Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH:8]([N:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](OCC)=[O:4].[CH3:23][NH2:24]>>[OH:1][CH:2]([CH:8]([N:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([NH:24][CH3:23])=[O:4]
Reactant: CN
Reactant: CCOC(=O)C(O)C(c1ccccc1)N(C)c1ccccc1
Product: CNC(=O)C(O)C(c1ccccc1)N(C)c1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
A mixture of ethyl (2RS,3RS)-2-hydroxy-3-[methyl(phenyl)amino]-3-phenylpropanoate (Example 1, Step 1, 375 mg, 1.25 mmol) and ethanolic methylamine solution (33 weight % in absolute ethanol, 5 mL) was stirred at 80° C. in a sealed tube for 5 hours. After cooling, all volatiles were removed under reduced pressure. The resulting solid was recrystallized (warm chloroform/hexane/−25° C.) to yield 350 mg (99%) (2RS,3RS)-2-hydroxy-N-methyl-3-[methyl(phenyl)amino]-3-phenylpropanamide as white needles. MS (ESI) m/z 285 ([M+H]+); HRMS: calculated for C17H20N2O2+H, 285.1598; found (ESI, [M+H]+), 285.1592.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:9]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:10][N:11]([CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:12]=2)[CH:7]=1
Reactant: ClCCN1CCOCC1
Reactant: COc1ccc(Cl)cc1-c1[nH]ncc1NC(=O)c1cnn2cccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(CCN2CCOCC2)cc1NC(=O)c1cnn2cccnc12
Temperature: 50 °C
Reaction time: 5 h
Yield: 38 %

Procedure:
To a solution of N-(5-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (39.1 mg, 0.106 mmol) in 3 mL DMF was added cesium carbonate (109.7 mg, 0.3367 mmol) and 4-(2-chloroethyl)morpholine HCl. The reaction mixture was stirred at 50° C. for 5 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The mixture of regioisomer products was separated and purified by reverse phase HPLC and lyophilized to give 19.4 mg (38%) N-(3-(5-chloro-2-methoxyphenyl)-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; LCMS (ESI) m+H=482.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.50 (s, 1H), 9.31 (dd, 1H), 8.66 (d, 1H), 8.63 (s, 1H), 8.03 (s, 1H), 7.58 (dd, 1H), 7.54 (d, 1H), 7.32 (d, 1H), 7.27 (dd, 1H), 4.05 (m, 2H), 3.85 (s, 3H), 3.44 (m, 2H), 2.71 (m, 2H), 2.60 (m, 2H), 2.23 (m, 4H); and 9.3 mg (18%) of N-(5-(5-chloro-2-methoxyphenyl)-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; LCMS (ESI) m+H=482.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.67 (s, 1H), 9.31 (dd, 1H), 8.76 (d, 1H), 8.65 (s, 1H), 8.34 (s, 1H), 7.48 (dd, 1H), 7.39 (d, 1H), 7.30 (d, 1H), 7.38 (t, 1H), 4.29 (t, 2H), 3.84 (s, 3H), 3.58 (t, 2H), 2.77 (t, 2H), 2.46 (m, 4H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31]>C(#N)C>[O:14]1[C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[O:5][CH2:4][CH2:3][CH2:2][NH:31][CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[C:27]([F:26])([F:36])[F:37])=[N:13]1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1ccccc1CNCCCOc1cccc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 2-(trifluoromethyl)benzylamine, and acetonitrile essentially as described above in example 56. Purity by LC/MS (APCI)=98%, [M+H]+=433.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([C:10](=[O:12])[CH3:11])[CH2:6][C:7]#[C:8][CH3:9])=[CH2:4].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].N1C2C(=CC=CC=2)C=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]([C:10](=[O:12])[CH3:11])[CH2:6]/[CH:7]=[CH:8]\[CH3:9])=[CH2:4]
Reactant: C=C(OC)C(CC#CC)C(C)=O
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: C=C(OC)C(C/C=C\C)C(C)=O

