Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([O-])=O.[Na+].[C:5]([CH:11](C(C)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9].[C:20]([O:23]C(=O)C)(=O)[CH3:21]>O.C(O)(=O)C.[Zn]>[CH2:15]([O:14][C:12](=[O:13])[CH:11]([NH:1][C:20](=[O:23])[CH3:21])[C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC(=O)C(C(C)=O)C(=O)OCC
Reactant: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CCCCC(=O)C(NC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of sodium nitrite (41.3 g) in water was added slowly to a cooled solution of ethyl 2-valerylacetoacetate (118.7 g) in acetic acid (100 ml.), and the temperature was kept below 10°. Ice (100 g) was added, followed by acetic anhydride (105.0 g). Zinc dust (total 65.4 g) was added portionwise, keeping the temperature below 20° with stirring, until the reaction was complete. The mixture was allowed to stand overnight at room temperature, and it was then filtered. The solid was washed with chloroform, and the filtrate was extracted with chloroform. The chloroform extracts were washed with sodium carbonate solution and dried. The solvent was removed under vacuum, and the residue was purified by column chromatography (silica gel) eluting with petroleum ether (b.p. 60°-80°)/ethyl acetate, to yield ethyl-2-acetamido-3-oxoheptanoate, 13.5 g, which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[CH3:31][N:32](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:29][C@@H:24]1[C@@H:23]([N:13]2[C:12](=[O:30])[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[C:9]([CH2:8][C:5]4[CH:4]=[CH:3][C:2]([C:31]#[N:32])=[N:7][CH:6]=4)[CH:10]=3)[N:15]=[CH:14]2)[CH2:28][CH2:27][O:26][CH2:25]1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (0.100 g, 0.237 mmol) in 1 mL of DMF under an atmosphere of nitrogen was added zinc cyanide (Example 1, 0.084 g, 0.71 mmol) and tetrakis(triphenylphosphine)palladium(0) (13.7 mg, 0.012 mmol). The mixture was heated to 100° C. for 8 h, then at 140° C. for another 15 h. The reaction was cooled to rt, diluted with ethyl acetate, washed 3× with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 413.1603 for [M+H]+ [Calc'd for C24H21N4O3, [M+H]+=413.1608]: 1H NMR (400 MHz, CDCl3) δ 8.96-8.94 (m, 1H), 8.56 (s, 1H), 8.29 (s, 1H), 7.98 (s, 1H), 7.78-7.75 (m, 1H), 7.64-7.59 (m, 2H), 7.50 (s, 2H), 4.72-4.69 (m, 1H), 4.49 (s, 2H), 4.11-4.05 (m, 2H), 4.04-3.98 (m, 1H), 3.50-3.47 (m, 1H), 3.29-3.20 (m, 2H), 2.17-2.13 (m, 1H), 2.00-1.95 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21]I)[CH2:17][CH2:16]1)[CH2:11][CH2:12][CH2:13][CH3:14].C([Li])CCC.[CH:28]([N:30]1CCCCC1)=O.NOS(O)(=O)=O>O1CCCC1.CN(C)CCN(C)C>[CH2:10]([C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][O:9][C:3]2[CH:4]=[CH:5][C:6]([C:28]#[N:30])=[C:7]([F:8])[C:2]=2[F:1])[CH2:17][CH2:16]1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=CN1CCCCC1
Reactant: Oc1cccc(F)c1F
Reactant: CCCCC[C@H]1CC[C@H](CI)CC1
Agent: CN(C)CCN(C)C
Agent: NOS(=O)(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](COc2ccc(C#N)c(F)c2F)CC1

Procedure:
0.1 mole of 1-(trans-4pentylcyclohexyl-1-methoxy)-2,3-difluorobenzene (prepared from 2,3-difluorophenol and trans-4-pentylcyclohexylmethyl iodide analogously to Example 4) is deprotonated by means of n-butyllithium in tetrahydrofuran/tetramethylethylenediamine and is formylated by means of N-formylpiperidine. The formyl compound is reacted as in Example 1b) with hydroxylamine-O-sulfonic acid. Working up in the customary manner gives 4-(trans-4-pentylcyclohexylmethoxy)-2,3-difluorobenzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH2:6][N:7]=[C:8]=[O:9].[N+:13](=[C:15]1[N:19]=[CH:18][N:17]=[C:16]1[C:20]([NH2:22])=[O:21])=[N-:14]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH2:6][N:7]1[C:8](=[O:9])[N:19]2[CH:18]=[N:17][C:16]([C:20]([NH2:22])=[O:21])=[C:15]2[N:13]=[N:14]1
