Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[N:13]([CH:32]=[CH:33][N:34]=3)[N:14]=[C:15]([NH:17][C@H:18]3[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]3)[CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.CCOC1C=CC(N)=CC=1.C(Cl)(Cl)Cl.[Cl-].[NH4+]>[Zn].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[C:12]3[N:13]([CH:32]=[CH:33][N:34]=3)[N:14]=[C:15]([NH:17][C@H:18]3[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:22][CH2:23]3)[CH:16]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2cc(Nc3ccc([N+](=O)[O-])cc3)c3nccn3n2)CC1
Agent: CCOc1ccc(N)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2cc(Nc3ccc(N)cc3)c3nccn3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 50 ml round bottom flask was added tert-butyl(trans)-4-(8-(4-nitrophenylamino)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexylcarbamate (0.090 g, 0.19 mmol) from 1c, chloroform (2.0 ml), methanol (2.0 ml), ammonium chloride (0.12 g, 0.19 mmol) and zinc dust (0.13 g, 0.19 mmol). The reaction was allowed to stir for 30 min at room temperature. The reaction was then filtered through a plug of celite and rinsed with dichloromethane to afford 0.1 g of crude tert-butyl(trans)-4-(8-(4-aminophenylamino)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexylcarbamate.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C(OC([NH:35][C@@H:36]([CH2:40][CH2:41][O:42][Si](C(C)(C)C)(C)C)[C:37](O)=[O:38])=O)(C)(C)C.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl.CC(=O)OCC>[NH2:35][C@@H:36]([CH2:40][CH2:41][OH:42])[C:37]([NH:26][CH:23]1[CH2:24][CH2:25][N:20]([C:17]2[S:18][CH:19]=[C:15]([C:7]3[CH:6]=[CH:5][C:4]4[C:3]([CH3:27])([CH3:2])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=4[CH:8]=3)[N:16]=2)[CH2:21][CH2:22]1)=[O:38]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO[Si](C)(C)C(C)(C)C)C(=O)O
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NC(=O)[C@@H](N)CCO)CC4)n3)ccc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
50 mg (0.12 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrochloride and 44 mg (0.13 mmol) of (S)-2-tert-butoxycarbonylamino-4-(tert-butyldimethylsilanyloxy)butyric acid (preparation analogous to Tetrahedron, 2005, vol. 61, #43 p. 10277-10284) were dissolved in 1 ml of DCM together with 50 μl (0.29 mmol) of N-ethyldiisopropylamine and stirred at 0° C. for 5 min. 73 mg (0.14 mmol) of benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate and 50 μl (0.29 mmol) of ethyldiisopropylamine were then added. The mixture was stirred further at 0° C. for 1 h, diluted with EA and washed by shaking with water and a saturated sodium hydrogencarbonate solution and a saturated sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and evaporated. A 1.25 M HCl solution in methanol was then added to the residue, and the mixture was stirred for 1 h. The methanolic solution was evaporated, and the product was purified by means of preparative HPLC. The product is in the form of the hydrochloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.C(N(CC)CC)C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][S:37]([C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[N:13]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The operation is carried out as in Stage 1 of Example 10 starting from 280 mg of the product obtained in Stage 1 of Example 7, 3 ml of methylene chloride, 0.17 ml of triethylamine and 0.128 ml of 4-fluorobenzenesulphonic acid chloride in place of the 4-methyl-benzenesulphonic acid chloride then the reaction medium is agitated at ambient temperature for approximately 30 min. Then 2 ml of water is added, followed by extracting with 3×5 ml of methylene chloride, washing with 5 ml of saturated sodium chloride, drying, evaporating, impasting in 5 ml of ether then in 5 ml of pentane, separating and drying. In this way 360 mg of expected product is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28](O)=[O:29])[CH:21]=4)[O:16]3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[NH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][C:13]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28]([NH:31][O:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][O:34]5)=[O:29])[CH:21]=4)[O:16]3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: NOC1CCCCO1
Reactant: Cc1ccc(CCN2CCC3(CC2)CC(=O)c2cc(/C=C/C(=O)O)ccc2O3)cc1
Solvent: ClCCl
Product: Cc1ccc(CCN2CCC3(CC2)CC(=O)c2cc(/C=C/C(=O)NOC4CCCCO4)ccc2O3)cc1

