Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SH:6])[CH2:2][CH2:3][CH2:4][CH3:5].[H-].[Na+].CS(O[CH:14]1[CH2:17][N:16]([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15]1)(=O)=O.C([O-])(O)=O.[Na+]>CS(C)=O>[C:19]1([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:16]2[CH2:17][CH:14]([S:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:15]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCCCS
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCSC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a solution of pentanethiol (248 μL, 2.0 mmol) in DMSO (2.5 mL) at 0° C. under nitrogen was added NaH (60% in oil, 80 mg, 2.0 mmol). The suspension was stirred for 0.5 h at 0° C. then treated with 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (317 mg, 1.0 mmol; which may be prepared as described in Step 1) and the mixture allowed to warm to room temperature overnight. Saturated NaHCO3 (5 mL) was added and the mixture was extracted with diethyl ether. The organic layer was separated from the aqueous and the organic washed with brine, dried over Na2SO4 and concentrated to give the product (312 mg, 96%) as a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([C@@H:10]([OH:22])[C@@H:11]([OH:21])[C@@H:12]([NH2:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1C([N+]([O-])=O)=CC=C([O:32][C:33]([O:35][CH2:36][C:37]2[S:41][CH:40]=[N:39][CH:38]=2)=O)C=1>O1CCCC1.C(Cl)(Cl)Cl>[NH2:1][C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C@H:10]([OH:22])[C@H:11]([OH:21])[C@@H:12]([NH:20][C:33]([O:35][CH2:36][C:37]1[S:41][CH:40]=[N:39][CH:38]=1)=[O:32])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccccc1)[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1

Procedure:
A solution of 0.133 mmol of (2S,3R,4S,5S)-2,5-diamino-3,4-dihydroxy-1,6-diphenylhexane and 0.147 mmol of ((5-thiazolyl)methyl)-(4-nitrophenyl)carbonate in 10 ml of tetrahydrofuran was stirred at ambient temperature for 16 h. The resulting solution was diluted with 50 ml of chloroform, washed with several portions of 3N aqueous NaOH, dried over Na2SO4, and concentrated in vacuo. Silica gel chromatography of the residue provided the desired compound.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][C:13]1[N:14]([CH2:19][CH3:20])[N:15]=[C:16]([CH3:18])[CH:17]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:19]([N:14]1[C:13]([CH2:12][CH2:11][NH2:10])=[CH:17][C:16]([CH3:18])=[N:15]1)[CH3:20]
Reactant: CCn1nc(C)cc1CCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCn1nc(C)cc1CCN
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 93.4 %

Procedure:
[2-(2-Ethyl-5-methyl-2H-pyrazol-3-yl)-ethyl]-carbamic acid benzyl ester (818 mg, 2.85 mmol) was dissolved in methanol (8 ml) and added to a suspension of Pd—C (10%, 163 mg) in methanol (8 ml), put under an atmosphere of hydrogen (1 bar) and stirring at rt was continued for 45 minutes. The reaction mixture was filtered over a pad of celite and the filtrate was concentrated under reduced pressure to give 408 mg (93.7%) of 2-(2-Ethyl-5-methyl-2H-pyrazol-3-yl)-ethylamine. LC-MS: tR=0.20 min, broad peak; [M+H]+=no ionization.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].CN(C=O)C.C(N=C=NCCCN(C)C)C.[NH2:39][C:40]1[S:41][C:42]2[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:43]=2[N:44]=1>>[F:49][C:47]1[CH:46]=[CH:45][C:43]2[N:44]=[C:40]([NH:39][C:16](=[O:18])[C:15]3[CH:19]=[CH:20][CH:21]=[N:22][C:14]=3[NH:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[S:41][C:42]=2[CH:48]=1
Reactant: Nc1nc2ccc(F)cc2s1
Reactant: COc1cc(Nc2ncccc2C(=O)O)cc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncccc2C(=O)Nc2nc3ccc(F)cc3s2)cc(OC)c1OC
Temperature: 27 °C
Reaction time: 9 h

