Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][C:10]([CH2:12][P+:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[OH-].[Na+]>O>[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][C:10]([CH:12]=[P:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11]
Reactant: COCCOCCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCOCCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A solution of 21 g (41.7 mmol) of [[[2-(2-methoxyethoxy)ethoxy]carbonyl]methyl]triphenylphosphonium bromide in 600 ml of water was treated dropwise with about 50 ml of 1N sodium hydroxide solution up to an alkaline reaction. The reaction mixture was extracted with 500 ml of methylene chloride. The organic phase was dried over sodium sulphate and concentrated. There was obtained [[[2-(2-methoxy-ethoxy)ethoxy]carbonyl]methylene]triphenylphosphorane.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[S:20]1[C:28]2[CH2:27][CH2:26][NH:25][CH2:24][C:23]=2[CH:22]=[CH:21]1>>[S:20]1[C:28]2[CH2:27][CH2:26][N:25]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=4)[N:3]=3)[CH2:24][C:23]=2[CH:22]=[CH:21]1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: c1cc2c(s1)CCNC2
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCc4sccc4C3)n2)c1

Procedure:
B43 was prepared following the general procedure reported for B10 using A1 and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine; yield: 88.6 mg (22%), white amorphous solid. MS (ES) C17H18N6O2S2 requires: 402. found: 403 (M+H)+.
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][C:5]1[C:6]([NH:28][CH3:29])=[C:7]([O:11][CH2:12][CH:13]([OH:27])[CH2:14][NH:15][CH2:16][CH2:17][NH:18][C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[CH:8]=[CH:9][CH:10]=1.[CH:30](O)=O>>[ClH:1].[ClH:1].[CH3:29][N:28]1[C:6]2[C:7]([O:11][CH2:12][CH:13]([OH:27])[CH2:14][NH:15][CH2:16][CH2:17][NH:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:26])=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[CH:30]1
Reactant: O=CO
Reactant: CNc1c(N)cccc1OCC(O)CNCCNc1c(C)cccc1C
Agent: Cl
Product: Cc1cccc(C)c1NCCNCC(O)COc1cccc2ncn(C)c12

Procedure:
In a manner analogous to the preceding Example, by reacting 3-amino-2-methylamino-1-(2-hydroxy-3-[2-(2,6-dimethylphenylamino)-ethylamino]-propoxy)-benzene trihydrochloride with formic acid, there are obtained 2.1 g. (14% of theory) of the desired compound; m.p. 94°-96° C. (after recrystallization from ethanol/diethyl ether).
Reaction SMILES: [Br-].C([N+:9]12[CH2:17][C:13]([C:18]([O:20]CC)=[O:19])([CH2:14][CH2:15][CH2:16]1)[CH2:12][CH2:11][CH2:10]2)C1C=CC=CC=1.[H][H].[ClH:25]>C(O)C.[Pd]>[ClH:25].[N:9]12[CH2:17][C:13]([C:18]([OH:20])=[O:19])([CH2:14][CH2:15][CH2:16]1)[CH2:12][CH2:11][CH2:10]2
Reactant: CCOC(=O)C12CCC[N+](Cc3ccccc3)(CCC1)C2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: [Br-]
Solvent: CCO
Product: O=C(O)C12CCCN(CCC1)C2