Procedure:
A mixture of 9.96 g. (60 mmol.) of 2-methoxy-3-acetyl-1-hepten-5-yne, 0.50 g. of Lindlar catalyst, and 10 drops of synthetic quinoline in 100 ml. of ethyl acetate was stirred under one atmosphere of hydrogen until hydrogen absorption was complete, then filtered, concentrated and distilled to afford (Z)-2-methoxy-3-acetyl-1,5-heptadiene; b.p. 64°-66°, (2.0 mmHg).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1.[CH:21]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][C:32]=2[C:38]([F:41])([F:40])[F:39])[CH2:26][CH2:25]1)([CH3:23])[CH3:22]>C(Cl)Cl.CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([CH2:30][N:27]4[CH2:26][CH2:25][N:24]([CH:21]([CH3:23])[CH3:22])[CH2:29][CH2:28]4)=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:33]=3)=[O:19])=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1
Reactant: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)O
Reactant: CC(C)N1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)Nc1ccc(CN2CCN(C(C)C)CC2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 7 but using (4-imidazo[4,5-b]pyridin-3-yl-2-methyl-phenyl)-acetic acid (Step 60.1) and 4-(4-isopropyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (disclosed in WO 03/099771). Title compound: ES-MS: 551.3 [M+H]+; tR=3.23 min (System 1); Rf=0.28 (CH2Cl2/MeOH, 9:1+0.1% NH3aq).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=2)[N:11]=1.[OH-].[Na+].Cl>O1CCCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=2)[N:11]=1
Reactant: COC(=O)c1ccc2nc(-c3nc4ccccc4o3)c(N(C)C(C)C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a solution of methyl 2-(benzo[d]oxazol-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (100 mg, 0.27 mmol) in tetrahydrofuran (20 mL) and water (2 mL) was added sodium hydroxide (21 mg, 0.53 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (20 mL), adjusted the pH to 6 with hydrochloric acid (3N) and filtered to give 2-(benzo[d]oxazol-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (21.9 mg, 23%).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>S([O-])([O-])(=O)=O.[Cu+2].ClCCCl>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[N:17]/[S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16]
Reactant: O=Cc1cccc(F)c1F
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1cccc(F)c1F
Temperature: 55 °C
Yield: 92.6 %

Procedure:
To a oven dried round bottom flask with stir bar was added 2,3-difluorobenzaldehyde (0.5 g, 3.52 mmol), (R)-2-methylpropane-2-sulfinamide (0.469 g, 3.87 mmol) and DCE (7.04 mL). To this mixture was then added Copper (II) Sulfate (0.842 g, 5.28 mmol). Reaction mixture heated in a preheated oil bath to 55° C. for 24 hr. The reaction mixture was filtered through a celite pad washing solids with DCE. Combined filtrate was concentrated to afford a viscous yellow oil of (R,E)-N-(2,3-difluorobenzylidene)-2-methylpropane-2-sulfinamide (0.8007 g, 3.26 mmol, 93% yield). MS m/z 246.1 (M+H)+; Rt-0.91 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[CH:9]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>O1CCCC1>[C:4]([NH:6][C:7](=[S:8])[O:15][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)N=C=S
Reactant: OC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)NC(=S)OC1CCCCC1
Yield: 70.9 %

Procedure:
65.6 g of ethoxycarbonyl isothiocyanate were added to a mixture of 50.1 g of cyclohexanol, 100 ml of tetrahydrofuran and 10 ml of triethylamine and the mixture was refluxed for 20 hours after which the tetrahydrofuran was distilled under reduced pressure. Ether was added to the residue and the ether phase was extracted with aqueous potassium hydroxide solutions. The aqueous phase was recovered by decanting and was acidified with N hydrochloric acid. The aqueous phase was extracted with ether and the ether phase was dried and concentrated to dryness under reduced pressure to obtain 82 g of cyclohexyl N-carbethoxy-thiocarbamate. The product was purified by chromatography over silica gel with elution with an 8-2 cyclohexane-ethyl acetate mixture.
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([NH2:26])[CH:20]=1)([O-:18])=[O:17]>CC(C)=O>[N+:16]([C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][NH:26][C:21]=2[CH:20]=1)([O-:18])=[O:17]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CCOC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CNc2cc([N+](=O)[O-])ccc2O1

