Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[C:23]2[C:14](=[CH:15][C:16]3[O:21][CH2:20][CH2:19][O:18][C:17]=3[CH:22]=2)[O:13][CH2:12]1.N1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.Cl.Cl[CH2:47][C:48]1[C:53]([C:54]([F:57])([F:56])[F:55])=[CH:52][CH:51]=[CH:50][N:49]=1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:47][C:48]1[C:53]([C:54]([F:56])([F:55])[F:57])=[CH:52][CH:51]=[CH:50][N:49]=1)[C:8](=[O:11])[C:7]12[C:23]2=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=[C:14]2[O:13][CH2:12]1
Reactant: FC(F)(F)c1cccnc1CCl
Reactant: O=C1Nc2c(F)cccc2C12COc1cc3c(cc12)OCCO3
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Agent: Cl
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Product: O=C1N(Cc2ncccc2C(F)(F)F)c2c(F)cccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 7′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-(chloromethyl)-3-(trifluoromethyl)pyridine hydrochloride to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 7′-fluoro-1′-((3-(trifluoromethyl)pyridin-2-yl)methyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one was obtained (40%) as a colorless solid: mp 241-243° C. (dichloromethane); 1H NMR (300 MHz, CDCl3) δ8.62 (d, J=4.7 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.34-7.30 (m, 1H), 7.00-6.86 (m, 3H), 6.68 (s, 1H), 6.50 (s, 1H), 5.54 (d, J=17.1 Hz, 1H), 5.37 (d, J=17.1 Hz, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.73 (d, J=9.0 Hz, 1H), 4.21-4.19 (m, 2H), 4.15-4.14 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.9, 155.1, 153.0, 151.9, 149.2, 145.9, 144.7, 138.3, 135.5, 134.3, 129.2, 123.9, 121.9, 121.3, 119.6, 116.4, 116.2, 112.5, 99.2, 80.2, 64.6, 63.9, 58.5, 44.2; MS (ES+) m/z 473.0 (M+1).
Reaction SMILES: C[O:2][C:3](=O)/[CH:4]=[CH:5]/[C:6]1[N:7]([CH:22]([CH3:24])[CH3:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH:22]([CH3:23])[CH3:24])[C:6]=2/[CH:5]=[CH:4]/[CH2:3][OH:2])=[CH:16][CH:17]=1
Reactant: COC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)n1c(/C=C/CO)c(-c2ccc(F)cc2)c2ccccc21
Yield: 102.2 %

Procedure:
As in Example 227, (E)-3-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-2-propenoic acid methyl ester (4.43 g) in dry dichloromethane (60 mL) was treated with diisobutylaluminum hydride in toluene (1.5M; 30 mL) at -65° C. for 1 hour, then was worked up as previously described to give 4.15 g of (E)-3-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-2-propen-1-ol as a yellow oil. A portion (0.2 g) was purified by chromatography over silica gel (diethyl ether-hexane; 1:19) to furnish 0.175 g of the analytically pure alcohol as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[C:20]([CH2:26][OH:27])=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([O:27][CH2:26][C:20]2[C:19]([CH3:18])=[CH:24][C:23]([CH3:25])=[CH:22][N:21]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: Cc1cnc(CO)c(C)c1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cnc(COc2nc(N)nc(-c3ccco3)c2C#N)c(C)c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (3,5-dimethylpyridin-2-yl)methanol and DBU in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=1.[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[C:27]([CH:31]=1)[C:28](O)=[O:29]>>[CH3:20][N:19]([CH3:21])[C:11]1[N:10]=[C:9]([N:2]2[CH2:3][CH:4]3[CH:5]([CH2:6][N:7]([C:28]([C:27]4[CH:31]=[C:23]([CH3:22])[CH:24]=[CH:25][C:26]=4[C:32]4[N:33]=[CH:34][CH:35]=[CH:36][N:37]=4)=[O:29])[CH2:8]3)[CH2:1]2)[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=1
Reactant: CN(C)c1nc(N2CC3CNCC3C2)cc(C(F)(F)F)n1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)O)c1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CC3CN(c4cc(C(F)(F)F)nc(N(C)C)n4)CC3C2)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 36 and 5-methyl-2-pyrimidin-2-yl-benzoic acid. MS (ESI): mass calculated for C25H26F3N7O, 497.53; m/z found 498.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.67 (dd, J=20.0, 4.9, 2H), 8.20 (d, J=10.1, 1H), 7.34-7.30 (m, 1H), 7.19-7.15 (m, 1H), 7.13-7.03 (m, 1H), 5.85 (br s, 1H), 3.98-2.83 (m, 16H), 2.42 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=O)[CH2:9]1.Cl.[NH2:17][CH2:18][C:19]#[C:20][CH3:21].O1CCCC1>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][C:10]2[N:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:11]=2[C:12](=[O:14])[CH2:13]1
Reactant: CC#CCN
Reactant: O=C1CC(=O)CC(c2ccccc2Cl)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccnc2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.5 %

