Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH2:3][C:4]1C=CC(C#N)=CC=1.C[Mg]I.[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:22][OH:23].O>C1COCC1.C(OCC)C>[CH3:22][O:23][CH2:21][C:15]1[CH:20]=[CH:19][C:18]([C:3](=[O:2])[CH3:4])=[CH:17][CH:16]=1
Reactant: CO
Reactant: COCc1ccc(C#N)cc1
Reactant: Cc1ccccc1
Agent: C[Mg]I
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COCc1ccc(C(C)=O)cc1
Temperature: -10 °C
Reaction time: 5 h
Yield: 55 %

Procedure:
4-(Methoxymethyl)benzonitrile (6.0 g, 40.82 mmol) was dissolved in THF/diethyl ether (1:1, 60 mL) and the resulting solution was cooled to −10° C. 3 M solution of methyl magnesium iodide (13.57 g, 81.63 mmol) was added and the resulting mixture was stirred at this temperature for 5 hours. After completion of the reaction (TLC; toluene/methanol, 97:3), the mixture was poured into acidified water (50 mL; pH 3-4) and extracted with ethyl acetate (3×50 mL). The separated organic layers were combined, dried over Na2SO4 and concentrated in vacuo. The crude compound was purified by gradient flash chromatography, eluting with 8% ethyl acetate in hexane to afford the target compound (3.7 g, 55%).
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:19]#[N:20])=[CH:4][N:3]=1.[NH4+:21].[OH-:22].O([Si](C)(C)C)[K]>CCO>[NH2:21][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:19]([NH2:20])=[O:22])=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: [OH-]
Reactant: N#Cc1cnc(Cl)c2c1[nH]c1cc(C(F)(F)F)ccc12
Agent: C[Si](C)(C)O[K]
Solvent: CCO
Product: NC(=O)c1cnc(N)c2c1[nH]c1cc(C(F)(F)F)ccc12
Temperature: 150 °C

Procedure:
A mixture of 1-chloro-7-(trifluoromethyl)-5H-pyrido[4,3-b]indole-4-carbonitrile in a 3:2 (v/v) mixture of EtOH and conc. NH4OH (0.06 M) was heated at 150° C. for 2 h in a stainless steel pressure vessel. After cooling at room temperature, an excess of KOSiMe3 was added and the mixture was heated at 150° C. for 18 h. The reaction mixture was extracted with EtOAc and H2O. After evaporation of the organic solvent the residue was purified by flash chromatography (10% MeOH in EtOAc) to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1COCC1.[CH:9]([N:22]1[CH2:25][C:24](=O)[CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C.[C-:31]#[N:32].[K+]>CO>[CH:9]([N:22]1[CH2:25][C:24]([N:2]([CH3:3])[CH3:1])([C:31]#[N:32])[CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [C-]#N
Reactant: CNC
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)C1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
A solution of 2M dimethylamine in THF (3.92 ml, 7.83 mmol) was added to 1-benzhydrylazetidin-3-one (1.43 g, 6.03 mmol). After stirring 5 minutes, acetic acid (0.450 ml, 7.83 mmol), solid KCN (0.510 g, 7.83 mmol), and methanol (0.5 ml) were added at room temperature. After stirring for 5 minutes, the mixture was heated to 60° C. for 19 hours. The reaction was cooled and extracted from saturated aqueous NaHCO3 with ethyl acetate. The combined extracts were dried (Na2SO4), and concentrated, in vacuo, to afford I-3A-3a as a foam (1.77 g, quantitative): +ESI MS (M+1) 292.3; 1H NMR (400 MHz, CD2Cl2) δ 7.44 (d, J=7.5 Hz, 4H), 7.29 (t, J=7.5 Hz, 4H), 7.21 (t, J=7.3 Hz, 2H), 4.41 (s, 1H), 3.58 (d, J=8.3 Hz, 2H), 3.05 (d, J=8.3 Hz, 2H), 2.13 (s, 6H).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[C:6](Cl)(Cl)=[S:7].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:13][C:12]=1[Cl:22].Cl>C(Cl)Cl.O.C(Cl)Cl>[Cl:22][C:12]1[CH:13]=[C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:16][C:11]=1[N:10]=[C:6]=[S:7]
Reactant: S=C(Cl)Cl
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: O
Product: COC(=O)Cc1ccc(N=C=S)c(Cl)c1
Temperature: 0 °C
Yield: 107.9 %

