Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14].C(OCC)C>C1(C)C=CC=CC=1>[CH3:12][N:13]([CH3:15])/[CH:14]=[CH:2]/[C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccncc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CN(C)/C=C/C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To 4-acetylpyridine (23 mL) in 350 mL toluene was added 55 mL N,N-dimethylformamide dimethyl acetal. The solution was refluxed for 3 hours and allowed to stir at ambient temperature overnight. An additional 33 mL N,N-dimethylformamide dimethyl acetal of was added. After refluxing for 7 hours, the mixture was concentrated to leave an orange solid. This material was treated with diethyl ether. The resulting yellow solid was collected by vacuum filtration. A total of 25.85 g (71% yield) yellow solid was obtained. 1H NMR (CDCl3) was consistent with the desired structure. LC/MS indicated a single peak with a M+1 molecular ion of m/z 177.1 by positive ESI (electrospray ionization mass spectrometry).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[BH4-].[Na+].O.[OH-].[Na+]>C(O)C.ClCCl>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: O=C1CCN(CC2CC2)CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: OC1CCN(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.5 %

Procedure:
To a cold (0° C.) solution of 1-cyclopropylmethyl-piperidin-4-one (314 mg, 2 mmol, 1.0 eq.) in ethanol (4 mL) was added sodium borohydride (61 mg, 2 mmol, 0.75 eq.). The reaction mixture was stirred 16 h at room temperature. Water, sodium hydroxide and dichloromethane were added and the reaction mixture was stirred 2 h at room temperature. The aqueous layer was extracted with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered then concentrated to dryness in vacuo to yield 160 mg (50%) of the tide compound as colorless oil, witch was used in the next step without further purification. MS (m/e): 156.3 (MH+, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[N:3]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH:29]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31].O1CCCC1>C(OCC)C>[O:34]([CH:29]([O:9][C:4]1[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[N:3]=1)[C:30]([O:32][CH3:33])=[O:31])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cc(C)nc(O)n1
Reactant: COC(=O)C(Br)Oc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccccc1)Oc1nc(C)cc(C)n1
Reaction time: 48 h

Procedure:
Alternately, the tetrabutylammonium salt of 4,6-dimethyl-2-pyrimidinol was first prepared by placing 4,6-dimethyl-2-hydroxypyrimidine (13.0 g, 0.105 mol) in a flask, adding 65 g of 40 percent aqueous tetrabutylammonium hydroxide (0.10 mol), and removing the water by evaporation under reduced pressure at pressures down to about 10 mm Hg (1.33 kPa) at 40°-45° C. The residue amounted to 42.7 g and appeared to be a dihydrate of the desired salt. A 10.9 g portion of this (25 mmol) was placed in a 500 mL flask containing 25 mL of tetrahydrofuran. A cloudy solution formed. To this was added with stirring at ambient temperature 14 mL of a solution of methyl 2-bromo-2-phenoxyacetate in tetrahydrofuran (containing about 25 mmol). The resulting mixture was allowed to stir for 2 days. Analysis by gas-liquid chromatography indicated only one significant compound was present. A 250 mL portion of diethyl ether was added and the resulting mixture was extracted 5 times with 100 mL portions of water and then with brine. The ethereal solution was dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain the title compound in crude form as a dark borwn oil. This was filtration chromatographed on silica gel eluting first with a 10:90 mixture of diethyl ether and hexane and then with a 15:85 mixture of ethyl acetate and hexane. The product containing eluate was concentrated by evaporation under reduced pressure to obtain 2.50 g (35 percent of theory) of the title compound as a pale yellow oil. This oil solidified on standing to a light orange solid melting at 50°-53° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[CH3:1]
Reactant: CO
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc([N+](=O)[O-])c1C

