Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:3]([CH3:6])(=[O:5])=[O:4])=[CH2:2].[NH2:7][CH2:8][C:9]([NH:12][C:13]1[C:14]([CH3:33])=[N:15][C:16]2[C:21]([N:22]=1)=[C:20]([C:23]1[NH:31][C:30]3[CH2:29][CH2:28][NH:27][C:26](=[O:32])[C:25]=3[CH:24]=1)[CH:19]=[CH:18][CH:17]=2)([CH3:11])[CH3:10]>C1COCC1.CC(O)C>[CH3:33][C:14]1[C:13]([NH:12][C:9]([CH3:11])([CH3:10])[CH2:8][NH:7][CH2:2][CH2:1][S:3]([CH3:6])(=[O:5])=[O:4])=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[C:23]2[NH:31][C:30]3[CH2:29][CH2:28][NH:27][C:26](=[O:32])[C:25]=3[CH:24]=2)[N:15]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)CN
Reactant: C=CS(C)(=O)=O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)CNCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.4 %

Procedure:
A solution of methyl vinyl sulfone (0.016 mL, 0.178 mmol) (Sigma-Aldrich) in THF (1.0 mL) was added to a mixture of 2-(3-((1-amino-2-methylpropan-2-yl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (341) (65 mg, 0.18 mmol) in 2-Propanol (2.00 mL); the reaction mixture was stirred at RT for 16 h when only a small amount of product was observed via lcms. More methyl vinyl sulfone (0.16 mL, 1.78 mmol) was added to the reaction mixture before it was heated in the microwave at 110° C. for 75 min when mostly product was observed via lcms. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 1-6% of 2 M NH3 in MeOH/DCM to give 2-(2-methyl-3-((2-methyl-1-((2-(methylsulfonyl)ethyl)amino)propan-2-yl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (342, 58 mg, 0.12 mmol, 69% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.63 (s, 6H) 2.57 (s, 3H) 2.91 (s, 2H) 2.92 (s, 3H) 2.97 (t, J=6.94 Hz, 2H) 3.18-3.25 (m, 2H) 3.25-3.31 (m, 2H) 3.65 (td, J=6.85, 2.35 Hz, 2H) 5.52 (br. s., 1H) 5.92 (s, 1H) 7.09 (d, J=1.76 Hz, 1H) 7.36 (t, J=7.82 Hz, 1H) 7.64 (dd, J=8.12, 1.08 Hz, 1H) 7.91 (dd, J=7.63, 0.98 Hz, 1H) 12.49 (br. s., 1H). MS (ESI, pos. ion) m/z: 471.4 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH:11]=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:13][Si:14](Cl)([CH3:16])[CH3:15].C(N(CC)CC)C>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH:10]=[CH:11][O:12][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(CCC=O)c1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)OC=CCc1cccc(C#N)c1

Procedure:
A stirred solution of 3-(3-cyanophenyl)propanal (3.1 g), trimethylsilyl chloride (3.0 ml) and triethylamine (6.5 ml) in dimethylformamide (45 ml) was heated under reflux on an oil bath at 150°-160° C. for 4 hours. The mixture was cooled and filtered and the filtrate was diluted with hexane (200 ml) and rapidly washed successively with cold sodium bicarbonate solution, cold dilute hydrochloric acid and cold sodium bicarbonate solution again. The hexane solution was dried and evaporated and the residue was distilled under vacuum in a bulb-to-bulb apparatus to give the product as a colourless oil, b.p. 140°-150° C./0.1 mm.
Reaction SMILES: [H-].[Na+].[Br-].[CH:4]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5]1.[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][CH:31]=1)=[O:29].O>O1CCCC1>[C:4]1(=[CH:36][C:33]2[CH:34]=[CH:35][C:30]([C:28]([O:27][CH3:26])=[O:29])=[CH:31][CH:32]=2)[CH2:6][CH2:5]1
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CC2)cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C=C2CC2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
To a suspension of sodium hydride (60%, 0.27 g) in tetrahydrofuran (40 mL) was added cyclopropyltriphenylphosphonium bromide (2.6 g), and the mixture was stirred at 70° C. for 2 hours. To the reaction mixture was added methyl terephthalaldehydate (1.0 g), and the mixture was stirred at 70° C. for 7 days. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/dichloromethane=1/1) to give methyl 4-(cyclopropylidenemethyl)benzoate (0.80 g).
Reaction SMILES: [Br:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][CH:7]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][C@H:9]([OH:26])[C@@H:10]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CO[C:49](OC)([CH3:51])[CH3:50]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:11]([C@H:10]1[C@H:9]([CH2:8][CH:7]([NH:27][C:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:37])[CH2:6][C:5]2[CH:38]=[CH:39][C:2]([Br:1])=[CH:3][CH:4]=2)[O:26][C:49]([CH3:51])([CH3:50])[N:18]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CC(Cc1ccc(Br)cc1)NC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccccc2)[C@H](CC(Cc2ccc(Br)cc2)NC(=O)OCc2ccccc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A solution containing the product from Example 128A (3.37 mmol) in 2,2-dimethoxypropane (35 mL) was treated with p-toluenesulfonic acid monohydrate (0.032 g, 0.17 mmol), stirred at 25° C. for 1 hour, treated with triethylamine (0.14 mL, 1.0 mmol), and the reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to give the product (1.16 g, 54% yield), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:4]([C:19](=O)[CH3:20])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:4]([CH:19]([NH2:28])[CH3:20])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c(C)c([N+](=O)[O-])c1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1[N+](=O)[O-]
Temperature: 65 °C

