Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>O1CCCC1>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Br)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Diisopropylethylamine (2.09 mL, 11.7 mmol) was added at 0° C. to a stirred solution of piperidine (0.40 g, 4.7 mmol) in tetrahydrofuran (10 mL) and the reaction mixture was stirred at room temperature for 15 minutes. A 0.1 M solution of 4-bromo-benzenesulfonyl chloride (1.20 g, 4.7 mmol) in tetrahydrofuran was added at room temperature and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated off under reduced pressure. The residue was diluted with ethyl acetate, and the inorganic salts were filtered through a celite bed. The filtrate was washed with 2 N aqueous HCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 1-(4-bromobenzenesulfonyl)-piperidine, which was used in subsequent reactions without further purification. MS cald. for C11H14BrNO2S [M+] 304, obsd. 304.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[C:9]([N:11]3[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12]3)[N:8]=[C:7]([NH:18][C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=3)[CH:6]=2)[CH2:2]1.ClCCl.C(N(C(C)C)C(C)C)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>CN(C1C=CN=CC=1)C>[F:16][C:13]1([F:17])[CH2:14][CH2:15][N:11]([C:9]2[CH:10]=[C:5]([CH:3]3[CH2:2][N:1]([C:41](=[O:43])[CH3:42])[CH2:4]3)[CH:6]=[C:7]([NH:18][C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[CH:21][N:20]=3)[N:8]=2)[CH2:12]1
Reactant: FC1(F)CCN(c2cc(C3CNC3)cc(Nc3cc(C(F)(F)F)ccn3)n2)C1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC(c2cc(Nc3cc(C(F)(F)F)ccn3)nc(N3CCC(F)(F)C3)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.8 %

Procedure:
To a solution of 4-(azetidin-3-yl)-6-(3,3-difluoropyrrolidin-1-yl)-N-[4-(trifluoromethyl)-2-pyridyl]pyridin-2-amine (1-d, 180 mg, 0.4507 mmol) and DMAP (5.6 mg, 0.1 equiv., 0.04507 mmol) in dichloromethane (2 mL, 31.0 mmol) and N-ethyldiisopropylamine (0.47 mL, 6.0 equiv., 2.704 mmol) was added acetic anhydride (0.22 mL, 5.0 equiv., 2.253 mmol), and the brown solution was stirred at 25° C. for 2 h. DCM was removed, and the crude was submitted for HPLC purification to yield 9.5 mg (4.8%) off-white powder. 1H NMR (400 MHz, DMSO) δ (delta) 9.99-9.83 (s, 1H), 8.74-8.62 (s, 1H), 8.48-8.40 (d, J=5.1 Hz, 1H), 7.21-7.11 (d, J=5.2 Hz, 1H), 6.66-6.55 (s, 1H), 6.15-5.96 (s, 1H), 4.53-4.39 (t, J=8.6 Hz, 1H), 4.27-4.15 (t, J=9.2 Hz, 1H), 4.14-4.07 (dd, J=8.3, 6.1 Hz, 1H), 3.94-3.78 (m, 3H), 3.77-3.61 (m, 3H), 2.64-2.52 (dt, J=14.1, 7.0 Hz, 2H), 1.85-1.75 (s, 3H). LCMS: m/z 442 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:22])=[C:18]([CH:21]=1)[CH:19]=O>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:22])=[C:18]([CH2:19][C:10]2[S:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:12][CH:11]=2)[CH:21]=1
Reactant: Cc1cccc(-c2cccs2)c1
Reactant: O=Cc1cc(Br)ccc1Cl
Product: Cc1cccc(-c2ccc(Cc3cc(Br)ccc3Cl)s2)c1

