Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]1[N:19]=[N:20][N:21]=[C:14]1[C:13]([N+:22]([O-])=O)=[C:12]2[NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(#N)C.[Pt]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]1[N:19]=[N:20][N:21]=[C:14]1[C:13]([NH2:22])=[C:12]2[NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC(C)CNc1c([N+](=O)[O-])c2nnnn2c2ccc(OCc3ccccc3)cc12
Agent: [Pt]
Solvent: CC#N
Product: CC(C)CNc1c(N)c2nnnn2c2ccc(OCc3ccccc3)cc12
Reaction time: 5 h
Yield: 82.6 %

Procedure:
7-(Benzyloxy)-N-(2-methylpropyl)-4-nitrotetraazolo[1,5-a]quinolin-5-amine (10 g, 25.4 mmol) was shaken in 200 mL of acetonitrile with 5% platinum on carbon (1 g) under 50 psi (3.45×105 Pa) of hydrogen. After 5 hours, the mixture was filtered through CELITE filter agent. Some product was isolated as a solid on the top of the filter cake. This solid was collected, dissolved in warm DMF, and filtered again through fresh CELITE filter agent. The combined filtrates were cooled and allowed to sit overnight. The resulting precipitate was collected in 2 crops to yield 7.6 g of 7-(benzyloxy)-N5-(2-methylpropyl)tetraazolo[1,5-a]quinoline-4,5-diamine as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[C:9](O)(=[O:13])[C:10]([CH3:12])=[CH2:11]>>[CH3:11][CH:10]1[CH2:12][C:3]2[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]=2[NH:1][C:9]1=[O:13]
Reactant: NC1=CC(=O)CCC1
Reactant: C=C(C)C(=O)O
Product: CC1CC2=C(CCCC2=O)NC1=O

Procedure:
Prepared analogously to Example G from 1-amino- cyclohexen-3-one and methacrylic acid in an autoclave for a period of one hour at 180° C. Recrystallisation is from methanol and subsequently from a mixture of ethyl acetate/ethanol (3:1).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Li]CCCC.C(NC(C)C)(C)C.[CH3:21][C:22]1[O:26][N:25]=[CH:24][CH:23]=1.CS[C:29]1[S:30][CH2:31][CH2:32][N:33]=1>C1COCC1>[NH2:25][C:24]1[N:33]2[CH2:32][CH2:31][S:30][C:29]2=[CH:21][C:22](=[O:26])[CH:23]=1
Reactant: Cc1ccno1
Reactant: CSC1=NCCS1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Nc1cc(=O)cc2n1CCS2
Reaction time: 20 h
Yield: 50.8 %

Procedure:
To a solution of lithium diisopropylamide (LDA), prepared from n-BuLi (106.6 ml, 0.16M) and diisopropylamine (16.7 g, 23.1 ml, 0.16M), in dry THF (100 ml) was added under N2 at -10° C., 5-methylisoxazole (6.8 g, 0.08M). The resultant yellow suspension was mechanically stirred at -10° C. for 30 min before the 4,5-dihydro-2-methylthiothiazole (11 g, 0.08M) was added dropwise. After the addition was complete, an orange oil separated, and the mixture was allowed to warm to ambient over a period of 20 hr. A mixture of MeOH (60 ml) and glacial acetic acid (4.5 ml, 0.08M) was slowly added and the resultant reddish solution was stirred at ambient overnight. The solvents were evaporated in vacuo, and the residual oil was flash column chromatographed on silica gel (EM-60) with 30% MeOH in CH2Cl2 as the eluent to give the desired amine (7 g), which was further recrystallized from MeOH/Et2O to give the title compound (5.4 g, 40%), mp>241° C. TLC (30% MeOH in CH2Cl2); Rf=0.33. IR (KBr) cm1, 3350-3000 (broad), 1675, 1625.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:37]([S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)(=[O:40])=[O:39])[C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:17]4[C:18]([C:23]5[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:32]6[CH2:36][CH2:35][CH2:34][CH2:33]6)=[O:31])=[CH:25][CH:24]=5)=[N:19][N:20]([CH3:22])[CH:21]=4)=[C:11]3[CH:10]=2)=[CH:5][CH:4]=1)=O.[CH2:47]([NH:49][CH2:50][CH2:51][OH:52])[CH3:48].ClCCl>ClC(Cl)C>[CH2:47]([N:49]([CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:37]([S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)(=[O:39])=[O:40])[C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:17]4[C:18]([C:23]5[CH:24]=[CH:25][C:26]([NH:29][C:30]([N:32]6[CH2:36][CH2:35][CH2:34][CH2:33]6)=[O:31])=[CH:27][CH:28]=5)=[N:19][N:20]([CH3:22])[CH:21]=4)=[C:11]3[CH:10]=2)=[CH:5][CH:4]=1)[CH2:50][CH2:51][OH:52])[CH3:48]
Reactant: CCNCCO
Reactant: Cn1cc(-c2ccnc3c2cc(-c2ccc(C=O)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N3CCCC3)cc2)n1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCN(CCO)Cc1ccc(-c2cc3c(-c4cn(C)nc4-c4ccc(NC(=O)N5CCCC5)cc4)ccnc3n2S(=O)(=O)c2ccccc2)cc1

