Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:12]([O-])([OH:14])=[O:13].N([O-])=O.[Na+]>C(OCC)(=O)C>[N+:12]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[CH:7][C:8]=1[OH:11])([O-:14])=[O:13]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=[N+]([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
Commercially available 4-t-butyl phenol (30 g, 0.2 mole) is dissolved in 200 ml ethyl acetate in a 500 ml round bottom flask fitted with a mechanical stirrer, and cooled to 0° C. The mixture is treated with nitric acid (13 ml, in 13 ml water) dropwise over 10 minutes and then a catalytic amount of NaNO2. After 45 minutes the reaction is washed with excess 1N HCl and the organic layer is dried over MgSO4 and stripped to yield 37 g of 2-nitro-4-t-butyl phenol. This nitrophenol (37 g, 0.19 mole) is dissolved in 100 ml ethyl acetate and placed into a parr bottle with a teaspoon of 10% Pd/C. The mixture is placed on a hydrogenator under 50 psi hydrogen with agitation for one hour. The catalyst is filtered off through celite, and the ethyl acetate is stripped off under vacuum. The material crystallizes with the addition of about 200 ml heptane to give 25.6 g of the corresponding amine (2-amino-4-t-butyl phenol).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]=[C:14]1[CH2:18][CH2:17][C:16]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[O:15]1.[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>C1COCC1>[O:13]=[C:14]1[CH:18]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([F:31])=[CH:33][CH:34]=2)[CH2:17][C:16]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[O:15]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)O2)CC1
Reactant: Fc1ccc(CBr)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(Cc1ccc(F)cc1)C(=O)O2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
A solution of diisopropyl amine (0.36 mL, 2.6 mmol) in 7.5 mL dry THF was cooled to −78° C. and n-butyllithium (1.5 mL, 1.6 M in hexane, 2.4 mmol) was added. The mixture was warmed to 0° C. for 15 min then recooled to −78° C. A solution of 2-oxo-8-(t-Butoxycarbonyl)-8-aza-1-oxaspiro[4.5]decane (510 mg, 2.0 mmol, from Step B) in 2 mL THF was added dropwise. After 30 min at −78° C. 4-fluorobenzyl bromide (0.32 mL, 2.6 mmol) was added and after 30 min the mixture was warmed to room temperature and quenched with sat'd ammonium chloride. The mixture was extracted with ethyl acetate and the organic portion was dried over sodium sulfate and concentrated. Flash chromatography (3/1 hexane/EtOAc) afforded 510 mg (70%) of the desired product. 1H NMR (400 MHz, CDCl3). δ 1.44 (s, 9H), 1.51-1.81 (5H), 2.03-2.19 (m, 1H), 2.76-2.81 (dd, 1H), 2.99-3.04 (m, 1H), 3.18-3.3 (m, 3H), 3.72-3.81 (m, 2H), 6.97-7.03 (m, 2H), 7.11-7.18 (m, 2H). The lactone was separated into its enantiomers by semiprep chiral HPLC (chiralpak AD, 9/1 hexane/IPA→8/1 hexane/IPA) to afford the two enantiomers (enantiomer A, 92% ee and enantiomer B, 73% ee). The two enantiomers were converted to the spiro tetrahydrofuran derivatives as described below for enantiomer B.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[CH2:11]=[C:12]1[O:16][C:14](=[O:15])[CH2:13]1.C(N(CC)CC)C.[C:24]1(C)[CH:29]=CC=C[CH:25]=1>>[C:12]([C:13]1[C:9](=[O:10])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:24]([CH3:29])=[CH:25][C:14]=1[OH:15])(=[O:16])[CH3:11]
Reactant: Cc1ccccc1
Reactant: O=C=Nc1ccccc1Cl
Reactant: C=C1CC(=O)O1
Solvent: CCN(CC)CC
Product: CC(=O)c1c(O)cc(C)n(-c2ccccc2Cl)c1=O

Procedure:
A mixture of 2-chlorophenylisocyanate (3.0 g, 19.53 mmol), and diketene (3.3 g, 39.28 mmol) in toluene (10.0 mL) containing triethylamine (0.05 mL) was heated to reflux for 6 h, under an atmosphere of argon. Toluene was distilled in vacuo and the resulting residue was purified by silica gel flash chromatography using 25% EtOAc in hexanes as the eluent to afford the title compound (0.85 g, see ref: Heterocycles 27 (9), 2063, 1988.) as a pale yellow solid: 1H-NMR (CD3OD) δ: 7.63 (m, 1H), 7.52 (m, 2H), 7.4 (m, 1H), 6.14 (s, 1H), 2.58 (s, 3H), and 1.95 (s, 3H); ES-MS m/z=278 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].N12CCCN=C1CCCCC2.N[C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.CS(C)=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[O:10])=[CH:4][C:3]=1[C:12]([F:13])([F:14])[F:15]
Reactant: Nc1ccc(O)cc1
Reactant: NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Solvent: CC#N
Product: O=C(Nc1ccc(O)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