Procedure:
A mixture of 5-(2-chlorophenyl)-1,3-cyclohexanedione (1.1 g), 1-amino-2-butyne hydrochloride (0.5 g), molecular sieve 4A (2 g) and tetrahydrofuran (20 ml) was combined with triethylamine (0.48 g), stirred at room temperature for 1 hour, and then heated under reflux for 12 hours. After cooling, insolubles were filtered off, and the solvent was distilled off under reduced pressure. The residue was stirred at 220° C. for 4 hours. Ethyl acetate and aqueous sodium hydrogen carbonate were added, and the organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was subjected to a column chromatography on a silica gel (EtOAc/hexane) to obtain a crystal which was then recrystallized from ethyl acetate-hexane to obtain 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinoline-5-one (0.20 g) as a colorless crystal.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C(C)=CC=CC=1.[OH-].[K+].Br[C:26]1[CH:32]=[C:31]([CH3:33])[C:29]([NH2:30])=[C:28]([CH3:34])[CH:27]=1>Cl[Cu].O>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:26]2[CH:32]=[C:31]([CH3:33])[C:29]([NH2:30])=[C:28]([CH3:34])[CH:27]=2)=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Br)cc(C)c1N
Reactant: Oc1ccc(Cc2ccccc2)cc1
Agent: Cl[Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1cc(Oc2ccc(Cc3ccccc3)cc2)cc(C)c1N
Reaction time: 12 h

Procedure:
A mixture of 64,4 g (0.35 mole) of p-benzylphenol, 500 ml of xylene and 28 g (0,45 mole) of pulverised potassium hydroxide is heated for 4 hours under reflux. The water formed is removed from the reaction mixture. Then 60 g (0,3 mole) of 4-bromo-2,6-dimethylaniline and 1 g of CuCl are added and the xylene is distilled off under nitrogen until the temperature in the reaction mixture is 160°-170°. The reaction mixture is stirred at this temperature for 12 hours, allowed to cool to 70°-80° C., and then taken up in 500 ml of toluene and filtered. The filtrate is diluted with diethyl ether, washed twice with 10% potassium hydroxide solution and three times with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue is purified over a column of silica gel with a 1:3 mixture of ethyl acetate/hexane as eluant. The eluant is evaporated off to give 4-(p-benzylphenoxy)-2,6-dimethylaniline as a dark liquid which after a time forms crystals with a melting point of 61°-63° C.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([N:30]3[CH2:33][CH2:32][CH2:31]3)=[O:29])[CH:23]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.N1(C(C2C=CC=C(NCC3CCCC3)C=2)=O)CCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[N:30]1([C:28]([C:24]2[CH:23]=[C:22]([N:15]([CH2:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:13](=[O:14])[NH:12][C:10]3[S:11][C:7]([S:6][CH2:5][C:4]([OH:34])=[O:3])=[CH:8][N:9]=3)[CH:27]=[CH:26][CH:25]=2)=[O:29])[CH2:31][CH2:32][CH2:33]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(C(=O)N3CCC3)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: O=C(c1cccc(NCC2CCCC2)c1)N1CCC1
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(C(=O)N3CCC3)c2)s1

Procedure:
The title compound was prepared via (2-{3-[3-(azetidine-1-carbonyl)-phenyl]-3-cyclopentylmethyl-ureido}-thiazol-5-ylsulfanyl)-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using azetidin-1-yl-[3-(cyclopentylmethyl-amino)-phenyl]-methanone and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].C1C=CC=CC=1.S(=O)(=O)(O)[OH:13].[C:17]1([CH:24]=[CH:23][C:21]([OH:22])=[CH:20][CH:19]=1)O>O>[C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[C:21]1(=[O:22])[O:13][CH2:20][CH2:19][CH2:17][CH2:24][CH2:23]1
Reactant: Oc1ccc(O)cc1
Reactant: O=S(=O)(O)O
Agent: C=CC(=O)O
Solvent: c1ccccc1
Solvent: O
Product: O=C1CCCCCO1
Temperature: 85 °C
Yield: 60 %

