Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([Cl:12])[CH:3]=1.[NH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(N(CC)CC)C>C(O)CCC>[C:24]([O:23][C:21]([N:18]1[CH2:19][CH2:20][CH:15]([CH2:14][NH:13][C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([Cl:12])[CH:3]=2)[CH2:16][CH2:17]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(Cl)cc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 84 %

Procedure:
A solution of methyl 4,6-dichloronicotinate (1.20 g, 5.8 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (1.24 g, 5.8 mmol) and triethylamine (4.09 mL, 29.1 mmol) in n-butanol (13 mL) was heated at 120° C. for 90 minutes by microwave irradiation. The solvent was evaporated and the mixture was purified by flash chromatography on silica, eluting with ethyl acetate-hexane (1:4), to give methyl 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloronicotinate as a colourless solid (1.87 g, 84%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][CH:3]=1.[CH:9]1([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:15]2[CH2:16][CH2:17][CH:12]([CH:9]3[CH2:11][CH2:10]3)[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)cc1
Reactant: C1CC(C2CC2)CCN1
Solvent: CCN(C(C)C)C(C)C
Product: Brc1ccc(N2CCC(C3CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A round bottomed flask was charged with 1-bromo-4-fluorobenzene (1.93 g, 11.0 mmol), 4-cyclopropylpiperidine (1.65 g, 13.2 mmol) and DIEA (7.67 g, 44.0 mmol). The flask was purged with nitrogen. Anhydrous 1-methyl-2-pyrrolidinone (25 mL) was added, and the resulting mixture was degassed via nitrogen sparge. The mixture was then placed in a pre-heated oil bath (180° C.), and was held at this temperature for 2 days, whereupon it was allowed to cool to ambient temperature, then was poured into water. The aqueous phase was extracted with ethyl acetate and the organic phase was washed with brine. The organic phase was then dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by chromatography on silica gel (0 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 281.8 [M+H]+; 1H NMR (500 MHz, CD2Cl2) δ 7.30 (d, J=8.8 Hz, 2 H),6.79 (d, J=8.8 Hz, 2 H),3.62 (d, J=12.2 Hz, 2 H),2.62 (t, J=12.1 Hz, 2 H),1.83 (d, J=12.8 Hz, 2 H),1.56-1.42 (m, 2 H),0.69-0.53 (m, 2 H),0.41 (d, J=7.5 Hz, 2 H),0.11 (d, J=4.5 Hz, 2 H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[CH2:41][C@H:40]([NH:45][S:46]([CH:49]([CH3:51])[CH3:50])(=[O:48])=[O:47])[CH2:39]3)O1.Cl[CH2:54][C:55]1[N:59]([CH2:60][CH3:61])[N:58]=[C:57]([C:62]([F:65])([F:64])[F:63])[CH:56]=1>C1COCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH2:60]([N:59]1[C:55]([CH2:54][C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[CH2:41][C@H:40]([NH:45][S:46]([CH:49]([CH3:50])[CH3:51])(=[O:47])=[O:48])[CH2:39]3)=[CH:56][C:57]([C:62]([F:64])([F:63])[F:65])=[N:58]1)[CH3:61]
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: CCn1nc(C(F)(F)F)cc1CCl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCn1nc(C(F)(F)F)cc1Cc1ccc2c(c1)C[C@@H](NS(=O)(=O)C(C)C)C2
Temperature: 100 °C
Yield: 6.4 %

Procedure:
Tris(dibenzylideneacetone)dipalladium (0) chloroform adduct (0.014 mmol, 14.17 mg) was dissolved in THF (1 mL) and triphenylphosphine (0.027 mmol, 7.18 mg) added. The mixture was stirred at room temperature for 30 m before addition of N-bromosuccinimide (0.027 mmol, 4.87 mg). Stirring was continued for a further 30 min before addition of (S)—N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (0.137 mmol, 50 mg) in 500 μL THF, 5-(chloromethyl)-1-ethyl-3-(trifluoromethyl)-1H-pyrazole (0.137 mmol, 29.1 mg) in 500 μL THF and 2M Na2CO3 solution (2 mL). The mixture was heated to 100° C. for 10 min in the microwave before the mixture was filtered through a filter tip and concentrated to dryness. The residue was partitioned between DCM/Water and the organic phase collected and dried using a hydrophobic filter. TLC (1:1 EtOAc/Heptane) shows complex mix (see in process)—difficulty to assign product spot. The residue was purified using silica chromatography (20% EtOAc/Heptane) to give a residue which was further purified on basic HPLC to give the desired compound (3.6 mg, 8.7 μmol, 6.3%). MS (ESI): m/z [M−H]− 414.4.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[NH:10][CH:9]=1.[CH3:19][NH:20][CH3:21].C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C>[CH3:19][N:20]([CH3:21])[CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[NH:10][CH:9]=1
Reactant: N#Cc1ccc2[nH]cc(CC3CCCC3=O)c2c1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CN(C)C1CCCC1Cc1c[nH]c2ccc(C#N)cc12
Reaction time: 0.08 h
Yield: 25.6 %

