Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH:3]([O:7][C:8]1[CH:12]=[C:11]([C:13](O)=O)[N:10]([CH3:16])[N:9]=1)[C:4]([OH:6])=[O:5])C.CCN=C=NCCCN(C)C.Cl.[CH2:29]([N:32]1[C:39]([NH2:40])=[C:38]([NH2:41])[C:36](=[O:37])[N:35]([CH2:42][CH:43]=[CH2:44])[C:33]1=[O:34])[CH:30]=[CH2:31]>CO>[CH2:42]([N:35]1[C:36](=[O:37])[C:38]2[NH:41][C:13]([C:11]3[N:10]([CH3:16])[N:9]=[C:8]([O:7][CH2:3][C:4]([OH:6])=[O:5])[CH:12]=3)=[N:40][C:39]=2[N:32]([CH2:29][CH:30]=[CH2:31])[C:33]1=[O:34])[CH:43]=[CH2:44]
Reactant: C=CCn1c(N)c(N)c(=O)n(CC=C)c1=O
Reactant: CCC(Oc1cc(C(=O)O)n(C)n1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: C=CCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CC=C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (5-carboxy-1-methylpyrazol-3-yl)oxyacetic acid (0.5 mmol) and EDCl (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-diallyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[5-(1,3-diallyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33][CH2:32]3)O1>>[C:41]([O:40][C:38]([N:34]1[C:35]2[C:31](=[CH:30][C:29]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]4=[O:20])=[CH:37][CH:36]=2)[CH2:32][CH2:33]1)=[O:39])([CH3:44])([CH3:42])[CH3:43]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC(C)(C)OC(=O)N1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4c(c3)CCN4C(=O)OC(C)(C)C)ccn2c1=O
Yield: 98.1 %

Procedure:
Methyl 8-(1-(tert-butoxycarbonyl)indolin-5-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (75 mg, 0.26 mmol) and tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline-1-carboxylate (106.4 mg, 0.31 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (121 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:9](=[O:11])[CH2:8][C:6]=2[CH:7]=1
Reactant: O=C(O)Cc1cc(Cl)ccc1Oc1ccccc1
Solvent: O
Product: O=C1Cc2cc(Cl)ccc2Oc2ccccc21
Temperature: 120 °C
Yield: 73.9 %

Procedure:
Polyphosphoric acid, 500 grams, is heated to 120° C. and 30.5 grams of (5-chloro-2-phenoxyphenyl)acetic acid, prepared in accordance with the procedure of Example 2, is slowly added under an atmosphere of nitrogen with stirring. The reaction mixture is maintained at 120° C. for a period of about two hours, poured over a mixture of ice and water, and extracted into ethyl ether. The combined ether extracts are washed with water until the water washings appear neutral, extracted with a 2 N solution of sodium hydroxide, washed again with water until the water washings are neutral, dried over anhydrous sodium sulfate and filtered. The dried organic solvent is removed from the filtrate by distillation and the residue distilled in vacuo to yield 21 grams of 2-chlorodibenzo[b,f]oxepin-10(11H)-one having a b.p. of 127°-134° C./0.005 mm Hg. Upon recrystallization from methanol, a compound is obtained having an m.p. of 75°-76° C.
Reaction SMILES: [OH2:1].[OH2:2].[C:3]1([CH:9]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21]3[CH:22]=[CH:23][C:24]4[N:25]([CH:27]=[C:28]([C:30]([CH3:35])([CH3:34])[C:31]([OH:33])=[O:32])[N:29]=4)[N:26]=3)[CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[C:36]1([CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21]3[CH:22]=[CH:23][C:24]4[N:25]([CH:27]=[C:28]([C:30]([CH3:35])([CH3:34])[C:31]([O:33][C:34](=[O:2])[C:30]([CH3:35])([C:28]5[N:29]=[C:24]6[CH:23]=[CH:22][C:21]([NH:20][CH2:19][CH2:18][CH2:17][N:14]7[CH2:15][CH2:16][CH:11]([O:1][CH:9]([C:36]8[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=8)[C:3]8[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=8)[CH2:12][CH2:13]7)=[N:26][N:25]6[CH:27]=5)[CH3:31])=[O:32])[N:29]=4)[N:26]=3)[CH2:15][CH2:16]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C(=O)O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Reactant: O
Solvent: CCO
Product: CC(C)(C(=O)OC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Yield: 90.8 %

Procedure:
In 500 mL of ethanol, 3.20 g (5.67 mmol) of the 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionic acid dihydrate obtained in Example 135A was dissolved under heating, followed by concentrating at atomospheric pressure until the total volume became 250 mL. After standing at room temperature, the crystals formed were collected by filtration, washed with ethanol and dried to yield 2.67 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[C:23]([OH:25])=O.S(Cl)(Cl)=O.[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.ClCCl>[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH:34][C:23]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)=[N:5][C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:7][C:2]=1[CH3:1])=[O:25]
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(=O)O
Reactant: CN(C)CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(=O)NCCN(C)C
Reaction time: 2 h

