Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:10]([N:12]1[CH2:26][CH2:25][CH2:24][C@H:13]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(OC)C=CC=CC=1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[NH2:1][C@@H:2]([C:10]([N:12]1[CH2:26][CH2:25][CH2:24][C@H:13]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:42][C:43]([C:44]([OH:46])=[O:45])([F:48])[F:47]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 85 %

Procedure:
To a stirring solution of Boc-D-Phe-Pro-OBn (68 g, 150 mmol) in dichloromethane (50 mL) at 0° C., was added anisole (20 mL) followed by trifluoroacetic acid (400 mL). After stirring for 3 hours, the solvents were evaporated in vacuo and the thick oily residue was dissolved in diethyl ether (1.5 L) and refrigerated (72 hours). The white precipitate was filtered, washed with diethyl ether (300 mL) and dried to yield 59.4 g (85%) of white powder.
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].[C:6]1([C:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH4+:21].[OH-]>CC(C)=O>[NH2:21][S:2]([C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:13])=[CH:20][CH:19]=1)(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: [NH4+]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: [OH-]
Solvent: CC(C)=O
Product: NS(=O)(=O)c1ccc(CC(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 28.8 %

Procedure:
Chlorosulfonic acid (1781 g, 1018 mL, 15.29 mol) was treated portionwise with deoxybenzoin (400 g, 2.04 mol) at such a rate that the internal temperature was maintained between 5° and 15° C. The mixture was warmed to room temperature and maintained at that temperature for an additional 14 hours. The mixture was poured cautiously into ice water. The crude sulfonyl chloride was filtered and added portionwise to a solution of acetone (600 mL) and concentrated NH4OH (551 mL, 8.15 mol), yielding a pale yellow suspension. The crude precipitate was collected by vacuum filtration, and triturated with boiling acetone (1.5 L). Filtration afforded 2-[4-aminosulfonylphenyl]-1-phenyl-ethan-1-one (162 g, 29%) as an off-white powder: 1H NMR (DMSO-d6, 300 MHz) 8.05 (d, J=7.25 Hz, 2H), 7.76 (d, J=8.26 Hz, 2H), 7.65 (t, J=7.85 Hz, 1H), 7.54 (t, J=7.85 Hz, 2H), 7.44 (d, J=8.26, 2H), 7.30 (br s, 2H), 4.52 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH2:7][CH:8]=[CH2:9])[C:3](OC)=[O:4].O.[NH2:12][NH2:13]>CO>[CH3:1][C:2]([CH3:10])([CH2:7][CH:8]=[CH2:9])[C:3]([NH:12][NH2:13])=[O:4]
Reactant: C=CCC(C)(C)C(=O)OC
Reactant: NN
Solvent: O
Solvent: CO
Product: C=CCC(C)(C)C(=O)NN
Temperature: 60 °C

Procedure:
To a solution of methyl 2,2-dimethyl-4-pentenoate (1 g) in MeOH (2 ml) was added hydrazine monohydrate (2.7 ml). The solution was heated in a close microwave vial at 60° C. for 12 h. Volatiles were evaporated in vacuo to give 1 g of the title compound as a yellow pale foam, which was used without further purification.
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:14])/[CH:7]=[C:8](\[NH2:13])/[C:9]([F:12])([F:11])[F:10])C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[C:18]([N+:25]([O-:27])=[O:26])[CH:17]=1>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:6](=[O:14])[CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[NH:13][C:23]2=[O:24])=[C:18]([N+:25]([O-:27])=[O:26])[CH:17]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: O=C=Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: -30 °C
Reaction time: 0.33 h

Procedure:
To a suspension of sodium hydride (60% dispersion in oil, 2.5 g) in anhydrous N,N-dimethylformamide (100 ml) was added dropwise a solution of ethyl-3-amino-4,4,4-trifluorocrotonate in toluene (50 ml) at 0° C. under nitrogen atmosphere. After addition, the mixture was stirred for 20 min at same temperature, then cooled to −30° C. A solution of (4-chloro-2-nitrophenyl)isocyanate in toluene (50 ml) was added dropwise. After stirring for 20 min, the cold bath was removed and the resulting mixture was stirred overnight at ambient temperature. The reaction mixture was partitioned between ethyl acetate and 1N-hydrochloric acid. The organic phase was washed with brine (×2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel eluted with ethyl acetate and hexane (1:1) to afford 3-(4-chloro-2-nitrophenyl)-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (10.2 g) as a yellow solid.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C(OC(=O)C)(=O)C.[BrH:12].[CH2:13]([N:16]([CH2:29][CH2:30][CH3:31])[CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([OH:28])[C:23]=2[NH2:27])[CH2:18]1)[CH2:14][CH3:15].C(OCC)C>C(Cl)Cl>[BrH:12].[CH2:29]([N:16]([CH2:13][CH2:14][CH3:15])[CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([OH:28])[C:23]=2[NH:27][C:1](=[O:4])[CH3:2])[CH2:18]1)[CH2:30][CH3:31]
Reactant: CCCN(CCC)C1CCc2c(ccc(O)c2N)C1
Reactant: CC(=O)O
Agent: Br
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: CCCN(CCC)C1CCc2c(ccc(O)c2NC(C)=O)C1
Reaction time: 1 h