Procedure:
Compound 13 (185 mg, 1 mmol) and 3,4,5-methoxy aniline (20, 183 mg, 1 mmol) was taken in ethylene glycol and refluxed at 160° C. for 6 h. Then the reaction mixture was cooled and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain Ethyl 2-(3,4,5-trimethoxy anilino) nicotinate (27) as pure product. Ethyl2-(3,4,5-trimethoxy anilino) nicotinate (27, 332 mg, 1 mmol) were refluxed with 2N NaOH in ethanol for 2 h. The reaction mixture was cooled and left acidified with 2N HCl white solids obtained, filtered and washed with water to give pure compound of 2-(3,4,5-trimethoxyphenylamino) nicotinic acid (34). To a stirred solution of 2-(3,4,5-trimethoxyphenylamino) nicotinic acid (34, 244 mg, 1 mmol) in dry DMF (10 mL) hydroxy benzotriazole HOBt (1.2 mmol) were added at 0° C. After 10 min 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) (1.2 mmol) was added and finally 2-amino 6-fluoro benzothiazole (36, 117 mg, 0.7 mmol) were added Then the resulting mixture was stirred at room temperature (27° C.) for 8-10 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (11) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:36]([F:37])=[CH:35][C:17]3[N:18]=[C:19]([C:21]4[C:25]([N+:26]([O-])=O)=[CH:24][N:23]([CH:29]5[CH2:34][CH2:33][CH2:32][CH2:31][O:30]5)[N:22]=4)[NH:20][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:36]([F:37])=[CH:35][C:17]3[N:18]=[C:19]([C:21]4[C:25]([NH2:26])=[CH:24][N:23]([CH:29]5[CH2:34][CH2:33][CH2:32][CH2:31][O:30]5)[N:22]=4)[NH:20][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3[nH]c(-c4nn(C5CCCCO5)cc4[N+](=O)[O-])nc3cc2F)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cc3[nH]c(-c4nn(C5CCCCO5)cc4N)nc3cc2F)CC1
Yield: 177 %

Procedure:
A suspension of 540 mg of 4-{6-fluoro-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-3H-benzimidazol-5-yl}piperazine-1-carboxylic acid tert-butyl ester in 15 mL of methanol and 54 mg of palladium-on-charcoal is hydrogenated under 1 bar of hydrogen pressure at ambient temperature for 16 hours. The reaction medium is filtered through celite and the filtrate is concentrated under reduced pressure in a rotary evaporator. 900 mg of 4-{2-[4-amino-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-6-fluoro-3H-benzimidazol-5-yl}piperazine-1-carboxylic acid tert-butyl ester are obtained in the form of a black solid. 1H NMR (400 MHz, DMSO-d6, δ in ppm): from 1.30 to 2.20 (m, 6H); 1.42 (s, 9H); 3.00 (m, 4H); 3.52 (m, 4H); 3.67 (m, 1H); 3.96 (m, 1H); 5.55 (broad d, J=10.0 Hz, 1H); 7.22 (d, J=7.5 Hz, 1H); 7.46 (d, J=12.5 Hz, 1H); 8.17 (s, 1H). ES mass spectrum: m/z=486 MH+ (base peak).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:22]C(=O)C)[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:22])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1
Reactant: CC(=O)Nc1ccc(OCCN2CCCCC2)c(-c2ccnn2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nccc1-c1cc(N)ccc1OCCN1CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetamide (1.0 g, 2.92 mmol) was dissolved in ethanol (15 mL) then aqueous sodium hydroxide (2.5 mL, 50% w/w) was added and the reaction mixture stirred at 80° C. overnight then concentrated. Water and brine were added then extracted with EtOAc three times. The organic layers were combined, dried over anhydrous Na2SO4 then solvent removed under reduced pressure to afford 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenylamine as a brown oil in 97.1% yield.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[OH:9][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[C:1][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CC(O)CCCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCC(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, rac-1-octyn-3-ol (61 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 supra) using (Ph3P)2PdC[2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield rac-(Z)-1,3-dihydro-4-(3-hydroxy-1-octynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 88 mg, 60%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)#[N:20].[Cl-].[NH4+]>CN(C)C=O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([O:27][C:24]2[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=2)[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2ccc(C#N)cc2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 68.8 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate and 0.16 g of 4-cyanophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.2 g of 4-(2-butynyloxy)-6-(4-cyanophenoxy)pyrimidine (the present compound (41)), m.p.: 162.0° C.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:5]([CH2:6][O:7][C:8](=[O:10])[NH2:9])[N:4]([S:11]([OH:14])(=[O:13])=[O:12])[C:3]1=[O:15].[NH2:16][C:17]1[S:18][CH:19]=[C:20](/[C:22](=[N:26]/[O:27][CH2:28][CH2:29][S:30]([CH3:33])(=[O:32])=[O:31])/[C:23](O)=[O:24])[N:21]=1>>[NH2:16][C:17]1[S:18][CH:19]=[C:20](/[C:22](=[N:26]/[O:27][CH2:28][CH2:29][S:30]([CH3:33])(=[O:31])=[O:32])/[C:23]([NH:1][C@H:2]2[C@@H:5]([CH2:6][O:7][C:8](=[O:10])[NH2:9])[N:4]([S:11]([OH:14])(=[O:12])=[O:13])[C:3]2=[O:15])=[O:24])[N:21]=1
Reactant: CS(=O)(=O)CCO/N=C(\C(=O)O)c1csc(N)n1
Reactant: NC(=O)OC[C@@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Product: CS(=O)(=O)CCO/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1COC(N)=O)c1csc(N)n1

