Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]1([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH2:9][CH2:8][CH2:7][C@:4]2([O:6][CH2:5]2)[CH2:3]1.[CH2:22]([NH2:25])[C:23]#[CH:24].C1N=CN([C:31](N2C=NC=C2)=[O:32])C=1.O1CCOCC1>CO>[CH3:1][C@:2]1([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH2:9][CH2:8][CH2:7][C@:4]2([O:6][C:31](=[O:32])[N:25]([CH2:22][C:23]#[CH:24])[CH2:5]2)[CH2:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C#CCN
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CO2)C1
Solvent: CO
Solvent: C1COCCO1
Product: C#CCN1C[C@@]2(CCC[C@](C)(Cn3cnc4ccc(C#N)cc43)C2)OC1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 10.1 %

Procedure:
To a 20 mL microwave tube was added 1-{[(3S,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile (840 mg, 2.99 mmol) and propargyl amine (822 mg, 14.93 mmol) in MeOH (5 mL). The tube was sealed and heated at 100° C. for 2 h on a hotplate. The reaction mixture was then evaporated down directly to a crispy foam, codistilled 2× with DCM, and left on highvac for 3 h to remove any residual MeOH and the volatile amine. The yellow residue was then treated with CDI (2.42 g, 14.93 mmol) and 1,4-dioxane (5 mL) was added. The reaction mixture was stirred and heated at 100° C. for 2 h, then left at RT overnight. LCMS then indicated the reaction was not complete. The reaction mixture was then heated at 120° C. for 6 h. The mixture (dark orange oil) was loaded onto florisil and purified using silica gel chromatography CISCO): 0.5-5% MeOH/DCM (30 min), 5% (10 min), 120 g silica. The desired product eluted at 18 min. The product was dried under vacuum at RT overnight to yield 1-{[(5S,7S)-7-methyl-2-oxo-3-(2-propyn-1-yl)-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile as an yellow oil (109 mg, 5% yield). MS (m/z) 363 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:10][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:12]([CH2:14][CH:15]=[CH2:16])[CH3:13].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[CH3:10][N:11]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH:12]([CH2:14]/[CH:15]=[CH:16]/[C:5]1[CH:4]=[N:3][C:2]([NH2:1])=[C:7]([CH3:8])[CH:6]=1)[CH3:13]
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Reactant: Cc1cc(Br)cnc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(/C=C/CC(C)N(C)C(=O)OC(C)(C)C)cnc1N
Temperature: 140 °C
Yield: 123.5 %

Procedure:
A mixture of 2-amino-5-bromo-3-methylpyridine (1.41 g, 7.53 mmol), N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (1.50 g, 7.53 mmol), palladium(II) acetate (33.8 mg, 0.15 mmol), tri-o-tolylphosphine (183.2 mg, 0.60 mmol), triethylamine (4.50 mL, 32.3 mmol), and anhydrous acetonitrile (8 mL) was stirred and heated at 130–132° C. in a sealed glass tube for 18 h. The mixture was further heated at 140° C. for 84 h. The resulting dark-brown solution was cooled to ambient temperature and concentrated by rotary evaporation. The residue was diluted with water (25 mL) and extracted with CH2Cl2 (3×25 mL). the combined CH2Cl2 extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation, and vacuum dried producing a dark-brown oil (2.84 g). The crude product was purified by column chromatography on silica gel (135 g), eluting with ethyl acetate-hexane (3:1, v/v) to remove impurities, followed by elution with CH3OH-Et3N (98:2, v/v) to collect the product. Fractions containing the product (Rf 0.70) were combined and dissolved in CHCl3. The CHCl3 solution was dried (Na2SO4), filtered, concentrated by rotary evaporation, and vacuum dried to give 1.11 g (48.4%) of an amber-brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[N:20]1[C:21]([C:32](O)=[O:33])=[CH:22][N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[S:25][C:24]=12>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:32]([C:21]1[N:20]=[C:24]2[N:23]([CH:22]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[S:25]2)=[O:33]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1cn2c(n1)sc1ccccc12
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1cn2c(n1)sc1ccccc12