Procedure:
A 2000 ml glass reaction flask was equipped with a stirrer, thermometer and condenser, Dean-Stock trap air inlet and heating mantle and used as the reaction vessel. 300 grams of a trihydroxyfunctional polycaprolactone polyol with an average hydroxyl number of 310 and an average molecular weight of 540 (TONE-0305 obtained from Union Carbide Corporation), 88.4 g. of glacial acrylic acid, 150 ml. of benzene, 5 ml. of concentrated sulfuric acid and 5 g. of hydroquinone were added to the reaction flask at room temperature. The contents of the flask were then heated to about 85° C. over a period of one hour and maintained at reflux at atmospheric pressure until no further water was produced (about 4.5 hours). During the reaction, air was continually bubbled through the reaction. The reaction mixture was cooled to about 60° C. in a separatory funnel and about 50 ml of benzene added. Then, about 200 g of a 15 percent aqueous sodium hydroxide solution was dripped through the separatory funnel. A second aliquot of 200 g of a 15 percent aqueous sodium hydroxide solution was added and then the contents shaken. Excess acid and hydroquinone inhibitor were washed out by shaking the solution three times with 50 g of a 15 percent aqueous sodium hydroxide solution. After the contents settled, 10 g of magnesium sulfate was added while stirring to remove any remaining water, then the contents filtered to remove the magnesium sulfate. 100 parts per million of methylethyl hydroquinone based on the final product was added and the contents were then stripped of solvent. A 60 to 70% yield was obtained. The product had a viscosity of 250 centipoise.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3]C1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[CH:10]=1.OC1C=CC=CC=1C(=O)C.CN1CCC2(CC(N)C3C(=CC=CC=3)O2)CC1>>[F:8][C:9]1[CH:10]=[C:11]2[C:12]([C:15](=[O:17])[CH2:16][C:5]3([O:18]2)[CH2:4][CH2:3][O:7][CH2:1][CH2:6]3)=[CH:13][CH:14]=1
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: O=C1CCCCC1
Agent: CC(=O)c1ccccc1O
Agent: CN1CCC2(CC1)CC(N)c1ccccc1O2
Product: O=C1CC2(CCOCC2)Oc2cc(F)ccc21

Procedure:
The title compound was prepared using the procedure as described in Example 1A, substituting tetrahydro-4H-pyran-4-one for cyclohexanone and 4′-fluoro-2′hydroxyacetophenone for 2′-hydroxyacetophenone. 1 NMR (300 MHz, DMSO-d6) δ ppm 7.80 (dd, J=8.81, 6.78 Hz, 1H), 6.87-7.01 (m, 2H), 3.62-3.74 (m, 4H), 2.86 (s, 2H), 1.73-1.86 (m, 4H). MS (DCI+) m/z 237 (M+H), 254 (M+NH4).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([S:11](=[O:18])(=[O:17])[NH:12][C:13]([F:16])([F:15])[F:14])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[OH:19][CH:20]([CH:23]1[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]1)[CH2:21][NH2:22]>>[OH:19][CH:20]([CH:23]1[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]1)[CH2:21][NH:22][C:5](=[O:7])[C:4]1[C:8]([S:11](=[O:18])(=[O:17])[NH:12][C:13]([F:16])([F:15])[F:14])=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=1
Reactant: CC1(C)OCC(C(O)CN)O1
Reactant: O=C(O)c1cc(F)ccc1S(=O)(=O)NC(F)(F)F
Product: CC1(C)OCC(C(O)CNC(=O)c2cc(F)ccc2S(=O)(=O)NC(F)(F)F)O1

Procedure:
Analogously to Example 22(a), 4.31 g (15 mmol) of 3-fluoro-6-(trifluoromethylsulfamoyl)-benzoic acid is reacted with 3.22 g (20 mmol) of 2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamine and the crude product is purified by chromatography on silica gel with ethyl acetate/hexane. 4.93 g=76.3% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:28])[CH2:18][CH2:17][C:16]([CH2:26][NH2:27])([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH:27][CH2:26][C:16]1([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:28])[CH2:14][CH2:15]1)=[O:6]
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Product: Cc1ccc(Cl)c(C(=O)NCC2(c3ccc(F)nc3)CCC(F)(F)CC2)c1