Procedure:
A solution of 3-(2-oxo-cyclopentylmethyl)-1H-indole-5-carbonitrile (45 mg, 0.19 mMol), dimethylamine (1.92 mL, 3.78 mMol, 2.0 M/THF), sodium cyanoborohydride (0.12 g, 1.9 mMol) and acetic acid (0.2 mL) in ethanol (10 mL) was stirred for 16 h. The solution was cooled in an ice-bath and quenched with aqueous hydrochloric acid (2 mL, 1 N). The mixture was stirred for 5 min and then poured into a saturated aqueous solution of sodium bicarbonate (15 mL) and brine (10 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude material was purified by silica gel column chromatography using a step gradient of 0.5% MeOH/CHCl3-30% MeOH/CHCl3 to give 3-(2-dimethylamino-cyclopentylmethyl)-1H-indole-5-carbonitrile (13.0 mg, 26%) as a mixture of diastereomers. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (1H, s), 7.50 (1H, d, J=8.4 Hz), 7.38 (2H, m), 2.89 (1H, m), 2.33 (9H, m), 1.82 (2H, m), 1.57 (2H, m), 1.42 (2H, m); LCMS (Method A: 4.6×50 mm XTERRA C-18 S5 column, 5 mL/min, 0–100% MeOH/H2O/0.1% TFA, 2 min gradient): Tr=1.09 min, m/e 268 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:36][O:35][C:33](=[O:34])[CH2:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:2]([Cl:1])[CH:3]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)Cc1ccc(COc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1

Procedure:
In analogy to Example 1, step 7, 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (Example 19, Step 5) was reacted with methyl 4-(bromomethyl)phenylacetate and potassium carbonate to give the title compound as a colorless waxy solid. MS (m/e)=528.1 [M+H+].
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH:3]=[O:2])=[CH:5][CH:6]=2)[CH:11]=1
Reactant: COC(=O)c1ccc(-c2cccnc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=Cc1ccc(-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of 4-pyridin-3-yl-benzoic acid methyl ester (124 mg in 5.0 mL dry methylene chloride) at -78° C. was added 1.46 mL of a 1M solution of diisobutylaluminum hydride in methylene chloride and the mixture stirred at low temperature. After 2 hours, the reaction was quenched by the addition of acetone, warmed to room temperature and stirred for 20 minutes with 1.5 mL of a 1M solution of tartaric acid. At this time the mixture was extracted with methylene chloride and the combined organics dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane, 1:1; then methylene chloride:methanol, 95:5) gave the title compound (104 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2(Br)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:8][C:7]=1[CH2:18]Br)=[O:5])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=2)=[N:8][C:7]=1[CH2:18][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1oc(C2(Br)CCCCC2)nc1CBr
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1oc(C2=CCCCC2)nc1CN1CCOCC1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
1.25 g 2-(1-Bromo-cyclohexyl)-4-bromomethyl-oxazole-5-carboxylic acid ethyl ester was dissolved in 15 ml tetrahydrofuran. 1.38 ml morpholine and 0.5 ml DBU were added and the reaction mixture stirred at 65° C. for three hours. The solvent was removed in vacuo and the resulting crude material was purified by reversed phase HPLC. The lyophilisate was dissolved in ethyl acetate and washed with saturated NaHCO3 and 2N NaOH solution the organic layer was dried over MgSO4. The solvent was removed in vacuo to obtain 580 mg 2-Cyclohex-1-enyl-4-morpholin-4-ylmethyl-oxazole-5-carboxylic acid ethyl ester as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH:21][CH2:22][CH2:23][CH3:24]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:21]([CH3:20])[CH2:22][CH2:23][CH3:24])[C:11]([CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)cc1Cl
Reactant: CCCNC
Solvent: CS(C)=O
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C

