Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8].[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=2)[C:7]([NH:9][CH3:10])=[O:8])[CH2:20][CH2:19]1
Reactant: OCCN1CCNCC1
Reactant: CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(N2CCN(CCO)CC2)ccc1[N+](=O)[O-]

Procedure:
A solution of 5-fluoro-N-methyl-2-nitrobenzamide, 1-(2-hydroxyethyl)piperazine, and Hunig's base in 20 mL of DMF was stirred at room temperature over the weekend. The resulting mixture was rotavaped to dryness, and the residue was purified by flash column SF40-150 at 2%-10% MeOH/CH2Cl2. Product came out at 7% MeOH/CH2Cl2. MS (ES) m/e 309 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].Br[CH:11]([CH2:17][CH3:18])[C:12]([O:14]CC)=[O:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[OH-].[Na+].Cl>CN(C)C(=O)C.C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:18][CH2:17][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)C(Br)CC
Reactant: Cc1ccc(C)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C)c(OCCCC(=O)O)c1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
2,5-Dimethylphenol (6.1 g, 0.05 mol) and ethyl bromobutyrate were dissolved in 60 ml of N,N-Dimethylacetamide (DMAC). Potassium carbonate (11 g) and potassium iodide 0.5 g (0.003 mol) were added to this solution. The mixture was stirred at 70-80° C. for 24 hours. The filtrate was added to distilled water (200 ml). An oily precipitate formed and was extracted with methylene chloride (100 ml). The organic layer was washed with 5% sodium carbonate (3×150 ml), dried over anhydrous sodium sulfate, and concentrated to give al oily residue. The oil was dissolved in ethanol (5 ml). The solution was mixed with 2N sodium hydroxide (30 ml). The mixture was stirred at 70-80° C. until the ester was hydrolyzed (determined by HPLC). The solution was acidified with 3N hydrochloride to pH 1 to form a precipitate. The precipitate was collected by filtration and dissolved in 4% sodium bicarbonate. Insoluble materials were removed by filtration. The filtrate was acidified to pH 1 to form a precipitate. The precipitate was collected by filtration and air-dried. 6.6 g of 4-(2,5-dimethylphenoxy) butyric acid was recovered. Melting point: 63-65° C. Combustion analysis: % C. 69.21 (calcuated), 69.04 (found); % H, 7.74 (calculated); 7.49 (found). 1H NMR Analysis (d6-DMSO). δ 6.98, d, 1H; 6.71, s, 1H; 6.62, d, 1H; 3.94, t, 2H; 2.40, t, 2H; 2.24, s, 3H; 2.09, s, 3H; 1.95, p, 2H.
Reaction SMILES: [CH2:1]([O:8]C1C=CC(C=O)=NC=1CS(C)(=O)=O)C1C=CC=CC=1.C1OC2C=CC(C([N+]#[C-])(C)C)=CC=2O1.[OH:36][C:37]1[CH:38]=[CH:39][C:40]([CH:48]([CH2:50][NH:51][CH:52]([CH3:61])[CH2:53][C:54]2[CH:59]=[CH:58][C:57]([OH:60])=[CH:56][CH:55]=2)[OH:49])=[N:41][C:42]=1[CH2:43][S:44]([CH3:47])(=[O:46])=[O:45]>>[OH:36][C:37]1[CH:38]=[CH:39][C:40]([CH:48]([CH2:50][NH:51][CH:52]([CH3:61])[CH2:53][C:54]2[CH:55]=[CH:56][C:57]3[O:60][CH2:1][O:8][C:58]=3[CH:59]=2)[OH:49])=[N:41][C:42]=1[CH2:43][S:44]([CH3:47])(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cc1nc(C=O)ccc1OCc1ccccc1
Reactant: CC(Cc1ccc(O)cc1)NCC(O)c1ccc(O)c(CS(C)(=O)=O)n1
Agent: [C-]#[N+]C(C)(C)c1ccc2c(c1)OCO2
Product: CC(Cc1ccc2c(c1)OCO2)NCC(O)c1ccc(O)c(CS(C)(=O)=O)n1