Procedure:
From 2-chloro-5-methylbenzoic acid and C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=397.2, tR (minutes, Method C)=1.11
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([C:16]1[C:24]([F:25])=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[C:18](Cl)[N:17]=1)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([C:16]1[C:24]([F:25])=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[C:18]([O:34][C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)[N:17]=1)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc(F)c(C2CC3CCC(C2)N3Cc2ccccc2)nc1Cl
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(F)c(C2CC3CCC(C2)N3Cc2ccccc2)nc1Oc1ccc(F)cc1
Yield: 66.7 %

Procedure:
Exo-N-(8-Benzyl-8-aza-bicyclo[3.2.1]oct-3-yl-2-chloro-5-fluoro-nicotinamide (7.9 g, 21 mmol) (see Preparation 33), 4-fluorophenol (2.6 g, 23 mmol) and caesium carbonate (13.8 g, 42 mmol) were stirred in N,N-dimethylformamide (200 ml) at 70° C. under an atmosphere of nitrogen for 20 hours. The reaction mixture was then partitioned between ethyl acetate (300 ml) and water (300 ml) and the organic layer separated. The organic phase was then washed with a saturated aqueous solution of sodium chloride (3-fold 200 ml), concentrated in vacuo and the residue purified by flash column chromatography on silica gel eluting with a solvent gradient of 20:80 changing to 100:0, by volume, ethyl acetate:pentane. The product was triturated with pentane (30 ml) giving exo-N-(8-benzyl-8-aza-bicyclo[3.2.1]oct-3-yl-5-fluoro-2-(4-fluoro-phenoxy)-nicotinamide (6.3 g) as a white solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:24][O:23][CH2:22]2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[O:23]1[CH2:24][CH:21]([N:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2COC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CN(C2COC2)CCN1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TFA (2 mL) was added to a solution of 4-oxetan-3-ylpiperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.62 mmol) in DCM (10 mL) and the mixture was stirred at ambient temperature for 30 min, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to give 1-oxetan-3-ylpiperazine as a colourless oil. A solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (200 mg, 0.51 mmol), 1-oxetan-3-ylpiperazine (88 mg, 0.62 mmol) and molecular sieves (4 Å, powdered, 1 g) in DCE (10 mL) was stirred at ambient temperature for 5 h. Sodium triacetoxyborohydride (162 mg, 0.76 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 100:0 to 99:1 to 98:2 to 95:5) to afford 513 as a white solid (98 mg, 37%). LCMS (Method I): RT=2.43 min, M+H+=518. 1H NMR (CDCl3, 400 MHz) δ 8.01 (dd, J=6.9, 2.4 Hz, 1 H); 7.78 (m, 1 H); 7.33-7.23 (m, 2 H); 4.70-4.60 (m, 4 H); 4.35 (m, 4 H); 3.97-3.75 (m, 7 H); 3.79 (s, 2 H); 3.57-3.49 (m, 1 H); 3.37 (q, J=7.5 Hz, 2 H); 2.66 (m, 4 H); 2.42 (m, 4 H); 1.46 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([NH2:40])(=[O:39])=[O:38])([O-:30])=[O:29]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:40][S:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N+:28]([O-:30])=[O:29])(=[O:38])=[O:39])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 2-nitrobenzenesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (22%); 1H NMR (d6-DMSO) δ 8.18 (d, J=5.2 Hz, 1H), 7.99 (d, J=5.9 Hz, 1H), 7.94-7.84 (m, 2H), 7.44-7.08 (m, 13H), 6.86 (d, J=8.1 Hz, 2H), 6.50 (d, J=15.7 Hz, 1H), 2.36 (q, J=7.4 Hz, 2H), 0.82 (t, J=7.4 Hz, 3H); APcI m/z: 539 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)=O.CN(C)CCN>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([NH:26][CH2:27][CH2:28][N:24]([CH3:25])[CH3:22])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)CCN
Solvent: C1CCOC1
Product: C[C@@H](C(=O)NCCN(C)C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
A solution of (S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole), 1,1'-carbonyldiimidazole (3.21 g, 0.0198 mole) in tetrahydrofuran (100 ml) was stirred at room temperature for two hours with nitrogen bubbling through it. A solution of N,N-dimethylethylenediamine (4.41 g, 0.050 mole) in tetrahydrofuran (5.5 ml) was added and the reaction mixture was stirred at room temperature under nitrogen overnight. The solvents were removed under reduced pressure and the solid was triturated in water (100 ml). The solid was collected by filtration, rinsed once with water, twice with 5% potassium hydroxide solution and twice with water. The solid was recrystallized from hot isopropyl ether to give 1.99 g (32%) of a solid. A 0.5-g sample was dried under high vacuum to give 0.49 g of title compound, mp 130°-133° C.
Reaction SMILES: Cl.[CH3:2][S:3]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:5])=[O:4].C(N(C(C)C)CC)(C)C.Cl[C:22]1[N:23]([CH2:44][C:45]([F:48])([F:47])[F:46])[C:24]2[C:29]([N:30]=1)=[C:28]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[N:27]=[C:26]([C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=1)[N:25]=2>CN1CCCC1=O>[CH3:2][S:3]([CH:6]1[CH2:11][CH2:10][N:9]([C:22]2[N:23]([CH2:44][C:45]([F:46])([F:48])[F:47])[C:24]3[C:29]([N:30]=2)=[C:28]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[N:27]=[C:26]([C:37]2[CH:42]=[N:41][C:40]([NH2:43])=[N:39][CH:38]=2)[N:25]=3)[CH2:8][CH2:7]1)(=[O:5])=[O:4]
Reactant: CS(=O)(=O)C1CCNCC1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC(F)(F)F)c3n2)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)C1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 31.2 %

