Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[NH:60][CH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C.O>[Cl:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[NH:60][CH:61]1[CH2:66][CH2:65][N:64]([C:11](=[O:13])[CH2:10][NH:9][C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:63][CH2:62]1
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Reactant: Clc1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 48.8 %

Procedure:
To a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid (0.134 g, 0.00053 mol) in DMF (2 mL) was added DIPEA (0.185 g, 0.00143 mol), HOBt (0.0646 g, 0.00048 mol) and EDCI.HCl (0.1098 g, 0.00057 mol) at ambient temperature. After 2 minutes (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (0.118 g, 0.00048 mol) was added and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by preparative TLC using 30% ethyl acetate in hexane as eluent afforded 0.105 g (45%) of biphenyl-4-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 448 (M+1)+, 97.78%, 1H NMR (CDCl3): δ 7.94 (d, 2H), 7.74-7.6 (m, 4H), 7.5-7.38 (m, 2H), 7.2-7.1 (m, 1H), 6.75-6.6 (m, 2H), 4.5 (m, 1H), 4.3 (d, 2H), 4.25 (d, 1H), 3.9 (m, 1H), 3.6 (m, 1H), 3.3 (m, 2H), 3.1 (m, 1H), 2.2 (bt, 2H), 1.5 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(=O)=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@H:10]([O:14][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]/[CH:27]=[CH:26]\[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Reactant: CCCCCC/C=C\CCCCCCCCOS(C)(=O)=O
Product: CCCCCC/C=C\CCCCCCCCO[C@@H]1CN(Cc2ccccc2)C[C@H]1OCCCCCCCC/C=C\CCCCCC

Procedure:
Compound VI-6 (231 mg, 48.0%) was obtained in the same manner as that in Reference Example 1, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 146 mg, 0.753 mmol) and (Z)-hexadec-9-enyl methanesulfonate (Nu-Chek Prep, Inc; 600 mg, 1.88 mmol).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]([F:39])([F:38])[C:14]1[CH:37]=[CH:36][C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([CH2:26][S:27][C:28]3[NH:32][C:31]4=[CH:33][S:34][CH:35]=[C:30]4[N:29]=3)[CH:21]=2)=[CH:16][CH:15]=1>ClCCl>[F:39][C:13]([F:12])([F:38])[C:14]1[CH:37]=[CH:36][C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([CH2:26][S:27]([C:28]3[NH:32][C:31]4=[CH:33][S:34][CH:35]=[C:30]4[N:29]=3)=[O:9])[CH:21]=2)=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1ccc(COc2ccnc(CSc3nc4cscc4[nH]3)c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(Cc1cc(OCc2ccc(C(F)(F)F)cc2)ccn1)c1nc2cscc2[nH]1