Procedure:
Reacting 5-benzyloxy-6-methanesulfonylmethyl-2-pyridinecarboxaldehyde with 3,4-methylenedioxyphenylisopropyl isocyanide followed by reduction of the intermediate amide and hydrogenation of the amine gives 5-hydroxy-6-methanesulfonylmethyl-α-[2-(3,4-methylenedioxyphenyl)-1-methylethylaminomethyl]-2-pyridinemethanol.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH:20]=[CH:19][C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[C:1]([NH:9][C:10]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH:20]=[CH:19][C:11]=1[C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1NC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2cccc(Cl)c2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(benzamido)-4-(3-chlorophenyl)benzoate and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and methanol was added to the obtained residue and a solid substance was separated by filtration to obtain 21 mg of 2-(benzamido)-4-(3-chlorophenyl)benzoic acid as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH2:14][C:15]4[S:16][C:17]([C:20]5[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=5)=[CH:18][C:19]=4[C:12]=3[N:11](COCC[Si](C)(C)C)[N:10]=2)=[CH:5][CH:4]=1.Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH2:14][C:15]4[S:16][C:17]([C:20]5[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=5)=[CH:18][C:19]=4[C:12]=3[NH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(OC)nc4)cc2-3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2n[nH]c3c2Cc2sc(-c4ccc(OC)nc4)cc2-3)cc1
Temperature: 100 °C
Yield: 87 %

Procedure:
6-(4-Methoxy-phenyl)-2-(6-methoxy-pyridin-3-yl)-4-(2-trimethylsilan yl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.35 g, 0.69 mmol) was dissolved in MeOH and treated with concentrated HCl (0.21 mL, 6.9 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 6-(4-Methoxy-phenyl)-2-(6-methoxy-pyridin-3-yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.55 g, 0.6 mmol) as white solid in 87% yield.
Reaction SMILES: [H-].[Na+].[CH:3]([CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)=[CH2:4].[C:11]([C@H:19]([CH3:23])[C:20](Cl)=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1(C)C=CC=CC=1>[C:11]([C@H:19]([CH3:23])[C:20]([N:9]1[C@H:5]([CH:3]=[CH2:4])[CH2:6][CH2:7][C:8]1=[O:10])=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=CC1CCC(=O)N1
Reactant: C[C@H](C(=O)Cl)C(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C[C@@H]1CCC(=O)N1C(=O)[C@@H](C)C(=O)c1ccccc1
Temperature: 25 °C
Yield: 45 %

Procedure:
To 60% sodium hydride (336 mg, 10.0 mmol) in toluene (20 mL) at 0° C. was added dropwise a solution of 5-vinylpyrrolidin-2-one (1.0 mg, 9.0 mmol) in toluene (10 mL) over a 10 min period. The cooling bath was removed and the solution was allowed to warm to 25° C. to ensure complete generation of the anion. To the anion at 25° C. was added dropwise a solution of (2S)-2-benzoylpropanoyl chloride (21, 2.7 g, 12.6 mmol) in toluene (10 mL) over a 10 min period. TLC indicated that the reaction was complete upon addition of the acid chloride (silica gel plates; hexane and t-butyl methyl ether, 1:1). Water (50 mL) as added to the reaction mixture and the phases were separated. The aqueous phase was extracted with diethyl ether (2×40 mL). The combined organic phases were washed with a saturated aqeous sodium bicarbonate solution (1×100 mL) and dried (MgSO4). Concentration and purification by flash chromatography on silica gel (EM 60, 0.040-0.063 partical size, 230-400 Mesh, column size: 6.5 cm diameter×20 cm length) using hexane and t-butyl methyl ether (10:1) afforded 1.1 g (42%) of (5S)-N-((2S)-2-benzoylpropanoyl)-5-ethenylpyrrolidin-2-one (24a) as a thick oil: 1H NMR (CDCl3) δ1.44-1.46 (d, J=6.5 Hz ,3 H), 1.64-1.80 (m, 1 H), 2.12-2.20 (m, 1 H), 2.42-2.84 (m, 2 H), 4.12-4.21 (q, J=6.4 Hz, 1 H), 4.38-4.47 (m, 1 H), 4.58-4.67 (m, 1 H), 4.89-4.91 (m, 1 H), 5.06-5.19 (m, 2 H), 5.77-5.85 (m, 1 H), 7.28-7.40 (m, 5 H); 13C NMR (CDCl3) δ174.8, 173.5, 137.7, 135.3, 128.0, 127.7, 127.4, 115.1, 74.6, 71.6, 31.3, 24.0, 18.1; IR (neat) 3066 (w), 3033 (w), 2939 (w), 1740 (vs), 1708 (vs), 1455 (s), 1370 (s), 1277 (s), 1148 (s), 1113 (s), 739 (s) cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O[CH2:19][CH:20]([CH2:22]O)O>>[N:1]1[C:2]2[C:3](=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)[CH:22]=[CH:20][CH:19]=1
Reactant: CC(C(=O)O)c1ccc(N)cc1
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Product: CC(C(=O)O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The mixture of 2-(4-Amino-phenyl)-propionic acid (1.70 g), FeSO4 7H2O (0.30 g), glycerol (4.04 g) and sulfuric acid (2 mL) was refluxed with stirring for 5 h. After cooled to room temperature, the reaction mixture was concentrated under reduced vacuum. The aqueous solution was treated with 12N—NaOH solution. The precipitated solid was filtered and the filtrate was acidified with AcOH. The resulting mixture was extracted and the combined organic layer was dried over magnesium sulfate, filtered, concentrated in vacuo. The resulting residue was chromatographed on silica gel (CH2Cl2:MeOH=15:1 to 10:1) to afford the product as a brown solid. (0.83 g, 40.0%)
Reaction SMILES: [C:1]([SH:5])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[CH2:23]([C@H:30]([CH2:41][C:42]([CH2:44]Cl)=[O:43])[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:23]([C@H:30]([CH2:41][C:42](=[O:43])[CH2:44][S:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(CCl)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)S
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)SCC(=O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Yield: 73 %

