Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-])=O.[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br.ClC1C2C=C(N(C)C)N=CC=2N=CN=1.N>C(O)C.ClCCl>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: Fc1ccccc1CBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CN(C)c1cc2c(Cl)ncnc2cn1
Agent: N
Solvent: CCO
Solvent: ClCCl
Product: Nc1ccc(OCc2ccccc2F)cc1

Procedure:
4-(2-Fluorobenzyloxy)aniline was prepared from 4-nitrophenol (Aldrich) and 2-fluorobenzylbromide (Aldrich) according to Procedure D. This was reacted with 4-chloro-6-(N,N-dimethylamino)pyrido[3,4-d]pyrimidine according to Procedure A to give the product; tlc (dichloromethane:ethanol:aq.ammonia, 100:8:1) Rf 0.48; m/z (M+1)+390.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C@H:12]3[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14][CH2:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(N(CC)CC)C.[CH:26]1([CH:29]=O)[CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.FC(F)(F)C([O-])=O>COC(OC)OC.CN(C=O)C>[CH:26]1([CH2:29][NH:18][C@H:15]2[CH2:14][CH2:13][C@H:12]([O:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[CH:1]=[N:2][CH:3]=[CH:4]4)[CH2:17][CH2:16]2)[CH2:28][CH2:27]1
Reactant: N[C@H]1CC[C@H](Oc2ccc3cnccc3c2)CC1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: c1cc2cc(O[C@H]3CC[C@H](NCC4CC4)CC3)ccc2cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 69.7 mg (0.25 mmol) trans-4-(isoquinolin-6-yloxy)-cyclohexylamine (17), 52.7 μL triethyl amine (1.25 mmol, 5 eq.) and 21 mg cyclopropanecarbaldehyde (0.3 mmol, 1.2 eq.) in 3 mL trimethylorthoformate was stirred at room temperature for 1 h. Then a solution of 321.6 mg sodium triacetoxy borohydride (1.25 mmol, 5 eq) and 72 μL acetic acid (75.1 mg, 1.25 eq) in 2 mL DMF was added. The reduction was complete after 10 min. Then the solvents were removed in vacuo and the product was isolated via preparative HPLC to yield 41 mg of the title compound as trifluoroacetate. Rt=0.89 min (Method #1). Detected mass: 297.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([Sn](CCCC)(CCCC)CCCC)[S:5][CH:6]=1.Br[C:21]1[S:22][C:23]2[C:29]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)=[C:28]([C@H:37]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:27]([CH3:48])=[CH:26][C:24]=2[N:25]=1.[Li+].[Cl-]>O1CCOCC1.CCOC(C)=O.[Cu]I.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>[Br:1][C:2]1[N:3]=[C:4]([C:21]2[S:22][C:23]3[C:29]([C:30]4[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=4)=[C:28]([C@H:37]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:27]([CH3:48])=[CH:26][C:24]=3[N:25]=2)[S:5][CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(Br)cs1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3nc(Br)cs3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
In a 10 mL reaction vial, 4-bromo-2-(tributylstannyl)thiazole (125 mg, 0.251 mmol) and (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (114 mg, 0.251 mmol) were dissolved in dioxane (3 mL) at room temperature under argon atmosphere. The solution was bubbled with argon for 5 min. Then CuI (10.6 mg, 0.055 mmol), LiCl (31.7 mg, 0.753 mmol) and Pd(PPh3)4 (52.3 mg, 0.0417 mmol) were added sequentially. The reaction mixture was then sealed and heated in oil bath at 100° C. for 3.5 h. The reaction mixture was then diluted with EtOAc (10 mL), filtered and the filtrate was concentrated and purified on silica gel column with 0-10% EtOAc/Hex to afford title compound. LCMS-ESI+: calc'd for: C25H24BrClN2O3S2: 581.0, 579.0, 582.0, 583.0, 580.0 (M+H+); found: 581.1, 579.0, 582.2, 583.1, 580.3 (M+H+).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=O)C.[CH3:27][C:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[CH:30][N:29]=1>>[O:7]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:32]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:27])[CH:33]=2)[CH:13]=1)[C@@H:6]1[S:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2cncc(O[C@@H]3SC[C@@H](O)[C@H](O)[C@H]3O)c2)ccn1

