Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([OH:16])=[O:15])(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li+].[OH-].[CH3:22]O>>[CH3:22][O:15][C:14](=[O:16])[C@@H:13]1[CH2:17][CH2:18][CH2:19][N:12]1[S:9]([C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:10])=[O:11]
Reactant: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Reactant: CO
Agent: [Li+]
Agent: [OH-]
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Yield: 90 %

Procedure:
To a solution of 24.8 g (0.15 mol) of L-Proline methyl ester hydrochloride in 500 mL of CH2Cl2 was added 70 mL (0.5 mol) of triethylamine with stirring to give copious white precipitate. The mixture was filtered, and the filtrate cooled to 0° C. (ice bath) with stirring. To the cooled solution was added a solution of 36.8 g (0.15 mol) of 3,5-dichlorobenzenesulfonyl chloride in 70 mL of CH2Cl2 dropwise quickly over five minutes. The addition funnel was rinsed with an additional 30 mL of CH2Cl2, and the cloudy yellow mixture was allowed to warm to room temperature with stirring overnight. The mixture was washed 2× with 400 mL of 1N HCl, 2× with 400 mL of 1N NaOH, then brine, then dried (MgSO4), filtered, and concentrated to a yellow oil which crystallized on standing. The material was recrystallized three times from ethyl acetate/hexanes to give 39.3 g (0.116 mol, 77%) of N-(3,5-dichlorobenzenesulfonyl)-Proline methyl ester (MW=338) as white needles (TLC on silica vs. 2:1 hexanes/ethyl acetate, Rf=0.51). M/z=339.3 (M+H+). N-(3,5-diChlorobenzenesulfonyl)-Proline: To a solution of 39.3 g (0.116 mol) of the above methyl ester in 250 mL methanol was added 115 mL (0.23 mol) of freshly-prepared 2M aqueous LiOH with stirring to give a colorless solution. This was stirred for three hours, after which HPLC showed no starting material. The solution was reduced by 50% in vacuo and partitioned between 1N HCl and CH2Cl2 (˜200 mL each). The phases were separated and the aqueous layer was washed again with CH2Cl2. The organic phases were combined, dried (MgSO4), and concentrated to a white, foamy solid. This was recrystallized twice from ethyl acetate/hexanes to give 33.8 g (0.104 mol, 90%) of the title compound as colorless, broad, flat needles. M/z=325.2 (M+H+).
Reaction SMILES: C[CH:2](Cl)[CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[I-:21].[Na+]>CC(=O)CC>[I:21][CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1
Reactant: [I-]
Reactant: CC(Cl)CCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CCC(C)=O
Product: Clc1ccc(C(CCCI)c2ccc(Cl)cc2)cc1
Yield: 93.2 %

Procedure:
A solution of methyl 1-chloro-4,4di-(4-chlorophenyl)butane (1.77 g, 5.64 mmol) in 2-butanone (20 ml) was treated with sodium iodide (1.5 g) and heated under reflux for 18 h. The solid formed was filtered, the filtrate was evaporated and purified on silica gel (elution hexane-toluene 96:5) to give 2.13 g (93%) of the title material as a clear oil.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(OCC)C.[Ag-]=O>[CH3:6][O:5][C:1](=[O:4])[CH2:2][O:3][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CO
Reactant: BrCc1ccccc1
Agent: O=[Ag-]
Solvent: CCOCC
Product: COC(=O)COCc1ccccc1
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a stirred solution of methyl glycolate (2 g, 22.2 mmol) in anhydrous diethyl ether (100 mL), at room temperature, under a nitrogen atmosphere, was added silver(I)oxide (10.3 g, 44.4 mmol). The suspension was stirred for 15 minutes and benzyl bromide (4.5 g, 26.3 mmol) was added. The mixture was stirred at the same temperature for 24 h and the insoluble materials were removed by filtration through a short pad of celite. The filtrate was concentrated under reduced pressure and the crude product chromatographed over a column of silica gel, eluting with 20% diethyl ether-petroleum ether to give 70, as a colorless liquid in 70% yield (2.8 g).
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:39][CH3:40])[C:31]=2[C:35]([F:38])([F:37])[F:36])[C:26]=1[C:41](O)=[O:42].Cl.[C:45]([O:49][C:50](=[O:53])[CH2:51][NH2:52])([CH3:48])([CH3:47])[CH3:46].C(N(CC)CC)C>CN(C)C=O.O>[Cl:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:39][CH3:40])[C:31]=2[C:35]([F:37])([F:38])[F:36])[C:26]=1[C:41]([NH:52][CH2:51][C:50]([O:49][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:53])=[O:42]
Reactant: CC(C)(C)OC(=O)CN
Reactant: COc1ccc2c(C(=O)O)c(Cl)ccc2c1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc2c(C(=O)NCC(=O)OC(C)(C)C)c(Cl)ccc2c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
1-Hydroxybenzotriazole hydrate (2.45 g, 1.5 eq) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.78 g, 1.2 eq) was added to a stirred solution of 2-chloro-6-methoxy-5-(trifluoromethyl)naphthoic acid (3.69 g, 12.11 mmol, prepared by the process of Step 3, Example 12) in dry dimethylformamide (78 mL). After stirring 11/2 hours at room temperature, glycine t-butyl ester hydrochloride (4.06 g, 2 eq) and triethylamine (dried over KOH, 5.8 mL, 3.3 eq) were added. After stirring 3 hours the reaction mixture was diluted with water (1 L) and extracted with ether (3×350 mL). Silica gel was added to the extracts and the solvent was removed. The absorbate was flash chromatographed (70:30 petroleum ether:ethyl acetate) to give the title compound as a white solid (3.95 g, 80%), m.p. 166°-167° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[NH:6][CH2:5]1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][N:20]([CH2:2][CH2:3][CH:4]2[O:8][C:7](=[O:9])[NH:6][CH2:5]2)[CH2:19][CH2:18]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: O=C1NCC(CCCl)O1
Product: O=C1NCC(CCN2CCN(c3ccccc3F)CC2)O1