Procedure:
4-Methanesulfonylpiperidine hydrochloride (385 mg, 1.93 mmol), diisopropylethylamine (672 μg, 3.9 mmol), and N-methyl-2-pyrrolidone (2 ml) were added to 5-[8-chloro-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (200 mg, 0.48 mmol) and the resulting mixture was stirred at 100° C. for 12 hours. The reaction mixture was partitioned with ethyl acetate and water, the organic layer was dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give the title compound (81 mg, 33%) as a pale yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12].[CH2:28]([O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35](F)=[C:34]([F:39])[CH:33]=1)[CH3:29].C(OCC)(=O)C>CC(N(C)C)=O>[F:39][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][C:35]=1[O:7][C:8]1[CH:9]=[C:10]([C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=2)=[O:12])[CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:31]([O:30][CH2:28][CH3:29])=[O:40]
Reactant: C[C@@H](CO)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: CCOC(=O)c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(Oc2cc(O[C@@H](C)CO)cc(C(=O)Nc3ccn(C)n3)c2)c(F)c1
Temperature: 115 °C
Yield: 31 %

Procedure:
Cesium carbonate (8.3 g, 25.4 mmol) was added to a mixture of 3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (3.7 g, 12.7 mmol) and ethyl-3,4-difluorobenzoate (2.36 g, 12.7 mmol) in dimethylacetamide (60 mL) and the stirred mixture heated at 115° C. for 3 hours. The mixture was allowed to cool to RT and ethyl acetate (100 mL) added. The mixture was washed with water (5×40 mL), brine (40 mL), dried (MgSO4), filtered, and reduced in vacuo. The residue was chromatographed on silica, eluting with 50% ethyl acetate in isohexane, to give the desired compound (1.8 g).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[Cl:17][C:18]1[S:22][C:21]([CH2:23][C:24](O)=[O:25])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[S:22][C:21]([CH2:23][C:24]([NH:1][N:2]2[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:16])=[O:25])=[CH:20][CH:19]=1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)s1
Product: O=C(Cc1ccc(Cl)s1)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
The product of Example 11B and 2-(5-chlorothiophen-2-yl)acetic acid were treated using a method similar to that described in Example 5 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.96-11.98 (bs, 1H), 8.43 (d, J=8.4 Hz, 1H), 8.11-8.17 (m, 1H), 7.97-8.10 (m, 2H), 7.01 (d, J=3.8 Hz, 1H), 6.93 (d, J=3.8 Hz, 1H), 3.96 (d, J=0.8 Hz, 2H); MS (ESI) m/z 388 (M+H)+.