Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:24][CH:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:14](=[O:34])[N:13]1[CH:9]([CH2:10][CH:11]([OH:35])[CH2:12]1)[C:8](=[O:36])[NH:7]2)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.[CH2:46]([O:48][CH2:49]Cl)[CH3:47]>ClCCl>[CH2:1]([O:3][C:4]([C:6]12[CH2:24][CH:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:14](=[O:34])[N:13]1[CH:9]([CH2:10][CH:11]([O:35][CH2:49][O:48][CH2:46][CH3:47])[CH2:12]1)[C:8](=[O:36])[NH:7]2)=[O:5])[CH3:2]
Reactant: CCOCCl
Reactant: CCOC(=O)C12CC1C=CCCCCCN(Cc1ccc(OC)cc1)C(=O)N1CC(O)CC1C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOCOC1CC2C(=O)NC3(C(=O)OCC)CC3C=CCCCCCN(Cc3ccc(OC)cc3)C(=O)N2C1
Temperature: 25 °C

Procedure:
To a stirred solution of the alcohol 27 (1.35 g, 2.70 mmol, 75% purity) and N-ethyl-diisopropylamine (1.42 ml, 8.1 mmol) in dichloromethane (15 ml) at 0° C. was added chloromethyl ethyl ether (0.5 ml, 5.4 mmol). After stirring at rt on the reaction mixture was cooled to 0° C. and more N-ethyldiisopropylamine (1 ml, 5.7 mmol) and chloromethyl ethyl ether (0.3 ml, 3.2 mmol) was added, then stirred additional 16 h at rt. The reaction mixture was then directly applied on a silicagel column and eluted using stepwise gradient elution (ethyl acetate in hexane 50-80%). Concentration of the appropriate fractions gave the title compound as a slight brown syrup which crystallized upon standing (0.8 g, 53%). LR-MS: Calcd for C30H44N3O7: 558. Found: 558 [M+H].
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6](C(OC(C)CC)=O)[C:7]3[C:8]([N:24]=2)=[N:9][CH:10]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]4[O:22][CH2:21][CH2:20][NH:19][CH2:18][C:17]=4[CH:23]=2)[CH:12]=3)[CH2:4][CH2:3]1.Cl[C:33]1[C:38]([CH2:39][CH:40]2[CH2:42][CH2:41]2)=[C:37]([CH3:43])[N:36]=[C:35]([CH3:44])[N:34]=1>>[CH:2]1([C:5]2[NH:6][C:7]3[C:8]([N:24]=2)=[N:9][CH:10]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]4[O:22][CH2:21][CH2:20][N:19]([C:33]5[C:38]([CH2:39][CH:40]6[CH2:41][CH2:42]6)=[C:37]([CH3:43])[N:36]=[C:35]([CH3:44])[N:34]=5)[CH2:18][C:17]=4[CH:23]=2)[CH:12]=3)[CH2:4][CH2:3]1
Reactant: Cc1nc(C)c(CC2CC2)c(Cl)n1
Reactant: CCC(C)OC(=O)n1c(C2CC2)nc2ncc(-c3ccc4c(c3)CNCCO4)cc21
Agent: Cl
Product: Cc1nc(C)c(CC2CC2)c(N2CCOc3ccc(-c4cnc5nc(C6CC6)[nH]c5c4)cc3C2)n1