Procedure:
10 ml of acetic acid and 0.46 ml of acetic anhydride are added to 1.5 g of 2-dipropylamino-5-amino-6-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (obtained in accordance with Example 1(d)) in 25 ml of methylene chloride at 0° C. The mixture is stirred for one hour, diethyl ether is added and the solid is recrystallised from ethanol. This gives 1.2 g of a product melting at 244.5° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=1)=[O:11].Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:29]=2[N:30]=1>>[Cl:35][C:32]1[CH:33]=[CH:34][C:28]2[O:27][C:26]([NH:1][CH2:2][C@@H:3]3[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]3[C:10]([C:12]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=3)=[O:11])=[N:30][C:29]=2[CH:31]=1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: Clc1ccc2oc(Cl)nc2c1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A2 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6′-methyl-[2,3′-bipyridin]-2′-yl)methanone and 2,5-dichlorobenzoxazole. MS (ESI) 476 (M+H).
Reaction SMILES: [C:1]([O-])([O-])=O.[Cs+].[Cs+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][CH:20]=[C:21]3[C:24]([OH:26])=[O:25])=[N:16]2)=[CH:11][CH:10]=1)#[N:8].IC>CN(C=O)C.CCOC(C)=O>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][CH:20]=[C:21]3[C:24]([O:26][CH3:1])=[O:25])=[N:16]2)=[CH:11][CH:10]=1)#[N:8]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(-n2cc3c(C(=O)O)cccc3n2)cc1
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2nn(-c3ccc(C#N)cc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cs2CO3 (1.2 eq.) was added to a solution of (C6) in dry DMF (0.2 M). The resulting white suspension was stirred at RT for 30 min. After cooling down to 0° C., iodomethane (7 eq.) was added, then, the reaction mixture was stirred at RT for 90 min. The solution was diluted with EtOAc and washed with brine (2×) and dried (Na2SO4). Evaporation of the solvent afforded the title compound that was used in the next step without further purification. 1H NMR (300 MHz, CDCl3, 300K) δ 9.02 (1H, s), 8.14 (2H, d, J=8.7 Hz), 8.01-7.95 (2H, m), 7.85 (2H, d, J=8.5 Hz), 7.42 (1H, t, J=7.4 Hz), 4.02 (3H, s). MS (ES+) C16H11N3O2 required: 277, found: 278 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:38][C:39]1[CH:47]=[CH:46][CH:45]=[CH:44][C:40]=1[C:41](O)=[O:42].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][C:41](=[O:42])[C:40]3[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=3[Cl:38])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C(O)c1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1

