Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([N:14]=[N+]=[N-])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[CH:8][CH:7]=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[NH:14][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[C:9]([S:12][CH3:13])[CH:10]=2)=[O:17]
Reactant: COC(=O)C(=Cc1ccc(SC)cc1)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: COC(=O)c1cc2ccc(SC)cc2[nH]1
Reaction time: 8 h
Yield: 61 %

Procedure:
A solution of methyl-2-azido-3-(4-methylthiophenyl)-propenoate (20.6 g, 83 mmol) in xylene (200 ml) was added dropwise to boiling xylene (250 ml) over a period of 2 hours. The reaction mixture was allowed to heat at reflux temperature for an additional 2 hours, then cooled slowly and placed in a freezer overnight. The solids were filtered, washed with a small amount of CH2Cl2 /hexane (1:3) and dried to give 11.2 g (61.0%) of methyl-6-methylsulfanyl-1H-indole-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][N:11]([Si](C(C)C)(C(C)C)C(C)C)[C:8]2=[N:9][CH:10]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.7 %

Procedure:
To 1-Triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (531, 0.950 g, 2.9 mmol) in tetrahydrofuran (20.0 mL) was added tetrabutyl-ammonium fluoride, trihydrate (1.20 g, 3.8 mmol). The reaction was stirred at room temperature for 10 minutes. The reaction was concentrated and purified with silica gel column chromatography eluting with 4% methanol in methylene chloride to give the compound as a white solid (532, 300 mg, 60%). MS(ESI) [M+H+]+=177.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:23][C:11]3=[N:12][C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[C:14](I)[CH:15]=[C:10]3[C:9]=2[C:24]([NH:26][CH3:27])=[O:25])=[CH:4][CH:3]=1.[B:28]([OH:33])([OH:32])B(O)O.CC([O-])=O.[K+]>CCO.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:23][C:11]3=[N:12][C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([B:28]([OH:33])[OH:32])[CH:15]=[C:10]3[C:9]=2[C:24](=[O:25])[NH:26][CH3:27])=[CH:4][CH:3]=1
Reactant: OB(O)B(O)O
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(I)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(B(O)O)cc12
Temperature: 80 °C
Reaction time: 5 h
Yield: 197.8 %

Procedure:
To a degassed solution of 2-(4-fluorophenyl)-5-iodo-N-methyl-6-(N-methylmethylsulfonamido)furo[2,3-b]pyridine-3-carboxamide (prepared according to International Patent Application Publication No. WO2011131709, 3.0 g, 6 mmol), hypodiboric acid (1.08 g, 1.2 mmol) and KOAc (1.8 g, 1.8 mmol) in EtOH (60 mL) was added Pd(OAc)2 (50 mg) and Ad2n-BuP (50 mg) under nitrogen atmosphere. The reaction mixture was stirred at 80° C. for 5 h, concentrated in vacuo to remove EtOH. The residue was purified by column chromatography (EA:DCM=1:1˜DCM:MeOH=5:1) to afford the desired product of (2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)furo[2,3-b]pyridin-5-yl)boronic acid (1 g, yield: 40%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.53 (d, J=4.4 Hz, 1H), 8.24 (s, 1H), 8.00˜8.04 (m, 3H), 7.40 (t, J=8.8 Hz, 2H), 4.08 (br s, 1H), 3.17 (s, 3H), 3.06 (s, 3H), 2.85 (d, J=4.8 Hz, 3H). MS (M+H)+: 422.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].C(O)(C(F)(F)F)=O.[CH2:19]([N:26]([CH2:30][Si](C)(C)C)[CH2:27]OC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH2:19]([N:26]1[CH2:30][CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:4]([N+:1]([O-:3])=[O:2])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (E)-(2-nitrovinyl)benzene (110 g, 0.738 mol) and TFA (8.42 g, 0.073 mol) in DCM (500 mL) was added N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)-methanamine (351.4 g, 1.476 mol) in DCM (500 mL) drop-wise at 0° C. for a period of 30 min. Then the reaction mixture was stirred at room temperature for 48 h. After completion of the reaction, the mixture was concentrated in vacuo, dissolved in water, and extracted into EtOAc (×2, 1.0 L). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified via flash chromatography (20-80% petroleum ether/EtOAc) to afford (3S and R, 4R and S)-1-benzyl-3-nitro-4-phenylpyrrolidine. MS ESI calc'd. For C17H18N2O2 [M+1]+ 283. found 283.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:33])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH:20]=[CH:19][CH:18]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[O:17]2)=[CH:12][CH:11]=1>CCOC(C)=O.O=[Pt]=O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:33])[C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=3)[O:17]2)=[CH:14][CH:15]=1
Reactant: COc1cc(C2C=CC(c3ccc(C(=O)Nc4ccccc4N)cc3)O2)cc(OC)c1OC
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: COc1cc(C2CCC(c3ccc(C(=O)Nc4ccccc4N)cc3)O2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 229.2 %

