Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:9]#[N:10].Cl[CH2:21][CH2:22][N:23]1[CH:28]([CH3:29])[CH2:27][CH2:26][CH2:25][CH:24]1[CH3:30]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:15])[CH3:16])([CH2:21][CH2:22][N:23]1[CH:28]([CH3:29])[CH2:27][CH2:26][CH2:25][CH:24]1[CH3:30])[C:9]#[N:10]
Reactant: CC1CCCC(C)N1CCCl
Reactant: CC(C)N(CCC(C#N)c1ccccc1F)C(C)C
Product: CC(C)N(CCC(C#N)(CCN1C(C)CCCC1C)c1ccccc1F)C(C)C

Procedure:
Substitution of equivalent quantities of α-(o-fluorophenyl)-α-[2-(diisopropylamino)ethyl]acetonitrile and 1-(2-chloroethyl)-2,6-dimethylpiperidine in the procedure of Example 2, Method B, and substantial repetition of the procedure detailed therein, affords α-(o-fluorophenyl)-α-[2-(diisopropylamino)ethyl]-α-[2-(2,6-dimethyl-1-piperidinyl)ethyl]acetonitrile, as an oil boiling at about 170°-175° C. at 0.3 mm. pressure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[C:13]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:12]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][OH:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47].O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[C:13]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:12]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][O:37][S:46]([CH3:45])(=[O:48])=[O:47])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CO)n(CCNC(=O)OC(C)(C)C)c2c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3COS(C)(=O)=O)n(CCNC(=O)OC(C)(C)C)c2c1

Procedure:
To a solution of methyl 1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-2-(2-hydroxymethylphenyl)-1H-indole-6-carboxylate (100 mg, 0.19 mmol) in chloroform (2 ml) was added triethylamine (0.04 ml, 0.28 mmol) and methanesulfonyl chloride (0.02 ml, 0.25 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 10 min. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was so successively washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-2-(2-methanesulfonyloxymethylphenyl)-1H-indole-6-carboxylate as a crude product. The obtained crude product was used for Step 10 without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:20][C:19](N)=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.N(OC(C)(C)C)=O.C(Br)(Br)[Br:30]>>[Br:30][C:19]1[S:20][C:3]2[C:2]([Cl:1])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[N:5][C:4]=2[N:18]=1
Reactant: BrC(Br)Br
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Agent: CC(C)(C)ON=O
Product: Fc1cccc(CSc2nc(Cl)c3sc(Br)nc3n2)c1F
Temperature: 60 °C

Procedure:
The product of example 4 step (b) (8.0 g) was suspended in bromoform (200 ml) followed by addition of tert-butyl nitrite (8 ml) and the whole heated at 60° C. for 30 minutes. The solvents were removed by reduced pressure and the residue purified by column chromatography (silica—1:1 dichloromethane/isohexane) to give a yellow solid (5.6 g).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([NH:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[O:9].[C:19]([O:23][C:24]([NH:26][C@@H:27]([CH2:31][CH3:32])[C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[Br:7][C:4]1[CH:5]=[CH:6][N:2]([NH:1][C:28](=[O:29])[C@@H:27]([NH:26][C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:31][CH3:32])[C:3]=1[C:8](=[O:9])[NH:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nn1ccc(Br)c1C(=O)Nc1cc(F)cc(F)c1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1ccc(Br)c1C(=O)Nc1cc(F)cc(F)c1
Yield: 14 %