Procedure:
The title compound was prepared from 5-n-butyl-2-(2-chloro-5-nitrophenyl)-2,4-dihydro-4[(2'-sulfamoylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Step C) and 2-chlorobenzoic acid (2 eq), CDI (2 eq), and DBU (2 eq) according to the procedure of Example 51 to give a 48% yield of the desired material as a cream-colored solid after flash chromatography, mp >160° C. (gradual), homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 681 (M+1)+.
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:22][CH3:23])[N:13]2C2CCCCO2)=[C:9]([NH2:24])[N:8]=1)[CH2:3][CH2:4][CH3:5].[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>CO>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:22][CH3:23])[NH:13]2)=[C:9]([NH2:24])[N:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)[nH]c2n1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
2-{[(1S)-1-Methylbutyl]oxy}-8-(methyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (6 g, 17.89 mmol) was dissolved in methanol (50 ml). Trifluoroacetic acid (20.67 ml, 268 mmol) was added dropwise, and the mixture stirred at 20° C. for 72 hours under an atmosphere of nitrogen. The solvent was removed in vacuo, and the resulting solid was washed with ethyl acetate and filtered. The filtrate was stripped and the residue washed with ethyl acetate. The combined solid residues were dried in the vacuum oven for 2 hours to give the title compound as an off white solid (5.3 g). LCMS (System C): tRET=0.76 min; MH+ 252, 253
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:20]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23]([N:25]1[CH2:26][CH2:27][CH:28]([NH:31][C:4]2[CH:5]=[CH:6][C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])=[C:2]([NH2:1])[N:3]=2)[CH2:29][CH2:30]1)=[O:24])[CH3:21]
Reactant: COc1ccc(F)cc1C(=O)c1ccc(Cl)nc1N
Reactant: CCOC(=O)N1CCC(N)CC1
Product: CCOC(=O)N1CCC(Nc2ccc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (Example 19) and ethyl-4-amino-1-piperidine carboxylate (Aldrich 96) using the procedure described in Step B. Example 6. HRMS, observed: 417.1938, Calcd for (M+H)+: 417.1933.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][C@@H:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH2:11])[CH:6]=[CH:5][N:4]=1.[CH3:17][C:18]([O:21][C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23])([CH3:20])[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[C:18]([O:21][C:22]([NH:24][CH2:25][C:26]([NH:11][C@H:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=1)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOC(=O)[C@@H](N)Cc1ccnc(OC)c1
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: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](Cc1ccnc(OC)c1)NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.3 %

Procedure:
To a 100-mL round-bottomed flask was added ethyl 3-(2-methoxy-4-pyridinyl)alaninate (1.47 g, 6.56 mmol), N-α-t-boc-glycine (1.26 g, 7.22 mmol, Aldrich, St. Louis, Mo.), HATU (2.99 g, 7.87 mmol, Aldrich, St. Louis, Mo.) and N,N-diisopropylethylamine (3.42 mL, 19.68 mmol, Aldrich, St. Louis, Mo.) in DMF (6 mL). The reaction mixture was stirred room temperature for 18 h, diluted with water (50 mL), and extracted with EtOAc (2×20 mL). The organic extract was washed with saturated NaCl (30 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 60% EtOAc/hexanes to give ethyl N-(tert-butoxycarbonyl)glycyl-3-(2-methoxy-4-pyridinyl)alaninate (2.31 g) as a colorless oil.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CN1CCOCC1.[C:13]([O:17][C:18]([NH:20][C@H:21]([CH2:25][C:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22](O)=[S:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(OC(Cl)=O)(C)C>ClCCl.O1CCCC1>[CH3:5][O:4][N:3]([CH3:2])[C:22](=[S:23])[C@H:21]([NH:20][C:18]([O:17][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:19])[CH2:25][C:26]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)=S
Reactant: CNOC
Agent: CC(C)OC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CON(C)C(=S)[C@@H](CC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C
Temperature: -30 °C

Procedure:
The title compound was synthesized essentially according to the procedure described by O. P. Goel, U. Krolls, M. Stier, and S. Kesten in Organic Syntheses, 1988, 67, 69-75. Thus N,O-dimethyl-hydroxylamine hydrochloride (1.05 g, 10.82 mmol) and N-methyl-morpholine (1.22 mL, 11.14 mmol) were stirred in dichloromethane (6 mL) under nitrogen at 0° C. for 30 min. In a separate flask, 2(R)-tert-butoxycarbonylamino-3-triphenylmethyl-thiopropionic acid (5.02 g, 10.82 mmol) in tetrahydrofuran (11.5 mL, dry) and methylene chloride (45 mL) were cooled to -20° C., and N-methylmorpholine (1.22 mL, 11.14 mmol) and isopropylchloroformate (10.82 mL of 1M solution in toluene) were added via syringe, maintaining the temperature less than -15° C. The reaction was stirred at -30° C., and the suspension of N,O-dimethylhydroxylamine hydrochloride and N-methylmorpholine in methylene chloride added all at once. The cooling bath was removed and the reaction allowed to warm to room temperature over 4 h. The reaction was cooled to 0° C. and quickly washed with two portions of 0.2N hydrochloric acid, two portions of 0.5N sodium hydroxide, and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and reduced in vacuo to obtain the title compound as a clear gum, 5.50 g. NMR (300 MHz, DMSO-d6) δ 7.30 (15H, m), 4.43 (1H, br s), 3.56 (3H, s), 2.99 (3H, s), 2.30 (2H, m), 1.36 (9H, s).
Reaction SMILES: [CH3:1][N:2]([CH:9]=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:11]=[CH:9][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C=O)c1ccccc1
Reactant: Nc1ccccn1
Product: CN(C=Nc1ccccn1)c1ccccc1