Procedure:
Calcium carbonate (626 mg, 6.25 mmol) and thiophosgene (191 μl, 2.51 mmol) were suspended in methylene chloride-water (10 ml, 1:1, v/v). To the resulting suspension was added a solution of methyl 4-amino-3-chlorophenylacetate (500 mg, 2.50 mmol) in methylene chloride (5 ml) under stirring at 0° C. The temperature of the reaction mixture was raised from 0° C. to room temperature over 1.5 hours. The reaction mixture was acidified with 1N HCl, followed by extraction with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent to give methyl 3-chloro-4-isothiocyanatophenylacetate (652 mg, 100%) as a yellow oil.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@@:9]1([CH3:16])[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[C:18]([C:20]1[CH:39]=[CH:38][CH:37]=[CH:36][C:21]=1[O:22][C:23]1[CH:35]=[CH:34][C:26]([CH2:27][C@@H:28]([C:30]([O:32][CH3:33])=[O:31])[NH2:29])=[CH:25][CH:24]=1)#[N:19].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@@:9]1([CH3:16])[C:10]([NH:29][C@H:28]([C:30]([O:32][CH3:33])=[O:31])[CH2:27][C:26]1[CH:25]=[CH:24][C:23]([O:22][C:21]2[CH:36]=[CH:37][CH:38]=[CH:39][C:20]=2[C:18]#[N:19])=[CH:35][CH:34]=1)=[O:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: COC(=O)[C@@H](N)Cc1ccc(Oc2ccccc2C#N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(Oc2ccccc2C#N)cc1)NC(=O)[C@]1(C)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 90.8 %

Procedure:
To a solution of 131 mg of N-Boc-2-(S)-methyl-(L)-proline, 190 mg 4-(2-cyanophenoxy)-phenylalanine, methyl ester hydrochloride, 297 mg PyBOP, and 4 mL of methylene chloride at 0° C. was added 300 μL of diisopropylethylamine via syringe. The reactants were allowed to warm to room temperature and said reaction was run over the weekend. The reaction was then diluted with methylene chloride, washed with water, 1N hydrochloric acid), saturated sodium bicarbonate solution, and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The product was purified via silica gel chromatography, eluted with 80% hexane:20% acetone to yield 263 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:36])[N:9]([C:25]2[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=2)[C:28]([O:30]CC)=[O:29])[CH2:10][CH2:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][C:3]=1[C:37]1[CH:42]=[CH:41][C:40]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])=[CH:39][CH:38]=1.O.[OH-].[Li+]>CO>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH2:10][CH2:11][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=2)[C:28]([OH:30])=[O:29])=[O:36])=[N:4][C:3]=1[C:37]1[CH:38]=[CH:39][C:40]([NH:43][S:44]([CH3:47])(=[O:45])=[O:46])=[CH:41][CH:42]=1
Reactant: CCOC(=O)c1cccc(N(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2nc(-c3ccc(NS(C)(=O)=O)cc3)c(Cl)s2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(-c2nc(NC(=O)N(CCC(c3ccccc3)c3ccccc3)c3cccc(C(=O)O)c3)sc2Cl)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 3-(3-(5-chloro-4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-1-(3,3-diphenylpropyl)ureido)benzoate 73 (0.366 g, 0.531 mmol) in MeOH (20 mL) was added lithium hydroxide hydrate (0.440 g, 10.5 mmol). The reaction mixture was heated to 60° C. After 3 h, the reaction mixture was partially concentrated, neutralized with 1 M HCl, and diluted with EtOAc. The organic phase was washed with brine (1×), dried over MgSO4, filtered, and concentrated to give 3-(((5-chloro-4-(4-((methylsulfonyl)amino)phenyl)-1,3-thiazol-2-yl)carbamoyl)(3,3-diphenylpropyl)amino)benzoic acid 74. Mass spectrum, calculated for C33H29ClN4O5S2 660.1; found 661.1 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([N:20]3[CH2:25][CH2:24][C:23]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)([OH:26])[CH2:22][CH2:21]3)[C:15](=O)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[OH2:36]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]([OH:36])[CH:14]([N:20]3[CH2:25][CH2:24][C:23]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)([OH:26])[CH2:22][CH2:21]3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: O=c1oc2cc(OCc3ccccc3)ccc2cc1N1CCC(O)(c2ccc(F)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: OC1c2ccc(OCc3ccccc3)cc2OCC1N1CCC(O)(c2ccc(F)cc2)CC1
Reaction time: 8 h
Yield: 60 %

