Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NCCC#N.[OH-].[K+:7].[S:8](=[O:12])(=[O:11])([OH:10])[OH:9].[K].[NH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]>>[NH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[S:8]([O-:12])([O-:11])(=[O:10])=[O:9].[K+:7].[K+:7]
Reactant: O=S(=O)(O)O
Agent: N#CCCN
Agent: NCCC(=O)O
Agent: [K+]
Product: O=S(=O)([O-])[O-]

Procedure:
Briefly the instant process is based on the discovery that the hydrolysis of beta-amino propionitrile with aqueous potassium hydroxide followed by sulfuric acid conversion of the potassium salt of beta alanine produces free beta alanine and insoluble potassium sulfate, the entrained portions of which, amounting to about 10% by weight, do not interfere with the subsequent conversion to calcium beta alanate, provided essentially anhydrous conditions are maintained. And, quite unexpectedly the presence of the potassium sulfate impurities does not interfere with the subsequent reaction of the pantoyl lactone to produce relatively pure calcium pantothenate (dl). Furthermore, the reactions are carried out using ordinary stainless steel or steel equipment, using inexpensive materials and no complicated purification or resin treatment steps are necessary.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]2[N:15]=[C:14]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[C:13]([Cl:23])=[CH:12][N:11]=2)=[C:4]([CH3:24])[CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[O:36]1[CH:41]=[CH:40][CH2:39][CH2:38][CH2:37]1.C([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]2[N:15]=[C:14]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[N:19]([CH:37]4[CH2:38][CH2:39][CH2:40][CH2:41][O:36]4)[N:18]=3)[C:13]([Cl:23])=[CH:12][N:11]=2)=[C:4]([CH3:24])[CH:3]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(Br)cc3C)ncc2Cl)n[nH]1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2ncc(Cl)c(Nc3cc(C)n(C4CCCCO4)n3)n2)c(C)cc1Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of N2-(4-bromo-2,5-dimethylphenyl)-5-chloro-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (280 mg, 0.69 mmol) in THF (3 mL) was added p-TSA (119 mg, 0.69 mmol) and 3,4-dihydro-2H-pyran (348 mg, 2.86 mmol). The mixture was stirred at room temperature for 14 h and then poured into saturated aqueous NaHCO3 solution (10 mL). The resulting mixture was extracted with EtOAc (3×10 mL) and the combined organic layers were concentrated. The resulting residue was purified by flash column chromatography (silica gel, 0-50% EtOAc in hexanes gradient) to provide N2-(4-bromo-2,5-dimethylphenyl)-5-chloro-N4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid; ESMS m/z 491.1 (M+H+).
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.CS(C)=O.Br[CH2:14][C:15]1[O:19][N:18]=[C:17]([CH:20]([C:22]#[CH:23])[OH:21])[CH:16]=1.OP([O-])(O)=O.[K+]>C(Cl)Cl>[OH:21][CH:20]([C:17]1[CH:16]=[C:15]([CH:14]=[O:5])[O:19][N:18]=1)[C:22]#[CH:23]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C#CC(O)c1cc(CBr)on1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: C#CC(O)c1cc(C=O)on1
Reaction time: 5 h
Yield: 292.3 %

Procedure:
9.8 g of 4-methyl morpholine oxide, 68 cm3 of dimethylsulphoxide and 34 cm3 of methylene chloride are added at 0° C. to a solution containing 4 g of the product prepared in Stage C and 30 cm3 of methylene chloride. The mixture is allowed to return to 20° C. and agitated for 5 hours. It is poured into an aqueous solution of potassium acid phosphate. Extraction is carried out with ethyl acetate, the extracts are dried, filtered and brought to dryness. 8.18 g of product is obtained which is chromatographed on silica, eluting with a hexane-ethyl acetate mixture (1-1). In this way 1.96 g of desired product is obtained.