Procedure:
By carrying out the operation analogously to example 239, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 2-methyl-4-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=28%).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH:12]=O)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][CH:18]1[CH2:23][NH:22][CH2:21][CH2:20][N:19]1[C:24]1[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH2:12][N:22]2[CH2:21][CH2:20][N:19]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)[CH:18]([CH3:17])[CH2:23]2)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(N2CCNCC2C)c1
Reactant: CCCc1cc(CCC=O)n(C(C)(C)C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3cccc(C)c3)C(C)C2)n(C(C)(C)C)n1

Procedure:
190 mg (98%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.450 mmol), 2-methyl-1-m-tolylpiperazine (86 mg, 0.450 mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)3 (286 mg, 1.350 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([C:29]([NH2:31])=[O:30])[C:25]=1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([C:29]([NH2:31])=[O:30])[C:25]=1[C:37]1[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: NC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1I
Product: NC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(F)cc1

Procedure:
5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-iodo-isoxazole-3-carboxylic acid amide (0.45 g, 0.80 mmol) was cross coupled to 4-fluorophenylboronic acid (0.17 g, 1.5 equiv.) using the standard conditions described above. The crude product, an orange solid (0.40 g), was taken on to the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[N:26]=[C:27]2[N:31]([C:32]=1[C:33](O)=[O:34])[CH:30]=[CH:29][S:28]2>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:32]2[N:31]3[C:27]([S:28][CH:29]=[CH:30]3)=[N:26][C:25]=2[Cl:24])=[O:34])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1c(Cl)nc2sccn12
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(Cl)nc3sccn23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 6-Chloro-imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.90 min; [M+H]+=511.9.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C)C=O.O.CCOCC>[CH2:29]([O:28][C:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[C:3]1[N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)=[O:27])[CH3:30]
Reactant: Cc1c(-n2ccnc2)[nH]c2ccccc12
Reactant: CCOC(=O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CCCCCCCn1c(-n2ccnc2)c(C)c2ccccc21

Procedure:
3-Methyl-2-(1-imidazolyl)indole (0.78 g) in dimethylformamide (8 ml) is added dropwise to a suspension of sodium hydride (50% dispersion in mineral oil, 0.20 g) in dimethylformamide (8 ml) stirred under nitrogen at 5°-10°. The resulting solution is stirred at 5°-10° for 1/2 hour. A solution of ethyl 8-bromooctanoate (1.00 g) in dimethylformamide (5 ml) is added dropwise. The reaction mixture is stirred at 5°-10° for 1/2 hour and then overnight at room temperature. The mixture is diluted with water (50 ml) and extracted into methylene chloride (3×25 ml). The extract is washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated in vacuo to give a two-phase oil. This oil is dissolved in ether (50 ml) and the solution is washed with water (5×25 ml) to remove dimethylformamide. The ether layer is dried over MgSO4, filtered, and concentrated in vacuo to give 1-(7-ethoxycarbonylheptyl)-2-(1-imidazolyl)-3-methylindole a viscous oil; NMR (CDCl3): δ 4.12 (q, 2H), 3.82 (t, 2H), 2.20 (s, 3H), 1.23 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].[OH-].[Na+]>O.C(O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:17]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: NCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCC(=O)O
Yield: 70 %