1-(4-chloro-3-(trifluoromethyl)phenyl)urea (100 g, 0.04191 mol), 1,8-diazabicyclo[5.4.0]undec-7-ene (9.4 ml, 0.0628 mol) and 4-amino phenol (5.48 g, 0.050 mol) were mixed with dimethyl sulfoxide (25 ml) and the reaction mass was heated to 80°-90° C. for 8-9 hours. It was then cooled to room temperature and quenched in water (150 ml). The quenched mass was extracted repeatedly with ethyl acetate and the combined ethyl acetate layer was then back washed with water. The residue was then dried over sodium sulfate and evaporated under vacuum to obtain solid. The solid thus obtained was then slurried in acetonitrile (100 ml) at ambient temperature and filtered. It was washed repeatedly with acetonitrile till clear filtrate was obtained. The obtained cake was suck dried for 10 minutes and vacuum dried at 50° C. to give 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea (9.8 g).
Reaction SMILES: [CH:1]([CH:3]1[CH:8]([CH3:9])[CH:7]2[CH2:10][CH:4]1[CH:5]=[CH:6]2)=O.[C:11]([CH2:13]C(O)=O)#[N:12].[OH-].[NH4+].CN(C)C=O>C1C=CC=CC=1>[C:11]([CH2:13][CH:1]=[C:3]1[CH:8]([CH3:9])[CH:7]2[CH2:10][CH:4]1[CH:5]=[CH:6]2)#[N:12]
Reactant: N#CCC(=O)O
Reactant: CC1C2C=CC(C2)C1C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC1C(=CCC#N)C2C=CC1C2
Yield: 75.4 %

Procedure:
A stirred solution of 136 g (1.0 mole) of 2-formyl-3-methylbicyclo[2.2.1]hept-5-ene, 91 g (1.05 mol) of cyanoacetic acid, 3 g (0.05 mol) of ammonium hydroxide (58%), 132 ml of dimethylformamide, and 170 ml of benzene was heated to reflux and the water removed with a Dean-Stark trap. The reaction was allowed to continue until the carbon dioxide evolution ceased (approx. 31 hrs). Upon completion, the reaction was cooled and the solvent removed under reduced pressure. The residual oil was distilled under vacuum to give 120 g (75.5% yield) of 2(2-cyanoethylidene)-3-methylbicyclo[2.2.1]hept-5-ene: b.p. 70°-80° C./1 mm; nD20 1.5080; ir 3060, 2250, 1460, 1380, 760, 740, 726, 700; nmr 1.15 (3H, d, J=7 Hz, methyl), 4.9-5.5 (1H, m, vinyl H), 5.7-6.1 (2H; m, vinyl H); ms 159.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([CH3:23])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:26](OC)[N:27]([CH3:29])[CH3:28].N1CC[CH2:34][CH2:33]1.CN(C=O)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17](/[CH:23]=[CH:29]/[N:27]3[CH2:26][CH2:34][CH2:33][CH2:28]3)[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C#N
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)c(/C=C/N3CCCC3)c2)CC1
Temperature: 110 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
94.6 g (0.3 mol) 4-(4-Cyano-3-methyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester, 87.6 mL (0.66 mol) N,N-Dimethylformamide dimethylacetal, 109 mL (1.32 mol) pyrrolidine and 60.4 mL DMF (0.78 mol) were mixed and the mixture was heated within 30 min to 90° C. and kept at this temperature for 1 h. All volatile content was allowed to distil off. The temperature was raised to 110° C. and kept at this temperature for 2 h. The temperature was brought to 120° C. and kept at this temperature for 7.5 h. Heating was discontinued and the mixture was chilled to ambient temperature. Then, 200 mL water and 400 mL isopropanol were added. The mixture was stirred for 3 h at ambient temperature and 1 h at 5° C. to precipitate the product. The solid was collected rinsed with isopropanol/water (70/30) collected and dried to yield 113.7 g (yield 95.5%, purity 93.3%) of 4-[4-Cyano-3-((E)-2-pyrrolidin-1-yl-vinyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH:18]1[CH2:23][CH2:22][O:21][C:19]1=[O:20].O>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH:18]1[CH2:23][CH2:22][O:21][C:19]1=[O:20])([O-:3])=[O:2]
Reactant: O=C1OCCC1Br
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1OCCC1Oc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2-nitrophenol (20 g, 0.14 mol) and K2CO3 (25.2 g, 0.18 mol) in 280 mL DMF was cooled to 0° C. 2-Bromobutyrolactone was added dropwise, the reaction was stirred for 45 min at 0° C., then stirred at room temperature for 3 hours (h). The mixture was poured into 2 L water containing approx. 200 g salt, and the solution was washed with 6×100 mL of 1:1 diethyl ether/ethyl acetate. The combined organics were washed with 2×100 mL sat'd aq. K2CO3, 5×100 mL water and 100 mL brine, dried (Na3SO4), and filtered. Solvent was removed in vacuo to yield the title compound as an off-white solid (21.88 g, 0.1 mol). 1H (CDCl3): 7.84 (d, 1H, J=7.9), 7.57 (t, 1H, J=7.5), 7.49 (d, 1H, J=7.9), 7.16 (t, 1H, J=7.5), 5.03 (t, 1H, J=7.4), 4.58 (m, 1H), 4.42 (m, 1H), 2.8-2.6 (m, 2H).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[OH-:5].[K+].[CH3:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl>CO.C(OCC)(=O)C>[O:5]([CH2:2][C:1]([OH:4])=[O:3])[C:9]1[CH:8]=[CH:7][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)[O-]