Procedure:
A solution of ethyl 1-benzyl-1-azoniabicyclo[3.3.1]-non-5-ylcarboxylate bromide (D2, 7.90 g, 0.021 mole) in ethanol (150 ml) was hydrogenated over 10% Pd/C (700mg) at atmospheric pressure and 40° C. until the uptake of hydrogen ceased. The reaction mixture was filtered through a pad of kieselguhr and the filtrate concentrated in vacuo to leave a yellow solid, which was treated with 8M hydrochloric acid (130 ml) and heated under reflux until TLC indicated that hydrolysis was complete. The solution was concentrated to dryness in vacuo to give the title compound (D14) as a yellow solid (4.8 g), which was used in the next stage without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCCN=C=NCC.ClC(Cl)C(O)=O>C1(C)C=CC=CC=1.CS(C)=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[C:24](=[O:29])[C:25]([F:27])([F:28])[F:26])=[O:21])[C:15]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
To a solution of 2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide (0.537 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide (1.9 g) in toluene (4 mL) and dimethyl sulfoxide (4 mL) was added dichloroacetic acid (0.33 mL) and the resulting solution was allowed to stir for 0.5 h. The reaction mixture was diluted with ethyl acetate, washed (saturated ammonium chloride, water), dried and evaporated to provide a white solid which was collected and washed with ether:hexane (1:1) to give 2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.330 g). Chromatography of the mother liquor with ethyl acetate:dichloromethane (5:95, 10:90) as the eluent gave additional 2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide as a white solid (0.190 g); NMR (DMSO/D2O): 8.46 (s,1), 7.44 (m,10), 5.20 (s,2), 4.54 (m,2 ), 4.05 (d,1), 2.23 (m,1), 0.85 (d,3), 0.75 (d,3); MS: m/z=531(M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6](O)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C(C1C=CC([OH:20])=CC=1)(C)C>>[CH:1]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=1[OH:20])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(O)cc1
Reactant: CC(C)c1cccc(O)c1
Product: CC(C)c1ccccc1O

Procedure:
3-isopropylphenol; 4-isopropylphenol;
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N:28]5[CH2:33][CH2:32][CH:31]([N:34]6[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]6)[CH2:30][CH2:29]5)[CH:23]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: CN1CCN(C2CCN(c3cccc(Br)c3)CC2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(C2CCN(c3cccc(Nc4nc5c(-c6ccc(S(C)(=O)=O)cc6)cccn5n4)c3)CC2)CC1

Procedure:
1-[1-(3-Bromo-phenyl)-piperidin-4-yl]-4-methyl-piperazine was prepared from 3-bromophenylboronic acid (0.50 g, 2.5 mmol) and 1-methyl-4-piperidin-4-yl-piperazine (0.23 g, 1.2 mmol) in a manner analogous to Step 49a. The reaction product was isolated as a brown viscous oil (0.069 mg, 16%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.08 (t, J=8.0 Hz, 1H), 7.03 (s, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 3.72 (d, J=11.7 Hz, 2H), 2.78-2.33 (m, 11H), 2.30 (s, 3H), 1.93 (d, J=12.9 Hz, 2H), 1.69-1.57 (m, 2H). MS=338, 340 (MH)+. 58b) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyri din-2-yl]-{3-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (55.0 mg, 0.191 mmol) and 1-[1-(3-bromo-phenyl)-piperidin-4-yl]-4-methyl-piperazine (69.0 mg, 0.204 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.035 g, 34%). MP=237-239° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.5 Hz, 1H), 8.25 (d, J=6.9 Hz, 2H), 8.08 (d, J=7.7 Hz, 2H), 7.65 (d, J=7.1 Hz, 1H), 7.31 (s, 1H), 7.24-7.18 (m, 1H), 7.04-6.95 (m, 2H), 6.82 (s, 1H), 6.60 (d, J=7.9 Hz, 1H), 3.81 (d, J=11.4 Hz, 2H), 3.10 (s, 3H), 2.77 (t, J=12.2 Hz, 2H), 2.72-2.33 (m, 9H), 2.30 (s, 3H), 1.96 (d, J=11.2 Hz, 2H), 1.75-1.63 (m, 2H). MS=546 (MH)+.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[C:8]=3[C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[C:50]([Si:52]([CH3:55])([CH3:54])[CH3:53])#[CH:51]>CN1CCCC1=O.C(OCC)(=O)C.[Cu](I)I>[CH3:17][O:16][C:14]1[CH:13]=[C:12]([O:18][CH3:19])[C:8]2[C:9](=[O:11])[CH2:10][C:4]3[C:3]([C:51]#[C:50][Si:52]([CH3:55])([CH3:54])[CH3:53])=[CH:2][CH:21]=[CH:20][C:5]=3[O:6][C:7]=2[CH:15]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(OC)c2c(c1)Oc1ccc(Br)cc1CC2=O
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1cc(OC)c2c(c1)Oc1cccc(C#C[Si](C)(C)C)c1CC2=O
Temperature: 80 °C
Yield: 80.1 %

