Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=2)[NH2:9])=[CH:4][CH:3]=[N:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25](O)=[O:26])=[C:16]([C:29]([O:31]C)=[O:30])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25]([NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:6]([C:5]3[O:1][N:2]=[CH:3][CH:4]=3)[CH:7]=2)=[O:26])=[C:16]([CH:15]=1)[C:29]([OH:31])=[O:30]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Nc1cccc(-c2ccno2)c1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccno2)c1

Procedure:
Using the same method as in Example 15-(i), 3-(isoxazol-5-yl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([3-(isoxazol-5-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 56%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[C:19]2[O:26][N:25]=[C:24]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[C:20]=2[N:21]=[CH:22][N:23]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[C:19]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=4)[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)c1ccc(-c2noc3c(Cl)ncnc23)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c(-c4ccc(S(C)(=O)=O)cc4)noc23)CC1
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.49 mmol) was dissolved in anhydrous THF (5 mL) and treated with NaH, 60% oil dispersion (20 mg, 0.49 mmol) at ambient temperature. After stirring for 10 min, 7-chloro-3-(4-methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidine (0.15 g, 0.49 mmol) was added. The reaction was stirred for 3 h and concentrated under vacuum. The residue was purified by column chromatography using ethyl acetate and hexane (1/1) to afford 4-[3-(4-methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.14 g, 61%). 1H NMR (400Mz, DMSO-d6) δ 8.51 (s, 1H), 8.42 (d, J=7.1, 2H), 8.34 (d, J=7.1, 2H), 4.11˜3.83 (m, 4H), 3.52 (m, 1H), 3.26 (s, 3H), 1.41˜1.22 (m, 4H). LCMS 475.3[M+H].
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[Cl:5][C:6]1[CH:7]=[N:8][N:9]([OH:11])[CH:10]=1>C(#N)C>[CH3:1][NH:2][C:3](=[O:4])[O:11][N:9]1[CH:10]=[C:6]([Cl:5])[CH:7]=[N:8]1
Reactant: CN=C=O
Reactant: On1cc(Cl)cn1
Solvent: CC#N
Product: CNC(=O)On1cc(Cl)cn1
Reaction time: 12 h

Procedure:
8 g of methyl isocyanate, dissolved in 50 g of acetonitrile, are added to 15 g of 4-chloro-1-hydroxypyrazole and 150 g of acetonitrile at 25° C., while stirring. Stirring is continued for 12 hours, after which the reaction mixture is evaporated down and the residue is digested 3 times with a total of 150 g of petroleum ether. 17.8 g (80% of theory) or 4-chloropyrazol-1-yl N-methylcarbamate of melting point 125° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:23])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:30]([C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1)#[N:31].O>O1CCOCC1>[Cl:23][C:4]1[CH:3]=[C:2]([C:35]2[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[N:33][CH:34]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:22])[C:9]([OH:14])([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: Cc1cc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C(O)(C(C)c2ccc(-c3ccc(C#N)nc3)cc2Cl)C(F)(F)F)ccn1

Procedure:
A mixture of 3-(4-bromo-2-chloro-phenyl)-1,1,1-trifluoro-2-(2-methyl-pyridin-4-yl)-butan-2-ol (Example 60 step 1, 40 mg), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palldadium(II) (7 mg), Cs2CO3 (96 mg) and 2-cyanopyridine-5-boronic acid pinacol ester (CAS Reg. No. 741709-63-7, 45 mg) in dioxane (2 ml) and water (0.2 ml) was heated at 100° C. for 10 min in a sealed tube. The mixture was purified by prep. HPLC (C18-column, solvent gradient 30-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (32 mg) as a yellow solid. MS (m/e)=432.2 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([CH3:30])[C:10]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][C:14]=3[N:13]=[C:12]([NH:23]C(=O)C(C)(C)C)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([CH3:30])[C:10]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][C:14]=3[N:13]=[C:12]([NH2:23])[N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N(C)c2nc(NC(=O)C(C)(C)C)nc3[nH]c4ccccc4c23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cccc(N(C)c2nc(N)nc3[nH]c4ccccc4c23)c1
Yield: 93 %