Reactant: CCCCCC
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)COc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A portion of 16a (15.8 g; 29.9 mmol) was dissolved in 748 mL of MeOH. 35% aq. KOH (262 mL) was added in portions over 5 min. The reaction was heated to reflux. After 1 h TLC (30% ethyl acetate:hexane) indicated no starting material remained. After 4 h, TLC (100% ethyl acetate) indicated a heavy UV active spot above the origin. The reaction mixture was cooled to RT, then placed in an ice bath. 2M HCl (600 mL) was added to acidify the reaction to pH 5. The reaction mixture was diluted with 1.6 L of ethyl acetate and washed with sat. NaCl (1.6 L). The organic layer was dried over anhydrous sodium sulfate. The solvent was filtered through a sintered glass funnel. The filtrate was concentrated in vacua to recover 15.1 g of 17 as viscous oil which was taken onto the next step.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:17][CH2:16][CH2:15][C@H:9]2[C:10]([O:12]CC)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[ClH:20]>C1COCC1.CCO.O>[ClH:20].[C:1]1([CH2:7][N:8]2[CH2:17][CH2:16][CH2:15][C@H:9]2[C:10]([OH:12])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)[C@@H]1CCCN1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Ethyl 1-(phenylmethyl)-L-prolinate (13.20 g, 56.57 mmol) was dissolved in a mixture of THF (40 mL), EtOH (40 mL) and H2O (16 mL). To this solution was added solid sodium hydroxide (6.789 g, 169.73 mmol), and the mixture was stirred at room temperature overnight. The solution was adjusted to pH 2 with 1N aq. HCl and then extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo, and the resulting crude product was 1-(phenylmethyl)-L-proline hydrochloride (0.8 g). The aqueous layers were concentrated in vacuo, the residue was suspended in MeOH, and the resulting solid precipitate was collected by filtration and combined with the product from the organic extracts to provide 1-(phenylmethyl)-L-proline hydrochloride (13.30 g, 97%). LCMS: (M+H)+: 206.1
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[C@H:22]([CH3:23])[CH2:21][O:20][C@H:19]([C:24]([OH:26])=O)[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1[F:27])#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[C@H:22]([CH3:23])[CH2:21][O:20][C@H:19]([C:24]([NH:61][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)=[O:26])[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1[F:27])#[N:2]
Reactant: Nc1ccccc1
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)O)OC[C@H]2C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)Nc3ccccc3)OC[C@H]2C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
A mixture of (2S,5R)-4-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-5-methyl-2-morpholinecarboxylic acid (300 mg, 0.81 mmol), HATU (340 mg, 0.89 mmol), and Hünig's base (0.21 mL, 1.20 mmol) in DMF (5 mL) was stirred at room temperature for 10 minutes. Aniline (0.085 mL, 0.93 mmol) was then added, and stirring continued at room temperature for 17 hours. LC-MS indicated about 50% conversion, so another portion each of Hünig's base (0.21 mL, 1.20 mmol) and HATU (340 mg, 0.89 mmol) were added. After about 10 minutes more aniline (0.085 mL, 0.93 mmol) was added, and the mixture was stirred for an additional 1.5 hours. It was then diluted with EtOAc (25 mL) and washed successively with water, saturated aqueous NaHCO3, and brine (25 mL each). The organic phase was then dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (40 g SiO2, 10-35% EtOAc in hexanes gradient) to give the title compound (340 mg, about 80% purity) as a yellow oil. LC-MS (ES) m/z=447 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[CH2:26]([NH2:28])[CH3:27]>>[CH2:26]([NH:28][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])[CH3:27]
Reactant: CCN
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccncc3)noc2C)nn1
Product: CCNC(=O)c1ccc(OCc2c(-c3ccncc3)noc2C)nn1
Yield: 33 %

Procedure:
