Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2].[OH-].[Li+].C(O)(=O)C>C(O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(C#N)cn2)C[C@H](C)N3C(C)=O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of methyl 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinate (for a preparation see Intermediate 6) (580 mg, 1.273 mmol) in ethanol (10 mL) was treated with a aqueous lithium hydroxide solution (1N, 2.55 mL, 2.55 mmol) and the resulting mixture was stirred for 2 h. The bulk of ethanol was evaporated in vacuo and the residue was diluted with water (ca. 5 mL). The cloudy mixture was treated with acetic acid (0.146 mL, 2.55 mmol) and the precipitate formed was isolated by filtration, washed with Et2O and dried at 60° C. for 16 h to give 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinic acid (410 mg, 0.959 mmol, 75% yield) as a pale yellow solid which was used in the next step without further purification. LCMS (HpH, 2 min), Rt=0.63 min, MH+=428.
Reaction SMILES: [N:1]([CH2:4][CH2:5][OH:6])=[N+:2]=[N-:3].CCN(CC)CC.[Br:14][C:15]([CH3:20])([CH3:19])[C:16](Br)=[O:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:1]([CH2:4][CH2:5][O:6][C:16](=[O:17])[C:15]([Br:14])([CH3:20])[CH3:19])=[N+:2]=[N-:3]
Reactant: CC(C)(Br)C(=O)Br
Reactant: [N-]=[N+]=NCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(Br)C(=O)OCCN=[N+]=[N-]

Procedure:
2-Azidoethanol (17.40 g, 0.2 mol), freshly distilled methylene chloride (150 mL), and Et3N (21.21 g, 0.21 mol) were added into a three-neck round-bottom flask equipped with a condenser and a dropping funnel. Under nitrogen atmosphere and magnetic stirring, freshly distilled anhydrous methylene chloride (150 mL), DMAP (1.7 g, 14 mmol), and freshly distilled anhydrous Et3N (46.5 g, 0.46 mol) were sequentially added. After the flask was immersed into an ice-water bath, 2-bromoisobutyryl bromide (48.28 g, 0.21 mol) was added dropwise into the previous solution. Twenty-four hours later, the reaction mixture was washed successively with 1M HCl (3×200 mL) solution and deionized water (1×200 mL). The organic phase was dried over anhydrous MgSO4 overnight. After filter and removal of methylene chloride on a rotary evaporator, the obtained residues were distilled under reduced pressure to give a colorless viscous liquid. The yield was: 33.4 g, 70%. 1H NMR (CDCl3, δ, ppm): 4.24 (t, 2H, N3CH2CH2), 3.52 (t, 2H, N3CH2), 1.96 (s, 6H, (CH3)2Br).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[N:12]([CH3:15])=[C:13]=[S:14].O1CCC[CH2:17]1>>[NH2:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([O:7][CH3:17])=[O:6])=[CH:3][C:2]=1[NH:1][C:13]([NH:12][CH3:15])=[S:14]
Reactant: CN=C=S
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: C1CCOC1
Product: CNC(=S)Nc1cc(C(=O)OC)ccc1N
Yield: 56 %

Procedure:
A mixture of 3,4-diaminobenzoic acid (15 g, 0.09 mol) and isothiocyanatomethane (6.6 g, 0.09 mol) was dissolved in tetrahydrofuran (90 mL). The reaction was heated at reflux for 3 hours and was then concentrated. The residue was poured into ice water. The resulting precipitate was filtered, washed with water, and dried under vacuum to give methyl 4-amino-3-(3-methylthioureido)benzoate (12.0 g, 56%).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][C:16]([Cl:26])=[CH:15][N:14]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>C1COCC1>[Cl:26][C:16]1[CH:17]=[C:18]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:13]([NH:12][C:10]([NH2:9])=[S:11])=[N:14][CH:15]=1
Reactant: O=C(NC(=S)Nc1ncc(Cl)cc1Oc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=S)Nc1ncc(Cl)cc1Oc1ccccc1
Temperature: 90 °C
Yield: 94.7 %

Procedure:
A 250 mL round-bottomed flask was charged with 1-benzoyl-3-(5-chloro-3-phenoxypyridin-2-yl)thiourea (13.752 g, 35.826 mmol) and THF (100 mL). 3M NaOH (119.42 mL, 358.26 mmol) was added and the reaction mixture was heated to 90° C. for 18 hours. The reaction mixture was cooled to room temperature and concentrated. The resulting solids were filtered, washed with water, and dried to provide the title compound (9.49 g, 94.689% yield) as a yellow solid. 1H NMR (d6-DMSO) δ 9.97 (s, 1H), 9.25 (s, 1H), 8.87 (s, 1H), 8.11 (d, 1H), 7.49 (t, 2H), 7.31 (d, 1H), 7.28 (m, 2H), 7.23 (d, 2H); Mass spectrum (apci) m/z=279.9 (M+H).
