Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH2:12][CH2:13][NH:14][CH2:15][C:16]=3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:23][CH3:24].[CH:25](OCC)=[O:26]>C1COCC1>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11]3[CH2:12][CH2:13][N:14]([CH:25]=[O:26])[CH2:15][C:16]=3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:23][CH3:24]
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)C1=C2CNCC1
Reactant: CCOC=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1OC)CC(c1ccccc1)C1=C2CN(C=O)CC1

Procedure:
To a solution of the free base 7,8-dimethoxy-5-phenyl-1,2,3,4,5,6-hexahydrobenzo[h]isoquinoline, (390 mg, 1.2 mmol, from Example 200) in THF (25 mL) was added ethyl formate (40 mL). The resulting solution was heated at reflux for 17 hours, concentrated, and the concentrate was chased with THF. The crude product was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CN1CCC[C@@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@H]5CCCN5C)n4c3)c3ccccc32)cc1

Procedure:
A solution of Intermediate 60b (123 mg, 0.339 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 140 mg, 0.346 mmol) in 1,4-dioxane (4 mL) and DIPEA (91 μL, 0.52 mmol) was stirred at 93° C. for 3.25 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-20% MeOH in DCM, to give the impure product. Further purification by HPLC (C, 18 X-select column, 25-70% MeCN in H2O, 0.1% formic acid) gave the title compound as a white powder after freeze-drying (118 mg, 56%). LCMS (Method 5): Rt 3.67 min, m/z 619.2 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.80-2.27 (1H, m), 2.31-2.40 (4H, m), 3.11-3.18 (1H, m), 3.98 (1H, t, J 8.2), 4.78-4.86 (1H, m), 5.42 (1H, t, J 4.3), 6.32 (1H, s), 7.09 (1H, d, J 8.5), 7.26-7.42 (9H, m), 7.75 (1H, dd, J 9.7, 1.0), 8.03 (1H, s), 8.28 (1H, d, J 1.0).
Reaction SMILES: CO.C(OC(=O)[C:7](=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:8]([O:10]CC)=[O:9])C.[C-:22]#[N:23].[K+]>O>[C:22]([CH:13]([C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[CH2:7][C:8]([OH:10])=[O:9])#[N:23]
Reactant: CCOC(=O)C(=Cc1ccc(O)cc1)C(=O)OCC
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#CC(CC(=O)O)c1ccc(O)cc1
Temperature: 70 °C
Yield: 72.3 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged with methanol (6 mL) and water (1 mL). To the stirred solvent was added 2-(4-hydroxy-benzylidene)-malonic acid diethyl ester (1 g, 3.8 mmol), followed by potassium cyanide (0.492 g, 7.6 mmol). The RM was heated at 70° C. for 2 h. The RM was concentrated, diluted with saturated NaHCO3 solution (50 mL) and washed with ethyl acetate (50 mL×2). The aqueous layer was acidified to pH 3 with 1N hydrochloric acid and extracted with ethyl acetate (50 mL×2). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as brown liquid. (0.6 g, yield: 72.3%); MS (ESI, 120 eV): m/z=190.0 (M−H)+; 1H NMR (300 MHz, DMSO-d6): δ 12.69 (s, 1H), 9.58 (s, 1H), 7.22-7.24 (d, 2H), 6.75-6.78 (d, 2H), 4.28-4.40 (m, 1H), 2.77-3.12 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:14]([C:17](=O)[CH3:18])[C:15]#[N:16].Cl.Cl.[NH2:22][NH2:23].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:18][C:17]1[C:14]([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH2:10][CH2:11][O:12][CH3:13])[C:3]=2[O:2][CH3:1])=[C:15]([NH2:16])[NH:23][N:22]=1
Reactant: COCCOc1cccc(C(C#N)C(C)=O)c1OC
Reactant: NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COCCOc1cccc(-c2c(C)n[nH]c2N)c1OC
Yield: 64.6 %

