Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][Si:20]([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)c1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a solution of 1-(4-bromophenyl)ethan-1-ol (2.8 g, 13.93 mmol) and imidazole (2.84 g, 41.79 mmol) in DMF (35 mL) was added TBDMSCl (4.18 g, 27.86 mmol) at r.t., and the reaction was stirred overnight. The reaction was diluted with water (70 mL) and extracted with EtOAc (50 mL×3). Organics were washed with brine (50 mL), dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=100:1) to give 4.08 g (95%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1](Br)[CH3:2].[CH3:4][CH2:5][C@@H:6]([C:17]([O-:19])=[O:18])[C@H:7]([CH2:15][OH:16])[CH2:8][C:9]1[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=1.[Na+].O>CS(C)=O>[CH3:4][CH2:5][C@H:6]([C:17]([O:19][CH2:1][CH3:2])=[O:18])[C@H:7]([CH2:15][OH:16])[CH2:8][C:9]1[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=1
Reactant: CCBr
Reactant: CC[C@@H](C(=O)[O-])[C@H](CO)Cc1cncn1C
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)[C@@H](CC)[C@H](CO)Cc1cncn1C
Temperature: 25 °C
Reaction time: 60 h

Procedure:
9.80 mmoles of ethylbromide (1068 mg) were added dropwise within about an hour to a solution containing 9.80 mmoles (2432 mg) of pilocarpic acid sodium salt in 60 ml of dimethyl sulfoxide. The solution was stirred at room temperature for 48-72 hours and poured into 100 ml of distilled water. The mixture was extracted with two portions of each 150 ml of ethyl acetate. The combined ethyl acetate extracts were washed with 150 ml of distilled water, with 150 ml of 2% sodium bicarbonate solution and with 150 ml of distilled water. The ethyl acetate extracts were dried on calcium sulfate (30 min) and the ethyl acetate evaporated under reduced pressure, and the pilocarpic acid ethyl ester obtained was crystallized from a chloroform/ petroleum ether-mixture, whereby 448 mg (1.76 mmoles) of the ester were obtained.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[N:14]3[N:15]=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:17]=[C:18]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:31][NH2:32]>C(O)CCC>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][C:8]([C:10]3[N:14]4[N:15]=[C:16]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:17]=[C:18]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]4=[N:12][CH:11]=3)=[CH:7][CH:6]=2)[NH:32][N:31]=1
Reactant: NN
Reactant: CC(C)CNc1cc(-c2ccccc2)nn2c(-c3ccc(C#N)c(F)c3)cnc12
Solvent: CCCCO
Solvent: O
Product: CC(C)CNc1cc(-c2ccccc2)nn2c(-c3ccc4c(N)n[nH]c4c3)cnc12
Temperature: 120 °C
Yield: 53 %

Procedure:
To a solution of 46 mg (119 μmol) 2-fluoro-4-[8-(isobutylamino)-6-phenylimidazo[1,2-b]pyridazin-3-yl]benzonitrile which was prepared according to intermediate example 11a in 2.5 mL n-butanol were added 232 μL hydrazine hydrate and the mixture was heated at 120° C. overnight. The precipitate was filtered, washed with 2-propanol and dried to give 26.5 mg (53%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([CH:14]=1)[CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>CC(O)=O.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:15])=[C:6]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CN1CCOCC1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc(Cl)cc1CN1CCOCC1
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a solution of 4-(5-chloro-2-nitrobenzyl)morpholine (5.1 g, 19.9 mmol) in HOAc (75 mL) is carefully added zinc dust (3.9 g, 59.6 mmol). After 2 hours, the reaction is filtered through a bed of Celite and the filtrate is concentrated to remove most of the HOAc. The residue is then taken up in 2M aqueous K2CO3 and extracted with ethyl acetate. The organic layer is dried (Na2SO4) and concentrated to afford a brown oil. The crude material is purified by flash column chromatography using a gradient of 0-5% methanol/CH2Cl2 to afford the title compound (4.0 g, 12.4 mmol, 70% purity).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:31]([C:34](O)=[O:35])=[CH:30][CH:29]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([C:31]5[CH:32]=[CH:33][C:28]([C:37]6[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=6)=[CH:29][CH:30]=5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(-c2ccccc2)cc1