Procedure:
20 g (110.4 mmol) of 2-methyl-3-nitrobenzoic acid is refluxed in 100 ml of methanol for 10 hours after 2 ml of concentrated sulfuric acid is added. The product that crystallizes out during cooling is suctioned off and dried. The filtrate is evaporated to the dry state, the solid residue is taken up in ethyl acetate, and the solution is washed twice with saturated sodium bicarbonate solution. After drying on Na2SO4, another product is obtained. Together, 16.4 (76.3%) of the desired compound is obtained.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8](=[O:28])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:11][CH:10]=1.Cl[CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(#N)C>[F:38][C:2]([F:37])([F:1])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8](=[O:28])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:23][CH2:24][N:25]([CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45])[CH2:26][CH2:27]2)=[N:11][CH:10]=1
Reactant: OCCOCCCl
Reactant: Cc1ccccc1-c1cc(N2CCNCC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccccc1-c1cc(N2CCN(CCOCCO)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 85 °C
Reaction time: 48 h
Yield: 64.4 %

Procedure:
A mixture of 400 mg (0.746 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-piperazin-1-yl-4-o-tolyl-nicotinamide (Example 53), 0.18 ml (1.7 mmol) 2-(2-chloroethoxy)-ethanol and 0.189 g (1.35 mmol) potassium carbonate in 8 ml acetonitrile was stirred at 85° C. for 48 h. After cooling to room temperature 40 ml 1 N sodium hydroxide solution were added. Extraction with 3 60-ml portions of dichloromethane, drying with sodium sulfate and concentration gave 528 mg of the crude product. Flash column chromatography afforded 300 mg (64.4%) of the title compound as a light-brown solid.
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[C:43]([CH3:44])=[CH:42][C:37]([C:38]([O:40]C)=[O:39])=[CH:36][C:35]=5[CH3:45])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:46]4[CH2:49][CH:48]([F:50])[CH2:47]4)[N:21]=3)[C@H:14]2[CH3:51])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Li+]>O1CCOCC1>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[C:43]([CH3:44])=[CH:42][C:37]([C:38]([OH:40])=[O:39])=[CH:36][C:35]=5[CH3:45])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:46]4[CH2:49][CH:48]([F:50])[CH2:47]4)[N:21]=3)[C@H:14]2[CH3:51])[CH:4]=[C:3]([C:2]([F:53])([F:52])[F:1])[CH:8]=1
Reactant: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(N4CC(F)C4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ncc(-c2c(C)cc(C(=O)O)cc2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(3-fluoroazetidin-1-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoate (Step A, 55.6 mg, 0.074 mmol) was dissolved in 1,4-dioxane (1500 μl). Added 0.5N lithium hydroxide (750 μl, 0.375 mmol) and stirred at room temperature for 3 hours at which time LCMS shows complete hydrolysis. The reaction was quenched by adding 0.375 mL of 1N HCl, followed by water. The reaction was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, filtered and evaporated. Purified on Biotage SNAP 13 g C18 column, eluting with 25-100% CH3CN/water (0.05% TFA) and recovering purified fractions by partitioning them between pH 7 phosphate buffer and ethyl acetate. Extracted the aqueous a second time with ethyl acetate, then washed the combined organics with pH 7.0 buffer and brine. The organic was dried over sodium sulfate, filtered and evaporated to give the titled compound. LCMS (M+H)+: 734.5. 1H NMR (CDCl3, 500 MHz): δ8.17 (s, 1H), 8.04 (d, 1H), 7.89 (s, 1H), 7.86 (d, 2H), 7.75 (s, 2H), 7.30 (d, 1H), 5.71 (d, 1H), 5.51 (m, 0.5H), 5.40 (m, 0.5H), 4.71 (d, 1H), 4.45 (m, 3H), 4.30 (m, 2H), 4.00 (d, s, 4H), 2.16 (d, 6H), 0.75 (d, 3H). RTA IC50: 7 nM
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].CS(C)=O>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: O=Cc1ccc(F)cc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CS(C)=O
Product: O=Cc1ccc(N2CCC(O)CC2)cc1
Temperature: 95 °C