Procedure:
The title compound was prepared from 1-amino-3-bromo-N-(3,5-difluorophenyl)-1H-pyrrole-2-carboxamide (1 g, 3.16 mmol) and (S)-2-(tert-butoxycarbonylamino)butanoic acid following the experimental procedure described in Preparation 45a. 0.26 g (14% yield) of the desired compound were obtained.
Reaction SMILES: CN.Cl[C:4](=[O:10])[C:5]([O:7]CC)=[O:6].[CH2:11]([N:13](CC)[CH2:14]C)[CH3:12]>C1COCC1>[CH2:11]([N:13]([CH3:14])[C:4](=[O:10])[C:5]([OH:7])=[O:6])[CH3:12]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)C(=O)Cl
Agent: CN
Solvent: C1CCOC1
Product: CCN(C)C(=O)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
Methylamine (1.5 g, 23 mL of a 1 M THF solution, 48.38 mmol) solution was added dropwise to a −10° C. solution of ethyl chlorooxoacetate (5.0 g, 36.76 mmol) and triethylamine (5.6 g, 7.6 mL, 55.44 mmol) in dry THF (100 mL) under an argon atmosphere. After stirring at 0° C. for 1 h, then reaction was quenched with water (5 mL). Following another 20 min, the reaction mixture was extracted into ethyl acetate (2×30 mL) and the combined organic extracts were washed with water (2×100 mL), dried and concentrated in vacuo. The residue was purified by column chromatography using 40% EtOAc/hexanes to give monoethyl N-methyloxalamic acid (3.95 g, 82%) as a white powder. TLC: 75% EtOAc/hexane, Rf≈0.4; 1H NMR (CDCl3, 300 MHz) δ 4.35 (q, 2H, J=7.0 Hz), 2.92 (d, 3H, J=5.2 Hz), 1.37 (t, 3H, J=7.3 Hz).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].C(O)(=O)C.O=[C:21]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[N:10]=[C:21](/[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)\[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCCCC(=O)c1ccccc1
Reactant: NNc1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCCC/C(=N\Nc1ccc(Br)cc1)c1ccccc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 98.2 %

Procedure:
A mixture of 1.91 g (8.55.10−3 mol) of 4-bromophenylhydrazine hydrochloride and 0.73 g (8.9.10−3 mol) of sodium acetate in 17 ml of water is prepared and 2.05 ml (35.8.10−3 mol) of acetic acid are added. This mixture is subsequently heated to 70° C., with stirring, and a suspension of 2.0 g (8.54.10−3 mol) of ethyl ε-oxobenzenehexanoate in 27 ml of water is then added slowly. The reaction mixture is stirred at 70-80° C. for 45 min and then at room temperature for 12 hours, after which it is extracted with 2 times 50 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 3.38 g of the expected compound, which is used directly in the next step.
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C@@H:7]1[CH:22]=[C:21]2[C@@H:11]([CH2:12][C:13]3[C:23]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]2=4)[NH:15][C:14]=3[Br:24])[N:9]([CH3:10])[CH2:8]1)=[O:6].Cl>C(O)C>[Br:24][C:14]1[NH:15][C:16]2[C:23]3[C:13]=1[CH2:12][C@@H:11]1[C:21]([C:20]=3[CH:19]=[CH:18][CH:17]=2)=[CH:22][C@@H:7]([C:5](=[O:4])[OH:6])[CH2:8][N:9]1[CH3:10]
Reactant: COC(=O)[C@@H]1C=C2c3cccc4[nH]c(Br)c(c34)C[C@H]2N(C)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1C[C@H](C(=O)O)C=C2c3cccc4[nH]c(Br)c(c34)C[C@H]21
Temperature: 80 °C
Reaction time: 1 h

Procedure:
20 ml of 20% aqueous potassium hydroxide solution are added to the solution of 1 g of 2-bromolysergic acid methyl ester in 6 ml of ethanol, then the solution is stirred in a bath of 80° C. for one hour. The pH value of the solution cooled down is adjusted to 7 by adding aqueous hydrochloric acid. The crystalline precipitate obtained on cooling is filtered off, washed with water and dried to give the title compound in a yield of 0.5 g (0.0014 mole, 50%).
Reaction SMILES: IC1C=CC(C(N2CCN(C3C(C)=CC(C)=C(C)N=3)CC2)=O)=CC=1.COC1C=CC(CN2C(=O)C(C)NC2=O)=CC=1.COC1C=CC(C[N:49]2[C:53](=[O:54])[CH:52]([CH3:55])[N:51]([C:56]3[CH:61]=[CH:60][C:59]([C:62]([N:64]4[CH2:69][CH2:68][N:67]([C:70]5[C:75]([CH3:76])=[CH:74][C:73]([CH3:77])=[C:72]([CH3:78])[N:71]=5)[CH2:66][CH2:65]4)=[O:63])=[CH:58][CH:57]=3)[C:50]2=[O:79])=CC=1>>[CH3:55][CH:52]1[N:51]([C:56]2[CH:61]=[CH:60][C:59]([C:62]([N:64]3[CH2:65][CH2:66][N:67]([C:70]4[C:75]([CH3:76])=[CH:74][C:73]([CH3:77])=[C:72]([CH3:78])[N:71]=4)[CH2:68][CH2:69]3)=[O:63])=[CH:58][CH:57]=2)[C:50](=[O:79])[NH:49][C:53]1=[O:54]
Reactant: COc1ccc(CN2C(=O)C(C)N(c3ccc(C(=O)N4CCN(c5nc(C)c(C)cc5C)CC4)cc3)C2=O)cc1
Agent: COc1ccc(CN2C(=O)NC(C)C2=O)cc1
Agent: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C)cc3)CC2)nc1C