Procedure:
The title compound, white solid (93 mg, 73%), MS (ISP) m/z=511.6 [(M+H)+], mp 232° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and biphenyl-4-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=4[F:51])[CH:34]=3)[O:32][C@@:10]1([CH:52]=[O:53])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:54][Mg]Br>O1CCCC1>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=4[F:51])[CH:34]=3)[O:32][C@@:10]1([CH:52]([OH:53])[CH3:54])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C=O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.2 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl) methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carbaldehyde 23o (1.30 g, 1.75 mmol) in dry tetrahydrofuran (20 mL) was added dropwise methylmagnesium bromide (1.75 mL, 5.25 mmol, 3 M in ethyl ether) under N2 at 0° C. The mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=12/1 to give the title compound 23p as a white solid (0.48 g, 36%). The compound was characterized by the following spectroscopic data: 1H NMR (600 MHz, CDCl3) δ(ppm): 7.38 (m, 11H), 7.22 (m, 5H), 6.93 (m, 2H), 6.66 (s, 1H), 6.53 (m, 1H), 4.99 (m, 1H), 4.94 (d, 1H), 4.80 (m, 2H), 4.31 (m, 2H), 4.04 (m, 5H), 3.95 (m, 2H), 3.83 (m, 2H), 3.70 (m, 1H), 1.45 (t, 3H), 1.28 (d, 3H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11]C=O)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:14][CH:15]([CH2:27][OH:28])[CH2:16][O:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20].[NH3:29]>>[NH2:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[O:14][CH:15]([CH2:27][OH:28])[CH2:16][O:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])=[C:2]([NH2:29])[N:10]=1
Reactant: CCOP(=O)(COCC(CO)On1cnc2c(Cl)nc(NC=O)nc21)OCC
Reactant: N
Product: CCOP(=O)(COCC(CO)On1cnc2c(N)nc(N)nc21)OCC
Reaction time: 5 h
Yield: 28 %

Procedure:
A solution of 6-chloro-9-[1-(diethoxyphosphorylmethoxy)-3-hydroxyprop-2-oxy]-2-formamidopurine (400 mg, 0.91 mmol) in saturated ethanolic ammonia (20 ml) was placed in an autoclave and kept at 110° C. for 5 h. After cooling, the solvent was evaporated in vacuo and the residue chromatographed on silica, eluting with chloroform-methanol 10:1, affording 2,6-diamino-9-[1-(diethoxyphosphorylmethoxy)-3-hydroxyprop-2-oxy]purine (100 mg, 28%) as an oil. νmax (CHCl3) 3500, 3400, 1620 and 1600 cm-1 ; δH [(CD3)2SO] 1.24, (6H, t, J7.1 Hz, 2×CH2CH3), 3.58 (2H, m, CH2OH), 3.80 (2H, d, J5.0 Hz, CH2OCH2P), 3.92 (2H, d, J8.2 Hz, CH2P), 4.05 (4H,m,2×CH 2 CH3), 4.39 (1H, t, J5.0 Hz, CHON), 5.35 (1H, br.s, D2O exchangeable, OH), 6.00 (2H br.s, D2O exchangeable, NH2), 6.87 (2H, br.s, D2O exchangeable, NH2), 7.87 (1H, s, H-8); m/z (FAB+ve Ion), 391 (MH+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:16]=[C:15]2[C:6]([S:7][C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([C:17](O)=[O:18])[C:13]=3[NH:14]2)=[CH:5][CH:4]=1.C(Cl)(Cl)[Cl:23].P(Cl)(Cl)Cl>CN(C)C=O>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:16]=[C:15]2[C:6]([S:7][C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([C:17]([Cl:23])=[O:18])[C:13]=3[NH:14]2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1cccc2c1Nc1cc(C(F)(F)F)ccc1S2
Reactant: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Product: O=C(Cl)c1cccc2c1Nc1cc(C(F)(F)F)ccc1S2
Reaction time: 4 h