Procedure:
The title compound was prepared from (5-chloro-4-methyl-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example B8) (3.5 g, 12.2 mmol) and N-methylpropylamine (6.5 ml, 61.0 mmol) in DMSO (35 mL) at 55° C. according to the general procedure C. Obtained as a yellow oil (3.89 g, 98%).
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:19]3[C:20](O)=[CH:21][C:22]4[O:26][CH2:25][CH2:24][C:23]=4[CH:27]=3)([CH2:17][OH:18])[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([CH2:17][O:18][C:20]4[CH:21]=[C:22]5[C:23](=[CH:27][C:19]3=4)[CH2:24][CH2:25][O:26]5)[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(CO)c1cc2c(cc1O)OCC2
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure described in EXAMPLE 1, and making non-critical variations using 1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (51%) as a white solid: MS (ES+) m/z 446.3 (M+1).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].FC(F)(F)C(O)=O.[NH2:15][C:16]1[C:21]2=[C:22]([C:37]3[S:38][C:39]4[C:45]([O:46][CH3:47])=[CH:44][C:43]([CH3:48])=[CH:42][C:40]=4[CH:41]=3)[C:23]([CH2:32][NH:33][C:34](=[O:36])[CH3:35])=[C:24]([CH2:25][N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:20]2[N:19]=[CH:18][N:17]=1.C(Cl)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.ClCCl.CO.O>[C:3]([N:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:24]2[N:20]3[C:21]([C:16]([NH2:15])=[N:17][CH:18]=[N:19]3)=[C:22]([C:37]3[S:38][C:39]4[C:45]([O:46][CH3:47])=[CH:44][C:43]([CH3:48])=[CH:42][C:40]=4[CH:41]=3)[C:23]=2[CH2:32][NH:33][C:34](=[O:36])[CH3:35])[CH2:31][CH2:30]1)(=[O:4])[CH3:2]
Reactant: COc1cc(C)cc2cc(-c3c(CNC(C)=O)c(CN4CCNCC4)n4ncnc(N)c34)sc12
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C)cc2cc(-c3c(CNC(C)=O)c(CN4CCN(C(C)=O)CC4)n4ncnc(N)c34)sc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of Example 63 (110 mg, 229 μmol) and acetyl chloride (32 μl, 458 μmol) in THF/dichloromethane (1:2, 3 ml) was treated with sodium carbonate (194 mg, 1.83 mmol) and stirred at rt overnight. Then, the mixture was diluted with methanol (2 ml) and water (1 ml) and stirred at rt for 1 h. After evaporation, the residue was purified by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. formic acid). Lyophilization from 1,4-dioxane and re-purification by column chromatography on silica gel (dichloromethane/methanol 50:1→100% methanol) afforded 35 mg (28% of th.) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:34])=[C:6]([C:8]2[N:9]=[C:10]([NH:24][C:25]3[C:30](C(O)=O)=[CH:29][N:28]=[CH:27][CH:26]=3)[C:11]3[CH:17]=[CH:16][C:15](NCCN(C)C)=N[C:12]=3[N:13]=2)[CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CN.[CH3:49][N:50]([CH:52]=[O:53])C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:34])=[C:6]([C:8]2[N:9]=[C:10]([NH:24][C:25]3[C:30]([C:52]([NH:50][CH3:49])=[O:53])=[CH:29][N:28]=[CH:27][CH:26]=3)[C:11]3[CH2:17][CH2:16][CH2:15][C:12]=3[N:13]=2)[CH:7]=1
Reactant: CN(C)C=O
Reactant: CN(C)CCNc1ccc2c(Nc3ccncc3C(=O)O)nc(-c3cc(Cl)ccc3F)nc2n1
Agent: CN
Agent: O=C(n1ccnc1)n1ccnc1
Product: CNC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
To a suspension of substituted nicotinic acid, 4-[2-(5-Chloro-2-fluoro-phenyl)-7-(2-dimethylamino-ethylamino)-pyrido[2,3-d]pyrimidin-4-ylamino]-nicotinic acid (0.030 g) in dry DMF (1 ml) was added Carbonyldiimidazole (0.020 g) followed by methylamine (156 uL, 2 M solution if THF). The reaction mixture was stirred at room temperature for 16 h. The crude residue was purified by preparative HPLC (Acetonitrile/water 5% to 95% gradient) to give 4-[2-(5-Chloro-2-fluoro-phenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-N-methyl-nicotinamide (280 mg, 68%) as a white solid.
Reaction SMILES: C(OC(=O)C(C)(C)CC1C=CC(S)=CC=1)C.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([OH:39])([CH3:38])[C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([C:27]1[CH:32]=[CH:31][C:30]([C@@:33]([OH:39])([CH3:38])[C:34]([F:36])([F:37])[F:35])=[CH:29][CH:28]=1)(=[O:26])=[O:25]
Reactant: CC(O)(c1ccc(S(=O)(=O)c2ccccc2Cl)cc1)C(F)(F)F
Agent: CCOC(=O)C(C)(C)Cc1ccc(S)cc1
Product: C[C@](O)(c1ccc(S(=O)(=O)c2ccccc2Cl)cc1)C(F)(F)F

