Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1)[CH3:34]>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:45]1[CH2:44][CH2:43][N:42]([C:39]2[CH:38]=[CH:37][C:36]([O:35][CH2:33][CH3:34])=[CH:41][CH:40]=2)[CH2:47][CH2:46]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: CCOc1ccc(N2CCN(C(=O)[C@@H]3C[C@H](NCc4ccc(F)cc4F)CN3Cc3ccccc3)CC2)cc1
Yield: 2.4 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(4-ethoxy-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (1.7 mg, 2.4%) as light yellow oil. MS m/e=535.5 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[CH:14][CH:13]=3)=[N:8][C:7]=2[CH:22]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>COCCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:14][CH:13]=3)=[N:8][C:7]=2[CH:22]=1
Reactant: C1CCNC1
Reactant: COc1ccc2sc(Nc3ccc(OCCCl)cc3)nc2c1
Solvent: COCCO
Product: COc1ccc2sc(Nc3ccc(OCCN4CCCC4)cc3)nc2c1

Procedure:
A mixture of 5-methoxy-2-[4-(2-chloroethoxy)anilino]benzothiazole (200 g.), pyrrolidine (144 ml.) and 2-methoxyethanol (1 liter) is boiled under reflux for 16 hours. The mixture is evaporated from the steam bath at reduced pressure and the residue dissolved in approximately 2N hydrochloric acid. The solution is washed with ethyl acetate, basified with 40% sodium hydroxide solution and extracted with chloroform. The chloroform is washed with water, dried over magnesium sulphate and passed through a column of alumina. The column is washed with chloroform and the combined chloroform solutions evaporated. The residue is recrystallised from 2-methoxyethanol to give 5-methoxy-2-[4-(2-pyrrolidin-1-ylethoxy)anilino]benzothiazole, m.p. 167° - 168°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.Cl.[F:16][C:17]([F:26])([F:25])[CH:18]1[NH:23][C:22]([NH2:24])=[N:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:24]=[C:22]3[NH:23][CH:18]([C:17]([F:26])([F:16])[F:25])[CH2:19][CH2:20][N:21]3[C:9](=[O:11])[CH:8]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: NC1=NCCC(C(F)(F)F)N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1cc(-c2ccncc2)nc2n1CCC(C(F)(F)F)N2
Yield: 55.9 %

Procedure:
A mixture of 5.62 g (29.09 mmol) of ethyl 3-(pyridin-4-yl)-3-oxopropionate, 7 g (29.09 mmol) of 6-(trifluoromethyl)-1,4,5,6-tetrahydro-2-pyrimidinamine hydrochloride (1:2) and 10.05 g (72.72 mmol) of potassium carbonate in 50 ml of ethanol was heated at reflux temperature for 12 h. The cooled solution was evaporated to remove solvent, the residue was treated with water and the precipitate was filtered to give 4.82 g of product as a yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[F:42][C:43]([F:55])([F:54])[C:44]1[CH:45]=[C:46]([S:50](Cl)(=[O:52])=[O:51])[CH:47]=[CH:48][CH:49]=1>C(#N)C>[F:55][C:43]([F:42])([F:54])[C:44]1[CH:45]=[C:46]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:52])[CH:47]=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cccc(C(F)(F)F)c3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 58 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0298 g, 0.0646 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.388 mmol) and 3-trifluoromethylbenzenesulfonyl chloride (0.0310 mL, 0.194 mmol) to obtain 4-(3-trifluoromethylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0251 g, yield 58%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:18]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[Br:18][C:12]1[NH:11][CH:10]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: CCOC(=O)c1c[nH]cc1-c1cccc(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]c(Br)c1-c1cccc(F)c1
Yield: 33.4 %