Procedure:
Prepared according to the method of example 6 by using 1-methylpropyl 2-cyclopropyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate hydrochloride (reagent preparation 19) and 4-chloro-5-(cyclopropylmethyl)-2,6-dimethylpyrimidine (reagent preparation 8) in step 3. 1H NMR (400 MHz, methanol-d4) δ 8.71 (s, 1H), 8.25 (s, 1H), 7.78 (d, 1H), 7.58 (dd, 1H), 7.09 (d, 1H), 5.14 (s, 2H), 4.50 (m, 2H), 4.29 (m, 2H), 2.72 (d, 2H), 2.52 (s, 3H), 2.51 (s, 3H), 2.39 (m, 1H), 1.43 (m, 4H), 0.88 (m, 1H), 0.50 (m, 2H), 0.10 (m, 2H); MS (EI) for C28H30N6O: 467 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[C:13]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([NH:23][NH2:24])=[O:22])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>C(O)(=O)C>[C:13]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([NH:23][N:24]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:22])=[CH:19][CH:18]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: CC(C)(C)c1ccc(C(=O)NN)cc1
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 75 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-tert-butylbenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 168 mg of the title compound (75%) as a yellow solid in 99.8% purity by HPLC (Rt: 6.65, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[C:23]([CH3:26])([CH3:25])[CH3:24])[C:9]=2[C:10]=1[CH2:11][CH2:12][CH3:13])=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C:9]=2[C:10]=1[CH2:11][CH2:12][CH3:13])=[O:5])[CH3:2]
Reactant: CCCc1c(C(=O)OCC)oc2cccc(OCCCN(C(=O)OC(C)(C)C)C(C)(C)C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1c(C(=O)OCC)oc2cccc(OCCCNC(C)(C)C)c12
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a dichloromethane (0.5 ml) solution of 4-[3-(tert-butoxycarbonyl-tert-butyl-amino)-propoxy]-3-propyl-benzofuran-2-carboxylic acid ethyl ester (5.0 mg) was added trifluoroacetic acid (0.5 ml) at room temperature. After stirring overnight, the reaction mixture was concentrated in vacuo to dryness. The residue was purified by silica gel column chromatography developed by dichloromethane-methanol to give 4-(3-tert-butylamino-propoxy)-3-propyl-benzofuran-2-carboxylic acid ethyl ester (2.4 mg) as a pale yellow oil. FAB-MS: m/z 362 (MH+); 1H-NMR (CDCl3): δ 0.91 (3H, t, J=7.3 Hz), 1.34 (s, 9H), 1.25-1.45 (5H, m), 1.64 (2H, quintet, J=7.3 Hz), 2.23 (2H, quintet, J=7.3 Hz), 3.07 (2H, t, J=7.3 Hz), 3.16 (2H, t, J=7.3 Hz), 4.09 (2H, t, J=5.9 Hz), 4.42 (2H, q, J=6.9 Hz), 6.52 (1H, d, J=8.3 Hz), 7.12 (1H, d, J=8.3 Hz), 7.28 (1H, dd, J=8.3 Hz, 8.3 Hz).
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.Cl[CH2:34][CH2:35][C:36]1[NH:40][N:39]=[N:38][N:37]=1>>[CH:19]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:34][CH2:35][C:36]3[NH:40][N:39]=[N:38][N:37]=3)=[CH:14][N:15]=2)=[O:9])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: ClCCc1nnn[nH]1
Reactant: N#CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: O[C@H](CS)[C@@H](O)CS
Product: O=C(Nc1ncc(SCCc2nnn[nH]2)s1)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 5-(2-chloroethyl)-1H-tetrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=O)[C:6]([CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[N:5]2.P(Cl)(Cl)([Cl:25])=O>CN(C)C1C=CN=CC=1>[Cl:25][C:7]1[C:6]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:5][C:4]2[C:9](=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: O=c1[nH]c2cc(Cl)c(Cl)cc2nc1C=Cc1ccc(F)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Product: Fc1ccc(C=Cc2nc3cc(Cl)c(Cl)cc3nc2Cl)cc1
Yield: 83 %