Reaction SMILES: [CH2:1]([C:9]1[C:10]([C:22]([F:25])([F:24])[F:23])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CCN)CC)C.[S:34](Cl)(=[O:37])(=[O:36])[NH2:35]>ClCCl>[CH2:1]([C:9]1[C:10]([C:22]([F:25])([F:24])[F:23])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH:20]([S:34]([NH2:35])(=[O:37])=[O:36])[CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NS(=O)(=O)Cl
Reactant: FC(F)(F)c1c(CCc2ccccc2)cc2c3c1ccn3CCNC2
Agent: CCN(CC)CCN
Solvent: ClCCl
Product: NS(=O)(=O)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a solution of 6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (93 mg, 0.24 mmol) in dichloromethane (3 mL) was added diethylaminoethyl amine (0.13 mL, 0.73 mmol) and sulfamoyl chloride (42 mg, 0.37 mmol). After stirring overnight, another portion of sulfamoyl chloride (42 mg) was added at 0° C., and the resulting mixture stirred for 2 h at room temperature. The resulting mixture was then concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography (gradient 42%→90% TFA-H2O:acetonitrile) to yield 6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indole-2(1H)-sulfonamide (32 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C@@H:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:51][CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59]>ClCCl.O>[OH:61][C:54]1[C:53]([CH2:52][NH:51][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([C@@H:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:12])=[CH:10][C:2]=2[CH3:1])=[C:58]([CH3:59])[CH:57]=[C:56]([CH3:60])[N:55]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1cc([C@H](C)Oc2ccccc2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc([C@H](C)Oc3ccccc3)cc2C)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
To a solution of (S)-2-methyl-4-(1-phenoxyethyl)benzoic acid (5.3 g, 19.5 mmol) in dichloromethane (100 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (11.1 g, 29.3 mmol) and triethylamine (8.6 mL, 62.2 mmol). The mixture was stirred at room temperature for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (3.15 g, 21 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was poured into water (100 mL) and extracted with dichloromethane (50 mL*2). The combined organic phase was separated, dried by sodium sulphate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, methanol/dichloromethane=1:10) to give (S)—N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-4-(1-phenoxyethyl)benzamide (Compound I-55) as a white solid (4.5 g, 59%). LRMS (M+H+) m/z: calcd 390.19. found 390. HPLC purity (214 nm): 100%. 1H NMR (300 MHz, CD3OD): δ 7.28-7.22 (m, 3H), 7.12-7.09 (m, 2H), 6.83-6.79 (m, 3H), 6.10 (s, 1H), 5.36-5.34 (m, 1H), 4.44 (s, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 2.23 (s, 3H), 1.57 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[C:5]([NH2:14])=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]1[C:46]([C:47](O)=[O:48])=[C:45]([CH3:50])[O:44][N:43]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:14][C:5]1[N:6]=[C:7]([N:8]2[CH2:9][CH2:10][N:11]([C:47]([C:46]3[C:42]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[O:35][CH3:34])=[N:43][O:44][C:45]=3[CH3:50])=[O:48])[CH2:12][CH2:13]2)[C:2]([Cl:1])=[CH:3][C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: Nc1nc(N2CCNCC2)c(Cl)cc1[N+](=O)[O-]
