Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][O:12][CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1F.[H-].[Na+].O>CN(C=O)C.C(OCC)C>[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1[N:11]([O:12][CH3:13])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:14]([O-:16])=[O:15])[CH:4]=1)(=[O:10])=[O:9]
Reactant: CONS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CON(c1ccc([N+](=O)[O-])cc1Cl)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 12 %

Procedure:
To a solution of 4-chloro-N-methoxy-3-nitrobenzenesulfonamide (0.53 g (1.99 mmol)) and 3-chloro-4-fluoronitrobenzene (1.05 g (5.98 mmol) in 5.0 ml of DMF, sodium hydride (60%, 0.09 g (2.25 mmol)) was added bit by bit with stirring under cooling with ice, and the mixture was stirred under cooling with ice for one hour and at room temperature for 2 hours. Water and diethyl ether were added to the resulting mixture and insolubles were removed by filtration. The filtrate was allowed to stand somewhile and then, the organic layer was separated and washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:5) as eluent to give 0.10 g (12%) of the title compound as pale yellow-white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](=O)[CH2:5]Br.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:26][C:27]([NH2:29])=[S:28])[CH:17]=[CH:18][C:19]=1[N:20]1[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]1>C(Cl)Cl.C(OCC)C.C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]1[N:29]=[C:27]([NH:26][C:16]2[CH:17]=[CH:18][C:19]([N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]3)=[C:14]([O:13][CH3:12])[CH:15]=2)[S:28][CH:5]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: O=C(CBr)c1ccccc1Cl
Solvent: CCO
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(Nc2nc(-c3ccccc3Cl)cs2)ccc1-n1cnc(C)c1
Yield: 99.1 %

Procedure:
The title compound was prepared in analogy to example 1 step e) from 77 mg (0.33 mmol) 2-chlorophenacylbromide and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The solvent was evaporated under reduced pressure and the crude reaction was stirred with methylene chloride/diethyl ether/ethanol for 15 minutes at room temperature. The product was filtered off and dried to yield 118 mg (100%) [4-(2-chloro-phenyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a light yellow solid. MS ISP (m/e): 397.1/399.2 (100/44) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.71 (s, 1H), 9.27 (s, 1H), 7.98 (s, 1H), 7.93 (d, 1H), 7.67 (s, 1H), 7.56 (d, 1H), 7.51-7.38 (m, 4H), 7.27 (d, 1H), 3.88 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=1)#[CH:2].I[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=1>C(N)(CC)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=2)=[CH:4][CH:5]=1
Reactant: CSc1nccc(I)n1
Reactant: C#Cc1ccc(CC(C)NC(C)=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCC(C)N
Solvent: O
Product: CSc1nccc(C#Cc2ccc(CC(C)NC(C)=O)cc2)n1
Temperature: 25 °C

Procedure:
To 0.52 g (2.58 mmol) N-[2-(4-ethynyl-phenyl)-1-methyl-ethyl]-acetamide (I58.3) and 0.50 g (1.98 mmol) 4-iodo-2-(methylthio)pyrimidine in 3 mL sec-butylamine and 3 mL water are added 0.14 g (0.20 mmol) bis(triphenylphosphine)dichloro-palladium and the mixture is stirred at r.t. over night. The reaction mixture is diluted with water and extracted with DCM. The organic layer is dried with Na2SO4 and the solvent is removed in vacuo. The residue is purified by column chromatography (silica gel, DCM/MeOH 96/4). The resulting product is triturated with diethylether.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][NH:19][C:18]2=[O:22])[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[H-].[Na+].[CH2:25](I)[CH2:26][CH2:27][CH3:28]>CN(C)C=O>[CH2:25]([N:19]1[CH2:20][CH2:21][N:17]([CH:14]2[CH2:13][CH2:12][N:11]([C:1]([O:3][CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:2])[CH2:16][CH2:15]2)[C:18]1=[O:22])[CH2:26][CH2:27][CH3:28]
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCNC2=O)CC1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O