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with benzo[d]imidazo[2,1-b]thiazole-2-carboxylic acid. MS: 460.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]([OH:10])=O)[CH:6]=1.C(Cl)(C(Cl)=O)=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32]3[CH2:31][CH2:30][CH2:29][NH:28][C:27]=3[CH:26]=[N:25]2)=[CH:20][CH:19]=1.CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]([N:28]2[CH2:29][CH2:30][CH2:31][C:32]3[N:24]([C:21]4[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=4)[N:25]=[CH:26][C:27]2=3)=[O:10])[CH:6]=1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cn1cc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cn1cc(Cl)cn1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
A mixture of 2-[(4-chloro-pyrazol-1-yl)]acetic acid (0.050 g, 0.31 mmol), (COCl)2 (0.060 mL, 0.70 mmol) and DMF (1 drop) in CH2Cl2 (1 mL) was stirred for 30 min at rt. It was then evaporated to dryness on a high vacuum pump. The obtained oil was added to a mixture containing 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.020 g, 0.092 mmol) and NEt3 (0.070 mL, 0.50 mmol) in CH2Cl2 (1 mL). The resulting mixture was then stirred at rt for 30 min. It was then quenched with water and partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to afford the desired product (0.012 g, 36%). 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.60 (s, 1H), 7.51 (s, 1H), 7.44 (dd, J=8.8, 4.6 Hz, 2H), 7.17 (dd, J=9.2, 8.8 Hz, 2H), 5.16 (s, 2H), 3.82 (m, 2H), 2.85 (t, J=6.2 Hz, 2H), 2.09 (m, 2H); MS: (ES) m/z calculated for C17H15ClFN5O [M+H]+ 360.1, found 360.1.
Reaction SMILES: [OH:1][C@H:2]1[CH:6]=[CH:5][C@@H:4]([O:7][Si](C(C)(C)C)(C)C)[CH2:3]1.CC[O:17][C:18]([CH3:20])=[O:19].[CH3:21][CH2:22]CCCC>>[OH:1][C@@H:2]1[CH:6]=[CH:5][C@H:4]([O:7][CH:20]([CH2:21][CH3:22])[C:18]([OH:17])=[O:19])[CH2:3]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C=C[C@H](O)C1
Reactant: CCCCCC
Reactant: CCOC(C)=O
Product: CCC(O[C@H]1C=C[C@@H](O)C1)C(=O)O
Yield: 77 %

Procedure:
Compound 14 was subjected to general procedure D. Yield=77%. TLC: Rf=0.29 (10% EtOAc/Hexane). 1H NMR (400 MHz, CDCl3): δ0.05 (s, 6H), 0.90 (s, 9H), 1.25 (t, 3H), 1.60 (m, 1H), 2.65 (m, 1H), 4.10 (s, 2H), 4.20 (q, 2H), 4.55 (m, 1H), 4.65 (m, 1H), 5.95 (m, 2H). Subsequent subjection of the product to general procedure I gave compound 15. Yield=79%. TLC: Rf=0.65 (EtOAc). 1H NMR (400 MHz, CDCl3): δ1.25 (t, 3H), 1.65 (m, 1H), 1.75 (s, 1H), 2.65 (m, 1H), 4.10 (s, 2H), 4.20 (q, 2H), 4.45 (m, 1H), 4.65 (m, 1H), 6.05 (m, 2H).
Reaction SMILES: CN(C=O)C.[C:6]1([C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][NH:15][C:14](=[O:24])[CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35]>O>[O:24]=[C:14]1[N:15]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[N:16]=[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:13]1
Reactant: COC(=O)CCCCCCCCBr
Reactant: O=c1cc(-c2ccccc2)c(-c2ccccc2)n[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
Sodium hydride (840 mg of a 60% dispersion in oil, 20 mmol) was washed twice with hexanes, covered with DMF (25 mL) and 5,6-diphenyl-3(2H)-pyridazinone (4 g, 16 mmol), obtained according to P. Schmidt, et al., Helvetica Chim. Acta., 37, 134-140 (1954), added. After gas evolution had ceased, the mixture was stirred at room temperature for 30 minutes before adding methyl 9-bromononanoate (4.45 g, 18 mmol). The mixture was heated briefly to 110° C. to give a solution and then allowed to cool before being stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with diethyl ether (3×). The combined extracts were washed with water, dried over sodium sulfate and concentrated to leave an oil. Chromatography on a column of silica gel afforded methyl 6-oxo-3,4-diphenyl-1(6H)-pyridazine nonanoate (6.44 g, 95%) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]2)[CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:15])=[N:10][CH:9]=1)[CH3:2].[N:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH:23]2[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]2)[CH:17]2[CH2:22][CH2:21][N:20]([C:37]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:38])[CH2:19][CH2:18]2)=[O:15])=[N:10][CH:9]=1)[CH3:2].[CH3:29][C@H:26]1[CH2:25][CH2:24][C@H:23]([N:16]([CH:17]2[CH2:18][CH2:19][N:20]([C:37]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:38])[CH2:21][CH2:22]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:6][CH2:5][C:4]([OH:3])=[O:30])=[CH:9][N:10]=2)[CH2:28][CH2:27]1
Reactant: CCOC(=O)CCSc1cnc(NC(=O)N(C2CCNCC2)[C@H]2CC[C@H](C)CC2)s1
Reactant: O=C(Cl)N1CCOCC1
Product: CCOC(=O)CCSc1cnc(NC(=O)N(C2CCC(C)CC2)C2CCN(C(=O)N3CCOCC3)CC2)s1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCC(=O)O)s2)C2CCN(C(=O)N3CCOCC3)CC2)CC1