Procedure:
Following the procedure described in Intermediate 101 using N-(4-{4-[2-(4-formylphenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-methyl-1H-pyrazol-3-yl}phenyl)-1-pyrrolidinecarboxamide and 2-(ethylamino)ethanol in dichloroethane (instead of dichloromethane) provided the title compound. ESMS [M+H]+: 704.6.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+].Cl>C(#N)C>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccccc1CCCc1ccccc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1ccccc1CCCc1ccccc1NS(=O)(=O)c1ccc(C)cc1
Temperature: 20 °C
Reaction time: 20 h
Yield: 26.7 %

Procedure:
1 g of methyl 2-[3-(2-aminophenyl)propyl]benzoate obtained in Example 5 (3.7 mM), 0.71 g of 4-methylphenylsulfonyl chloride (3.7 mM) and 34 mg of NaHCO3 (4.1 mM) are added to 15 ml of acetonitrile in a 50 ml reactor. The reaction medium is stirred at 20° C. for 20 hours. 5 ml of 1M HCl are then added and the mixture is extracted with ethyl acetate. The organic phase is separated out after settling of the phases, washed and then dried over Na2SO4. After evaporation under vacuum, an oil is obtained, which is precipitated from ethyl ether. The solid is filtered off and washed with ether. 0.42 g of a grey-white solid is obtained (yield: 27%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Br:14])[C:12]=1[CH3:13].CN([CH:18]=[O:19])C.[NH4+].[Cl-]>CCCCCC>[Br:14][C:11]1[C:12]([CH3:13])=[C:7]([CH:18]=[O:19])[CH:8]=[N:9][CH:10]=1
Reactant: CN(C)C=O
Reactant: Cc1c(Br)cncc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: Cc1c(Br)cncc1C=O
Temperature: -100 °C
Reaction time: 0.08 h

Procedure:
Under argon, an n-butyllithium solution in hexane (1.55N, 4.6 ml) is added dropwise to a 3,5-dibromo-4-methylpyridine solution (intermediate 10.1, 1.76 g, 7 mmol) kept at −100° C. After stirring for 5 min, DMF (0.84 ml, 1.54 equiv.) is added dropwise. The stirring is maintained for 20 min at −100° C. and then for 1 h at −78° C. An aqueous NH4Cl solution is added and the reaction mixture is extracted with a diethyl ether/water mixture. The yellow solid obtained is purified on silica gel (100 g), eluting with AcOEt/petroleum ether (1/4).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:12]2[CH:18]=C(C#N)[S:16][C:13]=2[NH:14][N:15]=1.S(=O)(=O)(O)O.[C:26]([OH:29])(=[O:28])[CH3:27]>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:12]2[CH:18]=[C:27]([C:26]([OH:29])=[O:28])[S:16][C:13]=2[NH:14][N:15]=1
Reactant: N#Cc1cc2c(-c3ccc4ccccc4c3)n[nH]c2s1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc2c(-c3ccc4ccccc4c3)n[nH]c2s1
Temperature: 110 °C