Procedure:
Using (4-iodophenyl) [4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (348 mg) described in Preparation Example 120 and 3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione (187 mg) described in Preparation Example 51 and by the reaction and treatment in the same manner as in Example 508, the title compound (166 mg) was obtained via 3-(4-methoxybenzyl)-5-methyl-1-{4-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidine-2,4-dione.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8](Br)[N:7]([CH:11]([CH3:13])[CH3:12])[CH:6]=1)=[O:4].[CH3:14][O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19](B(O)O)=[CH:18][N:17]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:19]2[C:20]([O:22][CH3:23])=[N:21][C:16]([O:15][CH3:14])=[N:17][CH:18]=2)[N:7]([CH:11]([CH3:13])[CH3:12])[CH:6]=1)=[O:4]
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COC(=O)c1cc(-c2cnc(OC)nc2OC)n(C(C)C)c1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 5-bromo-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step D4) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a yellow solid. tR: 0.97 min (HPLC 3); ESI-MS: tR=0.97 min, [M+H]+ 306 (LC-MS 1); TLC: Rf=0.43 (1:1 EtOAc/heptanes).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:22])[C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][CH3:20])[C:13]=2[CH3:21])=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.[C:23](OCC)(=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:19]([C:14]1[C:13]([CH3:21])=[C:12]([CH:17]=[CH:16][C:15]=1[OH:18])[O:11][C:5]1[C:4]([CH3:22])=[CH:3][C:2]([NH:1][C:23](=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]2[C:6]=1[CH2:7][CH2:8][CH2:9]2)[CH3:20]
Reactant: CCc1c(O)ccc(Oc2c(C)cc(N)c3c2CCC3)c1C
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)Nc1cc(C)c(Oc2ccc(O)c(CC)c2C)c2c1CCC2
Temperature: 120 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
To 4-(7-amino-5-methylindan-4-yloxy)-2-ethyl-3-methylphenol (12 mg) was added diethyl oxalate (150 mg), and the mixture was stirred under an argon atmosphere at 120° C. for 3 hours. The reaction mixture was purified by thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate=2/1) to give the title compound (15 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>CS(C)=O>[CH2:3]([O:10][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: Clc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc(COc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a suspension of sodium hydride (80% dispersed in oil, 876 mg, 29.2 mmol) in DMSO (10 ml) was added benzyl alcohol (3 ml, 29.2 mmol) and the mixture stirred at room temperature for 1 hour. To this was added 4-chloropyridine (3.3 g, 29.2 mmol) and the reaction stirred at room temperature overnight. The precipitated sodium chloride was removed by filtration and the filtrate diluted with water (100 ml) and extracted with ether (3×120 ml). The combined organic layers were dried (MgSO4) and evaporated in vacuo to yield the title compound as an oil (4.8 g, 95%); δH (CDCl3) 5.11 (2H, s, PhCH2O), 6.87 (2H, d, J 6.3 Hz, 3-H, 5-H), 7.29-7.42 (5H, m, Ph), and 8.42 (2H, d, J 6.3 Hz, 2-H, 6-H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].CO.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1)#[N:12]>C(OCC)(=O)C>[C:11]([C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:21])=[CH:17][CH:18]=1)#[N:12]
Reactant: NCCC(=O)O
Reactant: N#Cc1ccc(N=C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1ccc(NC(=O)NCCC(=O)O)cc1
Temperature: 40 °C
Reaction time: 15 h
Yield: 61.3 %

