Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]N(C)C=O.P(Cl)(Cl)(Cl)=O.[C:11]1([NH:17][C:18]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)CCl>[CH3:27][O:26][C:24]([C:18]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:1][C:12]2[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:17]=1)=[O:25]
Reactant: COC(=O)C=C(Nc1ccccc1)C(=O)OC
Reactant: CN(C)C=O
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc2ccccc2nc1C(=O)OC
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of dimethylformamide (DMF, 0.10 mol) in ethylene dichloride (EDC, 100 mL), cooled in an ice bath, is added dropwise with stirring phosphorous oxychloride (POCl3, 0.10 mol). The resulting solution is stirred for one and one-half hours at room temperature and then cooled in an ice bath. To the cooled solution is then added, in small increments, a solution of dimethyl 3-phenylaminobut-2-ene-dioate (0.10 mol) in ethylene dichloride. The resulting mixture is thereafter heated to reflux for three hours, cooled, and washed with half saturated brine. The organic phase is washed with half saturated brine. The organic phase is separated from the aqueous phase and dried. The solvent is removed under vacuum, and the residue recrystallized from methanol to afford 18.2 g (0.074 mol) of dimethyl-2,3-quinolinedicarboxylate, mp 105°-106.5° C.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].ClOC(C)(C)C.ClNC1C(=CC=CC=1)C([O-])=O.[S:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl.C(N(CC)CC)C>[NH2:4][C:3]1[C:5]([CH:30]2[CH2:31][CH2:32][CH2:33][S:29]2)=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccccc1N
Reactant: C1CCSC1
Agent: CC(C)(C)OCl
Agent: O=C([O-])c1ccccc1NCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(C2CCCS2)c1N
Reaction time: 2 h

Procedure:
A solution of methyl anthranilate (75.5 g; 0.5 mole) in CH2Cl2 (1.0 l) is cooled to -70° and a solution of tert-butyl hypochlorite (54 g; 0.5 mole) in CH2Cl2 (150 ml) is added slowly keeping the temperature at -70°. The resultant N-chloroanthranilate solution is stirred for 1.0 hr and then tetrahydrothiophene (110 ml) is added at such a rate as to maintain the exotherm to less than 10°. The dark solution is stirred at -70° for 2.0 hr, triethylamine (125 ml) is added dropwise, and the solution is stirred for 24 hrs. The solvents are removed and the residue is diluted with CH2Cl2, washed with (1 N) NaOH solution, water and dried. Removal of solvents gives an oil. Unreacted methyl anthranilate is removed under reduced pressure (b.p. 95°-100°/0.35 mm) at bath temperature at 150°. The residue is dissolved in CH 2 Cl2 and partially chromatographed through silica gel. The solid residue is recrystallized from methanol. Yield 27.0 g; mp 75°-9°.
Reaction SMILES: [CH3:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2=[C:10]3[C:15](=[N:16][C:17]4=[CH:18][CH:19]=[CH:20][C:4](=[C:5]24)[O:3]1)[CH2:14][CH2:13][CH2:12][CH2:11]3.[CH3:21]C(C)([O-])C.[K+].CI>O1CCCC1>[CH3:21][N:7]1[C:6]2=[C:10]3[C:15](=[N:16][C:17]4=[CH:18][CH:19]=[CH:20][C:4](=[C:5]24)[O:3][CH:2]([CH3:1])[C:8]1=[O:9])[CH2:14][CH2:13][CH2:12][CH2:11]3
Reactant: CC(C)(C)[O-]
Reactant: CC1Oc2cccc3nc4c(c(c23)NC1=O)CCCC4
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1Oc2cccc3nc4c(c(c23)N(C)C1=O)CCCC4
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a suspension of 1,3,9,10,11,12-hexahydro-3-methyl-2H-quino[4,3,2-ef][1,4]-benzoxazepin-2-one (5.0 g) in dry tetrahydrofuran (150 ml) was added potassium t-butoxide (3.15 g), with stirring. After 15 mins, methyl iodide (1.39 ml) was added, and the reaction mixture was stirred at room temperature overnight. Additional methyl iodide (0.4 ml) was added. The reaction mixture was refluxed for two hrs, cooled, and concentrated. Saturated potassium carbonate solution was added and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was adhered to silica, and flash chromatographed (30-60% ethyl acetate/hexane). The appropriate fractions were concentrated, and the residue was triturated with diethyl ether to give 4.21 g (80%) of 1,3-dimethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([O:13][C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)=[N:10][C:9]([C:19]1[NH:23][C:22](=[O:24])[NH:21][N:20]=1)=[CH:8]2.CC1C=CC=C(C)N=1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>C(Cl)Cl>[C:33]([N:16]1[CH2:17][CH2:18][C@H:14]([O:13][C:11]2[C:12]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[Cl:2])[CH:8]=[C:9]([C:19]3[NH:23][C:22](=[O:24])[NH:21][N:20]=3)[N:10]=2)[CH2:15]1)(=[O:36])[CH:34]=[CH2:35]
Reactant: O=c1[nH]nc(-c2cc3cccc(Cl)c3c(O[C@H]3CCNC3)n2)[nH]1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3cccc(Cl)c23)C1
Temperature: -20 °C
Yield: 49.2 %

