Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[O:4][C:5]2[C:6](=[C:8]([C:20]#[N:21])[C:9]([CH3:19])=[C:10]([C:13]3[N:14]=[C:15]([CH3:18])[S:16][CH:17]=3)[C:11]=2F)[N:7]=1.C(N(CC)CC)C.[CH3:30][N:31]([CH3:37])[C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1>CS(C)=O.C(OCC)(=O)C>[CH3:1][N:2]([CH3:22])[C:3]1[O:4][C:5]2[C:6](=[C:8]([C:20]#[N:21])[C:9]([CH3:19])=[C:10]([C:13]3[N:14]=[C:15]([CH3:18])[S:16][CH:17]=3)[C:11]=2[N:34]2[CH2:35][CH2:36][C@H:32]([N:31]([CH3:37])[CH3:30])[CH2:33]2)[N:7]=1
Reactant: Cc1nc(-c2c(C)c(C#N)c3nc(N(C)C)oc3c2F)cs1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2c(C)c(C#N)c3nc(N(C)C)oc3c2N2CC[C@H](N(C)C)C2)cs1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
2-(Dimethylamino)-7-fluoro-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-1,3-benzoxazole-4-carbonitrile (I-171) (0.44 g, 1.39 mmol) was suspended in dimethyl sulfoxide (10 ml), then triethylamine (0.42 ml 3.03 mmol) and (3S)-3-(dimethylamino)pyrrolidine (0.38 ml, 3.00 mmol) were added, followed by stirring at an external temperature of about 110° C. for 4 hours. This was diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=50:1 to 10:1) to obtain a brown amorphous substance (0.51 g, 83%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[NH:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:8]=2[N:9]=1.F[B-](F)(F)F.[O:22]=[N+:23]=[O:24]>[N+](C)([O-])=O>[CH3:1][O:2][C:3](=[O:16])[NH:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([N+:23]([O-:24])=[O:22])=[C:10]([O:14][CH3:15])[C:8]=2[N:9]=1.[CH3:1][O:2][C:3](=[O:16])[NH:4][C:5]1[O:6][C:7]2[C:13]([N+:23]([O-:24])=[O:22])=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)cccc2o1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: C[N+](=O)[O-]
Product: COC(=O)Nc1nc2c(OC)c([N+](=O)[O-])ccc2o1
Product: COC(=O)Nc1nc2c(OC)ccc([N+](=O)[O-])c2o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32 %
Yield: 32 %

Procedure:
To a stirred solution of 780 mg (3.51 mmol) (4-methoxy-benzooxazol-2-yl)-carbamic acid methyl ester in 40 ml nitromethane at 0° C. was added 699 mg (5.27 mmol) nitronium tetrafluoroborate and stirring continued for 18 h while the reaction mixture was allowed to warm gradually to room temperature. The mixture was then concentrated in vacuo. Flash chromatography (ethyl acetate/hexane) afforded 300 mg (32%) (4-methoxy-5-nitro-benzooxazol-2-yl)-carbamic acid methyl ester as an orange solid, and 220 mg (32%) (4-methoxy-7-nitro-benzooxazol-2-yl)-carbamic acid methyl ester as a yellow solid. ES-MS m/e (%): 268 (M+H+, 100).