Procedure:
25 g of 1-(1-carbobenzoxy-4-piperidyl)-imidazolidin-2-one are added in portions to a mixture, which has been warmed to 80° C., of 2.4 g of sodium hydride in 100 ml of absolute dimethylformamide, with stirring. The mixture is stirred for a further 2 hours at 80° C. and 18.2 g of n-butyl iodide are then allowed to run in slowly dropwise (highly exothermic reaction). After stirring for a further 2 hours at 80° C., the reaction mixture is evaporated under reduced pressure and the residue is freed from dimethylformamide which is still adhering, by treatment with toluene. The reaction product is dissolved in 250 ml of ethyl acetate and the solution is washed twice with, in each case, 50 ml of water, dried over sodium sulphate and evaporated to dryness. The residue is chromatographed on 1.5 kg of silica gel using a mixture of chloroform/methyl alcohol (95:5) as the eluant mixture. In this way, 3-n-butyl-1-(1-carbobenzoxy-4-piperidyl)-imidazolidin-2-one is obtained in the form of a colourless oil.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([CH2:13][C:14]1[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12].O.COC(CC1C(Cl)=C(N)C=CC=1C(OC)=O)=O>C(#N)C>[CH3:9][O:10][C:11]([CH2:13][C:14]1[CH:23]=[C:22]([NH2:24])[C:21]([Cl:1])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)Cc1cc(N)ccc1C(=O)OC
Agent: COC(=O)Cc1c(C(=O)OC)ccc(N)c1Cl
Solvent: CC#N
Solvent: O
Product: COC(=O)Cc1cc(N)c(Cl)cc1C(=O)OC
Temperature: 25 °C

Procedure:
N-Chlorosuccinimide (1.0 g, 7.3 mmol) was added to a solution of methyl 2-methoxycarbonylmethyl-4-aminobenzoate (1.5 g, 6.6 mmol) in acetonitrile (10 mL). The mixture was stirred while heating under reflux for 1 hour. After the reaction solution was cooled to room temperature, water was added thereto and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Then, the resulting solid was washed with ethyl acetate to give a 0.9:1 mixture of the title compound and methyl 2-methoxycarbonylmethyl-4-amino-3-chlorobenzoate (1.5 g, 88%).
Reaction SMILES: F[C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3CCN(CCN4C(O)C5C(=CC=CC=5)C4=O)[CH2:11][CH2:10]3)=N[O:8][C:4]=2[CH:3]=1.CCN(CC)CC.C(Cl)(=[O:47])CCCCCCCCC>C(Cl)Cl>[C:4]([OH:8])(=[O:47])[CH2:3][CH2:2][CH2:29][CH2:28][CH2:5][CH2:6][CH2:9][CH2:10][CH3:11]
Reactant: O=C1c2ccccc2C(O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: CCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)O
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-2,3-dihydro-3-hydroxy-I H-isoindol-1-one (1.4 g, 3.5 mmol) in DCM (30 ml) was added Et3N (1.2 ml, 8.8 mmol) followed by decanoyl chloride at 0 C under nitrogen. After stirring for 1 h in the cooling bath, the solvent was removed using a stream of nitrogen. The remaining residue was diluted with EtOAc and the precipitated triethylamine hydrochloride was filtered off. The filtrate was concentrated and the remaining oil was flushed through alumina with ether to give 1.6 g (83%) of the desired product as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:5]=1.[ClH:17]>>[ClH:17].[N:11]1([CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:16])=[O:2])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1cccc(CN2CCCC2)c1
Agent: Cl
Product: O=C(O)c1cccc(CN2CCCC2)c1