Procedure:
A 2 liter three necked flask fitted with a mechanical stirrer, thermometer and condenser is charged with 180 g of 4-hydroxypiperidine, 74.4 g of 4-fluorobenzaldehyde, 1 ml of Aliquat 336, 750 ml of dimethylsulfoxide and 82.8 g of anhydrous potassium carbonate. The mixture is heated at 95° C. for three days, then the product mixture is cooled and poured into 3 liters of ice water. The resultant solid precipitate is filtered, washed with water, and vacuum dried. The crude product is recrystallized from toluene, m.p. 115°-118° C.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)(OCC)=O)C.CC(C)([O-])C.[K+].C1COCC1.[CH:30]([C:32]1[S:33][CH:34]=[CH:35][N:36]=1)=O>O>[S:33]1[CH:34]=[CH:35][N:36]=[C:32]1/[CH:30]=[CH:9]/[C:10]1[CH:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][CH:15]=1
Reactant: CCOP(=O)(Cc1ccc(C(=O)O)cc1)OCC
Reactant: O=Cc1nccs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(/C=C/c2nccs2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 1.9 %

Procedure:
A mixture of 4-(diethoxyphosphorylmethyl)benzenecarboxylic acid (440 mg) produced according to JP-A 11-60537, potassium tert-butoxide (340 mg) and THF (5.5 mL) was stirred at room temperature for about 1.5 hours, and then a THF solution (1.0 mL) of 2-formylthiazole (200 mg) was dropwise added thereto. After heated overnight under reflux, water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate/methanol=9/1), and the resulting purified product was further purified through reversed-phase HPLC to obtain the entitled compound (7 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:55]=[CH:54][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[C:11]3[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]4[CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43][CH2:42]4)[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:11]3[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]4)[C:10]=3[N:9]=2)=[CH:54][CH:55]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCCCC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(OCc2nc3c(OCCCCCC4CCNCC4)cccc3n2CCCCCC2CCNCC2)cc1

Procedure:
The title compound is prepared from 2-(4-chlorophenoxymethyl)-4-[5-[1-(t-butoxycarbonyl)piperidin-4-yl]pentoxy]-1-[5-[1-(t-butoxycarbonyl)piperidin-4-yl]pentyl]benzimidazole by standard deprotection techniques using trifluoroacetic acid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[N:40]=[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][N:42]4[CH:47]=3)=[CH:35][CH:34]=2)O1.NC1N=CN=C2N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=C(C3C=CC(NC4OC5C=CC=CC=5N=4)=C(F)C=3)C=12>>[N:40]1[C:39]([C:36]2[CH:37]=[CH:38][C:33]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[N:8][C:9]=4[NH2:11])[N:4]([C@H:12]4[CH2:17][CH2:16][C@@H:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH2:14][CH2:13]4)[N:3]=3)=[CH:34][CH:35]=2)=[CH:47][N:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=12
Reactant: CC1(C)OB(c2ccc(-c3cn4ccccc4n3)cc2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(-c5cn6ccccc6n5)cc4)c4c(N)ncnc43)CC2)CC1