Procedure:
To tert-butylmercaptan (0.11 ml) in dimethylformamide (5 ml) at 0° C. was added potassium bis(trimethylsilyl)amide in toluene (1.80 ml, 0.90 mmol, 0.5M) followed by the resultant compound from Example 34 (259.6 mg, 0.785 mmol) in dimethylformamide (3 ml). After 16 h at room temperature the mixture was diluted with ethyl acetate, washed with water and brine, then dried over Na2SO4 and evaporated. Chromatography of the residue on silica gel with 10% ethyl acetate in hexane afforded 219.6 mg (73%) of a colorless oil. 1H NMR (CDCl3) δ7.10-7.40 (m,10H), 5.07 (s,2H), 3.25 (s,2H), 3.18-3.29 (m,1H), 2.97-3.07 (m,2H), 2.78 (dd,1H), 2.71 (dd,1H), 1.25 (s,9H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Br:6][C:7]1[C:12]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:11][CH:10]=[CH:9][N:8]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[Br:6][C:7]1[C:12]([O:13][CH2:14][C:15]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:17])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CCNCC
Reactant: O=C(O)COc1cccnc1Br
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)C(=O)COc1cccnc1Br
Yield: 87.7 %

Procedure:
Diethylamine (0.874 g) was slowly added with cooling to [(2-bromo-3-pyridinyl)oxy]acetic acid (2.58 g) in toluene (10 ml). The solution was then dded to phosphorous pentoxide (1.87 g) and diethylamine (1.74 g) in toluene (10 ml). After the addition the mixture was heated under reflux overnight. The dark solution was diluted with water (20 ml), made alkaline with 8% sodium bicarbonate (20 ml) and extracted with ethyl acetate (3×30 ml). The combined organic extracts were dried and the solvent was evaporated in vacuo to give the title compound as a brown oil (2.8 g). t.l.c. (toluene-ethanol-0.88 ammonia 80:20:1) Rf 0.47.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C@@H:16]3[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]3)[CH2:10][C:9]2=[O:17])[CH2:4][CH2:3]1.C[O-].[Na+].[CH3:21][C:22]1[CH:36]=[CH:35][CH:34]=[CH:33][C:23]=1[C:24]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)=[O:25].C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH3:21][C:22]1[CH:36]=[CH:35][CH:34]=[CH:33][C:23]=1[C:24]([N:26]1[CH2:27][CH2:28][CH:29]([N:2]2[CH2:3][CH2:4][CH:5]([N:8]3[C@@H:16]4[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]4)[CH2:10][C:9]3=[O:17])[CH2:6][CH2:7]2)[CH2:30][CH2:31]1)=[O:25]
Reactant: Cc1ccccc1C(=O)N1CCC(=O)CC1
Reactant: O=C1C[C@H]2CCCC[C@@H]2N1C1CCNCC1
Agent: C[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: Cc1ccccc1C(=O)N1CCC(N2CCC(N3C(=O)C[C@H]4CCCC[C@@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.4 %