Reactant: COc1ccccc1-c1noc(C)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccccc1-c1noc(C)c1C(=O)N1CCN(c2nc(N)c([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-3-nitro-6-(piperazin-1-yl)pyridin-2-amine, TFA (0.192 mmol) in DMF (2 ml) was added DIEA (0.134 ml, 0.768 mmol), 3-(2-methoxyphenyl)-5-methylisoxazole-4-carboxylic acid (44.8 mg, 0.192 mmol) and HATU (73.0 mg, 0.192 mmol). The reaction was stirred at room temperature for 1 h. The reaction mixture was purified by preparative HPLC to afford 69 mg (73.7% for 3 steps) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 8.25 (1H, s), 7.58 (1H, dd, J=7.5, 1.7 Hz), 7.52-7.39 (1H, m), 7.08-7.06 (1H, m), 6.97 (1H, d, J=7.9 Hz), 3.79 (3 H, s), 3.72 (2H, br. s.), 3.55 (2H, br. s.), 3.16 (2H, br. s.), 2.98 (2H, br. s.), 2.55 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.FC1C2C(=O)OC(=O)[NH:31]C=2C=CC=1>>[NH:16]1[CH2:20][CH2:19][N:31]=[C:17]1[CH2:18][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10]
Reactant: O=c1[nH]c2cccc(F)c2c(=O)o1
Reactant: Nc1cccc(F)c1C(=O)N1CCCC1
Reactant: C1CCNC1
Product: O=C(c1c(F)cccc1NCC1=NCCN1)N1CCCC1

Procedure:
{2-Amino-6-fluorophenyl}(1-pyrrolidinyl)methanone (prepared from pyrrolidine and 5-fluoro-2H-3,1-benzoxazine-2,4(1H)-dione using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give {2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]-6-fluorophenyl}(1-pyrrolidinyl)methanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[C:15]([OH:23])[C:16]3[CH:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].O[C@H:25]([C@H:27]1[CH2:31][N:30]([C@H:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH3:33])[C:29](=[O:42])[CH2:28]1)[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([C@@H:32]([N:30]2[CH2:31][C@H:27]([C@H:25]([O:23][C:15]3[N:14]=[C:13]([C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=4)[CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][CH:19]=[N:20]4)[CH3:26])[CH2:28][C:29]2=[O:42])[CH3:33])=[CH:35][CH:36]=1
Reactant: COc1cc(-c2cc3ncccc3c(O)n2)cc(OC)c1OC
Reactant: COc1ccc([C@H](C)N2C[C@H]([C@H](C)O)CC2=O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc([C@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4cc(OC)c(OC)c(OC)c4)cc4ncccc34)CC2=O)cc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
114.6 g of powdered 7-(3,4,5-trimetoxy-phenyl)-[1.6]naphthyridine-5-ol is suspended in 900 mL tetrahydrofurane. A solution of 115.9 g of (R)-4-[(S)-1-hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one and 136 g triphenylphosphine in 1000 mL tetrahydrofurane is added. The suspension is cooled to 0° C. During 40 minutes a solution of 105 mL diisopropylazodicarboxylate [DIAD] in 400 mL tetrahydrofurane is added at 0° C. to 2° C. The suspension is stirred for 3.5 hours at this temperature and then warmed up to 20° C. The solvent is evaporated under reduced pressure. The residue is suspended in 680 mL of tert-butylmethylether. Seeding crystalls of triphenylphosphinoxid are added and the mixture is stirred 16 hours at 20° C. The precipitate is filtered and and washed with tert.-butylmethylether. The fitrate is evaporated under reduced pressure. The crude product is dissolved in a mixture of 220 mL of 2-propanol and 1100 mL of isopropyl acetate at 40° C. 48 mL of trimethylchlorosilane are added during 15 minutes. The suspension is stirred for 2 hours at 20° C. The precipitate is filtered and washed with isopropyl acetate and dried at 60
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[C:6]([F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH2:13].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[Br:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[C:6]([F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][C:14](=[O:16])[CH3:15]
Reactant: CCOc1c(F)cc(Cl)c(N)c1Br
Reactant: CC(=O)OC(C)=O
Product: CCOc1c(F)cc(Cl)c(NC(C)=O)c1Br
Yield: 76 %

Procedure:
A solution of 30-5 (16 g, 59.7 mmol) in acetic anhydride (50 mL) was stirred at room temperature for one hour. The precipitate was filtered and washed with ether to afford 30-6 (14 g, 76%) as a white solid. LRMS: calc 308.9 and found: 309.9 [M+1].