Procedure:
Using the general procedure described above, the reaction of 9 (90 mg, 0.22 mmol) and 1 N NaOH provided 66 mg of AAG105 as a white solid in 93% yield. TLC Rf 0.27 (chloroform-methanol 15:1); mp 245.3-245.7° C.; 1H NMR (DMSO-d6) δ 3.48 (s, 3H, OCH3), 3.71 (s, 3H, NCH3), 6.20 (s, 2H, NH2, exch), 5.75-7.15 (m, 8H, Ar—H), 11.22 (s, 1H, 9-NH, exch). Anal. Calculated (C18H17N5O. 0.17H2O): C, 67.05; H, 5.42; N, 21.72. Found: C, 67.06; H, 5.37; N, 21.56.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=4)=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[NH:3]1.[N-:38]=[N+:39]=[N-:40].[Na+].O>[Zn+2].[Br-].[Br-].O>[C:28]1([C:27]2[C:20]([C:17]3[CH:16]=[CH:15][C:14]([CH2:13][N:10]4[CH2:9][CH2:8][CH:7]([N:6]5[C:5]6[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=6[NH:3][C:2]5=[O:1])[CH2:12][CH2:11]4)=[CH:19][CH:18]=3)=[N:21][CH:22]=[C:23]([C:24]3[NH:40][N:39]=[N:38][N:25]=3)[CH:26]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cnc(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)c(-c2ccccc2)c1
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Product: O=c1[nH]c2ccccc2n1C1CCN(Cc2ccc(-c3ncc(-c4nnn[nH]4)cc3-c3ccccc3)cc2)CC1

Procedure:
A mixture of 6-(4-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-5-phenylnicotinonitrile (1-5; TFA salt) (71 mg, 0.1 mmol), 2M of NaN3 water solution (0.75 mL, 1.5 mmol), 2M of ZnBr2 water solution (0.5 mL, 1.0 mmol) was microwaved (Smith-Synthesizer) at 165° C. for 15 min. After this time, the solution was concentrated. The residue was re-dissolved in DMSO (1 mL) and purified by LCMS to afford the pure desired product (1-6; TFA salt) as a slightly yellow solid. Analytical LCMS: single peak (214 nm), 2.248 min. 1H NMR (500 MHz, DMSO-d6): δ 10.94 (s, 1H), 9.74-9.90 (s, 1H), 9.33 (d, J=2.1 Hz, 1H), 8.44 (d, J=2.1 Hz, 1H), 7.47-7.50 (s, 4H), 7.36-7.40 (m, 3H), 7.26-7.30 (m, 3H), 6.98-7.02 m, 3H), 4.45-4.54 (m, 1H), 4.33-4.38 (s, 2H), 3.49 (d, J=12.7 Hz, 2H), 3.13-3.23 (m, 2H), 2.58-2.69 (m, 2H), 1.95 (d, J=12.8 Hz, 2H); HRMS, calc'd for C31H29N8O (M+1), 529.2459; found 529.2449.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]4[CH:30]=[CH:29][N:28]=[N:27]4)[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:10]1)=O)(C)(C)C.Cl>ClCCl.C(O)C>[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]4[CH:30]=[CH:29][N:28]=[N:27]4)[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: N[C@@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(5R)-3-(4-((3R)-3-(t-Butoxycarbonyl)aminopyrrolidin-1-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (532 mg, 1.2 mM), was dissolved in dichloromethane (10 ml), and treated with a solution of hydrogen chloride in ethanol (3.8M, 2 ml). After stirring 4 hours at ambient temperature, the precipitated hydrochloride of the product (230 mg) was filtered, and the filtrate diluted with diethyl ether to deposit more product (218 mg).
Reaction SMILES: N([O-])=O.[Na+].FC(F)(F)C([O-])=O.[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][C:23]([NH3+])=[C:22]([F:27])[C:21]=12)=[O:16])[CH3:13].[BrH:28]>O>[Br:28][C:23]1[CH:24]=[CH:25][N:20]2[N:19]=[CH:18][C:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])=[C:21]2[C:22]=1[F:27]
Reactant: Br
Reactant: CCOC(=O)c1cnn2ccc([NH3+])c(F)c12
Agent: O=C([O-])C(F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cnn2ccc(Br)c(F)c12
Reaction time: 0.5 h