Reaction SMILES: [Mg].[I-].[Li+].[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Cl)=[CH:8][CH:7]=1.[CH:14]1[C:27]2[C:26]3([CH2:29][N:30]4[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]4)[CH2:28][CH:19]([C:20]4[C:25]3=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]=2[CH:17]=[CH:16][CH:15]=1>O1CCCC1.C(OCC)C>[CH:24]1[C:25]2[C:26]3([CH2:29][N:30]4[CH2:35][CH2:34][C:33]([CH2:10][C:9]5[CH:12]=[CH:13][C:6]([O:5][CH3:4])=[CH:7][CH:8]=5)([OH:36])[CH2:32][CH2:31]4)[CH2:28][CH:19]([C:18]4[C:27]3=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:20]=2[CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: COc1ccc(CCl)cc1
Agent: [I-]
Agent: [Li+]
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CC2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)cc1
Reaction time: 18 h
Yield: 68.1 %

Procedure:
Magnesium turnings (0.32 g, 1.32 mmol, 1.3 eq) were stirred in the absence of solvent for 15 min under nitrogen. Diethyl ether (20 mL) and catalytic lithium iodide were added, and the suspension was stirred vigorously for an additional 15 min at which time 4-methoxybenzyl chloride (1.08 mL, 7.0 mmol, 8 eq) was syringed into the reaction flask in portions. The reaction was refluxed for 3 h to assure Grignard formation and recooled to room temperature. 1-(9,10-Dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) (0.30 g, 1.00 mmol) was added dropwise as a tetrahydrofuran solution (25 mL). After stirring for 18 h, the reaction was quenched with water (10 mL). The aqueous phase was extracted with ethyl acetate (200 mL). The organic extract was washed with water (2×100 mL), dried with anhydrous sodium sulfate, filtered, and reduced to an oil. The reaction mixture was purified by flash chromatography over silica gel (25 mL, eluent: 20% ethyl acetate in hexane) to yield 0.29 g (69%) of the title compound as a white solid. 1H NMR (CDCl3, 300 MHz) 7.23 (m, 2H), 7.13 (m 4H), 6.88 (m, 6H), 4.25 (s, 1H), 3.78 (s, 3H), 3.41 (s, 2H), 2.76 (m, 2H), 2.66 (s, 2H), 2.57 (d, J=1.2 Hz, 2H), 2.52 (m, 2H), 1.67 (m, 2H), 1.47 (m, 2H), 1.57 (s, 1H) MS (CI, CH4) m/z 426 (M+1,100), 454 (M+29,13), 408 (20) The free base was dissolved in methanol and methylene chloride, acidified with ethereal HCl and the salt precipitated with ether dilution. The hydrochloride salt was filtered, rinsed with fresh ether, and dried in vacuo (50° C., 10 pascal, 18 h) to yield a white solid, mp 267°-268° C. (dec).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:29][CH2:30][CH:31]([N:34]6[CH2:35][CH2:36][O:37][CH2:38][CH2:39]6)[CH2:32][CH2:33]5)=[CH:24][CH:23]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: Brc1ccc(N2CCC(N3CCOCC3)CC2)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(N5CCC(N6CCOCC6)CC5)cc4)nc23)cc1

Procedure:
A round bottom flask equipped with a drying tube was charged with 4-piperidin-4-yl-morpholine (0.21 g, 1.2 mmol), cupric acetate (0.34 g, 1.9 mmol), 4-bromobenzeneboronic acid (0.50 g, 2.5 mmol), pyridine (0.20 mL, 2.5 mmol) and dichloromethane (5 mL, 80 mmol). The blue suspension was stirred open to the air for 6 days at room temperature. Water (25 mL) was added to the green-brown suspension and stirred for 10 minutes. The mixture was extracted with ethyl acetate (3×25 mL). The combined organic layer was washed with saturated aqueous sodium chloride (25 mL), dried over magnesium sulfate, filtered and evaporated. The residue was purified via chromatography using silica gel column (40 g) and 0%→8% methanol: dichloromethane solvent gradient. 4-[1-(4-Bromo-phenyl)-piperidin-4-yl]-morpholine was isolated as a tan solid (0.168 g, 41%). MP=146-149° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.32 (d, J=7.5 Hz, 2H), 6.79 (d, J=7.8 Hz, 2H), 3.76-3.71 (m, 4H), 3.68 (d, J=12.8 Hz, 2H), 2.71 (t, J=12.3 Hz, 2H), 2.60-2.54 (m, 4H), 2.37-2.27 (m, 1H), 1.93 (d, J=11.3 Hz, 2H), 1.69-1.58 (m, 2H). MS=325, 327 (MH)+. 49b) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (50.0 mg, 0.173 mmol) and 4-[1-(4-bromo-phenyl)-piperidin-4-yl]-morpholine (65.0 mg, 0.200 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (20.0 mg, 0.0366 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.044 g, 48%). MP=253-254° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (d, J=6.3 Hz, 1H), 8.23 (d, J=7.5 Hz, 2H), 8.08 (d, J=8.2 Hz, 2H), 7.63 (d, J=7.3 Hz, 1H), 7.47 (d, J=7.1 Hz, 2H), 7.01-6.95 (m, 3H), 6.68 (s, 1H), 3.77-3.72 (m, 4H), 3.69-3.62 (m, 2H), 3.10 (s, 3H), 2.74-2.65 (m, 2H), 2.62-2.57 (m, 4H), 2.36-2.28 (m, 1H), 1.98-1.92 (m, 2H), 1.75-1.63 (m, 2H). MS=533 (MH)+.