Reactant: COc1cccc(CN=C=O)c1
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Solvent: CS(C)=O
Product: COc1cccc(Cn2nnc3c(C(N)=O)ncn3c2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Meta-methoxybenzyl isocyanate (Sigma Aldrich) (0.390 g, 2.4 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.274 g, 2 mmol) in dry dimethylsulfoxide (2.5 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of ice and the solid product (off-white) removed by filtration, washed with water and ethyl acetate, and recrystallised from chloroform. Yield: 0.335 g, 56%. IR vmax/cm−1 3092, 1730, 1678, 1601. 1H NMR δH (DMSO-d6) 3.76 (3H, s, Me), 5.49 (2H, s, CH2Ar), 6.89-6.92 (1H, m, ArH), 7.00-7.02 (1H, m, ArH), 7.28-7.32 (1H, s, ArH), 7.70 (1H, br s, NH), 7.82 (1H, br s, NH), 8.84 (1H, s, 6-H). δC (DMSO-d6) 52.2, 55.6, 113.7, 114.0, 120.4, 129.5, 130.1, 131.4, 134.9, 137.6, 139.7, 159.9, 162.0. Found 301.1091. Calc for (M+H): 301.1049. Found C, 51.3; H 3.9; N 27.8. Calc. for C13H12N6O3C, 52.0; H, 4.0; N, 28.0%.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[CH2:8][N:9]([OH:13])[CH2:10][CH2:11][CH:12]=1)[C:5]#[N:6].[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][O:2][N:3]=[C:4]([C:7]1[CH2:8][N:9]([O:13][C:21]([NH:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:22])[CH2:10][CH2:11][CH:12]=1)[C:5]#[N:6]
Reactant: O=C=Nc1ccccc1
Reactant: CON=C(C#N)C1=CCCN(O)C1
Product: CON=C(C#N)C1=CCCN(OC(=O)Nc2ccccc2)C1
Yield: 33 %

Procedure:
α-(Methoxyimino)-α-(1-hydroxy-1,2,5,6-tetrahydropyridin-3-yl)acetonitrile (E2) (0.45 g, 0.0025 moles) was treated with phenyl isocyanate as in the method of Example 8. The residue obtained was chromatographed on silica gel eluting with 0-1% methanol/chloroform to give a crystalline solid. Recrystallisation from ethyl acetate/60-80 petrol gave the title compound (E9) as white crystals (0.245 g, 33%) m.p. 128°-130° C.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[N:24](OCCCC)=[O:25].C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.O>[N:24]([N:12]1[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][CH2:8][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:25]
Reactant: CCCCON=O
Reactant: c1ccc(C2COc3ccccc3N2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=NN1c2ccccc2OCC1c1ccccc1
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a mixture of 3-phenyl-3,4-dihydro-2H-1,4-benzoxazine (17 g, 80.5 mmol) in ethyl ether (100 mL) is added trifluoroacetic acid (6.2 mL 80.5 mmol). The resulting solution is chilled to 5° C. in an ice bath, to which n-butyl nitrite (9.4 mL 80.5 mmol) is added dropwise. The mixture is stirred for 1 h and transferred to a separatory funnel to which is slowly added potassium carbonate (2.6 g, 18.8 mmol) in water (200 mL). Solids formed in the ether layer. The layers are separated and ethyl ether (100 mL) is added to dissolve the solids. The ether layer is washed twice with water (200 mL), dried over magnesium sulfate, filtered and concentrated. The resulting oil is chilled in the refrigerator overnight. The solids formed from the oil are ground-up in hexanes and collected by filtration to give 15.7 g (81%) of 4-nitroso-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[C:13]([NH2:18])([CH2:16][CH3:17])([CH3:15])[CH3:14]>C(O)C>[CH3:14][C:13]([NH:18][CH2:12][C@@H:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[N:2][N:1]=2)[CH:9]=1)[OH:11])([CH3:15])[CH2:16][CH3:17]
