Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:9]=[C:10]([C:14]([O:16]C)=O)[Se:11][C:12]=1[CH3:13])[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:9]=[C:10]([C:14]([NH2:2])=[O:16])[Se:11][C:12]=1[CH3:13])[CH3:5]
Reactant: COC(=O)c1cc(N=NN(C)C)c(C)[se]1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1[se]c(C(N)=O)cc1N=NN(C)C
Temperature: 25 °C
Reaction time: 40 h
Yield: 42 %

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (40 mL) was added a solution of methyl 4-[(dimethylamino)diazenyl]-5-methylselenophene-2-carboxylate (550 mg) in THF (10 mL) for 5 min and stirred at rt for 40 h. The solution was poured into ice cooled water and extracted with chloroform (3×100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (96:4) as eluents to give the product as off-white solid (220 mg, 42%), mp 170-172° C. IR (neat) νmax 3385, 3188, 2914, 1644, 1604, 1326, 1120, 1066 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.87 (1H, s, H-3), 5.67 (2H, br s, —CONH2), 3.28 (6H, br s, N(CH3)2), 2.63 (3H, s, Ar—CH3); LC-MS (positive ion mode): m/z 261, 259 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[C:12]2[O:13][CH2:14][C:15]3[S:19][C:18]([SH:20])=[N:17][C:16]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)C.[C:22]1([CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH:28]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:29][S:20][C:18]2[S:19][C:15]3[CH2:14][O:13][C:12]4[C:7]([O:6][CH2:5][C:4]([OH:3])=[O:21])=[CH:8][CH:9]=[CH:10][C:11]=4[C:16]=3[N:17]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)COc1cccc2c1OCc1sc(S)nc1-2
Reactant: ICC(c1ccccc1)c1ccccc1
Product: O=C(O)COc1cccc2c1OCc1sc(SCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 41 %

Procedure:
Using ethyl[(2-mercapto-4H-[1]benzopyrano[4,3-d]thiazol-6-yl)oxy]acetate and 2,2-diphenylethyl iodide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 41%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[Cl:11].[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[Cl:11][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Cl:1])[NH:8][C:9]([NH:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:31])[CH3:32])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1)=[O:10]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)Nc3ccc(Cl)c(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure P and Scheme AB using 1,2-dichloro-4-isocyanatobenzene and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 493.2 (M+H)+.
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)=[C:41]([S:52]([CH3:55])(=[O:54])=[O:53])[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)=[C:41]([S:52]([CH3:55])(=[O:53])=[O:54])[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1cc(Br)ccc1-c1ccc(Cl)cc1
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(-c2ccc(Cl)cc2)c(S(C)(=O)=O)c1

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-bromo-4′-chloro-2-(methylsulfonyl)biphenyl (Intermediate 211), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1.[O:24]1[CH2:29][CH2:28][CH:27]([C:30]2([NH2:33])[CH2:32][CH2:31]2)[CH2:26][CH2:25]1>>[OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:33][C:30]3([CH:27]4[CH2:28][CH2:29][O:24][CH2:25][CH2:26]4)[CH2:32][CH2:31]3)=[O:12])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: COc1cc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccn1
Reactant: NC1(C2CCOCC2)CC1
Product: COc1cc(-c2cnn(-c3ccc(C(=O)NC4(C5CCOCC5)CC4)cn3)c2O)ccn1

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid and 1-(tetrahydro-2H-pyran-4-yl)cyclopropanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82-1.03 (m, 5 H) 1.25 (s, 1 H) 1.45-1.67 (m, 3 H) 1.74 (d, J=12.4 Hz, 2 H) 3.37 (t, J=11.6 Hz, 2 H) 4.03 (dd, J=11.4, 3.5 Hz, 2 H) 4.09 (s, 3 H) 7.22 (s, 1 H) 7.31 (d, J=6.1 Hz, 1 H) 7.41 (s, 1 H) 7.83 (d, J=8.6 Hz, 1 H) 7.90 (s, 1 H) 8.13 (d, J=6.1 Hz, 1 H) 8.37 (dd, J=8.7, 2.1 Hz, 1 H) 8.83 (d, J=1.8 Hz, 1 H). MS m/z [M+H]+ 436.4.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[F-:13].[K+].O>CC(N(C)C)=O>[F:13][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: [F-]
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=Cc1cc(F)ccc1[N+](=O)[O-]
Yield: 71 %