Procedure:
To (S)-3-(8-chloro-1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride (42.6 mg, 0.116 mmol) in DCM (25 mL) was added 2,6-dimethylpyridine (37.24 mg, 0.35 mmol). The resulting mixture was cooled to −20° C. Acryloyl chloride (26.1 mg, 0.29 mmol, 10 mg/mL in dry DCM) was added dropwise and the reaction mixture was warmed to 0° C. for 30 minutes. The reaction was quenched with MeOH (5 mL) and the mixture was concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (22.02 mg, 49.25%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.09 (s, 1H), 11.87 (s, 1H), 8.01-7.98 (m, 2H), 7.71-7.70 (d, J=4.0 Hz, 2H), 6.67-6.57 (m, 1H), 6.26-6.14 (m, 2H), 5.72-5.63 (m, 1H), 4.01-3.71 (m, 4H), 2.33-2.24 (m, 2H); ESI-MS m/z [M+H]+ 386.1.
Reaction SMILES: [OH-].[Na+].O.NN.[CH2:6]([O:13][C:14]1[C:19]([Br:20])=[CH:18][C:17]([C:21](=O)[CH3:22])=[C:16]([O:24][CH3:25])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)COCCOCCO>[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([O:24][CH3:25])[C:17]([CH2:21][CH3:22])=[CH:18][C:19]=1[Br:20])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1cc(OCc2ccccc2)c(Br)cc1C(C)=O
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: CCc1cc(Br)c(OCc2ccccc2)cc1OC
Temperature: 170 °C
Yield: 41.5 %

Procedure:
Sodium hydroxide (0.39 g, 9.7 mmol) and hydrazine monohydrate (0.57 mL, 11.7 mmol) were added to a solution of 1-(4-benzyloxy-5-bromo-2-methoxy-phenyl)-ethanone (1.3 g, 3.9 mmol) dissolved in triethylene glycol (5 mL). The reaction mixture was heated to 170° C. for 24 hours and then partitioned between 1N HCl and EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash silica gel chromatography (0% to 5% EtOAc in hexanes) to give the title compound (0.52 g, 40%). 1H NMR (400 MHz, CDCl3): δ 1.14 (t, J=7.3 Hz, 3H), 2.53 (q, J=7.3 Hz, 2H), 3.75 (s, 3H), 5.14 (s, 2H), 6.48 (s, 1H), 7.26 (s, 1H), 7.32 (m, 1H), 7.39 (m, 2H), 7.49 (d, J=8.3 Hz, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][C:12]2[CH:14]=[C:15]([O:18]C)[CH:16]=[CH:17][C:11]=2[C:10]=1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:24][CH:23]=1)=[O:21].C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][C:12]2[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=2[C:10]=1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)=[CH:24][CH:23]=1)=[O:21]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3OC)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccccc2O)sc2cc(O)ccc12
Yield: 48.5 %

