Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:54]1[CH:59]=[CH:58][N:57]=[CH:56][C:55]=1[C:60](Cl)=[O:61]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:60]([C:55]2[CH:56]=[N:57][CH:58]=[CH:59][N:54]=2)=[O:61])[CH2:51][CH2:52]1
Reactant: O=C(Cl)c1cnccn1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cnccn1)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 50 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and pyrazine-2-carbonyl chloride as the starting materials in 50% yield. LCMS for C29H30ClN8O2 (M+H)+: m/z=557.0.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.[CH3:26][O:27][CH2:28][C@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>CS(C)=O>[CH3:26][O:27][CH2:28][C@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC[C@H]1CCCN1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1CCCN1c1nc2cc(C(=O)OC)ccc2[nH]c1=O
Temperature: 75 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (600 mg, 2.51 mmol) in DMSO (8 mL) was added DIEA (650 mg, 5.03 mmol), and (2R)-2-(methoxymethyl)pyrrolidine (318 mg, 2.76 mmol). The solution was stirred for 4 h at 75° C. Then the reaction was quenched by the addition of water (50 mL) to give the precipitate, which was collected by filtration to afford methyl 3-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a gray solid (650 mg, 81%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH2:18])[CH:12]2[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[CH3:20][C:21]1[CH:22]=[N+:23]([O-])[C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH:12]2[CH2:13][C:14]([CH3:16])([CH3:17])[CH2:15]2)[NH:18][C:22]2[C:21]([CH3:20])=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C(N)C2CC(C)(C)C2)cc1
Reactant: Cc1cc2ccccc2[n+]([O-])c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(C(Nc2nc3ccccc3cc2C)C2CC(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 28 h
Yield: 64.3 %

Procedure:
(+/−)-4-[amino-(3,3-dimethyl-cyclobutyl)-methyl]-benzoic acid ethyl ester (Intermediate 24) (45 mg, 0.17 mmol) was combined with 3-methylquinoline-N-oxide (27.4 mg, 0.172 mmol, Alfa Aesar, Ward Hill, Mass., USA) and dichloromethane (2 mL). Diisopropylethylamine (0.112 mL, 0.645 mmol) was added followed by bromotripyrrolidinophosphonium hexafluorophosphate (109 mg, 0.224 mmol). The solution was stirred at room temperature for 28 h before partitioning between ethyl acetate and aq. sat. NaHCO3. The separated aqueous layer was extracted with additional ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave (+/−)-4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoic acid ethyl ester (44.0 mg) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=8.4 Hz, 2H) 7.56-7.62 (m, 2H) 7.46-7.53 (m, 3H) 7.38-7.46 (m, 1H) 7.12-7.20 (m, 1H) 5.33 (dd, J=9.5, 6.7 Hz, 1H) 4.77 (d, J=6.6 Hz, 1H) 4.34 (q, J=7.2 Hz, 2H) 2.67 (sxt, J=8.8 Hz, 1H) 2.30 (s, 3H) 1.97 (ddd, J=11.1, 8.1, 3.2 Hz, 1H) 1.74-1.85 (m, 1H) 1.66-1.73 (m, 2H) 1.36 (t, J=7.1 Hz, 3H) 1.16 (s, 3H) 1.10 (s, 3H); MS (M+1): 403.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:27][OH:28])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:29](Cl)([CH3:32])(=[O:31])=[O:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@@H:12]([CH2:27][O:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=2)=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cccc(NC(=O)[C@H](CO)NS(=O)(=O)c2ccc(Cl)cc2)c1
Product: CCOC(=O)c1cccc(NC(=O)[C@H](COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
The procedure described in Example 65 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-hydroxypropanamide (1.38 g) was reacted with mesyl chloride to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (915 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:15]1[CH:20]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[C:18]([N+:25]([O-:27])=[O:26])=[CH:17][N:16]=1.O>CS(C)=O>[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([O:21][CH:22]([CH3:23])[CH3:24])[C:18]([N+:25]([O-:27])=[O:26])=[CH:17][N:16]=2)[CH2:10][CH2:9]1
Reactant: CC(C)Oc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1cc(N2CCN(C)CC2)ncc1[N+](=O)[O-]
Temperature: 105 °C
Yield: 92.9 %