Procedure:
2-Bromo-7,9-dimethoxy-10,11-dihydrodibenzo[b,f]oxepin-10-one 500 mg (F. W. 349.18, 1.43 mmol) prepared in the first stage of Production Example 79, triphenylphosphine 75 mg (F. W. 262.29, 0.062 mmol), trisbenzylidene acetone dipalladium chloroform complex 74 mg (F. W. 1035.08, 0.015 mmol), diisopropylethylamine 575 μl (F. W. 98.22, d=0.742, 2.86 mmol), ethynyl trimethylsilane 350 μl (F. W. 98.22, d=0.742, 2.86 mmol) and copper iodide 27.5 mg (F. W. 190.44, 0.143 mmol) were dissolved in N-methyl-2-pyrrolidone (5 ml) and, after substituting with argon atmosphere, they were stirred with heating at 80° C. for one hour. The reaction mixture was diluted with ethyl acetate and washed with water and saturated sodium chloride solution. The organic layer was dried and concentrated and the resulting residue was purified by a silica gel column chromatography to give the title compound 420 mg (F. W. 367.419, 66%). The peaks of this compound in 1H-NMR (400 MHz, CDCl3) were as follows.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([OH:9])=O)=[O:4].[NH2:20][C@H:21]([C:31]([NH:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:32])[CH2:22][CH2:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].S(O)(C1C=CC(C)=CC=1)(=O)=O.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([NH:20][C@H:21]([C:31]([NH:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:32])[CH2:22][CH2:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:9])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)CNC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
2.7 g (10 mmoles) of Boc-Gly-Pro-OH and 4.5 g (10 mmoles) of H-Glu(O-But)-Gly-OMe.TosOH are dissolved in 20 ml of dimethylformamide. 1.28 ml (10 mmoles) of N-ethylmorpholine and 2.2 g (10.6 mmoles) of dicyclohexylcarbodiimide are added and the mixture is left to stand at room temperature overnight. The dicyclohexylurea is then filtered off, the solvent is distilled off in vacuo, the residue is taken up in ethyl acetate and the solution is washed with citric acid, bicarbonate solution and water, as described above, dried over sodium sulfate and evaporated to dryness. The residue is dissolved in ether and a precipitate is obtained with petroleum ether and filtered off.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1.N1CCCCC1.[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH:19]=O.[BH4-].[Na+]>ClCCl.CO.C(OCC)(=O)C>[Cl:8][C:5]1[S:4][C:3]([NH:2][CH2:19][C:18]2[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:17]=2[O:16][CH3:15])=[N:7][CH:6]=1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: Nc1ncc(Cl)s1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc(CNc2ncc(Cl)s2)c(OC)c1
Temperature: 45 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
Nitrogen was bubbled through a suspension of 2-amino-5-chlorothiazole hydrochloride (25.0 g, 146 mmol) in dichloromethane (1000 ml) for 10 minutes before the addition of piperidine (13.0 g, 15.0 ml, 150 mmol) via syringe. 2,4-Dimethoxybenzaldehyde (22.1 g, 133 mmol) was added followed by freshly dried 3 Å molecular sieves (ca. 40 g). The mixture was stirred at 45° C. under nitrogen fro 16 hours. Upon cooling to room temperature the mixture was filtered through a pad of Celite™, washing with dichloromethane (2000 ml) before concentrating in vacuo to give a yellow solid, 58.2 g. This residue was dissolved in methanol (1250 ml) and sodium borohydride (13.0 g, 340 mmol) was added portionwise. Upon complete addition the mixture was heated to 50° C. for 30 minutes before cooling to room temperature and stirring under nitrogen for 16 hours. The solvent was concentrated in vacuo and the residue partitioned between ethyl acetate (300 ml) and water (500 ml). The layers were separated and the aqueous was extracted with ethyl acetate (3×300 ml). The combined organics were washed with water (300 ml), saturated aqueous sodium chloride solution (300 ml), dried over magnesium sulphate, filtered and concentrated in vacuo to give a red-brown solid, 41.6 g. This residue was dissolved in ethyl acetate and passed through a plug of silica. Concentration in vacuo afforded a red-brown solid, 39.3 g, which was subsequently triturated with diethyl ether (ca. 500 ml) and stirred for 60 hours. The solid was filtered and air-dried to give the title compound as a white solid, 12.1 g, 32% yield. The mother liquor was concentrated in vacuo to give a brown solid, 25 g, which was stirred in diethyl ether: heptane (2:3, 500 ml). The solid material was filtered and air-dried to give the title compound as an off-white solid, 13.2 g, 35% yield.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.C([O-])(O)=O.[Na+].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[CH2:14]([O:21][C:22]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCC1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)N1CCCC(CO)C1
Reaction time: 5 h