Procedure:
(E)-3-{1′-[2-(4-Methyl-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (257 mg, 0.581 mmol) was suspended in DCM (5 ml). TEA (0.12 ml, 0.87 mmol) was added and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-[2-(4-methyl-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (265 mg) as a yellow solid. The resulting product was dissolved in DCM (5 ml) and treated with 4 M HCl in dioxane (0.5 ml, 2 mmol) as described in Example 55, Step D, giving the desired hydroxamic acid as a light yellow solid (204 mg, hydrochloride salt).
Reaction SMILES: [C:1]([CH:4]([C:9](=O)[CH3:10])[CH2:5][C:6]([OH:8])=[O:7])(=O)[CH3:2].[CH:12]1[C:17]([NH:18][NH2:19])=[CH:16][CH:15]=[C:14]([Cl:20])[CH:13]=1.OS(O)(=O)=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:2][C:1]1[C:4]([CH2:5][C:6]([OH:8])=[O:7])=[C:9]([CH3:10])[N:18]([C:17]2[CH:16]=[CH:15][C:14]([Cl:20])=[CH:13][CH:12]=2)[N:19]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CC(=O)C(CC(=O)O)C(C)=O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nn(-c2ccc(Cl)cc2)c(C)c1CC(=O)O
Temperature: 60 °C
Yield: 102 %

Procedure:
4.0 grams 3,3-diacetyl-propionic acid, 4.9 grams p-chlorophenylhydrazine-sulfate, 2.1 grams anhydrous sodium acetate and 30 milliliters glacial acetic acid were mixed and the mixture was heated to 60° C. for 3 hours. The reaction mixture was evaporated and water was added to the residue. The precipitate formed thereby was separated by filtration and recrystallized from a mixture of ethanol and of water. 5.5 grams 3,5-dimethyl-1-(p-chlorophenyl)-pyrazol-4-acetic acid, melting at 176°-177° C., were obtained, representing a yield of 82%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:31])=[CH:4][N:3]=1.[CH3:32][O:33][C:34]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][C:35]=1B(O)O>>[F:31][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([S:12]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])[CH:7]=2)[C:2]([C:35]2[CH:36]=[CH:37][C:38]([C:40]([F:43])([F:42])[F:41])=[CH:39][C:34]=2[O:33][CH3:32])=[N:3][CH:4]=1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)cc1
Product: COc1cc(C(F)(F)F)ccc1-c1ncc(F)c2cc(S(=O)(=O)Nc3ccncn3)ccc12

Procedure:
Example 216 was synthesized in a similar manner to Example 212, except that 1-chloro-4-fluoro-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (Intermediate QQQ) and (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid were used as the coupling partners. The final compound was purified via column chromatography (12 g silica gel column, gradient elution 25 to 100% EtOAc:Heptane) to afford 4-fluoro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.74 (s, 1H), 8.59 (d, J=17.3 Hz, 2H), 8.35-8.13 (m, 1H), 8.06 (d, J=8.9 Hz, 1H), 7.77 (d, J=9.1 Hz, 1H), 7.62-7.56 (m, 1H), 7.54-7.46 (m, 2H), 3.75 (s, 3H). m/z (ESI) 479.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][CH:32]([O:35][CH2:36][CH:37]=[CH2:38])[CH2:31][CH2:30]1.ClC1C=CC=C(C(OO)=[O:47])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[O:47]1[CH2:38][CH:37]1[CH2:36][O:35][C@H:32]1[CH2:31][CH2:30][C@H:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:34][CH2:33]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOC1CCC(n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc23)CC1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3CO3)CC2)c2ncnn12
Temperature: 50 °C
Reaction time: 15 h

Procedure:
A mixture of 4′-({5-oxo-4-[4-(prop-2-en-1-yloxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (1.1 g), m-chloroperbenzoic acid (1.8 g) and acetonitrile (10 mL) was stirred at 50° C. for 15 hr. Saturated aqueous sodium hydrogen carbonate solution and aqueous sodium thiosulfate solution were added to the reaction mixture, and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.25 g, 20%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)(=[O:20])=[O:19])=[CH:14][CH:15]=2)[C:10]([CH3:28])=[N:9]1)=O)(C)(C)C.I[Si](C)(C)C>C(Cl)(Cl)Cl>[F:27][C:23]1[CH:22]=[C:21]([S:18]([NH:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][N:9]=[C:10]3[CH3:28])(=[O:19])=[O:20])[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: Cc1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Yield: 59 %