Procedure:
3-(2-{3-(4-Methyl-cyclohexyl)-3-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-ureido}-thiazol-5-ylsulfanyl)-propionic acid ethyl ester was prepared in a similar manner to Example 554 using 3-{2-[3-(trans-4-methyl-cyclohexyl)-3-piperidin-4-yl-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester and 4-morpholinecarbonyl chloride. Hydrolysis using general procedure (F) gave the title compound
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[CH2:30])[C:21]3[C:20](=[O:31])[N:19](COC(=O)C(C)(C)C)[C:18](=[O:40])[N:17]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>O1CCCC1.CO.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[CH2:30])[C:21]3[C:20](=[O:31])[NH:19][C:18](=[O:40])[N:17]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2CC(=O)OCC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 82.1 %

Procedure:
4-[1-(2,2-Dimethylpropionyloxymethyl)-3-ethoxycarbonylmethyl-2,6-dioxo-7-(2-vinylphenyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (89 mg) was dissolved in tetrahydrofuran (1 ml) and methanol (2 ml), sodium hydride (7 mg) was added to the solution, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and filtered, followed by concentration of the filtrate under reduced pressure. The residue was purified by silica gel column chromatography to give 60 mg of the title compound from the elution fraction of hexane-ethyl acetate (1:2).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13](S(C)(=O)=O)=[N:14][N:15]=2)[CH:8]=[C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[OH:24])([CH3:4])[CH3:3].[CH2:25]([CH2:27][NH2:28])[OH:26]>C(O)(C)C>[CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([NH:28][CH2:27][CH2:25][OH:26])=[N:14][N:15]=2)[CH:8]=[C:7]([C:20]([CH3:22])([CH3:21])[CH3:23])[C:6]=1[OH:24])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(-c2nnc(S(C)(=O)=O)s2)cc(C(C)(C)C)c1O
Reactant: NCCO
Solvent: CC(C)O
Product: CC(C)(C)c1cc(-c2nnc(NCCO)s2)cc(C(C)(C)C)c1O
Yield: 84 %

Procedure:
To a solution of 2,6-bis(1,1-dimethylethy)-4-[5-(methylsulfonyl)-1,3,4-thiadiazole-2-yl]phenol (4.0 g, 0.0109 mole) in isopropyl alcohol (15 ml) is added ethanolamine (1.9 g, 0.0326 mole). The resulting mixture is heated to reflux for 18 hours. The reaction is cooled and concentrated in vacuo. The resulting solid is recrystallized from methanol/water to give 3.2 g (3.8 g theor., 83%) of 2,6-bis(1,1-dimethylethyl)-4-[5-[(2-hydroxyethyl)amino]-1,3,4-thiadiazol-2-yl]phenol after drying in vacuo at 65° C., mp 212°-213.5° C.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([CH:8]2[O:12]C(=O)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[CH:23]=2)[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[N:7]=[C:6]([CH:8]([OH:12])[CH:9]([NH:10][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:33])([F:34])[CH:30]([F:31])[F:32])[CH:23]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2cccc(F)n2)C1Cc1cccc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
To a solution of 1,1-dimethylethyl(4RS,5RS)-5-(6-fluoropyridin-2-yl)-2-oxo-4-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-1,3-oxazolidine-3-carboxylate (2.40 g, 4.91 mmol) in methanol (12 ml) was added a solution (11.8 ml, 5.90 mmol) of 0.5N sodium hydroxide in methanol, and the mixture was stirred at room temperature for 10 min. To the reaction solution was added water (50 ml) and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (1.92 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].I[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:17]
Reactant: CCOC(=O)CI
Reactant: OCCc1ccccc1Cl
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCOC(=O)COCCc1ccccc1Cl

