Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[C:8]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][N:4]=1)[CH3:2].[CH3:20][C:21]([O:24][C:25]([NH:27][C@H:28]([CH2:32][CH3:33])[C:29](O)=[O:30])=[O:26])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([C:3]1[C:7]2[C:8]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH:19][C:29]([C@H:28]([NH:27][C:25](=[O:26])[O:24][C:21]([CH3:23])([CH3:22])[CH3:20])[CH2:32][CH3:33])=[O:30])=[CH:15][CH:14]=3)=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][N:4]=1)[CH3:2]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCc1noc2cccc(Oc3ccc(N)cn3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1noc2cccc(Oc3ccc(NC(=O)[C@@H](CC)NC(=O)OC(C)(C)C)cn3)c12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
6-[(3-ethyl-1,2-benzisoxazol-4-yl)oxy]-3-pyridinamine (Intermediate 33) was dissolved in DMF (0.5 mL) and added to a mixture of (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (7.7 mg, 0.038 mmol), DIPEA (0.008 mL, 0.047 mmol) and HATU (14.4 mg, 0.038 mmol) in 1 ml of DMF. The reaction mixture was then stirred at 50° C. for 2 hours. After the removal of DMF, water was added and the mixture was extracted with ethyl acetate. The gathered organic layers were dried over sodium sulphate, filtered and evaporated. The residue was then charged on a silica gel column (Biotage SP1 system) and eluted with Cyhexane/EtOAc (from all 10/0 to 7/3, then 7/3) to afford the title compound (4.4 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:22]=[CH:21][C:14]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:13][C:12]=2[O:23][CH3:24])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:36]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:24][O:23][C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][C:11]=1[N:10]=[N:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:1][C:35]([O:37][C:38]2[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=2)=[O:36])=[CH:4][CH:5]=1)[O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)COc1ccc(N=Nc2ccc(CO)cc2)c(OC)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)COc1ccc(N=Nc2ccc(COC(=O)Oc3ccc([N+](=O)[O-])cc3)cc2)c(OC)c1
Reaction time: 0.17 h

Procedure:
Compound 4 (0.1 g, 0.0302 mmol) was dissolved in DCM (15 mL) and freshly activated 4° A M.S (0.15 g) was added and reaction mixture stirred for 10 minutes. DIPEA (0.215 mL, 1.2 mmol) and DMAP (0.05 g) were added and reaction mixture cooled to 0° C. p-Nitrophenyl chloroformate (0.15 g, 0.0757 mmol) in DCM was added slowly and reaction mixture stirred at 0° C. for 1 hour, followed by an additional 4 hours at room temperature. The remaining procedure was followed as described for compound 5 to obtain compound 6 (E:Z isomers). Yield: 0.11 g (76%). 1H NMR (500 MHz, CDCl3) δ 3.79 (s, 3H, Hn (OMe), for Z), 3.82 (s, 3H, Hn (OMe), for E), 3.99 (s, 3H, aromatic-OMe for Z), 4.00 (s, 3H, aromatic-OMe for E), 4.58 (s, 2H, Hf for Z), 4.71 (s, 2H, Hf for E), 5.21 (s, 2H, Hl for Z), 5.34 (s, 2H, Hi for E), 6.22-6.28 (m, 1H, Hb for Z), 6.44-6.50 (m, 2H, Hb for E), 6.52-6.60 (m, 1H, He for Z), 6.64-6.70 (m, 1H, He for E), 6.84-6.95 (m, 2H, He for Z), 7.30-7.40 (m, 2H, He for E), 7.42-7.50 (m, 1H, Ha for Z), 7.50-7.54 (m, 1H, Ha for E), 7.54-7.58 (m, 2H, Hn for Z), 7.68-7.75 (m, 2H, Hn for E), 7.80-7.90 (m, 4H, Hd for Z and E), 8.08-8.14 (m, 2H, Ho for Z), 8.22-8.30 (m, 2H, Ho for E). 13C NMR (125 MHz, CD3SOCD3) δ 52.3, 52.44 (Cn), 55.4, 56.34 (aromatic-OMe), 65.2, 65.2 (Cf), 67.3, 67.4 (Cl), 70.1, 70.4, 100.2 (Cc), 104.2, 105.3 (Cb), 115.62, 116.9 (Ci), 118.0, 120.04, 121.5, 121.7, 121.75, 122.8, 122.9, 125.3, 126.0, 128.7, 128.9, 129.2, 135.9, 137.3, 145.3, 152.3, 154.4, 155.4, 158.7, 161.7, 168.7 (CO). ESI-MS: [M+H]+ C24H22N3O9 calcd 496.1356, obsd 496.12.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[P:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=1[CH:29]([CH3:31])[CH3:30].O.NN.[OH-].[K+]>>[CH3:32][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:10])[P:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18]([CH:29]([CH3:30])[CH3:31])=[CH:19][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:21][C:22]=1[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC(=O)CC2(C)C)c(C(C)C)c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CCCC2(C)C)c(C(C)C)c1
Temperature: 200 °C
Reaction time: 5 h
Yield: 97.3 %