Procedure:
A solution of 0.5 g (2.5 mmol, 85%) of m-chloroperbenzoic acid in 10 ml of dichloromethane is added dropwise with stirring at 0° to 5° C. to 1.0 g (2.37 mmol) of the title compound from Example 6 in a two-phase mixture of 200 ml of dichloromethane and 100 ml of aqueous KH2PO4 /Na2HPO4 buffer solution (pH=7.5). The organic phase is separated off, shaken with saturated aqueous NaHCO3 solution, dried over MgSO4, clarified over activated charcoal and concentrated. The crystalline evaporation residue is treated with ethyl acetate, filtered off with suction and washed twice with a little ethyl acetate. The colorless crystalline product is dried in vacuo, m.p. 149° C. with decomposition.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]2[OH:19])(=O)=O)=CC=1.O[C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][N:30]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:40])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[OH:19][C@H:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C@@H:13]1[CH2:12][O:11][C:25]1[CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][N:30]2[C:31](=[O:40])[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]2=[O:39])[CH:22]=[CH:21][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCC[C@@H]2O)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OC[C@H]2CCCC[C@@H]2O)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of ((1R,2S)-2-hydroxycyclohexyl)methyl 4-methylbenzenesulfonate (0.334 g, 1.24 mmol), compound 58 (0.432 g, 1.54 mmol), cesium carbonate (0.562 g, 1.73 mmol) in anhydrous DMF (8 mL) was stirred at 60° C. under argon for 18 hrs, and then concentrated under reduced pressure. Water was added and the product was extracted with EtOAc three times. Combined fractions were washed with sat. NH4Cl, brine, and concentrated under reduced pressure. The residue was purified by flash chromatography (20% to 70% EtOAc/hexanes gradient) to afford 2-(3-(3-(((1R,2S)-2-hydroxycyclohexyl)methoxy)phenyl)propyl)isoindoline-1,3-dione as a colorless oil. Yield (0.191 g, 41%). 1H NMR (400 MHz, DMSO-d6) δ 7.76-7.85 (m, 4H), 7.09 (t, 7.6 Hz, 1H), 6.69-6.74 (m, 2H), 6.61-6.65 (m, 1H), 4.34 (d, J=4.1 Hz, 1H), 3.91 (dd, J=7.0, 9.2 Hz, 1H), 3.86-3.89 (m, 1H), 3.67 (dd, J=6.9, 9.2 Hz, 1H), 3.53-3.60 (m, 2H), 2.50 (t, J=7.6 Hz, 2H), 1.80-1.91 (m, 2H), 1.73-1.80 (m, 1H), 1.51-1.66 (m, 3H), 1.28-1.44 (m, 4H), 1.17-1.25 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4](CCO)[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1.OCCNC1C=CC(O)=C([N+]([O-])=O)C=1.C1OC1.C.NC1C=CC(O)=C([N+]([O-])=O)C=1>COCCOC.O>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([NH2:12])[CH:6]=1
Reactant: O=[N+]([O-])c1cc(N(CCO)CCO)ccc1O
Agent: Nc1ccc(O)c([N+](=O)[O-])c1
Agent: O=[N+]([O-])c1cc(NCCO)ccc1O
Solvent: O
Solvent: C1CO1
Solvent: COCCOC
Product: Nc1cc(NCCO)ccc1O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Preparation of 4-[bis(2-hydroxyethyl)-amino]-2-nitrophenol by ethoxylation (B5.c): 397 g (2 mol) 4-(2-hydroxyethylamino)-2-nitrophenol is added to a mixture of 1.6 liters of water and 1.1 liters of 1,2-dimethoxyethane. The system is closed with a bubble counter and heated with stirring to 60° C. Ethylene oxide is conducted into this solution so that no ethylene oxide escapes through the bubble counter. After 5 hours the temperature is increased to 85° C., 9.2 g activated charcoal and 4.6 g Celite are added, and stirring is continued for 15 minutes. Then the mixture is filtered with suction. The residue is washed with 100 ml of 1,2-dimethoxyethane/water (1:1 v/v). 500 ml of 1,2-dimethoxyethane is distilled off the solution. The product which precipitates is filtered off with suction and dried. (This product is obtained starting from 4-amino-2-nitrophenol according to this procedure.)
Reaction SMILES: [CH2:1]([N:8]([C@H:13]([CH2:17][OH:18])[C:14]([OH:16])=[O:15])[C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(C)(C)C.[K+]>C(O)(C)(C)C>[CH2:1]([N:8]1[C:9](=[O:12])[CH2:10][O:18][CH2:17][C@@H:13]1[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H](CO)N(Cc1ccccc1)C(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C(O)[C@H]1COCC(=O)N1Cc1ccccc1
Temperature: 110 °C
Yield: 58.9 %

Procedure:
To a solution of (R)-2-(N-benzyl-2-chloroacetamido)-3-hydroxypropanoic acid (1.53 g, 5.63 mmol) in tert-butanol was added potassium tert-butanolate and the reaction mixture heated to 110° C. for three h, then cooled to room temperature and concentrated to dryness. The residue was acidified with 1 N HCl to pH 1 and the aqueous solution extracted with EtOAc (3×250 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 10 to 30% CH3OH in CH2Cl2 with 1% acetic acid) to provide (R)-4-benzyl-5-oxomorpholine-3-carboxylic acid (780 mg, 59%) as a yellow foam. 1H NMR and MS consistent.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:6]([C:15]([OH:17])=O)[CH2:5][O:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(Cl)CCl>C(Cl)Cl>[O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@@H:6]([C:15]([NH:42][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:17])[CH2:5][O:4][CH2:3]1
Reactant: NCc1ccccc1
Reactant: O=C(O)[C@H]1COCC(=O)N1Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(NCc1ccccc1)[C@H]1COCC(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
A mixture of (3R)-5-oxo-4-(phenylmethyl)-3-morpholinecarboxylic acid (69.67 g, 296.2 mmol) and 1-hydroxybenzotriazole (48.01 g, 355.4 mmol) in DCM (990 mL) was cooled to 0° C. To the mixture was added 4-methylmorpholine (163 mL, 1483 mmol), benzyl amine (35.6 mL, 325.9 mmol), and EDC (62.46 g, 325.8 mmol). The yellow solution was stirred overnight at room temperature, and was then washed with water (500 mL), 6 N aqueous HCl (300 mL), and water (200 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give crude (3R)-5-oxo-N,4-bis(phenylmethyl)-3-morpholinecarboxamide (97.05 g, >100% crude yield) as a yellow foam. LCMS: (M+H)+: 325.2.
Reaction SMILES: [CH3:1][C:2]([S:5]([N:7]=[C:8]1[CH2:11][O:10][CH2:9]1)=[O:6])([CH3:4])[CH3:3].[Si]([C:16]#[N:17])(C)(C)C>C(Cl)Cl.[Cl-].[Na+].O.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[C:16]([C:8]1([NH:7][S:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[O:6])[CH2:11][O:10][CH2:9]1)#[N:17]
Reactant: CC(C)(C)S(=O)N=C1COC1
Reactant: C[Si](C)(C)C#N
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)S(=O)NC1(C#N)COC1
Reaction time: 0.17 h
Yield: 77.9 %