Procedure:
To a solution of 2-(2-(methyloxy)-3-{[2-(methyloxy)ethyl]oxy}phenyl)-3-oxobutanenitrile (0.17 g, 0.65 mmol) in ethanol (5 mL) was added hydrazine dihydrochloride (99 mg, 0.94 mmol). The resulting mixture was heated at reflux for 1 hour. It was cooled, poured into a saturated sodium bicarbonate solution (10 mL), and the mixture was extracted with ethyl acetate (3×10 mL). The combined extract was washed with aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by flash chromatography (silica gel, 5% methanol in dichloromethane) to provide 3-methyl-4-(2-(methyloxy)-3-{[2-(methyloxy)ethyl]oxy}phenyl)-1H-pyrazol-5-amine (115 mg, 0.42 mmol, 65% yield). MS (EI) for C14H19N3O3: 278 (MH+).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH3:23])[C:5](O)=[O:6].CN(C)C=O.C(Cl)([Cl:31])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH3:23])[C:5]([Cl:31])=[O:6]
Reactant: CON=C(C(=O)O)c1ccccc1COc1cc(C)ccc1C
Reactant: O=C(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CON=C(C(=O)Cl)c1ccccc1COc1cc(C)ccc1C
Reaction time: 5 h

Procedure:
To 232 g of a toluene solution containing 50.1 g (0.160 mol, E/Z=23/77) of α-methoxyimino-2-(2,5-dimethylphenoxymethyl)phenylacetic acid produced in accordance with Example 5-(1) and 0.117 g (0.0016 mol) of dimethylformamide was added dropwise a mixed solution of 23.8 g (0.240 mol) of phosgene and 45.1 g of toluene over 5 hours while keeping at 60°-65° C., and the reaction was subsequently allowed to proceed at the same temperature for 5 hours, which afforded 239.0 g of a toluene solution of α-methoxyimino-2-(2,5-dimethylphenoxymethyl)phenylacetyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.C([Li])CCC.[B:26](OC)([O:29]C)[O:27]C.Cl>CCCCCC.O1CCCC1>[CH:10]1[C:9]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([B:26]([OH:29])[OH:27])=[CH:7][CH:6]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc(-n2c3ccccc3c3ccccc32)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(-n2c3ccccc3c3ccccc32)cc1
Reaction time: 2 h
Yield: 66 %

Procedure:
In a 500 mL three-neck flask was put 21.8 g (67.5 mmol) of 9-(4-bromophenyl)-9H-carbazole. The atmosphere in the flask was replaced with nitrogen. To the mixture was added 200 mL of tetrahydrofuran (THF). The temperature of this solution was set to −78° C., and then 48.9 mL (74.3 mmol) of n-butyllithium (a 1.52 mol/L hexane solution) was dripped to the solution. The mixture was stirred at the same temperature for 2 hours. After that, 17.4 mL (155 mmol) of trimethyl borate was added to the mixture, followed by stirring for 1 hour at the same temperature. Then, the mixture was stirred for 24 hours while the temperature thereof is returned to room temperature. After that, 200 mL of 1.0 mol/L hydrochloric acid was added to this solution, followed by stirring for 1 hour at room temperature. The organic layer of the mixture was washed with water, and the aqueous layer was extracted with ethyl acetate. The extract and the organic layer were combined, washed with saturated brine, and then dried with magnesium sulfate. After that, this mixture was suction filtered. The resulting filtrate was concentrated to give a residue. This residue was recrystallized with a mixed solvent of chloroform and hexane to give 4-(9H-carbazol-9-yl)phenylboronic acid which was the desired substance as 13 g of a white powdered solid in a yield of 66%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[CH3:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:32]2[CH:31]=[N:30][C:29]([CH3:28])=[N:34][CH:33]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)ccc2N2CC[C@@H](O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 1 using (R)-3-bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 2.1) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine to afford a white solid. UPLC-MS (condition 1) tR=2.46 min, m/z=459.1-460.1 [M+H]+, m/z=457.2-458.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.76 (d, J=3.91 Hz, 1H) 1.82-1.93 (m, 1H) 2.65-2.72 (m, 1H) 2.68 (s, 3H) 3.00-3.11 (m, 2H) 3.18-3.27 (m, 1H) 4.17-4.25 (m, 1H) 4.86 (d, J=3.67 Hz, 1H) 6.96 (d, J=8.80 Hz, 1H) 7.33 (d, J=8.56 Hz, 2H) 7.81 (d, J=2.20 Hz, 1H) 7.83-7.88 (m, 2H) 7.92 (dd, J=8.80, 2.20 Hz, 1H) 8.73 (s, 2H) 10.08 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:9]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCC1CCCCN1
Reactant: ClCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: OCC1CCCCN1Cc1ccccc1
Yield: 52.8 %