Procedure:
Under a nitrogen blanket, a mixture of β-alanine (4.4 g; 49 mmoles), sodium hydroxide (2.0 g; 50 mmoles) and methanol (300 ml) was added rapidly to a suspension of 4-cyanophenylisocyanate (8.0 g; 55 mmoles) in ethyl acetate (300 ml). The mixture was stirred at 40° C. for 15 hrs and the volume was reduced to about 150 ml by distillation at reduced pressure. The solid was filtered off, washed with ethyl acetate and dried to yield 7 g of crude product. FAB-MS: MH+=232.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][C@H:14]1[CH2:19][NH:18][CH2:17][C@@H:16]([CH3:20])[NH:15]1.C(#N)C>O>[CH3:13][C@H:14]1[NH:15][C@@H:16]([CH3:20])[CH2:17][N:18]([C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH2:19]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Solvent: CC#N
Solvent: O
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2C#N)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
2-Chloro-5-nitrobenzonitrile (13.3 g) and cis-2,6-dimethylpiperazine (25 g) were added to acetonitrile (25 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added to water and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether to give cis-2-(3,5-dimethylpiperazin-1-yl)-5-nitrobenzonitrile (14.3 g), melting point: 109–110° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:19])[CH3:18]
Reactant: Nc1cccc(-c2ccc(C(=O)O)cc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-c2ccc(C(=O)O)cc2)c1

Procedure:
3′-Aminobiphenyl-4-carboxylic acid (0.2 g) was mixed with pyridine (0.7 g) and acetic anhydride (180 mg) and, after 14 hours, volatile fractions were removed. The residue was taken up in sodium hydroxide solution (2N) and washed with diethyl ether. The aqueous phase was acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 255.28 (C15H13NO3); MS (ESI): 256 (M+H+).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br.[NH2:18][C:19]1[N:28]=[C:27]([NH2:29])[C:26]2[C:21](=[N:22][CH:23]=[C:24]([CH2:30]Br)[N:25]=2)[N:20]=1.CO>C1COCC1>[NH2:18][C:19]1[N:28]=[C:27]([NH2:29])[C:26]2[C:21](=[N:22][CH:23]=[C:24]([CH2:30][N:15]3[C:16]4[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=4[O:8][C:9]4[C:14]3=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:25]=2)[N:20]=1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(N)c2nc(CN3c4ccccc4Oc4ccccc43)cnc2n1
Reaction time: 0.17 h

Procedure:
NaH (60% oil suspension containing 51 mg, 2.0 mmol) was added to a stirred solution of phenoxazine (147 mg, 0.784 mmol) in dry THF (10 mL) at 0° C. under N2. After 10 min. 2,4-diamino-6-bromomethylpteridine hydrobromide (100 mg, 0.392 mmol) was added and the reaction mixture was allowed to come to room temperature and left to stir for 2 days. The excess NaH was decomposed with MeOH (1 mL), and the mixture was concentrated to dryness by rotary evaporation. Flash chromatography on silica gel yielded the title compound, N-[(2,4-diaminopteridin-6-yl)methyl]phenoxazine, as a brown solid; yield 47 mg (34%); mp >250° C. dec. Anal. Calcd. for C19H15N7O0.4H2O: C, 62.60; H, 4.37. Found: C, 62.84; H, 4.10.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[NH2:22][C:23]1[C:28]([F:29])=[C:27](Cl)[N:26]=[C:25]([C:31]([O:33][CH3:34])=[O:32])[C:24]=1[CH:35]=[CH2:36].C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>[Cl-].[Na+].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.O>[NH2:22][C:23]1[C:28]([F:29])=[C:27]([C:3]2[CH:4]=[CH:5][C:6]([C:9]([F:10])([F:11])[F:12])=[C:7]([F:8])[C:2]=2[F:1])[N:26]=[C:25]([C:31]([O:33][CH3:34])=[O:32])[C:24]=1[CH:35]=[CH2:36]
Reactant: C=Cc1c(C(=O)OC)nc(Cl)c(F)c1N
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)c(F)c2F)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Solvent: O
Product: C=Cc1c(C(=O)OC)nc(-c2ccc(C(F)(F)F)c(F)c2F)c(F)c1N
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 24.98 %