Procedure:
To a solution of 33 mg of 3-(naphthalen-2-yl)-1H-thieno[2,3-c]pyrazole-5-carbonitrile in 1.0 mL of acetic acid and 0.3 mL of water was added 0.3 mL of concentrated sulfuric acid at room temperature and stirred at 110° C. for a day. After cooling the solution to room temperature, 10 mL of ice water was added, and the precipitated crystals were collected by filtration and washed with water, to afford 33 mg of the title compound as pale brown crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([O:19][CH3:20])[CH:3]=1.C([Li])CCC.CCCCCC.[B:32](OC(C)C)([O:37]C(C)C)[O:33]C(C)C>O1CCCC1>[CH3:20][O:19][C:4]1[CH:3]=[C:2]([B:32]([OH:37])[OH:33])[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:18])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(Br)ccc1NC(=O)CCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(B(O)O)ccc1NC(=O)CCc1ccccc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 23.3 %

Procedure:
A solution of N1-(4-bromo-2-methoxyphenyl)-3-phenylpropanamide (1.004 g, 3 mmol) in anhydrous tetrahydrofuran (30 mL) at −78° C. was treated with a solution of 1.6 M n-butyl lithium in hexane (4.7 mL, 7.5 mmol). The reaction mixture was stirred at −78° C. for 40 min. Tri-isopropyl borate(1.05 mL, 4.5 mmol) was added to this reaction mixture, and stirred at −78° C. for 20 min. The acetone/dry ice bath was removed. The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was quenched with 2.5 N hydrochloric acid solution (30 mL). The organic layer was removed under reduced pressure. Ethyl acetate was added to the acidic aqueous layer. The layers were partitioned, and the aqueous layer was extracted with ethyl acetate (250 mL). The combined organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel, using 1:1 dichloromethane:ethyl acetate as eluent. The gradient was changed to 15% methanol in dichloromethane to remove the baseline product to give 0.209 g (23%) of 3-methoxy-4-[(3-phenylpropanoyl)amino]phenylboronic acid. 1H NMR (DMSO-d6, 400 MHz) δ 9.08 (s, 1H), 7.89-7.95 (m, 3H), 7.45-7.42 (s, 1H), 7.35-7.16 (m, 5H), 3.82 (s, 3H), 2.91-2.81 (m, 2H), 2.74-2.70 (s, 2H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.389 min (95%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[N:8]2[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC1(C)C(=O)Nc2cc(Br)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)C(=O)N(COCC[Si](C)(C)C)c2cc(Br)ccc21
Temperature: 0 °C

Procedure:
A solution of 6-bromo-3,3-dimethylindolin-2-one (example 14a, 4.87 g, 20.3 mmol) in THF (135 ml) was cooled to 0° C. and a solution of sodium bis(trimethylsilyl)amide in THF (1M, 24.3 ml, 24.3 mmol) was added during 15 minutes. Then a solution of (2-(chloromethoxy)ethyl)trimethylsilane (4.27 g, 4.54 ml, 24.3 mmol) in THF (5 ml) was added during 15 minutes. After 4 hours at 0° C. the reaction mixture was poured into ice-water.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[NH2:16][C@H:17]([CH3:24])[C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=[O:20].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:21][C:19](=[O:20])[C:18]([CH3:23])([CH3:22])[C@H:17]([NH:16][C:9]1[C:4]2[N:5]([CH:14]=[C:2]([Br:1])[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:11]([NH2:13])=[O:12])[CH3:24]
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: C[C@@H](N)C(C)(C)C(N)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C(C)(C)C(N)=O
Temperature: 100 °C
Reaction time: 12 h
Yield: 70.8 %

Procedure:
To a solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (400 mg, 1.457 mmol) in DMF (30 mL) was added (R)-3-amino-2,2 dimethylbutanamide hydrochloride (486 mg, 2.91 mmol) and DIPEA (1.273 ml, 7.29 mmol) at RT and the reaction mixture was allowed to stir at 100° C. for 12 h. It was then quenched with water (300 ml) and extracted with EtOAc (3×150 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. Crude product was purified by combi-flash (12 g silica column, 85% EtOAc: Pet-Ether) to afford an off white solid (380 mg, 70.8% yield). 1HNMR (400 MHz, DMSO) δ ppm: 1.13-1.18 (m, 9H), 4.51-4.55 (d, J=16 Hz, 1H), 6.98 (s, 3H), 7.05-7.05 (d, J=1.6 Hz, 1H), 7.272 (s, 1H), 7.88-7.89 (d, J=4.0 Hz, 1H), 8.236 (s, 1H), 10.88-10.90 (d, J=8.0 Hz 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:19](OC)(OC)(OC)[CH3:20]>CN(C=O)C>[CH3:16][O:15][CH:14]([O:17][CH3:18])[CH2:13][N:12]1[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]=[C:19]1[CH3:20]
Reactant: COC(C)(OC)OC
Reactant: COC(=O)c1cccc(N)c1NCC(OC)OC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2nc(C)n(CC(OC)OC)c12
Yield: 73.7 %