Procedure:
383 mg of potassium carbonate and 185 mg of 1-methylpiperazine are added to a solution of 400 mg of 2-chloro-5-nitro-4-(propan-2-yloxy)pyridine in 3.7 ml of DMSO. The reaction medium is heated for 1 hour at 105° C. After cooling, the mixture is run into water, extracted with ethyl acetate, washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is taken up in diisopropyl ether, and the insoluble material is filtered off and dried under vacuum, so as to give 481 mg of 1-methyl-4-[5-nitro-4-(propan-2-yloxy)pyridin-2-yl]piperazine in the form of an orangey-coloured solid.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[H-].[Na+].C([Li])CCC.[C:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CCCCCC.O1CCCC1>[CH2:17]([C:16]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:22][C:1](=[O:6])[CH:2]=[CH:3][CH2:5]1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC(=O)c1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCC1(c2ccccc2)CC=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 1 using 10 mmol of methyl acetoacetate, 11 mmol of NaH 60% dispersion in oil, 10.5 mmol of 1.6M n-butyl lithium in hexane, 10 mmol of hexanophenone and 28 mL of tetrahydrofuran. Upon concentrating the reaction a solid precipitated out which was triturated with ether and filtered (m.p. 123°-124° C.). 1H NMR (CDCl3) δ0.83 (t, 3H), 1.1-1.4 (m, 6H), 1.9-2.0 (m, 2H), 2.90 (d, 1H), 2.92 (d, 1H), 3.25 (d, 1H), 3.35 (d, 1H), 7.2-7.5 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH:17]3[CH2:22][CH2:21][Si:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[F:8].[H][H]>C(OCC)(=O)C.[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C@H:11]2[CH2:12][CH2:13][C@H:14]([CH:17]3[CH2:18][CH2:19][Si:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:21][CH2:22]3)[CH2:15][CH2:16]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [H][H]
Reactant: CCCCC[Si]1(c2ccccc2)CCC([C@H]2CC[C@H](C=Cc3ccc(F)c(F)c3)CC2)CC1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCCCC[Si]1(c2ccccc2)CCC([C@H]2CC[C@H](CCc3ccc(F)c(F)c3)CC2)CC1

Procedure:
40.0 g of the thus obtained 4-(trans-4-(2-(3,4-difluorophenyl)ethenyl)cyclohexyl)-1-n-pentyl-1-phenyl-1-silacyclohexane was dissolved in 200 ml of ethyl acetate and hydrogenated in the presence of 200 mg of platinum oxide at a pressure of 0.1 MPa of hydrogen. After theoretical consumption of hydrogen, the catalyst was removed by filtration and the resultant filtrate was concentrated to obtain 40.2 g of 4-(trans-4-(2-(3,4-difluorophenyl)ethyl)cyclohexyl)-1-n-pentyl-1-phenyl-1-silacyclohexane. The results of IR analysis of the product are as follows.
Reaction SMILES: S(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)=[CH:16][CH:15]=2)[CH:8]=1)(=O)(=O)C.[C-:32]#[N:33].[Na+]>CS(C)=O>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:9]2[CH:8]=[C:7]([CH2:6][C:32]#[N:33])[CH:12]=[CH:11][CH:10]=2)=[CH:19][CH:18]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCc1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1

Procedure:
3-(4-(2-Quinolinylmethyloxy)benzyl)benzyl alcohol mesylate (0.0018 mol) with sodium cyanide (0.0036 mol) in dimethylsulfoxide (10 ml) is stirred at ambient temperature. After the consumption of sulfate, the reaction is diluted with water and extracted with ethyl acetate. The organic extracts are dried and evaporated to give 3-(4-(2-quinolinylmethyloxy)benzyl)phenylacetonitrile.
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])([CH3:5])[CH3:4].Br[CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=1.[Br-].[Na+]>COCCOC>[CH:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24][CH3:25])=[CH:22][CH:23]=1)([CH3:5])[CH3:4]
Reactant: CC(C)OCCCCO
Reactant: CSc1ccc(OCCCCBr)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1ccc(OCCCCOCCCCOC(C)C)cc1
Reaction time: 6 h