Reaction SMILES: Cl.[C:2](=[NH:10])([NH2:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.CCN(CC)CC.[Cl:18][C:19]([SH:22])(Cl)Cl.[OH-].[Na+]>C(Cl)Cl.O>[Cl:18][C:19]1[S:22][N:9]=[C:2]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[N:10]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)c1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1nc(-c2ccncc2)ns1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A mixture of isonicotinimidamide hydrochloride (1.0 g, 6.35 mmol) and NEt3 (3.21 g, 4.42 mL, 31.7 mmol) in 50 mL DCM was cooled to −5 and −10° C. Perchloromethyl mercaptan (1.3 g, 763 μl, 6.98 mmol) in 10 mL DCM was added drop wise over 1 h. The mixture was warmed to 0° C. over 30 min and stirred for 2 h. Water (50 mL) and 2M NaOH (10 mL) was added. The suspension was filtrated. The organic layer was extracted with DCM and washed with brine (50 mL) and the aqueous layer was extracted with DCM (50 mL). The organic layers were combined, dried over Na2SO4 and filtered off. The crude product was concentrated under vacuum and the residue dissolved in DCM, taken up on Isolute® and purified by column chromatography on silica eluting with a gradient formed from heptane and EtOAc to yield after evaporation of the product containing fraction 0.43 g (34%) of the title compound as a brown solid. MS (m/e): 198.1 (MH+).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:23]=[N:24][C:25]([O:29]C)=[C:26]([CH3:28])[CH:27]=5)[C:19]([CH3:31])=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:7][CH:8]=2)[CH2:3][O:2]1.[Si](I)(C)(C)C>C(#N)C.C(Cl)Cl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:31])=[C:20]([C:22]5[CH:27]=[C:26]([CH3:28])[C:25](=[O:29])[NH:24][CH:23]=5)[N:21]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:7][CH:8]=2)[CH2:3][O:2]1
Reactant: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)COC5)CC3)ccc2C)cc1C
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)COC4)CC2)nc1-c1c[nH]c(=O)c(C)c1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-(1,3-dihydroisobenzofuran-5-yl)-N-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (40 mg, 0.1 mmol) in acetonitrile (2 mL) was added TMS-Iodide (54.8 μL, 0.39 mmol). The reaction was stirred at 50° C. for 20 min. The reaction solution was diluted with CH2Cl2 and washed with saturated NaHSO3 (2×), brine, dried over MgSO4 and concentrated. The crude product was dissolved in DMSO (1 mL) and purified by reverse phase HPLC (10-99% CH3CN/water). ESI-MS m/z calc. 401.1. found 402.5 (M+1)+. Retention time 1.29 minutes.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[CH3:7][N:6]1[C:2]([C:21]2[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=2)=[C:3]([C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[N:4]=[CH:5]1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(C(F)(F)F)cc1
Yield: 93 %

Procedure:
The title compound was prepared in 93% yield from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-(trifluoromethyl)phenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C17H11F3N4, 329. Found, 329.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[CH2:5]([C@:7]12[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][C@H:8]1[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]3[C:18](=[CH:19][C:20]=12)[CH:17]=[N:16][N:15]3[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH3:6].