Procedure:
In the same manner as described in Example 9, from 12 g of (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid and 2-(2-amino-4-thiazolyl)-2-[(Z)-[2-(methylsulphonyl)ethoxy]imino]-acetic acid there are obtained 1.15 g of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[2-(methylsulphonyl)ethoxy]imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid.
Reaction SMILES: [C-:1]#[N:2].[F:3][C:4]1[C:9]([B:10]([C:22]2[C:27]([F:28])=[C:26]([F:29])[C:25]([F:30])=[C:24]([F:31])[C:23]=2[F:32])[C:11]2[C:16]([F:17])=[C:15]([F:18])[C:14]([F:19])=[C:13]([F:20])[C:12]=2[F:21])=[C:8]([F:33])[C:7]([F:34])=[C:6]([F:35])[C:5]=1[F:36].[F:37][C:38]1[C:43]([B:44]([C:56]2[C:61]([F:62])=[C:60]([F:63])[C:59]([F:64])=[C:58]([F:65])[C:57]=2[F:66])[C:45]2[C:50]([F:51])=[C:49]([F:52])[C:48]([F:53])=[C:47]([F:54])[C:46]=2[F:55])=[C:42]([F:67])[C:41]([F:68])=[C:40]([F:69])[C:39]=1[F:70].[K+].Cl[C:73]([C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1)([C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1)[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1>ClCCl>[C-:1]#[N:2].[F:28][C:27]1[C:22]([B:10]([C:9]2[C:4]([F:3])=[C:5]([F:36])[C:6]([F:35])=[C:7]([F:34])[C:8]=2[F:33])[C:11]2[C:12]([F:21])=[C:13]([F:20])[C:14]([F:19])=[C:15]([F:18])[C:16]=2[F:17])=[C:23]([F:32])[C:24]([F:31])=[C:25]([F:30])[C:26]=1[F:29].[F:62][C:61]1[C:56]([B:44]([C:43]2[C:38]([F:37])=[C:39]([F:70])[C:40]([F:69])=[C:41]([F:68])[C:42]=2[F:67])[C:45]2[C:46]([F:55])=[C:47]([F:54])[C:48]([F:53])=[C:49]([F:52])[C:50]=2[F:51])=[C:57]([F:66])[C:58]([F:65])=[C:59]([F:64])[C:60]=1[F:63].[C:74]1([C+:73]([C:80]2[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=2)[C:86]2[CH:87]=[CH:88][CH:89]=[CH:90][CH:91]=2)[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Product: c1ccc([C+](c2ccccc2)c2ccccc2)cc1
Temperature: -78 °C

Procedure:
Potassium bis(tris(pentafluorophenyl)borane)cyanide (827.5 mg, 0.7598 mmol) and chlorotriphenylmethane (211.8 mg, 0.7597 mmol) were placed in a 50 mL flask. The stirred solids were taken up in 10 mL of dichloromethane, added via syringe under argon counter-flow. An immediate reaction gave a deep yellow solution and a colorless solid. The solid was removed by filtration and washed (four times 4 mL) until all color was gone. The filtrate was reduced under vacuum to 4 mL, cooled to −78° C. and diluted with 10 mL of hexanes. The resulting suspension of brown oil was allowed to warm and stir. The oil solidified and then digested to a canary-yellow solid after stirring for 30 minutes. The yellow solid was isolated by filtration and dried under high vacuum. Yield, 935.3 mg, 95.20 percent.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.N[C:10](N)=[O:11]>O>[NH:7]1[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][C:3]=2[NH:8][C:10]1=[O:11]
Reactant: NC(N)=O
Reactant: Nc1ccncc1N
Solvent: O
Product: O=c1[nH]c2ccncc2[nH]1
Reaction time: 18 h