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Reactant: CCC(C)(C)N
Solvent: CCO
Product: CCC(C)(C)NC[C@H](O)c1ccc2nnnn2c1
Yield: 96.1 %

Procedure:
A solution of 250 mg (1.54 mmol) of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane and 663 mg (7.61 mmol) of tert amylamine in 0.6 ml of absolute ethanol in a pressure tube was heated at 100° C. (bath temperature) for two hours. The reaction mixture was concentrated under reduced pressure to yield 369 mg of crude product which was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:12]([O:14]CC)=[O:13])[S:11][CH2:10][CH2:9][CH2:8][S:7]1.[Li+].[OH-].CO>C1COCC1.O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:12]([OH:14])=[O:13])[S:7][CH2:8][CH2:9][CH2:10][S:11]1
Reactant: CCOC(=O)C1(CCCCCl)SCCCS1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1(CCCCCl)SCCCS1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.9 %

Procedure:
Step AS (2): To a solution of ethyl 2-(4-chlorobutyl)-1,3-dithiane-2-carboxylate (550 mg, 1.94 mmol) in THF (5 mL) was added a solution of LiOH (233 mg, 9.72 mmol) in water (2 mL). Methanol (2 mL) was added and the resulting mixture was stirred at rt for 2 d. The solvents were removed in vacuo. Aqueous 1 N HCl (50 mL) was added. The mixture was extracted with EtOAc (80 mL). The organic layer was washed with water, dried over sodium sulfate, filter, and concentrated in vacuo to afford 2-(4-chlorobutyl)-1,3-dithiane-2-carboxylic acid (400 mg, 1.57 mmol, 81% yield). LC-MS (M+H)+ 253.0. The crude product was used for subsequent chemistry without purification.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([NH:22][CH2:23][CH2:24][CH3:25])[CH:6]=1)C>[OH-].[Na+]>[O:15]([C:8]1[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:5]([C:4]([OH:26])=[O:3])=[CH:6][C:7]=1[NH:22][CH2:23][CH2:24][CH3:25])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCNc1cc(C(=O)OCC)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
Ethyl-4-phenoxy-3-n-propylamino-5-sulphamyl-benzoate (1 g) was dissolved in 1N sodium hydroxide (15 ml), and heated on a steam bath for 1 hour. After cooling, the 4-phenoxy-3-n-propylamino-5-sulphamyl-benzoic acid was precipitated by addition of 4N hydrochloric acid until the pH was 2.5; the melting point was 223°-224°C.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]2)[N:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:6][NH:5]1.Br[CH2:31][C:32]1[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:34][CH:33]=1>CN(C)C=O>[C:39]([O:38][C:36]([C:35]1[CH:43]=[CH:44][C:32]([CH2:31][N:5]2[C:4](=[O:3])[C:8]3([CH2:9][CH2:10][N:11]([C:14]([O:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[O:15])[CH2:12][CH2:13]3)[N:7]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:6]2)=[CH:33][CH:34]=1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.1 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.46 g, 0.0114 mol) was added portionwise at 0° C. to benzyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (4.00 g, 0.0109 mol) in N,N-dimethylformamide (40 mL) and the mixture stirred at 0° C. for 10 minutes. tert-Butyl 4-(bromomethyl)benzoate (3.27 g, 0.0120 mol) was added dropwise at 0° C., the mixture then allowed to warm to room temperature, and stirred for 2 hours. The reaction was quenched with 2M