Procedure:
8-Trifluoromethylphenothiazine-1-carboxylic acid (62.2 g., 0.20 mol.) was added to a stirred mixture of 300 ml. of chloroform and 300 ml. of phosphorus trichloride. The resulting brown suspension was cooled in an ice-bath while 50 ml. of dimethylformamide was added slowly until a reddish brown solution formed. After stirring the mixture for 4 hours at 25°, the chloroform and excess phosphorus trichloride were evaporated under reduced pressure. The resulting reddish brown solid residue was dissolved in 1500 ml. of boiling n-hexane. The hot, clear, reddish solution was decanted from a viscous, insoluble material and, on cooling, large red needles formed. The solid was collected by filtration and washed with hexane to give 8-trifluoromethylphenothiazine-1-carboxylic acid chloride, m.p. 124°-126°.
Reaction SMILES: [Si:1]([Cl:5])(Cl)([Cl:3])[Cl:2].[CH3:6][Si:7]([CH3:14])([CH3:13])[NH:8][Si](C)(C)C>>[Cl:2][Si:1]([Cl:5])([Cl:3])[NH:8][Si:7]([CH3:14])([CH3:13])[CH3:6]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: Cl[Si](Cl)(Cl)Cl
Product: C[Si](C)(C)N[Si](Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 88.6 %

Procedure:
In accordance with J. P. Moser, H. Noth and W. Tinhof in Z. Naturforsch. B 29, 166 (1974), 68.98 g (0.406 mol) silicon tetrachloride and 12.3 g (0.076 mol) hexamethyl disilazane are combined in a 250 ml three-necked flask and stirred for 14 hours at room temperature. Subsequent fractional distillation in a short Vigreux column gives 15 g (88%) of the colorless liquid.
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:15]([CH3:18])([CH3:17])[CH3:16].Cl[C:20]([S:22]Cl)=[O:21]>>[OH:1][C:2]1[C:10]([C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:9][C:5]([C:6]2[O:7][C:20](=[O:21])[S:22][N:8]=2)=[CH:4][C:3]=1[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(C(N)=O)cc(C(C)(C)C)c1O
Reactant: O=C(Cl)SCl
Product: CC(C)(C)c1cc(-c2nsc(=O)o2)cc(C(C)(C)C)c1O

Procedure:
The procedure of Example 1 is repeated using 3.03 grams of 4-hydroxy-3,5-di-tert-butylbenzamide and 3.18 grams of chlorocarbonylsulfenyl choride. Recrystallization from toluene:heptane (1:1) affords the title compound as a white crystalline solid: mp 155°-157° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:14][C:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH:20]=3)[O:13][CH2:12][CH2:11][O:10]2)[CH:6]=[CH:7][CH:8]=1.[H][H]>[Pt].CC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)[O:13][CH2:12][CH2:11][O:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: CCOC(=O)N1CC=C(CC2(c3cccc(OC)c3)OCCO2)CC1
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(CC2(c3cccc(OC)c3)OCCO2)CC1

Procedure:
A mixture of 30 parts of ethyl 2,3-dihydro-4-[2-(3-methoxyphenyl)-1,3-dioxolan-2-ylmethyl]-1(6H)-pyridinecarboxylate and 450 parts of methylbenzene is hydrogenated at normal pressure and at room temperature with 4 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 30 parts of ethyl 4-[2-(3-methoxyphenyl)-1,3-dioxolan-2-ylmethyl]-1-piperidinecarboxylate as a residue.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:13]3[CH:14]=[C:15]([C:18](N(C)OC)=[O:19])[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1.[CH3:24][Mg+].[Br-]>C(Cl)Cl>[CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]([CH3:24])=[O:19])[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1
Reactant: C[Mg+]
Reactant: CON(C)C(=O)c1ccc2ncn(-c3ccnc(SC)n3)c2c1
Agent: [Br-]
Solvent: ClCCl
Product: CSc1nccc(-n2cnc3ccc(C(C)=O)cc32)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 2-methylthio-4-[6-(N-methyl-N-methoxyaminocarbonyl)benzimidazol-1-yl]pyrimidine (26 mg, 0.079 mmol) in CH2Cl2 (0.8 mL) at 0° C. was added CH3MgBr (255 μL, 1.4M) dropwise and stirred for 3 h at 0° C. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with CH2Cl2. The combined extracts were washed with brine and dried over Na2SO4. The crude material was purified by preparative thin layer chromatography eluting with 3% MeOH/CH2Cl2 to obtain 15.7 mg of the title compound. Partial 1H NMR (500 MHz, CDCl3): δ 8.94 (s, 1H); 8.79 (s, 1H); 8.67 (d, J=5.0 Hz, 1H); 8.04 (d, J=7.5 Hz, 1H); 7.9 (d, J=7.5 Hz, 1H); 7.28 (d, J=5.0 Hz, 1H); 2.74 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:26])([CH3:25])[C:19]=3[CH:27]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:28]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:25])([CH3:26])[C:19]=3[CH:27]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dichloro-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[I:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[I:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:26]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccccc1I
Yield: 66.5 %