Procedure:
To a stirred solution of 3-hydroxymethylpiperidine (5 g, 43.4 mmol, 1 eq) in CHCl3 (150 mL) was added saturated aqueous NaHCO3 (150 mL). To the vigorously stirred mixture was added benzyl-chloroformate (6.8 mnL, 47.74 mmol, 1.1 eq) via syringe. The mixture was stirred 5 h. The layers were separated and the aqueous layer was extracted 2× with CH2Cl2. The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated. The material was used crude.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5](=[O:10])[C:4]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:3]1.CCN(CC)CC.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[C:33]([F:36])([F:35])[F:34].O>C1(C)C=CC=CC=1>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:14]2[CH2:13][CH2:12][N:11]([C:4]3[C:5](=[O:10])[N:6]([CH3:9])[C:7](=[O:8])[N:2]([CH3:1])[N:3]=3)[CH2:16][CH2:15]2)=[C:27]([C:33]([F:34])([F:35])[F:36])[CH:28]=1
Reactant: Cn1nc(N2CCNCC2)c(=O)n(C)c1=O
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1nc(N2CCN(Cc3ccc(F)cc3C(F)(F)F)CC2)c(=O)n(C)c1=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
The compound 54 is prepared according to the synthesis method 2: 0.26 g (1.17 mmol) of derivative 12a is placed in 3 mL of toluene in the presence of 0.24 mL (1.75 mmol) of NEt3 and of 0.3 g (1.17 mmol) of 1-bromomethyl-4-fluoro-2-trifluoromethyl-benzene. This mixture is stirred 2 h at 110° C. The medium is taken up with water and extracted with AcOEt. After drying on MgSO4, the organic phase is dry concentrated. The obtained residue is purified by flash chromatography on silica (CH2Cl2-AcOEt: 95-5). 0.37 g of a yellow oil are isolated (yield: 79%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH2:8][NH2:9].[CH3:12][O:13][CH:14]([O:19][CH3:20])[C:15](OC)=[O:16].CCN(C(C)C)C(C)C>CO>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH2:8][NH:9][C:15](=[O:16])[CH:14]([O:19][CH3:20])[O:13][CH3:12]
Reactant: COC(=O)C(OC)OC
Reactant: NCc1cc(Br)ccc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(OC)C(=O)NCc1cc(Br)ccc1F
Temperature: 60 °C

Procedure:
A mixture of 5-bromo-2-fluorobenzylamine hydrochloride (15.0 g, 62 mmol), methyl dimethoxyacetate (10.0 g, 75 mmol), and DIPEA (10.3 mL, 62 mmol) in methanol (15 mL) was heated at 60° C. for 16 h in a bomb apparatus. After cooling to RT, the solvent was evaporated and DCM (150 mL) was added. The solution was washed with water (2×30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. It was purified by column chromatography on silica gel using EtOAc/Hexanes (1:1) to give the title compound. 1H NMR (CDCl3, 300 MHz) δ=3.42 (s, 6H), 4.53 (d, J=4.8 Hz, 2H), 4.81 (s, 1H), 6.96 (t, J=6.8 Hz, 1H), 7.40-7.42 (m, 1H), 7.51-7.54 (m, 1H). MS(ES+): m/z=305.73/307.69 [MH+]. HPLC: tR=2.89 min (polar—5 min, ZQ2).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@@H:9]1[C:10](O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16]O>>[C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@@H:9]1[C:10]#[CH:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: CO
Product: C#C[C@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from N-BOC-(R)-proline according to the procedures of Examples 1a-c above. [α]D≤ +113.0 (c 0.94, MeOH).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][CH:4]=[CH:5][CH2:6][C:7]1[C:8](=[O:19])[C:9]2[C:14]([C:15](=[O:18])[C:16]=1[OH:17])=[CH:13][CH:12]=[CH:11][CH:10]=2.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[C:8](=[O:19])[C:9]2[C:14]([C:15](=[O:18])[C:16]=1[OH:17])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: [H][H]
Reactant: CC(C)(C)CC=CCC1=C(O)C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)CCCCC1=C(O)C(=O)c2ccccc2C1=O
Yield: 404.8 %