Procedure:
A mixture of 1-(4-chloro-3′-fluoro-5-methyl-6-nitrobiphenyl-2-yl)ethanone (50 mg, 0.2 mmol) and ammonium acetate (130 mg, 1.7 mmol) in methanol (1 mL) and acetonitrile (1 mL) was heated at 65° C., in a sealed tube, for 30 min. The mixture was cooled to room temperature and sodium cyanoborohydride (22 mg, 0.35 mmol) was added. The reaction was heated at 65° C. for another 4 hours, cooled to room temperature, quenched with saturated sodium bicarbonate, and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in next step. LCMS calculated for C15H15ClFN2O2 (M+H)+: m/z=309.1. found: 309.1.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:20]=[C:19]([CH2:21]Cl)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C>[N:23]([CH2:21][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([N:7]2[C:8]([NH2:10])=[CH:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]2)[CH:20]=1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1cc(N)n(-c2cc(CCl)c3ccccc3c2)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(N)n(-c2cc(CN=[N+]=[N-])c3ccccc3c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To a solution of 3-t-butyl-1-[4-(chloromethyl)naphthalen-2-yl]-1H-pyrazol-5-amine (1.5 g, 4.8 mmol) in DMF (8 mL) was added NaN3 (325 mg, 5.0 mmol). The mixture was stirred at RT overnight, then poured into ice-H2O and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, concentrated and purified via column chromatography to afford 1-[4-(azidomethyl)naphthalen-2-yl]-3-t-butyl-1H-pyrazol-5-amine (1.35 g, 88% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.06 (m, 2H), 8.04 (m, 1H), 7.85 (s, 1H), 7.54-7.57 (m, 2H), 5.41 (s, 1H), 5.35 (brs, 2H), 4.96 (s, 2H), 1.21 (s, 9H); MS (ESI) m/z: 321 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1.Br[CH2:9][CH2:10][OH:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:11][CH2:10][CH2:9][N:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1
Reactant: O=Cc1cn[nH]c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1cnn(CCO)c1
Temperature: 150 °C

Procedure:
Combine 1H-pyrazole-4-carbaldehyde (0.110 g, 1.14 mmol), 2-bromoethanol (0.172 g, 1.37 mmol), and potassium carbonate (0.236 g, 1.71 mmol) in acetonitrile (2 mL). Heat in microwave at 150° C. for 20 min. Cool to room temperature and filter, washing with acetonitrile. Concentrate filtrate to give the title preparation (0.155 g, 97%). GC-MS: m/z=140 [M+].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8](=O)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[CH2:4][CH2:3]1.Cl.[NH2:18][OH:19].C([O-])(=O)C.[NH4+]>C(O)C.O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8](=[N:18][OH:19])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[CH2:4][CH2:3]1
Reactant: NO
Reactant: CN1CCC(C(=O)c2ccccc2F)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN1CCC(C(=NO)c2ccccc2F)CC1
Yield: 54 %