Procedure:
A solution of 3-pyrrolidin-1-ylmethyl-benzoic acid methyl ester (800 mg, 3.6 mmol) in aqueous 25% hydrochloric acid (15 mL) was stirred at 90° C. for 4 hours. The solvent was evaporated affording the title compound as brown oil (quantitative) that was used as such for the next step.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[C:14]([O:21][CH3:22])=[N:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:27]2=[O:34].[Cl-].[NH4+]>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:27]2([C:13]1[C:14]([O:21][CH3:22])=[N:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=1)[OH:34]
Reactant: COc1ncc(Br)c(OC)n1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ncc(C2(O)C(=O)Nc3ccc(Cl)cc32)c(OC)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
A 1.6 M solution of n-butyllithium in hexane (10 ml, 16 mmol) was added dropwise to a solution of 5-bromo-2,4-dimethoxypyrimidine (3.29 g, 15 mmol) in THF (50 ml) at −78° C. After stirring at −78° C. for 0.5 h, a suspension of 5-chloroisatin (1.27 g, 7.0 mmol) in THF (50 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature and then saturated ammonium chloride solution was added. The mixture was extracted three times with ethyl acetate, and the combined organic layers were washed with saturated brine. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography (silica gel, 50% ethyl acetate in dichloromethane) resulted in 0.97 g of the intermediate.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=4[CH:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH:32]1[C:37]2[CH2:38][CH2:39][CH2:40][C:36]=2[CH:35]=[C:34]([CH:41]=O)[N:33]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[ClH:1].[CH:32]1[C:37]2[CH2:38][CH2:39][CH2:40][C:36]=2[CH:35]=[C:34]([CH2:41][NH:3][CH:4]2[CH2:5][CH2:6][N:7]([CH2:10][C@H:11]3[N:21]4[C:22]5[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=5[CH:18]=[CH:19][C:20]4=[O:23])[CH2:12]3)[CH2:8][CH2:9]2)[N:33]=1
Reactant: O=Cc1cc2c(cn1)CCC2
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1ccc2ccc(=O)n3c2n1C[C@H]3CN1CCC(NCc2cc3c(cn2)CCC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.9 %

Procedure:
A suspension of (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride (82 mg, 0.220 mmol) (for a preparation see Example 5(j)) in chloroform (5 ml) and methanol (0.2 ml) at rt under argon was treated with triethylamine (92 μl, 0.659 mmol) and stirred at rt for 0.25 h. The solution was then treated with 6,7-dihydro-5H-cyclopenta[c]pyridine-3-carbaldehyde (32.3 mg, 0.220 mmol) and stirred for a further 0.5 h. The solution was then treated with NaBH(OAc)3 (140 mg, 0.659 mmol) and stirred at rt for 0.5 h. The reaction was then treated with saturated aqueous NaHCO3 (100 ml) and extracted with 20% methanol/DCM (3×200 ml). The combined organic extracts were dried (MgSO4), filtered, evaporated and chromatographed (0-20% methanol/DCM) to give the free base of the title compound as a light brown solid (39 mg, 41%).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:4][CH2:3]1.O[Li].O>C1COCC1.O>[CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)=[CH:7][C:6]=2[C:5]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C(C)(C)C)=CCC3(C)C)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
A solution of 24.0 mg (0.06 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoate (Compound 71) and 6.5 mg (0.16 mmol) of LiOH—H2O in 3 mL THF/water (3:1, v/v) was stirred overnight (22 hours) at room temperature. The reaction mixture was extracted with Et2O and the layers were separated. The aqueous layer was acidified with HCl (1M aqueous solution) and then extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid.
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.OS(O)(=O)=O.[C:13]([O-])(O)=[O:14].[Na+]>CO>[OH:14][CH2:13][CH2:4][CH2:3][CH2:2][C:1]([O:6][CH3:5])=[O:7]
Reactant: O=C1CCCCO1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCCO
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
To prepare 2, freshly distilled δ-valerolactone (1) (856 mg) in methanol (17 ml) was treated with concentrated H2SO4 (100 μl) and refluxed for 12 hours. The solution was cooled to −20° C., treated with NaHCO3 (80 mg), and stirred for 10 minutes. The reaction mixture was filtered and the solvent was removed in vacuum. The residue was taken up in DCM (10 ml), dried over Na2SO4, filtered, and concentrated in vacuum to give methyl 5-hydroxypentanoate (2) (Huckstep et al., Synthesis 10:881-82 (1982), which is hereby incorporated by reference in its entirety) (1071 mg, 94%) as a colorless oil, which was used directly without any further purification. 1H NMR (400 MHz, acetone-d6): δ 1.55 (2H, m), 1.68 (2H, m), 2.35 (2H, t, J=7.4 Hz), 3.57 (2H, m), 3.64 (3H, s); 13C NMR (100 MHz, acetone-d6): δ 22.2, 32.9, 34.1, 51.5, 61.9, 174.2. See FIGS. 75A-B.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH2:6][C:7]1[N:11]=[CH:10][NH:9][CH:8]=1)[NH2:5].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH2:6][C:7]1[N:11]=[CH:10][NH:9][CH:8]=1)[N:5]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1c[nH]cn1)N=Cc1ccccc1

