Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:20])[C:9]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C1C=CN=CC=1)C.O>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]=[CH:24][CH:23]=[C:22]2[O:20][C:8]1[C:9]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:11]([CH3:12])=[C:6]([CH3:5])[CH:7]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cc(O)c(-c2ncccc2C)nc1C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3cc(C)c(C)nc3-c3ncccc3C)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
Dimethyl sulfoxide (1.4 ml) was added to 5,6,3′-trimethyl-[2,2′]bipyridin-3-ol (30 mg), 4-chloro-6,7-dimethoxyquinoline (94 mg), cesium carbonate (137 mg), and 4-(N,N-dimethylamino)-pyridine (51 mg), and the mixture was stirred at 140° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (29 mg, yield 52%).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([C:15](=[O:17])[CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)[CH2:30][CH2:29]1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: Fc1ccccc1N1CCNCC1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCN(c3ccccc3F)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-(2-fluoro-phenyl)-piperazine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a yellow oil. MS (ES) for C22H25FN2O5 [M+H]+: 417.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C@@H:11]1[CH2:15][O:14]C(C)(C)[O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C>[CH2:1]([NH:8][C:9](=[O:10])[C@@H:11]([OH:12])[CH2:15][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@@H](C(=O)NCc2ccccc2)O1
Solvent: CC(=O)O
Product: O=C(NCc1ccccc1)[C@@H](O)CO