aqueous hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extracts were washed with brine, dried (MgSO4), and evaporated. The residue was purified by Biotage flash column chromatography (gradient 0 to 30% ethyl acetate/hexanes) to give product as an oil (4.97 g, 82%); 1H NMR (DMSO-d6); δ1.53 (s, 9H); 1.72 (d, J=13.6 Hz, 2H); 2.34-2.42 (m, 2H); 3.57 (m, 2H); 3.99-4.03 (m, 2H); 4.61 (s, 2H); 4.63 (s, 2H); 6.69 (d, J=8 Hz, 2H); 6.78 (t, J=7.2 Hz, 1H); 7.18 (dd, J=7.2 Hz and 8.8 Hz, 2H); 7.32-7.39 (m, 5H); 7.42 (d, J=8.4 Hz, 2H); 7.90 (d, J=8.4 Hz, 2H);
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([OH:9])=[N:7][O:8][C:4]=2[CH:3]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:11]1[C:2]([CH3:1])=[CH:3][C:4]2[O:8][N:7]=[C:6]([OH:9])[C:5]=2[CH:10]=1
Reactant: Cc1ccc2c(O)noc2c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc2onc(O)c2cc1Br
Temperature: 80 °C
Reaction time: 20 h
Yield: 49.7 %

Procedure:
A 25 ml high-pressure tube equipped with a stir bar and a screw-on Teflon cap was charged with 6-methyl-benzo[d]isoxazol-3-ol (745 mg, 5.0 mmole, 1.0 eq) and glacial acetic acid (5.0 ml). Neat Br2 (774 μL, 15.0 mmoles, 3.0 eq) was added dropwise. After stirring at 80° C. for 20 hours, the reaction was allowed to cool slowly to room temperature. The resulting precipitate was collected by filtration and washed quickly with 3×1.0 ml of glacial acetic acid. Crystallization of this crude product (624 mg) from 50 ml of MeCN yielded 567 mg of the title compound (96% purity determined RP-HPLC). Additional crystallization from 70 ml of toluene provided 519 mg (46%) as a white solid (98.1% purity determined by HPLC). (1H DMSO-d6, 400 MHz) δ 12.45 (s, 1H), 7.94 (s, 1H), 7.61 (s, 1H), 2.45 (s, 3H); (13C CD3OD, 100 MHz) δ 165.96, 164.50, 142.34, 125.39, 119.73, 115.78, 112.67, 24.10.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([OH:29])=O)[C:24]3[C:19](=[C:20]([F:31])[CH:21]=[C:22]([F:30])[CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[NH:34]1[CH2:38][CH2:37][N:36]=[C:35]1[C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH2:47])=[CH:41][CH:40]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([NH:47][CH2:46][CH2:45][C:42]3[CH:43]=[CH:44][C:39]([C:35]4[NH:36][CH2:37][CH2:38][N:34]=4)=[CH:40][CH:41]=3)=[O:29])[C:24]3[C:19](=[C:20]([F:31])[CH:21]=[C:22]([F:30])[CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NCCc1ccc(C2=NCCN2)cc1
Reactant: O=C(O)CC1c2cc(F)cc(F)c2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O=C(CC1c2cc(F)cc(F)c2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1)NCCc1ccc(C2=NCCN2)cc1

Procedure:
The title compound was prepared from [5-(3,4-dichloro-benzenesulfonyl)-8,10-difluoro-5,6-dihydro-phenanthridin-6-yl]-acetic acid and 2-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethylamine dihydrochloride (Reference Example 2) according to the method described in Example 1e. MS (EI) 656.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[O:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].[Na].Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[O:14][C:13](=[O:15])[N:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]1=[O:16]
Reactant: CCOC(=O)Cl
Reactant: COc1cccc(Cl)c1C1OC(=O)NC1=O