Procedure:
To a degazed solution of 289 (43 mg, 0.096 mmol) in AcOEt (4 mL) was added PtO2 (3 mg, 0.01 mmol) and the reaction mixture was stirred at room temperature under a 1 atm pressure of H2 for 16 h. The reaction flask was purged with N2 then the reaction mixture was filtered through celite, rinsed with MeOH and concentrated. The crude residue was purified three times by flash chromatography on silica gel (MeOH/DCM: 2/98, AcOEt/DCM: 30/70 and AcOEt/CHCl3: 30/70) to afford the title compound 290 (10 mg, 0.22 mmol, 23% yield).1H NMR (CDCl3) δ (ppm): 8.10 (s, 1H), 7.91 (d, J=8.0 Hz, 2H), 7.50 (d, J=8.0 Hz, 2H), 7.34 (d, J=7.5 Hz, 1H), 7.10 (t, J=7.5 Hz, 1H), 6.96-6.85 (m, 2H), 6.64 (s, 2H), 5.33 (t, J=7.0 Hz, 1H), 5.21 (t, J=7.0 Hz, 1H), 3.89 (s, 6H) 3.85 (s, 3H), 2.59-2.40 (m, 2H), 2.09-1.88 (m, 2H).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:38][C:39]#[CH:40])[C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1[CH:19]=[C:20]([CH:35]=[CH:36][CH:37]=1)[O:21][CH:22]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]1)=[O:11])=O)(C)(C)C.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>ClCCl>[NH2:8][C@@H:9]([CH2:38][C:39]#[CH:40])[C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1[CH:37]=[CH:36][CH:35]=[C:20]([O:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=1)=[O:11].[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCC#Cc1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CC[C@H](N)C(=O)NCCCC#Cc1cccc(OC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of (S)-tert-butyl 4-(3-(5-(2-(tert-butoxycarbonylamino)pent-4-ynamido)pent-1-ynyl)phenoxy)piperidine-1-carboxylate (0.26 g, 0.47 mmol) in dichloromethane (4.0 ml), TFA (1.0 ml) was added. The resulting solution was stirred at room temperature for 1 hr, then concentrated. The resulting residue was purified over Gilson HPLC to yield the title compound as its corresponding TFA salt, as a white solid. MH+ 354.31
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[S:9]1[CH2:14][CH2:13][CH:12]([CH:15]=[O:16])[CH2:11][CH2:10]1>>[Br:8][C:4]1[N:3]=[C:2]([CH:15]([CH:12]2[CH2:13][CH2:14][S:9][CH2:10][CH2:11]2)[OH:16])[CH:7]=[CH:6][CH:5]=1
Reactant: O=CC1CCSCC1
Reactant: Brc1cccc(Br)n1
Product: OC(c1cccc(Br)n1)C1CCSCC1

Procedure:
The title compound was prepared as described in Example 162, Step 1 with 2,6-dibromopyridine (3.64 g, 15.36 mmol) and tetrahydro-2H-thiopyran-4-carbaldehyde (2.00 g, 15.36 mmol) as the starting materials.
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].O.[OH-].[K+].[CH2:11](Br)[CH3:12]>CO>[CH2:11]([CH:2]([C:3]([CH3:5])=[O:4])[C:1]([NH2:7])=[O:6])[CH3:12]
Reactant: CC(=O)CC(N)=O
Reactant: CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C(C)=O)C(N)=O
Temperature: 25 °C
Yield: 52.4 %