Procedure:
Cis-3-(4-imidazo[1,2-a]pyridin-2-ylphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine was prepared from cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.453 mmol) and 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazo[1,2-a]pyridine (0.250 g, 0.679 mmol) in a manner similar to that used for the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as a white powder (0.021 g, 9%). 1H NMR (DMSO-d6, 400 MHz) 1.57-1.73 (m, 4H), 2.08-2.50 (m, 12H), 2.16 (s, 3H), 3.37 (m, 1H), 4.82 (m, 1H), 6.92 (t, 1H), 7.27 (t, 1H), 7.61 (d, 1H), 7.74 (d, 2H), 8.15 (d, 2H), 8.24 (s, 1H), 8.56 (d, 1H); RP-HPLC Rt 8.16 min, 97% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 508 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:12]([OH:14])=O.[CH3:15][N:16]([CH3:34])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[CH3:15][N:16]([CH3:34])[C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:24]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:27][CH:26]=2)[C:12]([CH:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[O:8][CH2:7][CH2:6]2)=[O:14])=[CH:21][CH:22]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: O=C(O)C1CCOc2ccc(F)cc21
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCOc3ccc(F)cc32)cc1
Yield: 64.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 6-fluorochroman-4-carboxylic acid (1.96 g) and [(4-dimethylaminophenyl)methyl] (4-isopropylphenyl) amine (2.68 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-6-fluoro-N-(4-isopropylphenyl)chroman-4-carboxamide (2.89 g) was obtained. melting point: 95-98° C.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.N1C2C(=CC=C(C(OC)=O)C=2)C=C1.C([O-])([O-])=O.[Na+].[Na+].[F:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[C:43]([OH:50])[CH:42]=1>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[NH:3][C:2]=2[C:44]2[CH:45]=[CH:46][C:41]([F:40])=[CH:42][C:43]=2[OH:50])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OB(O)c1ccc(F)cc1O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC(=O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: COCCOC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(F)cc3O)[nH]c2c1
Temperature: 100 °C
Yield: 61 %

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in WO2004087714 from commercially available methyl indole-6-carboxylate) in a mixture of DME and EtOH (5:2, v/v, 0.2 M) were added 2.6 eq. of Na2CO3 (2 M aqueous solution), 1.3 eq. of 4-fluoro-2-hydroxy-phenylboronic acid and 0.1 eq. of tetrakis(triphenylphosphine)palladium(0). The mixture was degassed thoroughly with a stream of argon and then heated to 100° C. overnight. The reaction mixture was allowed to cool to RT, diluted with EtOAc and washed with 1N hydrochloric acid and with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (1:5 EtOAc/PE) to afford the title compound as a beige solid (61%); MS (ES+) m/z 368 (M+H)+.
Reaction SMILES: [Na+].[OH:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1)S([O-])(=O)=O.[OH-].[Na+]>O>[CH:22]([N:19]1[CH2:20][CH2:21][N:16]([C:14]([C:11]2[CH:10]=[CH:9][C:8]([CH:3]=[O:2])=[CH:13][CH:12]=2)=[O:15])[CH2:17][CH2:18]1)([CH3:24])[CH3:23]
Reactant: CC(C)N1CCN(C(=O)c2ccc(C(O)S(=O)(=O)[O-])cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxy-[4-(4-isopropyl-piperazine-1-carbonyl)-phenyl]-methanesulfonic acid sodium salt (49.0 g, 135 mmol) in de-ionized H2O (490 mL) at 0° C. was added 1 N NaOH (100 mL) in 10 mL portions with vigorous stirring. A clear solution resulted (pH 12), which was stirred at 0° C. for 1 h, then at room temperature for 30 min. The aqueous solution was extracted with EtOAc (3×200 mL), followed by CH2Cl2 (3×200 mL). The organic layers were combined, washed with brine (1×300 mL), dried (Na2SO4) and concentrated to yield the title compound as a pale yellow oil.
Reaction SMILES: Cl.[F:2][C:3]([F:31])([F:30])[C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:28]C)[CH:24]=4)[CH:19]=3)[CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1.[BrH:32]>C(O)(=O)C>[BrH:32].[F:30][C:3]([F:2])([F:31])[C:4]1[CH:5]=[C:6]([C:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([OH:28])[CH:24]=4)[CH:19]=3)[CH2:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc2cc(CCN3CC=C(c4cccc(C(F)(F)F)c4)CC3)ccc2c1
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: Oc1ccc2cc(CCN3CC=C(c4cccc(C(F)(F)F)c4)CC3)ccc2c1