Procedure:
0.75 g (0.00394 mol) of 1-benzyl-4-hydroxy-piperidine and 0.546 ml (0.00394 mol) of triethylamine were dissolved in 50 ml of toluene and treated with 1.0 g (0.00375 mol) of 2-iodo-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (4:5). 1.05 g (66%) of 1-benzyl-piperidin-4-yl 2-iodo-benzoate were obtained as yellow crystals; m.p. 73°-74°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[N:6][CH:7]=1.Br[C:16]1[CH:24]=[C:23]2[C:19]([C:20]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][C:21]=3[N:22]2[CH3:25])=[CH:18][CH:17]=1>>[CH3:25][N:22]1[C:23]2[C:19](=[CH:18][CH:17]=[C:16]([N:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=4)=[CH:9][C:10]3=[O:14])[CH:24]=2)[C:20]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][C:21]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Reactant: Cc1ccc(-c2cc[nH]c(=O)c2)nc1
Product: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CN(C(=O)OC(C)(C)C)CC5)c(=O)c2)nc1
Yield: 36.4 %

Procedure:
4-(5-methylpyridin-2-yl)pyridin-2(1H)-one (150 mg, 0.81 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (294 mg, 0.805 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (138 mg, 36%) as a yellow/green solid: 1H NMR (500 MHz, CDCl3) δ 8.56 (s, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.63-7.61 (m, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.37 (s, 1H), 7.17 (d, J=1.6 Hz, 1H), 7.09 (dd, J=8.3, 1.7 Hz, 1H), 7.04 (dd, J=7.2, 1.9 Hz, 1H), 4.65 (br m, 2H), 3.76 (br m, 2H), 3.65 (s, 3H), 2.82 (br m, 2H), 2.42 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][C@H:4]([N:8]1[CH2:12][C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[CH:10][C:9]1=[O:24])[C:5](O)=[O:6].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:47][C:48]1([CH3:60])[O:52][C@H:51]([CH2:53][N:54]2[CH:58]=[CH:57][C:56]([NH2:59])=[N:55]2)[CH2:50][O:49]1>ClCCl>[CH3:47][C:48]1([CH3:60])[O:52][C@H:51]([CH2:53][N:54]2[CH:58]=[CH:57][C:56]([NH:59][C:5](=[O:6])[C@@H:4]([N:8]3[CH2:12][C:11]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[CH:10][C:9]3=[O:24])[CH2:3][CH:2]([CH3:25])[CH3:1])=[N:55]2)[CH2:50][O:49]1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(C(F)(F)F)c2)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc(C(F)(F)F)c2)=CC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.6 %