Procedure:
To a 500 mL, 5-necked flask, equipped with a circulating jacket, a thermometer, a nitrogen blanket line atop a condenser, an addition funnel, a syringe pump, and a mechanical stirrer, were charged 101.1 g of acetoacetamide (1.00 mol), 100 mL of deionized water and 100 g of methanol. The mixture was stirred at ambient temperature until all solids were dissolved. A 45% aqueous potassium hydroxide solution (99.6 g, 0.80 mol) was then added to the above solution through the addition funnel over a period of 5 minutes. The resulting mixture was stirred for 30 minutes and then cooled to 15° C. Ethyl bromide (130.8 g, 1.20 mol) was added to the mixture through the syringe pump over a period of 30 minutes. The resulting mixture was stirred at 15° C. for 16 hours. All volatiles were then removed at 60° C./20 mmHg. The solid residue was dissolved in 300 mL of water and extracted with chloroform. A total of six chloroform extractions were performed (60 mL+5×200 mL). The first extraction contained a high level of 2,2-diethylacetoacetamide and was discarded. The remaining extraction solutions were combined. After chloroform was removed in vacuo, 67.7 g of 2-ethylacetoacetamide was obtained. Crude yield: 66% (based on KOH charge).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: CSc1ccc(Br)cc1
Product: CSc1ccc(NCc2ccccc2)cc1
Yield: 87.6 %

Procedure:
Using the general procedure, 4-bromothioanisole (203 mg, 1.0 mmol) was coupled with benzylamine (164 μL, 1.5 mmol). Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (15:1) as eluent afforded the desired product as a white solid (201 mg, 88% yield). Rf=0.4 (hexane/ethyl acetate=10:1).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([NH:36][CH3:37])[CH2:32][CH2:31]3)=[N:24]2)=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH:33]([N:36]([CH3:37])[C:12]([C:9]4[CH:10]=[CH:11][C:5]5[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)=[O:14])[CH2:34][CH2:35]3)=[N:24]2)=[CH:19][CH:18]=1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: CNC1CCN(CCSc2cnc3ccc(OC)cc3n2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2ncc(SCCN3CCC(N(C)C(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.2 %

Procedure:
3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (26 mg, 0.11 mmol, 1.0 eq) is added at room temperature to a stirred solution of {1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-methyl-amine (40 mg, 0.11 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL), followed by 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (45 mg, 0.11 mmol, 1.0 eq), and triethylamine (16 μL, 0.11 mmol, 1.0 eq). After 4 hours stirring at room temperature, solvent is evaporated and the residue is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-methyl-amide as a yellow solid (22 mg, 35% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[N:23]1([CH:29]2[CH2:35][CH2:34][C:33]3[CH:36]=[C:37]([NH2:40])[CH:38]=[CH:39][C:32]=3[CH2:31][CH2:30]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)=[N:7][C:2]([NH:40][C:37]2[CH:38]=[CH:39][C:32]3[CH2:31][CH2:30][CH:29]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH2:35][CH2:34][C:33]=3[CH:36]=2)=[N:3][CH:4]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)c(-n2cccn2)c1
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Product: COc1ccc(Nc2nc(Nc3ccc4c(c3)CCC(N3CCOCC3)CC4)ncc2Cl)c(-n2cccn2)c1

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(4-methoxy-2-pyrazol-1-yl-phenyl)-amine, of Example 611c, was reacted with 7-Morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclo hepten-2-ylamine, in a similar manner as Example 601b, to yield desired product 5-Chloro-N*4*-(4-methoxy-2-pyrazol-1-yl-phenyl)-N*2*-(7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)-pyrimidine-2,4-diamine as a lyophylate (25%); 1H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 9.64 (bs, 1H), 9.33 (s, 1H), 8.75 (s, 1H), 8.11 (s, 1H), 8.00 (d, J=8.97 Hz, 1H), 7.83 (s, 1H), 7.41 (s, 1H), 7.25 (m, 2H), 7.1-6.95 (m, 2H), 6.54 (s, 1H), 4.00 (m, 2H), 3.88 (s, 3H), 3.8-3.7 (m, 2H), 3.6-3.5 (m, 1H), 3.4-3.1 (m, 4H), 2.8-2.6 (m, 4H), 2.29 (m, 2H), 1.42 (m, 2H); MS (m/e) 546.37 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.Cl.[NH2:14][OH:15].[OH-].[Na+]>CO.O>[CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:14][OH:15])[CH2:3]1
Reactant: CC1(C)CC(=O)c2ccccc21
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CC(=NO)c2ccccc21
Temperature: 80 °C
Yield: 97.4 %