Procedure:
Benzyloxy-2-methyl-4-pyrone, prepared as described under Example 10, (20 g) and beta-alanine (9 g) dissolved in 3:2 v/v water/ethanol (500 ml) containing NaOH (10 g) to provide a solution with a pH of at least 13. The solution is refluxed for 15 minutes whereupon it turns from a light orange to an intense red colour. The solution is acidified to pH 7.0 and the ethanol is removed by rotary evaporation. The resulting aqueous solution is washed twice with ethylacetate (100 ml). This solution is then subjected to rotary evaporation until the volume is reduced to 100 ml and this reduced volume of solution is acidified to pH 3.0 to give a white precipitate, which is filtered off to give 3-benzyloxy-1-(2'-carboxyethyl)-2-methylpyrid-4-one in 70% yield, m.p. 156°-157° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]([NH:10][C:11]([C@H:13]1[C@@H:17]([CH2:18][OH:19])[CH2:16][N:15]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:14]1)=O)([CH3:9])[CH3:8]>C1COCC1>[CH2:20]([N:15]1[CH2:14][C@@H:13]([CH2:11][NH:10][CH:7]([CH3:8])[CH3:9])[C@@H:17]([CH2:18][OH:19])[CH2:16]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)NC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1CO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)NC[C@@H]1CN(Cc2ccccc2)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a ice-cooled solution of LiAlH4 (0.56 g, 14.76 mmol) in THF (25 mL), is added dropwise a solution of (3S*,4R*)-1-benzyl-4-hydroxymethyl-pyrrolidine-3-carboxylic acid isopropylamide (1.02 g, 3.69 mmol) in THF (5 mL). The reaction mixture is refluxed overnight and quenched with Na2SO4.10H2O (4 g) at 0° C. Ether is added, the mixture is stirred for 2 h at room temperature. The crude material is filtered over a pad of Celite and concentrated to give the title compound which is used without further purification in the next step. TLC, Rf (CH2Cl2/MeOH 95:5)=0.28. MS (LC-MS): 263.2 [M+H]+; ]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/2.5 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 2.94 min.
Reaction SMILES: ClCCCC(OC(=O)C)CCCCC.BrCC=CC(OC(=O)C)CCCCC.C([CH:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]([CH2:45]/[CH:46]=[CH:47]/[CH:48]([O:54]C(=O)C)[CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[S:41]([CH3:44])(=[O:43])=[O:42])[C:32]([OH:34])=[O:33])C>>[OH:54][CH:48]([CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])/[CH:47]=[CH:46]/[CH2:45][N:40]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:31][C:32]([OH:34])=[O:33])[S:41]([CH3:44])(=[O:42])=[O:43]
Reactant: CCCCCC(/C=C/CN(CCCCCC(CC)C(=O)O)S(C)(=O)=O)OC(C)=O
Agent: CCCCCC(C=CCBr)OC(C)=O
Agent: CCCCCC(CCCCl)OC(C)=O
Product: CCCCCC(O)/C=C/CN(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-bromo-4-acetoxy-2-nonene (Example H). The product of Step A is thus ethyl 7-[N-(4-acetoxy-(E)-2-nonenyl)methanesulfonamido]heptanoic acid (B).
Reaction SMILES: [NH:1]([C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=1)[NH2:2].[Cl:21][CH2:22][C:23](=O)[CH2:24][Cl:25]>O1CCCC1>[Cl:21][CH2:22][C:23](=[N:2][NH:1][C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=1)[CH2:24][Cl:25]
Reactant: NNC1=Nc2ccccc2C(c2ccccc2Cl)=NC1
Reactant: O=C(CCl)CCl
Solvent: C1CCOC1
Product: ClCC(CCl)=NNC1=Nc2ccccc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 1, 2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1,3-dichloropropanone under nitrogen to give 2-[[2-chloro-1-(chloromethyl)ethylidene]-hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([N+:8]([O-])=O)[CH:7]=1.C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].P.[OH-].[Na+]>Cl[Pd]Cl.O.C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:7]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Agent: Cl[Pd]Cl
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Agent: P
Solvent: Cc1ccccc1C
Solvent: O
Product: Nc1cc(Cl)ccc1O

Procedure:
A degassed solution of 10 mmol of 5-chloro-2-hydroxynitrobenzene (starting material) and 40 ml of xylene are placed in an autoclave (volume: 200 ml).0.25 mmol of TPPTS (in the form of 4.6 g of an aqueous solution containing 0.546 mol of TPPTS/kg of solution) as phosphine and 0.6 g (15 mmol) of NaOH, 41 ml of H2O and 0.25 mmol of PdCl2 are added. The pH is from 10 to 10.5.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1.[S:14](Cl)(=[O:17])(=[O:16])[NH2:15]>C(#N)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]([O:13][S:14](=[O:17])(=[O:16])[NH2:15])[CH:10]=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1cccc(O)c1
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Product: Cc1nccn1-c1cccc(OS(N)(=O)=O)c1
Yield: 31.6 %