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)OC(c2c(Cl)cccc2OC)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Anhydrous sodium 5-(2-chloro-6-methoxyphenyl)oxazolidine-2,4-dione (542 mg., 2.06 moles) from Example 119 and ethyl chloroformate (291 mg., 2.68 mmoles) were combined with 20 ml. of toluene and the mixture refluxed for 3 hours, cooled to room temperature, stirred for a further 16 hours, and evaporated to solids (415 mg.). The solids were recrystallized from toluene to yield purified 5-(2-chloro-6-methoxyphenyl)-3-ethoxycarbonyloxazolidine-2,4-dione. (212 mg., m.p. 196°-200° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9]([C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])[CH:8]=3.CC1(C)C(C)(C)OB([C:34]2[N:35]=[CH:36][S:37][CH:38]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[N:17]1([C:15]([C:9]2[CH:8]=[C:7]3[C:12]([C:13]4[CH:14]=[C:2]([C:34]5[N:35]=[CH:36][S:37][CH:38]=5)[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]=4[NH:6]3)=[CH:11][CH:10]=2)=[O:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Reactant: CC1(C)OB(c2cscn2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(-c2cscn2)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 105 °C
Yield: 42.6 %

Procedure:
3-Bromo-7-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide (50 mg, 0.112 mmol, Example 144A), Pd(Ph3P)4 (7 mg, 6.06 nmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (37 mg, 0.175 mmol), aqueous Na2CO3 (0.15 mL, 0.300 mmol), MeOH (1 mL) and Toluene (2 mL) were combined in a 5 ml microwave vial. The vial was sealed, flushed with nitrogen and heated to 105° C. for 4 hours in an oil bath. Additional Pd(Ph3P)4 (20 mg, 15 nmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (65 mg, 0.308 mmol) and aqueous Na2CO3 (0.30 mL, 0.60 mmol) were added, the vial flushed with nitrogen again and heat to 105° C. for 5 additional hours. The reaction mixture was evaporated to dryness, suspended in water and the crude product was collected by filtration through a medium porosity glass frit. The crude was washed with water, then dissolved off the frit with DMSO and purified by prep HPLC. Product containing fractions were combined and concentrated in vacuum to give 19.4 mg 7-(morpholine-4-carbonyl)-3-(thiazol-4-yl)-9H-carbazole-1-carboxamide. MS (ESI) m/e+=407, m/e−=405, consistent with [M−H]− and [M+H]+. 1H NMR (CD3OD+CDCl3) δ ppm 9.11 (d, 1H, J=2.1), 8.91 (d, 1H, J=1.5), 8.57 (d, 1H, J=1.5), 8.26 (d, 1H, J=8.0), 7.96 (d, 1H, J=1.8), 7.72 (s, 1H), 7.32 (dd, 1H, J=7.9, 1.2), 3.90-3.50 (b, 8H). HPLC retention time 8.02 min. (Sunfire C18 3.5 μm, 4.6×150 mm column, 15 min gradient, 10-100% B, 1 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([CH:9]2[CH2:11][CH2:10]2)[C:7]2[C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:3].[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>C(O)CCC>[NH2:20][C:21]1[N:22]=[CH:23][N:24]=[C:25]([NH:1][C@H:2]([C:4]2[N:8]([CH:9]3[CH2:10][CH2:11]3)[C:7]3[C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=3[N:5]=2)[CH3:3])[C:26]=1[C:27]#[N:28]
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: COC(=O)c1cccc2nc([C@H](C)N)n(C3CC3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3C#N)n(C3CC3)c12
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-methyl 2-(1-aminoethyl)-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylate (140 mg, 0.54 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (83 mg, 0.54 mmol) and 1,1′-dimethyltriethylamine (190 μL, 1.1 mmol) in n-butanol (3 mL) was stirred at 120° C. After 18 h, the mixture was cooled to rt and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 0 to 10% gradient of MeOH in DCM-EtOAc (1:1) with 0.2% NH4OH as eluent to give (S)-methyl 2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylate: LC-MS (ESI) m/z 378.