[CH2:33]([C@@:35]12[CH2:59][CH2:58][C:57](=[O:60])[CH2:56][C@@H:36]1[CH2:37][CH2:38][CH2:39][C:40]1[CH:41]=[C:42]3[C:46](=[CH:47][C:48]=12)[CH:45]=[N:44][N:43]3[C:49]1[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=1)[CH3:34]>C1COCC1>[CH2:5]([C@:7]12[CH2:31][CH2:30][C@:29]([C:1]#[CH:2])([OH:32])[CH2:28][C@@H:8]1[CH2:9][CH2:10][CH2:11][C:12]1[C:20]2=[CH:19][C:18]2[CH:17]=[N:16][N:15]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:14]=2[CH:13]=1)[CH3:6].[CH2:33]([C@@:35]12[CH2:59][CH2:58][C@@:57]([C:1]#[CH:2])([OH:60])[CH2:56][C@H:36]1[CH2:37][CH2:38][CH2:39][C:40]1[C:48]2=[CH:47][C:46]2[CH:45]=[N:44][N:43]([C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=3)[C:42]=2[CH:41]=1)[CH3:34]
Reactant: CC[C@@]12CCC(=O)C[C@@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Reactant: CC[C@]12CCC(=O)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#C[C@@]1(O)CC[C@@]2(CC)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCC[C@@H]2C1
Product: C#C[C@]1(O)CC[C@]2(CC)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCC[C@H]2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
Ethynylmagnesium bromide (0.5 M solution in THF, 6.00 mL, 3.00 mmol) was added dropwise over about 15 min to a mixture of (4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazole-3 (2H)-one; compound with (4aS,12bS)-12b-ethyl-9-(4-fluorophenyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3 (2H)-one (9, R1=4-Fluorophenyl, R2=Ethyl) (0.200 g, 0.531 mmol) and THF (2.5 mL) under a nitrogen atmosphere at about 0° C. After about 90 min, the ice bath was removed and the solution was stirred at rt for about 1 h. Sat. aq. NH4Cl (10 mL) and water (10 mL) were added. The solution was extracted with DCM (2×20 mL). The combined organics were dried over Na2SO4 and filtered. Silica gel (2 g) was added and the organic volatiles were removed under reduced pressure. The resulting solid was purified on silica gel (12 g) using a gradient of 0-3% EtOAc in DCM. The fractions containing product were combined and concentrated under reduced pressure to afford (3R,4aR,12bR)-12b-ethyl-3-ethynyl-9-(4-fluorophenyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol; compound with (3S,4aS,12bS)-12b-ethyl-3-ethynyl-9-(4-fluorophenyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (11, R1=4-Fluorophenyl, R2=Ethyl, R3=Ethynyl) (0.116 g, 54% yield). LC/MS, method 2, Rt=2.78 min, MS m/z 403 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.26 (d, J=0.7 Hz, 1H), 7.91 (s, 1H), 7.83-7.76 (m, 2H), 7.55 (s, 1H), 7.45-7.36 (m, 2H), 5.48 (s, 1H), 3.24 (s, 1H), 3.22-3.11 (m, 1H), 2.98-2.88 (m, 1H), 2.32-2.23 (m, 1H), 2.20-1.48 (m, 11H), 1.41-1.26 (m, 1H), 0.37 (t, J=7.3 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([OH:10])=O)[N:6]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[O:28]=[C:29]1[N:36]2[C@H:31]([CH2:32][O:33][C:34]([CH:49]3[CH2:53][CH2:52][CH2:51][O:50]3)=[C:35]2[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=[O:38])[C@@H:30]1[NH:54]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C)C=O.N1C=CC=CC=1>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([NH:54][C@@H:30]2[C:29](=[O:28])[N:36]3[C@@H:31]2[CH2:32][O:33][C:34]([CH:49]2[CH2:53][CH2:52][CH2:51][O:50]2)=[C:35]3[C:37]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)=[O:38])=[O:10])[N:6]=1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Reactant: COc1ccc(COC(=O)C2=C(C3CCCO3)OC[C@@H]3[C@H](NC(c4ccccc4)(c4ccccc4)c4ccccc4)C(=O)N23)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(C3CCCO3)OC[C@H]12)c1csc(N)n1