Procedure:
A slurry of 8.7 g (0.05 mole) of 3-(2-methyl-1H-imidazol-1-yl)phenol in 150 ml of acetonitrile was treated with a solution of 0.05 mole of sulfamoyl chloride in 20 ml of acetonitrile. The mixture dissolved and slowly deposited off-white crystals over the period of 24 hr. The precipitate was collected and triturated with hot absolute ethanol. The slurry was cooled and the precipitate was collected and dried to give 4.0 g (32%) of off-white powder, monohydrochloride, mp 197°-200° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([O:20]C)[CH:14]=[C:13]([O:22]C)[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31].Cl.N1C=CC=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([OH:20])[CH:14]=[C:13]([OH:22])[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31]
Reactant: COc1cc(OC)c2c(=O)cc(-c3c(F)cccc3F)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4c(F)cccc4F)oc23)[C@@H]1CO

Procedure:
Compound of example 79 (0.09 g, 0.208 mmol) subjected to demethylation using pyridine hydrochloride (1 g, 8.66 mmol), as described in example 17, afforded the title compound.
Reaction SMILES: [Br-].[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[CH:9]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[C:19]1([CH2:18][CH2:17][C:9]2[N:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]3=[N:2][C:10]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(=O)C(CCc1ccccc1)[n+]1ccccc1N
Agent: [Br-]
Solvent: CCO
Product: CCOC(=O)c1nc2ccccn2c1CCc1ccccc1
Yield: 93.3 %

Procedure:
To a solution of ethyl 3-bromo-2-oxo-5-phenylpentanoate (1.9 g) in THF (10 ml) was added 2-aminopyridine (600 mg) at room temperature, and the reaction mixture was heated under reflux for 15 hr. The precipitated crystals were collected by filtration, washed with THF to give 2-amino-1-[3-ethoxy-2,3-dioxo-1-(2-phenylethyl)propyl]pyridinium bromide (1.36 g). 2-Amino-1-[3-ethoxy-2,3-dioxo-1-(2-phenylethyl)propyl]pyridinium bromide (1.36 g) was dissolved in ethanol (10 ml), and the mixture was refluxed under heating for 3 hr. The reaction mixture was concentrated, and dissolved in dichloromethane. The solution was washed successively with aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-diethyl ether to give the object product (950 mg).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.Cl.[NH2:17][CH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:24]([OH:25])=[C:22]([OH:23])[CH:21]=1>>[OH:23][C:22]1[CH:24]=[CH:26][C:27]([C:6]([N:8]2[CH2:15][CH2:14][CH2:13][C@H:9]2[C:10]([NH:17][CH2:18][CH2:19][C:20]2[CH:27]=[CH:26][C:24]([OH:25])=[C:22]([OH:23])[CH:21]=2)=[O:12])=[O:7])=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Product: O=C(NCCc1ccc(O)c(O)c1)[C@@H]1CCCN1C(=O)c1ccc(O)cc1
Yield: 69.1 %

Procedure:
The title compound was prepared from N-(tert-butoxycarbonyl)-L-proline (108 mg, 0.50 mmol) in a coupling reaction with dopamine hydrochloride (189 mg, 1.0 mmol) according to example 6. Purification by flash column chromatography (5% MeOH/CHCl3) provided the desired compound as a syrup (128 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:33])[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C@H:15]([NH:19][C:20]3[S:21][CH:22]=[C:23]([CH2:25][C:26]([O:28]C)=[O:27])[N:24]=3)[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:32])[CH3:31])=[CH:4][CH:3]=1.Cl>[OH-].[Na+].C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:33])[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C@H:15]([NH:19][C:20]3[S:21][CH:22]=[C:23]([CH2:25][C:26]([OH:28])=[O:27])[N:24]=3)[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:31])[CH3:32])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1csc(N[C@@H](C(=O)N2CC[C@](O)(c3ccc(Cl)cc3)C(C)(C)C2)C(C)C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)[C@@H](Nc1nc(CC(=O)O)cs1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Yield: 41.9 %