Reaction SMILES: C[C:2]1[C:12](=[O:13])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH:3]=1.[F:14][C:15]([F:28])([F:27])[O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](O)=O)=[CH:19][CH:18]=1.[K+].[Br-]>CC(=O)OCC>[CH3:2][C:3]1[C:4](=[O:5])[C:6]2[C:11]([C:12](=[O:13])[C:24]=1[CH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:15]([F:28])([F:27])[F:14])=[CH:18][CH:19]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Reactant: CC1=CC(=O)c2ccccc2C1=O
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC1=C(Cc2ccc(OC(F)(F)F)cc2)C(=O)c2ccccc2C1=O
Yield: 78 %

Procedure:
As starting materials for the coupling reaction menadione and 4-(trifluoromethoxy)phenylacetic acid were used. Synthesis is realized according to the general procedure described in general procedure of example 1. After chromatography on silica gel (petroleum ether:CH2Cl2=1:1, UV), 494 mg (1.43 mmol, 78% yield) of P_TM97 were isolated as yellow solid. Melting point: 64-65° C. —1H-NMR (300 MHz, CDCl3): δ=8.03-8.10 (m, 2H), 7.65-7.71 (m, 2H), 7.34 (d, 3J=8.74 Hz, 2H), 7.09 (d, 3J=8.08 Hz, 2H), 4.01 (s, 2H), 2.23 (s, 3H). —13C-NMR (75 MHz, CDCl3): δ=185.17 (Cq), 184.52 (Cq), 147.42 (Cq), 144.72 (Cq), 144.57 (Cq), 136.76 (Cq), 133.57 (CH), 132.07 (Cq), 131.92 (Cq), 129.87 (CH), 126.47 (CH), 126.33 (CH), 121.15 (CH), 120.44 (q, 1JCF=256.91 Hz), 31.78 (CH2), 13.27 (CH3). —EI MS (70 eV, m/z (%)): 346.0 ([M]+, 32), 331.1 (100), 261.1 (8), 175.1 (71), 76.0 (10), 28.0 (49). —IR (KBr): 3077 cm−1 (w), 3047 (w), 3021 (w), 3003 (w), 2963 (w), 2948 (w), 2853 (w), 2143 (w), 2004 (w), 1975 (w), 1901 (w), 1876 (w), 1664 (vs), 1620 (m), 1596 (s), 1508 (s), 1446 (w), 1435 (w), 1378 (m), 1333 (s), 1297 (vs), 1271 (vs), 1217 (vs), 1188 (vs), 1166 (vs), 1111 (m), 1019 (w), 976 (m), 793 (w), 770 (w), 708 (s), 692 (w). —EA: obs. C, 65.78%; H, 3.98%, calcd. C, 65.90%; H, 3.78% for C19H13F3O3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:15])[CH2:13]Br)[CH3:10]>CC(C)=O>[C:5]1([CH3:8])[CH:6]=[CH:7][C:2]([NH:1][CH2:13][C:12]([O:11][CH2:9][CH3:10])=[O:15])=[CH:3][CH:4]=1
Reactant: Cc1ccc(N)cc1
Reactant: CCOC(=O)CBr
Solvent: CC(C)=O
Product: CCOC(=O)CNc1ccc(C)cc1
Yield: 35.9 %

Procedure:
The compound was prepared according to general procedure E. To a solution of p-toluidine (4.7 mmol) in dry acetone (20 ml), ethylbromoacetate (4.7 mmol) was added. The mixture was refluxed for 3 hours. After cooling, the solvent was removed under reduced pressure. The residue was chromatogaphed on a silica gel column (dichloromethane/ethyl acetate 9/1 as eluent) to give 326 mg of ethyl 2-(p-tolylamino)acetate (yield 36%). 1H NMR (500 MHz, CDCl3): δ 1.29 (t, J=7.4 Hz, 3H), 2.28 (s, 3H), 3.90 (s, 2H), 4.26 (q, J=7.4 Hz, 2H), 6.58 (d, J=8.2 Hz, 2H), 7.05 (d, J=8.2, 2H) 13C NMR (126 MHz, CDCl3): δ 15.6, 21.8, 47.7, 62.5, 114.8, 131.2, 146.3, 172.8. MS (ESI): m/z 193.9 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1F)[CH:7]=[O:8])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>CS(C)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1F
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOc1cc(C=O)ccc1-n1ccnc1
Yield: 83.5 %

Procedure:
3-Ethoxy-4-fluoro-benzaldehyde (0.081 g, 0.482 mmol) was dissolved in 1 ml of DMSO and treated with potassium carbonate (0.166 g, 2.5 eq.) and imidazole (0.066 g, 2 eq.), and the mixture was allowed to react under a balloon of argon for 2 h at 105° C. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, AcOEt) produced 0.087 g of the title compound as off-white crystals.