Procedure:
(S)-N-benzyl-2,3-dihydroxypropionamide was prepared in the following manner: (S)-N-benzyl-2,2-dimethyl-1,3-dioxolane-4-carboxamide (3.49 g, 14.8 mmol) in a 50% aqueous acetic acid solution (86 mL) was heated at reflux (30 min). The solvent was evaporated in vacuo, and the resulting residue was purified by silica gel column chromatography (10% MeOH-CHCl3) to obtain the desired product as a white solid (2.26 g, 78%); mp 83°-84° C.; Rf 0.35 (10% MeOH-CHCl3); [α]23D=-35.1° (c=0.10, MeOH); IR (KBr) 3337, 1649, 1623, 1546, 1109, 1049, 971, 739, 697 cm-1 ; 1H NMR (DMSO-d6) δ 3.45-3.59 (m, CHH'OH), 3.60-3.66 (m, CHH'OH), 3.90-3.98 (m, CHOH), 4.29 (d, J=6.3 Hz, CH2Ph), 4.65-4.85 (m, OH), 5.40-5.65 (m, OH), 7.15-7.40 (m, PhH), 8.25 (t, J=6.0 Hz, NH); 13C NMR (DMSO-d6) 41.8 (CH2Ph), 64.1 (CH2OH), 73.2 (CHOH), 126.7 (C4 '), 127.2 (2C2 ' or 2C3 '), 128.3 (2C2 ' or 2C3 '), 139.7 (C1 ') 172.4 (C(O)NH) ppm; MS (+Cl) 196 (M+ +1); Mr (+Cl) 196.097 09 [M+ +1] (calcd. for C10H14NO3 196.097 37); Anal (C10H13NO3) C, H, N.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]([F:23])([F:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:7]=1[F:31])[CH3:2].Cl.CO.N#N>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([NH:13][CH2:14][C:15]([F:22])([F:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:7]=1[F:31])[CH3:2]
Reactant: CCOC(=O)Cc1c(Cl)cnc(N(CC(F)(F)c2ccccn2)C(=O)OC(C)(C)C)c1F
Agent: Cl
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)Cc1c(Cl)cnc(NCC(F)(F)c2ccccn2)c1F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Through a 0° C. solution of 0.6 g (1.6 mmol) ethyl(2-{(tert-butoxycarbonyl)[2,2-difluoro-2-(2-pyridinyl)ethyl]amino}-5-chloro-3-fluoro4-pyridinyl)acetate 1-4 in 12 mL EtOAc was passed a steady stream of HCl gas for 20 min, then the reaction mixture was allowed to stir at 0° C. for 20 min. A precipitate formed so 1 mL MeOH was added to make the reaction homogeneous and HCl gas was passed through the mixture for another 15 min., then a stream of N2 gas for 5 min, then the mixture poured into 300 mL EtOAc/100 mL 2M NaOH/15 mL conc NaOH and the layers mixed and separated. The aqueous, layer was back extracted with 50 mL EtOAc and the combined organic layers washed with 150 mL water, and brine, then dried over Na2SO4, filtered, concentrated, to give ethyl(5-chloro-2-{[2,2-difluoro-2-(2-pyridinyl)ethyl]amino}-3-fluoro-4-pyridinyl)acetate 1-5 which was used without further purification. 1H NMR (400 mHz, CDCl3) δ8.66 (br d, 1H, J=4.76 Hz); 7.88 (s, 1H); 7.82 (ddd, 1H, J=7.7, 7.7, and 1.64 Hz); 7.69 (d, 1H, J=7.87 Hz); 7.39 (dd, 1H, J=4.76 and 7.33 Hz); 5.21 (br m, 1H); 4.43 (dt, 2H, J=13.9 and 6.05 Hz); 4.18 (q, 2H, J=7.14 Hz); 3.75 (d, 2H, J=1.65 Hz); 1.26 (t, 3H, J=7.14 Hz). Mass spectrum (electrospray) M+H=374.1
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:15]([O:32][CH3:33])=[C:16]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([NH2:30])=[O:29])=[C:24]([F:31])[CH:23]=2)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:20][C:18]1[C:17]([CH3:21])=[C:16]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([NH2:30])=[O:29])=[C:24]([F:31])[CH:23]=2)[C:15]([O:32][CH3:33])=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:19]=1
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1-c1ccc(C(N)=O)c(F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1-c1ccc(C(N)=O)c(F)c1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (13 mg, 0.065 mmol), 3′-(1-aminoethyl)-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxamide (20 mg, 0.06 mmol), and N,N-diisopropylethylamine (0.021 mL, 0.12 mmol) in isopropyl alcohol (0.2 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C22H21ClFN6O2 (M+H)+: m/z=455.1. found: 455.0.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].O.C1C=CC2N(O)N=NC=2C=1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH:39]1[CH:44]=[CH:43][C:42]([CH2:45][O:46][C:47]([CH2:49][NH2:50])=[O:48])=[CH:41][CH:40]=1.CCN=C=NCCCN(C)C>CN(C=O)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:50][CH2:49][C:47]([O:46][CH2:45][C:42]1[CH:43]=[CH:44][CH:39]=[CH:40][CH:41]=1)=[O:48])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
To a solution of 6.00 g of BOC-Leu-OH.H2O, 3.49 g of HOBT and 9.59 of H-Gly-OBzl.TosOH dissolved in 30 ml of DMF, under cooling at -5° C. and stirring, a solution of 4.97 ml of WSC dissolved in 10 ml of DMF was added dropwise, and after one hour, the temperature was regulated to room temperature, at which stirring was continued overnight. The reaction mixture was concentrated under reduced pressure to evaporate DMF, and the residue was dissolved in ethyl acetate. The ethyl acetate layer was washed successively with 1N hydrochloric acid, water, 5% aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 9.2 g of BOC-Leu-Gly-OBzl as oily product. Rf1 =0.59.
Reaction SMILES: FC1C=CC=CC=1N1C(=S)C2C=CC=CC=2[Se]1.[CH2:18]1O[C:25]2[CH:24]=[CH:23][C:22]([N:27]3[C:31](=[S:32])[C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[Se:28]3)=[CH:21][C:20]=2[O:19]1.C1(CN2C(=S)C3C=CC=CC=3[Se]2)C=CC=CC=1.C1(CCCCN2C(=S)C3C=CC=CC=3[Se]2)C=CC=CC=1.C(N1C(=S)C2C=CC=CC=2[Se]1)C.CC1C=CC=CC=1N1C(=S)C2C=CC=CC=2[Se]1.C(N1C(=S)C2C=CC=CC=2[Se]1)CCC>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([N:27]2[C:31](=[S:32])[C:30]3[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=3[Se:28]2)[CH:23]=[CH:24][CH:25]=1
Reactant: S=c1c2ccccc2[se]n1-c1ccc2c(c1)OCO2
Agent: CCCCn1[se]c2ccccc2c1=S
Agent: CCn1[se]c2ccccc2c1=S
Agent: Cc1ccccc1-n1[se]c2ccccc2c1=S
Product: COc1cccc(-n2[se]c3ccccc3c2=S)c1