Procedure:
Following the procedure of Example 35, the title compound was prepared from 5-(2-chloroethyl)-2-oxazolidinone and 1-(2-fluorophenyl)piperazine, mp 121°-124° C.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1([CH3:19])[C@H:10](/[CH:11]=[CH:12]/[C:13](=[O:15])[CH3:14])[C@H:9]1[C:16](Cl)=[O:17].[CH2:20]([OH:22])[CH3:21].Cl>C1C=CC=CC=1>[CH3:7][C:8]1([CH3:19])[C@H:10](/[CH:11]=[CH:12]/[C:13](=[O:15])[CH3:14])[C@H:9]1[C:16]([O:22][CH2:20][CH3:21])=[O:17]
Reactant: CCO
Reactant: CC(=O)/C=C/[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H]1[C@@H](/C=C/C(C)=O)C1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2 ml of pyridine, 2.9 g of (1R,trans) 2,2-dimethyl-3-[(E)-3-oxo-1-butenyl]-cyclopropane-1-carboxylic acid chloride, 1 ml of ethanol and 25 ml of benzene was stirred at 0° to 5° C. for 20 minutes and at room temperature for 2 hours and was then poured into iced aqueous N/6 hydrochloric acid solution. The mixture was extracted with ether and the organic phase was washed with water, dried and evaporated to dryness at 40° C. under reduced pressure. The 4.19 g of oil residue were chromatographed over silica gel and eluted with a 7-3 cyclohexane-ethyl acetate mixture to obtain 1.43 g of ethyl (1R,trans) 2,2-dimethyl-3-[(E)-3-oxo-1-butenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+82°±3° (c=0.5% in benzene).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[S:3](OC1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1Cl)N=C(C)C=C2)(=[O:5])=[O:4].[Br:28][C:29]1[C:38]([OH:39])=[C:37]([CH3:40])[CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][C:33]([C:41]([F:44])([F:43])[F:42])=[N:34]2>>[F:1][C:2]([F:27])([F:26])[S:3]([O:39][C:38]1[C:29]([Br:28])=[C:30]2[C:35](=[CH:36][C:37]=1[CH3:40])[N:34]=[C:33]([C:41]([F:42])([F:43])[F:44])[CH:32]=[CH:31]2)(=[O:5])=[O:4]
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c(OS(=O)(=O)C(F)(F)F)c(Cl)cc2n1
Reactant: Cc1cc2nc(C(F)(F)F)ccc2c(Br)c1O
Product: Cc1cc2nc(C(F)(F)F)ccc2c(Br)c1OS(=O)(=O)C(F)(F)F