Procedure:
0.320 g (7.35 millimols) of 55% sodium hydride dispersion in oil are added by portions, over the course of 15 minutes and while stirring, to 1.02 g (7.7 millimols) of 4-isopropoxybutanol and 1.82 g (7.0 millimols) of 1-(4-bromo-butyloxy)-4-(methylthio)-benzene in 20 cc of absolute 1,2-dimethoxy ethane. The mixture is stirred at 20° for 18 hours and subsequently at 60° for 6 hours. The resulting sodium bromide is suction filtered, washed with ether and the filtrate is evaporated. After chromatography of the residue on silica gel with hexane/ethyl acetate (97:3) and (95:5), 1-[4-(4-isopropoxy-butyloxy)-butyloxy]-4-(methylthio)-benzene is obtained as a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[CH2:8][C@H:7]1[C:12]([OH:14])=O)=[O:5])[CH3:2].Cl.[NH2:16][C:17]1([C:20]#[N:21])[CH2:19][CH2:18]1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[CH2:8][C@H:7]1[C:12](=[O:14])[NH:16][C:17]1([C:20]#[N:21])[CH2:19][CH2:18]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(=O)C[C@H]1C(=O)O
Reactant: N#CC1(N)CC1
Agent: Cl
Product: CCOC(=O)[C@@H]1CC(=O)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
The reaction of (1R,2R)-4-oxo-cyclopentane-1,2-dicarboxylic acid monoethyl ester and 1-amino-cyclopropanecarbonitrile hydrochloride performed in analogy to example 1, step 8 yielded the title compound as a colorless solid. MS: 265.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:24])[CH2:9][C:10]([N:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][O:14][C:13]2=[O:23])=[O:11])=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].CC(C1C=C(C(C)C)C(S([N:50]=[N+:51]=[N-:52])(=O)=O)=C(C(C)C)C=1)C.C(O)(=O)C.C([O-])(=O)C.[K+]>C1COCC1>[N:50]([C@@H:9]([C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH3:24])[C:10]([N:12]1[C@@H:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][O:14][C:13]1=[O:23])=[O:11])=[N+:51]=[N-:52]
Reactant: C[C@H](CC(=O)N1C(=O)OC[C@@H]1c1ccccc1)c1ccc(F)cc1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(F)cc1)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of the product from Step B (1.18 g, 3.61 mmol) in anhydrous THF (40 mL) was added potassium hexamethyldisilazide (8.7 mL, 0.5M in toluene, 4.35 mmol) at −78° C. The resultant mixture was stirred at −78° C. for 30 min. A precooled solution of trisyl azide (1.56 g, 5.04 mmol) in THF (30 mL) was added via cannula. After 1.5 min the reaction was quenched with glacial acetic acid (0.95 mL, 16.6 mmol) and potassium acetate (1.77 g, 18.1 mmol). The cooling bath was removed, and the reaction was stirred at room temperature for 12 h. The solution was partitioned between ethyl acetate and brine. The aqueous phase was extracted with three portions of ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, and evaporated in vacuo. Purification by flash chromatography (silica gel, 80:20 hexanes/ethyl acetate) afforded the desired product.
Reaction SMILES: I[CH2:2][CH3:3].[F:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:2]([NH:9][C:8]1[CH:10]=[CH:11][C:5]([F:4])=[CH:6][CH:7]=1)[CH3:3]
Reactant: CCI
Reactant: Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNc1ccc(F)cc1
Reaction time: 18.5 h