Procedure:
Histidine methyl ester, 185 mg (1 mmole), is treated with 1.06 g (1 mmole) of benzaldehyde in 25 ml of CHCl3 for 3 hours. MgSO4, 0.2 g, is added for the last hour. The mixture is filtered and the solvent is evaporated, to leaving compound 2.I as a residue.
Reaction SMILES: CNCCN(C)C.[CH2:8]([Li])[CH2:9][CH2:10]C.[Cl:13][C:14]1[C:19]([CH:20]=[O:21])=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cu]C#N.C(Br)C=C.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:10]([C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:13])[C:19]=1[CH:20]=[O:21])[CH:9]=[CH2:8]
Reactant: O=Cc1ccccc1Cl
Reactant: [Li]CCCC
Agent: N#C[Cu]
Agent: CNCCN(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: C=CCBr
Product: C=CCc1cccc(Cl)c1C=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under an atmosphere of protective gas, a solution of 10.89 g (0.107 mol) of trimethylethylenediamine in 50 ml of anhydrous tetrahydrofuran was cooled to −10° C. and admixed dropwise with 66.6 ml of a 1.6 molar solution of n-butyllithium in hexane (0.107 mol). After 10 minutes, 15 g (0.107 mol) of 6-chlorobenzaldehyde in 70 ml of tetrahydrofuran were added dropwise, and the mixture was admixed with a further 0.214 mol of n-butyllithium in hexane (146.8 ml) and stirred at 0° C. for 2.5 hours. The mixture was cooled to −200° C., 12.42 g (0.139 mol) of copper(I) cyanide were added, the mixture was stirred at −10° C. for 30 minutes, and 28.42 g of allyl bromide in 100 ml of tetrahydrofuran were then added dropwise. The mixture was stirred at 0° C. for another 2.5 hours, and 230 ml of saturated ammonium chloride solution were then added dropwise. The resulting solid was separated off and the aqueous phase was extracted with diethyl ether. The combined organic phases were then washed with saturated ammonium chloride solution and dried, and the solvent was removed under reduced pressure. This gave 17.0 g of 2-allyl-6-chlorobenzaldehyde (89%) in the form of a dark oil.
Reaction SMILES: N(O[CH2:4][CH2:5][CH:6](C)C)=O.[C:9]([OH:18])(=O)[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)N.O1C=CC=C1.[OH-].[Na+]>C(COC)OC>[CH:15]1[CH:16]=[C:10]2[C:11]([CH:6]3[O:18][CH:9]2[CH:4]=[CH:5]3)=[CH:13][CH:14]=1
Reactant: CC(C)CCON=O
Reactant: Nc1ccccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: c1ccoc1
Product: C1=CC2OC1c1ccccc12
Yield: 51 %