Procedure:
A flask was charged with 1.05 g of 2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinan-4-one (2.33 mmol, 1.0 equiv), the atmosphere was sparged with argon and 12 mL of argon-sparged diethylene glycol was added. The flask was mounted with a Dean-Stark trap and condenser to collect distillate. The mixture was charged with 1.05 mL of hydrazine hydrate (55 wt % hydrazine, 11.7 mmol, 5 equiv) and 0.77 g of potassium hydroxide (88 wt %, 12.1 mmol, 5 equiv) and the mixture was immersed in an oil bath at 115° C. under an argon atmosphere. The temperature of the bath was gradually increased to 200° C. over two hours and kept at that temperature for 5 h. The reaction mixture was cooled to room temperature under argon gas. The reaction mixture was partitioned between heptane and water. The organic solution was washed once with 0.1 M aqueous hydrochloric acid, once with 10 wt % aqueous sodium carbonate and once with water. The organic solution was concentrated in vacuo with gentle heating and the residue dried in vacuo to give 0.99 g of 2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinane (97 area % by HPLC, 94% yield) as a white solid. 1H NMR (C6D6, 500 MHz), 6=0.93 (d, 6H, J=10 Hz), 1.11 (d, 6H, J=7 Hz), 1.13 (d, 6H, J=19 Hz), 1.23 (d, 6H, J=7 Hz), 1.31-1.26 (m, 2H), 1.42 (d, 6H, J=7 Hz), 1.57-1.50 (m, 1H), 1.65-1.57 (m, 1H), 1.88-1.83 (m, 2H), 2.79 (sept, 2H, J=7 Hz), 2.84 (sept, 1H, J=7 Hz), 7.12-7.11 (m, 2H), 7.22 (s, 2H), 7.27-7.24 (m, 1H), 7.98-7.93 (m, 1H); 31P NMR (C6D6, 202 MHz), δ ppm −0.4 (br singlet).
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.[F:13][C:14]([F:21])([F:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].C(I)C>C1COCC1>[CH2:1]([CH:16]([CH2:15][C:14]([F:21])([F:20])[F:13])[C:17]([OH:19])=[O:18])[CH3:2]
Reactant: O=C(O)CCC(F)(F)F
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CCI
Solvent: C1CCOC1
Product: CCC(CC(F)(F)F)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (17.1 g, 169 mmol) in THF (180 mL) was stirred under nitrogen at 0° C. n-Butyl lithium (n-BuLi—67.6 mL, 2.5 M in hexane) was added dropwise over 15 min and the resulting solution stirred for 0.5 h at 0° C. After this time period, the reaction was cooled to −78° C., and 4,4,4-trifluorobutyric acid (10.0 g, 70.4 mmol) in THF (20 mL) was added dropwise over 0.5 h. The resulting solution was stirred for an additional 0.5 h at −78° C. After this time period, ethyl iodide (6.19 mL, 77.4 mmol) was added dropwise over 15 min. The resulting solution was stirred for 15 min. at −78° C. then warmed to 25° C. for 24 h. After this time period, the reaction mixture was quenched by slow addition of H2O (˜20 mL). After concentration, the residue was acidified to pH 1 with 2 N aq. HCl and then extracted with Et2O (400 mL). The organic layer was then dried using MgSO4. After concentration, the resulting residue was used directly in the next reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:25]=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([NH2:31])([CH3:30])([CH3:29])[CH3:28].C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:25][NH:31][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)NC[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 18.3 %