Procedure:
37 g (0.2 mol) of 5-chloro-2-nitrobenzaldehyde and 23.2 g (0.4 mol) of potassium fluoride in 300 ml of dimethylacetamide are stirred for 3 hours at 150° C. The solvent is then stripped off in vacuo and the residue is stirred with 200 ml of water. The aldehyde is extracted with methylene chloride, and the organic phase is separated off, dried and evaporated down. 24 g of 5-fluoro-2-nitrobenzaldehyde with a content of 86% are obtained.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:64])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](O)[CH:46]([O:51]S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH2:45]2)[CH:7]([CH3:65])[CH:6]([O:66][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:74])[CH3:2].[N-:75]=[N+:76]=[N-:77].[Na+].O>CN(C=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:64])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:75]=[N+:76]=[N-:77])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:65])[CH:6]([OH:66])[CH2:5][C:4]1=[O:74])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OS(=O)(=O)c4ccccc4[N+](=O)[O-])C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Yield: 40.9 %

Procedure:
A solution of 17-ethyl-1,14-dihydroxy-12-[2'-[4"-(2"'-nitrobenzenesulfonyloxy)-3"-hydroxycyclohexyl]-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (105 mg, Example 64, compound A) in dry DMF (1 ml) with sodium azide (22 mg) was heated to 50° C. for 3 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and purified by column chromatography on silica gel (2:1 ethyl acetate/hexane) to gave 32 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-azido-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. This material (30 mg) and triphenylphosphine (15 mg) in 1 ml of wet benzene was refluxed for 6.5 h. The solvent was removed in vacuo and the residue was purified on silica gel (eluted first with 5% MeOH/CH2Cl2, then 1% NH4OH in 5% MeOH/CH2Cl2) to give 12 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[N:6][CH:7]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:20])([CH3:19])[CH2:17][NH2:18])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:18][CH2:17][C:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)([CH3:20])[CH3:19])=[N:6][CH:7]=1
Reactant: CC(C)(CN)c1ccc(F)cc1
Reactant: Fc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)(CNc1ncc(Br)cn1)c1ccc(F)cc1
Temperature: 120 °C
Yield: 63.3 %