Procedure:
A mixture of 5.2 g of 1-methyl-4-(2-fluorobenzoyl)piperidine, 2.5 g of hydroxylamine hydrochloride, 5.4 g of ammonium acetate and 50+15 ml of ethanol-water was heated under reflux for 22 hrs. Most of the ethanol was removed under reduced pressure. The aqueous mixture was made basic with aqueous sodium hydroxide and the mixture was extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate and the chloroform was evaporated in vacuo to give a solid. The solid was triturated with ether. Recrystallization from ethanol-water gave 3.0 g (52.6%) of product, mp, 136°-139°.
Reaction SMILES: [OH-].[Na+].O.[CH:4](=[O:9])[CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11]1>CCCCCC>[OH:9][CH:4]([CH:11]1[CH2:12][CH2:13][CH2:14][C:10]1=[O:15])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C1CCCC1
Reactant: CCCCC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Product: CCCCC(O)C1CCCC1=O
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
Into a 2-litter four-neck flask fitted with a thermometer, a reflux condenser and a stirrer were added sodium hydroxide (3.2 g) and water (300 ml). Then, a mixture of pentanal (86 g) and cyclopentanone (152 g) was added dropwise with stirring at 0-5° C. over a period of 2 hours. After the addition, the reaction mixture was stirred at room temperature for 1 hour to complete the reaction. Hexane (150 ml) was added to the reaction mixture and the layers were separated from each other. The resulting organic layer was washed with an aqueous solution (200 ml) of acetic acid (1 g) and then separated. The resulting organic layer was washed with saturated brine and separated. The organic layer was evaporated on a rotary evaporator under reduced pressure to recover hexane and unreacted cyclopentanone, whereby a crude product (173 g) was obtained. The product was distilled using a Claisen distillation apparatus to obtain 127 g of 2-(1-hydroxypentyl)cyclopentanone (boiling point: 115° C./933 Pa; GC purity: 95%). The remaining 5% was 2-pentylidenecyclopentanone which is a dehydration product.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([C@H:20]2[CH2:25][C@H:24]([CH2:26][CH:27]=[CH2:28])[S:23][N:22]([CH:29]([CH3:31])[CH3:30])[C@@H:21]2[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[CH:17]=[CH:18][CH:19]=1.CI.[Li+].CC([N-]C(C)C)C>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([C@H:20]2[CH2:25][C@:24]([CH3:1])([CH2:26][CH:27]=[CH2:28])[S:23][N:22]([CH:29]([CH3:31])[CH3:30])[C@@H:21]2[C:32]2[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)NC(C)C
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(C)C)S1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(C)C)S1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a degassed solution of diisopropylamine (300 μL, 2.123 mmol) in THF (1.0 ml) was added dropwise at −78° C. n-butyllithium, 2.5 M in hexanes (800 μL, 2.000 mmol). After stirring the solution at −78° C. for 10 min, the reaction was warmed to room temperature. In a separate flask, a degassed solution of 111.9 mg (0.255 mmol) of (3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-6-(2-propen-1-yl)-1,2-thiazinan (Example 117, Step E) and methyl iodide (0.6 ml, 9.62 mmol) in THF (1.0 