Procedure:
To a slurry of 7-benzyloxy-3-[4-(4-fluorophenyl)-4-hydroxy-piperidine-1-yl]-chromenone (8.24 g, 18.5 mmol) in ethanol (400 mL) and tetrahydrofuran (600 mL) was added sodium borohydride (7.0 g, 185 mmol). The mixture was stirred overnight. Additional sodium borohydride (7.0 g) was added and the reaction mixture was stirred for 3 days. Water was added and the solvent was removed at reduced pressure at 45° C. The solids which formed were collected and washed well with water and then ether. The solid was further dried in vacuo overnight to give 5.01 g, 60% of 3R*4S*7-benzyloxy-3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-chroman-4-ol which was suitable for use without further purification. A sample recrystallized from ethyl acetate/chloroform had mp. 194-195° C.; NMR δ7.56-7.30 (m, 8H), 7.06 (long range coupled t, J=8.7 Hz, 2H) 6.63 (dd, J=2.4, 8.5 Hz, 1H), 6.47 (d, J=2.4 Hz, 1H), 5.04 (s, 2H), 4.77 (d, J=4.5Hz, 1H), 4.37 (dd, J=3.5, 10.4Hz, 1H), 4.13 (t, J=10.4 Hz, 1H), 3.82 (brs, 1H), 3.11 (br d, J=11.2 Hz, 1H), 2.92-2.71 (m, 4H), 2.21-2.06 (m, 2H), 1.87-1.73 (m, 2H), 1.54 (s,1H).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH:5]=[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:7][CH2:8][N:9]([CH3:11])[CH3:10]>[Pd].C(O)C>[ClH:2].[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:7][CH2:8][N:9]([CH3:11])[CH3:10]
Reactant: CN(C)CCC(=CCCCl)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN(C)CCC(CCCCl)c1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 10 g. (0.037 mole) of 6-chloro-N,N-dimethyl-3-phenyl-3 -hexenylamine hydrochloride in 150 ml. of 95% ethanol was hydrogenated using palladium on carbon catalyst. Hydrogenation was complete after 15 minutes at room temperature. The catalyst was removed by filtration and the filtrate was evaporated to a solid. Recrystallization of the solid from isobutyl methyl ketone gave 7 g. (70%) of a hygroscopic solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][Br:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:30])[CH2:15][CH:16]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:23][C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH3:4])([CH3:3])[CH3:2].[C:31]1([P:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1(C)C=CC=CC=1>[Br-:12].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][P+:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:7][C:6]=1[NH:13][C:14](=[O:30])[CH2:15][CH:16]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:23][C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)c1ccc(CBr)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Product: [Br-]
Temperature: 25 °C
Yield: 94.2 %

Procedure:
A solution of 2.52 g (5.42 mmol) of N-[2-t-butyl-5-bromomethylphenyl]-2-(9H-xanthen-9-yl)acetamide [prepared as described in step (i) above] and 1.58 g (6.02 mmol) of triphenylphosphine in 25 ml of toluene was heated under reflux for 5 hours whilst vigorously stirring. At the end of this time, it was cooled to room temperature, and the resulting precipitate was collected by filtration and pulverized. This precipitate was then washed with toluene and with hexane, in that order, and dried over anhydrous sodium sulfate, to give 3.71 g (yield 90%) of the title compound as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[N:45][CH:44]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([N:26]([S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:42](=[O:49])[C:43]5[CH:48]=[CH:47][CH:46]=[N:45][CH:44]=5)[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCS(=O)(=O)N(C(=O)c1cccnc1)c1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Yield: 29.4 %

Procedure:
The title compound was prepared according to the procedure as described in Example 3 using N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.1 g, 0.2 mmol), triethylamine (228 μL, 1.6 mmol) and nicotinoyl chloride hydrochloride (146 mg, 0.2 mmol) in CHCl3 (10 mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v)=2/1) to afford the title compound as a white solid (35 mg, 28.9%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:31](O)=[O:32]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:28]([O:27][CH2:26][CH2:25][CH2:24][OH:23])[CH:29]=2)[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: COc1ccc(C(=O)O)cc1OCCCO
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)c3ccc(OC)c(OCCCO)c3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methylquinoline-3-carboxylate (Example 26b) and 3-(3-hydroxypropoxy)-4-methoxybenzoic acid as a brown solid. MS 512 (MH+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17]
Reactant: [H][H]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CO/C=C(/C(=O)OC)c1ccccc1O
Yield: 99 %