Procedure:
The above 6,7-dichloro-3-[2-(4-fluorophenyl)vinyl]-1H-quinoxalin-2-one (2.0 g, 6 mmol), 4-dimethylaminopyridine (0.2 g) and phosphorous oxychloride (POCl3) were mixed and refluxed for 30 minutes. After cooling, the mixture was poured onto ice (500 ml). The solid was filtered, washed with water and dried in vacuo at 30° C. overnight to afford 1.8 g (83%) of the title compound.
Reaction SMILES: C1([ClH]P([ClH]C2C=CC=CC=2)(Cl)=O)C=CC=CC=1.[OH:18][C@@H:19]([C@H:21]1[C:42](=[O:43])[N:23]2[CH:24]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C:25](=O)[C@H:26]([CH3:27])[C@H:22]12)[CH3:20].[SH:44][C@@H:45]1[CH2:49][N:48]([C:50]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=2)=[O:51])[C@H:47]([C:63]([N:65]2[CH2:68][CH:67]([NH:69][C:70]([O:72][CH2:73][C:74]3[CH:79]=[CH:78][C:77]([N+:80]([O-:82])=[O:81])=[CH:76][CH:75]=3)=[O:71])[CH2:66]2)=[O:64])[CH2:46]1>C(#N)C.C(OCC)(=O)C>[N+:80]([C:77]1[CH:76]=[CH:75][C:74]([CH2:73][O:72][C:70]([NH:69][CH:67]2[CH2:66][N:65]([C:63]([C@@H:47]3[CH2:46][C@H:45]([S:44][C:25]4[C@H:26]([CH3:27])[C@@H:22]5[C@@H:21]([C@H:19]([OH:18])[CH3:20])[C:42](=[O:43])[N:23]5[C:24]=4[C:29]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=4)=[O:30])[CH2:49][N:48]3[C:50]([O:52][CH2:53][C:54]3[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=3)=[O:51])=[O:64])[CH2:68]2)=[O:71])=[CH:79][CH:78]=1)([O-:82])=[O:81]
Reactant: O=C(NC1CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC(NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 32.3 %

Procedure:
167 μl of diphenylphosphoric acid chloride and 140 μl of ditsopropylethylamine were added dropwise at the same time, whilst ice-cooling, to a solution of 278 mg of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 4 ml of dry acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. At the end of this time, a solution of 430 mg of (2S,4S)-4-mercapto-2-[3-(4-nitrobenzyloxycarbonylamino)azetidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 113) in 4 ml of dry acetonitrile and 134 μl of ditsopropylethylamine were added dropwise at the same time to the mixture, whilst ice-cooling. The resulting mixture was then stirred at the same temperature for 2 hours, after which it was left to stand overnight whilst ice-cooling. The reaction mixture was then diluted with ethyl acetate and washed with water and with an aqueous solution of sodium chloride. The ethyl acetate layer was dehydrated over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the fractions obtained by elution with a 98:2 by volume mixture of ethyl acetate and methanol were combined and concentrated by evaporation under reduced pressure, to give 224 mg of the title compound, as a powder.
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)[CH2:2][CH3:3].Br[CH2:14][C:15]1[CH:35]=[CH:34][C:18]2/[C:19](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:20]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[C:21]=3[O:22][CH2:23][C:17]=2[CH:16]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:20]2=[C:21]([C:24]=1[F:29])[O:22][CH2:23][C:17]1[CH:16]=[C:15]([CH2:14][N:8]3[C:7]4[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=4[N:5]=[C:4]3[CH2:1][CH2:2][CH3:3])[CH:35]=[CH:34][C:18]=1/[C:19]/2=[C:30](/[CH3:33])\[C:31]#[N:32]
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2c1ccc(F)c2F
Reactant: CCCc1nc2ccccc2[nH]1
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)COc1c(ccc(F)c1F)/C2=C(\C)C#N
Yield: 90 %