Procedure:
2-(3-Methylphenyl)thiophene obtained in Reference Example 83-(1) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 9 to give the target compound. APCI-Mass m/Z 377/379/381 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:15]([O-])=O)=[C:4]2[C:8](=[CH:9][C:10]=1Br)[CH2:7][CH:6]([C:12]([OH:14])=[O:13])[CH2:5]2.[C:18](O)(=[O:22])[C:19](O)=[O:20]>C(O)C.O1CCCC1.Cl.[Pd]>[O:20]=[C:19]1[NH:15][C:3]2[C:4]3[CH2:5][CH:6]([C:12]([OH:14])=[O:13])[CH2:7][C:8]=3[CH:9]=[CH:10][C:2]=2[NH:1][C:18]1=[O:22]
Reactant: O=C(O)C(=O)O
Reactant: Nc1c(Br)cc2c(c1[N+](=O)[O-])CC(C(=O)O)C2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1Cc2ccc3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 90 °C
Reaction time: 30 h

Procedure:
A mixture of 5-amino-6-bromo-4-nitroindane-2-carboxylic acid (5.5 g, 18 mmol) and 20% Pd/C (0.5 g) in 95% ethanol (250 mL) and tetrahydrofuran (250 mL) was shaken on a Parr hydrogenation apparatus under a hydrogen atmosphere (51 psi) for 30 h. After removing the catalyst, the solvent was evaporated to give a solid. The solid was dissolved in 2N HCl (150 mL) and treated with oxalic acid (4.6 g), and then the mixture was heated at 90° C. for 5 h. After cooling to room temperature, the precipitate was collected by filtration and dried in vacuo (4.0 g).
Reaction SMILES: [C:1]([CH:5]([CH2:11][CH:12]=[CH2:13])[CH2:6][CH2:7][CH2:8][C:9]#[N:10])([O:3][CH3:4])=[O:2].Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([CH:5]([CH2:11][CH:12]=[CH:13][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:6][CH2:7][CH2:8][C:9]#[N:10])([O:3][CH3:4])=[O:2]
Reactant: C=CCC(CCCC#N)C(=O)OC
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C(CC=Cc1cccnc1)CCCC#N
Temperature: 25 °C

Procedure:
A mixture of 23.5 g of 5-carbomethoxy-oct-7-enenitrile, 20.07 g of 3-bromopyridine and 0.79 g of tri-o-tolylphosphine in 200 mL of 2:1 acetonitrile and triethylamine is stirred at room temperature under nitrogen for one half hour. Palladium acetate (0.27 g) is added and the mixture is stirred under reflux for 40 hours. An additional 0.13 g of palladium acetate is added and the reaction mixture is further heated under reflux for 20 hours. The reaction mixture is evaporated to dryness and the residue is taken up in ethyl acetate. The ethyl acetate solution is washed with water, and then with 3N hydrochloric acid. The acid extract is washed with ethyl acetate, made basic to pH 8-9 with ammonium hydroxide solution and reextracted with ethyl acetate. The ethyl acetate extract is dried and evaporated to dryness to yield 5-carbomethoxy-8-(3-pyridyl)-oct-7-enenitrile.
Reaction SMILES: ClC1C=CC(O)=C(C2C(C#CC3C=CC(NC([C@H]4CCCCN4)=O)=CC=3)=CN(CCO)N=2)C=1.C(OC([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH:42]1[C:47](=[O:73])[NH:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]#[C:56][C:57]2[C:58]([C:65]3[CH:70]=[C:69]([Cl:71])[CH:68]=[CH:67][C:66]=3[OH:72])=[N:59][N:60]([CH2:62][CH2:63][OH:64])[CH:61]=2)=[CH:51][CH:50]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:71][C:69]1[CH:68]=[CH:67][C:66]([OH:72])=[C:65]([C:58]2[C:57]([C:56]#[C:55][C:52]3[CH:53]=[CH:54][C:49]([NH:48][C:47]([CH:42]4[CH2:43][O:44][CH2:45][CH2:46][NH:41]4)=[O:73])=[CH:50][CH:51]=3)=[CH:61][N:60]([CH2:62][CH2:63][OH:64])[N:59]=2)[CH:70]=1
Reactant: CC(C)(C)OC(=O)N1CCOCC1C(=O)Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1
Agent: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)[C@H]1CCCCN1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)C1COCCN1
Yield: 74 %