Procedure:
NaNO2 (2.26 g, 32.89 mmol) in water (7 mL) was added dropwise at 0° C. to a solution of 3-(ethoxycarbonyl)-4-fluoropyrazolo[1,5-a]pyridin-5-aminium 2,2,2-trifluoroacetate (7 g, 97.5 mmol) in aq. 47% HBr (56 mL) and continued stirring at same temperature for 30 min. CuBr (6.29 g, 44 mmol) in aq. 47% HBr (56 mL) was added dropwise to above solution at 0° C. and stirring was continued at 28° C. for 1 hr. Reaction mixture was quenched with ice water, extracted into EtOAc, washed it with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude. The crude obtained was purified by column purification (using 60-120 silicagel and 5% EtOAc in Hexane as eluant) to afford ethyl 5-bromo-4-fluoropyrazolo[1,5-a]pyridine-3-carboxylate. NMR (300 MHz, DMSO-d6) δ 9.45-9.43 (d, 1H), 8.51 (s, 1H), 8.33-8.30 (d, 1H), 4.35-4.28 (m, 2H), 1.36-1.31 (t, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([N:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32](=[O:34])[CH3:33])([C:26]([O:28]CC)=O)[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]2([N:31]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:32](=[O:34])[CH2:33][C:26]2=[O:28])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C1(N(C(C)=O)c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C1CC(=O)C2(CCN(Cc3ccccc3)CC2)N1c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine (1.54 g, 15 mmol) was dissolved in THF (50 mL) and then the mixture was cooled to −78° C. n-Butyl lithium (6.1 mL, 2.5 M in hexane) was added dropwise at −78° C. After addition, the reaction mixture was stirred for 30 min at −78° C. Ethyl 1-benzyl-4-(N-phenylacetamido)piperidine-4-carboxylate (2.9 g, 7.6 mmol) was added dropwise at −78° C. The mixture was continued to stir for 1 h at −78° C. The reaction was quenched by dropwise addition of water (10 mL) at −78° C. and then allowed to warm to room temperature. The organic layer was separated. The aqueous phase was acidified to pH 6-7 with acetic acid and extracted with EtOAc (3×20 mL). The combined organics were washed with brine, dried over Na2SO4 and evaporated under vacuum to give crude product as a solid, which was washed with ether to give 8-benzyl-1-phenyl-1,8-diazaspiro[4.5]decane-2,4-dione. 1H NMR (300 MHz, MeOD) δ 7.12-7.47 (m, 15H), 4.04 (s, 2H), 3.65-3.66 (m, 2H), 3.51-3.57 (m, 1H), 3.02-3.06 (m, 2H), 2.66-2.73 (m, 2H), 1.93-2.00 (m, 5H), 1.82-1.87 (m, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:15]2[O:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([CH3:22])[C:11](=[O:23])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][S:5][C:6]2[C:15]3[O:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[C:12]([CH3:22])[C:11](=[O:23])[C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:34][CH2:33]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Cc1c(-c2ccccc2)oc2c(SCCCCl)cccc2c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1N1CCN(CCCSc2cccc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
A mixture of 4.4 g of Intermediate XXXIV, 2.5 g of 1-(2-methoxyphenyl)-piperazine, 1 g of potassium iodide and 1.8 g of anhydrous potassium carbonate in 40 ml of dimethylformamide was stirred at 100° C. for 3 hours. After cooling to 20°-25° C., the reaction mixture was poured into 350 ml of water and extracted with dichloromethane. The organic extracts were washed with water and dried on anhydrous sodium sulfate, and the solvent was then evaporated off in vacuo. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate: petroleum ether 3:2, and by crystallization from ethanol, yielding 3.9 g of the title compound, m.p. (70) 96°-99° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4](=[CH2:10])[CH2:5][C:6](OC)=[O:7].[NH3:12]>CO>[O:7]=[C:6]1[NH:12][CH2:10][CH:4]([C:3]([O:2][CH3:1])=[O:11])[CH2:5]1
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: N
Solvent: CO
Product: COC(=O)C1CNC(=O)C1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
To a solution of 2-methylene-succinic acid dimethyl ester (158 g, 1 mol, 1 eq) in MeOH (150-160 mL) was added dropwise anhydrous liquid ammonia (17 g, 1 mol, 1 eq). The mixture was stirred at room temperature for 1.5-2 h, keeping the outlet of the flask connected with a small mercury trap (1-2 cm Hg), and left to stand overnight. Most part of MeOH was evaporated on a water bath and then residual MeOH was evaporated in vacuo until the mixture transformed into a semisolid mass. This mass was distilled in vacuo. Starting compound was distilled (bp 60-70° C. at 1 mm Hg) followed by distillation of title compound (bp 140-150° C. at ˜1 mm Hg) as colorless liquid, which crystallized very fast (72 g, 0.5 mol, 50%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:7]=1[CH3:14])=[O:4].[C:15]([C:17]1[CH:18]=[C:19]([S:23]([N:26]2[C@H:31]([CH3:32])[CH2:30][NH:29][CH2:28][C@@H:27]2[CH3:33])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1)#[N:16]>>[C:15]([C:17]1[CH:18]=[C:19]([S:23]([N:26]2[C@@H:31]([CH3:32])[CH2:30][N:29]([CH2:2][C:3]([NH:5][C:6]3[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:7]=3[CH3:14])=[O:4])[CH2:28][C@H:27]2[CH3:33])(=[O:24])=[O:25])[CH:20]=[CH:21][CH:22]=1)#[N:16]
Reactant: C[C@@H]1CNC[C@H](C)N1S(=O)(=O)c1cccc(C#N)c1
Reactant: Cc1ccc(C#N)cc1NC(=O)CCl
Product: Cc1ccc(C#N)cc1NC(=O)CN1C[C@@H](C)N(S(=O)(=O)c2cccc(C#N)c2)[C@@H](C)C1