Procedure:
Using 2-propyl-1H-benzo[d]imidazole (Synthetic Communication, 2002, vol. 32, p 3703; 17 mg, 0.10 mmol) and (E)-2-[8-(bromomethyl)-3,4-difluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (40 mg, 0.12 mmol) obtained in Reference Example 4, and in the same manner as in Reference Example 1A, the title compound (41 mg, 87%) was obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1O[C:15](=O)[C:14]([C:18]#[N:19])=[C:13]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:12]=1.[H-].[Na+]>C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:12]2[CH2:11][C:2]3[C:1](=[CH:10][CH:5]=[CH:4][CH:3]=3)[C:15]=2[C:14]([C:18]#[N:19])=[C:13]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:12]=1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccc3ccccc3c2)oc1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c(N2CCCCC2)cc(-c2ccc3ccccc3c2)c2c1-c1ccccc1C2

Procedure:
A mixture of 6-(naphthalen-2-yl)-2-oxo-4-(piperidin-1-yl)-2H-pyran-3-carbonitrile (330 mg), indanone-1 (132 mg) and NaH (39 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude, solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 136-138° C.; ESIMS 401 (M++1); IR (KBr) 2214 cm−1 (CN); HRMS calcd. for C2H24N2 400.1940 Found 400.1939.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]([C:14]2[N:23]=[C:17]3[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][N:16]3[N:15]=2)[CH:11]=[N:12][CH:13]=1.[CH:24]1(B(O)O)[CH2:26][CH2:25]1.C(Cl)Cl>O1CCOCC1.O>[CH:24]1([C:8]2[CH:9]=[C:10]([C:14]3[N:23]=[C:17]4[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][N:16]4[N:15]=3)[CH:11]=[N:12][CH:13]=2)[CH2:26][CH2:25]1
Reactant: OB(O)C1CC1
Reactant: Cc1ccc2nc(-c3cncc(Br)c3)nn2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc2nc(-c3cncc(C4CC4)c3)nn2c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Cesium carbonate (0.45 g, 0.0013 mol) was added to a stirred solution of 2-(5-bromopyridin-3-yl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine (44-2; 0.2 g, 0.00069 mol) and cyclopropylboronic acid (0.119 g, 0.00138 mol) in a mixture of 1,4-dioxan (9 mL) and water (3 mL). The reaction mixture was purged with argon for 20 min. Pd(dppf)2Cl2.DCM (0.028 g, 0.000034 mol) was added and the reaction flask was again purged with argon for 10 min. The reaction mixture was then stirred at 100° C. for 18 h. The reaction mixture was filtered through a filter bed of CELITE and the filter bed was thoroughly washed with ethyl acetate (2×50 mL). The collected organic factions were concentrated under vacuum to afford the crude product, which was purified by silica gel column chromatography to afford the title compound. 1H NMR (400 MHz, DMSO) δ 9.08-9.07 (d, J=1.2 Hz, 1H), 8.83 (s, 1H), 8.50-8.49 (d, J=2.4 Hz, 1H), 8.04 (s, 1H), 7.78-7.76 (d, J=8.8 Hz, 1H), 7.57-7.55 (d, J=9.2 Hz, 1H), 2.37 (s, 3H), 2.08-2.05 (m, 1H), 1.08-1.03 (m, 2H), 0.84-0.80 (m, 2H), MS (M+1): 251.2.
Reaction SMILES: [Br:1]Br.[CH3:3][NH:4][N:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1>C(O)(=O)C.C(#N)C>[CH3:3][NH:4][N:5]=[C:6]([Br:1])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: CNN=Cc1ccc(Cl)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CC#N
Product: CNN=C(Br)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 61 %