Procedure:
A solution consisting of 2.86 g (8 mmol) N-tert-butoxycarbonyl-O-benzyl-L-tyrosinal (Example 4, Step A) and 0.846 mL (8 mmol) tert-butyl amine (Aldrich, Milwaukee, Wis.) in 36 mL methanol containing 1% acetic acid was stirred at 25° C. for 20 minutes, at which time a solution of 1.06 g (16 mmol) sodium cyanotrihydridoborate (Aldrich, Milwaukee, Wis.) in 12 mL methanol was added and the resulting mixture stirred for 48 hours. The reaction was quenched by the addition of 3 M HCl in 3 mL increments until the vigorous bubbling subsided. The mixture was neutralized with saturated NaHCO3 solution then extracted with three 100 mL portions of ethyl acetate. The combined extracts were washed with 100 mL brine, dried over anhydrous sodium sulphate and evaporated at reduced pressure to give a pale amber oil which was chromatographed on a silica gel column using 1% to 2% methanol in ethyl acetate as eluant to give 604 mg (18%) of the title compound as waxy white crystals; mp 77-79° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]2[N:15]=[C:16]([CH3:19])[C:17]([I:18])=[C:4]2[N:3]=1.CCN(C(C)C)C(C)C.[NH:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH2:34][OH:35]>C(#N)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]3[N:15]=[C:16]([CH3:19])[C:17]([I:18])=[C:4]3[N:3]=[C:2]([N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[CH2:34][OH:35])[CH:7]=2)=[CH:9][CH:10]=1
Reactant: OC[C@@H]1CCCN1
Reactant: Cc1nn2c(-c3ccc(F)cc3)cc(Cl)nc2c1I
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nn2c(-c3ccc(F)cc3)cc(N3CCC[C@H]3CO)nc2c1I
Yield: 61.2 %

Procedure:
5-Chloro-7-(4-fluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidine (241 mg), DIPEA (0.2 mL) and (S)-2-pyrrolidinemethanol (152 mg) are stirred at 90° C. for 16 hours in an acetonitrile (60 mL) solvent. The reaction solvent is removed by distillation under reduced pressure. The remainder is purified by column chromatography to yield the target compound (172 mg). 1H NMR (CDCl3, 300 MHz); δ 7.92 (m, 2H), 7.22 (m, 2H), 6.10 (s, 1H), 4.45 (br, 1H), 3.85-3.57 (m, 4H), 2.38 (s, 3H), 2.08-2.01 (m, 3H), 1.72 (m, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:3][CH2:2]1.[C:19]([O-:22])(=[S:21])[CH3:20].[K+].O>CC(CC(C)C)=O>[O:1]1[CH2:2][CH2:3][CH:4]([CH2:7][S:21][C:19](=[O:22])[CH3:20])[CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CC(=O)SCC1CCOCC1
Temperature: 70 °C
Reaction time: 4.5 h
Yield: 95.4 %

Procedure:
To a solution of 224 g (0.83 mol) of toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester in methyl isobutylketone (1.6 L) are added 189 g (1.66 mol) of potassium thioacetate. The beige suspension is stirred at 70° C. for 4.5 h. The reaction mixture is cooled to room temperature and water (1.8 L) is added. The organic layer is washed with 10% aqueous K2CO3 solution (1.8 L) and water (1 L). The organic layer is filtered through Celite® (20 g), activated charcoal (20 g) and Na2SO4 (20 g) and the filtrate is concentrated under reduced pressure. The residual oil is azeotroped with methylcyclohexane (200 mL) and n-heptanes (250 mL) to afford 138 g of thioacetic acid S-(tetrahydro-pyran-4-ylmethyl) ester as a yellow-orange oil (CAUTION: Stench!). Yield: 96%; ES-MS: m/z 175 [M+H]; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.23-1.40 (2H, m), 1.59-1.78 (3H, m), 2.33 (3H, d, J=4.16 Hz), 2.82 (2H, dd, J=6.24, 3.79 Hz), 3.27-3.39 (2H, m), 3.88-4.02 (2H, m)
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4][C:3]1([CH3:18])[CH3:17].[Br:19][C:20]1[CH:21]=[C:22]2[C:27](Cl)=[C:26]([C:29]([NH2:31])=[O:30])[CH:25]=[N:24][N:23]2[CH:32]=1>>[Br:19][C:20]1[CH:21]=[C:22]2[C:27]([NH:1][C@@H:2]3[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[O:8])[CH2:4][C:3]3([CH3:18])[CH3:17])=[C:26]([C:29](=[O:30])[NH2:31])[CH:25]=[N:24][N:23]2[CH:32]=1
Reactant: CC1(C)CN(C(=O)OCc2ccccc2)CC1N
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Product: CC1(C)CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12