Procedure:
29.2 g of ethyl 2,3-dibromopropionate was added dropwise to a refluxing mixture of 19 g of anhydrous potassium carbonate, 70.9 g of 4-nitro-2-aminophenol and 500 ml of dry acetone. This procedure was repeated thrice. The reaction mixture was refluxed for 17 hours, then filtered. The solvent was evaporated from the filtrate under reduced pressure. The residue was washed with dilute sodium hydroxide solution, extracted with ether, then with methylene chloride. The solvent was evaporated separately from each extract. Thin layer chromatographic analysis indicated that the produce from each of the extracts was the same. The products was combined and recrystallized from ether to give 4, as a solid, m.p.: 88°-90° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[N:3]=1.O.[NH2:11][NH2:12]>CCO>[NH:11]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[N:3]=1)[NH2:12]
Reactant: NN
Reactant: COc1nccc(Cl)n1
Solvent: CCO
Solvent: O
Product: COc1nccc(NN)n1
Temperature: 85 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a stirred solution of 4-chloro-2-methoxypyrimidine (5.7 g, 39.4 mmol) in EtOH (100 mL) under Ar was added hydrazine hydrate (3.83 mL, 79 mmol) and the reaction mixture was heated up and stirred at 85° C. for 1 hr. Volatiles were removed under reduced pressure and the resulting crude material was purified by silica gel column chromatography (CH2Cl2/MeOH/1-5%/NH3 1%) to afford the title product (4.40 g, 31.4 mmol, 80% yield) as white solid. ESI-MS: 141 [M+H]+ (LC-MS 2); Rf=0.47 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[CH:7]([C:8](=[O:33])[O:9][C:10]3[C@H:11]4[C@:24]([CH3:32])([CH2:25][CH2:26][C:27]=32)[C@@H:14]([C@H:15]([CH3:23])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:22])[CH2:20][OH:21])[CH2:13][CH2:12]4)[CH2:6]1.C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.ClCCl>[CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[CH:7]([C:8](=[O:33])[O:9][C:10]3[C@H:11]4[C@:24]([CH3:32])([CH2:25][CH2:26][C:27]=32)[C@@H:14]([C@H:15]([CH3:23])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:22])[CH:20]=[O:21])[CH2:13][CH2:12]4)[CH2:6]1
Reactant: COCOC1CC[C@]2(C)C3=C(OC(=O)C2C1)[C@@H]1CC[C@H]([C@H](C)CCCC(C)CO)[C@@]1(C)CC3
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COCOC1CC[C@]2(C)C3=C(OC(=O)C2C1)[C@@H]1CC[C@H]([C@H](C)CCCC(C)C=O)[C@@]1(C)CC3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.7 %

Procedure:
To a dichloromethane solution (2 mL) containing compound 62 (10.8 mg, 0.0234 mmol) obtained in Example 52, Molecular Sieves 4 Å (200 mg), 4-methylmorpholin-N-oxide (10 mg, 0.085 mmol) and tetrapropylammonium perruthenate (3.0 mg, 0.0085 mmol) were added, followed by stirring at room temperature for 15 minutes. The reaction mixture was filtered, and the filtrate was concentrated, followed by purification by silica gel column chromatography (20 to 50% ethyl acetate/n-hexane) to obtain the title compound (4.5 mg, 42%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][CH:24]([CH2:27][CH:28]([CH3:31])[CH2:29][OH:30])[CH2:25][OH:26])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:32])=[N:5]1)([CH3:3])[CH3:2].CCN(CC)CC.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][CH:24]([CH2:25][O:26][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:27][CH:28]([CH3:31])[CH2:29][O:30][S:41]([CH3:40])(=[O:43])=[O:42])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:32])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(CO)CC(C)CO)cc2OCC3)n(C(C)C)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(COS(C)(=O)=O)CC(C)COS(C)(=O)=O)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-4-methylpentane-1,5-diol (90 mg, 0.2038 mmol) and Et3N (85 uL, 0.6114 mmol) in DCM (10 mL) cooled at 0° C. was added methanesulfonyl chloride (40 uL, 0.51 mmol) and stirring at RT was continued for 1.5 h. The mixture was diluted with DCM, washed with a saturated solution of NaHCO3, followed by water, then dried (Na2SO4) and concentrated in vacuo affording Methanesulfonic acid 4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-5-methanesulfonyloxy-2-methylpentyl ester as a colorless gum (quantitative). LCMS: RT 3.07 min [M+H]+ 598.1
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([O:23]C)=[O:22])[CH2:12][CH2:11]2)=[CH:2]1.[H-].[Na+].[CH2:31](Br)[CH:32]=[CH2:33]>>[CH2:33]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([OH:23])=[O:22])[CH2:14][CH2:15]2)=[CH:2]1)[CH:32]=[CH2:31]
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Product: C=CCn1cc(C2CCN(CCOc3ccccc3C(=O)O)CC2)c2ccccc21