Procedure:
9.5 g (0.06 mol) of bromine were added dropwise at (-5) to (-7)° C. to a solution of 10 g (0.06 mol) of 4-chlorobenzaldehyde (N-methyl)hydrazone in 50 ml of acetic acid and 20 ml of acetonitrile. After the mixture had been stirred for 3 hours, the product which had precipitated was separated off and washed with a small amount of pentane. Yield: 61%.
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)C.CNC.Cl[C:12]1[N:20]2[CH:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][O:23][C:18]3=[C:19]2[C:14](=[C:15]([F:37])[CH:16]=[C:17]3[C:30]2[C:31]([CH3:36])=[N:32][O:33][C:34]=2[CH3:35])[N:13]=1>CN1CCCC1=O.CO>[CH3:36][C:31]1[C:30]([C:17]2[C:18]3[O:23][CH2:22][CH:21]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[N:20]4[C:12]([N:3]([CH3:4])[CH3:1])=[N:13][C:14]([C:19]=34)=[C:15]([F:37])[CH:16]=2)=[C:34]([CH3:35])[O:33][N:32]=1
Reactant: Cc1noc(C)c1-c1cc(F)c2nc(Cl)n3c2c1OCC3c1cccnc1
Reactant: CCN(CC)CC
Agent: CNC
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1noc(C)c1-c1cc(F)c2nc(N(C)C)n3c2c1OCC3c1cccnc1
Temperature: 150 °C
Yield: 19.1 %

Procedure:
Triethylamine (16 μL, 0.12 mmol) and dimethylamine (0.2 mL, 4 mmol) were added to 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (15 mg, 0.040 mmol) in N-methylpyrrolidinone (0.41 mL) and the mixture was heated in a microwave at 150° C. for 20 min. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to afford the title compound (3.0 mg, 19%). LCMS calc. for C21H21FN5O2 (M+H)+: m/z=394.2. found: 394.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23])=[O:17])([CH3:14])([CH3:13])[CH3:12]>O1CCCC1>[C:11]([O:15][C:16](=[O:17])[NH:18][CH2:22][CH2:21][CH2:20][C:19]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:23])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: COc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: COc1cccc(C(=O)CCCNC(=O)OC(C)(C)C)c1
Temperature: -40 °C
Reaction time: 1 h
Yield: 113 %

Procedure:
Add 3-methoxyphenylmagnesium bromide (1.0 M in tetrahydrofuran, 91.0 mL, 91.0 mmol) dropwise to 1-(tert-butoxycarbonyl)-2-pyrrolidinone (11.9 mL, 70.0 mmol) in tetrahydrofuran (230 mL) at −40° C. After stirring at −40° C. for one hour, warm to 0° C. for 2 h before quenching with 2 M hydrochloric acid (70 mL). Dilute with methylene chloride (250 mL), separate the layers, and extract the aqueous layer with methylene chloride (2×200 mL). Dry the combined organic layers over magnesium sulfate, filter, and concentrate under reduced pressure to obtain the title compound (23.20 g, >100%). MS (APCI+): 194 [C16H23NO4—C5H8O2+H]+; 1H NMR (300 MHz, CDCl3): δ 7.55-7.47 (m, 2H), 7.39-7.33 (m, 1H), 7.12-7.08 (m, 1H), 4.66 (bs, 1H), 3.85 (s, 3H), 3.29-3.18 (m, 2H), 3.01 (t, J=7.1 Hz, 2H), 1.93 (quintet, J=7.0 Hz, 2H), 1.42 (s, 9H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH:29][CH2:30][C@H:31]([OH:44])[C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:33]=4)=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>CO>[OH:44][C@H:31]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:33]=1)[CH2:30][NH:29][CH2:28][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([NH:20][CH:17]2[CH2:16][CH2:15][N:14]([C:12]([N:9]3[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)=[O:13])[CH2:19][CH2:18]2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)C1CCN(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)cc3)CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCCc2ccc(NC3CCN(C(=O)N4CCC(C(=O)O)CC4)CC3)cc2)ccc1O
Temperature: 25 °C
Yield: 23.5 %