Procedure:
To a yellow solution of 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (1 g, 5.71 mmol) in CH2Cl2 (20 ml) in a 100 round-bottomed flask was added titanium tetraethoxide (0.651 g, 2.85 mmol) and the reaction mixture stirred for 10 min. TMSCN (1.530 ml, 11.41 mmol) was then added, and the resulting reaction mixture stirred at r.t. for overnight. The reaction mixture was poured into saturated brine solution, and then the suspension was filtered through a pad of Celite. The organic layer was separated, and the aqueous layer extracted with ethyl acetate (3×25 ml). The combined organic solution was washed with saturated brine solution, dried over Na2SO4, filtered and concentrated. The crude product was purified over neutral alumina column using 4% methanol in dichloromethane as eluent. Desired fractions were collected and concentrated to give the titled product as colorless oil (0.9 g, 78%).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:29]=O)[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[F:20][C:21]1[CH:22]=[C:23]([CH2:29][NH:8][C:6]2[CH:5]=[CH:4][C:3]([CH2:9][C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=4)[NH:12][CH:11]=3)=[C:2]([F:1])[N:7]=2)[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=1
Reactant: Cn1cc(F)cc(C=O)c1=O
Reactant: Cc1cnc2[nH]cc(Cc3ccc(N)nc3F)c2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1cnc2[nH]cc(Cc3ccc(NCc4cc(F)cn(C)c4=O)nc3F)c2c1
Temperature: 80 °C
Yield: 50.3 %

Procedure:
To 6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (137, 3.99 g, 15.59 mmol) and 5-fluoro-1-methyl-2-oxo-1,2-dihydro-pyridine-3-carbaldehyde (33, 2.66 g, 17.15 mmol) in 50 mL of acetonitrile, triethylsilane (9.96 mL, 62.4 mmol) and trifluoroacetic acid (4.80 mL, 62.4 mmol) were added. The reaction was stirred at 80° C. for several hours, then concentrated under vacuum and the residue was taken up in ethyl acetate and poured into aqueous potassium carbonate. The organic layer was separated, concentrated under vacuum, and the residue purified by silica gel column chromatography, eluting with 0-5% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum, and the residue triturated with methanol to provide the desired compound (P-2156, 3.1 g, 7.84 mmol, 50.3% yield).
Reaction SMILES: [NH2:1][C:2]1[N:6](C2C=CC=CC=2)[N:5]=[C:4]([C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=2)[C:3]=1[C:22]#[N:23].[C:24]([C:30]([O:32][CH3:33])=[O:31])#[C:25][C:26]([O:28][CH3:29])=[O:27]>>[NH2:23][CH:22]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([C:30]([O:32][CH3:33])=[O:31])[N:1]=[C:2]2[N:6]=[N:5][C:4]([C:13]3[S:14][C:15]4[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=4[CH:17]=3)=[C:3]12
Reactant: COC(=O)C#CC(=O)OC
Reactant: N#Cc1c(-c2cc3ccccc3s2)nn(-c2ccccc2)c1N
Product: COC(=O)C1=C(C(=O)OC)C(N)C2=C(c3cc4ccccc4s3)N=NC2=N1

Procedure:
Using 3.16 g (10 mmol) of 5-amino-3-(benzothiophen-2-yl)-1-phenylpyrazole-4-carbonitrile and 1.42 g (10 mmol) of dimethyl acetylenedicarboxylate, the entitled product having a melting point of 218° to 220° C. was obtained in the same manner as in Example 2-(2).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:27])[NH2:26].Cl[CH2:29][C:30](=O)[CH3:31].CN(C)C=O>O>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:4][N:3]1[C:25]1[S:27][CH:29]=[C:30]([CH3:31])[N:26]=1
Reactant: CC(=O)CCl
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=S)OCO3
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(N2N=C(c3ccc([N+](=O)[O-])cc3)c3cc4c(cc3CC2C)OCO4)n1
Temperature: 85 °C
Reaction time: 0.67 h
Yield: 82.5 %