Procedure:
3-Fluoro-N-(3-methyl-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 6 from 1.35 g of N-(N-tert-butoxycarbonyl-3-methyl-1H-indazol-5-yl)-3-fluorobenzenesulfonamide, 13.5 ml of chloroform and 0.47 ml of iodotrimethylsilane. 0.6 g of 3-fluoro-N-(3-methyl-1H-indazol-5-yl)-benzenesulfonamide is thus obtained in the form of a white foam melting at 120° C. (analysis: C14H12FN3O2S.0.39CH2Cl2 % calculated, C, 55.07; H, 3.96; F, 6.22; N, 13.76; O, 10.48; S, 10.50. % found C, 54.99. H, 2.70; N, 13.81; S, 10.18).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[C:24]([O:31][CH3:32])=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:19]([F:33])=[CH:18][N:17]=1>>[CH3:13][O:12][C:10]([CH:8]1[CH2:7][C:6]2[CH:14]=[C:2]([NH:1][C:16]3[N:21]=[C:20]([NH:22][C:23]4[C:24]([O:31][CH3:32])=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)[C:19]([F:33])=[CH:18][N:17]=3)[CH:3]=[CH:4][C:5]=2[O:9]1)=[O:11]
Reactant: COc1ccc(Nc2nc(Cl)ncc2F)c(OC)n1
Reactant: COC(=O)C1Cc2cc(N)ccc2O1
Product: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(OC)nc4OC)n3)ccc2O1

Procedure:
In like manner to the preparation of (±)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine, the reaction of (±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran with 2-chloro-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-4-pyrimidineamine gave (±)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.03 (bs, 2H), 8.18 (d, 1H, J=4.8 Hz), 7.68 (bd, 1H, J=8.1 Hz), 7.27 (bs, 1H), 6.98 (bd, 1H, J=8.1 Hz), 6.69 (d, 1H, J=8.7 Hz), 6.44 (d, 1H, J=8.1 Hz), 5.33 (dd, 1H, J=5.7 Hz), 3.88 (s, 3H), 3.86 (s, 3H), 3.69 (s, 3H), 3.42 (dd, 1H, J=10.8 and 11.1 Hz), 3.10 (dd, 1H, J=6.3 and 6.6 Hz); LCMS: purity: 99%; MS (m/e): 442 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[N+:17]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl-].[NH4+]>CO.C(OCC)(=O)C.[Zn]>[NH2:17][C:11]1[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=1[C:9]([NH:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)Nc2cccnc2Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(N)c(C(=O)Nc2cccnc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
A solution of N-(2-chloropyridin-3-yl)-5-methyl-2-nitrobenzamide (5.07 g, 17.38 mmol), ammonium chloride (5.30 g, 99.1 mmol) in methanol (170 mL) was treated with zinc dust (8.1 g, 123.9 mmol) and stirred for 1 hour at room temperature. The mixture was diluted with ethyl acetate (300 mL) then filtered and concentrated under reduced pressure. The crude product was dissolved in refluxing methanol (350 mL) then cooled to room temperature and treated with water (300 mL) to give a white precipitate which was filtered, washed with water (50 mL) and dried under high vacuum at 60° C. to give 2-amino-N-(2-chloropyridin-3-yl)-5-methylbenzamide (3.3 g). M.p.=187-190° C.; 400 MHz 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.25 (dd, J=2.0, 4.8 Hz, 1H), 8.02 (dd, J=2.0, 8.0 Hz, 1H), 7.52 (s, 1H), 7.45 (dd, J=4.8, 8.0 Hz, 1H), 7.04 (dd, J=2.0, 8.8 Hz, 2H), 6.67 (d, J=8.4 Hz, 1H), 6.21 (s, 2H), 2.19 (s, 3H); LCMS [M+H]: 262.
Reaction SMILES: [OH-].[Li+].C([O:7][C:8](=[O:36])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[CH2:19][O:20][C:21](=[O:35])[N:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=1)(C)(C)C>CO.O1CCCC1>[C:29]1([N:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:21]([O:20][CH2:19]/[CH:18]=[CH:17]/[C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[O:10][CH2:9][C:8]([OH:36])=[O:7])=[O:35])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)COc1cccc(/C=C/COC(=O)N(c2ccccc2)c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)COc1cccc(/C=C/COC(=O)N(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
1.0M Lithium hydroxide (1.46 mL, 1.46 mmol) was added to a solution of trans-[3-(3-diphenylcarbamoyloxypropenyl)phenoxy}acetic acid tert-butyl ester (0.56 g, 1.22 mmol) in methanol (2 mL), tetrahydrofuran (2 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated, water was added followed by 2N hydrochloric acid to pH 1-2, and the product was extracted with ethyl acetate. The extract was washed with water, brine, dried over magnesium sulfate, and concentrated to dryness. Recrystallization in diethyl ether gave trans-[3-(3-diphenylcarbamoyloxypropenyl)phenoxy}acetic acid as a white crystalline solid (0.38 g, 78%), m.p. 112.4-113.7° C.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14]CC)=[O:13])[C:6](=[S:17])[C:5]=3[CH:18]=[CH:19][CH:20]=2>CO.[OH-].[Na+]>[Br:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6](=[S:17])[C:5]=3[CH:18]=[CH:19][CH:20]=2
Reactant: CCOC(=O)CN1C(=S)c2cccc3c(Br)ccc1c23
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN1C(=S)c2cccc3c(Br)ccc1c23
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.6 %