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl.[C:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])#[CH:18]>C(O)(C)(C)C.C(O)(C)C>[ClH:1].[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([C:17]#[CH:18])[CH:20]=1)([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc2ncnc(Cl)c2c1
Reactant: C#Cc1cccc(N)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CC(C)(C)O
Product: C#Cc1cccc(Nc2ncnc3ccc(C(=O)OC)cc23)c1

Procedure:
4-Chloro-6-carbomethoxyquinazoline (100 mg, 0.450 mmol) and 3-ethynylaniline hydrochloride (53.4 mg, 0.456 mmol) were refluxed in 2 mL of tert-butyl alcohol for 2 hours, cooled, diluted with 2 mL of isopropyl alcohol and filtered to afford solid title product which was washed with 10 mL of diethyl ether and dried, in vacuo, at 70° C., 122 mg (80%); mp 232°-233° C. (dec).
Reaction SMILES: [Cl:1]C(OC(Cl)=O)C.C([N:21]1[CH2:24][CH:23]([O:25][CH2:26][CH2:27][C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[CH2:22]1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>ClCCl>[ClH:1].[ClH:1].[S:29]1[CH:30]=[CH:31][CH:32]=[C:28]1[CH2:27][CH2:26][O:25][CH:23]1[CH2:24][NH:21][CH2:22]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: c1ccc(C(c2ccccc2)N2CC(OCCc3cccs3)C2)cc1
Solvent: ClCCl
Solvent: CCO
Product: Cl
Product: c1csc(CCOC2CNC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Chloroethylchloroformate (361 μL, 3.33 mmol) was added to a solution of 1-benzhydryl-3-(2-(thiophen-2-yl)ethoxy)azetidine (1.11 g, 3.17 mmol) in dichloromethane (15 mL) at room temperature. The reaction mixture was stirred overnight at room temperature, then 1 hour at 70° C. After cooling down to room temperature, ethanol (15 mL) was added and the reaction mixture was stirred at 70° C. for 1 hour. After concentration to dryness, the crude mixture was triturated in pentane (2×15 mL) to give a yellow oil (698 mg, quantitative) which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.Cl.[NH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:20][CH2:19]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)[CH2:20][CH2:19]2)=[O:14])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: CC(=O)c1ccc(OCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(OCC(=O)NC2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)cc1
Reaction time: 12 h
Yield: 29.2 %

Procedure:
(4-Acetylphenyloxy)acetic acid (2.0 g) and 4-amino-1-(3,4-dichlorobenzyl)piperidine dihydrochloride (3.4 g) were suspended in DMF (50 mL), and triethylamine (2.9 mL), EDC hydrochloride (2.4 g) and HOBt (1.9 g) were added to the suspension. The suspension was stirred for 12 hrs. The reaction mixture was washed with water and then saturated brine and dried, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to crystallize to give the title compound (1.3 g) as a white solid. melting point: 113° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][N:6]1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26]/[CH:27]=[C:28]1/[C:29]2[CH:42]=[C:41]([C:43]([OH:46])([CH3:45])[CH3:44])[CH:40]=[CH:39][C:30]=2[O:31][CH2:32][C:33]2[N:38]=[CH:37][CH:36]=[CH:35][C:34]/1=2>C(#N)C.O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([CH2:25][CH2:26][CH:27]=[C:28]2[C:34]3[CH:35]=[CH:36][CH:37]=[N:38][C:33]=3[CH2:32][O:31][C:30]3[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]2=3)[CH2:8][CH2:7][N:6]1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:4]