Procedure:
To a solution of 5-bromo-2-fluoropyrimidine (1.0 g, 5.6 mmol, 1.0 equiv) and 2-(4-fluorophenyl)-2-methylpropan-1-amine (1.05 g, 6.3 mmol. 1.1 equiv) in isopropanol (12 mL) in a microwave vial equipped with a stir bar was added potassium carbonate (3.68 g, 11.2 mmol, 2.0 equiv). The vial was fitted with a microwave vial cap and heated to 120° C. for 45 min. The reaction mixture was filtered to remove the solid potassium carbonate and concentrated in vacuo. After the residue was redissolved in EtOAc and water, the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (3%-5% MeOH/DCM) provided the title compound as a yellow solid (1.15 g, 65%), (m/z [M+H]=324.2).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:20])([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:10]=[N:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][N:22]([C:27]1[CH:28]=[C:29]([CH:42]=[C:43]([C:45]#[CH:46])[CH:44]=1)[C:30]([NH:32][C@@H:33]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[CH3:34])=[O:31])[S:23]([CH3:26])(=[O:25])=[O:24].C(N(CC)CC)C>CN(C=O)C>[CH3:21][N:22]([C:27]1[CH:28]=[C:29]([CH:42]=[C:43]([C:45]2[O:12][N:11]=[C:10]([C@@:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH3:20])[CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:46]=2)[CH:44]=1)[C:30]([NH:32][C@@H:33]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[CH3:34])=[O:31])[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(C=NO)Cc1ccccc1
Reactant: C#Cc1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(N(C)S(C)(=O)=O)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cc(-c2cc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)no2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-2-tert-butoxycarbonylamino-2-methyl-3-phenylpropanal oxime (Intermediate L, 30 mg, 0.11 mmol) in 0.5 mL DMF, cooled to 5° C., was added a solution of N-bromosuccinimide from Step B (29 mg, 0.165 mmol) in 0.5 mL DMF dropwise. After stirring at 5° C. for 1 h, a solution of 3-(N-methyl-N-(methylsulfonyl)amino)-5-ethynyl-N—((R)-1-(4-fluorophenyl)ethyl)benzamide (124 mg, 0.33 mmol) and triethylamine (0.023 mL, 0.165 mmol) in 0.2 mL DMF was added. The reaction was stirred at rt for 1 week and then heated to 50° C. overnight. Purification by reverse phase preparative HPLC (5-95% CH3CN in water containing 0.1% TFA) gave 3-(N-methyl-N-(methylsulfonyl)amino)-5-(3-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)isoxazol-5-yl)-N—((R)-1-(4-fluorophenyl)ethyl)benzamide. 1H NMR (CDCl3) δ 8.02 (s, 1H), 7.90 (m, 1H), 7.86 (m, 1H), 7.38 (m, 2H), 7.26 (m, 3H), 7.08 (m, 4H), 6.60 (s, 1H), 6.44 (d, J=7.6 Hz, 1H), 5.31 (m, 1H), 5.01 (bs, 1H), 3.53 (d, J=12.9 Hz, 1H), 3.39 (s, 3H), 3.34 (m, 1H), 2.89 (s, 3H), 1.63 (m, 6H), 1.44 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17](Cl)=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:27]#[N:28])=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccccc3)c(Cl)nn2)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccccc3)c(C#N)nn2)CC1
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
To a mixture of zinc cyanide (0.077 g, 0.66 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.1 g, 0.09 mmol) was added a solution of 4-(6-chloro-5-phenyl-pyridazin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (D13) (0.137 g, 0.36 mmol) in N,N-dimethylformamide (3.5 ml). The resulting mixture was stirred at 160° C. for 30 min, under microwave irradiation. The solvent was evaporated in vacuo to yield D14 (0.133 g, quant.). C20H23N5O2 requires 365; Found 366 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([CH:20]=[CH2:21])=[C:15]([F:22])[CH:14]=1)(=[O:12])=[O:11].ClC1C=C(C=CC=1)C(OO)=[O:32]>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([CH:20]2[CH2:21][O:32]2)=[C:15]([F:22])[CH:14]=1)(=[O:12])=[O:11]
Reactant: C=Cc1c(F)cc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2cc(F)c(C3CO3)c(F)c2)c(C)c1
Reaction time: 24 h