Procedure:
(E)-Methyl 2-(2'-benzyloxyphenyl)-3-methoxyacrylate (5.44 g) was dissolved in ethyl acetate (50 ml) and 5% palladium on carbon (0.25 g) was added. The stirred mixture was hydrogenated at three atmospheres pressure, with stirring, until no more hydrogen was taken up, then filtered through celite and silica gel (50 g, Merck 60). Concentration of the filtrate under reduced pressure afforded (E)-methyl 2-(2'-hydroxyphenyl)-3-methoxyacrylate as a white crystalline solid (3.76 g; 99% yield), mp. 125°-126° C.; infrared max. (nujol mull): 3400, 1670 cm-1 ; 1H NMR (270 MHz): delta 3.80 (3H,s), 3.90 (3H,s), 6.20 (1H,s), 6.80-7.00 (2H,m), 7.10-7.30 (2H,m), 7.60 (1H,s)ppm.
Reaction SMILES: [F:1][CH:2]([F:35])[C:3]1[N:7]([C:8]2[N:13]=[C:12]3[N:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[N:15]=[CH:16][C:11]3=[C:10]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:5]=2[N:4]=1.CCN(C(C)C)C(C)C.Cl[CH2:46][CH2:47][S:48](Cl)(=[O:50])=[O:49].O>C(Cl)Cl>[F:35][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]3[N:14]([CH:17]4[CH2:22][CH2:21][N:20]([S:48]([CH:47]=[CH2:46])(=[O:50])=[O:49])[CH2:19][CH2:18]4)[N:15]=[CH:16][C:11]3=[C:10]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2cnn(C3CCNCC3)c2n1
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: C=CS(=O)(=O)N1CCC(n2ncc3c(N4CCOCC4)nc(-n4c(C(F)F)nc5c(OC)cccc54)nc32)CC1
Temperature: -15 °C
Yield: 44.8 %

Procedure:
A mixture of 0.41 g (0.84 mmol) of 6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1-(4-piperidinyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 8) and 0.27 g (2 mmol) DIPEA in CH2Cl2 was cooled to −15° C., and 200 mg (1.2 mmol) of 2-chloroethanesulfonyl chloride was added. The mixture was allowed to warm to 0° C. over 1 hr, and water was added. The organic layer was dried and concentrated. Chromatography on silica, eluting with CH2Cl2/EtOAc (1:1), gave 216 mg (45% yield) of 6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1-[1-(vinylsulfonyl)-4-piperidinyl]-1H-pyrazolo[3,4-d]pyrimidine: mp (CH2Cl2-MeOH) 243-246° C.; 1H NMR (CDCl3) δ 8.00 (s, 1H), 7.81 (dd, J=8.4, 0.7 Hz, 1H), 7.44 (t, JHF=53.5 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 6.51 (dd, J=16.6, 9.9 Hz, 1H), 6.29 (d, J=16.6 Hz, 1H), 6.07 (d, J=9.9 Hz, 1H), 4.81 (tt, J=11.2, 4.1 Hz, 1H), 4.07 (s, 3H), 4.06 (m, 4H), 3.96 (m, 1H), 3.91 (m, 4H), 3.88 (m, 1H), 2.95 (dt J=12.4, 2.6 Hz, 2H), 2.43 (ddd, J=24.5, 11.8, 4.2 Hz, 2H), 2.14 (dd, J=11.8, 4.2 Hz, 2H); Anal. Calcd. for C25H28F2N8O4S: C, 52.3; H, 4.9; N, 19.5. Found: C, 52.3; H, 4.7; N, 19.8%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([C:22]#[N:23])[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([NH:19][CH2:30][CH3:31])[CH:16]=[C:15]([C:22]#[N:23])[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: N#Cc1cc(-c2nc(-c3ccc(F)cn3)no2)cc([N+](=O)[O-])c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNc1cc(C#N)cc(-c2nc(-c3ccc(F)cn3)no2)c1
Temperature: 140 °C
Yield: 17.6 %