Procedure:
This compound was prepared following the procedure described in Example 138 (part B) starting with 2.8 g (7.4 mmol) of methyl 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoate, 0.38 g (9.6 mmol) of NaH in 60% of mineral oil and 0.77 mL (8.9 mmol) of allyl bromide. The crude mixture was hydrolised following the procedure described in Example 138 (part C) and purified by chromatography over silica gel affording 0.62 g (23% of yield) of the desired product.
Reaction SMILES: [C:1](Cl)(=O)C.[Br:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1>CO>[CH3:1][O:14][C:13](=[O:15])[CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([Br:5])[CH:7]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 967 %

Procedure:
Acetyl chloride (0.70 ml, 9.30 mmol) was slowly added to a solution of (3-bromo-phenyl)-acetic acid (20.0 g, 93 mmol) in methanol (500 ml) at 0° C. under nitrogen and the reaction was allowed to warm gradually to room temperature over a period of 5 hours. The solvent was removed in vacuo and the residual oil was dissolved in dichloromethane, dried (sodium sulfate) and concentrated in vacuo to give the title compound as a colourless oil (20.6 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=O)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([NH2:26])[C:22]([NH2:25])=[CH:23][CH:24]=1>O>[Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12]3[NH:26][C:21]4[CH:20]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:24]=[CH:23][C:22]=4[N:25]=3)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Solvent: O
Product: FC(F)(F)c1ccc2nc(-c3ccc(-c4ncccc4Cl)cc3)[nH]c2c1
Temperature: 150 °C
Reaction time: 20 h
Yield: 65.3 %

Procedure:
To a solution of 0.70 g (3.0 mmol) 4-(3-chloropyridin-2-yl)benzoic acid in 25 g polyphosphoric acid was added 0.44 g (2.5 mmol) 4-trifluoromethylbenzene-1,2-diamine, followed by stirring at 150° C. for 20 hours. Then, the solution was cooled to room temperature, dissolved in distilled water and adjusted to pH 9 to form precipitates. These precipitates were purified using column chromatography (developing solvent: chloroform/methanol=30/1) to afford 0.61 g of 2-[4-(3-chloropyridin-2-yl)phenyl]-6-trifluoromethyl-1H-benzoimidazole (yield 65%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=O)[C:9]2=[O:18])=[CH:4][CH:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[N:24][C:23]3[CH:25]=[CH:26][CH:27]=[C:21]([C:20]([F:19])([F:28])[F:29])[CH:22]=3)[C:9]2=[O:18])=[CH:4][CH:3]=1
Reactant: O=C1C(=O)N(Cc2ccc(Cl)s2)c2ccccc21
Reactant: Nc1cccc(C(F)(F)F)c1
Product: O=C1C(=Nc2cccc(C(F)(F)F)c2)c2ccccc2N1Cc1ccc(Cl)s1
Temperature: 140 °C
Yield: 55.6 %

Procedure:
A mixture of 1-[(5-chloro-2-thienyl)methyl]-2H-indole-2,3-dione (25 mg, 0.09 mmol) (prepared as described below) and 3-trifluoromethylaniline (11.3 μL, 0.09 mmol) was heated neat at 140° C. for 2 h. The crude material was purified by preparative TLC using a mixture of 3:7 ethyl acetate in hexane as the eluent, giving the desired product (23 mg 0.05 mmol, 61%). 1H NMR (400 MHz): δ (major isomer) 7.57 (t, J=7.7, 1H), 7.53 (t, J=7.8, 1H), 7.33 (t, J=7.8, 1H), 7.28 (s, 1H), 7.19 (d, J=7.6, 2H), 6.94-6.72 (m, 4H), 6.56 (d, J=7.7, 1H), 5.02 (s, 2H); ESI-MS m/z found 421 (MH+).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.CO[C:11](OC)([CH3:13])[CH3:12]>C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[CH3:12][C:11]1([CH3:13])[N:7]2[C:6](=[O:8])[CH2:5][CH2:4][C@@H:3]2[CH2:2][O:1]1
Reactant: O=C1CC[C@H](CO)N1
Reactant: COC(C)(C)OC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: CC1(C)OC[C@H]2CCC(=O)N21
Temperature: 88 °C
Reaction time: 0.08 h
Yield: 45.3 %