Procedure:
Using the methods described above in Example 12, but substituting 2-chlorobenzenethiol for 3-(4-mercaptophenyl)-2,2-dimethylpropionic acid ethyl ester in step a, 2-[4-(2-chlorobenzenesulfonyl)phenyl]-1,1,1-trifluoropropan-2-ol was prepared. 1H NMR (CDCl3, 400 MHz) δ 8.27 (dd, J=2.0 Hz, 7.6 Hz, 1H), 7.98 (d, J=8.6 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.57-7.44 (m, 3H), 2.61 (s, 1H), 1.80 (s, 3H). The racemic product was resolved by chiral HPLC. The flow rate was 20 mL/min on a Chiralcel OD-H 20 mm i.d.×250 mm, 5 μ column (Daciel chemical Industries LTD), using isopropyl alcohol/hexanes (10/90) as the eluent.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[O:12])[CH3:11].[CH2:13](Br)[CH2:14][C:15]([CH3:17])=[CH2:16]>[OH-].[K+]>[OH:1][C:2]1[C:7]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[C:6]([OH:8])[C:5]([CH2:7][CH:2]=[C:3]([CH3:10])[CH3:4])=[C:4]([OH:9])[C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)c1c(O)cc(O)cc1O
Reactant: C=C(C)CCBr
Agent: [K+]
Agent: [OH-]
Product: CC(=O)c1c(O)c(CC=C(C)C)c(O)c(CC=C(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
1-(2,4,6-trihydroxyphenyl]ethanone (2.0 mg, 11.9 mmol) was dissolved in a 5% potassium hydroxide aqueous solution (20 mL). After the mixture was cooled below 0° C., isopentenyl bromide (3.6 g, 24 mmol) was slowly added dropwise within 30 min. The reaction mixture was stirred at room temperature for 2 hours, then poured into an ice water and acidified to pH 2. The reaction mixture was extracted with ethyl acetate. The extract was collected and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography (dichloromethane as eluent) to give the desired compound (0.7 g, yield 20%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=[O:10].CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O>CN(C=O)C>[O:10]=[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CBr)CC1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CCOCC1)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Morpholine (0.22 g, 2.59 mmol), 42-1 (0.61 g, 1.99 mmol) and DIEA (0.33 g, 2.59 mmol) were dissolved in DMF (2 mL) and stirred for 18 hours at room temperature. The DMF was then removed under reduced pressure and the residue partitioned between water and methylene chloride. The methylene chloride was drawn off, dried and evaporated to a solid to afford 42-2. This recovered product was treated with neat trifluoroacetic acid and the excess trifluoroacetic acid evaporated off. The resulting residue was partitioned between methylene chloride and aqueous Na2CO3. The free base did not extract from the aqueous so the aqueous was evaporated to dryness, washed the methanol, and the solids filetred off to afford 42-2. 1H-NMR(CD3OD): 3.69(t, 4H); 3.59 (t, 2H); 3.54(t, 2H); 3.22(s, 2H); 2.83(t, 2H); 2.77(t, 2H); 2.49(t, 4H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[NH:20][CH:21]=[C:22]([NH:23][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=4)[C:15]=23)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.Cl.[Pd]>[N:11]1([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[NH:20][CH:21]=[C:22]([NH:23][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=4)[C:15]=23)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: O=C(Nc1c[nH]c2nccc(N3CCN(Cc4ccccc4)CC3)c12)c1cccnc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C(Nc1c[nH]c2nccc(N3CCNCC3)c12)c1cccnc1
Reaction time: 8 h
Yield: 81.6 %