Procedure:
A mixture of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-nitrophenyl) -1,2,4-oxadiazole (30 mg, 0.11 mmol), potassium carbonate (29 mg, 0.21 mmol) and ethyl iodide (98 μL, 1.2 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 140° C. for 2 hours. The reaction was cooled, diluted with ethyl acetate, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 3:1:4 afforded 6 mg (38%) of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-ethylaminophenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.69 (d, 1H), 8.26 (dd, 1H), 7.80 (s, 1H), 7.61 (m, 2H), 6.99 (s, 1H), 4.12 (br, s, 1H), 3.26 (q, 2H), 1.32 (t, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.F[C:20]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23].C(O[K])(C)(C)C.O>CN(C)C(=O)C>[CH3:28][C:27]1[C:20]([O:18][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]=[CH:10][N:9]=[C:8]3[NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23]
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Reactant: Cc1cccc(C#N)c1F
Agent: CC(C)(C)O[K]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cccc(C#N)c1Oc1ccc2ncnc(Nc3ccn(C)n3)c2c1
Temperature: 110 °C
Reaction time: 4 h
Yield: 23.3 %

Procedure:
4-[(1-Methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (90 mg; 0.373 mmol) and 100 mg (0.741 mmol) of 2-fluoro-3-methylbenzonitrile were added to a solution of 105 mg (0.937 mmol) of tert-butoxy potassium in 5 ml of N,N-dimethylacetamide and the mixture was stirred at 110° C. for 4 hours. Water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was dried and concentrated and the resulting residue was purified by a silica gel chromatography (chloroform:methanol=12:1) to give 31 mg (yield: 23%) of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25](OCC)=[O:26])=[C:20]([F:30])[CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[C:20]([F:30])[CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1F
Solvent: C1CCOC1
Product: Cl
Product: OCCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 1171.2 %

Procedure:
To a solution of ethyl 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)-2-fluorophenyl)acetate (0.075 g, 0.18 mmol) in THF (2 mL) was added borane dimethyl sulfide complex solution (2.0 M in THF, 0.027 g, 0.35 mmol) at 0° C. The reaction mixture was slowly warmed to rt and stirred overnight. After this time, the mixture was quenched with 0.5 N HCl, and then basified with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the residue purified by column chromatography (silica, dichloromethane/methanol), followed by the formation of the hydrochloride salt to afford the title compound (0.442 g, 44%) as a tan solid. MW=382.86. 1H NMR (DMSO-d6, 500 MHz) δ 14.11 (s, 1H), 9.78 (s, 1H), 7.92 (t, J=1.8 Hz, 1H), 7.75-7.71 (m, 1H), 7.69-7.65 (m, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.27-7.19 (m, 2H), 7.12 (s, 1H), 3.63 (1, J=6.9 Hz, 2H), 3.16 (t, J=7.6 Hz, 2H), 2.93 (t, J=7.6 Hz, 2H), 2.78 (t, J=6.9 Hz, 2H), 2.24 (quin, J=7.6 Hz, 2H); APCI MS m/z 383 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:8][CH:7](OS(C)(=O)=O)[CH2:6][N:5]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:3].C1COCC1.[F-:26].C([N+](CCCC)(CCCC)CCCC)CCC.O>ClCCl>[NH2:1][C:2]([C@@H:4]1[CH2:8][C@H:7]([F:26])[CH2:6][N:5]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:3]
Reactant: [F-]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)CC1C(N)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(N)=O
Temperature: 0 °C

Procedure:
In a 5.0 L 4-necked RB flask, fitted with a mechanical stirrer and reflux condenser, were added tert-butyl 2-(aminocarbonyl)-4-[(methylsulfonyl)oxy]pyrrolidine-1-carboxylate (100 gm, 0.32 M), THF (500 ml), a tetrabutylammonium fluoride solution (153.4 gm, 0.48 mol in 500 ml THF) and water (35 ml) at 25-35° C. while stirring. The reaction mixture was brought to 55-60° C. and maintained for 48-60 hrs while stirring. The progress of the reaction was monitored by HPLC and after ascertaining completion, the reaction mixture was poured slowly into an ice cold water (1.5 L) and dichloromethane (0.72 L) mixture. The aqueous layer was washed with additional MDC (210 ml×3). The organic layers were combined and washed with a saturated brine solution (0.5 L). The dichloromethane layer was distilled below 40° C. under vacuum and hexane (500 ml) was added to the resulting mass. The trace dichloromethane was distilled off. The resulting mass was taken as such to the next stage.