Procedure:
In a microwave vessel, a suspension of 2-(2,3-difluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (commercially available) (0.641 g, 2.081 mmol), methyl 4-amino-6-chloro-5-fluoro-3-vinylpicolinate (Head G) (0.4 g, 1.734 mmol), bis(triphenyl phosphine)palladium(II) chloride (0.122 g, 0.173 mmol) and sodium carbonate (0.368 g, 3.47 mmol) in a 3:1 mixture of acetonitrile (3.25 mL) and water (1.084 mL) was stirred under microwave irradiation (120° C., 20 min). The reaction mixture was poured into an half saturated brine solution and was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative reverse phase HPLC (water/acetonitrile gradient) to afford the title compound as a brown solid (0.163 g, 0.433 mmol, 24.98%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:13]C.B(Br)(Br)Br.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:11])[CH3:12])=[CH:4][C:3]=1[OH:13]
Reactant: COc1cc2c(cc1F)C(C)(C)CC2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC1(C)CCc2cc(O)c(F)cc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a solution of 6-fluoro-5-methoxy-1,1-dimethyl-indan (1.40 g, 7.21 mmol) in 20.0 ml of DCM at −78° C. was added BBr3 (1.40 ml, 14.4 mmol) in DCM (10.0 ml). The reaction mixture was stirred at −78° C. for two hours before being treated with 2.0 ml of methanol. This mixture was stirred for few minutes after which a saturated solution of NaHCO3 was carefully added and the resulting mixture stirred for an additional 1 hour. The mixture was extracted with DCM (3×40 mL) and the combined organic extracts were washed with brine and dried over Na2SO4. Flash column chromatography on silica gel (2-10% ethyl acetate/heptanes) afforded 0.985 g of the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[O:14]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>O.ClCCCl>[O:14]([C:21]1[CH:22]=[C:23]([NH:24][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[C:6]([CH:2]3[CH2:3][CH2:4][CH2:5][O:1]3)[CH:7]=2)[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cccc(C2CC=CO2)c1
Reactant: Nc1cccc(Oc2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: c1ccc(Oc2cccc(NCc3cccc(C4CCCO4)c3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
To a 1,2-dichloroethane (4 mL) solution of the aldehyde (0.19 g, 1.1 mmol) from EX-608D was added 3-phenoxyaniline (0.20 g, 1.1 mmol), NaB(OAc)3H (0.30 g, 1.4 mmol) and acetic acid (0.065 mL, 1.1 mmol). The cloudy solution was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried (MgSO4) and evaporated to yield 0.32 g (84%) of the desired N-(3-phenoxyphenyl)-[[3-(tetrahydro-2-furanyl)phenyl]methyl]amine product as a yellow oil which was used without further purification. The formation of the desired product was monitored by TLC.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:25]3[CH:33]=[CH:34][C:35]([C:37](O)=[O:38])=[CH:36][C:24]=3[N:23]=2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClCCl>CN(C)C=O>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)[C:25]3[CH:33]=[CH:34][C:35]([C:37]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:38])=[CH:36][C:24]=3[N:23]=2)=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Yield: 57.5 %

Procedure:
Methanesulfonamide (0.0188 g, 0.198 mmol), sodium hydride, and the acid chloride of 49 (0.0083 g, 0.019 mmol) were reacted in dimethylformamide and dichloromethane according to the procedure described for example 8. The crude material was purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.05% trifluoroacetic acid) to afford the product as a white solid (0.0055 g, 52%). 1H NMR (CDCl3) δ 8.68 (s, 1H), 8.17 (d, 1H, J=8.8 Hz), 7.91 (d, 1H, J=8.8 Hz), 7.69 (d, 2H, J=8.5 Hz), 7.48-7.37 (m, 5H), 7.24 (d, 2H, J=8.7 Hz), 5.18 (s, 2H), 4.57 (m, 1H), 3.34 (s, 3H), 2.34 (br m, 2H), 2.06 (br m, 4H), 1.85 (br m, 1H), 1.39 (br m, 3H); ESI-MS m/e 504.3 (M+1); HPLC purity (ELSD)>95%.
Reaction SMILES: [CH2:1]([O:6][CH:7]([CH3:11])[CH2:8][CH2:9][OH:10])[CH2:2][CH2:3][CH2:4][CH3:5].CN(C)C1C=CC=CC=1.CCOCC.[C:26]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)(=[O:28])[CH3:27]>O>[C:26]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([O:10][CH2:9][CH2:8][CH:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH3:11])=[O:35])=[CH:32][CH:31]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: CCCCCOC(C)CCO
Solvent: CN(C)c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCCCCOC(C)CCOC(=O)c1ccc(OC(C)=O)cc1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
Separately, 9.0 g of 3-pentyloxybutanol and 6.82 g of N,N-dimethylaniline were added to 20 ml of ether, and under stirring at room temperature, 11.5 g p-acetyloxybenzoic acid chloride was added thereto dropwise. Then, the mixture was heat-refluxed for 3.5 hours. The crystal was dissolved by adding 50 ml of water and extracted with ether. The ether layer was washed successively with 10% H2SO4 aqueous solution and water and dried with anhydrous Na2SO4, followed by distilling-off of the solvent to obtain 17.5 g of 4-(3-pentyloxybutoxycarbonyl)phenyl acetate.