Procedure:
A mixture of 12.9 g of 2-piperidine methanol, 13.2 g of benzyl chloride, 10.5 g of triethylamine and 50 ml of toluene was stirred at reflux for 4 hours. The reaction mixture was filtered, the filtrate was concentrated, and the concentrate was distilled under reduced pressure to obtain 11.3 g of 1-benzyl-2-piperidine methanol (yield: 52.9%). b.p.: 107° C./2 mmHg
Reaction SMILES: [Br:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([NH:12][CH:13]([CH3:15])[CH3:14])[CH2:7][C:6]=2[C:5]([O:16][CH3:17])=[CH:4][CH:3]=1.[CH:18](=O)[CH2:19][CH3:20].C([BH3-])#N.[Na+].C(Cl)(Cl)Cl>CO>[Br:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([N:12]([CH:13]([CH3:14])[CH3:15])[CH2:18][CH2:19][CH3:20])[CH2:7][C:6]=2[C:5]([O:16][CH3:17])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)c2c1C[C@@H](NC(C)C)CO2
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCN(C(C)C)[C@H]1COc2c(Br)ccc(OC)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
(R)-8-Bromo-3-(N-isopropylamino)-5-methoxy-3,4-dihydro-2H-1-benzopyran (3.8 g, 11.3 mmol) was dissolved in anhydrous methanol (80 mL) and to this was propanal (8.1 mL, 0.113 mol) added. The reaction was cooled (ice-bath) then sodium cyanoborohydride (1.3 g, 20.3 mmol) was added, the pH was adjusted to 5, and the reaction was allowed to stir at room temperature overnight. The solvent was removed in vacuo, the remains were twice with diethyl ether. The combined ether portions were treated with brine, dried (Na2SO4) filtered, and taken into a 1M solution of Na2CO3 and then extracted the solvent removed in vacuo to give the crude residue. Chromatography on silica (eluent: 7% ethyl acetate/hexane) gave 3.75 g (97% yield) of the title compound as a clear oil [α]21D =-82.5° (C=0.1 CHCl3). GC-MS (70 eV) M=343 (29%). The hydrochloride salt was made by dissolving the base in diethyl ether and dropping an excess of an ethereal HCl solution. The salt was recrystallized from ethanol/diethyl ether to give a white solid. Mp: 177°-9° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH2:17][CH:18]([NH:23][C:24]1[C:25]([CH3:39])=[C:26]3[C:30](=[CH:31][CH:32]=1)[N:29](C1CCCCO1)[N:28]=[CH:27]3)[CH2:19]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH2:8]([N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH2:17][CH:18]([NH:23][C:24]1[C:25]([CH3:39])=[C:26]3[C:30](=[CH:31][CH:32]=1)[NH:29][N:28]=[CH:27]3)[CH2:19]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(NC2CC3CCC(C2)N3Cc2ccccc2)ccc2c1cnn2C1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(NC2CC3CCC(C2)N3Cc2ccccc2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution of the N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine (273 mg, 0.634 mmol) obtained in Example 499 in dichloromethane (9 ml), and the resulting mixture was stirred at room temperature for 30 minutes. Then, trifluoroacetic acid (1 ml) was added thereto and stirred for another 30 minutes, and the resulting mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a preparative thin-layer chromatography (200×200×0.5 mm, 6 plates, eluent: chloroform/methanol=6/1) to obtain N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1H-indazol-5-amine (142 mg, 65%).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](O)=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:6]1(=[O:20])=[O:19])[CH2:2][CH2:3][CH3:4].CN(C=O)C.C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([Cl:29])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:6]1(=[O:20])=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCN1C(=O)C(O)=C(c2ccc(Cl)cc2)S1(=O)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C(Cl)=C(c2ccc(Cl)cc2)S1(=O)=O
Yield: 86.8 %