Procedure:
Prepared following the procedure of Example 1 from N-methylformanilide and 2-aminopyridine. Vacuum distillation of the crude product gave pure 3 as a pale yellow oil: bp 164°-165° C. @ 0.5 mm Hg. 1H-NMR (CDCl3) 8.94 (S, 1H), 8.30 (d, 1H, J=5 Hz), 7.6-6.9 (m,8H), 3.52 (S, 3H); IR(neat) 3045, 1620, 1580, 1555, 1500, 1460, 1435, 1235; MS (m/e) 211 (M+), 106 (base).
Reaction SMILES: [CH2:1]([Se:8][C:9]1[C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>ClCCl>[CH2:1]([Se:8][C:9]1[C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=[CH:14][C:10]=1[C:11]([NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2c(c1[Se]Cc1ccccc1)OCO2
Reactant: Nc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1ccc2c(c1[Se]Cc1ccccc1)OCO2

Procedure:
To a solution of 1.6 g (0.0048 mol) 2-benzylseleno-3,4-methylenedioxybenzoic acid and 0.48 g triethylamine in 50 ml dichloromethane at 0° C. is added in one portion 1.22 g (0.0048 mol) solid bis[2-oxo-3-oxazolidinyl]phosphoryl chloride. After stirring for 30 min 0.44 g (0.44 ml) aniline in 5 ml dichloromethane are added at 0° C. dropwise with stirring followed after 1 hour by a solution of 0.48 g (0.66 ml) triethylamine in 10 ml dichloromethane. After 90 minutes at room temperature the reaction mixture is extracted successively with 50 ml 1N HCl and 50 ml water. The organic phase is dried over sodium sulfate and the solvent removed in vacuum. The crude product is purified by recrystallization from 2-propanol.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:7]=2[CH2:6][CH2:5]1)[C:2]#[CH:3].Cl[C:17]1[N:22]=[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:20]([Cl:35])=[CH:19][N:18]=1>>[Cl:35][C:20]1[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[N:22][C:17]([NH:15][C:12]2[CH:13]=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:1][C:2]#[CH:3])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:18][CH:19]=1
Reactant: C#CCN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: C#CCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc2CC1

Procedure:
N-{(1R,2R)-2-[5-Chloro-2-(3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide was prepared from 3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 322. Product isolated as a pale yellow solid (90 mg, 36%). m.p.=193-196° C.; LCMS (m/e) 503 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 7.35-7.25 (m, 1H), 7.08 (d, 1H, J=7.8 Hz), 6.82 (s, 1H), 5.40 (d, 1H, J=7.5 Hz), 5.38-5.32 (m, 1H), 3.94-3.83 (m, 1H), 3.45 (d, 2H, J=2.0 Hz), 3.31-3.20 (m, 1H), 3.00-2.90 (m, 4H), 2.80 (s, 3H,), 2.83-2.71 (m, 4H), 2.28-2.18 (m, 3H), 1.89-1.79 (m, 2H), 1.45-1.33 (m, 4H).
Reaction SMILES: C([C:3]1[C:4]([Br:11])=[C:5]([OH:10])[CH:6]=[CH:7][C:8]=1[Cl:9])C.C(=O)([O-])[O-].[K+].[K+].Cl[CH:19]1[CH2:23][CH2:22][CH2:21][C:20]1=[O:24]>CC(C)=O>[Br:11][C:4]1[CH:3]=[C:8]([Cl:9])[CH:7]=[CH:6][C:5]=1[O:10][CH:19]1[CH2:23][CH2:22][CH2:21][C:20]1=[O:24]
Reactant: O=C1CCCC1Cl
Reactant: CCc1c(Cl)ccc(O)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CCCC1Oc1ccc(Cl)cc1Br
Temperature: 100 °C
Yield: 71 %

