, t), 2.83-2.71 (2H, m), 2.64-2.54 (2H, m), 2.32-2.19 (1H, m), 2.02-1.90 (1H, m+2H, t), 1.16-1.09 (3H, t).