Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]#[N:10])[CH2:8][CH2:7]1)=[O:5])C.COC(=O)C(C)(C)CN>>[CH3:1][O:3][C:4]([C:6]1([CH2:9][NH2:10])[CH2:8][CH2:7]1)=[O:5]
Reactant: CCOC(=O)C1(C#N)CC1
Agent: COC(=O)C(C)(C)CN
Product: COC(=O)C1(CN)CC1

Procedure:
1-aminomethyl-cyclopropanecarboxylic acid methyl ester was prepared by hydrogenation of 1-cyano-cyclopropanecarboxylic acid ethyl ester, by the method similar to the preparation of 3-amino-2,2-dimethyl-propanoic acid methyl ester, above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:16]=1[C:17]([OH:19])=O>>[Cl:24][C:21]1[CH:20]=[C:16]2[C:15](=[CH:23][CH:22]=1)[NH:14][C:12](=[O:13])[N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:10])[C:17]2=[O:19]
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Product: O=c1[nH]c2ccc(Cl)cc2c(=O)n1S(=O)(=O)c1ccc(Cl)cc1
Yield: 48.3 %

Procedure:
630 mg (2.90 mmol) of 4-chlorobenzenesulfonylisocyanate and 500 mg (2.92 mmol) of 2-amino-5-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 520 mg of the above-identified compound (yield 47.9%). Properties; colorless crystal, Melting point: 223°-225° C., PMR (δppm, DMSO-d6): 7.11 (1H,d), 7.69 (1H,q), 7.78 (3H,m), 8.15 (2H,d), 11.67 (1H,s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1(Br)[CH2:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: BrC1CCC1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OC2CCC2)cc1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
2.50 g (14.5 mmol) 4-bromophenol, 2.05 mL (21.7 mmol) cyclobutylbromide and 7.99 g (57.8 mmol) K2CO3 are dissolved in 25 mL DMF and stirred at 120° C. for 12 h. Afterwards the reaction mixture is diluted with water and extracted with EtOAc. The organic layer is dried over MgSO4 and the solvent is removed in vacuo. The crude product is used without further purification.
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([OH:24])[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12])[CH3:6].Br[C:27]1[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[N:31][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CC(N(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]Br>[F:25][CH:2]([F:1])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24][C:27]2[CH:32]=[N:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12])[CH3:6]
Reactant: CS(=O)(=O)c1ccc(Br)cn1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@@H](C)COC(F)F)c2)cn1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(O[C@@H](C)COC(F)F)c2)cn1

Procedure:
A mixture of 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamide (190 mg, 0.54 mmol), 5-bromo-2-methylsulfonyl-pyridine (CAS no. 98626-95-0) (140 mg, 0.59 mmol), cesium carbonate (350 mg, 1.08 mmol) and bromotris(triphenylphosphine)copper(I) (101 mg, 0.11 mmol) in DMA (5 mL) was stirred in a microwave reactor at 160° C. for 6 hours. Ethyl acetate (50 mL) was added and the mixture washed with water (50 mL), brine (50 mL), dried (MgSO4) and reduced in vacuo. The crude residue was chromatographed on silica, eluting with 10-100% ethyl acetate in isohexane, to give the desired compound (19 mg).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[N:16]([CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:15]1=[O:38])=[O:12])[CH3:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[NH2:8][C@H:9]([C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[N:16]([CH2:31][C:32](=[O:37])[C:33]([CH3:35])([CH3:34])[CH3:36])[C:15]1=[O:38])=[O:12])[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1N=C(c2ccccn2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)C(=O)NC1N=C(c2ccccn2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O
Yield: 93 %