Reaction SMILES: [CH2:1]([C:5]1[C:10]([O:11][CH3:12])=[C:9]([CH3:13])[C:8]([CH3:14])=[C:7]([O:15][CH3:16])[C:6]=1[CH3:17])[CH2:2][C:3]#[CH:4].C([Li])CCC.Cl[C:24]([O:26][CH3:27])=[O:25].[Cl-].[NH4+]>C1COCC1>[CH3:12][O:11][C:10]1[C:9]([CH3:13])=[C:8]([CH3:14])[C:7]([O:15][CH3:16])=[C:6]([CH3:17])[C:5]=1[CH2:1][CH2:2][C:3]#[C:4][C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)Cl
Reactant: C#CCCc1c(C)c(OC)c(C)c(C)c1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CCCc1c(C)c(OC)c(C)c(C)c1OC
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution of 5 g (21.5 mmol) of 1-(3-butynyl)-3,6-dimethoxy-2,4,5-trimethylbenzene in 80 ml of THF was cooled to -78° C. and treated firstly with 13.4 ml of a 1.6M n-butyllithium solution and then with 2.2 g (23.3 mmol) of methyl chloroformate. The mixture was left at -78° C. for 1 hour, then warmed to -20° C., held at this temperature for 2 hours and finally poured into saturated ammonium chloride solution. Extraction with ethyl acetate yielded, after washing the extracts with water and drying over sodium sulphate, a yellow oil which was purified on silica gel (eluent: hexane/ethyl acetate 95:5→90:10). There were obtained 3.6 g of spontaneously crystallizing methyl 5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-2-pentynoate. M.P. 71°-72° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:48]1[CH:49]=[C:50]2[C:55](=[CH:56][CH:57]=1)[N:54]=[C:53]([CH2:58][CH:59]([CH3:61])[CH3:60])[C:52]([C:62]#[N:63])=[C:51]2[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[F:70].[C:71]([OH:75])([CH3:74])([CH3:73])[CH3:72].CC(C)([O-])C.[Na+].Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:71]([O:75][C:48]1[CH:49]=[C:50]2[C:55](=[CH:56][CH:57]=1)[N:54]=[C:53]([CH2:58][CH:59]([CH3:61])[CH3:60])[C:52]([C:62]#[N:63])=[C:51]2[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[F:70])([CH3:74])([CH3:73])[CH3:72]
Reactant: CC(C)Cc1nc2ccc(Br)cc2c(-c2ccccc2F)c1C#N
Reactant: CC(C)(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)Cc1nc2ccc(OC(C)(C)C)cc2c(-c2ccccc2F)c1C#N
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
Palladium acetate (0.015 g, 0.65 mmol) and racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.12 g, 0.19 mmol) were added to toluene (10 ml) under a nitrogen atmosphere and the mixture was stirred at 40° C. for 30 min. The reaction mixture was cooled to room temperature and 6-bromo-4-(2-fluorophenyl)-2-isobutylquinoline-3-carbonitrile (0.50 g, 1.30 mmol), tert-butanol (0.25 ml, 2.61 mmol) and sodium tert-butoxide (0.188 g, 1.96 mmol) were added, and the mixture was stirred under a nitrogen atmosphere at 90° C. for 1 hr. The reaction mixture was cooled and 0.1N hydrochloric acid (10 ml) was added and the mixture was stirred at room temperature for 30 min. Toluene (50 ml) was added to the reaction mixture. The organic layer was washed with water (10 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography and crystallized from n-hexane to give 6-tert-butoxy-4-(2-fluorophenyl)-2-isobutylquinoline-3-carbonitrile (0.40 g; yield 82%) as pale-yellow crystals.