Procedure:
A combination of pyridine-3,4-diamine (1.0 g, 9.16 mmol) and urea (3.3 g, 54.9 mmol) were stirred as a melt at 165° C. for 4 h, then cooled and H2O (100 mL) was added. The aqueous mixture was heated at reflux until all solid dissolved and the solution was allowed to cool and aged for 18 h. The precipitate was isolated by filtration to give the title compound. MS: m/z=136 (M+1).
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C@H:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([O:33]C)[CH:29]=3)[C@H:24]2[CH2:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[C:8]([F:15])=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:10]=1.B(Br)(Br)Br>C(Cl)Cl>[ClH:1].[ClH:1].[ClH:1].[NH2:4][C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C@H:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([OH:33])[CH:29]=3)[C@H:24]2[CH2:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[C:8]([F:15])=[C:9]([S:11]([NH2:14])(=[O:12])=[O:13])[CH:10]=1
Reactant: COc1ccc2c(c1)CC[C@H](NCCCCCCc1cc(N)cc(S(N)(=O)=O)c1F)[C@@H]2Cc1cccnc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Nc1cc(CCCCCCN[C@H]2CCc3cc(O)ccc3[C@H]2Cc2cccnc2)c(F)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Aminotetralin sulfonamide 8 from the previous reaction (0.160 g, 0.246 mmol) was placed in a 50 mL round-bottom flask along with a stir bar. Methylene chloride (25 mL) was added and the slurry was cooled on an ice bath for several minutes. Boron tribromide in methylene chloride (1M, 1.25 mL, 1.25 mmol) was added to the reaction. The flask was flushed with argon, capped and allowed to warm up to ambient temperature and the mixture was stirred over 16 hours at which time the reaction was quenched by the addition of methanol (1 mL). The solvents were removed in vacuo and an additional aliquot of methanol was added to the resultant residue. Evaporation of the solvent from this mixture afforded crude product which was purified via reverse-phase chromatography (Bondapak C18, 3×(40×100 mm), gradient of H2O/CH3CN (+0.1% TFA)). The appropriate fractions were collected and lyophilized. The resultant material was subsequently treated with ethanolic-hydrogen chloride, followed by evaporation and drying under vacuum to give the phenolic product 9 as a white tris-hydrochloride salt (0.145 g, 0.228 mmol). NMR(d6-DMSO): δ 10.77 (br, 1H), 10.01 (br, 1H), 9.31 (br, 1H), 8.79 (d, 1H), 8.67 (m, 4H), 8.37 (d, 1H), 7.97 (m, 2H), 7.81 (dt, 1H), 7.72 (m, 1H), 7.52–7.36 (m, 2H), 6.57 (s, 1H), 6.22 (dd, 1H), 5.69 (d, 1H), 3.79 (m, 1H), 3.68–3.30 (m, 5H), 3.04 (m, 1H), 2.92–2.68 (m, 4H), 2.33–2.10 (m, 2H), 1.73–1.56 (m, 2H), 1.55–1.32 (m, 4H); MS: MH+=527 (FIG. 3).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1CCCCC1>C(O)C>[CH:17](=[N:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=O)c1c(Nc2cccnc2)n[nH]c1N
Reactant: O=Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccnc2)n[nH]c1N=Cc1ccccc1
Yield: 57 %