Procedure:
Compound 7C was prepared following the procedure used to prepare compound 1F of Example 1 except that 5-bromo-7-methyl-2-(trifluoromethyl)quinolin-6-ol (7B) was used instead of compound 1E. LCMS-ESI+ (m/z): 437.8, 439.8 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][Si](C(C)(C)C)(C)C)[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[C@H:31]1[CH2:36][CH2:35][C@H:34]([NH:37][C:38]2[N:43]=[CH:42][C:41](Br)=[CH:40][N:39]=2)[CH2:33][CH2:32]1)(=O)=O>CN1C(=O)CCC1.CCOC(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][C@@H:31]2[CH2:36][CH2:35][C@H:34]([NH:37][C:38]3[N:39]=[CH:40][CH:41]=[CH:42][N:43]=3)[CH2:33][CH2:32]2)[CH:3]=1
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](Nc2ncc(Br)cn2)CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Br)cc2nccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Brc1cc(O[C@H]2CC[C@@H](Nc3ncccn3)CC2)c2nccnc2c1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
As shown in step 8-i of Scheme 8, to a mixture of 7-bromoquinoxalin-5-ol (compound 1018, 200 mg, 0.89 mmol) and cesium carbonate (579 mg, 1.78 mmol) in NMP (4.0 mL) was added (trans)-4-(pyrimidin-2-ylamino)cyclohexyl methanesulfonate (compound 1014, 241.1 mg, 0.8887 mmol). The mixture was stirred for 18 hours at 90° C., at which time an additional 0.5 eq of compound 1014 (241 mg, 0.89 mmol) was added. After stirring at 90° C. for an additional 6 hours, the reaction mixture was diluted with EtOAc, washed with H2O, dried over Na2SO4, concentrated, and purified by medium pressure silica gel chromatography (0-5% MeOH/DCM) to provide N-((cis)-4-((7-bromoquinoxalin-5-yl)oxy)cyclohexyl)pyrimidin-2-amine (compound 1025): 1H-NMR (300 MHz, CDCl3) δ 9.01-8.77 (m, 2H), 8.29 (d, J=4.8 Hz, 2H), 7.89 (d, J=1.9 Hz, 1H), 7.25 (d, J=2.0 Hz, 1H), 6.53 (t, J=4.8 Hz, 1H), 5.43-5.22 (m, 1H), 4.79 (td, J=5.2, 2.5 Hz, 1H), 4.18-3.95 (m, 1H), 3.51 (s, 1H), 2.22 (td, J=10.2, 9.6, 5.4 Hz, 2H), 2.09-1.86 (m, 6H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:9]([C:11]1[CH:30]=[CH:29][C:14]2[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]3[S:21][C:22]([C:25](=[NH:27])[NH2:26])=[CH:23][N:24]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[OH-].[Na+]>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:9]([C:11]1[CH:30]=[CH:29][C:14]2[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]3[S:21][C:22]([C:25](=[NH:26])[NH2:27])=[CH:23][N:24]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ncc(C(=N)N)s1)n2C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CNc2ncc(C(=N)N)s2)nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc21

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(5-amidinothiazol-2-yl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([CH3:6])=[O:5].[O:7]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO.[OH-].C[N+](C)(C)CC1C=CC=CC=1>O1CCCC1.C(Cl)Cl>[CH3:6][S:4]([C:3]([S:2][CH3:1])=[CH:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=1)=[O:5]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CSCS(C)=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CSC(=Cc1cccc(Oc2ccccc2)c1)S(C)=O
Yield: 61.2 %

Procedure:
FAMSO (1.27 g) and 2.00 g of m-phenoxybenzaldehyde were dissolved in 10 ml of tetrahydrofuran, and 1 ml of a 40% methanol solution of trimethylbenzylammonium hydroxide was added. The mixture was heated under reflux for 26 hours. Methylene chloride (50 ml) was added, and the reaction mixture was washed with 3N dilute sulfuric acid. The product was dried over anhydrous potassium carbonate, concentrated under reduced pressure, and chromatographed on a silica gel column using methylene chloride as an eluant to afford 1.88 g of 1-methylsulfinyl-1-methylthio-2-(m-phenoxyphenyl)ethylene as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:34][CH2:35]Br.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH:34]=[CH2:35])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: BrCCBr
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Temperature: 90 °C