Procedure:
A mixture of 0.76 g (1.98 mmol) of the starting material I, 1.10 g (11.88 mmol) of chloroacetone and 15 ml of dimethylformamide was stirred at 80-90° C. for 40 min. Then the reaction mixture was diluted with water, the precipitated crystals were filtered off, dried and purified by refluxing in ethanol to yield 0.69 g (82%) of the title compound; Mp.: 188-189° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([N+:18]([O-])=O)[CH:17]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)=[O:7]>CC(O)=O.CCO.[Fe]>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([CH:15]=[C:5]([C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)=[O:7])[CH:4]=1)[NH2:18]
Reactant: COc1cc(C(=O)N2CCN(C)CC2)cc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(N)cc(C(=O)N2CCN(C)CC2)c1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
1-(3-Methoxy-5-nitrobenzoyl)-4-methylpiperazine (900 mg; 3.22 mmol; 1 eq) and iron powder (719.82 mg; 12.89 mmol; 4 eq) are heated for 1 h at 100° C. in a mixture of AcOH (10 mL) and EtOH (10 mL). The reaction mixture is cooled down to room temperature, concentrated under vacuum and basified with aqueous Na2CO3. The product is extracted with EtOAc. The organic phase is dried over MgSO4 and the solvent evaporated under reduced pressure to afford 500 mg (62%) of the title compound as an orange oil. 1H NMR (DMSO-d6) δ 6.20-6.17 (m, 1H), 6.11-6.10 (m, 1H), 6.01-5.99 (m, 1H), 5.35-5.27 (m, 2H), 3.66 (s, 3H), 3.55-3.53 (m, 4H), 2.30-2.28 (m, 4H), 2.18 (s, 3H). LC/MS: (ES+): 250.4.
Reaction SMILES: [CH2:1]([N:8]1[CH2:25][CH:24]([CH:26]([OH:29])CO)[O:23][C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(=CC)C.[O-]Cl=O.[Na+].[N+](=C[Si](C)(C)C)=[N-].C1C[O:49][CH2:48]C1>O.C1(C)C=CC=CC=1.CO.C(O)(=O)C.CC(O)(C)C>[CH2:1]([N:8]1[CH2:9][C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:11]2)[O:23][CH:24]([C:26]([O:49][CH3:48])=[O:29])[CH2:25]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1ccccc1)CC(C(O)CO)O2
Agent: CC=C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CC(C)(C)O
Product: COC(=O)C1CN(Cc2ccccc2)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67 %