Procedure:
The title compound was prepared from the product of step (i) (0.19 g) and the product from Example 80 step (ii) (0.2 g) by the method of Example 80 step (iii) as a white solid. Yield: 0.25 g
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][C:21](OCC)=[O:22])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.C1COCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:26])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH2:21][OH:22])(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: CCOC(=O)CCC1CCCCN1S(=O)(=O)c1c(C)cc(OC)cc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCO)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl 3-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)propanoate (3.39 mmol. 1 eq) in THF (10 ml) was slowly to a suspension of LAH (7.47 mmol, 2.2 eq) in THF (7.5 ml) at 0° C. and the mixture was stirred for 30 min. The mixture was subsequently warmed to room temperature and stirred for 1 h. A water/THF mixture was then added, the mixture was filtered over Celite and the filtrate was concentrated in vacuo. The crude product (0.88 g) was employed in the following stage without further purification.
Reaction SMILES: [N:1]([C@@H:4]([CH:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[C:5]([OH:7])=[O:6])=[N+]=[N-].C(O)(=O)C>[Pd].O>[NH2:1][C@@H:4]([CH:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[C:5]([OH:7])=[O:6]
Reactant: CCC(CC)[C@H](N=[N+]=[N-])C(=O)O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: CCC(CC)[C@H](N)C(=O)O
Temperature: 70 °C
Reaction time: 20 h
Yield: 78.9 %

Procedure:
A mixture of the product from Example 4 (31.7 g, 0.185 mol), 10% palladium on carbon (7.9 g), glacial acetic acid (370 mL), and water (926 mL) was placed under an atmosphere of hydrogen (40 psi) and shaken on a Parr hydrogenator. After 20 h, the reaction mixture was filtered through a pad of Celite (½″), which was rinsed well with water (200 mL). The filtrate was concentrated under reduced pressure in a bath heated to 70° C. to produce a white solid. The solid was triturated with ethyl acetate (500 mL), filtered, and washed once more with ethyl acetate (500 mL), and then air dried. This gave the title compound as a white solid (21.2 g, 79%): Opt. Rot. [α]D25=+12.01° (1% solution, H2O); 1H NMR (D2O, 500 MHz): δ4.65 (s, 3H), 3.69 (d, J=3.4 Hz, 1H), 1.69 (m, 1H), 1.44 (m, 1H), 1.03-1.10 (m, 3H), 0.83 and 0.81 (two overlapping triplets, J=7.5 Hz, 6H); MS(−ESI): [M−H]−, 144 (100%); Anal. Calc. for C7H15NO2: C, 57.90; H, 10.41; N, 9.65. Found: C, 57.75; H, 10.89; N, 9.40. Chiral HPLC (Symmetry C18 column, eluant: solvent A=50 mM triethylamine pH adjusted to 3.0 with phosphoric acid, solvent B=AcCN, gradient 80% A/20%B to 50% A/50%B over 20 min, flow rate 1.0 mL/min, detection at 340 nm, S isomer has a retention time of 12.26 min and R isomer has a retention time of 15.46 min) of the amino acid derivatized by Marfey's reagent (N-α-(2,4-dinitro-5-fluorophenyl)-L-alaninamide) gave an enantiomeric ratio of 99.5:0.5 (2S:2R).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=2)=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.[C:22]([Cu])#[N:23]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([C:9]2[C:8]3[N:7]=[CH:6][CH:5]=[N:4][C:3]=3[C:2]([C:22]#[N:23])=[CH:11][CH:10]=2)[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1
Reactant: COc1cc(OC)cc(-c2ccc(Br)c3nccnc23)c1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1cc(OC)cc(-c2ccc(C#N)c3nccnc23)c1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
A mixture of 5-bromo-8-(3,5-dimethoxy-phenyl)-quinoxaline (Step 1.4) (4.54 g, 13.2 mmol) and CuCN (1.54 g, 17.1 mmol, 1.3 equiv) in NMP (50 mL) was stirred for 2 h at 180° C., under an argon atmosphere. The reaction mixture was allowed to cool to rt, diluted with EtOAc (10% aqueous solution of ethylenediamine) (150 mL), and filtered to afford 1.19 g (batch 1) of the title compound as a yellow solid. The filtrate was extracted with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was triturated in EtOAc to provide 2.31 g (batch 2) of the title compound: ESI-MS: 292.1 [M+H]+; tR=4.53 min (System 1).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH2:9]([CH:11]([NH2:14])[CH2:12][CH3:13])[CH3:10]>CCO>[CH3:10][CH2:9][CH:11]([NH:14][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1)[CH2:12][CH3:13]
Reactant: CCC(N)CC
Reactant: Clc1cncc(Cl)n1
Solvent: CCO
Product: CCC(CC)Nc1cncc(Cl)n1