Procedure:
To a solution of 38.3 g (164 mmol) of ethyl 4-(3-fluorophenyl)-1H-pyrrole-3-carboxylate in 380 ml of tetrahydrofuran are added, over 30 minutes, 32.1 g (181 mmol) of N-bromosuccinimide (CAS 128-08-5), and the mixture is then stirred for 3 hours at reflux. After cooling, 200 ml of aqueous 5% sodium thiosulfate solution are added and the reaction product is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure, to give 17.1 g of ethyl 5-bromo-4-(3-fluorophenyl)-1H-pyrrole-3-carboxylate in the form of a white powder after recrystallizing from diisopropyl ether, filtering off and drying.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:12]=3[O:11]2)[CH:6]=[CH:7][CH:8]=1.[C:21](Cl)(=[O:23])[CH3:22].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21](=[O:23])[CH3:22])=[CH:19][C:12]=3[O:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)Cl
Reactant: COc1cccc(C=C2Oc3cc(O)ccc3C2=O)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cccc(C=C2Oc3cc(OC(C)=O)ccc3C2=O)c1
Temperature: 25 °C

Procedure:
After 2-[(3-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, acetyl chloride 0.172 ml was added, and the mixture was refluxed for 2.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml twice. After the ethyl acetate solution was dehydrated with anhydrous magnesium sulfate, it was concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 371.6 mg.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]12([C:15](Cl)=[O:16])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2.[F:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.CCCCCCC.C1(C)C=CC=CC=1>ClCCCl>[C:5]12([C:15]([C:24]3[CH:23]=[CH:22][C:21]([OH:25])=[CH:20][C:19]=3[F:18])=[O:16])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2
Reactant: Oc1cccc(F)c1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClCCCl
Solvent: CCCCCCC
Product: O=C(c1ccc(O)cc1F)C12CC3CC(CC(C3)C1)C2
Yield: 53.8 %

Procedure:
To a mixture of AlCl3 (45 g, 0.337 mol) in 1,2-dichloroethane (DCE, 250 ml) at 0° C. was added 1-adamantyl carbonyl chloride (36.6 g, 0.228 mol) in DCE (150 ml). 3-fluorophenol (21 g, 0.183 mol) in DCE (100 ml) was added slowly at 0° C. The reaction was followed by TLC (heptane/toluene 50/50). The mixture was poured onto HCl 2N, extracted with AcOEt, washed with NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under vacuum. Purification by flash chromatography (heptane/toluene 8/2) gave 27 g of 1-adamantyl (2-fluoro-4-hydroxyphenyl)methanone (48% as solid).
Reaction SMILES: I[Si](C)(C)C.[C:6]([NH:14][C:15]1[S:16][CH2:17][CH:18]2[CH2:23][N:22](C(OCC3C=CC=CC=3)=O)[CH2:21][C:19]2([C:34]2[CH:39]=[C:38]([Br:40])[CH:37]=[CH:36][C:35]=2[F:41])[N:20]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(#N)C>[NH3:14].[Br:40][C:38]1[CH:37]=[CH:36][C:35]([F:41])=[C:34]([C:19]23[CH2:21][NH:22][CH2:23][CH:18]2[CH2:17][S:16][C:15]([NH:14][C:6](=[O:13])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:20]3)[CH:39]=1
Reactant: O=C(NC1=NC2(c3cc(Br)ccc3F)CN(C(=O)OCc3ccccc3)CC2CS1)c1ccccc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: N
Product: O=C(NC1=NC2(c3cc(Br)ccc3F)CNCC2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 187.6 %

Procedure:
Iodotrimethylsilane (2.21 mL, 15.46 mmol) is added drop wise to a room temperature solution of benzyl 2-benzamido-7a-(5-bromo-2-fluoro-phenyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (2.93 g, 5.15 mmol) in acetonitrile (44 mL). The reaction is stirred at room temperature for two hours and the solvent is removed in vacuo. The crude product is purified with an SCX column using 3:1 dichloromethane:methanol and then 2:1 dichloromethane:7 N ammonia in methanol to give the title compound (2.098 g, 94%). ES/MS (m/e): (79Br/81Br) 434/436 (M+H).
Reaction SMILES: Cl.Cl.NC1(C(O)=O)C[CH2:8][NH:7][CH2:6]C1.ClC([O:16][CH3:17])=O.C[CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22]>C1COCC1>[CH3:19][N:20]1[CH2:23][CH2:24][C:6]([CH2:17][OH:16])([NH:7][CH3:8])[CH2:22][CH2:21]1
Reactant: COC(=O)Cl
Reactant: NC1(C(=O)O)CCNCC1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: C1CCOC1
Product: CNC1(CO)CCN(C)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(1-Methyl-4-methylamino-piperidin-4-yl)-methanol is prepared from 4-amino-piperidine-4-carboxylic acid 2HCl. Methyl chloroformate (0.40 g, 4.2 mmol) is added dropwise to a mixture of 4-amino-piperidine-4-carboxylic acid 2HCl (0.278 g, 1.28 mmol) and Et3N (0.713 g, 7.04 mmol) in THF (10 ml) at room temperature. After 16 h, the reaction mixture is filtered, rinsed with EtOAc and concentrated. A solution of LAH in THF (5 ml of a 1 M solution) is added to the residue. After stirring at reflux for 4 h, the reaction mixture is cooled to 0° C. and carefully quenched with Na2SO4.10H2O. After warming to room temperature the reaction mixture is diluted with EtOAc and filtered through Celite. The filtrate is concentrated to give (1-methyl-4-methylamino-piperidin-4-yl)-methanol which is carried forward without purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:8])=[CH:9][CH:10]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(Br)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(Br)nc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79 %