ml) was heated to 50° C. After five minutes, the LDA solution was added dropwise to the other flask, and stirring continued for 14 hours at 50° C. Upon cooling to room temperature, the reaction was quenched with water (3 mL), then concentrated under reduced pressure. Purification by reverse-phase preparative HPLC using an Agilent Eclipse Plus C18 column (Agilent Technologies, Santa, Clara, Calif.), 0.1% TFA in CH3CN/H2O, gradient 60% to 80% over 25 minutes provided the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:28])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)=[N:4][CH:3]=1.Cl.C(O)C>C(Cl)(Cl)Cl>[NH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:6]=[CH:7][C:8]2=[O:28])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: NC1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Temperature: 40 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
A solution of 0.59 g of tert-butyl (1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 30 mL of a 2 mol/L hydrogen chloride/ethanol was stirred at room temperature for 18 hours. To the reaction mixture, 2 mL of chloroform was added, and the mixture was stirred at 40° C. for 4 hours, and stirred at room temperature for 18 hours. In the reaction mixture, the solvent was distilled off under reduced pressure, the mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and then the solvent was distilled off under reduced pressure. The resultant residue was washed with ethanol and, in the mother liquid, the solvent was distilled off under reduced pressure, and the resultant residue was purified with silica gel column chromatography using silica gel; Chromatorex-NH made by Fuji Silysia Chemical Ltd. and an eluent of chloroform:methanol=10:1 to obtain 421 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one as a light yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][CH:13]2[CH2:22][CH2:21][C:16]3([O:20][CH2:19][CH2:18][O:17]3)[CH2:15][CH2:14]2)=[CH:10][CH:9]=1.Br[CH2:26][CH2:27][CH2:28][Cl:29].C(OCC)C>CN(C)C=O>[Cl:29][CH2:28][CH2:27][CH2:26][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13]2[CH2:22][CH2:21][C:16]3([O:17][CH2:18][CH2:19][O:20]3)[CH2:15][CH2:14]2)=[CH:23][CH:24]=1
Reactant: ClCCCBr
Reactant: Oc1ccc(CC2CCC3(CC2)OCCO3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: ClCCCOc1ccc(CC2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A suspension of potassium carbonate 3.92 g) in a solution of 8-(4-hydroxybenzyl)-1,4-dioxaspiro[4.5]decane (1.41 g) and 1-bromo-3-chloropropane (2.81 mL) in N,N-dimethylformamide (35 mL) is stirred for 20 h at room temperature. Diethyl oxide (210 mL) is added and the suspension is filtered. The filtrate is washed with water (twice 50 mL), dried over magnesium sulfate and concentrated under reduced pressure to give 1.635 g of 8-[4-(3-chloropropoxy)benzyl]-1,4-dioxaspiro[4.5]-decane used without further purification.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1.[CH:17](/B(O)O)=[CH:18]/[CH3:19]>>[CH3:14][CH2:13][CH:12]([N:8]1[C:6]2=[N:7][C:2](/[CH:17]=[CH:18]\[CH3:19])=[CH:3][N:4]=[C:5]2[N:10]=[C:9]1[OH:11])[CH2:15][CH3:16]
Reactant: C/C=C\B(O)O
Reactant: CCC(CC)n1c(O)nc2ncc(Br)nc21
Product: C/C=C\c1cnc2nc(O)n(C(CC)CC)c2n1