Procedure:
To a solution of (3aR,7aS)-1-piperidin-4-yloctahydro-2H-indol-2-one hydrochloride (70 mg, 0.27 mmol) in MeOH (4 mL) was added sodium methoxide (62 μl, 0.27 mmol) followed by 1-(2-methylbenzoyl)piperidin-4-one (60 mg, 0.27 mmol) and the mixture stirred at room temperature for 10 minutes. A solution containing sodium cyanoborohydride (28 mg, 0.41 mmol) and zinc chloride (18 mg, 0.13 mmol) in MeOH (1 mL) was then added and the mixture stirred at room temperature overnight. The reaction was quenched with water and solvents were removed under reduced pressure. The mixture was diluted in dichloromethane (30 mL) and 1N NaOH (7 mL) was added. The phases were separated and aqueous phase was extracted with dichloromethane (2×20 mL). The combined organic phases were dried and concentrated in vacuo. The crude compound was purified by high pH prep LCMS (40-60%) to provide the title compound as a white solid (37 mg, 37%). 1H NMR (400 MHz, CHLOROFORM-D): δ ppm 1.12-1.41 (m, 5H), 1.42-1.54 (m, 1H), 1.54-1.70 (m, 4H), 1.70-1.99 (m, 7H), 2.11-2.39 (m, 4H), 2.23 (s, 3H), 2.39-2.55 (m, 1H), 2.72 (t, J=12.50 Hz, 1H), 2.78-3.07 (m, 4H), 3.48 (d, J=12.11 Hz, 1H), 3.83-4.01 (m, 1H), 4.80 (d, J=12.50 Hz, 1H), 7.01-7.28 (m, 4H). MS (M+1): 424.2
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)C(O)=O.[N:15]1([CH2:21][CH2:22][O:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[C:26]([NH2:35])=[N:27][C:28]([NH2:34])=[N:29]3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[F:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43](Cl)(=[O:45])=[O:44]>O1CCCC1>[F:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43]([N:18]1[CH2:19][CH2:20][N:15]([CH2:21][CH2:22][O:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[C:26]([NH2:35])=[N:27][C:28]([NH2:34])=[N:29]3)[CH2:16][CH2:17]1)(=[O:45])=[O:44]
Reactant: Nc1nc(N)c2c(OCCN3CCNCC3)cccc2n1
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(N)c2c(OCCN3CCN(S(=O)(=O)c4ccccc4F)CC3)cccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 310 %

Procedure:
In an 8 mL vial triethylamine (40 mg; 0.4 mmol) was added to a mixture of 5-(2-piperazin-1-yl-ethoxy)-quinazoline-2,4-diamine trifluoroacetate (50 mg; 0.1 mmol) in 1.5 mL of tetrahydrofuran. 2-Fluorobenzene-sulfonyl chloride was added and reaction stirred at room temperature for 16 hours. Reaction was purified by reprecipitation with ethanol and (0.5:1) 1N NaOH. Solids were filtered to obtain 14 mg of title compound. (310% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.77 (m, 3H), 7.48 (m, 2H), 7.32 (t, J=8.4 Hz, 1H), 7.18 (br s, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.50 (d, J=7.6 Hz, 1H), 5.87 (br s, 2H), 4.16 (t, J=5.2 Hz, 2H), 3.17 (br s, 4H), 2.77 (t, J=5.2 Hz, 2H), 2.52 (m, 4H).
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)CCN(C)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.[N:27]1[CH:32]=[CH:31][C:30]([CH:33]=[O:34])=[CH:29][CH:28]=1>C1COCC1>[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[CH:33]([C:30]1[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=1)[OH:34]
Reactant: COc1ccc(F)cc1
Reactant: O=Cc1ccncc1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(F)c(C(O)c2ccncc2)c1
Temperature: -75 °C
Reaction time: 2 h