Procedure:
Methyl 2-(2-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylamino)thiazol-4-yl)acetate (Example 520, 356 mg, 0.895 mmol) was stirred overnight in 1 N sodium hydroxide (2 mL) and ethanol (15 mL). The reaction was neutralized to pH 7 with 0.1N hydrochloric acid and the product was extracted with EtOAc:MeOH 95:5. The organic extracts were dried over sodium sulfate, filtered, and concentrated to yield the title compound (180 mg) which was used without further purification.
Reaction SMILES: I.[CH2:2]([N:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[S:8][C:7]1=[NH:15])[CH2:3][CH2:4][CH3:5].[C:16]1([N:26]=[C:27](OCC)[CH2:28][CH3:29])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>C(O)CCC>[CH2:2]([N:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[S:8]/[C:7]/1=[N:15]\[C:27](=[N:26][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[CH2:28][CH3:29])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCn1cc(C(C)(C)C)sc1=N
Reactant: CCOC(CC)=Nc1cccc2ccccc12
Agent: I
Solvent: CCCCO
Product: CCCCn1cc(C(C)(C)C)s/c1=N\C(CC)=Nc1cccc2ccccc12
Temperature: 85 °C
Reaction time: 48 h

Procedure:
To a 20-ml scintillation vial containing a magnetic stir bar were added the free base of Example 6A and the liquid imidate from Example 73A. Butanol was added to form a yellow solution. The reaction was heated to 85° C. in a heated shaker block and stirred for 48 h. The volatiles were removed by rotary evaporator to give a brown oil. Product purified by flash chromatography (silica gel: 5-40% ethyl acetate in hexanes) to give the title compound as a colorless oil. 1H NMR (DMSO-d6) δ0.96 (t, J=7.3 Hz, 3H), 1.04 (t, J=7.5 Hz, 3H),1.24 (s, 9H) 1.29-1.42 (m, 2H), 1.73-1.83 (m, 2H), 2.18 (q, J=7.5 Hz, 2H), 4.13 (t, J=7.1 Hz, 2H), 6.76 (dd, J=7.3, 1.2 Hz, 1H), 7.13 (s, 1H), 7.38-7.55 (m, 4H), 7.83-7.88 (m, 2H). MS (ESI+) m/z 394 (M+H)+.
Reaction SMILES: CS([C:5]1[N:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[N:10]=1)(=O)=O.[NH3:19].C1COCC1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:9]1[N:10]=[C:5]([NH2:19])[N:6]=[N:7][CH:8]=1
Reactant: CS(=O)(=O)c1nncc(-c2ccc(F)cc2F)n1
Reactant: N
Solvent: C1CCOC1
Product: Nc1nncc(-c2ccc(F)cc2F)n1
Yield: 53 %

Procedure:
5-(2,4-Difluorophenyl)-1,2,4-triazin-3-amine (0.45 g, 53%) was prepared from 3-(methylsulfonyl)-5-(2,4-difluorophenyl)-1,2,4-triazine (1.10 g, 4.05 mmol) and 0.5 M ammonia in THF (50 mL, 25 mmol) according to the general procedure of Preparation 2.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[C:16](=[O:17])[N:15]2[CH:18]=[N:19][C:20]([C:21]([NH2:23])=[O:22])=[C:14]2[N:13]=[N:12]1)(C(C)(C)C)(C)C.CC(O)=O.O>C1COCC1>[OH:8][CH2:9][CH2:10][N:11]1[C:16](=[O:17])[N:15]2[CH:18]=[N:19][C:20]([C:21]([NH2:23])=[O:22])=[C:14]2[N:13]=[N:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCn1nnc2c(C(N)=O)ncn2c1=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)c1ncn2c(=O)n(CCO)nnc12
Reaction time: 3 h

Procedure:
A solution of 3-(2-(tert-butyldimethylsilyloxy)ethyl)-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (50 mg, 0.148 mmol) in THF:AcOH:water (5 mL of a 1:3:1 v/v/v mixture) was stirred at room temperature. After 3 hours, the reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography (SiO2, gradient 0-100% acetonitrile in dichloromethane) to furnish the title compound as a white solid. Yield: 15 mg, 0.067 mmol, 45%. LCMS (ES+) m/z 225 (M+H)+ at 0.62 minutes. 1H NMR (400 MHz, d6-DMSO) δ: 8.84 (1H, s), 7.81 (1H, br s), 7.68 (1H, bs), 4.85 (1H, t) 4.34 (2H, t), 3.79 (2H, q).