Procedure:
A mixture of 1-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-2-(6-methoxy-naphth-2-yl)ethane hydrochloride (0.6 g, 0.0013 mol) (obtained as described in Example 3) and 33% HBr in acetic acid (20 ml) is refluxed for 4 hours.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccccn1
Reactant: O=C(O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid (prepared as in Example 22A, 263 mg, 1.0 mmol) in methylene chloride (10 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.6 mL, 1.2 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 15 min and at 25° C. for 30 min. The reaction mixture was then treated with a solution of 2-aminopyridine (200.6 mg, 2.14 mmol) in tetrahydrofuran (5 mL) and N,N-diisopropylethylamine (0.42 mL, 2.4 mmol). This solution was stirred at 25° C. for 48 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-nitro-phenyl)-N-pyridin-2-yl-propionamide (138.6 mg, 40.9%) as a pale yellow glass: EI-HRMS m/e calcd for C19H21N3O3(M+) 339.1581, found 339.1582.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([NH:15][C:16]2[S:17][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:19][N:20]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.[I-].[K+]>CN(C)C=O>[CH:21]([C:18]1[S:17][C:16]([NH:15][C:13](=[O:14])[CH2:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:7]=2)=[N:20][CH:19]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1cnc(NC(=O)Cc2cccc(OCCCCl)c2)s1
Reactant: C1COCCN1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1cnc(NC(=O)Cc2cccc(OCCCN3CCOCC3)c2)s1
Temperature: 100 °C
Yield: 87 %

Procedure:
A mixture of 2-[3-(3-chloropropoxy)phenyl]-N-(5-isopropyl-1,3-thiazol-2-yl)acetamide (1.00 g, 2.8 mmoles), morpholine (1.24 ml, 14.2 mmoles), potassium iodide (0.24 g, 1.4 mmoles) in anhydrous dimethylformamide (3.5 ml) was heated at 100° C. for 6 hours. The solution was acidified and extracted with ether to eliminate unreacted products; then the solution was basified and extracted with ether. The solvent was evaporated to dryness to give the product as an oily semisolid which was purified by flash chromatography with dichloromethane:methanol (97:3) as eluent (1.0 g, 87% yield)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[S:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].[CH3:21][S:22]([C:25]1[CH:56]=[CH:55][C:28]([C:29]([NH:31][C:32]2[CH:33]=[CH:34][C:35](/[CH:42]=[CH:43]/[C:44]3[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][C:45]=3[S:51]([OH:54])(=[O:53])=[O:52])=[C:36]([S:38]([O-:41])(=[O:40])=[O:39])[CH:37]=2)=[O:30])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[CH:3]([O:39][S:38]([C:36]1[CH:37]=[C:32]([NH:31][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:23])=[O:24])=[CH:56][CH:55]=2)[CH:33]=[CH:34][C:35]=1/[CH:42]=[CH:43]/[C:44]1[CH:49]=[CH:48][C:47]([NH:50][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([S:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)(=[O:14])=[O:13])[CH:5]=2)=[CH:46][C:45]=1[S:51]([O:54][CH:6]([CH3:7])[CH3:5])(=[O:52])=[O:53])(=[O:41])=[O:40])([CH3:11])[CH3:4]
Reactant: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(/C=C/c3ccc(N)cc3S(=O)(=O)O)c(S(=O)(=O)[O-])c2)cc1
Reactant: COc1ccc(C(=O)O)cc1S(=O)(=O)N1CCOCC1
Product: COc1ccc(C(=O)Nc2ccc(/C=C/c3ccc(NC(=O)c4ccc(S(C)(=O)=O)cc4)cc3S(=O)(=O)OC(C)C)c(S(=O)(=O)OC(C)C)c2)cc1S(=O)(=O)N1CCOCC1

Procedure:
From 4-methoxy-3-(morpholine-4-sulfonyl)-benzoic acid, Example 1a and 5-[[4-(methylsulfonyl)benzoyl]amino]-2-[(E)-2-[4-amino-2-sulfophenyl]ethenyl]benzenesulfonate, bis(1-methylethyl) ester, Example 28b (52%): MS (−ESI): [M−H]− 918.