Procedure:
By the method described in Example 2, the product of Example 9 (560 mg, 1.12 mmol), ethanethiol (0.42 mL, 5.77 mmol), and aluminum chloride (1.05 g, 7.88 mmol) were stirred in anhydrous CH2Cl2 (30 mL) to provide, after chromatography (silica gel, 5-10% methznol in CH2Cl2), 257 mg (49%) of the title product as a yellow foam: 1H NMR d 1.47 (m, 2H), 1.62 (m, 4H), 2.54 (m, 4H), 2.75 (t, J=5.4 Hz, 2H), 4.10 (t, J=5.4 Hz, 2H), 4.87 (br s, 2H), 6.64 (d, J=8.1 Hz, 1H), 6.72-6.85 (m, 4H), 7.02 (m, 1H), 7.25 (m, 2H), 7.47 (d, J=8.9 Hz, 1H), 7.67 (d, J=8.6 Hz, 2H); MS (FD) m/e 473 (M+); Anal. calc'd. for C28H27NO4S: C, 71.01; H, 5.75; N, 2.96. Found: C, 71.27; H, 5.82; N, 3.19.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].C(N(CC)CC)C.[OH:16][CH2:17][C:18]([CH3:35])([CH3:34])[C@@H:19]([O:26][Si:27]([CH3:33])([CH3:32])[C:28]([CH3:31])([CH3:30])[CH3:29])/[CH:20]=[CH:21]/[C:22]([O:24][CH3:25])=[O:23]>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:16][CH2:17][C:18]([CH3:35])([CH3:34])[C@@H:19]([O:26][Si:27]([CH3:33])([CH3:32])[C:28]([CH3:30])([CH3:29])[CH3:31])/[CH:20]=[CH:21]/[C:22]([O:24][CH3:25])=[O:23])(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)/C=C/[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)COS(=O)(=O)CCCCl
Yield: 84.3 %

Procedure:
Following the general procedure for the preparation of neopentyl sulfonylester intermediates of Description 10, 25.7 mL (37.4 g, 211.4 mmol) of 3-chloropropylsulfonyl chloride in 500 mL of anhydrous dichloromethane (DCM) in the presence of 25.8 g (211.4 mmol) of 4-(N,N-dimethylamino)pyridine (DMAP) and 29.5 mL (21.4 g, 211.4 mmol) of triethylamine (Et3N, TEA) was reacted at ca. 0° C. with 40.5 g (133.9 mmol) of methyl (2E)(4S)-6-hydroxy-5,5-dimethyl-4-(1,1,2,2-tetramethyl-1-silapropoxy)hex-2-enoate (4). After work-up and isolation, the crude material was purified by silica gel column chromatography using methyl tert-butyl ether (MTBE) and hexane (Hxn) mixtures (MTBE/Hxn=1:6→MTBE/Hxn=1:5→MTBE/Hxn=1:4) to provide 50.0 g (84% yield) of the title compound (15a) as a pale-yellow oil. Rf=0.46 (MTBE/Hxn=1:4). 1H NMR (400 MHz, CDCl3): δ=0.01 (s, 3H), 0.09 (s, 3H), 0.93 (s, 9H), 0.97 (s, 3H), 0.98 (s, 3H), 2.30-2.38 (m, 2H), 3.27-3.33 (m, 2H), 3.68-3.73 (m, 2H), 3.77 (s, 3H), 3.98 (d, J=9.6 Hz, 1H), 4.10 (d, J=9.2 Hz, 1H), 4.11 (dd, superimposed, J=6.4, 1.6 Hz, 1H), 5.97 (dd, J=15.6, 1.2 Hz, 1H), 6.90 (dd, J=15.6, 6.8 Hz, 1H) ppm. MS (ESI) m/z 442.9 (M+H)+, 464.9 (M+Na)+.
Reaction SMILES: [C:1]([C:4]1[N-:8][N:7]=[N:6][N:5]=1)(O)=[O:2].[K+].[CH3:10][NH:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH2:16][CH2:15]1>>[CH3:10][N:11]([CH2:12][CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=2)=[O:21])[CH2:18][CH2:19]1)[C:1]([C:4]1[N:8]=[N:7][NH:6][N:5]=1)=[O:2]
Reactant: O=C(O)c1nnn[n-]1
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: [K+]
Product: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)c1nn[nH]n1