Procedure:
Solutions of 20 ml of isoamyl nitrite in glyme (20 ml) and of 13.7 g of anthranilic acid in glyme (45 ml) were added simultaneously by drops to a refluxing mixture of glyme (50 ml) and furan (50 ml). Refluxing was continued for ten minutes and the brown solution was cooled, made basic with aqueous sodium hydroxide (1 N), and extracted with petroleum ether. The extract was washed thoroughly with water, clarified with Norit®, dried, and evaporated to give an oil. The oil solidified on cooling to give 7 g (51% yield) of light yellow solid. Recrystalization of the yellow solid from petroleum ether gave colorless crystalline solid of 1,4-dihydronaphthalene-1,4-endo-oxide (IIIa), m.p. 53°-54° C. (lit. m. p. 56° C.).
Reaction SMILES: [C:1]1([C:7]2[C:16]([N:17]3[CH2:21][CH2:20][CH2:19][C@@H:18]3[C:22]([F:25])([F:24])[F:23])=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:26]([O:28]C)=[O:27])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].CO>O>[C:1]1([C:7]2[C:16]([N:17]3[CH2:21][CH2:20][CH2:19][C@@H:18]3[C:22]([F:25])([F:23])[F:24])=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:26]([OH:28])=[O:27])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@@H]3C(F)(F)F)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@@H]3C(F)(F)F)nc2c1
Temperature: 50 °C
Reaction time: 0.13 h