Procedure:
According to the procedure described for Step 1 of Example 294, the title compound was prepared by coupling enantiopure Intermediate 11 with Intermediate 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH:21]([CH3:37])[C:22]([C:28]1[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=1)([OH:27])[C:23]([F:26])([F:25])[F:24])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[C:14]([F:17])([F:16])[F:15].Cl([O-])=[O:39].[Na+]>C(O)(C)(C)C.CC(=CC)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH:21]([CH3:37])[C:22]([C:28]1[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=1)([OH:27])[C:23]([F:26])([F:24])[F:25])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([OH:39])=[O:11])=[CH:8][C:7]=1[C:14]([F:17])([F:15])[F:16]
Reactant: [O-][Cl+][O-]
Reactant: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C=O)cc3C(F)(F)F)cc2Cl)C(F)(F)F)cn(C)c1=O
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C(=O)O)cc3C(F)(F)F)cc2Cl)C(F)(F)F)cn(C)c1=O

Procedure:
In analogy to Example 214, step 2, 4-{3-chloro-4-[2-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-3-trifluoromethyl-benzaldehyde was treated with sodium chlorite in the presence of sodiumdihydrogenphosphate-dihydrate in tert.-butanol, 2-methyl-2-butene and water to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=562.0 [M−H+].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH3:30])=[CH:19][C:20]([CH:26]4[CH2:29][CH2:28][CH2:27]4)=[C:21]([CH:25]=3)[C:22](O)=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)C([Cl:34])=O>ClCCl.CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH3:30])=[CH:19][C:20]([CH:26]4[CH2:29][CH2:28][CH2:27]4)=[C:21]([CH:25]=3)[C:22]([Cl:34])=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1cc(C2CCC2)c(C(=O)O)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C2CCC2)c(C(=O)Cl)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a round-bottom flask was added a solution of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoic acid (compound 234, 500 mg, 1.24 mmol, 1.00 equiv) in dichloromethane (5 mL). Oxalyl chloride (317 mg, 2.50 mmol, 2.00 equiv) and N,N-dimethylformamide (˜5 mg) were added dropwise to the mixture. The resulting solution was stirred for 1 h at 40° C., then concentrated and dried under reduced pressure to yield 480 mg (92%) of the title compound as a light yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[S-:18][C:19]#[N:20].[Na+].C(O)C>C(OCC)(=O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([C:6]2[CH:16]=[CH:17][C:3]([CH2:2][S:18][C:19]#[N:20])=[CH:4][CH:5]=2)=[O:8])=[CH:10][CH:11]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: N#C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#CSCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 41.5 %

Procedure:
4-bromomethyl-4'-chlorobenzophenone (5.7 g) and sodium thiocyanate (5.5 g) were added to ethanol (50 ml), and the mixture was stirred for one hour at 60° C. The reaction mixture was concentrated, and water was added to the residue. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. The residual solid was washed with a solvent mixture of n-hexane:ethyl acetate=10:1 to obtain the desired product (2.2 g, melting point: 129° to 131° C., yield:42%).
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]1>>[CH2:1]([N:8]([CH3:26])[C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:27]3[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)NC1CCNCC1
Reactant: CN(Cc1ccccc1)c1ccn(CCc2ccc(CBr)cc2)c(=O)c1
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(N(C)Cc4ccccc4)cc3=O)cc2)CC1

Procedure:
N-[1-(4-{2-[4-(Benzyl-methyl-amino)-2-oxo-2H-pyridin-1-yl]-ethyl}-benzyl)-piperidin-4-yl]-acetamide is prepared as example 30.1 from 150 mg (0.37 mmol) 4-(benzyl-methyl-amino)-1-[2-(4-bromomethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 14d) and 259 mg (1.82 mmol) N-piperidin-4-yl-acetamide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([NH:31][CH3:32])[CH2:27][CH2:26]1.[OH-].[Na+]>O1CCOCC1>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:7]=[C:2]([N:31]([CH3:32])[CH:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[N:3]=[C:4]([NH:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[N:5]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: CNC1CCN(C)CC1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC(CO)CO)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(NC(CO)CO)nc(N(C)C3CCN(C)CC3)n2)cc1Cl
Yield: 46.1 %

Procedure:
To 131 (0.979 g, 0.271 mmol) dissolved in 3 mL 1,4-dioxane was added methyl-4-(methylamino)piperidine (0.05 mL, 0.34 mmol) dissolved in 2 mL 1,4-dioxane followed by the addition of 2.5 N NaOH (aq) (0.11 mL, 0.275 mmol). The mixture was heated at reflux for 3 h 45 min, cooled to about room temperature, and then concentrated under reduced pressure. The resulting material was diluted with dichloromethane and filtered. The filtrate was then concentrated affording 56.5 mg of material. The crude material was purified by silica gel pipet column eluting with 100% methanol affording an white solid 132 (21.1 mg, 18%), mp 84° C.; MS (ESI): m/z 454 (34.7), 452 (M+H, 100), 422 (11.3), 248 (25.3), 247 (51.3), 157 (60.3), 129 (27.5).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:26]1[N:27]=[C:28]([N:31]2[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]2)[S:29][CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[N:27]=[C:28]([N:31]5[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]5)[S:29][CH:30]=4)[CH2:23][C:22](=[O:37])[NH:21][C:9]=3[CH:10]=2)=[CH:15][CH:16]=1
Reactant: Cc1cn(-c2nc(C(=O)CC(=O)Nc3cc(-c4ccc(F)cc4)ccc3NC(=O)OC(C)(C)C)cs2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cn(-c2nc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)cs2)cn1