Procedure:
A suspension of 6-bromo-2-thioxo-benz[cd]indole-1(2H)-acetic acid, ethyl ester (2.5 g, 7.1 mmol, described in Example 5) in methanol (70 mL) and 2 N aqueous sodium hydroxide (5.3 mL) was stirred at room temperature for 2 days and evaporated. The residue was dissolved in water (300 mL, with slight warming), and the solution was acidified. The precipitate was collected by filtration, dried, and crystallized from ethanol-water to give the title compound (2.05 g): mp 253° C. (245° C. darkening); Anal. Calcd for C13H8BrNO2S: C, 48.46% H, 2.50% N, 4.35% and Found: C, 48.32% H, 2.62% N, 4.38%; IR (mineral oil) 3100, and 1715 cm-1 ; UV max (methanol) 436 (ε12,830), 361 (4680), 342 (3130), 311 (8140), 302 (sh, 7950), and 273 nm (24,160); NMR (DMSO-d6)δ 5.08 (s, 2H), 7.30 (d, 1H), 7.90 (d, 1H), and 8.00 (m, 3 H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[NH:7]1[C:8]2[C:4](=[CH:3][CH:2]=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13]
Reactant: C1CCNCC1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Product: O=C(c1cc2ccccc2[nH]1)N1CCCCC1
Yield: 100 %

Procedure:
Treat 5-fluoro-1H-indole-2-carboxylic acid 3 (X═F, 1.7 g, 9.5 mmol) with piperidine as described in General Synthetic Procedure VIa to afford 5-fluoro-1H-indol-2yl-piperidin-1-yl-methanone 8 (X═F, R4=piperidin-1-yl; 2.3 g, 100%) as a white solid. 1H NMR (DMSO-d6) δ 11.7 (brs, 1H), 7.5-7.3 (m, 2H), 7.1-7.0 (m, 1H), 6.7 (s, 1H), 3.7 (m, 4H), 1.7-1.5 (m, 6H). Treat 5-fluoro-1H-indol-2yl-piperidin-1-yl-methanone (125 mg, 0.51 mmol) with 2-aminophenyldisulfide (347 mg, 1.4 equiv.) as described in General Synthetic Procedure VIIa to afford the title compound Iac (92 mg, 25%) as an ivory-colored solid, m/z=369 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[CH3:52][O:53][C:54]([C:56]1[CH:57]=[C:58](B(O)O)[CH:59]=[CH:60][CH:61]=1)=[O:55]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:52][O:53][C:54](=[O:55])[C:56]1[CH:57]=[CH:58][CH:59]=[C:60]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)[CH:61]=1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1cccnc1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2cccnc2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
4-Chloro-2-morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (317 mg, 1.00 mmol), palladium acetate (11 mg, 5 mol %), S-Phos (41 mg, 10 mol %) and 3-methoxycarbonylphenylboronic acid (637 mg) were dissolved in dimethylformamide (10 ml). Then, argon substitution was carried out three times under ultrasonic irradiation in reduced pressure. The reaction mixture was stirred at 100° C. for 2 hours, and the reaction mixture was allowed to cool to room temperature, and then poured onto water (100 ml). The reaction mixture was extracted twice with ethyl acetate/tetrahydrofuran (4/1, 100 ml), and the combined organic layers were washed with brine, followed by drying over sodium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=100/0 to 50/1), to obtain a colorless solid (374 mg, 90%).
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:8])=[CH:3][CH:2]=1.[H][H]>C(OCC)(=O)C.[Ni]>[C:1]1([CH3:22])[CH:2]=[CH:3][C:4]([C:7]([C:9]2[CH:10]=[C:11]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:19]=[CH:20][CH:21]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C=Cc1cccc(C(=O)c2ccc(C)cc2)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cccc(C(=O)c2ccc(C)cc2)c1
Reaction time: 2 h