Procedure:
A solution of 2,6-dichloropyrazine (2.2 g) and 1-ethylpropylamine (5 mL) in EtOH (10 mL) is heated at 140° C. in a Teflon-sealed tube. Resulting solution is concentrated in vacuo, diluted by water, and extracted twice with hexane-ethyl ether. Combined extracts are dried (sodium sulfate), filtered, concentrated in vacuo, and the residue is filtered through a short pad of silica gel. The filtrate is concentrated to give 2-(3-pentylamino)-6-chloropyrazine as brownish oil that solidifies on standing (3.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22](=[O:32])[NH:23][CH2:24][CH:25]([CH3:31])[CH2:26][C:27]([F:30])([F:29])[F:28])[CH:20]=2)[N:15]([CH3:33])[CH:14]=1)[C:6]([OH:8])=O.[CH3:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41]([NH2:44])(=[O:43])=[O:42]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22](=[O:32])[NH:23][CH2:24][CH:25]([CH3:31])[CH2:26][C:27]([F:28])([F:30])[F:29])[CH:20]=2)[N:15]([CH3:33])[CH:14]=1)[C:6]([NH:44][S:41]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[CH3:34])(=[O:42])=[O:43])=[O:8]
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C)c2ccc(C(=O)NCC(C)CC(F)(F)F)cc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(C)c2ccc(C(=O)NCC(C)CC(F)(F)F)cc12
Yield: 56.8 %

Procedure:
A solution of 3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)indol-3-yl-methyl]benzoic acid (250 mg), 4-dimethylaminopyridine (69.8 mg), I-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (127 mg) and 2-methylbenzenesulfonamide (95.4 mg) in methylene chloride (5 mL) was stirred under a nitrogen atmosphere 4or 24 hours. The mixture was diluted with methylene chloride, washed (10% (w/v) hydrochloric acid, water), and evaporated. The resulting rose-colored foam was dissolved in methylene chloride (5 mL), filtered through a 0.45 micron membrane filter, and precipitated by addition to hexane (50 mL). The solid was collected by filtration to give the title compound (189.2 mg, 57%) as a pale pink powder; mp 147°-149° C. Analysis for C31H32F3N3O5S: Calculated: C, 60.48; H, 5.24; N, 6.83. Found: C, 60.39; H, 5.60; N, 6.59.
Reaction SMILES: C([O:8][N:9]1[C@@H:12]([CH3:13])[C@H:11]([N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[C:10]1=[O:25])C1C=CC=CC=1>C1COCC1.[Pd]>[OH:8][N:9]1[C@@H:12]([CH3:13])[C@H:11]([N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[C:10]1=[O:25]
Reactant: C[C@H]1[C@H](N2C(=O)c3ccccc3C2=O)C(=O)N1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: C[C@H]1[C@H](N2C(=O)c3ccccc3C2=O)C(=O)N1O
Yield: 98.4 %

Procedure:
The O-benzyl derivative (51) (23.08 g) was taken up in THF (250 ml) and hydrogenolysed in the presence of 10% Pd/C until no starting material remained. The solution was filtered through Kieselguhr and the filtrate evaporated to give a white solid (52) (16.63 g), m.p. 94°-96° C. (from EtoAc--hexane), νmax (KBr) 3400, 1795, 1770, 1720, and 1400 cm-1, δ(CDCl3) 1.45(d, J 6.5 Hz, 3H) (irradiation at 4.18 caused this signal to collapse to a s), 4.18 (dq, j 6.5 and 2 Hz, 1H), 4.70(d, J 2 Hz, 1H) (irradiation at 4.18 caused this signal to collapse to a s), 7.3-8.0 (m, 4H), and 7.7-8.7br (1H, exch.), m/e 246(M+) and 187 (base peak). (Found: C, 58.28; H, 4.11; N, 11.46; M+ 246.0647. C12H10N2O4 requires C, 58.54; H, 4.09; N, 11.38%, M, 246.0681).