Procedure:
Using the same procedure for the preparation of 5A, treatment of compound 16A (870 mg) with TFA (10 mL) in methylene chloride (10 mL) gives compound 17A in 74.0% yield. 1H NMR (DMSO-d6, 500 MHz) δ 10.67 (s, 1H), 10.02 (s, 1H), 8.35 (s, 1H), 8.28 (s, 1H), 7.73 (d, 2H, J=8.0 Hz), 7.47 (d, 2H, J=8.5 Hz), 7.30 (d, 1H, J=9.0 Hz), 6.99 (d, 1H, J=8.5 Hz), 5.01 (br s, 1H), 4.26 (br s, 2H), 3.83 (d, 1H, J=7.5 Hz), 3.78 (d, 2H, J=2.5 Hz), 3.61 (m, 3H), 3.52 (m, 2H), 3.43 (t, 1H, J=10.0 Hz), 2.85 (d, 1H, J=13.0 Hz), 2.75 (t, 1H, J=11.0 Hz). LCMS (ESI) m/z 467.09 (MH+, 100); HPLC: tR=3.92 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Product: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(Cl)cc1NC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
The title compound was prepared from (2-amino-5-azetidin-1-yl-4-chloro-phenyl)-carbamic acid tert.-butyl ester (Example J16) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) according to the general procedure M. Obtained as a yellow solid (142 mg).
Reaction SMILES: O[C:2]1[C:3](=[O:12])[O:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:13][OH:14]>>[O:14]1[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:10]=2[C:11]([CH2:2][C:3]([OH:12])=[O:4])=[N:13]1
Reactant: O=c1oc2ccccc2cc1O
Reactant: NO
Product: O=C(O)Cc1noc2ccccc12

Procedure:
Hydroxycoumarin (5) is treated with hydroxylamine to obtain benzo[d]isoxazol-3-yl-acetic acid (6) which is brominated at the alpha position to give benzo[d]isoxazol-3-yl-bromoacetic acid (7) from which 3-bromomethyl-benzo[d]isoxazole (8) is obtained by decarboxylation. The development of this process is limited in that the starting intermediate (1) is not commercially available and therefore the preparation of zonisamide is very complex. In fact, Posner reaction for the preparation of acid (6) requires the use of metal sodium. Moreover, when metal sodium is used in alcoholic solution, besides acid (6) also remarkable amounts of O-hydroxy-acetophenone-oxime as by-product are obtained. Furthermore, the decarboxylation reaction to give compound (8) requires drastic conditions, namely the presence of a large excess of 50% sulfuric acid and reflux temperature, and the resulting product is thus difficult to be isolated.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH3:12][CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:34]3[CH:35]=[N:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]=2[CH:6]=[N:7]1)[CH3:13]
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Reactant: COc1ccc(B(O)O)cn1
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(OC)nc2)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for example 75 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (100 mg, 0.225 mmol) and [6-(methyloxy)-3-pyridinyl]boronic acid (52 mg, 0.337 mmol). The final product was collected as a white solid (72 mg, 67%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (br. s., 1H) 8.68 (br. s., 1H) 8.62 (br. s., 1H) 8.39 (s, 1H) 8.21 (br. s., 1H) 8.14 (s, 1H) 7.86 (s, 1H) 6.97 (d, J=8.59 Hz, 1H) 5.92 (s, 1H) 5.09-5.21 (m, 1H) 4.37-4.48 (m, 2H) 3.92 (s, 3H) 2.54 (br. s., 2H) 2.14 (s, 3H) 1.55 (m, 2H) 1.51 (br. s., 3H) 1.50 (br. s., 3H) 0.88 (t, J=7.20 Hz, 3H). LC-MS (ES) m/z=474.0
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[N:7]=1.ClC[CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26].CCC(O)CC>>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([O:20][CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[C:13]([CH:18]=1)[CH2:12][N:8]1[C:9]([CH3:11])=[CH:10][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:21])=[N:7]1
Reactant: COC(=O)CCc1cc(C)n(Cc2cc(Cl)ccc2O)n1
Reactant: CCC(CC)CCl
Solvent: CCC(O)CC
Product: CCC(CC)Oc1ccc(Cl)cc1Cn1nc(CCC(=O)O)cc1C