Procedure:
The title compound was synthesized using the procedure described in Example C-AE, Step C. A solution of 3-[(N-tert-butoxycarbonyl-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one (4.18 g, 8.01 mmol) was treated with TFA (13.6 mL, 176 mmol) to give 3.14 g (93% yield) the title compound as an off-white foam.
Reaction SMILES: [F:1][C:2]1[C:3]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=O)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14].Cl.[NH2:25][OH:26]>N1C=CC=CC=1>[F:1][C:2]1[C:3](/[C:15](/[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:25]\[OH:26])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: Cc1ccncc1-c1ccnc(C(=O)c2ccc(F)cc2)c1F
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccncc1-c1ccnc(/C(=N\O)c2ccc(F)cc2)c1F
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A solution of (3′-fluoro-4-methyl-3,4′-bipyridin-2′-yl)(4-fluorophenyl)methanone (0.029 g, 0.093 mmol) and hydroxylamine hydrochloride (0.044 g, 0.636 mmol) in pyridine (Volume: 0.467 ml) was refluxed for 1.5 hr, allowed to cool to room temperature, and then concentrated in vacuo. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed (required a few drops of MeOH). Purification of the crude material by silica gel chromatography using an ISCO machine (4 g column, 18 mL/min, 80-100% EtOAc in hexanes over 12 min, tr=2.5 min) gave the title compound (22 mg, 0.068 mmol, 72.4% yield) as a yellow solid. ESI MS (M+H)+=326.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][NH:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:4][C:3]=1[C@:16]12[CH2:25][O:24][C@@H:23]([CH3:26])[CH2:22][C@H:21]1[CH2:20][S:19][C:18]([NH:27]C(=O)C1C=CC=CC=1)=[N:17]2.FC1C=C(F)C(CNCC(F)(F)F)=CC=1[C@]12CO[C@@H](CF)C[C@H]1CSC(N)=N2>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][NH:10][CH2:11][C:12]([F:14])([F:15])[F:13])=[CH:4][C:3]=1[C@:16]12[CH2:25][O:24][C@@H:23]([CH3:26])[CH2:22][C@H:21]1[CH2:20][S:19][C:18]([NH2:27])=[N:17]2
Reactant: C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cc(CNCC(F)(F)F)c(F)cc2F)CO1
Agent: NC1=N[C@@]2(c3cc(CNCC(F)(F)F)c(F)cc3F)CO[C@@H](CF)C[C@H]2CS1
Product: C[C@H]1C[C@H]2CSC(N)=N[C@@]2(c2cc(CNCC(F)(F)F)c(F)cc2F)CO1

Procedure:
N-[(4aR,6S,8aS)-8a-(2,4-Difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C28) was converted to the product according to the method described for the synthesis of (4aR,6R,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine (8) in Example 8. Purification via silica gel chromatography (Gradient: 0% to 20% methanol in dichloromethane) afforded the product as a white solid. Yield: 12 mg, 25%. LCMS m/z 410 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 7.39 (t, J=8.7 Hz, 1H), 7.00 (dd, J=12.3, 9.6 Hz, 1H), 4.07 (dd, J=11.3, 2.0 Hz, 1H), 3.70-3.79 (m, 2H), 3.18 (q, J=9.3 Hz, 2H), 2.91-3.02 (m, 2H), 2.73 (dd, J=12.5, 2.7 Hz, 1H), 1.58-1.73 (m, 2H), 1.24 (d, J=8.0 Hz, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](B3OC(C)(C)C(C)(C)O3)[CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([CH:35]([NH:37][C:38]([C:40]2[O:41][C:42](Br)=[CH:43][CH:44]=2)=[O:39])[CH3:36])[CH:26]=[C:27]([F:34])[C:28]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31].C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:22][C:23]1[CH:24]=[C:25]([CH:35]([NH:37][C:38]([C:40]2[O:41][C:42]([C:6]3[CH:7]=[C:8]([CH:10]4[CH2:11][CH2:12]4)[CH:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[CH:5]=3)=[CH:43][CH:44]=2)=[O:39])[CH3:36])[CH:26]=[C:27]([F:34])[C:28]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31]
Reactant: CC1(C)OB(c2cc(C3CC3)cc(C3CC3)c2)OC1(C)C
Reactant: CC(NC(=O)c1ccc(Br)o1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1ccc(-c2cc(C3CC3)cc(C3CC3)c2)o1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 38.4 %