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Reactant: COC(=O)C1CNCCN1c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C1CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCN1c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(4-chloro-phenyl)-piperazine-2-carboxylic acid methyl ester (0.14 g, 0.53 mmol) in acetonitrile:water (4:1) was added potassium carbonate (0.083 g, 0.6 mmol) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (150 mg, 0.4 mmol) and the resulting mixture was stirred at 50° C. for 5 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by flash chromatography on silica using gradient elution from ethyl acetate (100%) to ethyl acetate/methanol (5%). 1H-NMR (CDCl3) δ: 1.05 (6H, s), 2.20–2.70 (8H, 2×m), 3.00 (1H, m), 3.10–3.40 (3H, 2×m), 3.55 (3H, s), 4.50 (1H, br,s), 5.30 (2H, br,s), 6.20 (1H, t), 6.70–6.90 (3H, 2×d), 7.10–7.35 (4H, m), 7.50 (2H, d), 8.50 (1H, dd). ESI-MS m/z: 548 (M+1), UV retention time: 1.62 min.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][C:8]([C:11]1[CH:17]=[C:16]([OH:18])[C:15]([C:19]([CH3:28])([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH3:20])=[CH:14][C:12]=1[OH:13])([CH3:10])[CH3:9])=[O:4].C(O)[C:30]1[O:34][CH:33]=[CH:32][CH:31]=1.C[O-].[Na+].[CH3:39][CH2:40][O:41][CH2:42][CH3:43]>>[CH2:1]([O:2][C:3]([CH2:5][CH2:6][CH2:7][C:8]([C:11]1[CH:17]=[C:16]([OH:18])[C:15]([C:19]([CH3:28])([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][C:33]2[O:34][CH:30]=[CH:31][CH:32]=2)=[O:25])[CH3:20])=[CH:14][C:12]=1[OH:13])([CH3:10])[CH3:9])=[O:4])[C:42]1[O:41][CH:40]=[CH:39][CH:43]=1
Reactant: CCOCC
Reactant: COC(=O)CCCC(C)(C)c1cc(O)c(C(C)(C)CCCC(=O)OC)cc1O
Reactant: OCc1ccco1
Agent: C[O-]
Agent: [Na+]
Product: CC(C)(CCCC(=O)OCc1ccco1)c1cc(O)c(C(C)(C)CCCC(=O)OCc2ccco2)cc1O

Procedure:
8.0 Parts of 2,5-bis-(5-methoxycarbonyl-2-methyl-pent-2-yl)-hydroquinone, 100 parts of furfuryl alcohol and 1.0 parts of sodium methoxide are heated on a steam-bath for 24 hours. The cooled reaction mixture is diluted with ether and washed with water. After removing the ether and excess furfuryl alcohol, the residue is triturated with 40°-60° petroleum ether containing ether to yield 2,5-bis-(5-furfuryloxycarbonyl-2-methyl-pent-2-yl)-hydroquinone, [formula (123)] m.p. 139°-142° C. Crystallisation from methanol containing 5% water yields crystals of m.p. 140°-143° C. with the following percentage composition by weight:
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]([CH3:31])([CH3:30])[CH2:5][C:6]1[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:8]2[C:13]([C:14]=1[S:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][C:11]([O:20][CH3:21])=[CH:10][CH:9]=2.C1COCC1.[Li+].[OH-].Cl>CO>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:7]2[C:8]3[C:13](=[CH:12][C:11]([O:20][CH3:21])=[CH:10][CH:9]=3)[C:14]([S:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[C:6]2[CH2:5][C:4]([CH3:31])([CH3:30])[C:3]([OH:32])=[O:2])=[CH:24][CH:25]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)c(SC(C)(C)C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
The compound from Step A was hydrolysed using 325 mL of THF, 600 mL of MeOH and 325 mL of 1.0M LiOH. The solution was heated to 80° C. for 3 h. The solution was acidified with 1N HCl and extracted with 3×200 mL of EtOAc. The organic phase was washed with water (2×150 mL) and dried over MgSO4. The solution was evaporated to dryness to provide the title compound. m.p. 190°-191° C.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][NH3+:16].[Cl:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][NH:16][CH2:23][C:21]1[S:22][C:18]([Cl:17])=[CH:19][CH:20]=1
Reactant: [NH3+]CCNc1ccc2ccccc2c1Cl
Reactant: O=Cc1ccc(Cl)s1
Agent: [Cl-]
Product: Clc1ccc(CNCCNc2ccc3ccccc3c2Cl)s1
Yield: 52 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)amino]ethanaminium chloride and 5-chlorothiophene-2-carbaldehyde in 52% yield as a white oil.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=O>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:25][C:24]2[CH:27]=[CH:28][C:29]([O:30][C:31]([F:32])([F:33])[F:34])=[C:22]([F:21])[CH:23]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc(OC(F)(F)F)c(F)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)(F)F)c(F)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 3-fluoro-4-(trifluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.94 min.; [M+H]+: 427.98 g/mol.