Procedure:
2-Butyl-5-(4-chlorophenyl)-4-hydroxyisothiazol-3(2H)-one 1,1-dioxide (0.9 g, ca. 60%, 1.71 mmol) was dissolved in DCM (50 mL). DMF (0.13 mL) was added. Under nitrogen atmosphere, oxalyl chloride (0.434 g, 3.42 mmol) was dropped in. The mixture was then heated to reflux for 2 h and then evaporated to dry. Water (30 mL) was added into the residue. It was then extracted with DCM (20 mL×3). The extracts were combined and washed with water (50 mL×3) and brine (20 mL), dried (MgSO4) and evaporated. The residue was then purified by column chromatography (ISOLUTE SI, 20 g/70 mL), eluting with DCM:heptane (25:75), to give the title compound (0.496 g, 87%); 1H NMR (400 MHz, CDCl3): δ 7.93 (d, 2H), 7.54 (d, 2H), 3.76 (t; 2H), 1.85-1.77 (m, 2H), 1.48-1.39 (m, 2H), 0.98 (t, 3H); 13C NMR (100 MHz, CDCl3): δ 155.8, 142.4, 139.0, 130.2, 129.9, 127.7, 121.8, 40.8, 30.2, 19.9, 13.4.
Reaction SMILES: CS(O)(=O)=O.C([O:13][C:14]1[CH:35]=[CH:34][C:17]([C:18]([O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31](=[NH:33])[NH2:32])[CH:27]=3)[CH:22]=2)=[O:19])=[CH:16][CH:15]=1)C1C=CC=CC=1>[Pd].CN(C=O)C>[OH:13][C:14]1[CH:35]=[CH:34][C:17]([C:18]([O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31](=[NH:32])[NH2:33])[CH:27]=3)[CH:22]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: N=C(N)c1ccc2cc(OC(=O)c3ccc(OCc4ccccc4)cc3)ccc2c1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CN(C)C=O
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(O)cc3)ccc2c1
Yield: 96.5 %

Procedure:
To 50 ml of anhydrous DMF, were added 4.0 g of 6-amidino-2-naphthyl 4-benzyloxybenzoate methanesulfonate and 0.4 g of 10% Pd-C. The mixture was subjected to catalytic hydrogenation. After absorption of a stoichiometric amount of hydrogen, the reaction mixture was removed of Pd-C by filtration. After adding ethylether to the stirred filtrate, the precipitate was collected by filtration and recrystallized from a DMF-ethylether mixture to obtain 2.4 g of a white powder of 6-amidino-2-naphthyl 4-hydroxybenzoate methanesulfonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[C@H:18]([NH:19][C:20]([C:22]3[S:23][C:24]4[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][C:29]=4[N:30]=3)=[O:21])[CH2:17][N:16]([S:32]([CH2:35][C:36]([O:38]C)=[O:37])(=[O:34])=[O:33])[CH2:15]1)=[O:12])=[CH:5]2.O.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[C@H:18]([NH:19][C:20]([C:22]3[S:23][C:24]4[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][C:29]=4[N:30]=3)=[O:21])[CH2:17][N:16]([S:32]([CH2:35][C:36]([OH:38])=[O:37])(=[O:34])=[O:33])[CH2:15]1)=[O:12])=[CH:5]2
Reactant: COC(=O)CS(=O)(=O)N1C[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCc2nc(C(=O)N[C@@H]3CN(S(=O)(=O)CC(=O)O)C[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reaction time: 4 h
Yield: 89.1 %