Reaction SMILES: Cl(O)(=O)(=O)=O.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(OC(N1CC[C@@H](N)C1)=O)(C)(C)C>>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)OC(=O)N1CCC(N)C1

Procedure:
column: manufactured by Daicel Chemical Industries, Ltd., {CROWNPAK 150×4.6 mm}, mobile phase: aqueous perchloric acid solution (pH 1.5), flow rate: 1.0 ml/min, detection: UV 210 nm, column temperature: 35° C., retention time: (S)-1-(tert-butoxycarbonyl)-3-aminopyrrolidine; 24.1 min, (R)-1-(tert-butoxycarbonyl)-3-aminopyrrolidine; 27.0 min
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C@H:18]2C(N)=O)[C:13]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C(O)(=O)C.CC#[N:56]>O>[NH2:56][C@H:18]1[C@@H:17]([N:14]2[CH2:15][CH2:16][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[C:13]2=[O:34])[CH2:22][CH2:21][C@@H:20]([NH:23][C:24](=[O:25])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:19]1
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(N)=O)C1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](N)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To the solution of (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxamide (2.0 g, 4.21 mmol; see Example 1, Step 5) in MeCN (150 mL) and H2O (205 mL), iodobenzene diacetate (1.357 g, 4.21 mmol) was added. The mixture was stirred at 0° C. for 1 h and then allowed to warm to room temperature in the melting ice bath over 14 h. The mixture was acidified to pH 4 with the addition of acetic acid, and then extracted with diethyl ether (2×60 mL). The aqueous layer was concentrated under reduced pressure to remove acetonitrile. The residual solution was extracted with methylene chloride (2×80 mL) after adjusting the pH to 9-10 using saturated NaHCO3. The methylene chloride layer was dried (Na2SO4) and concentrated in vacuo to give the desired tert-butyl (1R,3R,4S)-3-amino-4-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)cyclohexylcarbamate (1.8 g, 4.03 mmol, 96% yield). LC/MS found [M+H]+=447.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].ClCCl.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH3:35])[C:32](Cl)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(N(CC)CC)C>[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH3:35])[C:32]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(OCc1ccccc1)[C@@H]1CC2=C(CCCC2)N1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Introduce 200 g of benzyl (2S)-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate and 1.5 liters of dichloromethane into a reactor, then bring the temperature of the reaction mixture to 0° C. and add 107 ml of triethylamine and then 162 g of (2S)-2-[(tert-butoxycarbonyl)amino]propionyl chloride. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water and then with a dilute acetic acid solution. The benzyl (2S)-1-{(2S)-2-[(tert-butoxycarbonyl)amino]propionyl}-2,3-dihydro-1H-indole-2-carboxylate solution so obtained is used as it is in the following Step.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[C:15]1([C:21]2[S:22][CH:23]=[C:24]([C:26]([N:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH:29]3[CH2:41][O:42][C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)=[O:27])[N:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[ClH:1].[ClH:1].[C:15]1([C:21]2[S:22][CH:23]=[C:24]([C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH:29]3[CH2:41][O:42][C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)=[O:27])[N:25]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2csc(-c3ccccc3)n2)C(COc2cccnc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1csc(-c2ccccc2)n1)N1CCNCC1COc1cccnc1