Procedure:
To a solution of ethyl 2-bromo-4-chlorophenol (10.9 g, 52.5 mmol) in acetone (105 mL) was added potassium carbonate (14.5 g, 105 mmol), followed by 2-chlorocyclopentanone (6.3 mL, 63 mmol). The mixture was refluxed at 100° C. overnight, then filtered through celite, concentrated in vacuo and purified by flash chromatography on silica gel (20% EtOAc in hexanes) to provide 2-(2-bromo-4-chlorophenoxy)cyclopentanone (516B) (10.8 g, 71.0%) as a yellow oil.
Reaction SMILES: [OH-:1].[Na+].[C:3]([OH:10])(=[O:9])/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].OO>O.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[C@@H:4]1([C:3]([OH:10])=[O:9])[O:1][C@@H:5]1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: [OH-]
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@H]1O[C@H]1C(=O)O
Temperature: 90 °C

Procedure:
A solution was prepared by dissolving 67 grams of sodium hydroxide in 400 ml of water. To this solution were added 130 g of maleic acid while maintaining the solution at a temperature below 98° C. An aqueous solution of hydrogen peroxide (30%) was then added, followed by the addition of a solution containing 2.0 g of sodium tungstate dihydrate in 8.0 ml of water. The solution was heated in a 90° C. oil bath for 30 minutes and then cooled to ≤60° C. A solution containing 44 g of aqueous NaOH (50% by weight) was then added to bring the pH to 7.0. The product was analyzed by NMR, giving 14.7% by weight of cis-epoxysuccinic acid and 3.9% by weight of D,L-tartaric acid.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:13])=[N:6][C:7](Cl)=[C:8]([C:10]#[N:11])[CH:9]=1)(=[O:3])[CH3:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[C:1]([C:4]1[C:5]([CH3:13])=[N:6][C:7]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:8]([C:10]#[N:11])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C#N)c(Cl)nc1C
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(C#N)c(N2CCOCC2)nc1C
Temperature: 90 °C
Reaction time: 2 h

Procedure:
9.5 g (48.8 mmol) of 3-acetyl-6-chloro-5-cyano-2-methyl-pyridine are dissolved in 180 ml of toluene, 9.5 g (0.109 mol) of morpholine are added, and the mixture is stirred at 90° C. for two hours. To work up, the mixture is evaporated, and the residue is suspended in water, filtered with suction and carefully washed with water. Re-crystallization from methanol/water is used for purification.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][C:9]([C:11]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12]2)=[O:10])=[CH:5][C:4]=1[N:20]=[C:21]=S.[NH2:25][C:26]1[C:27]([NH:47][CH3:48])=[CH:28][C:29]([O:42][CH2:43][CH:44]([F:46])[F:45])=[C:30]([CH:41]=1)[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][CH:35]=1)=[O:32].CC(C)N=C=NC(C)C>CN(C=O)C>[Br:40][C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:31]([C:30]2[C:29]([O:42][CH2:43][CH:44]([F:45])[F:46])=[CH:28][C:27]3[N:47]([CH3:48])[C:21]([NH:20][C:4]4[CH:5]=[C:6]([CH2:7][NH:8][C:9]([C:11]5([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12]5)=[O:10])[CH:18]=[CH:19][C:3]=4[C:2]([F:24])([F:23])[F:1])=[N:25][C:26]=3[CH:41]=2)=[O:32])=[CH:35][CH:36]=1
Reactant: CNc1cc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)cc1N
Reactant: O=C(NCc1ccc(C(F)(F)F)c(N=C=S)c1)C1(C(F)(F)F)CC1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2C(F)(F)F)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21

Procedure:
The title compound was prepared in accordance with the procedure in Example 72, step (a) using N-(4-trifluoromethyl-3-isothiocyanato-benzyl)-1-(trifluoromethyl)cyclopropane carboxamide (184 mg; 0.50 mmol), 5-amino-N-(4-bromophenyl)-2-(2,2-difluoroethoxy)-4-(methylamino)benzamide (200 mg; 0.50 mmol), DIC (63 mg; 0.50 mmol) and DMF (4 mL). Yield: 59 mg (16%). 400 MHz 1H-NMR (DMSO-d6, ppm) 10.62 (0.57H, s, major tautomer) 10.09-9.96 (1H, m) 8.47-8.41 (0.38H, m, minor tautomer) 8.36-8.28 (1H, m) 7.72-7.61 (3H, m) 7.58-7.47 (3H, m) 7.36-7.28 (1H, m) 7.12-6.84 (2H, m) 6.67-6.35 (1H, m) 4.58-4.45 (2H, m) 4.34-4.25 (2H, m) 3.64 (0.96H, s, minor tautomer) 3.41 (1.93H, s, major tautomer) 1.31-1.17 (4H, m). MS m/z: 734, 736 [M+H]+.