Procedure:
To tert-butyl 8-benzyl-10-(1,2-dihydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (1.5 g, 3.69 mmol) in THF (35 mL) was added NaIO4 (2 g, 9.4 mmol) followed by the addition of H2O (13 mL). The reaction mixture was stirred at room temp for 2.5 hours. The reaction mixture was filtered, then concentrated in vacuo and the residue was partitioned between sat. aq. sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted further with ethyl acetate (2×50 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated in vacuo. To the intermediate aldehyde (˜1.4 g) was added tBuOH (17 mL) and 2-methylbut-2-ene (10.5 mL, 99.04 mmol) and the reaction mixture was cooled to 0° C. A solution of NaClO2 (1.1 g, 9.65 mmol) and NaH2PO4 (1.33 g, 9.67 mmol) in water (17 mL) was added dropwise over 5 minutes, and the reaction mixture was stirred for 30 minutes at 0° C. The reaction mixture was warmed to room temperature, then extracted with ethyl acetate (4×50 mL) and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to give the crude acid as a yellow oil. The oil was dissolved in toluene (2.5 mL) and methanol (2.5 mL), then diazomethyl(trimethyl)silane (1.85 mL of 2 M in hexanes, 3.69 mmol) was added dropwise until faint yellow color persisted. Acetic acid was added to make solution colorless (2 drops). The reaction mixture was concentrated in vacuo then purified by silica gel column chromatography using 0-70% EtOAc/hexane as eluent to give 9-tert-butyl 2-methyl 4-benzyl-1-oxa-4,9-diazaspiro[5.5]undecane-2,9-dicarboxylate (1 g, 67%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.37-7.20 (m, 5H), 4.43 (dd, J=10.5, 2.1 Hz, 1H), 3.74 (s, 3H), 3.57 (d, J=13.3 Hz, 3H), 3.45-3.29 (m, 2H), 3.14 (t, J=10.9 Hz, 1H), 3.08-3.01 (m, 1H), 2.56 (dd, J=11.3, 0.9 Hz, 1H), 2.30 (dd, J=8.7, 5.7 Hz, 1H), 2.13 (dd, J=19.9, 8.9 Hz, 1H), 1.91 (d, J=11.3 Hz, 1H), 1.69-1.46 (m, 3H), 1.43 (s, 9H). ESI-MS m/z calc. 404.5. found 405.7 (M+1)+; Retention time: 1.62 (3 min run).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([OH:19])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cc(OC)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
A suspension of 4.0 g (0.0165 mmol) methyl 3-(benzyloxy)-5-hydroxybenzoate (160), 6.84 g (0.0495 mmol) potassium carbonate, and 11.71 g (0.0825 mmol) iodomethane in the 200 mL of acetone was stirred at room temperature for 24 h. After the mixture was filtered and evaporated, the residue was washed with water. The methyl 3-(benzyloxy)-5-methoxybenzoate (161) was obtained as a white solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:30]([Cl:31])=[CH:29][N:28]=[CH:27][C:26]=3[Cl:32])[CH2:21][CH2:20]2)=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C[Si](I)(C)C>C(Cl)Cl>[Cl:31][C:30]1[CH:29]=[N:28][CH:27]=[C:26]([Cl:32])[C:25]=1[N:22]1[CH2:21][CH2:20][CH:19]([C:17]([N:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[O:18])[CH2:24][CH2:23]1
Reactant: O=C(OCc1ccccc1)N1CCN(C(=O)C2CCN(c3c(Cl)cncc3Cl)CC2)CC1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: O=C(C1CCN(c2c(Cl)cncc2Cl)CC1)N1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
To a solution of benzyl-4-(1-(3,5-dichloropyridin-4-yl)piperidine-4-carbonyl)piperazine-1-carboxylate 13 (40 mg, 0.080 mmol) in DCM (1 mL), cooled to 0° C. was added trimethylsilyliodide (24 μL, 0.16 mmol) and the solution was stirred at this temperature for 90 min, after which time trimethylsilyl iodide (48 μL, 0.32 mmol) was added and the mixture warmed to room temperature. After stirring for a further 45 min, the solution was concentrated under reduced pressure and the crude product was purified on an SCX-2 cartridge (MeOH followed by 0.5 M NH3 in MeOH) to furnish the title compound as a yellow solid (27 mg, 94%), m.p. 256-258° C.; m/z (ESI) C15H20C12N4NaO requires 365.0906, found [M+Na]+ 365.0909.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1)=O.[BH4-].[Na+].Cl>C(O)(C)C>[NH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[CH:2]=[CH2:1]
Reactant: CC(=O)c1cccc(N)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: C=Cc1cccc(N)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
135 g (1 mol) of 3-aminoacetophenone are suspended in 1,000 ml of isopropanol, and 19 g (0.5 mol) of sodium borohydride are slowly added. The reaction mixture is stirred at room temperature for 48 hours and then brought to a pH of 5 with concentrated hydrochloric acid, while cooling with ice. The salt which is precipitated is filtered off with suction, and the slightly reddish solution is concentrated on a rotary evaporator under a water pump vacuum. The desired 1-(3-aminophenyl)ethanol crystallizes overnight in the cold, is filtered off with suction and dried.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[NH:21]1[CH:25]=[C:24](B(O)O)[CH:23]=[N:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][N:12]([CH:13]([CH3:15])[CH3:14])[C:11]1[C:2]([C:24]2[CH:25]=[N:21][NH:22][CH:23]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2
Reactant: OB(O)c1cn[nH]c1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cn[nH]c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (170 mg, 0.58 mmol) in 1,4-dioxane (6 ml) was added (1H-pyrazol-4-yl)boronic acid (130 mg, 1.16 mmol), Pd(PPh3)4 (34 mg, 0.029 mmol), K3PO4 (367 mg, 1.74 mmol) and water (5 drops) with stirring for 1 h at 90° C. under an inert atmosphere of nitrogen in an oil bath. The reaction mixture was concentrated under vacuum to give the residue, which was purified via silica gel chromatography (1% to 10% ethyl acetate in petroleum ether) to afford methyl 3-[methyl(propan-2-yl)amino]-2-(1H-pyrazol-4-yl)quinoxaline-6-carboxylate as a yellow solid (150 mg, 79%).