Procedure:
The mixture of 6-bromonicotinic acid (700 mg, 3.5 mmol), morpholine (391 mg, 4.5 mmol), HATU (220 mg, 0.59 mmol) and DIPEA (0.3 mL) in 10 mL of dry THF was stirred at room temperature for 14 hours. The reaction solution was evaporated to dryness. To the residue was added 20 mL of 0.5N hydrochloride, and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was dried over sodium sulfate and concentrated to give (6-bromopyridin-3-yl)(morpholino)methanone (750 mg, 79%). LC-MS: 271, 273 [M+H]+, tR=1.290 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].O1CCCC1.C(N(CC)CC)C.C1C=[CH:25][C:26](=[O:39])[C:27]2C=1C(C(Cl)=O)=C1C=2C=CC=C1>ClCCl>[CH:26]([O:39][CH:8]([CH3:7])[CH3:9])([CH3:27])[CH3:25].[NH2:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[NH-:1]
Reactant: O=C(Cl)C1=c2ccccc2=C2C(=O)C=CC=C12
Reactant: N#Cc1ccc(N)c(N)c1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)OC(C)C
Product: N#Cc1ccc(N)c([NH-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 319.1 %

Procedure:
The procedure used in stage 1 of Example 1 is followed, but starting from 2.4 g of 3,4-diaminobenzonitrile and 30 ml of tetrahydrofuran, 4.6 ml of triethylamine and 4 g of fluoren-4-one-9-carboxylic acid chloride in 115 ml of dichloromethane. After stirring for 20 hours at room temperature, the precipitate that formed is filtered off, and washed with dichloromethane, with water, and then with a 10% saturated aqueous solution of sodium hydrogen carbonate and, finally, with water. After formation of a paste with diisopropyl ether, in this way we obtain 3.8 g of (2-amino-5-cyanophenyl)amide of 9-oxo-9H-fluorene-4-carboxylic acid, in the form of a beige powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [F:1][CH:2]([F:15])[C@@H:3]1[C@@H:12]([OH:13])[C@H:11]([OH:14])[C@H:6]2[NH:7][C:8](=[S:10])[O:9][C@H:5]2[CH2:4]1.[CH3:16]I.[OH-].[Na+]>CCO>[F:15][CH:2]([F:1])[C@@H:3]1[C@@H:12]([OH:13])[C@H:11]([OH:14])[C@H:6]2[N:7]=[C:8]([S:10][CH3:16])[O:9][C@H:5]2[CH2:4]1
Reactant: O[C@H]1[C@H](O)[C@@H](C(F)F)C[C@@H]2OC(=S)N[C@H]12
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](C(F)F)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a solution of (3aR,4R,5R,6S,7aS)-6-(difluoromethyl)-4,5-dihydroxyhexahydrobenzo[d]oxazole-2(3H)-thione (233 mg, 0.97 mmol) in EtOH (5 mL) was added MeI (277 mg, 1.95 mmol) and 5 N NaOH (0.21 mL, 1.1 mmol). The mixture was stirred at room temperature for 2 h. The solvents were evaporated to give the crude product. This was purified by SiO2 column, eluted with 3%-5% MeOH in DCM to give (3aR,4R,5R,6S,7aS)-6-(difluoromethyl)-2-(methylthio)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazole-4,5-diol (218 mg, 88%) as a pale yellow solid. MS m/z 254.1 (M+1, 100%); 1H NMR (400 MHz, MeOD) δ 6.16 (td, J=56.8 Hz, 1.8 Hz, 1H), 4.79-4.83 (m, 1H), 3.85 (t, J=7.6 Hz, 1H), 3.39 (t, J=9.0 Hz, 1H), 3.28 (t, J=7.9 Hz, 1H), 2.48 (s, 3H), 2.27 (dt, J=14.7 Hz, 3.6 Hz, 1H), 1.91-2.10 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][N:13]=1)[C:9]#N.[CH:14]1([Mg]Br)[CH2:16][CH2:15]1.Cl.[OH-:20].[Na+]>C1COCC1>[CH:14]1([C:9]([C:8]2[CH:11]=[CH:12][N:13]=[C:6]([CH2:5][O:4][CH2:3][O:2][CH3:1])[CH:7]=2)=[O:20])[CH2:16][CH2:15]1
Reactant: [OH-]
Reactant: COCOCc1cc(C#N)ccn1
Reactant: Br[Mg]C1CC1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOCc1cc(C(=O)C2CC2)ccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, to a solution of 2-((methoxymethoxy)methyl)isonicotinonitrile (1.87 g) in THF (20 mL) was added 0.70 M cyclopropylmagnesium bromide (30 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added 1N hydrochloric acid (50 mL) at 0° C., and the mixture was stirred at room temperature for 15 min. The reaction mixture was neutralized with aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with water and 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 (ethyl acetate/hexane) to give the title compound (1.20 g) as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[CH3:17])=[O:10].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[CH3:17])=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cnccc1C(=O)c1cc(Cl)ccc1N
Product: Cc1cnccc1C(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 123 mg of (2-Amino-5-chloro-phenyl)-(3-methyl-pyridin-4-yl)-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.32 (s, 9H), 2.19 (s, 3H), 7.04 (d, 1H, J=1.4 Hz), 7.21 (d, 1H, J=5.2 Hz), 7.48 (d, 2H, J=8.8 Hz), 7.52 (dd, 1H, J=8.8 Hz, 2.4 Hz), 7.77-7.83 (m, 3H), 8.64 (d, 1H, J=5.2 Hz), 8.71 (s, 1H), 10.75 (s, 1H). MS: m/z 443.0 (M++1).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][CH3:14])=[N:8][CH:9]=2)[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:21]1(Cl)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>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.O.CN(C=O)C>[CH:21]1([N:4]2[C:5]3=[N:6][C:7]([NH:11][CH2:12][CH2:13][CH3:14])=[N:8][CH:9]=[C:10]3[C:2]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:3]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: OB(O)c1ccccc1
Reactant: CCCNc1ncc2c(Br)n[nH]c2n1
Reactant: ClC1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNc1ncc2c(-c3ccccc3)nn(C3CCCCC3)c2n1
Temperature: 200 °C
Reaction time: 0.05 h
Yield: 67.1 %