Procedure:
Prepared from (4′-fluoro-3-{3-[2-(4-methyl-imidazol-1-yl)-thiazol-4-yl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example K76) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (101 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:20](=[O:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]([N:8]([C:15](=[O:19])[C:16](Cl)=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[CH3:30][O:31][CH2:32][CH2:33][OH:34].CCN(CC)CC>C1COCC1>[CH3:30][O:31][CH2:32][CH2:33][O:34][C:16](=[O:17])[C:15]([N:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[C:20](=[O:29])[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:19]
Reactant: O=C(Cl)C(=O)N(c1ccccc1)c1cc(F)ccc1C(=O)CCc1ccccc1
Reactant: COCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCOC(=O)C(=O)N(c1ccccc1)c1cc(F)ccc1C(=O)CCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of {[5-fluoro-2-(3-phenyl-propionyl)-phenyl]-phenyl-amino}-oxo-acetyl chloride (540 mg) in THF (3 mL) was added 2-methoxyethanol (0.12 mL), followed by Et3N (0.22 mL). The reaction mixture became a pale yellow slurry: additional THF (2 mL) was added, and the mixture allowed to stand for 1 h. The mixture was then quenched with NH4Cl (sat'd aq), extracted with EtOAc, washed with brine, and concentrated to yield N-[5-fluoro-2-(3-phenyl-propionyl)-phenyl]-N-phenyl-oxalamic acid 2-methoxy-ethyl ester (504 mg) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][C@H:15]([CH3:17])[C@H:14]([CH2:18][C:19]([OH:21])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][C@H:15]([CH3:17])[C@H:14]([CH2:18][C:19](=[O:21])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: C[C@H]1Cc2cc(Br)cc3[nH]c(=O)c(=O)n(c23)[C@H]1CC(=O)O
Reactant: Nc1ccccc1
Product: C[C@H]1Cc2cc(Br)cc3[nH]c(=O)c(=O)n(c23)[C@H]1CC(=O)Nc1ccccc1
Yield: 89.1 %

Procedure:
A procedure similar to that described in Example 5 was carried out with cis-9-bromo-5-carboxymethyl-6-methyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (100 mg, 0.283 mmol) and aniline (28 μL, 0.311 mmol) to give 108 mg of the title compound (89%): mp>300° C.; 1H NMR (270 MHz, DMSO-d6) δ12.03 (s, 1H), 9.89 (s, 1H), 7.45 (d, 2H, J=7.6 Hz), 7.27 (t, 2H, J=7.6 Hz), 7.19 (d, 1H, J=2 Hz), 7.17 (d, 1H, J=2 Hz), 7.02 (t, 1H, J=7.6 Hz), 5.16~5.26 (m, 1H), 2.70~2.85 (m, 2H), 2.63 (dd, 1H, J=14.2, 5.9 Hz), 2.24 (dd, 1H, J=14.2, 6.6 Hz), 2.10~2.26 (m, 1H), 1.13 (d, 3H, J=6.9 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[N:15][N:14]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[C:13]=2[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:28]([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[N:15][N:14]([CH:17]([CH3:21])[C:18]([O:20][CH3:28])=[O:19])[C:13]=2[CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)n1nnc2ccc(OCc3ccccc3)cc21
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(C)n1nnc2ccc(OCc3ccccc3)cc21

Procedure:
A mixture of 6-(benzyloxy)-α-methyl-1H-benzotriazole-1-acetic acid (36.6 g, 0.123 mole) and concentrated sulfuric acid (2.7 ml) in methanol is stirred at reflux temperature for 6 hours, cooled in an ice bath and treated with K2CO3 (25 g). The resulting mixture is stirred vigorously until a thick slurry results, diluted with methylene chloride and filtered. The filtrate is concentrated in vacuo to give a solid residue. Recrystallization of the residue from methanol affords the title product as a white solid, 27 g, mp 88°-91.5° C., identified by NMR and elemental analyses. Another 4.2 g (81.7% total yield) of the title product is obtained from the mother liquor.