Procedure:
In analogy to the procedure described in example 78.1, 2-(2-chloro-phenyl)-ethanol was reacted with ethyl iodoacetate in the presence of silver trifluoromethanesulfonate and 2,6-di-tert-butylpyridin to give [2-(2-chloro-phenyl)-ethoxy]-acetic acid ethyl ester as yellow liquid. 1H NMR (CDCl3): 1.28 (t, J=7.3 Hz, 3H), 3.09 (t, J=7.1 Hz, 2H), 3.78 (t, J=7.1 Hz, 2H), 4.09 (s, 2H), 4.21 (q, J=7.3 Hz, 2H), 7.13-7.23 (m, 2H), 7.29-7.37 (m, 2H).
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:30][CH:31]=2)[N:26]=[CH:25][C:24]=1[C:37]([O:39][CH2:40][CH3:41])=[O:38].Cl>CN(C=O)C.O>[CH2:40]([O:39][C:37]([C:24]1[CH:25]=[N:26][C:27]2[C:32]([C:23]=1[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:38])[CH3:41]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1Cl
Reactant: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
To a solution of 1.85 g (6.67 mmol) of N-benzyl 4-methoxyphenyl-sulphonamide in 15 mL of DMF was added, in one portion, 0.267 g (6.67 mmol) of 60% sodium hydride and the resulting mixture was stirred at room temperature under nitrogen for 15 min. Ethyl 4-chloro-7-trifluoromethyl-3-quinolinecarboxylate (2.02 g, 6.67 mmol) was then added to the solution in one portion and the resulting mixture was heated at 85° C. for 24 h. The reaction mixture was then cooled to room temperature, poured into a mixture of water (300 mL) and HCl (1N, aqueous, 100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was then chromatographed on silica gel eluting with 15%-50% ethyl acetate/hexane to give 3.11 g (88%) of the desired product. Electrospray Mass Spec 545.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](N)=[O:6].S(=O)(=O)(O)[OH:15]>>[Br:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:15])=[O:6]
Reactant: O=S(=O)(O)O
Reactant: NC(=O)c1cc(F)c(F)c(Br)c1F
Product: O=C(O)c1cc(F)c(F)c(Br)c1F
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 3-bromo-2,4,5-trifluorobenzamide (8.7 g) and 18N-sulfuric acid (50 ml) was stirred at 100° C. for 4 hours, and then poured into ice water (200 ml). The resulting precipitate was collected by filtration and recrystallized from dichloro-methane-n-hexane to give the title compound (6.9 g), mp 125°-127° C.
Reaction SMILES: [CH2:1]1O[CH2:2]1.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1.S(Cl)([Cl:27])=O>CO.C1(C)C=CC=CC=1>[ClH:27].[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=2)=[C:12]2[CH2:17][CH2:16][N:15]([CH2:1][CH2:2][Cl:27])[CH2:14][CH2:13]2)=[CH:23][CH:22]=1
Reactant: C1CO1
Reactant: O=S(Cl)Cl
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: Cl
Product: Fc1ccc(C(=C2CCN(CCCl)CC2)c2ccc(F)cc2)cc1
Temperature: -20 °C
Reaction time: 15 h

Procedure:
0.31 mol of ethylene oxide is dissolved in a solution of 0.28 mol of 4-[bis(4-fluorophenyl)methylene]piperidine (prepared according to the process described in U.S. Pat. No. 3,922,276) in one liter of anhydrous methanol at -10° C., and the reaction is completed by stirring for 15 hours at -20° C. and then for 3 hours at 45° C. The mixture is concentrated under vacuum. The product is purified by chromatography on 140 g of 230-400 mesh silica using a mixture of dichloromethane and methanol (95:5 V/V) as eluent. The oil obtained is solubilized in one liter of anhydrous toluene and 0.27 mol of thionyl chloride is then added. The mixture is brought to reflux for 30 min to complete the reaction. The mixture is cooled to 20° C. and the precipitate formed is filtered off.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][NH:27][CH3:28]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[N:27]([CH2:26][CH2:25][N:24]([CH3:29])[CH3:23])[CH3:28])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Reactant: CNCCN(C)C
Product: CN(C)CCN(C)c1c(C=O)c2ccccc2n1-c1ccc(C(C)(C)C)cc1
Yield: 42 %