Procedure:
The title compound was prepared following the methods described in example 1 and example 2 starting from (example 2 step 5) 3-[1-(5-Chloro-2-hydroxy-benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid methyl ester replacing the method in example 2 step 6 with Mitsunobu method and 3-chloromethylpentane with 3-pentanol.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>O1CCCC1>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)CSc1ccc(O)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 4-mercaptophenol (49.7 mg, 0.39 mmol) in tetrahydrofuran (2 mL) was added cesium carbonate (128 mg, 0.39 mmol) and ethyl bromoacetate (44 μL, 0.39 mmol) and the reaction was stirred at 50° C. overnight. The reaction was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with hexanes and EtOAc to afford ethyl 2-(4-hydroxyphenylthio)acetate (507).
Reaction SMILES: [CH3:1][C:2]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[Na].[CH3:23]Br>CN(C)C=O>[CH3:23][N:10]([C:2]([CH3:1])([CH3:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:12])=[O:13]
Reactant: CBr
Reactant: CC(C)(NS(=O)(=O)c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: CN(C(C)(C)c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
27.5 g (0.1 mole) of N-(α,α-dimethylbenzyl) benzenesulfonamide was added to 5.8 g (0.12 mole) of 50% sodium hydride in 200 ml of dry N,N-dimethyl formamide. The mixture was stirred at room temperature for 30 minutes to react them. To the resulting sodium salt of N-(α,α-dimethylbenzyl)benzenesulfonamide was added 16.1 g (0.17 mole) of methyl bromide. The mixture was heated to 60° C. and stirred for 1 hour. The N,N-dimethyl formamide was distilled off under reduced pressure, and cold water was added. The resulting white solid was recrystallized from methanol to afford N-methyl-N-(α,α-dimethylbenzyl)benzenesulfonamide in a yield of 87%. This compound is designated as compound No. 64 in Table 2 below, and its melting point and elemental analysis values are shown in Table 2.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[C:16]([O:20][C:21]([NH:23][CH:24]([C:28]([F:31])([F:30])[F:29])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>ClCCl>[F:29][C:28]([F:30])([F:31])[CH:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:17])([CH3:19])[CH3:18])[C:25](=[O:26])[NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:8])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nn1cccc1C(=O)Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NC(C(=O)Nn1cccc1C(=O)Nc1ccccc1)C(F)(F)F
Reaction time: 8 h
Yield: 47 %

Procedure:
1-Amino-N-phenyl-1H-pyrrole-2-carboxamide (570 mg, 2.83 mmol), 2-(tert-butoxycarbonylamino)-3,3,3-trifluoropropanoic acid (826 mg, 3.40 mmol), HATU (1.29 g, 3.40 mmol) and N-methylmorpholine (685 μl, 6.23 mmol) were suspended in 20 mL of dichloromethane and stirred overnight. The reaction mixture was diluted with more dichloromethane and the solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed in vacuum. The product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to obtain the title compound in a 47% yield (562 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:6][CH2:7][NH:8][CH3:9].[CH:15]([S:17]([F:20])(=[O:19])=[O:18])=[CH2:16]>CN(C=O)C>[F:20][S:17]([CH2:15][CH2:16][N:8]([CH2:7][CH2:6][C:5]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:9])(=[O:19])=[O:18]
Reactant: C=CS(=O)(=O)F
Reactant: CNCCc1ccc(OC)c(OC)c1
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)CCS(=O)(=O)F)cc1OC
Yield: 3.1 %