Procedure:
Ethyl 3-(4-toluoyl)cinnamate (Example 4) (3.0 g), in solution in ethyl acetate (90 mL) was shaken with hydrogen in the presence of Raney nickel catalyst until slightly more than 1 molar equivalent of hydrogen had been absorbed. After removal of the catalyst by filtration, the residue was dissolved in dichloro-methane (200 mL), barium manganate (14 g) was added and the mixture was stirred at 50° for 2 hours. The filtered solution was evaporated to leave pure ethyl 3-(3-(4-toluoyl)phenyl)propionate as a yellow oil. (A portion hydrolysed with dilute aqueous alcoholic sodium hydroxide gave the corresponding carboxylic acid, m.p. 137°-138.5°).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12](Br)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:30])[F:31])=[CH:26][CH:25]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2c1ccn2Cc1ccccc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)Oc1ccc(-c2cccc3c2ccn3Cc2ccccc2)cc1
Yield: 24.4 %

Procedure:
1-benzyl-4-[4-(trifluoromethoxy)phenyl]-1H-indole was prepared by coupling 1-benzyl-4-bromo-1H-indole (0.787 g, 2.75 mmol), and 4-trifluoromethoxyphenylboronic acid (0.683 g, 3.32 mmol), using [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.0679 g, 0.0831 mmol), and potassium carbonate (0.575 g, 4.16 mmol) in dioxane (21 mL) and water (2.1 mL) following the procedure described in Step 1 of Example 11. Purification by HPLC using hexane as the mobile phase yielded the title compound as a light yellow gum (0.246 g, 24%). 1HNMR (300 MHz, DMSO-d6): δ 6 7.75 (d, 2H, J=8.3 Hz), 7.65 (d, 1H, J=2.3 Hz), 7.45-7.55 (m, 3H), 7.1-7.4 (m, 7H), 6.6 (d, 1H, J=2.3 Hz), and 5.45 ppm (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12](I)[CH:11]=1)=[O:9].[CH2:18]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH3:27])[CH2:19][C:20]#[CH:21]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][C:20]([CH2:19][CH2:18][N:22]3[CH2:26][CH2:25][CH2:24][C@H:23]3[CH3:27])=[CH:21][C:12]=2[CH:11]=1)=[O:9]
Reactant: C#CCCN1CCC[C@H]1C
Reactant: O=C(c1ccc(O)c(I)c1)c1ccccc1F
Product: C[C@@H]1CCCN1CCc1cc2cc(C(=O)c3ccccc3F)ccc2o1

Procedure:
The product from Example 70A and a 0.1M solution of the product from Example 68B were processed as described in Example 68C to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.28 (d, 3H, J=6.1 Hz), 1.59 (m, 1H), 1.93 (m, 2H), 2.10-2.78 (m, 2H), 2.93 (m, 2H), 3.18 (m, 2H), 3.45 (m, 2H), 6.76 (s, 1H), 7.21-7.38 (m, 2H), 7-50-7.67 (m, 3H), 7.79 (d, 1H, J=8.9 Hz), 7.99 (s, 1H); MS (ESI) m/z 352.1 (M+H)+.