Procedure:
To a solution of N-(2,4-dimethylphenyl)-3,5-difluoro-N-isobutyl-4-vinylbenzenesulfonamide (1.5 g, 3.95 mmol) in dichloromethane (DCM) at 0° C. was added meta-chloroperoxybenzoic acid (mCPBA) (2.73 g, 15.81 mmol) and the reaction mixture stirred for 24 hours from 0° C. to 25° C. Additional mCPBA (1.364 g, 7.91 mmol) was then added and the reaction stirred for a further 6 hours. The reaction was then washed with water (2 mL), sodium hydroxide solution (2M, 2 mL) and brine (2 mL), then evaporated in vacuo. The crude was purified by flash silica (Si) chromatography (0-100% dichloromethane-cyclohexane gradient). The appropriate fractions were combined and evaporated in vacuo to give the required product, 926 mg, as a yellow oil. LCMS [LCMS2] Rt. 1.45, m/z (ES+) 396 (M+H).
Reaction SMILES: Br.[N:2]1([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].N1(C2C=C3C(=CC=2)NC(=O)CC3)CCNCC1.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][C:51]=1[O:52][CH3:53])[C:46](Cl)=[O:47]>CN(C)C=O.C(N(CC)CC)C>[CH3:41][O:42][C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][C:51]=1[O:52][CH3:53])[C:46]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH2:3][CH2:4]1)=[O:47]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
6-(1-Piperazinyl)-3,4-dihydrocarbostyril monohydrobromide (3.5 g) was suspended in 40 ml of dimethylformamide (hereafter referred to as DMF for brevity). After adding 960 mg of sodium hydrogencarbonate, the suspension was stirred at room temperature for 30 minutes to convert the starting compound to 6-(1-piperazinyl)-3,4-dihydrocarbostyril. Then, to the mixture was added 2.34 ml of triethylamine and the mixture was stirred at room temperature while slowly adding dropwise 10 ml of DMF solution containing 2.9 g of 3,4-dimethoxybenzoyl chloride. After completion of addition the reaction mixture was stirred for 30 minutes. The reaction mixture was poured into a large amount of saturated saline solution and extracted with chloroform. The extract was washed with saturated sodium hydrogen carbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from chloroform-ethanol to give 3.8 g of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 238°-239.5° C., colorless granules.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8].I[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:18]
Reactant: CCOC(=O)CI
Reactant: OCCc1ccc(F)c(Cl)c1
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCOC(=O)COCCc1ccc(F)c(Cl)c1

Procedure:
In analogy to the procedure described in example 78.1, 2-(3-chloro-4-fluoro-phenyl)-ethanol was reacted with ethyl iodoacetate in the presence of silver trifluoromethanesulfonate and 2,6-di-tert-butylpyridin to give [2-(3-chloro-4-fluoro-phenyl)-ethoxy]-acetic acid ethyl ester as colorless oil. MS: m/e=261.2 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22]Br.[CH3:24][O:25][P:26]([O:29]C)[O:27][CH3:28]>>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][P:26](=[O:29])([O:27][CH3:28])[O:25][CH3:24]
Reactant: COP(OC)OC
Reactant: Cc1ccc(-c2c(CBr)c(C)nc3sc4c(c23)CCCC4)cc1
Product: COP(=O)(Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3)OC

Procedure:
A solution of (2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)bromomethane (0.309 g; 0.8 mmol) in trimethylphosphite (8 mL) was heated at reflux for 18 h. The volatiles were removed under reduced pressure and the remaining residue was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:13][CH:12]3[C:14](=O)[CH:9]([CH2:10][CH2:11]3)[CH2:8][C:7]=2[CH:16]=1.Cl.[NH2:18][OH:19]>C(O)C.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:13][CH:12]3[C:14](=[N:18][OH:19])[CH:9]([CH2:10][CH2:11]3)[CH2:8][C:7]=2[CH:16]=1
Reactant: COc1ccc2c(c1)CC1CCC(C2)C1=O
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: COc1ccc2c(c1)CC1CCC(C2)C1=NO
Yield: 86.9 %

Procedure:
2-Methoxy-11-oxo-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene (20.0 g; 0.1 mole) is reacted with hydroxylamine hydrochloride (20.0 g; 0.29 mole) in ethanol (100 ml) and pyridine (100 ml) to yield 20.1 g of the title compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[C:13]1[CH:17]=[CH:16][NH:15][CH:14]=1.[Cl:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>C(Cl)Cl.C(OCC)(=O)C>[Cl:18][C:19]1[C:20]([C:21]([C:14]2[NH:15][CH:16]=[CH:17][C:13]=2[C:7]2[C:6]([Cl:5])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:12])=[O:22])=[CH:24][CH:25]=[CH:26][N:27]=1
Reactant: Clc1cccc(Cl)c1-c1cc[nH]c1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1cccnc1Cl)c1[nH]ccc1-c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 4.8 %