Procedure:
The following compounds were prepared analogously to the instructions of Example 2: 2-(2-fluorophenyl)-1,2-benzisoselenazole-3(2H)-thione, melting point 55°-57° C., 2-(3,4-methylenedioxyphenyl)-1,2-benzisoselenazol-3(2H)-thione, melting point 85°-88° C., 2-(phenylmethyl)-1,2-benzisoselenazole-3(2H)-thione, melting point 41° C., 2-(4-phenylbutyl)-1,2-benzisoselenazole-3(2H)-thione, oil, 2-ethyl-1,2-benzisoselenazole-3(2H)-thione, oil, 2-(2-methylphenyl)-1,2-benzisoselenazole-3(2H)-thione, melting point 65°-67° C. and 2-butyl-1,2-benzisoselenazole-3(2H)-thione, oil.
Reaction SMILES: [O-:1][N+:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4]([C@H:12]([NH:14]C(=O)OC(C)(C)C)[CH3:13])[CH:3]=1.[ClH:22]>O1CCOCC1>[ClH:22].[O-:1][N+:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[C:4]([C@H:12]([NH2:14])[CH3:13])[CH:3]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)[n+]([O-])c1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](N)c1ccc(C(F)(F)F)[n+]([O-])c1
Reaction time: 4 h
Yield: 106.4 %

Procedure:
To a solution of tert-butyl {(1R)-1-[1-oxido-6-(trifluoromethyl)-3-pyridinyl]ethyl}carbamate (140 mg, 0.457 mmol) in dioxane (2 mL) was added hydrogen chloride (4.0 M in dioxane; 0.343 mL, 1.371 mmol). The reaction mixture was stirred for 4 h. The reaction mixture was concentrated to dryness to give the hydrochloride salt of the title compound (118 mg). MS 207.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13].O1CCCC1>[Pt](=O)=O.C(O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)/C=C/c1ccc(OC)cc1F
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(OC)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
A mixture of ethyl (2E)-3-(2-fluoro-4-methoxyphenyl)acrylate (7.07 g, 31.5 mmol), tetrahydrofuran (50 mL), ethanol (5 mL) and platinum dioxide (300 mg) was stirred overnight under a hydrogen atmosphere at room temperature. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4:1) to give the title compound (5.97 g, yield 84%) as a colorless oil.
Reaction SMILES: [OH-].[Li+].[C:3]([C:6]#[C:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)([OH:5])=[O:4].[CH3:24]O>>[CH3:24][O:4][C:3]([C:6]#[C:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:5]
Reactant: CO
Reactant: O=C(O)C#CCc1c(-c2cccnc2)[nH]c2ccccc12
Agent: [Li+]
Agent: [OH-]
Product: COC(=O)C#CCc1c(-c2cccnc2)[nH]c2ccccc12

Procedure:
Treatment of 330 mg of 3-(3-methoxycarbonylprop-2-ynyl)-2-(3-pyridyl)indole in 10 ml of methanol with 3.0 ml of aqueous 1N lithium hydroxide at room temperature yields 3-(3-carboxyprop-2-ynyl)-2-(3-pyridyl) indole.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH3:19])[C:4]=1[NH2:20])[CH3:2].N1C=CC=CC=1.S(=[N:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34])=O>ClCCl>[NH2:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([NH:20][C:4]1[C:5]([CH3:19])=[CH:6][C:7]([C:9]([F:18])([C:10]([F:11])([F:12])[F:13])[C:14]([F:15])([F:16])[F:17])=[CH:8][C:3]=1[CH2:1][CH3:2])=[O:34]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Reactant: O=S=Nc1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2-ethyl-6-methyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenylamine (2.09 g, 6.9 mmol) (prepared according to EP 1,006,102) in dichloromethane (30 ml) under stirring at 25° C., was added sequentially pyridine (0.8 ml, 9.9 mmol) and a solution of 3-sulfinylamino-benzoyl chloride (1.39 g, 6.9 mmol) (Example 1.1) in dichloromethane (7 ml). The reaction mixture was stirred at ambient temperature for 6 hours. The reaction mixture was quenched by addition of aqueous hydrochloric acid (2N) (4 ml) and stirred vigorously for 20 minutes. The mixture was diluted with water (20 ml) and the phases separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed successively with aqueous sodium hydrogen carbonate (saturated) and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:4 to 3:2). After evaporation of the solvents, the yellow oil was triturated with hexane, where it crystallized. The desired compound was isolated as white crystals. M.p. 143-145° C. 1H-NMR as described for Example 3.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:29]=[CH:30][CH:31]=2)[C:12]([NH:14][C:15]2[CH:16]=[C:17]([NH:21]C(=O)OC(C)(C)C)[CH:18]=[CH:19][CH:20]=2)=[O:13])[C:5]([Cl:32])=[CH:4][N:3]=1.Cl>COCCO.O1CCOCC1>[ClH:1].[Cl:32][C:5]1[CH:4]=[N:3][C:2]2[NH:21][C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([CH:16]=3)[NH:14][C:12](=[O:13])[C:11]3[CH:10]=[C:9]([NH:8][C:6]=1[N:7]=2)[CH:31]=[CH:30][CH:29]=3
Reactant: CC(C)(C)OC(=O)Nc1cccc(NC(=O)c2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: O=C1Nc2cccc(c2)Nc2ncc(Cl)c(n2)Nc2cccc1c2
Temperature: 150 °C
Yield: 12.7 %