Procedure:
A solution of (S)-4-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid (0.71 g, 1.99 mmol) in dichloromethane (35 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.38 mL, 2.17 mmol) and 1-hydroxybenzotriazole (0.28 g, 2.07 mmol). The reaction was stirred at 25° C. for 20 min. At this time, the reaction was treated with 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.49 g, 2.48 mmol). The reaction mixture was stirred at 25° C. for 1.5 d. At this time, the reaction was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous ammonium chloride solution (2×50 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 50-100% ethyl acetate/hexanes) afforded (S)-4-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.54 g, 51%) as a light, orange solid: HR-ES-MS m/z calculated for C26H31N4O5F3 [M+H]+ 537.2320, observed 537.2319; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.4 Hz, 3H), 0.95 (d, J=6.4 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.47 (br. s., 1H), 1.54-1.64 (m, 1H), 1.70-1.82 (m, 1H), 3.74 (dd, J=8.4, 5.9 Hz, 1H), 3.94-4.05 (m, 1H), 4.05-4.17 (m, 2H), 4.21 (d, J=18.4 Hz, 1H), 4.35 (quin, J=5.8 Hz, 1H), 4.60 (d, J=18.4 Hz, 1H), 4.84-4.92 (m, 1H), 4.91 (s, 1H), 6.44 (d, J=2.1 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H), 7.65-7.78 (m, 4H), 10.79 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:18]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[C:3]=12.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:18]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:39]([NH:38][C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=4)=[O:40])=[CH:13][CH:12]=3)[C:3]=12
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2nc(-c3ccc(N)cc3)c3c(N)ncnc32)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2nc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of (R)-tert-butyl 3-(4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (0.100 g, 0.25 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this, 3-(trifluoromethyl)phenyl isocyanate (0.035 mL, 0.25 mmol) diluted in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to warm to room temperature and left stirring for 6 hours. The reaction proceeded until completion as judged by TLC and LC-MS, was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to afford AD79. ESI-MS m/z [M+H]+ found 583.5, calculated 583.2.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Br>CC(N(C)C)=O.CCOC(C)=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([S:16]([N:19]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[C:27]([F:37])([F:36])[F:26])(=[O:18])=[O:17])=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(S(=O)(=O)NCC(C)C)cc2)CC1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2ccc(S(=O)(=O)N(Cc3ccccc3C(F)(F)F)CC(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
A solution of 4-(4-acetyl-piperazin-1-yl)-N-isobutyl-benzenesulfonamide (100 mg, 0.295 mmol) in DMA (2 mL) was treated with NaH (60% dispersion in mineral oil, 18 mg, 0.443 mmol) and stirred at room temperature for 30 minutes. 2-(Trifluoromethyl)benzyl bromide (141 mg, 0.590 mmol) was added and the mixture heated at 90° C. for 1 hour. The cooled mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-100% EtOAc in DCM) gave the title compound (110 mg, 75%). 1H NMR (400 MHz, DMSO) δ 7.81 (d, J=7.9 Hz, 1H), 7.69-7.71 (m, 4H), 7.50 (t, J=7.6 Hz, 1H), 7.08 (d, J=8.8 Hz, 2H), 4.36 (s, 2H), 3.59 (d, J=5.26 Hz, 4H), 3.38 (dd, J=26.2, 5.0 Hz, 4H), 2.86 (d, J=7.2 Hz, 2H), 2.05 (s, 3H), 1.36 (t, J=6.7 Hz, 1H), 0.70 (d, J=6.6 Hz, 6H). LCMS (m/z Method B) ES+ 498.1 [M+1]+.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][N:6]1[C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][C:9](=[O:17])[C:8]2[CH:18]=[C:19]([OH:24])[C:20](=[O:23])C=C[C:7]1=2)C.[OH-].[K+].Cl>>[C:12]([C:11]1[N:6]([CH2:5][C:4]([OH:3])=[O:25])[C:7]2[C:20](=[O:23])[C:19]([OH:24])=[CH:18][C:8]=2[C:9](=[O:17])[CH:10]=1)([OH:14])=[O:13]
Reactant: CCOC(=O)Cn1c(C(=O)OCC)cc(=O)c2cc(O)c(=O)ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)Cn1c(C(=O)O)cc(=O)c2c1C(=O)C(O)=C2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 4,7-dihydro-4,7-dioxo-2-ethoxycarbonyl-6-hydroxy-1H-cyclohepta[b]pyridine-1-acetic acid ethyl ester (1.7 g, described in Example 15) and 1N potassium hydroxide (12 ml) is stirred at room temperature for 2.5 hr. Hydrochloric acid (19%) is added until the mixture is acidic. The precipitate is collected and washed with water, acetone and ether to obtain the title compound, mp > 270° C.