Reaction time: 8 h
Yield: 71 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(2-phenylthiazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (74.9 mg, 0.126 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired chromatography fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6 mL). This was concentrated under reduced pressure, yielding 40.4 mg (71%) of the desired product as a white solid. LC-MS: RT=4.45 min, [M+H]+=381.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2([C:14]1[C:15]([O:20][CH2:21][CH3:22])=[N:16][CH:17]=[CH:18][CH:19]=1)[OH:13].[CH3:23][N:24](C)C=O>O.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.[C-]#N.[Zn+2].[C-]#N>[CH2:21]([O:20][C:15]1[C:14]([C:5]2([OH:13])[C:4]3[C:8](=[CH:9][C:10]([F:11])=[C:2]([C:23]#[N:24])[CH:3]=3)[NH:7][C:6]2=[O:12])=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:22]
Reactant: CN(C)C=O
Reactant: CCOc1ncccc1C1(O)C(=O)Nc2cc(F)c(Br)cc21
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: O
Product: CCOc1ncccc1C1(O)C(=O)Nc2cc(F)c(C#N)cc21
Temperature: 150 °C
Reaction time: 1 h

Procedure:
161 mg (0.14 mmol) of tetrakis(triphenylphosphine)palladium (0) were added to a solution of 1.7 g (4.63 mmol) of 5-bromo-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-1,3-dihydroindol-2-one from example a.1 and 544 mg (4.63 mmol) of zinc cyanide in 18 ml of dimethylformamide (DMF), and the mixture was agitated in a Biotage microwave apparatus at 150° C. for 1 h. The reaction solution was worked up by diluting with 300 ml of water, extracting with ethyl acetate (3×) and washing with saturated sodium chloride solution (1×). The combined organic phases were dried over magnesium sulfate and filtered, and the solvent was removed in vacuo. 1.67 g of 3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile were obtained.
Reaction SMILES: C(OC(=O)[N:7]([CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][S:39]([CH:42]4[CH2:44][CH2:43]4)(=[O:41])=[O:40])=[O:37])=[CH:31][C:30]=3[F:45])[CH:20]=2)=[CH:17][CH:18]=1)[CH2:8][CH2:9][O:10][CH3:11])(C)(C)C.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[F:45][C:30]1[CH:31]=[C:32]([NH:35][C:36]([NH:38][S:39]([CH:42]2[CH2:43][CH2:44]2)(=[O:40])=[O:41])=[O:37])[CH:33]=[CH:34][C:29]=1[O:28][C:25]1[CH:24]=[CH:23][N:22]=[C:21]2[CH:20]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([CH2:12][NH:7][CH2:8][CH2:9][O:10][CH3:11])=[CH:14][N:15]=3)[S:27][C:26]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NS(=O)(=O)C5CC5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NS(=O)(=O)C5CC5)cc4F)c3s2)nc1
Reaction time: 4 h

Procedure:
To a solution of the 375 (140 mg, 0.208 mmol) in DCM (5 ml) was added HCl in dioxane (0.5 ml, 2 mmol, 9.6 eq, 4M in dioxane) and the reaction mixture was stirred for 4 hours. The mixture was diluted with EtOAc, made basic with NaHCO3 solution and extracted with EtOAc/acetone. The organic phase was collected and discarded. The aqueous phase was concentrated and the residue was suspended in a mixture of DCM and acetone. The solution phase was collected, dried with Na2SO4, filtered and concentrated to afford 376 as a beige solid after further trituration with Et2O (yield 8 mg, 7%). 1H NMR (DMSO-d6): 8.67 (s, 1H), 8.56 (s, 1H), 8.47 (d, J=5.28, 1H), 8.27 (s, 1H), 8.19 (d, J=8.02 Hz, 1H), 7.85 (m, 2H), 7.80 (s, 1H), 7.22 (m, 2H), 6.59 (d, J=5.28 Hz, 1H), 3.76 (s, 2H), 3.40 (m, 2H), 3.20 (s, 3H), 2.76 (m, 1H), 2.60 (m, 2H), 0.75 (m, 2H), 0.65 (m, 2H). LRMS(ESI): (calc.) 571.64 (found) 572.58 (MH)+.