Procedure:
A 10 mL microwave tube was charged with 3-bromo-N-propyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine (0.052 g, 0.2 mmol), K2CO3 (0.14 g, 1.0 mmol), DMF (2 mL), and cyclohexyl chloride (0.072 g, 0.6 mmol). The resulting mixture was heated at 200° C. for 30 minutes under microwave irradiation. After the reaction was cooled to room temperature, phenylboronic acid (0.37 g, 0.3 mmol), Pd(PPh3)4 (0.023 g, 0.02 mmol), and H2O (1 mL) were added sequentially. The mixture was stirred at room temperature for 3 min and then heated at 150° C. for 15 min. After cooled to room temperature, the mixture was partitioned in H2O and Et2O. The aqueous phase was extracted with ether (3×). The combined organic phase were dried (Na2SO4) and concentrated. The residue was purified by Isco to provide the 1-cyclohexyl-3-phenyl-N-propyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine (UNC702A) (0.045 g, 67%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 7.90 (d, J=8.0 Hz, 2H), 7.48 (t, J=6.0 Hz, 2H), 7.38 (t, J=6.0 Hz, 1H), 5.42 (s, 1H), 4.60 (tt, J=11.6, 4.1 Hz, 1H), 3.48 (dt, J=13.1, 6.8 Hz, 2H), 2.18-2.08 (m, 2H), 2.04-2.00 (m, 2H), 1.95-1.92 (m, 2H), 1.77-1.74 (m, 1H), 1.74-1.65 (m, 2H), 1.58-1.42 (m, 2H), 1.40-1.28 (m, 1H), 1.03 (t, J=7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.73, 155.38, 153.50, 143.71, 133.27, 129.06, 128.60, 127.09, 106.91, 56.10, 43.68, 32.16, 25.91, 25.61, 22.98, 11.77; MS m/z 336.2 [M+1].
Reaction SMILES: COC1C=CC(C)=CC=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.Cl.[F:30][C:31]([F:46])([F:45])[C:32]1[N:33]=[CH:34][C:35]([NH:38][C@H:39]2[CH2:43][CH2:42][CH2:41][C@@H:40]2[NH2:44])=[N:36][CH:37]=1.[F:47][C:48]1[C:56]([F:57])=[CH:55][CH:54]=[C:53]([N:58]2[N:62]=[CH:61][CH:60]=[N:59]2)[C:49]=1[C:50](O)=[O:51]>>[F:47][C:48]1[C:56]([F:57])=[CH:55][CH:54]=[C:53]([N:58]2[N:62]=[CH:61][CH:60]=[N:59]2)[C:49]=1[C:50]([NH:44][C@H:40]1[CH2:41][CH2:42][CH2:43][C@@H:39]1[NH:38][C:35]1[CH:34]=[N:33][C:32]([C:31]([F:30])([F:45])[F:46])=[CH:37][N:36]=1)=[O:51]
Reactant: O=C(O)c1c(-n2nccn2)ccc(F)c1F
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1c(-n2nccn2)ccc(F)c1F

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 126 mg, 0.45 mmol) and 2,3-difluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 39a; 120 mg, 0.535 mmol) except this was purified by column chromatography (silica, 40-100% ethyl acetate/petrol) and then further purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: N1C2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=C1.[H-].[Na+].[CH3:15]I.[CH3:17][N:18]([CH3:21])[CH:19]=O>>[CH3:17][N:18]1[C:21]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:15])=[O:11])[CH:8]=2)[CH:3]=[CH:19]1
Reactant: CI
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ccc2ccn(C)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1H-Indole-6-carboxylic acid 37 (0.20 g, 1.24 mmol) was dissolved in dimethylformamide (10 mL) and cooled to 0° C. for the portion-wise addition of sodium hydride (0.20 g, 4.96 mmol). After complete addition, the reaction mixture was allowed to warm to rt and stirred for 1 hr then methyl iodide (0.15 mL, 2.48 mmol) was added to the reaction mixture. Quenching with water followed by rotary evaporation led to the crude residue, which was taken up with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and evaporated to provide crude 166 (it was used crude in the next step). MS: 189.08 (calc), 190.1 (obs).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:25][C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:35]([F:38])([F:37])[F:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][O:40][C:41](=[O:44])[CH2:42][NH2:43].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.C(#N)C.O>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:30]([NH:43][CH2:42][C:41]([O:40][CH3:39])=[O:44])=[O:31])=[CH:33][CH:34]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:35]([F:38])([F:36])[F:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)CNC(=O)c1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To 4-{[3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamino]-methyl}-benzoic acid (130 mg, 0.254 nmol), glycine methyl ester (35 mg, 0.279 mmol) morpholine (102 mg, 1.014 mmol), EDCI (58 mg, 0.304 mmol), and HOBT (41 mg, 0.304 mmol) in CH2Cl2 (15 ml) were combined at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 15 hrs. Quenching with brine (15 ml), separation, drying MgSO4 of the organics and concentration in vacuo. RP-HPLC (gradient water:acetonitrile) afforded the ester as an off white powder (88 mg, 61% Yield). MS (ESI) m/z 582.