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (1.83 g) is dissolved in DMF (25 mL), and K2CO3 (1.38 g) and 1,2-dibromoethane (4.3 mL) are added. The reaction mixture is heated to 90° C. for 2 h. Water is added and the mixture is extracted with ethyl acetate and then chloroform. The combined organic layers are concentrated in vacuo to give 2.5 g of a dark oil. Column chromatography (elution with 1-3% MeOH/CHCl3) gave 0.378 g of 1-(1-bromoethyl)-N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide as a solid which is used without further purification. 1-(1-bromoethyl)-N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.347 g) is suspended in 1:1 THF/CH3CN (15 mL) and sodium carbonate (0.16 g) and ethylamine (0.4 mL) are added and the mixture is refluxed for 16 h. An additional amount of ethylamine (0.80 mL) is added and the mixture is refluxed for 16 h. An additional amount of ethylamine (0.80 mL) and DMF (5 mL) is added and the mixture is heated at 100° C. for 6 h, and then held at room temperature for 48 h. Potassium carbonate (0.193 g) is added and the mixture is heated at 100° C. for 3 h. The mixture is concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer is concentrated in vacuo to give 0.60 g of an oil. Column chromatography (elution with 1-5% MeOH/CHCl3) gave 0.118 g of the title compound as a solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([C:33]([F:44])([F:43])[F:32])[CH:39]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(C(F)(F)F)c1)N1CCN(C2CCC2)CC1
Yield: 60 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (60%).
Reaction SMILES: N1CCCCC1.[CH:7]1([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=2[O:22][CH3:23])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C([CH2:27][C:28]([NH:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34])=[O:29])(O)=O.Cl>C1(C)C=CC=CC=1.CCO.O>[CH:7]1([O:13][C:14]2[CH:21]=[CH:20][C:17](/[CH:18]=[CH:27]/[C:28]([NH:30][C:31]3[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=3[C:33]([OH:35])=[O:34])=[O:29])=[CH:16][C:15]=2[O:22][CH3:23])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: COc1cc(C=O)ccc1OC1CCCCC1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OC1CCCCC1
Yield: 60.4 %

Procedure:
Piperidine (0.45 mL, 4.5 mmol) was added to a suspension of 4-cyclohexyloxy-3-methoxybenzaldehyde (1.06 g, 4.54 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.92 g, 4.1 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recystallised from EtOH/water providing (E)-2-{[3-(4-cyclohexyloxy-3-methoxyphenyl)-1-oxo-2-propenyl]amino}benzoic acid (0.98 g, 60%) as a colourless crystalline solid; mp 90-92° C.; δH (400 MHz, DMSO-d6) 1.25-1.52 (m, 6H, CH2), 1.70 (m, 2H, CH2), 1.89 (m, 2H, CH2), 3.82 (s, 3H, OCH3), 4.33 (m, 1H, OCH), 6.76 (d, J=15.6 Hz, 1H, CH═CHCO), 6.99 (d, J5′,6′=8.4 Hz, 1H, H5′), 7.15 (t, =J3,4=J4,6=8.0 Hz, 1H, H4), 7.19 (d, J5,6=8.4 Hz, 1H, H6′), 7.35 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.29 (s, 1H, NH), 13.56 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 23.2, 25.1, 31.4, 55.7, 79.4, 111.2, 114.8, 116.6, 119.8, 120.3, 122.4, 122.6, 127.3, 131.1, 134.0, 141.1, 141.6, 148.6, 150.0, 164.2, 169.5; HRMS (ESI) calculated for C23H25NO5 [M+Na]+ 418.1625. found 418.1625; vmax 745, 1259, 1504, 1588, 1659, 2929, 3520 cm−1.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:16]([N:18]4[CH2:22][CH2:21][C@@:20]5([C:30]6[CH:29]=[CH:28][N:27]=[CH:26][C:25]=6[C:24](=[O:31])[O:23]5)[CH2:19]4)=[O:17])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(#N)C.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>>[CH3:42][S:43]([N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3([C:16]([N:18]4[CH2:22][CH2:21][C@@:20]5([C:30]6[CH:29]=[CH:28][N:27]=[CH:26][C:25]=6[C:24](=[O:31])[O:23]5)[CH2:19]4)=[O:17])[CH2:14][CH2:15]3)=[CH:11][CH:12]=2)[CH2:5][CH2:6]1)(=[O:45])=[O:44]
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(C5=CCNCC5)cc4)CC3)C2)c2ccncc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)N1CC=C(c2ccc(C3(C(=O)N4CC[C@@]5(C4)OC(=O)c4cnccc45)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R)-1′-({1-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (22 mg, 0.000053 mol) in acetonitrile (0.5 mL, 0.01 mol) were added triethylamine (16.8 μL, 0.000120 mol) and methane sulfonyl chloride. The reaction mixture was stirred at room temperature overnight. The crude product was purified by prep-HPLC. LC/MS: 494.2 (M+H+).
Reaction SMILES: CN(C=O)C.[NH:6]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:7]([C:15]([O:17]N1C(=O)CCC1=O)=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:32][C@H:33]([C:36]([OH:38])=[O:37])[CH2:34][OH:35].CCN(CC)CC>>[NH:6]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C@H:7]([C:15]([NH:32][C@H:33]([C:36]([OH:38])=[O:37])[CH2:34][OH:35])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N[C@@H](CO)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CO)C(=O)O
Yield: 31 %