Procedure:
To a solution of tert-butyl [3-({3-[(2,5-dichloropyrimidin-4-yl)amino]benzoyl}amino)phenyl]carbamate (20.0 mg, 0.042 mmol) in 2-methoxyethanol (0.2 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (63 μL). The resulting mixture was heated at 150° C. in the microwave for 15 min. After filtration of the reaction mixture, the crude was triturated with MeOH/EtOAc to give the desired product as an off-white powder (2 mg, 14%). LCMS for C17H12ClN5O (M+H)+: m/z=338.0. 1H NMR (400 MHz, CD3OD): δ 9.57 (s, 1H), 9.42 (s, 1H), 8.33 (s, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.29 (dd, J=7.9, 7.6 Hz, 1H), 7.15 (d, J=7.9 Hz, 1H), 7.10-7.05 (m, 2H), 6.90 (dd, J=8.2, 0.9 Hz, 1H), 6.84-6.81 (m, 1H), 4.11 (s, 2H).
Reaction SMILES: [ClH:1].[C:2]1([C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][C:10]2[CH:18]=[CH:17][C:13]([CH:14]([NH2:16])[CH3:15])=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[CH:27]([NH2:42])[C:28]1C=[CH:32][C:31](CCC2C=CC=CC=2)=[CH:30][CH:29]=1>>[ClH:1].[C:19]1([C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][C:10]2[CH:18]=[CH:17][C:13]([CH:14]([N:16]=[C:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:42]3)[CH3:15])=[CH:12][CH:11]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(N)c1ccc(C=C(c2ccccc2)c2ccccc2)cc1
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Agent: Cl
Product: CC(N=C1CCCCCN1)c1ccc(C=C(c2ccccc2)c2ccccc2)cc1

Procedure:
Following essentially the same procedure described in Example IV above and substituting ρ-(2,2-diphenylvinyl)-α-methylbenzylamine hydrochloride for the α-methyl-ρ-phenethylbenzylamine hydrochloride above, results in the formation of 2-[ρ-(2,2-Diphenylvinyl)-α-methylbenzylimino hexahydroazepine hydrochloride having a M.P. of 219°-21° C.
Reaction SMILES: [CH3:1]OP(CC(=O)C)(=O)OC.C([O-])([O-])=O.[K+].[K+].O=[CH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=1>CC#N.CO>[CH2:20]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=1)[CH2:19][C:18]#[CH:1]
Reactant: COP(=O)(CC(C)=O)OC
Reactant: COC(=O)Cc1ccc(CCC=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: C#CCCc1ccc(CC(=O)OC)cc1
Reaction time: 2 h

Procedure:
Dimethyl-2-oxopropylphosphonate (1.2 equiv, 1.5 g, 9.1 mmol) was added to a suspension of K2CO3 (3 equiv, 3.1 g, 23 mmol) and p-TsN3 (1.2 equiv, 1.8 g, 9.1 mmol) in MeCN (144 mL). The mixture was then stirred for 2 h. A solution of the methyl 2-(4-(3-oxopropyl)phenyl)acetate (1 equiv, 1.56 g, 7.6 mmol) in MeOH was then added in one portion and the reaction was stirred overnight. The solvent was evaporated under reduced pressure. The residue was partitioned between Et2O (100 mL) and water (100 mL). The aqueous phase was separated and extracted with Et2O (25 mL) twice. The organic phases were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column eluting with 0-30% EtOAc in hexanes to afford methyl 2-(4-(but-3-ynyl)phenyl)acetate in 980 mg (64%). LRMS: 202.5 (calc) 225.1 (found)(MNa)+.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)CCC>C1(C)C=CC=CC=1.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.C(C1(C)C(O)=C(C(C)(C)C)C=CC1)(C)(C)C>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[C:3]=3[F:17])[N:6]=2)[CH2:11][CH2:10]1
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C1=C(O)C(C)(C(C)(C)C)CC=C1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)c(F)c2oc(C3CC3)nc2c1C#N
Yield: 92.6 %