Procedure:
To a mixture of 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylic acid (9 g), dichloromethane (72 ml) and N,N-dimethylformamide (20 ml), thionyl chloride (2.1 ml) was added at 7° C. under ice cooling. After stirring for 1.5 hours at the same condition, 2-dimethylaminoethylamine (5.9 g) was added and stirred for 2 hours. The reaction mixture was adjusted to pH=8.5 by saturated potassium carbonate and extracted with chloroform. The organic layer was washed with water and brine and dried over magnesium sulfate. The solvent was distilled off to give a residue, which was chromatographed on alumina eluting with a mixture of n-hexane and ethyl acetate (5:1). The fractions containing the desired product were combined and concentrated in vacuo. The crystalline residue was recrystallized from diethyl ether to afford N-(2-dimethylaminoethyl)-6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[C:6]([CH3:23])=[C:5]2[C:24]([O:26][CH3:27])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:35][CH3:36]>CN(C)C=O.[NH4+].[Cl-]>[CH2:35]([O:12][C:11]1[CH:10]=[C:9]2[C:4]([C:5]([C:24]([O:26][CH3:27])=[O:25])=[C:6]([CH3:23])[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[N:8]2)=[CH:3][C:2]=1[F:1])[CH3:36]
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(O)c(F)cc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)OC)c2cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a mixture of methyl 6-fluoro-7-hydroxy-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (9.35 g, 24.64 mmol) and Cs2CO3 (24.08 g, 73.9 mmol) in N,N-dimethylformamide (100 mL) at room temperature was added iodoethane (3.98 mL, 49.3 mmol) slowly. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated aqueous NH4Cl and extracted with methylene chloride. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via column chromatography (ISCO, 120 g silica, 0-20% ethyl acetate/methylene chloride) to afford methyl 7-(ethyloxy)-6-fluoro-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (9.35 g, 93% yield). 1H NMR (400 MHz, DMSO-d6) 67.93-7.99 (m, 2H), 7.88 (d, J=7.78 Hz, 1H), 7.76 (t, J=7.65 Hz, 1H), 7.69 (d, J=8.53 Hz, 1H), 7.63 (d, J=12.30 Hz, 1H), 4.30 (q, J=7.03 Hz, 2H), 4.06 (s, 3H), 2.33 (s, 3H), 1.44 (t, J=6.90 Hz, 3H); MS (m/z) 408.1 (M+H+).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:32])[CH2:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30]Br)=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:39][C:40]([F:49])([F:48])[C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1>CN(C=O)C.O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:32])[CH2:15][C@H:16]([C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][O:47][C:44]2[CH:45]=[CH:46][C:41]([C:40]([F:39])([F:48])[F:49])=[CH:42][CH:43]=2)=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=C(C[C@@H](c1ccc(OCCBr)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(C[C@@H](c1ccc(OCCOc2ccc(C(F)(F)F)cc2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
The bromide 47.1 (100 mg, 0.2 mmol) was dissolved in DMF (2.0 mL). Cesium carbonate (260 mg, 0.8 mmol) and 4-trifluoromethylphenol (130 mg, 0.8 mmol) were added to the solution and the mixture was then heated with stirring for three hours. The reaction mixture was then cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with 1M lithium chloride solution (1×25 mL), water (1×25 mL) and brine (1×25 mL) and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue purified by medium pressure chromatography (silica, 0 to 60% EtOAc: hexanes) to obtain 47.2 (58 mg). MS ESI (pos.): m/e 581.2 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[N:15]#[C:16]Br.C(N(CC)CC)C>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:13][CH:14]=1)[C:8](=[O:9])[N:10]([C:16]#[N:15])[C:11]2=[O:12])([O-:3])=[O:2]
Reactant: N#CBr
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: N#CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
A 25 mL round-bottomed flask was charged with 4-nitrophthalimide (0.96 g, 5.0 mmol), cyanogen bromide (0.64 g, 6.0 mmol), and 10 mL of reagent grade acetone. The resulting suspension was cooled using an ice/salt bath, and triethylamine (1.0 mL, 7.1 mmol) was added dropwise over a 4 minute period. The mixture was allowed to stir for 20 minutes before being partitioned between ethyl acetate and water. The organic phase was washed with water, saturated brine, dried (MgSO4), and concentrated to give 0.95 g of a yellow solid. This material was recrystallized from ethyl acetate to afford 0.65 g (60%) of yellow crystals, mp 209.5°-210.5° C. (reported in Zh. Org. Khim. 1977, 13, 968 as 215° C.): IR (nujol) 2261 (nitrile), 1811 (carbonyl), 1769 (carbonyl), 1533 (nitro), 1343 (nitro) cm-1 ; 1H NMR (200 MHz, DMSO) δ 8.34 (d, 1, J=8.9 Hz), 8.70-8.78 (m, 2); 13C NMR (50 MHz, DMSO) δ 161.15, 160.92, 152.34, 135.19, 132.10, 131.16, 126.48, 119.76, 102.26; GC/MS (relative intensity) 217 (77.8), 149 (71.7), 103 (64.4), 75 (100), 74 (52.7).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH2:7][CH2:6]2.C(N(C(C)C)CC)(C)C.[CH3:24][O:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[N:8]([C:27](=[O:28])[CH2:26][O:25][CH3:24])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N1CCc2cc(OC)c([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 107.2 %