Reaction time: 0.5 h
Yield: 107 %

Procedure:
A stirred mixture of 2-(Z)-methoxyimino-2-(2-aminothiazol-4-yl)acetic acid (III) (54 mg) and N,N-diisopropylethylamine (0.047 ml) in dimethylformamide (0.3 ml) was cooled to -55° to -60° C. and methanesulphonyl chloride (0.021 ml) was added. The mixture was stirred at the same temperature for 0.5 h and then a solution of 4-methoxybenzyl (6S,7S)-7-amino-8-oxo-3-(tetrahydrofuran-2-yl)-1-aza-4-oxabicyclo[4.2.0]oct-2-ene-2-carboxylate (II) (91 mg)in dimethylformamide (1 ml) was added, followed by pyridine (0.022 ml). The mixture was then stirred at 0° C. for 1 h and then at room temperature for 0.5 h. The mixture was partitioned between ethyl acetate and aqueous citric acid solution and the organic phase was washed twice with water, then brine, dried over magnesium sulphate and evaporated. Column chromatography (silica gel, ethyl acetate as eluent) gave the title compound (88 mg). νmax (CHCl3) 1769, 1709, 1679 and 1613 cm-1 ; δ(CDCl3) 1.72-2.12 (4H, m), 3.35 (3H, s), 3.68-3.96 (4H, m), 3.76 (3H, s), 4.64 (1H, dd, J 9.19 and 15.89 Hz), 5.13 (3H, s), 5.20 (1H, t, J 6.77 Hz), 5.72 (1H, dd, J 4.14 and 8.91 Hz), 6.80 (1H, s), 6.93 (2H, d, J 8.68 Hz), 7.24 (2H, s), 7.37 (2H, d, J 8.66 Hz), 9.23 (1H, d, J 9 Hz).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>>[CH:33]1([C:36]([NH:1][C@@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=5[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:37])[CH2:35][CH2:34]1
Reactant: O=C(Cl)C1CC1
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@@H](N)CC3)c[nH]c12
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@@H](NC(=O)C4CC4)CC3)c[nH]c12

Procedure:
Starting from cis-4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A183) and cyclopropanecarbonyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[O:8]1[CH2:14][CH2:13][C:12]([C:15](Cl)=[O:16])=[CH:11][C:10]2[CH:18]=[CH:19][CH:20]=[CH:21][C:9]1=2>O1CCCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:15]([C:12]1[CH2:13][CH2:14][O:8][C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[CH:11]=1)=[O:16]
Reactant: Nc1ccccn1
Reactant: O=C(Cl)C1=Cc2ccccc2OCC1
Solvent: C1CCOC1
Product: O=C(Nc1ccccn1)C1=Cc2ccccc2OCC1

Procedure:
10 ml of 2-aminopyridine were dissolved in 10 ml thetrahydrofurane. 2,3-Dihydro-benzo[b]oxepine-4-carbonylchloride (1.1 mmol) dissolved in 2 ml tetrahydrofurane were added dropwise. The reaction mixture was quenched by water and extracted with diethylether. The diethylether phase was washed by 1 mol/l sodiumhydroxide and dried over sodiumsulfate. Evaporation of the solvent yielded 230 mg of crude product which was purified by preparative HPLC (Chromolith prep. RP18, Solvent A water:acetonitrile 90:10+0.1% formic acid, solvent B: water:acetonitrile 10:90+0.1% formic acid, flow: t=0 min 25 ml/min, t=1 min 50 ml/min, gradient: t=0 min 10% B, t=1 min 10% B, t=2 min 10% B, t=2.2 min 20% B, t=7.5 min 50% B, t=7.6 min 100% B, t=8.5 min 100% B). Form this 85 mg of 2,3-Dihydro-benzo[b]oxepine-4-carboxylic acid pyridin-2-ylamide. LC-MS 1.6 min, 267.2 (MH+) 1H-NMR: (DMSO-d6, 500 MHz) d [ppm] 10.358 (s, 1H), 8.370 (m, 1H, J=1 Hz), 8.109 (m, 1H, J=4 Hz), 7.815 (m, 1H, J=2.4 Hz), 7.474 (m, 1H, J=2.3 Hz), 7.392 (s, 1H), 7.277 (m, 1H, J=1.7 Hz), 7.140 (m, 1H, J=1.9 Hz), 7.068 (m, 1H, J=3.2 Hz), 6.983 (m, 1H, J=1.9 Hz), 4.259 (m, 2H, J=3.1 Hz), 2.985 (m, 2H, J=2.6 Hz)