Procedure:
2-(3,5-Dicyclopropyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (74 mg, 0.26 mmol) and 5-bromo-furan-2-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (110 mg, 0.26 mmol) was reacted using Pd(PPh3)2Cl2 (14 mg, 0.02 mmol), Cs2CO3 (254 mg, 0.78 mmol) as described above to give the title compound (50 mg, 38%) after purification by flash chromatography on silica gel (% EtOAc in hexane=30%˜70%).
Reaction SMILES: Br[C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:9][N:10]=2)[CH:7]=1.[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1B(O)O.C([O-])([O-])=O.[K+].[K+].ClC1C=CC(C2C(C3C=CC(Cl)=CC=3Cl)=CN3C(CC4C=NC(C(F)(F)F)=CC=4)=NN=C3C=2)=CC=1>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>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:3]2[C:2]([C:34]3[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][C:35]=3[Cl:37])=[CH:7][N:6]3[C:8]([CH2:11][C:12]4[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:16][CH:17]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)=[CH:24][CH:25]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: Cc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(Br)cn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4Cl)cn23)cn1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)cn12
Yield: 50.2 %

Procedure:
The title compound (5.5 mg, 50%) as a white powder was prepared from 6-bromo-7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (9.5 mg, 0.020 mmol), 2,4-dichlorophenylboronic acid (7.5 mg, 0.039 mmol), K2CO3 (8.2 mg, 0.059 mmol) and Pd(PPh3)4 (2.8 mg, 0.002 mmol) in 1,4-dioxane (0.28 mL) and H2O (0.09 mL) by the procedures analogous to those described for 7-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (Example 56E). LC/MS (method B): retention time =2.04 min, [M+H]+=547.2.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](B(O)O)[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: OB(O)c1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2cccnc2)cc1
Temperature: 80 °C
Yield: 73.3 %

Procedure:
To a solution of 1-iodo-4-nitrobenzene (1.00 g, 4.02 mmol) in nitrogen degassed dry DMF (20 mL) was added 3-pyridineboronic acid (0.592 g, 4.82 mmol), Cs2CO3 (5.23 g, 16.1 mmol), triphenylphosphine (0.158 g, 0.602 mmol) and Pd(OAc)2 (0.090 g, 0.40 mmol). The reaction mixture was heated at 80° C. for 18 hours, cooled to room temperature and concentrated to dryness in vacuo. The crude material was purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 20-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I22) (0.590 g, 73% yield) as a yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.90 (d, J=1.8 Hz, 1H), 8.70 (dd, J=4.8, 1.5 Hz, 1H), 8.39-8.32 (m, 2H), 7.93 (ddd, J=7.9, 2.4, 1.7 Hz, 1H), 7.78-7.72 (m, 2H), 7.44 (ddd, J=7.9, 4.8, 0.8 Hz, 1H). LCMS Method C: rt 4.62 min; m/z 201.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][OH:27])=[CH:21][CH:20]=1>CN1C(=O)CCC1.O>[CH:13]1([O:12][C:4]2[N:3]=[C:2]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][OH:27])=[CH:21][CH:20]=3)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: FC(F)(F)c1cc(Cl)nc(OC2CCCC2)n1
Reactant: Nc1ccc(CCO)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: OCCc1ccc(Nc2cc(C(F)(F)F)nc(OC3CCCC3)n2)cc1
Temperature: 120 °C
Yield: 69.7 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(cyclopentyloxy)-6-(trifluoromethyl)pyrimidine (0.090 g, 0.34 mmol) and (4-aminophenyl)ethyl alcohol (0.069 g, 0.51 mmol) in NMP (3 mL). The resulting mixture was heated at 120° C. under microwave irradiation for 1 h. After this time, the reaction mixture was cooled and diluted with water (50 mL) affording a solid. The solid was isolated by filtration and chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent to afford the title compound (0.087 g, 70%) as a white solid. MW=367.37. M.p. 173-175° C. 1H NMR (DMSO-d6, 500 MHz) δ 10.01 (s, 1H), 7.56 (br d, J=7.0 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 6.73 (s, 1H), 5.30 (septet, J=3.0 Hz, 1H), 4.61 (t, J=5.0 Hz, 1H), 3.62-3.57 (m, 2H), 2.70 (t, J=7.0 Hz, 2H), 2.00-1.90 (m, 2H), 1.80-1.66 (m, 4H), 1.65-1.55 (m, 2H); APCI MS m/z 368 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH3-])#N.[Na+].[NH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([CH2:32][CH2:33][CH2:34][CH3:35])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=1>C(O)(=O)C.C(O)C>[CH2:32]([CH:26]([CH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][NH:15][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:20][CH:21]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCC(Cc1ccc(OCCN)cc1)C(=O)OCC
Reactant: O=CCCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCC(Cc1ccc(OCCNCCCc2ccccc2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-phenylpropionaldehyde (0.23 ml), sodium cyanoborohydride (117 mg) and acetic acid (one drop) were added to a solution of ethyl 3-[4-(2-aminoethoxy)phenyl]-2-butylpropionate (500 mg), which is the product of Reference example 6, in ethanol (10 ml). The mixture was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the layers were separated. The ethyl acetate solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on silica gel column using dichloromethane/methanol=19/1 as the eluant to afford the desired compound (460 mg) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2(O)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]2=[O:31])=[C:4]([OH:33])[CH:3]=1.BrC1C=CC(C2(O)C3C(=CC=CC=3)N(CC3OC(C(F)(F)F)=CC=3)C2=O)=C(O)C=1>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]2=[O:31])=[C:4]([OH:33])[CH:3]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc(F)c(F)cc1O
Agent: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C1(O)c1ccc(Br)cc1O
Product: O=C1C(c2cc(F)c(F)cc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations using 3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one to replace 3-(4-bromo-2-hydroxyphenyl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one, 3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one was obtained (56%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ9.27 (br s, 1H), 7.37-7.12 (m, 12H), 6.94 (s, 1H), 6.87 (dd, J=11.3, 7.1 Hz, 1H), 6.76 (dd, J=11.2, 8.9 Hz, 1H), 6.58-6.56 (m, 1H), 5.12 (s, 1H); MS (ES+) m/z 428.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]1=[O:12].[OH:13]O>C(O)(=O)C>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:13])[C:3]1=[O:12]
Reactant: Cn1c(=O)cnc2ccccc21
Reactant: OO
Solvent: CC(=O)O
Product: Cn1c(=O)c(=O)[nH]c2ccccc21
Reaction time: 72 h