Procedure:
A slurry of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (Intermediate B99, 3.2 g, 13.87 mmol) in THF (100 mL) was treated with diisopropylethylamine (4.83 mL, 27.7 mmol), followed by (methyloxy)acetyl chloride (1.903 mL, 20.81 mmol). The resulting yellow slurry was stirred at rt for 3 days, then diluted with CH2Cl2 (300 mL), washed with water (150 mL), a saturated NaCl solution (150 mL), dried (Na2SO4) and concentrated to obtain 5-(methyloxy)-1-[(methyloxy)acetyl]-6-nitro-2,3-dihydro-1H-indole as an orange solid (3.96 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.24 (t, J=8.42 Hz 2H), 3.36 (s, 3H), 3.89 (s, 3H), 4.07 (t, J=8.42 Hz 2H), 4.19 (s, 2 H), 7.35 (s, 1H), 8.47 (s, 1H); ESIMS (M+H)+=266.87.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[Na+].[Na+].Br[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1>CN(C=O)C>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([O:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:15])[CH3:14])[C:2]=1[O:1][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)=[O:5]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)C(=O)Oc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2c(C=O)cccc2OC(=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 2-hydroxy-3-pivaloyloxybenzaldehyde (1.0 g, 4.5 mmole) in DMF (5 ml) was added Na2CO3 (0.859 g, 8.10 mmol) and methyl 4-bromomethylbenzoate (1.13 g, 4.93 mmol). The reaction was stirred at ambient temperature for 60 hours then partitioned between ethyl acetate/H2O. The organic phase was washed with water (x1) dried (MgSO4) and evaporated to give methyl 4-(2-formyl-6-pivaloyloxy-phenoxymethyl)benzoate as a product which was used in subsequent steps without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.[Cl-].[Li+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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.C(O)C>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])=[CH:29][CH:28]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1ccc(C)cc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C)cc1-c1ccc(F)cc1
Yield: 98.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium (9 g; 7.8 mmol) and ethanol (780 ml) was added to a suspension of methyl 4-methyl-2-trifluoromethanesulphonyloxybenzoate (58 g; 0.195 mol), 2M aqueous solution of sodium carbonate (250 ml; 0.5 mol), 4-fluorophenylboronic acid (30 g; 0.214 mol) and lithium chloride (16.5 g; 0.39 mol) in toluene (1.65 ml), under argon atmosphere. The mixture was refluxed for 4 hours, diluted with ethyl acetate (1 l), washed with aqueous sodium hydroxide solution 1N (1 l). The organic phase was evaporated and the residue purified by flash chromatography (ethyl acetate/petroleum ether: 95/5) to give methyl 2-(4-fluorophenyl)-4-methylbenzoate (46.8 g; 99%).
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH:13]([O:16]C)OC)[C:3]([NH:5][C:6]1[S:7][C:8]([SH:11])=[N:9][N:10]=1)=[O:4].Cl>O>[CH3:1][N:2]1[CH2:12][CH:13]([OH:16])[N:5]([C:6]2[S:7][C:8]([SH:11])=[N:9][N:10]=2)[C:3]1=[O:4]
Reactant: COC(CN(C)C(=O)Nc1nnc(S)s1)OC
Agent: Cl
Solvent: O
Product: CN1CC(O)N(c2nnc(S)s2)C1=O
Yield: 76.1 %