Procedure:
To a solution of 3,3-dimethylindan-1-one (1.16 g, 7.21 mmol) and hydroxylamine hydrochloride (1.31 g, 18.8 mmol) in MeOH (20.0 mL) was added a solution of sodium hydroxide (765 mg, 19.1 mmol) in water (10.0 mL). The mixture was heated to 80° C. for 2 h. The cooled reaction was concentrated in vacuo and partitioned between DCM and water. The organic layer was separated and concentrated in vacuo to afford the title compound as an oil (1.23 g, 97%). LC/MS: Rt=1.61 min, ES+ 176 (AA standard).
Reaction SMILES: C([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[O:23][C@@H:24]1[CH2:28][C@@H:27]([CH2:29][O:30][Si](C(C)(C)C)(C)C)[C@@H:26]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:25]1)C1C=CC=CC=1.C(O)=O.CO>[Pd]>[Si:39]([O:38][C@H:26]1[CH2:25][C@H:24]([O:23][C:13]2[N:12]=[CH:11][N:10]=[C:9]3[C:14]=2[N:15]=[C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:8]3)[CH2:28][C@H:27]1[CH2:29][OH:30])([C:42]([CH3:43])([CH3:44])[CH3:45])([CH3:40])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ncnc3c2nc(-c2ccccc2)n3Cc2ccccc2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](Oc2ncnc3[nH]c(-c4ccccc4)nc23)C[C@H]1CO
Reaction time: 8 h

Procedure:
A suspension of 9-benzyl-6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-8-phenyl-9H-purine (0.161 g, 0.000249 mol), 10% Pd/C (0.04 g, 0.00004 mol) and formic acid (0.1 mL, 0.003 mol) in methanol (11.0 mL, 0.272 mol) was stirred under an atmosphere of nitrogen overnight. Added formic acid (0.2 mL, 0.005 mol) and 10% Pd/C (0.04 g, 0.00004 mol) to the reaction and stirred 24 h. Added 10% Pd/C (0.060 g, 0.000056 mol) and formic acid (0.2 mL, 0.005 mol) to the reaction and stirred an additional 24 h. The reaction was purged with nitrogen and filtered the mixture through celite with DCM. The filtrate was concentrated, purified by flash chromatography (30 to 50% ethyl acetate/hexane) to obtain 30 mg (27%). LC/MS: Rt=2.08 min, ES+ 441.18 (AA standard).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1>CN(C)C=O.CO>[CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:16][CH2:17]2)=[CH:8][CH:7]=1)=[O:4]
Reactant: Nc1ccc(OCC2CCN(c3ccncc3)CC2)cc1
Reactant: CN=C=O
Solvent: CO
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc(OCC2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
Methyl isocyanate (0.18 g) was added to a stirred solution of 4-[(4-aminophenoxy)methyl]-1-[4-pyridyl]piperidine (see Preparation 4) (0.57 g) in dimethylformamide (10 ml) and the mixture was stirred at room temperature for 3 hours and then diluted with methanol (2 ml). The solid was filtered off and crystallised from methanol to give the title compound, (0.32 g), m.p. 222°-224°.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([Cl:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([Cl:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(O)c1cc(F)c(Cl)c(Cl)c1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(F)c(Cl)c(Cl)c1Cl