Procedure:
1-Methyl-2(1H)-quinoxalinone (5.3 grams) was allowed to stand at room temperature for 72 hours in a mixture of 60 ml. of acetic acid and 35 ml. of 30 percent hydrogen peroxide. The product separated out as needles after 48 hours. After 72 hours, no starting material was detectable in the supernatant liquid by TLC (ethyl acetate). The product was separated and washed sequentially with water and with ethanol, m.p. 287°-289°C. It was then recrystallized from water, 287°-290°C. (literature: 286°-287°C, G. W. H. Cheeseman, J. Chem. Soc. 1804 (1955); 285°-286°C., G. W. H. Cheeseman, J. Chem. Soc. 1246 (1961)). NMR also confirmed the identity of the product.
Reaction SMILES: [CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[C:7](O)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:40][C:41]1[CH:42]=[C:43]([CH:55]=[CH:56][CH:57]=1)[CH2:44][C:45]1([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:47][CH2:46]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)[C:7]([NH:40][C:41]2[CH:42]=[C:43]([CH:55]=[CH:56][CH:57]=2)[CH2:44][C:45]2([C:48]([O:50][C:51]([CH3:54])([CH3:52])[CH3:53])=[O:49])[CH2:47][CH2:46]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(N)c2)CC1
Reactant: O=C(O)C(c1ccc(C(F)(F)F)cc1)C1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C1(Cc2cccc(NC(=O)C(c3ccc(C(F)(F)F)cc3)C3CCCC3)c2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3.0 g (11.02 mmol) of (+/−)-cyclopentyl[4-(trifluoromethyl)phenyl]acetic acid were dissolved in 16.0 ml of DMF, and 1.79 g (13.22 mmol) of 1-hydroxy-1H-benzotriazole hydrate were added. The mixture was cooled to 0° C., and 3.8 ml (22.04 mmol) of N,N-diisopropylethylamine and 3.41 g (13.77 mmol) of tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate, dissolved in a little DMF, were added. 5.03 g (13.22 mmol) of HATU were then added in several portions, and the reaction mixture was slowly warmed to RT and then stirred at RT for 3 h. The reaction was then added to water. After phase separation, the aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1→10:1). This gave 4.89 g of the target compound (88.5% of theory).
Reaction SMILES: [CH2:1]([N:3]1[CH2:12][CH2:11][CH:10]2[C:5](=[C:6]([N+:14]([O-])=O)[CH:7]=[CH:8][CH:9]2[Br:13])[CH2:4]1)[CH3:2].[H][H]>[Ni].CC(C)=O.C1COCC1>[CH2:1]([N:3]1[CH2:12][CH2:11][CH:10]2[C:5](=[C:6]([NH2:14])[CH:7]=[CH:8][CH:9]2[Br:13])[CH2:4]1)[CH3:2]
Reactant: [H][H]
Reactant: CCN1CCC2C(=C([N+](=O)[O-])C=CC2Br)C1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCN1CCC2C(=C(N)C=CC2Br)C1
Reaction time: 1 h