Procedure:
The reaction between 3,4-dimethoxy-N-methylphenethylamine (15 mmol) and ethenesulfonyl fluoride (1.65 mL, 19 mmol) was carried out in DMF (30 mL) at ambient temperature for 3 hours as described in Example 16. There was obtained an orange liquid which was crystallized from ether/methanol to afford the title compound as a yellow solid (0.14 g, 11% yield), mp 200°-204° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.O.[NH2:27][NH2:28]>CCO>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:5]=3)=[CH:15][CH:14]=2)[NH:28][N:27]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(NCCc3ccccc3)nc(N)n2)cc1F
Solvent: O
Solvent: CCO
Product: Nc1nc(NCCc2ccccc2)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of 4-{2-amino-6-[(2-phenylethyl)amino]-4-pyrimidinyl}-2-fluorobenzonitrile (800 mg, 2.4 mmol) in EtOH (20 mL) was added hydrazine monohydrate (7 mL), and the resulting suspension was stirred overnight at 95° C. The clear reaction mixture was concentrated, and the resulting residue was purified by RPHPLC (CH3CN/H2O w/0.1% THF) to afford the title compound (500 mg, 42%) as a light yellow powder. LC-MS (ES) m/z=346 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 2.85 (t, J=7.2 Hz, 2H), 3.53 (m, 2H), 5.37 (s, 2H), 6.02 (s, 2H), 6.28 (s, 1H), 6.94 (s, 1H), 7.18-7.23 (m, 1H), 7.28-7.33 (m, 4H), 7.42 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.85 (s, 1H), 11.5 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].F[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].[I-].[K+]>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccccc1F
Agent: [I-]
Agent: [K+]
Product: O=[N+]([O-])c1ccccc1Nc1ccccc1F
Temperature: 23 °C

Procedure:
A mixture of 2-fluoroaniline (13.0 ml), 2-fluoronitrobenzene (14.2 ml) and potassium iodide (5.5 g) was heated at 180° for 18 h. The mixture was cooled to 23° C.; the solid materials were filtered off and the solution was concentrated in vacuo. The residue was purified by flash chromatography (eluting with CH-EA 7:3) then crystallized from absolute ethanol to give the title compound as an orange solid (9.30 g). T.l.c. CH-EA (7:3), Rf =0.69. M.p. 76°-77° C. IR: 3352 (NH), 1609 (C=C), 1510 and 1350 (NO2) cm-1.
Reaction SMILES: [NH2:1][C:2](=[S:13])[CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O>CCO.CCOC(C)=O>[C:18]1([C:16]2[N:1]=[C:2]([CH2:3][NH:4][C:5](=[O:12])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:13][CH:15]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: NC(=S)CNC(=O)c1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(NCc1nc(-c2ccccc2)cs1)c1ccccc1
Temperature: 80 °C
Yield: 88.2 %