Procedure:
Into a 25-mL round-bottom flask, was placed (R)-methyl 2-phenyl-3-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoxaline-6-carboxylate (40 mg, 0.10 mmol, 1.00 equiv), sodium hydroxide (20 mg, 0.50 mmol, 5.00 equiv), methanol (5 mL), water (1 mL). The resulting solution was stirred for 5 hs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was diluted in 5 mL of water. The PH value was aqueous solution was adjusted to 4 with aq hydrochloric acid (1N). The resulting solids were collected by filtration. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-1): Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (60% CH3CN up to 90% in 8 min, up to 100% in 1.5 min); Detector, UV 220 254 nm. This resulted in 12 mg (30%) of (R)-2-phenyl-3-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([S:17]([CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:19])=[O:18])[CH2:12]2)=[N:4][C:5](SC)=[N:6][CH:7]=1.C[Si](C)(C)CCOC[N:30]1[C:34]2=[N:35][CH:36]=[C:37]([Sn](C)(C)C)[N:38]=[C:33]2[CH:32]=[CH:31]1>>[CH3:22][CH:21]([CH3:23])[CH2:20][S:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@H:11]([NH:10][C:3]2[C:2]([C:37]3[N:38]=[C:33]4[CH:32]=[CH:31][NH:30][C:34]4=[N:35][CH:36]=3)=[CH:7][N:6]=[CH:5][N:4]=2)[CH2:12]1)(=[O:19])=[O:18]
Reactant: CSc1ncc(Br)c(N[C@H]2CCCN(S(=O)(=O)CC(C)C)C2)n1
Reactant: C[Si](C)(C)CCOCn1ccc2nc([Sn](C)(C)C)cnc21
Product: CC(C)CS(=O)(=O)N1CCC[C@H](Nc2ncncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
Starting with (5-bromo-2-methylsulfanyl-pyrimidin-4-yl)-[(S)-1-(2-methyl-propane-1-sulfonyl)-piperidin-3-yl]-amine from above and 5-(2-trimethylsilanyl-ethoxymethyl)-2-trimethylstannanyl-5H-pyrrolo[2,3-b]pyrazine described in step 3 of Example 76, and using similar synthetic procedures of steps 4-5 described herein from Example 76, gave [(S)-1-(2-methyl-propane-1-sulfonyl)-piperidin-3-yl]-[5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-4-yl]-amine. MS (ES+): 416.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C:10]#[N:11])[CH:5]=[CH:4][N:3]=1.[CH3:13][NH:14][NH2:15]>CO>[CH3:13][N:14]1[C:10]([NH2:11])=[CH:9][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[N:15]1
Reactant: CNN
Reactant: Cc1cc(C(=O)CC#N)ccn1
Solvent: CO
Product: Cc1cc(-c2cc(N)n(C)n2)ccn1
Temperature: 70 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a 100 ml flask was added 3-(2-methylpyridin-4-yl)-3-oxopropanenitrile 16.1.C, (465 mg, 2.9 mmole), 10 ml of MeOH and methyl hydrazine (249 μl, 7.26 mmole). The reaction was stirred at 70° C. for 8 hours at which time the solvent was removed with a stream of nitrogen. The crude product was purified by using a silica gel column (eluting with 5% MeOH in DCM) to give of 1-methyl-3-(2-methylpyridin-4-yl)-1H-pyrazol-5-amine 16.1.D as a yellow film (317 mg 49% yield). (Note: converted to HCl salt).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[C:17](O)=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.Br.[NH2:55][C:56]1[S:57][CH:58]=[C:59]([C:61]2[C:66]([CH3:67])=[CH:65][C:64]([CH3:68])=[CH:63][C:62]=2[CH3:69])[N:60]=1>CN(C)C=O>[CH3:67][C:66]1[CH:65]=[C:64]([CH3:68])[CH:63]=[C:62]([CH3:69])[C:61]=1[C:59]1[N:60]=[C:56]([NH:55][C:17]([CH:9]2[CH2:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[O:18])[S:57][CH:58]=1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC1C(=O)O
Reactant: Cc1cc(C)c(-c2csc(N)n2)c(C)c1
Agent: Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2csc(NC(=O)C3Cc4ccccc4N3C(=O)OC(C)(C)C)n2)c(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
21 g of 1-tert-butoxycarbonyl-indoline-2-carboxylic acid, then 35.2 g of 1-benzotriazolyl-oxytris (dimethylamino)phosphonium hexafluorophosphate (BOP) and the 24.2 g of triethylamine are added successively to a solution of 23.5 g of 2-amino-4-(2,4,6-trimethylphenyl)thiazole hydrobromide in 250 ml of dimethylformamide. The reaction mixture is stirred at ambient temperature for 12 h. The solvent is then evaporated under reduced pressure and 150 ml of ethyl acetate are poured onto the residue. The organic solution is washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulphate. The solid obtained after evaporation of the solvent is washed with diisopropyl ether. Yield: 95%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:6][C:5]=1[C:15]1[NH:16][C:17](=[O:28])[C:18]2[N:23]([CH3:24])[N:22]=[C:21]([CH2:25][CH2:26][CH3:27])[C:19]=2[N:20]=1)[CH3:2].C(OCC)(=O)C.O>CO.[Pd]>[CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][C:5]=1[C:15]1[NH:16][C:17](=[O:28])[C:18]2[N:23]([CH3:24])[N:22]=[C:21]([CH2:25][CH2:26][CH3:27])[C:19]=2[N:20]=1)[CH3:2]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(/C=C/C(=O)O)ccc3OCC)nc12
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(CCC(=O)O)ccc3OCC)nc12
Reaction time: 3 h
Yield: 54.4 %

Procedure:
A solution of (E)-4-Ethoxy-3-(1-methyl-7-oxo-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-5-yl)cinnamic acid (0.426 g, 0.0011 mol) in a mixture of methanol (28.5 ml), ethyl acetate (100 ml) and water (1.5 ml), was stirred with 5% palladium on charcoal catalyst (0.05 g) under a hydrogen atmosphere at room temperature and pressure for 3 hours. The catalyst was removed by filtration and the solvent removed by evaporation under vacuum. Crystallisation of the residue from ethyl acetate-hexane gave the title compound as beige crystals (0.23 g, 54%), m.p. 165°-167° C. Found: C,62.25; H,6.17; N,14.09. C20H24N4O4 requires C,62.39; H,6.33; N,14.41%