As described for example 69, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester (100 mg, 0.29 mmol) was converted, using ethylamine (2 M solution in THF) instead of isopropylamine, to the title compound (33 mg, 33%) which was obtained as a white solid. MS: m/e=340.1 [M+H]−.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]([CH3:21])[NH:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][CH2:2][CH2:3][C:4]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]([CH3:21])[NH:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:12][CH:13]=1)=[O:5]
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Reactant: O=C(Cl)CCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1NC(=O)NN=C1c1ccc(NC(=O)CCCl)cc1
Reaction time: 0.5 h

Procedure:
β-Chloropropionyl chloride (1.25 ml) was added dropwise to a stirred solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.04 g) and triethylamine (1.53 ml) in N,N-dimethylformamide (DMF) (10.5 ml) under ice cooling and the stirring was continued for 30 minutes. The solution was evaporated in vacuo and the residue as triturated with water under ice-cooling. The precipitates were collected by filtration, washed with water and dried to give 6-[4-(β-chloropropionylamino)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.55 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[C:19]([Cl:32])[CH:18]=2)=[C:6]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=O)[CH:7]=1.[NH2:33][CH2:34][CH:35]([OH:38])[CH2:36][OH:37]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[C:19]([Cl:32])[CH:18]=2)=[C:6]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([NH:33][CH2:34][CH:35]([OH:38])[CH2:36][OH:37])=[O:14])[CH:7]=1
Reactant: NCC(O)CO
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2NC(=O)CCC(=O)O)cc1Cl
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2NC(=O)CCC(=O)NCC(O)CO)cc1Cl

Procedure:
The reaction and work up was conducted as described in the preparation of compound 211. Starting compounds were N-(5-bromo-2-{[3-chloro-4-(2-methylbenzoyl)phenyl]amino}phenyl)-succinamic acid (600 mg, 1.16 mmol) (prepared as described in WO 01/05746) and 3-amino-1,2-propane-diol (117 mg, 1.28 mmol). The crude product was purified by flash chromatography using EtOAc followed by EtOAC/MeOH 95:5 as the eluent to afford the title compound as a solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[O:18]1[C:22]2[CH:23]=[CH:24][C:25](B(O)O)=[CH:26][C:21]=2[O:20][CH2:19]1>>[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:2]3[C:10]4[N:9]5[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]5=[C:7]([CH3:16])[C:6]=4[CH:5]=[C:4]([Cl:17])[CH:3]=3)=[CH:26][C:21]=2[O:20][CH2:19]1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: Cc1c2n(c3c(-c4ccc5c(c4)OCO5)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (78 mg, 88%), MS (ISP) m/z=355.4 [(M+H)+], mp 244.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available benzo[d][1,3]dioxol-5-ylboronic acid (53.9 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([F:18])([F:17])[F:16])=[N:12]2)=[C:7]([OH:19])[CH:6]=1)=[O:4].[N+:20]([O-])([OH:22])=[O:21].CCCCCC.C(OCC)(=O)C>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([F:18])([F:16])[F:17])=[N:12]2)=[C:7]([OH:19])[C:6]=1[N+:20]([O-:22])=[O:21])=[O:4]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc(O)c2ccc(C(F)(F)F)nc2c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1cc2nc(C(F)(F)F)ccc2c(O)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
5-Hydroxy-2-trifluoromethyl-quinoline-7-carboxylic acid methyl ester (46.0 g) is dissolved in concentrated sulfuric acid (200 mL, 97%) at 0-5° C. To this cooled solution is added drop wise fuming nitric acid (7 mL, 100%). After the addition is complete, the reaction mixture is allowed to warm to room temperature. TLC analysis (hexane/ethyl acetate=4:1) after 30 min shows reaction completion. The reaction mixture is slowly poured onto an ice/water mixture (ca. 2 mL) and the crystals were filtered off, washed thoroughly with water and dried in vacuum to afford 47.0 g of the title compound of the formula
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:21]Br>>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:21][N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]1=[N:5][C:4]1[CH:6]=[CH:7][C:8]([F:9])=[C:2]([F:1])[CH:3]=1
Reactant: Fc1ccccn1
Reactant: Nc1ccc(F)c(F)c1
Reactant: Fc1ccc(CBr)cc1F
Product: Fc1ccc(Cn2ccccc2=Nc2ccc(F)c(F)c2)cc1F

Procedure:
The title compound was prepared in four steps from 3,4-difluoroaniline, 2-fluoropyridine and 3,4-difluorobenzyl bromide as described in Procedure B. The crude product was purified by preparative LC-MS to give the title compound as the free base (yellowish solid). MS (ES+) m/z 333 ([M+1]+, 100); HR-MS: 333.1008 ([M+1]+, C18H13F4N2; calc. 333.101485).