Procedure:
Aluminum chloride (1.4 g, 10.5 mmol) was added to a mixture of 3-(2,6-dichloro-phenyl)-1H-pyrrole (2 g, prepared according to JOC, 62, 1997, 2650) and 2-chloronicotinoyl chloride (1.8 g, 10.5 mmol) in DCM (55 mL) at 0° C. The mixture was stirred at 0° C. for 30 mins and at room temperature for 1.5 hours. The reaction was diluted with ethyl acetate and washed with brine, 2N NaOH, brine, dried and concentrated. The residue was purified on silica gel column to give 160 mg of (2-chloro-pyridin-3-yl)-[3-(2,6-dichloro-phenyl)-1H-pyrrol-2-yl]-methanone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][CH2:9][NH2:10])=[N:6][CH:7]=1.C(N(CC)CC)C.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][CH2:9][NH:10][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[C:19]([F:18])([F:29])[F:30])=[N:6][CH:7]=1
Reactant: NCCc1ncc(Br)cn1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCc1ncc(Br)cn1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.4 %

Procedure:
To 0.06 g of 2-(5-bromopyrimidin-2-yl)ethanamine (3.0 mmol) and triethylamine (0.03 g, 1.0 equivalent) in THF (5 ml), at room temperature whilst stirring, was added the 2-trifluoromethyl benzoyl chloride (0.062 g, 1.0 equivalent) and the mixture was left to stir at room temperature overnight. The solvent was removed by evaporation in vacuo and saturated sodium bicarbonate (10 mls) was added. The mixture was extracted with dichloromethane and the organic phase was collected, dried over MgSO4, and evaporated in vacuo to give the crude product which was purified by chromatography on silica using 1:1 heptane/ethyl acetate to yield to 0.036 g of N-[2-(5-bromopyrimidin-2-yl)ethyl]-2-(trifluoromethyl)benzamide (Compound A-1) (32%).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[F:18][C:19]1[C:24](O)=[C:23]([F:26])[C:22]([F:27])=[C:21]([F:28])[C:20]=1[F:29].C1CCC(N=C=NC2CCCCC2)CC1.O>CN(C=O)C>[F:18][C:19]1[C:24]([O:16][C:15](=[O:17])[C@H:12]([CH2:13][OH:14])[NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])=[C:23]([F:26])[C:22]([F:27])=[C:21]([F:28])[C:20]=1[F:29]
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N[C@@H](CO)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCc1ccccc1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
A mixture of N-Cbz-L-serine (Novabiochem) (100 g, 0.42 mol) and pentafluorophenol (Aldrich) (84.7 g, 0.46 mol) in anhydrous DMF (250 ml) are cooled with stirring under N2 to -10° C. To this solution, a solution of DCC (95.0 g, 0.46 mol) in anhydrous DMF (125 ml) is added over 30 min while keeping the reaction temperature at -10° C. The reaction mixture is stirred at -10° to -5° C. for an additional 30 min and then at room temperature for 3 hours. The reaction mixture is poured into water (3.76 1). After stirring for 15 min, the solid that precipitated out is filtered, washed over the filter with water (3×500 ml) and air dried at room temperature. The solid is then taken up in EtOAc (1 l) and the residual solid (mainly dicyclohexylurea) is filtered off and washed with more EtOAc (3×150 ml). The combined EtOAc solutions are evaporated to dryness under reduced pressure. The residual solid is dissolved in hot CH2Cl2 (3.2 l). The hot solution is gravity filtered and the solvent is boiled off until solid began to crystallize. The solid which crystallized is filtered and air dried to ambient temperature to give N-Cbz-L-serine pentafluorophenyl ester as a white solid.