Procedure:
The title compound was prepared by reacting 6-bromo-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyrazin-2-ol (1.0 equiv), (Z)-prop-1-enyl boronic acid (1.5 equiv) and (DPPF)PdC12 (0.15 equiv) in a manner analagous to Exmple 1(d). LCMS m/z (APCI)=247.0 (M+H).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[N:9]([CH2:18][C:19]2[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=2[O:29][CH3:30])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([Cl:17])=[CH:12][CH:11]=2)=[O:7])C>C(O)C>[C:25]([C:23]1[CH:22]=[CH:21][C:20]([O:29][CH3:30])=[C:19]([CH:24]=1)[CH2:18][N:9]1[C:10]2[C:15](=[CH:14][C:13]([Cl:17])=[CH:12][CH:11]=2)[CH:16]=[C:8]1[C:6]([OH:7])=[O:5])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1Cc1cc(C(C)(C)C)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(C)(C)C)cc1Cn1c(C(=O)O)cc2cc(Cl)ccc21
Temperature: 45 °C
Yield: 98.2 %

Procedure:
A solution of 4M aqueous sodium hydroxide (1.10 ml) was added to a solution of 1-(5-tert-butyl-2-methoxybenzyl)-5-chloro-1H-indole-2-carboxylic acid ethyl ester (1.13 g, 2.82 mmol) in ethanol (15 ml) and the reaction heated at 45° C. for 3 h. After concentrating the mixture to 5.0 ml, a solution of 2M aqueous HCl (2.0 ml) was added to precipitate the product as a pale solid which was filtered, washed with water (3×30 ml) and dried under vacuum, affording 1-(5-tert-butyl-2-methoxybenzyl)-5-chloro-1H-indole-2-carboxylic acid (1.03 g, 2.77 mmol, 98%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28][O:29][CH2:30][CH2:31]Br>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[N:21]([CH2:31][CH2:30][O:29][CH3:28])[S:22]([CH3:25])(=[O:23])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(NS(C)(=O)=O)c2cc(OCc3ccccc3)ccc2O1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COCCN(C1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
8.9 g (25 mmol) of 6-benzyloxy-4-(methylsulfonyl)amino-2,2-dimethylchroman (Example 1e) were introduced in portions at 10° C. into a suspension of 0.54 g (30 mmol) of sodium hydride (60% dispersion) in 80 ml of DMA. After stirring at 50° C. for 30 min, 2.2 ml (22 mmol) of 2-methoxyethyl bromide were added dropwise at RT. The mixture was then heated to 110° C. for 1 h, concentrated in vac., the residue was treated with water and aqueous hydrochloric acid, the resinous product was taken up with EA, the solution was dried and concentrated, and the residue was chromatographed on silica gel using toluene/EA (3:1). 2.2 g of product were crystallized from appropriate fractions using petroleum ether, m.p. 66-68° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](=[O:14])[N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[O:25]
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1C(=O)Nc1ccncc1
Reactant: CCNCC
Product: CCN(CC)C(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1

Procedure:
Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with diethyl amine gives “A87”; method 1: HPLC/MS: 1.36 min, [M+H]=390;
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[CH:32]=[CH:31][O:30][CH:29]=1)(=[O:27])=[O:26].[OH-].[NH4+:34]>>[NH2:34][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:22])([CH3:23])[CH3:21])=[N:9][C:8]=2[C:7]2[C:2]([Cl:1])=[C:3]([NH:24][S:25]([C:28]3[CH:32]=[CH:31][O:30][CH:29]=3)(=[O:27])=[O:26])[CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccoc3)c2Cl)c(-c2ccnc(Cl)n2)s1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccoc3)c2Cl)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide (130 mg, 0.255 mmol) and ammonium hydroxide (3 mL), the title compound was obtained as an off-white solid (48 mg, 38% yield). MS (ESI): 490 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)(=[O:4])=[O:3].[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CS(=O)(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 40 %

Procedure:
1-methanesulfonyl-3-trifluoromethylbenzene (220 mg; 1 mmol) was dissolved at 0° C. in 3 mL 98% sulfuric acid and 2 mL of 100% HNO3 were added. The mixture was heated 2 hours at 80° C. and then poured onto ice; a precipitate was isolated: 110 mg (0.40 mmol; 40% yield) of 1-methanesulfonyl-3-nitro-5-trifluoromethylbenzene were obtained as a solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[C:12]([NH:14][CH3:15])=[O:13])[C:7](=O)[CH:6]1[CH2:28][CH:29]1[CH2:31][CH2:30]1)=[O:4].[C:40]([O:44][C:45]([NH:47][C:48]1([C:51]([OH:53])=O)[CH2:50][CH2:49]1)=[O:46])([CH3:43])([CH3:42])[CH3:41].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C>[C:40]([O:44][C:45](=[O:46])[NH:47][C:48]1([C:51](=[O:53])[NH:1][CH:2]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:3]([N:5]2[CH2:10][CH2:9][N:8]([CH:11]([C:12](=[O:13])[NH:14][CH3:15])[CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[CH2:7][CH:6]2[CH2:28][CH:29]2[CH2:31][CH2:30]2)=[O:4])[CH2:49][CH2:50]1)([CH3:41])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(N)Cc2ccc(F)cc2)C(CC2CC2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)C2(NC(=O)OC(C)(C)C)CC2)C(CC2CC2)C1
Reaction time: 3 h

Procedure:
To a solution of 2-{4-[2-amino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide, 18, (62 mg, 0.12 mmol) in DMF (2 mL) are added tert-butoxycarbonylamino-cyclopropanecarboxylic acid (28.5 mg, 0.14 mmol), 1-hydroxybenzotriazole (36 mg, 0.266 mmol), N-methylmorpholine (74 mg, 0.74 mmol) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (29 mg, 0.15 mmol) consecutively. The reaction mixture is stirred for 3 hours, quenched with aqueous NH4Cl and extracted several times with ethyl acetate. The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo to a residue, which is purified over silica gel (CH2Cl2/CH3OH, 13:1) to afford the desired product.