Reaction SMILES: [NH:1]1CC[CH2:6][CH:2]1[C:3](O)=O.C(=O)([O-])[O-].[K+].[K+].I[C:16]1[CH:17]=[C:18]([C:22]2[N:23]=[C:24]3[C:30]([C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:29][NH:28][C:25]3=[N:26][CH:27]=2)[CH:19]=[CH:20][CH:21]=1.C(N)(C)C>[Cu](I)I.CS(C)=O>[CH:2]([NH:1][C:16]1[CH:17]=[C:18]([C:22]2[N:23]=[C:24]3[C:30]([C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:29][NH:28][C:25]3=[N:26][CH:27]=2)[CH:19]=[CH:20][CH:21]=1)([CH3:6])[CH3:3]
Reactant: O=C(O)C1CCCN1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(I)c3)nc12
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)N
Product: CC(C)Nc1cccc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 16.5 %

Procedure:
DMSO (1.5 mL) was added to a mixture of copper iodide (10.6 mg; 0.056 mmol), d,l-proline (12.8 mg; 0.11 mmol), potassium carbonate (113 mg; 0.81 mmol), and 1-[2-(3-Iodo-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (150 mg; 0.37 mmol). Isopropyl amine (0.315 mL; 0.219 g, 3.7 mmol) was added and the resulting mixture was stirred at 110° C. (oil bath) for 24 hrs. The reaction mixture was quenched with water and extracted 3 times with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to give a yellow oil. Preparative HPLC afforded 6.1 mg (5% yield) of 1-[2-(3-Isopropylamino-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a yellow solid
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([C:24]2[N:25]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:26]3[C:31]([CH:32]=2)=[CH:30][C:29]([CH:33]=O)=[CH:28][CH:27]=3)=[C:18]2[C:14]=1[CH2:15][NH:16][C:17]2=[O:42])(=[O:11])=[O:10])#[N:2].[NH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([C:24]2[N:25]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[C:26]3[C:31]([CH:32]=2)=[CH:30][C:29]([CH2:33][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[CH:28][CH:27]=3)=[C:18]2[C:14]=1[CH2:15][NH:16][C:17]2=[O:42])(=[O:11])=[O:10])#[N:2]
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccccc1C#N)CNC2=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cc(-c2cc3cc(CN4CCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccccc1C#N)CNC2=O

Procedure:
In a similar manner to Step 2 of Example 6, 4-(2-cyanobenzenesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (0.140 g, 0.238 mmol) was dissolved in acetonitrile (6.0 mL), and the solution was treated with pyrrolidine (0.398 mL, 4.77 mmol), acetic acid (0.273 mL, 4.77 mmol) and sodium triacetoxyborohydride (0.151 g, 0.715 mmol), followed by purification of the residue by flash column chromatography (chloroform/methanol=85/15, 80/20) to obtain 4-(2-cyanobenzenesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(pyrrolidin-1-ylmethyl)indol-2-yl]isoindolinone (0.0773 g, ESI-MS m/z: 643 [M+H]+; 1H-NMR (CD3OD)8(ppm): 1.18 (s, 9H), 1.83-1.92 (m, 4H), 2.88-2.96 (m, 4H), 3.25 (s, 3H), 4.04 (s, 2H), 4.49 (s, 2H), 6.55 (s, 1H), 7.00 (s, 1H), 7.28 (dd, J=1.6, 8.7 Hz, 1H), 7.52 (d, J=1.6 Hz, 1H), 7.77-7.93 (m, 3H), 8.08 (dd, J=1.6, 7.3 Hz, 1H), 8.17 (d, J=8.7 Hz, 1H).