Procedure:
6-Bromo-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-77) (200 mg, 0.68 mmol) was dissolved in toluene (4 ml), then 2-tributylstannylpyridine (299 mg, 0.81 mmol) and 2,6-di-tert-butylcresol (2 mg) and bis(triphenylphosphine)palladium(II) dichloride (24 mg, 0.03 mmol) were added, followed by heating under reflux for 17 hours under nitrogen atmosphere. The reaction liquid was cooled, the insoluble matter was separated by filtration through Celite, the solvent was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, followed by removing tin-derived side products with n-hexane and by elution with a mixed solvent of n-hexane/ethyl acetate (5:1-3:1, v/v) to obtain 2-cyclopropyl-7-fluoro-5-methyl-6-(2-pyridyl)-1,3-benzoxazole-4-carbonitrile (184 mg, 0.63 mmol, 92%) as a pale yellow transparent oily substance, A part of this (183 mg, 0.62 mmol) was dissolved in dimethyl sulfoxide (3.7 ml), triethylamine (219 μl, 1.56 mmol) and (3S)-3-(dimethylamino)pyrrolidine (103 μl, 0.81 mmol) were added, followed by stirring at 90° C. under nitrogen atmosphere for 15 hours. After cooling to room temperature, ethyl acetate was added, followed by fractionation with water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away, the resulting residue was recrystallized and purified with a mixed solvent of diisopropyl ether/n-hexane/ethyl acetate to obtain the entitled compound (108 mg, 45%) as a pale brown solid.
Reaction SMILES: C([O:4][C@H:5]([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17](COCC)[C:16]([Br:25])=[N:15][C:14]=2[N:13]([CH3:26])[C:11]1=[O:12])(=O)C.Cl>CO.CCOCC>[OH:4][C@H:5]([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][C:16]([Br:25])=[N:15][C:14]=2[N:13]([CH3:26])[C:11]1=[O:12]
Reactant: CCOCn1c(Br)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: C[C@@H](O)CCCCn1c(=O)c2[nH]c(Br)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.8 %

Procedure:
To a solution of (R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (prepared as described for CT12440) (3.8 g, 8.5 mmol ) in methanol (150 ml) was added a solution of hydrogen chloride in ether (1.0 M, 20 ml). The reaction mixture was stirred at room temperature for 24 hours. Evaporation of the solvent under reduced pressure provided (R)-1-(5-hydroxyhexyl)-8-bromo-3-methylxanthine (2.9 g, 98% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=2)[CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].CN1C(=O)CCC1.CO>ClCCl>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=1)(=[O:9])[NH2:10]
Reactant: COc1ccc(Nc2cc(Cl)nnc2C(N)=O)nc1OC
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)nc1OC
Temperature: 140 °C
Reaction time: 18 h
Yield: 59.7 %

Procedure:
A pressure tube was charged with 6-chloro-4-(5,6-dimethoxypyridin-2-ylamino)pyridazine-3-carboxamide (310 mg, 1.00 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (429 mg, 2.00 mmol) and NMP (4 mL). The reaction mixture was stirred at 140° C. for 18 h, then the NMP was distilled using a Kugelrohr under high vacuum and at 120° C. to afford a brown viscous oil. The crude oil was dissolved in dichloromethane and methanol then adsorbed onto silica and purified by chromatography (spherical silica 20-45 μm, 11 g, Versaflash from Supelco, eluting with 100% dichloromethane to 88:11.4:0.6 dichloromethane:methanol:NH4OH, 40 min) to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(5,6-dimethoxypyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate as a brown viscous oil (291.3 mg). This was dissolved in dichloromethane (2 mL) and TFA (740 mg, 500 μL, 6.49 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The TFA and the dichloromethane were removed in vacuo and the residue obtained was purified by chromatography (Spherical silica 20-45 μm, 50 g, Versaflash from Supelco, eluting with 0.1:1.9:98 NH4OH:methanol:dichloromethane to 0.6:11.4:88 NH4OH:methanol:dichloromethane, 40 min) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(5,6-dimethoxypyridin-2-ylamino)pyridazine-3-carboxamide (81 mg, 21%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.33 (br. s., 1H), 8.34 (br. s., 1H), 7.59 (br. s., 1H), 7.46 (s, 1H), 7.35 (d, J=8.08 Hz, 1H), 6.70 (d, J=7.83 Hz, 1H), 6.57 (d, J=8.34 Hz, 1H), 3.95 (s, 3H), 3.76 (s, 3H), 3.10 (br. s., 1H), 2.03 (br. s., 2H), 1.18-1.78 (m, 8H), 0.98-1.12 (m, 1H); LC-MS 388 [M+H]+.