Procedure:
Iodoethane (3.6 ml) was added to a mixture of 4-fluoroaniline (4.26 ml) and potassium carbonate (6.9 g) in dry DMF (100 ml). After 18.5 h at 23°, the resulting suspension was poured into water (400 ml) and extracted with EA (400 ml). The organic extract was washed with water (200 ml) then saturated brine (200 ml), dried and evaporated. The residual oil was chromatographed with 2 to 3 to 4% EA in hexane as eluent to give the title compound (3.667 g) as a yellow oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].N1C=CC=CC=1.Cl.Cl.[F:16][C:17]1[CH:18]=[C:19]([NH:28][C:29]([C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)=[O:30])[CH:20]=[CH:21][C:22]=1[CH:23]1[CH2:27][CH2:26][CH2:25][NH:24]1>C(Cl)(Cl)Cl>[C:1]([N:24]1[CH2:25][CH2:26][CH2:27][CH:23]1[C:22]1[CH:21]=[CH:20][C:19]([NH:28][C:29]([C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)=[O:30])=[CH:18][C:17]=1[F:16])(=[O:3])[CH3:2]
Reactant: O=C(Nc1ccc(C2CCCN2)c(F)c1)c1cnccn1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCCC1c1ccc(NC(=O)c2cnccn2)cc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1.5 ml of acetic anhydride was added to a pyridine (50 ml) solution of 4.3 g of N-(3-fluoro-4-pyrrolidin-2-ylphenyl)pyrazine-2-carboxamide dihydrochloride, and the reaction liquid was stirred at room temperature for 20 minutes. The reaction liquid was diluted with chloroform, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=50/1) to obtain the entitled compound as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH:17]([C:19]1[NH:20][C:21]([CH3:27])=[CH:22][C:23]=1[C:24]([OH:26])=[O:25])=O>>[CH3:27][C:21]1[NH:20][C:19]([CH:17]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])=[C:23]([C:24]([OH:26])=[O:25])[CH:22]=1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Product: Cc1cc(C(=O)O)c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)[nH]1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH:24]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH2:25].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2](/[CH:25]=[CH:24]/[S:26]([CH3:29])(=[O:28])=[O:27])=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: C=CS(C)(=O)=O
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(/C=C/S(C)(=O)=O)cc1-2
Yield: 73.1 %

Procedure:
A mixture of 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 (0.36 g, 0.92 mmol), methyl vinyl sulfone (0.24 mL, 2.8 mmol), bis(triphenylphosphine)palladium(II) chloride (64 mg, 0.092 mmol) and triethylamine (0.64 mL, 4.6 mmol) in DMF (10 mL) was heated under an argon atmosphere for 16 h. The reaction mixture was concentrated and purified by column chromatography (40 g column, 0-100% EtOAc/heptane) to provide 280 mg (73% yield) of 143. LC/MS (ESI+): m/z 417 (M+H). 1H NMR (400 MHz, DMSO) δ 8.59 (d, J=2.0, 1H), 8.11 (s, 1H), 7.71 (dd, J=8.4, 2.1, 1H), 7.59-7.26 (m, 2H), 7.17 (d, J=8.4, 1H), 5.88-5.67 (m, 1H), 4.43 (t, J=4.8, 2H), 3.48 (dd, J=12.3, 7.5, 2H), 3.12 (s, 1H), 1.58 (d, J=6.6, 6H)
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[CH2:20]([O:12][C:5]1[CH:4]=[C:3]([O:13][CH2:7][C:6]2[CH:11]=[CH:2][CH:3]=[CH:4][CH:5]=2)[C:2]([Br:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(Br)c(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
7.86 kg of methyl 5-bromo-2,4-dihydroxybenzoate and 9.65 kg of potassium carbonate are suspended in 100 l of acetonitrile at 0° C. The mixture is subsequently heated to 80° C., and 7575 ml of benzyl bromide are added via a dropping funnel over a period of 40 min. After stirring overnight at 80° C., the mixture is filtered, and the collected filtrate is evaporated in vacuo: 12.95 kg (95%) of methyl 2,4-bisbenzyloxy-5-bromobenzoate (slightly yellow crystals); MW 427.3.
Reaction SMILES: [C:1]([O:7]C)(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[H-].[Na+].CO.[C:13](#[N:16])[CH2:14][CH3:15]>C1(C)C=CC=CC=1>[CH3:15][CH:14]([C:1](=[O:7])[C:2]([CH3:5])([CH3:4])[CH3:3])[C:13]#[N:16]
Reactant: CCC#N
Reactant: COC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C#N)C(=O)C(C)(C)C