Procedure:
Butyl lithium (47.5 ml of 2.22M solution, 105.6 mmole) was added slowly to a solution of pentamethyldiethylenetriamine (15 ml) and 4-fluoroanisole (12.61 g, 0.1 mole) in THF (150 ml) at -70° C. The solution was stirred for 2 hr at -75° C. and a solution of pyridine-4-aldehyde (9.55 ml, 0.1 mole) in THF was added at -75° C. The mixture was allowed to warm to 25° C. slowly and then quenched with ammonium chloride solution. The mixture was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed with water and 3N hydrochloric acid. The acid washes were then basified with sodium hydroxide and extracted with ether and the ether solution concentrated in vacuo. The crude product was recrystallized from 80% ethanol to give (2-fluoro-5-methoxy-phenyl)-4-pyridylmethanol as a white powder (12.22 g +3.12 g second crop, 65.8% total yield).
Reaction SMILES: CC(O)C.[O:5]1[CH2:7][CH:6]1[CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.[NH3:18]>>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([O:9][CH2:8][CH:6]([OH:5])[CH2:7][NH2:18])=[CH:11][CH:12]=1)#[N:15]
Reactant: N
Reactant: N#Cc1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Product: N#Cc1ccc(OCC(O)CN)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 46 %

Procedure:
IPA (300 mL) was added to a stirred suspension of 4-(2-oxiranylmethoxy)benzonitrile (100 g; 571 mmol; see Example A above) in NH3 (500 mL; conc.), and the reaction mixture was stirred at rt. for 3 days. The precipitate was filtered off and the residue concentrated and recrystallized from MeCN to give the sub-title compound in a 46% yield.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[NH:4][N:3]=1.[F:12][C:13]([F:18])([F:17])[CH2:14][CH2:15]I>>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[N:4]([CH2:15][CH2:14][C:13]([F:18])([F:17])[F:12])[N:3]=1
Reactant: FC(F)(F)CCI
Reactant: Cc1ccc2[nH]nc(I)c2c1
Product: Cc1ccc2c(c1)c(I)nn2CCC(F)(F)F
Yield: 29 %

Procedure:
The title compound was prepared in 29% yield from 3-iodo-5-methyl-indazole and 1,1,1-trifluoro-3-iodopropane according to the general procedure for Preparation 10A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 2.49 (3H, s), 2.72-2.83 (2H, m), 4.59 (2H, t, J=7.2 Hz), 7.25-7.32 (3H, m).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([NH:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:28]#[N:29])[CH:5]=[CH:6][CH:7]=1.[CH2:30]([Sn](CCCC)(CCCC)C#CC)[CH2:31][CH2:32]C.CO>C1(C)C=CC=CC=1.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][NH:19][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][N:15]=2)[N:12]=[CH:11][C:10]([C:28]#[N:29])=[C:9]3[NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:30]#[C:31][CH3:32])[CH:3]=2)[CH2:23][CH2:24]1
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1cnc2cnc(NCCN3CCOCC3)cc2c1Nc1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CC#Cc1cccc(Nc2c(C#N)cnc3cnc(NCCN4CCOCC4)cc23)c1
Temperature: 150 °C
Yield: 41.1 %