Procedure:
A mixture of N-(2-amino-2-thioxoethyl)benzamide (300 mg, 1.54 mmol) and 2-bromoacetophenone (305 mg, 1.54 mmol) in EtOH (10 mL) was heated to 80° C. for 2 h. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The concentrated reaction mixture was diluted with EtOAc and the organic layer was washed with H2O and brine, and concentrated under reduced pressure to yield N-((4-phenylthiazol-2-yl)methyl)benzamide (0.4 g, yield 88%) as a white solid, which was carried through without further purification. 1H NMR (400 MHz, CDCl3) δ 8.69 (br s, 1H), 8.04-8.01 (dd, J=7.8 Hz, 1.5 Hz, 2H), 7.99-7.97 (m, 2H), 7.64 (s, 1H), 7.56-7.52 (m, 4H), 7.48-7.44 (m, 2H), 5.34 (d, J=6 Hz, 2H). MS (ESI) m/z: Calculated for C17H14N2OS: 294.08. found: 295.0 (M+H)+.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)(=[O:14])=[O:13].C(ON=O)(C)(C)C>C(O)(=O)C.C1COCC1>[F:9][C:8]([F:10])([F:11])[C:6]1[CH:5]=[C:4]2[C:3]([S:12](=[O:14])(=[O:13])[NH:15][C:16]3[C:17]2=[CH:18][CH:19]=[C:20]2[C:25]=3[N:24]=[CH:23][CH:22]=[CH:21]2)=[CH:2][CH:7]=1
Reactant: Nc1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S1(=O)Nc2c(ccc3cccnc23)-c2cc(C(F)(F)F)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
2-Amino-N-quinolin-8-yl-4-trifluoromethyl-benzenesulfonamide (Example Compound 35) (50 mg, 0.14 mmol) was dissolved in acetic acid/THF (1:1; 2 ml) and cooled to 0° C. Tert-butylnitrite (16.2 μl, 0.14 mmol) was added and the mixture was stirred for 1 h keeping the temperature between 0° C. -5° C. The reaction was quenched with water (3 ml), while keeping the temperature between 0° C. -5° C., and the organic phase was extracted with EtOAc (10 ml). The combined organic phases were washed with sat. sodium bicarbonate and concentrated in vacuo. The crude residue was purified by column chromatography with DCM as the eluent to give the title compound (11 mg, 23%)
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:15])OC(C)(C)C)[CH2:3]1.C([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:44]3[C:39](=[CH:40][C:41](C(O)=O)=[CH:42][CH:43]=3)[C:38]([CH3:48])=[C:37]2[CH3:49])=[CH:31][CH:30]=1)=[O:22])(C)(C)C>>[NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([C:41]2[CH:40]=[C:39]3[C:44](=[CH:43][CH:42]=2)[N:36]([CH2:35][C:32]2[CH:31]=[CH:30][C:29]([C:24]4[C:23]([C:21]([OH:22])=[O:20])=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:34][CH:33]=2)[C:37]([CH3:49])=[C:38]3[CH3:48])=[O:15])[CH2:3]1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: CC(C)(C)OC(=O)NC1CCCC(N)C1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NC3CCCC(N)C3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using tert-butyl 3-aminocyclohexylcarbamate and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 496 (M+H).
Reaction SMILES: [Cl:1][C:2]([C:4]12[CH2:13][C:8]3([OH:14])[CH2:9][CH:10]([CH2:12][C:6]([C:15]([Cl:17])=[O:16])([CH2:7]3)[CH2:5]1)[CH2:11]2)=[O:3].CN(C)C.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24]>C(Cl)Cl>[Cl:1][C:2]([C:4]12[CH2:13][C:8]3([O:14][Si:23]([CH3:25])([CH3:24])[CH3:22])[CH2:9][CH:10]([CH2:12][C:6]([C:15]([Cl:17])=[O:16])([CH2:7]3)[CH2:5]1)[CH2:11]2)=[O:3]
Reactant: O=C(Cl)C12CC3CC(O)(C1)CC(C(=O)Cl)(C3)C2
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C
Solvent: ClCCl
Product: C[Si](C)(C)OC12CC3CC(C(=O)Cl)(C1)CC(C(=O)Cl)(C3)C2

Procedure:
The 1,3-dichloroformyl-5-hydroxyadamantane was dissolved in methylene chloride. To this solution were added a small amount of trimethylamine, and then an equimolar amount of trimethylsilyl chloride. Reaction was carried out at room temperature to obtain 1,3-dichloroformyl-5-trimethylsiloxyadamantane.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.O.[Pd]>[CH3:21][O:20][CH:17]1[CH2:18][CH2:19][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:15][CH2:16]1
Reactant: [H][H]
Reactant: COC1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COC1CCN(C2CCNCC2)CC1
Reaction time: 8 h

Procedure:
A suspension of 2.1 (5.87 mmol) 1′-benzyl-4-methoxy-[1,4′]bipiperidinyl and 1.0 g 10% Pd/C in 50 mL MeOH and 20 mL water was hydrogenated for 8 h at RT and 3 bar hydrogen pressure. The catalyst was removed by suction filtering, the filtrate was concentrated by evaporation i.vac., the residue was triturated with diethyl ether, suction filtered and dried.