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide (1.0 g) was suspended in 10 mL of ethanol and benzaldehyde (463 μL, 1.0 eq.) and piperidine (0.10 eq, 47 μL) was added. Stirred the reaction at reflux until starting material was absent and confirmed by HPLC. After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-(benzylideneamino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide as a yellow to orange powder. The product was washed with ethanol to remove any excess benzaldehyde. Product was allowed to dry under vacuum for 1 hr (800 mg, 57% yield).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C[Al](C)C.C([O:18][C:19]([C:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:29][C:24]=2[O:23][N:22]=1)=O)C.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1.CCOC(C)=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([NH:6][C:19]([C:21]2[C:25]3[CH:26]=[CH:27][C:28]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:29][C:24]=3[O:23][N:22]=2)=[O:18])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1noc2cc(OCc3ccccc3)ccc12
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1noc2cc(OCc3ccccc3)ccc12
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In a dried vessel, 99 μl (0.79 mMol) 3-trifluoromethyl-aniline are dissolved in 14 ml toluene and cooled to 10° C. Then 1.2 ml Me3Al (2 M in toluene; 2.4 mMol) are added via syringe. After 1 h at rt, a solution of 236 mg (0.79 mMol) 6-benzyloxy-benzo[d]isoxazole-3-carboxylic acid ethyl ester in 3 ml THF is added and the reaction mixture stirred for 25 min in an oil bath at 110° C. The solution is cooled in ice and hydrolyzed with 30 ml of a sat. NH4Cl. After 15 min stirring, EtOAc and Celite are added. The mixture is filtered through Celite, the solid washed with EtOAc and water, the aq. phase separated from the filtrate and extracted with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Crystallisation from EtOAc/hexane gives the title compound: MS: [M−1]=411; TLC(hexane/EtOAc 3:1): Rf=0.51.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH:8]([C:18]#[N:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:27][CH2:28][CH2:29]Br>C1(C)C=CC=CC=1>[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:27][CH2:28][CH2:29][C:8]1([C:18]#[N:19])[C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[CH2:11][CH2:12][C:13]2[CH:3]=[CH:4][CH:5]=[CH:6][C:7]1=2
Reactant: N#CC1c2ccccc2CCc2ccccc21
Reactant: BrCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC1(CCCOC2CCCCO2)c2ccccc2CCc2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
In a 50 ml roundbottom flask equipped with magnetical stirring, thermometer and addition funnel, sodium hydride (0.8 g, 0.02 mol, 60% dispersion in oil) was suspended in dry toluene under an atmosphere of nitrogen. A solution of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-carbonitrile (3.0 g, 0.014 mol, prepared in a similar way as described in J. Med. Chem., 6, (1963), 251) in dry toluene (15 ml) was added. The reaction mixture was heated to reflux temperature in 30 minutes and then heated at reflux temperature for 150 minutes. After cooling to about 50° C., a solution of 3-bromopropyl tetrahydropyranyl ether (4.5 g, 0.02 mol) in dry toluene (6 ml) was added dropwise. The reaction mixture was heated at reflux temperature for 5 h and then left stirring at room temperature overnight. After filtration of precipitated salts, the solution was washed with 1N HCl (100 ml), diluted with more toluene (100 ml) and finally washed with water. After drying (MgSO4), the organic phase was evaporated in vacuo affording 7.2 g (99%) of 5-(3-(tetrahydropyran-2-yloxy)-1-propyl)-10,11-dihydro-5H-dibenzo-[a,d]cycloheptene-5-carbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])=[CH:7][CH:6]=1.F[C:26](F)(F)[CH2:27][S:28](Cl)(=[O:30])=[O:29]>>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[S:28]([CH2:27][CH3:26])(=[O:30])=[O:29])=[CH:7][CH:6]=1
Reactant: CC(Nc1ccc(Oc2ccc(F)cc2F)cc1)c1cccnc1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Product: CCS(=O)(=O)N(c1ccc(Oc2ccc(F)cc2F)cc1)C(C)c1cccnc1

Procedure:
Using the method of Example 342 using N-(4-(2,4-difluorophenoxy)phenyl)-1-pyrid-3-ylethylamine and 2,2,2-trifluoroethanesulfonyl chloride and purifying via radial chromatography eluting with 95:5 to 85:15 CHCl3/ethyl acetate gave the title compound. Anal Calcd for C21H17F5N2O3S.0.2H2O: C, 52.98; H, 3.68; N, 5.89. Found: C, 52.88; H, 3.73; N, 5.67. MS found 473.1 [M+H]+
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[CH3:30][NH:31][CH3:32]>>[CH3:30][N:31]([CH3:32])[CH2:3][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:1])[CH3:5]
Reactant: CNC
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)C=O)cn1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CN(C)C)cn1

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide was reacted with dimethylamine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 18.9, 26.1, 26.2, 35.9, 43.2, 47.9, 53.1, 59.3, 69.9, 102.9, 105.4, 112.4, 112.6, 131.7, 137.5, 169.2; MS m/z 436.2 (M+1),