Procedure:
2-(5,5-dimethylhex-2-enyl)-3-hydroxynaphthalene- 1,4-dione(3 91 mg) prepared in Example 45 was dissolved in ethyl acetate (15 ml) and hydrogenated as in Example 1(c) using hydrogen and 100 mg of Pd/C catalyst to provide 371 mg title compound.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C@@H:7]([CH:11]([CH3:13])[CH3:12])[C:8]([OH:10])=O)(=[O:5])=[O:4])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][NH2:45])=[CH:39][C:38]=1[O:46][CH3:47])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>O1CCCC1>[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][NH:45][C:8](=[O:10])[C@@H:7]([NH:6][S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH:11]([CH3:13])[CH3:12])=[CH:39][C:38]=1[O:46][CH3:47])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COc1cc(CCN)ccc1OCc1ccccc1
Reactant: CCS(=O)(=O)N[C@H](C(=O)O)C(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(OCc2ccccc2)c(OC)c1)C(C)C
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
21.1 g of (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid and 12 ml of N-methylmorpholine are cooled in 450 ml of tetrahydrofuran, with stirring, to −20° C. 13.2 ml of chloroformic acid isobutyl ester are added dropwise thereto over 10 min and the reaction mixture is subsequently stirred for 1 hour at −10° C. It is then cooled to −20° C. and a solution of 26.1 g of 2-(4-benzyloxy-3-methoxyphenyl)-ethylamine in 100 ml of tetrahydrofuran is added dropwise over 20 min. The reaction mixture is then stirred for 4 hours without cooling, the internal temperature gradually rising to room temperature. The reaction mixture is introduced into 400 ml of 2N hydrochloric acid and extracted twice with 500 ml of ethyl acetate each time. The organic phases are washed once with 250 ml of 2N hydrochloric acid, once with 250 ml of saturated sodium chloride solution, twice with 250 ml of 2N potassium hydrogen carbonate solution each time and once with 250 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated, yielding (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid N-[2-(4-benzyloxy-3-methoxyphenyl)-ethyl]-amide, which can be purified by recrystallisation from tert-butyl methyl ether, m.p. 140-142° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20](O)=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][OH:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C(=O)O)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2CO)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39.3 %

Procedure:
4-(2-Carboxyphenyl)piperazine-1-carboxylic acid t-butyl ester (3.5 g, 11.3 mmol, 1.0 eq.) and THF (91.3 mL) were combined at room temperature under nitrogen. Borane-dimethyl sulfide complex (2.00 mL, 22.5 mmol, 2.0 eq.) was added dropwise and the mixture was stirred for 5 minutes, then heated at the reflux temperature for 1.5 hours. The mixture was cooled to room temperature, and the reaction was quenched slowly with MeOH (20 ml), then concentrated by rotary evaporation. The material was azeotroped with MeOH (2×20 ml). The crude product was dissolved in EtOAc (50 ml), and washed with cold 1M HCl (2×25 ml), then NaHCO3 (2×25 ml). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the title compound (1.3 g) as a clear oil that solidified upon sitting.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:18]([CH2:21]Cl)=[N:19][N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:18]([CH2:21][N:29]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:27][CH3:28])=[N:19][N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3nnc(CCl)o3)c2[C@@H]2CCN12
Reactant: CCCNCCC
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nnc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)o1
Yield: 97.5 %

Procedure:
1.88 g (5 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature over the weekend with 1.12 g (11 mmol) of dipropylamine and 10 ml of N,N-dimethylformamide. After evaporating the reaction mixture the residue was dissolved in methylene chloride and the solution was washed twice with water and dried over magnesium sulfate. After evaporating the solvent and crystallizing the residue from ethyl acetate and hexane there were obtained 2.15 g (98%) of (S)-8-chloro-1-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 134°-136°, which was converted into the hydrochloride of melting point 235°-237°.