Procedure:
To a mixture consisting of (R)-5-hydroxymethyl-2-pyrrolidinone (50.0 g, 434 mmol) in 2,2-dimethoxypropane (533 mL, 4300 mmol) was added camphorsulfonic acid (2.85 g, 10.8 mmol). The stirring mixture was brought to reflux at 88° C. (for 1.5 hours, while removing methanol by distillation. The reaction mixture was subsequently heated to 95° C. for one hour, cooled to room temperature, treated with triethylamine (5 mL), and stirred for 5 minutes. The mixture was then diluted with hexanes-ethyl acetate (500 mL, 1:3 v/v) and washed sequentially with a 50% aqueous solution of sodium chloride and a saturated aqueous solution of sodium chloride. The organic phase was dried over sodium sulfate, filtered, and concentrated. The residue was purified by crystallization from hexanes to afford the title compound as white crystalline solid (30.48 g, 45%); TLC Rf 0.4 (solvent system: 5:95 v/v methanol:dichloromethane) MS (ESI+) m/z 156.1 (M+H)+, 178.1 (M+Na)+; 1H-NMR (CDCl3) δ 4.3-4.2 (m, 1H), 4.1 (dd, 1H), 3.5 (t, 1H), 2.9-2.7 (m, 1H), 2.6-2.5 (m, 1H), 2.2-2.1 (m, 1H), 1.9-1.7 (m, 1H), 1.7 (s, 3H), 1.5 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:11]=1[C:12](Cl)=[O:13]>O1CCOCC1>[NH2:8][C:4]1[N:3]=[C:2]([NH:1][C:12](=[O:13])[C:11]2[C:10]([F:9])=[CH:18][CH:17]=[CH:16][C:15]=2[F:19])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1cccc(N)n1
Solvent: C1COCCO1
Product: Nc1cccc(NC(=O)c2c(F)cccc2F)n1
Yield: 75.2 %

Procedure:
Using a method similar to Preparation 48, using 2,6-diaminopyridine (2.6 g, 24 mmol), dioxane (75 mL), and 2,6-difluorobenzoyl chloride (1.4 g, 8 mmol)(stir at 25° C. for 16 hr.), gives the title intermediate (1.5 g, 75% yield): mass spectrum (ion spray): m/z=250.1 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:11][C:10]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[N:9][N:8]=1.[CH3:34][NH2:35].C([O-])([O-])=O.[K+].[K+]>CCOCC>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:10]2[S:11][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:35][CH3:34])=[N:8][N:9]=2)(=[O:15])=[O:14])=[CH:17][CH:18]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CN
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(CCCCCBr)s2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(CCCCCNC)s2)cc1
Yield: 61 %

Procedure:
A mixture of N-(5-(5-bromopentyl)-1,3,4-thiadiazol-2-yl)-4-dodecylbenzenesulfonamide (100 mg, 0.18 mmol), CH3NH2 (0.42 mL, 40% solution in water, 5.4 mmol), K2CO3 (25 mg, 0.18 mmol), and KI (30 mg, 0.18 mmol) was heated at reflux for 2 d. The reaction mixture was diluted with ether (50 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatography over silica gel 60 (70-230 mesh) eluted with CH2Cl2:methanol 2:3 to give the product as a solid, mp 158-160° C., in 61% yield (56 mg, 0.11 mmol). 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3, J=7.2 Hz), 1.25-1.36 (m, 18), 1.53-1.67 (m, 8), 2.57-2.61 (m, 5), 2.68 (t, 2, J=7.2 Hz), 2.96 (t, 2, J=6.9 Hz), 7.20 (d, 2, J=8.4 Hz), 7.75 (d, 2, J=8.1 Hz); 13C NMR (75 MHz, CDCl3) δ 14.1, 22.7, 25.5, 28.3, 29.3, 29.4, 29.5, 29.7, 30.5, 31.2, 31.9, 33.1, 35.8, 60.0, 126.1, 128.5, 140.7, 146.7, 163.7, 170.7; HRMS (ESI+, m/z) calculated for C26H45N4O2S2 509.2984, observed 509.2972 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>ClC(Cl)C.N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([N:11]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[S:21]([CH2:19][CH3:20])(=[O:23])=[O:22])[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: CCS(=O)(=O)Cl
Reactant: COC(=O)c1cccc(NCc2cccnc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
Into a 0° C. solution of N-(3-methoxycarbonylphenyl) pyrid-3-ylmethylamine (204 g, 0.842 mole, 1 eq) in dichloroethane (3610 mL) and pyridine (1775 mL) was added ethanesulfonyl chloride (114 mL, 1.2 mole, 1.43 eq). The reaction was allowed to warm to room temperature overnight. The dark red reaction was stirred with potassium carbonate (204 g) for 30 minutes and then filtered and concentrated to dryness. The residue was purified by Biotage, eluting with 3:1 to 2:1 DCM/EtOAc mixture to give the title compound as a white solid (137.0 g, 49% yield).