Procedure:
Raney nickel was refluxed in acetone for 2 hours prior to use to deactivate the metal. The product from Example 26 (0.1 g, 0.35 mmol) was dissolved in THF (10 mL), the Raney nickel added, and the reaction vessel charged with hydrogen gas. After stirring for 1 hour, the Raney nickel was removed by filtration and the solvent removed by filtration to give N-ethyl-5-bromo-8-aminotetrahydroisoquinoline (used without further purification).
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][C:34]=1[O:35]C)[C:9]([NH:11][NH:12][C:13]([C:15]1[O:16][CH:17]=[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:14])=[O:10].ClCCl>O>[F:5][C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][C:34]=1[OH:35])[C:9]([NH:11][NH:12][C:13]([C:15]1[O:16][CH:17]=[C:18]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:14])=[O:10]
Reactant: COc1ccc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(NNC(=O)c1occ(-c2ccccc2)c1-c1ccccc1)c1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
Boron tribromide (1 M dichloromethane solution: 6.00 ml) was added dropwise to a mixture of the compound of Example 31 (0.86 g) and dichloromethane (20 ml) at 0° C., and the mixture was stirred at 25° C. overnight. Water was added to the reaction solution. The thus-precipitated crystals were collected by filtration, purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/3), and recrystallized from ethanol, thereby giving 0.64 g of the desired compound. Melting point: 243-245° C.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:21][CH:20]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:3]2[C:2]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:10]3[C:5]([N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7](=[O:13])[N:8]([CH3:12])[C:9]3=[O:11])=[CH:4]2)=[CH:24][CH:23]=1
Reactant: Nc1ccccc1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)n(Cc3ccc(-c4ccccn4)cc3)cc21
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n(Cc3ccc(-c4ccccn4)cc3)cc21
Temperature: 150 °C
Yield: 46 %

Procedure:
Crude 5-chloro-1-isobutyl-3-methyl-6-(4-(pyridin-2-yl)benzyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (0.032 mmol) is placed in a Biotage microwave tube, and then aniline (0.2 mL) is added. The mixture is heated at 150° C. for an hour, and then purified by a semi-preparative HPLC to give 7 mg of pure product (overall yield:46%). MS (ESI) m/z 480.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([CH3:15])=[C:7]([CH3:14])[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([O:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([CH3:15])=[C:7]([CH3:14])[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: Cc1c(C)c2ccc(O)c(C)c2oc1=O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc2c(C)c(C)c(=O)oc2c1C
Temperature: 0 °C

Procedure:
A solution of 7-hydroxy-3,4,8-trimethylcoumarin (5.19 g, 25.4 mmol) was refluxed in acetic anhydride (10 mL) for 1.5 hours. The solution was slowly poured into ice water (200 mL) and the resulting solid was filtered, then rinsed with water to yield 7-acetoxy-3,4,8-trimethylcoumarin, a beige solid (6.22 g, 99.5%). 1H NMR (CDCl3): δ7.47 (d, J=8.6 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 2.40 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H), 2.22 (s, 3H).