Procedure:
The compound (100 mg) obtained in Example 100 was dissolved in tetrahydrofuran (4 ml)-water (1 ml), and the mixture was cooled with ice. Lithium hydroxide monohydrate (7.8 mg) was added, and the resultant mixture was heated to room temperature and stirred for 4 hours. After the reaction mixture was neutralized with 1N hydrochloric acid, it was concentrated. Deposits were collected by filtration, washed with water and 50% ethanol and dried overnight at 50° C. under reduced pressure to obtain the title compound (87 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(O)cc1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Product: COc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C using 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-methoxyphenol: 1H NMR (300 MHz, CD3OD) δ 7.73 (d, J=9.0 Hz, 1H), 7.36 (d, J=2.3 Hz, 1H), 7.25 (dd, J=9.0 Hz, 2.5 Hz, 1H), 6.80 (app. s, 4H), 4.42 (q, J=8.9 Hz, 2H), 4.17 (t, J=5.1 Hz, 2H), 4.00 (t, J=5.1 Hz, 2H), 3.51 (s, 3H); MS (APCI) m/z 419 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)[CH3:3].C([Li])CCC.[F:19][C:20]([F:27])([F:26])[C:21](OCC)=[O:22]>O1CCCC1.CCOCC>[CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:21](=[O:22])[C:20]([F:27])([F:26])[F:19])=[CH:9][CH:8]=1)[CH3:3]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CN(C)CCOc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)CCOc1ccc(C(=O)C(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 39.5 %

Procedure:
To a solution of N,N-dimethyl-2-(4bromophenoxy)ethylamine (1.0 g, 4.1 mmol) in tetrahydrofuran (10 ml) at −78° C. was added dropwise n-butyllithium (1.5M in hexane, 2.7 ml, 4.1 mmol). The mixture was stirred at this temperature for 15 min. and then transferred via a cannula into a pre-cooled solution of ethyl trifluoroacetate (0.64 g, 4.5 mmol) in ether (8 ml) at −78° C. The resulting mixture was stirred and the temperature allowed to rise gradually to r.t. over a period of 1.5 h. The reaction mixture was then quenched with water (5 ml) and diluted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Bulb-to-bulb distillation (82-84° C./0.01 mmHg) afforded the title compound (423 mg, 39%) as a pale yellow oil. Analysis for C12H14F3NO2.0.3H2O calcd. C 54.05%, H 5.52%, N 5.25%; Found: C 54.12%, H 5.39%, N 5.28%.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][S:18][C:19]1[N:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=1>ClCCl>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][S:18]([C:19]1[N:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=1)=[O:9]
Reactant: Brc1cnc(SCc2cccs2)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(Cc1cccs1)c1ncc(Br)cn1
Reaction time: 18 h
Yield: 53 %

Procedure:
85% m-Chloroperbenzoic acid (1.5 mmol) was added to a solution of 2-(2-thienylmethylthio)-5-bromopyrimidine (1.5 mmol) in dichloromethane (25 ml) at -10° C. and the solution left at 0° C. for 18 h. The dichloromethane solution was then washed with saturated aqueous solutions of Na2SO and NaHCO3, and the dried (MgSO4) solution evaporated to leave the title compound; yield 53%, m.p. 108°-109° C. (iPrOH). 1H NMR (CDCl3) δ4.53 (CH2, 6.9 (H-3', H-4'), 7.16 (H-5'), 8.83 (H-4, H-6).
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][N:5]2[C:6](=[O:21])[C@@H:7]([CH2:11][C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][CH:13]=3)[NH:8][C:9](=[O:10])[C@@H:4]2[CH2:3]1.N1C=CN=C1.[C:28]([Si:32](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:31])([CH3:30])[CH3:29]>CN(C)C=O>[Si:32]([O:1][C@H:2]1[CH2:22][N:5]2[C:6](=[O:21])[C@@H:7]([CH2:11][C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][CH:13]=3)[NH:8][C:9](=[O:10])[C@@H:4]2[CH2:3]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1N[C@H](Cc2c[nH]c3ccccc23)C(=O)N2C[C@H](O)C[C@@H]12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](O[C@@H]1C[C@H]2C(=O)N[C@H](Cc3c[nH]c4ccccc34)C(=O)N2C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of (3R,7R,8aS)-7-hydroxy-3-(1H-indol-3-ylmethyl)-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (2.5 g) in dimethylformamide (30 mL) was added imidazole (1.7 g) and tert-butyl-chloro-diphenylsilane (4.35 mL). The resulting mixture was stirred overnight at room temperature and then partitioned between water and ethyl acetate. The organic layer was dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, EtOAc) to afford (3R,7R,8aS)-7-(tert-butyl-diphenylsilanyloxy)-3-(1H-indol-3-ylmethyl)-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (4.6 g, 99%) (intermediate 7).