Procedure:
1-(4-tert-Butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde is reacted with N,N,N′-trimethylethylenediamine as described in Step 2 of Example 29 to afford 1-(4-tert-butylphenyl)-2-[(2-dimethylaminoethyl)-methylamino]-1H-indole-3-carboxaldehyde (42% yield) as a light tan solid. TLC (silica gel, 7N NH3 in methanol/MeOH/Ethyl acetate (0.1:2:10 mL)) Rf=0.29. ESI/MS 378 (M+M); RT=3.43 min. NMR10.18 (1H, s); 8.10 (1H, d, J=9 Hz); 7.66 (2H, d); 7.48 (2H, d); 7.17 (1H, t); 7.08 (1H, t); 6.88 (1H, d, J=9 Hz); 3.21 (2H, t); 3.02 (3H, s); 2.18 (2H, t); 2.00 (6H, t); 1.36 (9H, s).
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C)=[CH:16]2)=[CH:11][C:10]=1[C:31]1[N:32]=[N:33][C:34]([N:37]([CH3:48])[CH:38]2[CH2:43][C:42]([CH3:45])([CH3:44])[NH:41][C:40]([CH3:47])([CH3:46])[CH2:39]2)=[CH:35][CH:36]=1>C(Cl)Cl.CO>[NH2:23][CH2:22][CH2:21][CH2:20][O:19][C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[C:10]([C:31]3[N:32]=[N:33][C:34]([N:37]([CH3:48])[CH:38]4[CH2:43][C:42]([CH3:44])([CH3:45])[NH:41][C:40]([CH3:47])([CH3:46])[CH2:39]4)=[CH:35][CH:36]=3)[C:9]([OH:8])=[CH:18]2)=[CH:13][CH:14]=1
Reactant: CN(c1ccc(-c2cc3ccc(OCCCNC(=O)OC(C)(C)C)cc3cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CN(c1ccc(-c2cc3ccc(OCCCN)cc3cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
TFA (1.5 ml, 19.47 mmol) was added to a solution of Example 20-4 (289.4 mg, 0.513 mmol) in DCM (6 ml) at RT. The reaction mixture was stirred at RT for 30 min, diluted with MeOH then adsorbed onto a MeOH conditioned SCX column (10 g). The column was washed several times with MeOH then eluted with 3 N NH3 in MeOH. Evaporation of the solvent afforded the title compound as a beige solid (178 mg, 75% yield). LCMS Rt=0.44 min (LCMS method Q); MS (M+1)=464.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.35 (s, 1H), 8.28 (d, J=9.60 Hz, 1H), 7.77 (d, J=9.09 Hz, 1H), 7.36 (d, J=9.60 Hz, 1H), 7.16-7.18 (m, 1H), 7.11 (d, J=2.53 Hz, 1H), 6.96 (dd, J=8.84, 2.27 Hz, 1H), 4.91-5.04 (m, 1H), 4.56 (s, 1H), 4.17 (t, J=6.32 Hz, 2H), 2.98 (s, 3H), 2.88 (d, J=7.07 Hz, 2H), 1.90-2.05 (m, 2H), 1.46-1.62 (m, 4H), 1.30 (s, 6H), 1.14 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[I:9].[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[OH:18].C1CCN2C(=NCCC2)CC1.[OH-].[Na+]>CN1C(=O)CCC1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[O:18][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[I:9]
Reactant: Nc1nccc(Cl)c1I
Reactant: Oc1cc(F)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Product: Nc1nccc(Oc2cc(F)ccc2F)c1I
Temperature: 170 °C
Reaction time: 6 h
Yield: 62.1 %

Procedure:
4-chloro-3-iodopyridin-2-amine (3.00 g, 11.79 mmol), 2,5-difluoro phenol (4.60 g, 35.4 mmol), DBU (1.777 ml, 11.79 mmol) were combined in NMP (15 mL) and solution was stirred at 170° C. for 6 h under microwave irradiation. The crude reaction mixture was poured into 1N NaOH solution (70 mL), the resultant suspension was filtered, washed with water (5×10 mL) and dried to afford crude product which was purified by silica gel chromatography (EtOAc-hexanes) to afford 4-(2,5-difluorophenoxy)-3-iodopyridin-2-amine as white solid. (2.55 g, 62.1% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.74 (d, J=7.6 Hz, 1H), 7.47 (m, 1H), 7.28 (m, 1H), 7.18 (On, 1H), 6.25 (br s, 2H), 5.88 (dd, J=5.6 Hz, 1H); MS (ESI) m/z: 349.03 (M+H+).