Procedure:
To a stirred solution of methyl 3-amino-2-(2,2-dimethoxyethylamino)benzoate (1.0 g, 3.9 mmol) from Step C of Example 13 in DMF (30 mL) was added trimethyl orthoacetate (1.5 mL, 11.8 mmol) and the reaction was refluxed overnight. The reaction mixture was washed with saturated aqueous sodium bicarbonate, extracted with methylene chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure to give the crude material which was purified by column chromatography (silica gel, 0% to 90% ethyl acetate in hexanes) to afford methyl 1-(2,2-dimethoxyethyl)-2-methyl-1H-benzo[d]imidazole-7-carboxylate (0.8 g, 72%): 1H NMR (300 MHz, DMSO-d6) δ 7.74 (dd, J=8.1, 1.2 Hz, 1H), 7.55 (dd, J=7.8, 1.2 Hz, 1H), 7.21 (t, J=7.5 Hz, 1H), 4.56 (d, J=4.8 Hz, 2H), 4.44 (t, J=4.8 Hz, 1H), 3.90 (s, 3H), 3.21 (s, 6H), 2.58 (s, 3H); MS (ESI+) m/z 279 (M+H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1O)#[N:17]>N1C=CC=CC=1>[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])#[N:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccc(C#N)c(O)c1
Solvent: c1ccncc1
Product: COc1ccc(C#N)c(OS(=O)(=O)C(F)(F)F)c1
Yield: 81.1 %

Procedure:
Trifluoromethanesulphonic anhydride (2.06 g) was added dropwise to a solution of 2-cyano-5-methoxyphenol (1.0 g) in dry pyridine (20 ml) at 0° C. under an atmosphere of argon. Volatile material was removed by evaporation and the residue was dissolved in ethyl acetate (30 ml). The solution was washed with water (60 ml) and saturated sodium chloride solution (30 ml) and dried (MgSO4). The solvent was removed by evaporation and the residue purified by flash chromatography, eluting with ethyl acetate/hexane (1:3 v/v), to give (2-cyano-5-methoxyphenyl)trifluoromethanesulphonate (1.53 g) as an oil; NMR (CDCl3): 3.9(s,3H), 6.95(d,1H), 7.0(d,1H), 7.7(d,1H).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: OB(O)c1ccccc1Br
Product: Oc1ccc2ncn(-c3ccccc3Br)c2n1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2-bromophenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=289.9[M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 6.59 (d, J=8.6 Hz, 1H), 7.52 (td, J1=7.9 Hz, J2=1.8 Hz, 1H), 7.61 (td, J1=7.5 Hz, J2=1.4 Hz, 1H), 7.67 (dd, J1=7.8, J2=1.7 Hz, 1H), 7.89 (dd, J1=8.0, J2=1.3 Hz, 1H), 8.01 (d, J=8.6 Hz, 1H), 8.28 (s, 1H), 10.86 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[Li]CCCC.CN([CH:21]=[O:22])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(OCC)(=O)C>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:21]=[O:22])[CH:11]=[CH:10]2
Reactant: CN(C)C=O
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1ccc2cc(O)ccc2c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 82.2 %