Procedure:
The title compound was prepared from potassium 5-carboxytetrazol-1-ide and 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1 step 3) analogously to Example 16;
Reaction SMILES: [OH:1][C@H:2]([C:21]1[S:22][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][C:13]([C:16](OCC)=[O:17])=[CH:12][CH:11]=1.[Li+].[BH4-].Cl.O>C1COCC1>[OH:1][C@H:2]([C:21]1[S:22][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:11]=[CH:12][C:13]([CH2:16][OH:17])=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1ccc([C@H]2CC(=O)N(C)[C@H]2[C@H](O)c2ccc(-c3ccccc3)s2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)C[C@H](c2ccc(CO)cc2)[C@@H]1[C@H](O)c1ccc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.6 %

Procedure:
(±)-(4R*,5R*)-5-[(1S*)Hydroxy(5-phenyl(2-thienyl))methyl]-4-(4-(ethoxycarbonyl)-phenyl)-1-methylpyrrolidin-2-one (0.046 g, 0.106 mmol) was dissolved in THF (1 mL) under Ar. A solution of LiBH4 (2M in THF, 0.10 mL, 0.21 mmol) was added and the resulting mixture was stirred at room temperature for 18 h. Additional LiBH4 solution (0.5 mL, 1.0 mmol) was added and the reaction was stirred for 24 h. The reaction was treated with a 1M HCl solution, followed by water and the resulting mixture was extracted with EtOAc. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by HPLC to yield (±)-(4R*,5R*)-5-[(1S*)hydroxy(5-phenyl(2-thienyl))methyl]-4-[4-(hydroxymethyl)-phenyl]-1-methylpyrrolidin-2-one (9 mg, 20%) as a white solid: mp 205° C.; TLC (EtOAc)Rf 0.24.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].Cl[C:11]1[S:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[O:9][C:11]1[S:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: COC(=O)c1cc([N+](=O)[O-])c(Oc2c(Cl)cccc2Cl)s1

Procedure:
Prepared according to the procedure described for step A of example 18 from 2,6-dichloro-phenol (368 mg, 2.26 mmol) and methyl 5-chloro-4-nitro-thiophene-2-carboxylate (500 mg, 2.26 mmol). The title compound was obtained as a white solid (500 mg, 65% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.12 (1H, m), 7.80 (2H, m), 7.58 (1H, m), 3.80 (3H, s). MS m/z: 365.07, 367.00 [M+H]+.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[F:23][C:24]1[CH:25]=[C:26](O)[CH:27]=[CH:28][CH:29]=1>>[CH:10]([N:8]1[CH2:9][CH:6]([O:5][C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=2)[CH2:7]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1cccc(F)c1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Product: Fc1cccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1
Yield: 80.9 %

Procedure:
The title compound (D22) (1.93 g) was prepared according to the experimental procedure described in Description 21 starting from 1-benzhydrylazetidin-3-yl methanesulfonate (D19) (2.5 g, 7.87 mmol) and 3-fluorophenol (0.642 ml, 7.16 mmol).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:10]2[NH:14][CH2:13][CH:12]([CH2:15][CH3:16])[O:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].[CH:19]([N:22]=[C:23]=[O:24])([CH3:21])[CH3:20]>CC(C)=O>[F:18][C:2]([F:17])([F:1])[C:3]1[CH:4]=[C:5]([CH:10]2[N:14]([C:23](=[O:24])[NH:22][CH:19]([CH3:21])[CH3:20])[CH2:13][CH:12]([CH2:15][CH3:16])[O:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CC(C)N=C=O
Reactant: CCC1CNC(c2ccc(Cl)c(C(F)(F)F)c2)O1
Solvent: CC(C)=O
Product: CCC1CN(C(=O)NC(C)C)C(c2ccc(Cl)c(C(F)(F)F)c2)O1
Reaction time: 8 h