Procedure:
To a solution of 1-[4-(4-{2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-ethyl}-phenylamino)-piperidine-1-carbonyl]-piperidine-4-carboxylic acid ethyl ester (0.135 g, 0.213 mmol) was dissolved in methanol (5 mL) and sodium hydroxide (0.5 mL, 1N, 0.5 mmol) was added. The mixture was stirred at ambient temperature for thirty minutes and 1N hydrochloric acid (0.55 mL, 0.55 mmol) was added. The solvent was removed and the mixture partitioned between dichloromethane and water. The organic layer was dried over magnesium sulfate and the solvent removed in vacuo to yield the title compound (0.031 g, 0.05 mmol).
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:7]([NH:8][C:9]2[N:10]=[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH2:6][CH2:5][O:4][CH2:3]1.C([O-])([O-])=[O:26].[K+].[K+]>CO.OO>[NH2:1][C@@H:2]1[C@H:7]([NH:8][C:9]2[N:10]=[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[C:12]([C:15]([NH2:16])=[O:26])=[N:13][CH:14]=2)[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(Nc2nc(N[C@@H]3CCOC[C@@H]3N)cnc2C#N)cc1
Agent: OO
Agent: [K+]
Solvent: CO
Product: Cc1ccc(Nc2nc(N[C@@H]3CCOC[C@@H]3N)cnc2C(N)=O)cc1

Procedure:
To a solution of 5-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-3-(p-tolylamino)pyrazine-2-carbonitrile in methanol (1 ml) was added K2CO3 (excess) and H2O2 (50%, a few drops). After completion, it was concentrated and purified by preparative HPLC to give 5-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-3-(p-tolylamino)pyrazine-2-carboxamide. MS found for C17H22N6O2 as (M+H)+ 343.3, UV: λ=251.2, 302.9.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[C:15]2[S:14](=[O:17])(=[O:16])[N:13]=[C:12]([CH2:18][C:19]([OH:21])=O)[NH:11][C:10]=2[S:9][CH:8]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.C([O:55][C:56](=O)[CH2:57][CH:58]([CH:68]1[CH2:70][CH2:69]1)[NH:59][CH2:60][C:61]1[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=1)C.[O-]CC.[Na+].C(O)C>CN(C)C=O>[CH:68]1([CH:58]2[N:59]([CH2:60][C:61]3[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=3)[C:19](=[O:21])[C:18]([C:12]3[NH:11][C:10]4[S:9][CH:8]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:15]=4[S:14](=[O:16])(=[O:17])[N:13]=3)=[C:56]([OH:55])[CH2:57]2)[CH2:70][CH2:69]1
Reactant: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)CC(NCc1ccc(F)cc1)C1CC1
Agent: CC[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CN1CCOCC1
Product: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(C1=C(O)CC(C3CC3)N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Reaction time: 17 h
Yield: 32.1 %

Procedure:
[7-(Methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.089 g, 0.252 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.106 g, 0.279 mmol) and 4-methylmorpholine (0.055 mL, 0.500 mmol) were added sequentially to a solution of 3-cyclopropyl-3-(4-fluoro-benzylamino)-propionic acid ethyl ester (0.067 g, 0.252 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 17 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was dissolved in ethanol (25 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (0.327 mL, 1.01 mmol) was added and the reaction mixture was heated to 60° C. for 3 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (Teledyne Isco RediSep column; 40-100% ethyl acetate in hexanes) to afford (after trituration with diethylether) rac-N-{3-[6-cyclopropyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.045 g, 0.081 mmol, 32%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: −0.03-0.01 (1H, m), 0.25-0.39 (2H, m), 0.67-0.74 (1H, m), 0.93-0.96 (1H, m), 0.98-1.06 (1H, m), 2.48 (1H, d, J=17.0 Hz), 2.76-2.79 (1H, m), 2.81 (3H, s), 3.02 (1H, dd, J1=6.9 Hz, J2=17.0 Hz), 4.10 (2H, d, J=6.1 Hz), 4.21 (1H, d, J=15.5 Hz), 4.94 (1H, d, J=15.8 Hz), 6.96-7.12 (2H, m), 7.12 (1H, s), 7.19-7.22 (2H, m), 7.51 (1H, t, J=6.3 Hz). LC-MS (ESI) calculated for C22H23FN4O6S3 554.08. found 555.1 [M+H+].