Procedure:
In a 10 ml solution of DMF containing 500 mg (1.38 mmol) of Boc-Phe-OSu was added 5 ml of an aqueous solution of H-Ser-OH.Et3N [preparation from 290 mg (2.76 mmol) of H-Ser-OH and 384 μl (2.76 mmol) of Et3N] and the mixture was stirred for 14 hr. The reaction mixture was evaporated and the residue was dissolved in ethyl acetate and washed with 1N-HCl and saturated sodium chloride aqueous solution, successively, together with salting out. The resultant solution was dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the resulting residue was purified with a silica gel column chromatography (CHCl3:MeOH). The eluate was mixed with ether and n-hexane to give crystals of 150 mg of the title compound with yield of 31%.
Reaction SMILES: [Cl:1][C:2]1[N:18]=[CH:17][C:5]2[NH:6][C:7](=[O:16])[CH:8]([CH3:15])[N:9]([CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[Cl:1][C:2]1[N:18]=[CH:17][C:5]2[N:6]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:7](=[O:16])[CH:8]([CH3:15])[N:9]([CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]=2[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)CCN1c2cc(Cl)ncc2NC(=O)C1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCN1c2cc(Cl)ncc2N(c2ccccc2)C(=O)C1C
Temperature: 25 °C
Reaction time: 30 h
Yield: 49 %

Procedure:
To a stirred solution of 7-chloro-2-methyl-1-(3-methylbutyl)-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one (103 mg, 0.38 mmol) in dichloromethane (7 mL) was added triethylamine (0.53 mL, 3.8 mmol), cupric acetate (140 mg, 0.77 mmol) and phenylboronic acid (94 mg, 0.77 mmol) followed by 4 Å molecular sieves (2.0 g). The reaction mixture was stirred for 30 h at rt with an air balloon. It was then filtered over celite to remove inorganic material, the organic phase was washed with aqueous sodium carbonate, dried with Na2SO4, and the solvent was removed under reduced pressure to give a crude residue, which was purified by silica gel flash column chromatography (eluent: 40% ethyl acetate in hexane) to give the desired product (Yield: 49%). 1HNMR (CDCl3, 300 MHz) δ 1.07-1.18 (m, 6H), 1.47 (d, J=6.6 Hz, 3H), 1.69-1.86 (m, 4H), 3.18-3.26 (m, 1H), 3.48-3.58 (m, 1H), 4.32 (q, J=6.9 Hz, 1H), 6.62 (s, 1H), 6.87-7.05 (m, 1H), 7.27-7.35 (m, 2H), 7.39 (s, 1H), 7.53-7.65 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](Cl)[N:7]=[C:6]([NH:11][CH:12]([CH2:14][CH3:15])[CH3:13])[CH:5]=1.[CH3:17][N:18](C)C(=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:17]#[N:18])[N:7]=[C:6]([NH:11][C@H:12]([CH2:14][CH3:15])[CH3:13])[CH:5]=1
Reactant: CCC(C)Nc1cc(C(=O)OC)cc(Cl)n1
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(C#N)n1
Temperature: 120 °C
Yield: 59 %

Procedure:
Add 2-sec-butylamino-6-chloro-isonicotinic acid methyl ester (1.22 g, 5.0 mmol), tris(dibenzylideneacetone)dipalladium (183 mg, 0.2 mmol), 1,1′-bis(diphenylphosphino)ferrocene (222 mg, 0.4 mmol), zinc cyamide (587 mg, 5.0 mmol), and zinc dust (78 mg, 1.2 mmol) in N,N-dimethylacetamide (10 mL) and heat in a sealed tube at 120° C. overnight. Cool to room temperature, filter through a filtering agent, concentrate and purify (silica gel chromatography, eluting with 10:90 to 15:85 ethyl acetate:hexanes) to give the title compound (703 mg, 59%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:8][N:9]=[C:10]2[NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)[CH2:16][CH2:15]2)=[CH:5][CH:4]=1.Cl.[NH+]1C=CC=CC=1.[OH-].[Na+]>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[N:8][N:9]=[C:10]2[NH:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)[CH2:18][CH2:19]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(-c3ccccc3)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1ccc2c(-c3ccccc3)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1
Temperature: 210 °C
Yield: 86.8 %

Procedure:
A mixture of 597 mg (1.25 mmol) of 7-methoxy-N-[1-(naphthalen-2-ylmethyl)piperidin-4-yl]-4-phenylphthalazin-1-amine (compound 1) and pyridinium hydrochloride is heated at 210° C. for 45 minutes. The reaction medium is cooled and 1N sodium hydroxide solution is then added. A precipitate forms, which is washed with water and with dichloromethane, and then dried under reduced pressure. 500 mg of a beige-coloured powder are obtained.