Procedure:
Four and six-tenths grams of 2-(3-trifluoromethyl-4-chlorophenyl)-5-ethyl-1,3-oxazolidine was combined with 1.5 g of isopropyl isocyanate in 25 ml of anhydrous acetone and allowed to stand overnight protected form moisture. The mixture was stripped on the rotary evaporator giving a gum. The structure was confirmed by NMR and infrared spectroscopy.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1)=[CH2:2].CS(C)=O.[C-:15]#[N:16].[K+]>O>[CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][C:15]#[N:16])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=Cc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 22.2 g 4-vinyl benzylchloride (0.131 mol), 60 mL dimethylsulfoxide, and 12.8 g potassium cyanide (0.196 mol) was stirred at room temperature for 17 hours. The mixture was poured into 500 mL water and extracted several times with ethyl acetate. The combined organic layers were washed with brine and concentrated under vacuum. The crude red oil was purified by column chromatography on silica gel using 7/93 ethyl acetate/hexane to give 4-vinylbenzylcyanide, a yellow oil (18.03 g, 96%).
Reaction SMILES: C(Cl)Cl.Cl[CH:5]1[NH:10][CH:9]=[CH:8][N:7]2[C:11]([CH:30]3[CH2:33][CH2:32][CH2:31]3)=[N:12][C:13]([C:14]3[CH:23]=[C:22]4[C:17]([N:18]=[CH:19][C:20]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:21]4)=[CH:16][CH:15]=3)=[C:6]12.[N:34]#N.N>CC(O)C>[CH:30]1([C:11]2[N:7]3[CH:8]=[CH:9][N:10]=[C:5]([NH2:34])[C:6]3=[C:13]([C:14]3[CH:23]=[C:22]4[C:17](=[CH:16][CH:15]=3)[N:18]=[CH:19][C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:21]4)[N:12]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: ClC1NC=Cn2c(C3CCC3)nc(-c3ccc4ncc(-c5ccccc5)nc4c3)c21
Reactant: N#N
Agent: N
Solvent: CC(C)O
Solvent: ClCCl
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc4ncc(-c5ccccc5)nc4c3)c12
Temperature: 100 °C

Procedure:
DCM solution of 7-(8-chloro-3-cyclobutyl-7,8-dihydroimidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoxaline (61 mg, 0.15 mmol) was evaporated to dryness by passing a stream of N2. The residue was suspended in anh. i-PrOH (4 mL) and the suspension was saturated with gaseous NH3 at 0° C. (2 min). The reaction vessel was sealed and heated to 100° C. (external temperature) for 63 h. Then the reaction was cooled to rt, concentrated under reduced pressure and purified by flash chromatography (silica gel, 0-5% MeOH in DCM) and then preparative TLC (4% MeOH in CH3CN) to afford the title compound as a light yellow solid; 1H NMR (400 MHz, CDCl3) δ 9.36 (d, J=4 Hz, 1H), 8.43 (s, 1H), 8.30-8.25 (m, 4H), 7.65-7.50 (m, 3H), 7.15 (m, 2H), 5.26 (br, 2H), 3.86 (quintet, J=8 Hz, 1H), 2.75-2.60 (m, 2H), 2.60-2.45 (m, 2H), 2.20 (q, J=8 Hz, 1H), 2.07 (br, 1H). MS (ES+): m/z 393.1 (100) [MH+]; HPLC: tR=2.30 min (OpenLynx, polar—5 min).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:28]([F:31])([F:30])[F:29])=[N:19][C:20]([C:21](=[O:27])[NH:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:23]([NH:22][C:21]([C:20]1[N:19]=[C:18]([C:28]([F:29])([F:30])[F:31])[N:15]2[CH2:16][CH2:17][N:12]([C:10](=[O:11])[CH2:9][C@H:8]([NH2:7])[CH2:32][C:33]3[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=3[F:41])[CH2:13][C:14]=12)=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
(R)-[3-(1-Butylcarbamoyl-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 43a (120 mg, 0.198 mmol) was dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (452 mg, 3.97 mmol) was then added to the solution. The reaction mixture was stirred at room temperature for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid butylamide 43 (70 mg, yield 70%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]([NH2:17])=[O:16])[C:5]([Cl:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:32]=[CH:31][C:23]2[N:24]([CH3:30])[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][C:22]=2[CH:21]=1.Cl>CC(O)C.O1CCOCC1>[Cl:18][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]([NH2:17])=[O:16])=[N:7][C:2]([NH:19][C:20]2[CH:32]=[CH:31][C:23]3[N:24]([CH3:30])[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][C:22]=3[CH:21]=2)=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CN1C(=O)CCCc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4C(N)=O)n3)ccc21
Yield: 82.2 %