Procedure:
A mixture of 4-(3-iodophenylamino)-6-(2-morpholinoethylamino)-1,7-naphthyridine-3-carbonitrile (105.6 mg, 0.21 mmol, 1 eq) and tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.02 mmol, 0.1 eq) was taken up in toluene (2.5 mL) in microwave tube. Tributyl(prop-1-ynyl)stannane (193 uL, 0.63 mmol, 3 eq) was added to the mixture. The tube was sealed and heated 150° C. for 1 hr. Work-up followed by chromatography (1-3% Methyl alcohol in dichloromethane), yielded 35.6 mg product (41% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 2.04 (s, 3 H) 2.40-2.46 (m, 4 H) 2.55 (t, J=6.69 Hz, 2 H) 3.30-3.40 (m, 2 H) 3.55-3.60 (m, 4 H) 6.64 (t, J=5.68 Hz, 1 H) 7.01 (s, 1 H) 7.23 (s, 1 H) 7.25 (s, 2 H) 7.34-7.40 (m, 1 H) 8.28 (s, 1 H) 8.84 (s, 1 H) 9.61 (s, 1 H).
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C@@H:8]([CH3:48])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33]C5CCCCO5)[CH:28]=4)=[C:25]([CH3:40])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([O:41]C5CCCCO5)[CH:23]=4)[O:18]3)=[CH:13][CH:12]=2)[CH2:4]1>C(O)(=O)C.O>[F:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C@@H:8]([CH3:48])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=4)=[C:25]([CH3:40])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([OH:41])[CH:23]=4)[O:18]3)=[CH:13][CH:12]=2)[CH2:4]1
Reactant: CC1=C(c2cccc(OC3CCCCO3)c2)C(c2ccc(OC[C@H](C)N3CC[C@@H](CF)C3)cc2)Oc2ccc(OC3CCCCO3)cc21
Solvent: O
Solvent: CC(=O)O
Product: CC1=C(c2cccc(O)c2)C(c2ccc(OC[C@H](C)N3CC[C@@H](CF)C3)cc2)Oc2ccc(O)cc21
Yield: 70.4 %

Procedure:
(3R)-3-(fluoromethyl)-1-((2S)-1-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)propan-2-yl)pyrrolidine (785 mg, 1.19 mmol) was stirred in 80% acetic acid/H2O (6.0 mL) at room temperature for 2 days. The solvents were removed on a rotary evaporator, and the residue was dissolved in ethyl acetate. The organic layer was washed with sat'd aqueous NaHCO3, washed with water, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. This crude material was then purified by silica gel chromatography (0-4% MeOH/DCM) to afford 2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol (410 mg, 70%) as pale pink solid. 1H NMR (DMSO-d6): δ 9.43 (s, 1H), 8.94 (s, 1H), 7.18 (d, 2H), 7.12 (t, 1H), 6.79 (d, 2H), 6.73 (m, 1H), 6.68 (dt, 1H), 6.65 (m, 1H), 6.61 (m, 1H), 6.49-6.45 (m, 2H), 5.83 (s, 1H), 4.35-4.30 (m, 1H), 4.23-4.18 (m, 1H), 3.99-3.93 (m, 1H), 3.74-3.70 (m, 1H), 2.69-2.60 (m, 2H), 2.58-2.52 (m, 2H), 2.45-2.32 (m, 2H), 2.02 (s, 3H), 1.82-1.75 (m, 1H), 1.36-1.30 (m, 1H), 1.07 (d, 3H); LCMS: 490.2 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CO.[NH2:9][C:10]1[N:14]([C:15]2[CH:24]=[CH:23][C:18]3[NH:19][C:20]([CH3:22])=[N:21][C:17]=3[CH:16]=2)[N:13]=[CH:12][C:11]=1[C:25]([C:27]1[N:28](S(C2C=CC=CC=2)(=O)=O)[C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)=[CH:31][CH:30]=2)=[O:26].O.N>O>[NH2:9][C:10]1[N:14]([C:15]2[CH:24]=[CH:23][C:18]3[NH:19][C:20]([CH3:22])=[N:21][C:17]=3[CH:16]=2)[N:13]=[CH:12][C:11]=1[C:25]([C:27]1[NH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)=[CH:31][CH:30]=2)=[O:26]
Reactant: Cc1nc2cc(-n3ncc(C(=O)c4cc5cc(CN6CCOCC6)ccc5n4S(=O)(=O)c4ccccc4)c3N)ccc2[nH]1
Agent: N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: Cc1nc2cc(-n3ncc(C(=O)c4cc5cc(CN6CCOCC6)ccc5[nH]4)c3N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.2 %

Procedure:
Cesium carbonate (1.29 g) was added to a methanol solution (20 ml) of [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(1-benzenesulfonyl-5-morpholin-4-ylmethyl-1H-indol-2-yl)-methanone (110 mg), and stirred at room temperature for 16 hours. Then, water (5 ml) and ammonia water (3 ml) were added to the reaction mixture and stirred for three hours. The reaction mixture was concentrated under reduced pressure. Water was added to the resulting residue. After ethyl acetate extraction, the extract was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol/dichloromethane=0/100 to 20/100) to give [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(5-morpholin-4-ylmethyl-1H-indol-2-yl)-methanone (33 mg).