Procedure:
In a 500 ml round bottom flask were mixed 1-methyl-1-(2,2-dimethoxyethyl)-3-(5-mercapto-1,3,4-thiadiazol-2-yl) urea (8.0 g, 0.03 mol), water (300 ml) and conc. hydrochloric acid (4 ml). The mixture was stirred vigorously and was heated to reflux for ~1 hour. The mixture was cooled and filtered to give a white solid product which was dried in vacuo, 5.3 g, 76.1% yield, mp 243° C. dec. NMR (NaOD in D2O) 6.0 (t, 1H), 3.5 (d, 2H), 3.0 (S, 3H). IR: (KBr) 3400, 3200, 2900, 1700, 1550, 1500, 1450, 1360, 1275, 1245, 1100, 1080, 1050, 1000, 900, 775, 725.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][C@@H:5]1[CH2:11][OH:12].[C:13]1([N:19]2[CH2:24][CH2:23][N:22]([C:25](OC3C=CC([N+]([O-])=O)=CC=3)=[O:26])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCCCCCC.C1COCC1>[C:13]1([N:19]2[CH2:20][CH2:21][N:22]([C:25]([O:12][CH2:11][C@H:5]3[CH2:6][N:7]([CH3:10])[CH2:8][CH2:9][N:4]3[CH3:3])=[O:26])[CH2:23][CH2:24]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN1CCN(C)[C@@H](CO)C1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CN1CCN(C)[C@@H](COC(=O)N2CCN(c3ccccc3)CC2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
Sodium hydride (1.14 g, 60% dispersion in mineral oil, 28.6 mmol) was suspended in heptane (10 mL) under an argon atmosphere. The heptane was decanted off, and the flask was charged with THF (20 mL) and cooled to 0° C. A solution of 1,4-dimethyl-(R)-2-hydroxymethyl piperazine (Intermediate 4; 1.38 g, 9.5 mmol) in THF (20 mL) was added drop-wise, followed by a solution of the 4-nitrophenyl 4-phenylpiperazine-1-carboxylate (Intermediate 2; 4.06 g, 12.4 mmol) in THF (20 mL). The reaction mixture was allowed to warm to room temperature, stirred for 16 hours, the reaction mixture was cooled to 0° C. then quenched with the drop-wise addition of sat aq NaHCO3 solution and concentrated in vacuo. The residue was dissolved in EtOAc (200 mL), washed with sat aq NaHCO3 solution (4×50 mL), dried (MgSO4) and concentrated in vacuo. The residue was suspended in water:formic acid solution [1:1] (20 mL), filtered and the filtrate was purified by reverse phase column chromatography (gradient eluting with methanol in water, with 1% formic acid in each solvent, 0-15%). The resulting residue was dissolved in DCM (50 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give [(2R)-1,4-dimethylpiperazin-2-yl]methyl 4-phenylpiperazine-1-carboxylate (1.93 g, 61%) as a pale yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CN(C(=O)Oc1ccc(I)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from methyl-phenyl-carbamic acid 4-iodo-phenyl ester and 4-trifluoromethylphenylboronic acid. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane 1:9) (42%, light brown crystals).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[OH:18][C@:19]([CH3:31])([C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[C:20](O)=[O:21].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[OH:18][C@:19]([CH3:31])([C:23]([NH:25][CH2:26][C:27]([F:28])([F:29])[F:30])=[O:24])[C:20]([NH:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2)=[O:21]
Reactant: C[C@](O)(C(=O)O)C(=O)NCC(F)(F)F
Reactant: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@](O)(C(=O)NCC(F)(F)F)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reaction time: 16 h
Yield: 77.3 %

Procedure:
A solution of 70.0 mg (0.31 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one and 73.9 mg (0.34 mmol) (R)-2-hydroxy-2-methyl-N-(2,2,2-trifluoro-ethyl)-malonamic acid in 6 ml tetrahydrofuran were cooled to 0° C. and 46.4 mg (0.34 mmol) 1-hydroxy-benzotriazole hydrate, 117 μl (0.69 mmol) diisopropylethylamine and 65.8 mg (0.34 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued for 16 hours. Removal of the solvent by distillation and chromatography on silicagel with heptane/ethylacetate (gradient 100/0 to 25/75) yielded 101 mg (77%) (R)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,2-trifluoro-ethyl)-malonamide, MS (m/e): 422.0 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=O)[C:6]2[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[C:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:7]=2)[CH2:3][CH2:2]1.B.CSC>C1COCC1>[CH3:21][O:20][CH2:19][CH2:18][CH2:17][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=1)[CH2:5][NH:4][CH:1]1[CH2:2][CH2:3]1
Reactant: COCCCc1cc(CCCOC)cc(C(=O)NC2CC2)c1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: COCCCc1cc(CCCOC)cc(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of N-cyclopropyl-3,5-bis(3-methoxypropyl)benzamide (1 eq.) from the previous step in THF (0.18 M) at 80° C. was added borane-dimethylsulfide (10 eq.). The reaction was distilled to about half volume and heated under reflux for 3 h. Then, the reaction was cooled to rt and slowly quenched with 10% HCl aqueous solution. The reaction was heated to reflex again and stirred for 45 min. After cooling to rt, the reaction was diluted with EtOAc and basified with aqueous NaOH solution (pH >10). The organic extract was washed with saturated aqueous NaHCO3, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 25% EtOAc in Hex plus 3% Et3N) to afford the title compound amine 3 as an oil.