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-trans-cyclohexanecarboxylic acid amide (50.1 mg, 0.173 mmol) and 7-amino-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (35.9 mg, 0.190 mmol) were slurried in iPrOH (2.0 mL) prior to adding ˜0.2 mL of 4N HCl in dioxane. This mixture was heated in a microwave reactor (sealed vessel) at 120° C. for 50 min. After quenching with saturated aqueous NaHCO3 solution (2 mL), the resulting precipitate was collected by filtration, successively washed with iPrOH (1×1 mL), water (4×2 mL) and ether (2×2 mL) to afford product (63 mg, 82%) as a white powder that had the following properties: m.p.=280-283° C.; LC/MS (ESI+): 443 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 9.25 (s, 1H), 7.92 (s, 1H), 7.77 (s, 1H), 7.55 (d, 1H, J=8.6), 7.17 (d, 1H, J=8.3), 7.06 (s, 1H), 6.77 (s, 1H), 6.56 (d, 1H, J=8.6), 4.17 (m, 1H), 3.19 (s, 3H), 2.65 (m, 2H), 2.41 (m, 1H), 2.16 (m, 2H), 2.04 (m, 3H), 1.90-1.65 (m, 3H), 1.45 (m, 1H), 1.40-1.15 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[O:6].[H-].[Na+].I[CH3:23]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])[CH3:23])=[O:6]
Reactant: COc1ccccc1NC(=O)c1ccc(Cl)c(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1N(C)C(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.8 %

Procedure:
To 3-bromo-4-chloro-N-(2-methoxy-phenyl)-benzamide (13.5 g, 39 mmol) in DMF (100 mL) at 0-5° C., was added NaH (1.9 g, 46.8 mmol, 60% in mineral oil) in several portions, followed by addition of iodomethane (3.15 mL, 50.7 mmol). The mixture was stirred at room temperature for 4 hrs and was partitioned between ethyl acetate and water. The organic layer was then washed with 1N HCl, saturated NaHCO3, brine and dried over MgSO4. Filtration over a silica gel pad followed by concentration and crystallization from ether/hexane yielded 3-bromo-4-chloro-N-(2-methoxy-phenyl)-N-methyl-benzamide (10.9 g) as a white solid. MS (M+H)+: 353.9, tR=2.812 min (method 1); NMR (CDCl3), δ, 7.62 (1H, d, J=1.5 Hz), 7.23-7.09 (3H, m), 7.06-7.00 (1H, m), 6.88-6.78 (2H, m), 3.75 (3H, s), 3.34 (3H, s)
Reaction SMILES: [N:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.Cl[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[CH3:19]>C(O)(C)C>[CH3:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[NH:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nn1ccc2ccccc21
Reactant: Cc1cnccc1Cl
Agent: Cl
Solvent: CC(C)O
Product: Cc1cnccc1Nn1ccc2ccccc21

Procedure:
The title compound was prepared from 1H-indol-1-amine and 4-chloro-3-methylpyridine hydrochloride in isopropanol at 90° C. for 6 hours in substantially the same manner as in Example 1, m.p. 78°-80° C.