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([O:11][CH2:12][CH2:13][N:7]3[CH:6]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18][CH:5]23)[CH:10]=1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1B(O)O.C>>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([O:11][CH2:12][CH2:13][N:7]3[CH:6]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18][CH:5]23)[CH:10]=1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([O:11][CH2:12][CH2:13][N:7]3[CH:6]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:17][CH2:18][CH:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC2c3cc(Br)cc4c3N(CCO4)C2CC1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: C
Product: CC(C)(C)OC(=O)N1CCC2c3cc(-c4ccc(Cl)cc4Cl)cc4c3N(CCO4)C2CC1
Product: Clc1ccc(-c2cc3c4c(c2)C2CCNCCC2N4CCO3)c(Cl)c1
Yield: 129.5 %

Procedure:
Tert-butyl 5-(2,4-dichlorophenyl)-1,2,6b,7,8,10,11,11a-octahydro-9H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole-9-carboxylate (510 mg, 65%) was prepared via coupling of tert-butyl 5-bromo-1,2,6b,7,8,10,11,11a-octahydro-9H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole-9-carboxylate (671 mg, 1.64 mmol) with 2,4-dichlorophenyl boronic acid (470 mg, 2.46 mmol) as illustrated by the general procedure described in Example 534 Step C. 1H NMR (CDCl3, 300 MHz) δ1.48 (s, 9H), 1.81-2.22 (m, 4H), 2.80-3.00 (m, 1H), 3.25 (d, 1H, J=11.5 Hz), 3.31-3.75 (m, 6H), 4.49-4.50 (m, 2H), 6.66 (s, 1H), 6.72 (s, 1H), 7.23 (s, 2H), 7.43 (s, 1H) ppm. CIMS (Methane) m/z=476 [MH]+. The corresponding hydrochloride salt of the title compound was formed from tert-butyl 5-(2,4-dichlorophenyl)-1,2,6b,7,8,10,11,11a-octahydro-9H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole-9-carboxylate (505 mg) using the procedure described in Example 534 Step D. Then, this salt was free-based using 6 N NaOH, to give the title compound (398 mg, 99%). 1H NMR (CDCl3, 300 MHz) δ1.60-2.30 (m, 5H), 2.70-3.30 (m, 6H), 3.40-3.60 (m, 1H), 3.70-3.80 (m, 1H), 4.30-4.60 (m, 2H), 6.70 (s, 1H), 6.73 (s, 1H), 7.28 (s, 1H), 7.29 (s, 1H), 7.43 (s, 1H) ppm. CIMS (Methane) m/z=376 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]2[CH2:8][O:9][C:10](=[O:11])[C:5]=2[CH:4]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[CH3:21])[C:3]=1[C:22]#[N:23].[C:24](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C=O)C>[CH3:24][N:7]1[C:2]([CH3:1])=[C:3]([C:22]#[N:23])[CH:4]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[CH3:21])[C:5]2[C:10](=[O:11])[O:9][CH2:8][C:6]1=2
Reactant: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C2=C(COC2=O)N1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C2=C(COC2=O)N1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 100 mg (0.326 mmol) 2-methyl-4-(3-methyl-1H-indazol-5-yl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile (Example 1) in DMF (2 ml) was cooled to 0° C. 128 mg (0.392 mmol) caesium carbonate were added at this temperature, and after 30 min 14 μl (0.229 mmol) methyl iodide were added dropwise. After stirring overnight at rt, additional methyl iodide (2 μl) was added, and stirring at rt was continued for further 3 h. Again, methyl iodide (6 μl) and a small amount of caesium carbonate were added, and the reaction mixture was stirred at rt overnight before water (1 ml) was added. The solution was directly purified first by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) followed by preparative TLC (eluent: dichloromethane/ethanol 20:1) to give 11 mg (11% of th.) of the title compound.