Procedure:
N-(4-(4-Benzylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.080 g, 0.19 mmol) was placed in MeOH (2 mL). Pd/C (0.0206 g, 0.0194 mmol) was then added, followed by the addition of 4 drops of concentrated HCl. The reaction was then placed under a balloon of H2 and stirred overnight. The reaction was filtered, washed with MeOH and concentrated to give the crude product N-(4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.050 g, 79.9% yield) which was used without further purification.
Reaction SMILES: COC1C([N+]([O-])=O)=C(CCN)C=CC=1.[C:15]1([CH:21]2[CH2:23][O:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH:21]([OH:22])[CH3:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(C2CO2)cc1
Agent: COc1cccc(CCN)c1[N+](=O)[O-]
Product: CC(O)c1ccccc1

Procedure:
2- 2-(3-Methoxy-2-nitrophenyl)ethylamino!-1-phenylethanol was synthesized in analogy to example 1D from 2-(3-methoxy-2-nitrophenyl)-ethylamine and phenyloxirane. White crystalline powder. M.p. 99°-101° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[CH3:14].C([Li])CCC.Cl[CH:21]([SiH3:23])Cl>CCCCCC.O>[CH3:21][SiH:23]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1
Reactant: [SiH3]C(Cl)Cl
Reactant: Cc1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: C[SiH]1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 1 L rb flask equipped with a Teflon covered magnetic stirring bar and a reflux condenser was placed potassium tert-butoxide (36 g; 0.32 mol), o-xylene (17 mL; 0.15 mol) and 700 mL of hexanes. n-Butyllithium (128 mL; 2.5M) in hexane was added to the above mixture via a syringe. The red color of the o-xylene dianion appeared. The resulting mixture was heated to reflux for 1 h. The reaction mixture was cooled to room temp. The suspension of the dianion was transferred via a cannula to a sintered glass filter. The solvent was removed by suction filtration. The precipitated dianion was rinsed with fresh hexane. It was then resuspended in 500 mL of hexane and the suspension returned via a cannula to the original apparatus. Freshly distilled dichloromethylsilane (17 mL; 0.16 mol) was added. The mixture was stirred overnight a room temperature. 50 mL water was added. The organic layer was washed three times with water, dried over anhydrous calcium chloride, filtered and the solvents removed by evaporation under reduced pressure. The residue was purified by fractional distillation through a 15 cm vacuum jacketed Vigreux column. A central fraction, b.p. 43°-44° C./0.7 mmHg, was obtained. Yield: 5.5 g(25%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[H-].[Na+].[C:13](=O)([O:16]C)[O:14][CH3:15].Cl>CN(C=O)C>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([CH2:1][C:13]([O:14][CH3:15])=[O:16])=[O:3])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)c1ccc(O)cc1
Reaction time: 0.25 h

Procedure:
A solution of 4-hydroxyacetophenone (500 g) in DMF (1.5 L) was slowly added to a suspension of sodium hydride (331 g) in DMF. The mixture was stirred for 15 min. till gas evolution had subsided. Dimethyl carbonate (1.55 L) was added and the reaction stirred overnight at room temperature. The reaction was worked up by pouring into ice (15 LB) followed by acidification to pH 2 with hydrochloric acid. The aqueous mixture was extracted with ethyl acetate (3×5 L) and this was washed with water (3×1 L) and brine, then dried (Na2SO4), filtered, and concentrated. The crude product was purified by chromatography on silica gel (10 Kg) with 15 to 40% ethyl acetate-hexane. The chromatographed product was recrystallized twice from ethyl acetate-hexane to yield 313 gm first crop material as a white powder with mp 90-92° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]=[CH:12]2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]=[CH:12]2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc2cnccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc2cnccc12
Reaction time: 72 h
Yield: 45.6 %

Procedure:
Methanesulfonyl chloride (3.2 ml, 0.042 mol) was added to a solution of 5-aminoisoquinoline (5.0 g, 0.035 mol) in pyridine (40 ml) and the mixture was allowed to stand for 72 hours. The reaction mixture was then poured into aqueous citric acid (10%, 400 ml) and extracted with ethyl acetate (2×230 ml). The organic layer was evaporated to give a residue which was purified on silica gel, eluting with dichloromethane:methanol (95:5, v/v), to afford the subtitle compound as a solid (3.55 g, 46%). Rf 0.03 (CH2Cl2:diethyl ether 4:1, v/v). 1H NMR (D6-DMSO) Γ: 3.07 (3H, s), 7.68 (1H, t), 7.75 (1H, d), 8.03 (1H, d), 8.10 (1H, d), 8.54 (1H, d), 9.32 (1H, s), 9.79 (1H, bs).