Reaction SMILES: CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:32]([N:39]([CH2:41][C:42]([OH:44])=O)[CH3:40])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].[NH2:45][C:46]1[C:55]([NH2:56])=[CH:54][CH:53]=[CH:52][C:47]=1[C:48]([O:50][CH3:51])=[O:49]>CN(C=O)C.O>[NH2:45][C:46]1[C:55]([NH:56][C:42](=[O:44])[CH2:41][N:39]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH3:40])=[CH:54][CH:53]=[CH:52][C:47]=1[C:48]([O:50][CH3:51])=[O:49]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(N)c1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(NC(=O)CN(C)C(=O)OC(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
First N-methyl-morpholine (4 eq.) and then HATU (2.0 eq.) was added to a solution of N-Boc-sarcosine (30.12 mmol, 1.0 eq.) in DMF (3 ml/mmol) at 0° C. The reaction mixture was stirred at room temperature for 15 min and then cooled again to 0° C. in order to add a solution of methyl 2,3-diaminobenzoate (30.12 mmol, 1.0 eq.) in DMF (1 ml/mmol). The reaction mixture was then stirred at room temperature for 16 h. For working up, the reaction mixture was diluted with water and extracted with ethyl acetate and the organic phase was washed with sat. NH4Cl solution, sat. NaHCO3 solution and sat. NaCl solution. The organic phase was dried over Na2SO4 and concentrated in vacuo in order to obtain the crude product. This was purified by a column chromatography (silica gel) to obtain the desired product. Yield: 60%
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH:37][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:29]
Reactant: NCc1ccccc1Cl
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccccc1Cl)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with 2-chlorobenzylamine (16 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was concentrated, the residue was suspended in water, and the solid was collected by vacuum filtration to afford 48 mg of the title compound as a colorless solid.
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=[O:6])C=1C#N)#N.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][C:25]2[S:40][C:28]3[N:29]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:30](=[O:35])[N:31]([CH3:34])[C:32](=[O:33])[C:27]=3[C:26]=2[C:41]([N:43]([O:45][CH3:46])[CH3:44])=[O:42])=[CH:16]1>C1COCC1.O>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]([C:25]2[S:40][C:28]3[N:29]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:30](=[O:35])[N:31]([CH3:34])[C:32](=[O:33])[C:27]=3[C:26]=2[C:41]([N:43]([O:45][CH3:46])[CH3:44])=[O:42])=[O:6])=[CH:16]1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: CON(C)C(=O)c1c(Cc2c[nH]c3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)c1c(C(=O)c2c[nH]c3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Reaction time: 2 h
Yield: 38.8 %

Procedure:
DDQ (0.25 g) was added to a stirred solution of the product of example 4 (0.25 g) in THF (9 ml) and water (1 ml). The solution was stirred for a further 2 h and the concentrated in vacuo. The residue was purified by flash silica chromatography eluting with ethyl acetate:isohexane (7:3) to give the title compound as a pale pink solid (0.1 g).