Procedure:
To a stirred cooled mixture of 6-bromo-2-hydroxynaphthalene (25.3 g, 0.113 mol) in THF (600 mL) at −78° C. was added n-BuLi (2.5 M, 100 mL, 0.250 mol) dropwise. The mixture turned yellow and the temperature rose to −64° C. After ca 5 min a suspension appeared. After addition, the mixture was maintained at −78° C. After 20 minutes, a solution of DMF (28.9 mL, 0.373 mol) in THF (100 mL) was added over 20 minutes. After addition, the mixture was allowed to warm slowly to RT. After 1 hour, the mixture was poured in ice/water (200 mL). To the mixture citric acid was added to a pH of 5. The mixture was stirred for 0.5 hour. Ethyl acetate (200 mL) was added and the organic layer was separated and washed with brine (100 mL), dried over Na2SO4 and concentrated. To the residue was added heptane with 20% ethyl acetate (ca 50 mL) and the mixture was stirred for 1 hour. The mixture was filtered and the solid was washed with ethyl acetate and dried in vacuo to afford 16 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:26]=[CH:27]/[C:28]([OH:30])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:39]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:26]=[CH:27]/[C:28]([NH2:39])=[O:30])=[CH:15][CH:14]=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(/C=C/C(=O)O)ccc2c1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(/C=C/C(N)=O)ccc2c1=O
Yield: 93.1 %

Procedure:
A solution of (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenic acid (0.33 g, 0.7 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.27 g, 1.4 mmol) and 1-hydroxybenzotriazole ammonium salt (0.21 g, 1.4 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenamide (0.31 g, 93.9%) as crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:17])=[CH:3][CH2:4][CH2:5][C:6]1[CH2:7][CH:8]2[C:13](=[O:14])[O:12][C:10](=[O:11])[CH:9]2[CH2:15][CH:16]=1.B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:17])[CH2:3][CH2:4][CH2:5][C:6]2[CH2:7][CH:8]3[C:13]([O:12][C:10](=[O:11])[CH:9]3[CH2:15][C:16]1=2)=[O:14]
Reactant: CC(C)=CCCC1=CCC2C(=O)OC(=O)C2C1
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC1(C)CCCC2=C1CC1C(=O)OC(=O)C1C2

Procedure:
1,2,3,6-tetrahydro-4-(4-methyl-3-pentenyl)phthalic anhydride (VIII, Z=O) (1000g) and boron trifluoride etherate (100 g.) in 1 liter of benzene was refluxed for one and one-half hours. Work-up, using standard techniques, gave in almost quantitative yield crude 1,2,3,4,5,6,7,8-octahydro-5,5-dimethyl-2,3-naphthalenedicarboxylic acid anhydride (VII, X=O; R is the radical C). The cyclized anhydride (1 mole) was heated slowly to 250° C. with 200 ml. of ammonium hydroxide (s.g. 0.91) until ammonia no longer was liberated, using a condenser of a length which allowed ready evaporation of water. The resulting 1,2,3,4,5,6,7,8-octahydro-5,5-dimethyl-2,3-naphthalenedicarboximide (VII, X=NH; R is the radical C) was dissolved in 500 ml. of 2N sodium hydroxide in ethyl alcohol with warming, the solution was evaporated to dryness in vacuo, and the resulting sodium salt of the imide was suspended in 500 ml. of dioxane and treated with trichloromethanesulfenyl chloride (1.1 moles) in 200 ml. of dioxane with gentle stirring. The reaction was completed by heating at 80° C. for thirty minutes. The mixture was allowed to stand overnight, concentrated in vacuo, and the residue was crystallized from ethyl alcohol (or benzene) to give a yield of 91% of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:40]([NH2:42])[CH3:41].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:26])([F:28])[F:27])=[N:20][C:21]([C:22](=[O:24])[NH:42][CH2:40][CH3:41])=[C:15]2[CH2:14]1)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: CCN
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (180 mg, 0.33 mmol) was dissolved in 10 mL of tetrahydrofuran, and ethylamine hydrochloride (269 mg, 3.3 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (168 mg, 0.66 mmol) and triethylamine (367 mg, 3.63 mmol) were then added to the solution. The reaction mixture was stirred at room temperature for 4 hours until thin lay chromatography showed the starting material disappeared, and then filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-ethylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 42a (190 mg, yield>100%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(O)cc1F
Reactant: Fc1ccc(CBr)cc1
Product: N#Cc1ccc(OCc2ccc(F)cc2)cc1F
Yield: 100 %

Procedure:
As described for example 1a, 2-fluoro-4-hydroxy-benzonitrile (5.0 g, 36 mmol) [using 4-fluorobenzyl bromide instead of 3-fluorobenzyl bromide] was converted to the title compound (8.9 g, 100%) which was obtained as a white solid. MS: m/e=245.0 (M+).