Procedure:
234.6 grams (2 moles) of methyl pivalate and 120 grams (2 moles) of sodium hydride (80 weight % suspension in white oil) were heated to 90° C. in 1500 ml of dry toluene. There were dropped in at this temperature after addition of 1 ml of methanol 233.3 grams (2 moles) of propionitrile within 2.5 hours. After the end of the development of hydrogen the suspension was extracted with a total of 1200 ml of water and after phase separation the aqueous phase was acidified with concentrated HCl to a pH of 2. The deposited oil was separated off, the water phase extracted with chloroform, the organic extracts combined, dried and concentrated. The residue was fractionated in a water jet vacuum. 2,4,4-trimethyl-3-oxopentanenitrile came over at 87° C./11 Torr in an amount of 226.1 grams (81.2% of theory).
Reaction SMILES: [ClH:1].[CH2:2]([N:9]1[C:16](=[O:17])[C@@H:15]2[C@@H:11]([CH2:12][N:13](CC3C=CC=CC=3)[CH2:14]2)[C:10]1=[O:25])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N#N>CO.O.[Pd]>[ClH:1].[CH2:2]([N:9]1[C:10](=[O:25])[C@@H:11]2[C@@H:15]([CH2:14][NH:13][CH2:12]2)[C:16]1=[O:17])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1[C@H]2CN(Cc3ccccc3)C[C@H]2C(=O)N1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Agent: N#N
Solvent: CO
Solvent: O
Product: O=C1[C@H]2CNC[C@H]2C(=O)N1Cc1ccccc1
Reaction time: 12 h
Yield: 82 %

Procedure:
Concentrated hydrochloric acid (28.4 mL, 341 mmol) was added to a suspension of 3,7-dibenzyl-3,7-diazabicyclo[3.3.0]octan-2,4-dione (109.0 g, 341 mmol; from step (a) above) in CH3OH under a N2 atmosphere. To the resulting solution there was added 10% Pd/C (w/w; 5 g). The N2 atmosphere was exchanged for H2 (1 atm of pressure) and the reaction was stirred for 12 h. The reaction was diluted with H2O (160 mL), filtered through a pad of cellulose to remove the catalyst and the filtrate concentrated in vacuo to afford a solid. Triturating with absolute EtOH afforded 74.6 g (82%) of the sub-title compound as an off-white solid after drying in a vacuum oven at 50° C./66.5 Pa (0.5 mm Hg).
Reaction SMILES: [CH3:1]C1(C)[C@@H]2O[C@@H]2C2C=C(C#N)C=CC=2O1.[C:16]([C:18]1[CH:19]=[CH:20][C:21]2[O:26][C:25]([CH3:28])([CH3:27])[C@H:24]([OH:29])[C@@H:23]([N:30]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=O)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:22]=2[CH:43]=1)#[N:17]>CO>[O:40]1[CH:41]=[CH:42][CH:1]=[C:38]1[CH2:37][N:30]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C@H:23]1[C:22]2[CH:43]=[C:18]([C:16]#[N:17])[CH:19]=[CH:20][C:21]=2[O:26][C:25]([CH3:28])([CH3:27])[C@@H:24]1[OH:29]
Reactant: CCOC(=O)CN(c1ccccc1)[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@H]2O[C@H]21
Solvent: CO
Product: CC1(C)Oc2ccc(C#N)cc2[C@H](N(Cc2ccco2)c2ccccc2)[C@H]1O

Procedure:
The title compound was prepared from (1aR-cis)-1a,7b-dihydro-2,2-dimethyl-2H-oxireno-[c][1]benzopyran-6-carbonitrile (the title A compound of Example 3) and the title A compound by the same procedure as described for the title compound of Example 1. The product was obtained as a colorless solid (1.07 g, 72%), mp 134°-135° C. [α]D =+92.20° (c=0.78, MeOH). Analysis calculated for C23H22N2O3 · 0.02 H2O: C, 73.70; H, 5.93; N, 7.47. Found: C, 73.65; H, 5.63; N, 7.52.