Procedure:
737 g (3.02 mols) of 2,3,4-trichloro-5-fluorobenzoic acid are introduced into 1.5 liters of thionyl chloride at room temperature, and the mixture is refluxed for 16 hours until the gas evolution ceases. Excess thionyl chloride is removed by distillation, and the residue is distilled.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.C(N(CC)CC)C.Cl.[NH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[BH4-].[Na+]>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CCN
Reactant: O=Cc1cccs1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)CCNCc1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Thiophene aldehyde (11.2 g) was dissolved in 100 mL of methanol, then 12.1 g of triethylamine and 16.1 g of ethyl 3-aminopropionate hydrochloride were added thereto in this order and the mixture was stirred overnight at room temperature. The reaction solution was cooled down to 0° C., 2.27 g of sodium borohydride was slowly added thereto little by little and the mixture was stirred at room temperature for 1 hour.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[C:20]1([C:26]#[CH:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:20]1([C:26]#[C:27][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([C:9]([F:12])([F:11])[F:10])[CH:4]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C#Cc1ccccc1
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Nc1ccc(C#Cc2ccccc2)cc1C(F)(F)F
Temperature: 70 °C
Yield: 66.7 %

Procedure:
A multinecked flask as described in Example 1 was charged with 10.0 g (0.042 mol) of 2-amino-5-bromobenzotrifluoride, 100 ml of dried, degassed triethylamine, 5.32 g (0.052 mol) of phenylacetylene, 0.48 g (0.41 mmol) of tetrakis(triphenylphosphine)palladium(O), 0.1 g (0.38 mmol) of triphenylphosphine, and 0.05 g (0.26 mmol) of cuprous iodide. The reaction mixture was heated at 70° C. for 48 hours at which point thin layer chromatography showed the reaction to be complete. The product mixture was cooled to room temperature and diluted with 50 ml of toluene. Filtration of the triethylamine hydrobromide salt by-product followed by concentration of the filtrate under reduced pressure gave the crude product as a yellow oil. Fractionation under reduced pressure (bp 146°-150° C./1.2 mm Hg) gave 7.22 g (0.028 mol, 66% yield) of the product as a viscous yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:8](O)([CH3:10])[CH3:9])[CH:7]=1.[CH2:14]([O:16][C:17](=[O:25])[C:18]([O:20][Si](C)(C)C)=[CH2:19])[CH3:15]>C(Cl)Cl>[CH2:14]([O:16][C:17](=[O:25])[C:18](=[O:19])[CH2:20][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:12][CH3:13])([CH3:10])[CH3:9])[CH3:15]
Reactant: COc1ccc(F)cc1C(C)(C)O
Reactant: C=C(O[Si](C)(C)C)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)C(=O)CC(C)(C)c1cc(F)ccc1OC
Temperature: -78 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
Stannic chloride (5 mL of 1 M solution in methylene chloride, 5 mmol) was added to a stirred solution of 2-(5-fluoro-2-methoxyphenyl)propan-2-ol (2.85 g, 15.5 mmol) and 2-trimethylsilanyloxy-acrylic acid ethyl ester (23.3 mmol, 4.37 g) in anhydrous methylene chloride (45 mL) cooled to −78° C. After 7 hours with the temperature maintained in the range of −78° C. to −50° C., TLC in hexanes-EtOAc (9:1) indicated that a significant amount of starting material remained. More stannic chloride (5 mL of 1 M solution in methylene chloride, 5 mmol) was added with the temperature around −50° C. After 2 hours, all the starting material had been consumed. The reaction mixture was treated with water (100 mL), stirred for 15 minutes and diluted with methylene chloride. The methylene chloride layer was separated, washed with two 50 mL portions of the water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a light brown oil. The crude product was purified by flash column chromatography over silica gel eluting with 10% EtOAc in hexanes and a fraction corresponding to Rf=0.28 was collected to give the title compound (35%) as a light brown oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[NH:13][C:12]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=3[N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:19][N:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]1=[O:35].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:24]2[CH:23]=[CH:22][C:21](=[O:35])[N:20]([CH3:19])[CH:25]=2)=[N:3][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=2[N:10]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Reactant: Cc1ccc2nc(-c3nc(Br)cnc3N)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(-c3nc(-c4ccc(=O)n(C)c4)cnc3N)[nH]c2c1
Temperature: 110 °C
Yield: 43.4 %

Procedure:
A mixture of 5-bromo-3-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-amine (100 mg, 0.3288 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (154.6 mg, 0.6578 mmol), potassium carbonate (136.4 mg, 0.9867 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (26.86 mg, 0.03289 mmol) in DMF (3 mL) were heated to 110° C. for 2 hours. The mixture was diluted with EtOAc, washed with water, and the organic layer concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (47.4 mg, 40% Yield). MS (ES+) 333