Reaction SMILES: [Br:1][C:2]1([C:8]2[O:9][C:10]3[C:18]([CH2:19]Br)=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C-:21]#[N:22].[Na+].O>CN(C)C=O>[Br:1][C:2]1([C:8]2[O:9][C:10]3[C:18]([CH2:19][C:21]#[N:22])=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=c1cc(C2(Br)CCCCC2)oc2c(CBr)cccc12
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1cccc2c(=O)cc(C3(Br)CCCCC3)oc12
Temperature: 10 °C
Yield: 42.1 %

Procedure:
2-(1-Bromocyclohexyl)-8-bromomethyl-4-oxo-4H-[1]-benzopyran (11.2 g, 0.028 mole) was dissolved in dimethylformamide (200 ml) and to the solution was added NaCN (1.5 g, 0.0305 mole) with stirring at 10° C. The mixture was stirred for 30 minutes. Water was added to the reaction mixture and crystals precipitated were filtered off. The crude crystals were purified by silica gel chromatography (eluent: chloroform-hexane (10:1)) to obtain the title compound (4.08 g), yield 44.7 %. The product was recrystallized from ethyl acetate to obtain prisms, m.p. 144°-145° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[C:20]5[CH2:29][NH:28][CH2:27][CH2:26][C:21]=5[N:22]([CH3:25])[C:23]=4[CH:24]=3)[C:12](=[O:30])[CH:11]=2)=[N:6][CH:7]=1.[C:31]1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:43].Cl>>[ClH:43].[ClH:43].[CH3:31][N:28]1[CH2:27][CH2:26][C:21]2[N:22]([CH3:25])[C:23]3[CH:24]=[C:16]([N:13]4[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=5)=[CH:11][C:12]4=[O:30])[CH:17]=[CH:18][C:19]=3[C:20]=2[CH2:29]1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)cc31)CNCC2
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Product: CN1CCc2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)cc3n2C)C1
Yield: 78 %

Procedure:
4-((5-Fluoropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (75 mg, 0.19 mmol) was reacted according to the procedure of Example 47 to provide the free-base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (71 mg, 78%) as a white solid: mp 215-230° C.; 1H NMR (500 MHz, CD3OD) δ 8.65 (d, J=2.6 Hz, 1H), 7.91 (overlapping ddd, J=9.6, 2.1 Hz, 1H), 7.83-7.20 (m, 2H), 7.61 (d, J=8.4 Hz, 1H), 7.53 (d, J=1.8 Hz, 1H), 7.09 (dd, J=8.4, 1.8 Hz, 1H), 6.59 (dd, J=7.5, 2.6 Hz, 1H), 6.36 (d, J=2.6 Hz, 1H), 5.41 (s, 2H), 4.76 (d, J=14.2 Hz, 1H), 4.39 (d, J=14.2 Hz, 1H), 3.94-3.82 (m, 2H), 3.74 (s, 3H), 3.65-3.58 (m, 2H), 3.13 (s, 3H); ESI MS m/z 419 [M+H]+; HPLC (Method B) 95.8% (AUC), tR=110 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH2:13].[Br:15]Br>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([Br:15])[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH2:13]
Reactant: BrBr
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a solution of 2.23 g (10.4 mmol) of 2-amino-3-nitro-benzoic acid methyl ester in 12 mL of acetic acid was added dropwise a solution of 0.53 mL (10.4 mmol) of Br2 in 2.0 mL of acetic acid. The mixture was stirred at r.t. for 30 min and poured into 100 g of ice. The solid was collected by filtration and dried to afford 2.5 g (82%) of 2-Amino-5-bromo-3-nitro-benzoic acid methyl ester. 1H NMR (CDCl3, 400 MHz): δ 8.6 (d, 1H), 8.53 (s, 1H), 3.95 (s, 3H) ppm.