Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)=O)CCCC1.S(Cl)(Cl)=O.[S:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[CH:1]1([C:6]([C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccsc1
Reactant: O=C(Cl)C1CCCC1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(O)C1CCCC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(c1cccs1)C1CCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Cyclopentanecarboxylic acid chloride, prepared from 100 mmol cyclopentanecarboxylic acid and 120 mmol of thionyl chloride, was dissolved in 100 mL of methylene chloride, and the solution was cooled in an ice bath. Thiophene (13.4 mL, 100 mmol) and SnCl4 (25 mL of a 1M solution in methylene chloride) were added. The reaction was warmed to room temperature and stirred for 72 hours. The reaction was quenched with 1 N HCl, and the mixture was extracted with three portions of methylene chloride. The organic extract was washed with satd aqueous NaHCO3, was dried over MgSO4, and filtered through a pad of silica gel. The solvent was removed by rotary evaporation to give 12.28 g of crude product, which was used without further purification.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.[Br:21][CH2:22][C:23](Br)=[O:24].Cl>ClCCl>[Br:21][CH2:22][C:23]([NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)=[O:24]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: O=C(Br)CBr
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CBr)C1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 76.1 %

Procedure:
A solution of (S)-3-amino-1-(tert-butoxycarbonyl)pyrrolidine (5.21 g) and triethylamine (4.68 ml) in dichloromethane (25 ml) was slowly added with bromoacetyl bromide (6.21 g, Wako Pure Chemical Industries) at 0° C., and the mixture was stirred at room temperature for 18.5 hours. The reaction mixture was added with 0.5 N hydrochloric acid, and the organic layer was separated. The aqueous layer was further extracted with dichloromethane, the combined organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (6.54 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8](Cl)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:33][CH2:34][CH3:35])=[C:17]([C:19]2[NH:20][C:21](=[O:32])[C:22]3[N:27]([CH3:28])[N:26]=[C:25]([CH2:29][CH2:30][CH3:31])[C:23]=3[N:24]=2)[CH:18]=1>>[CH2:34]([O:33][C:16]1[CH:15]=[CH:14][C:13]([NH:12][S:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)(=[O:10])=[O:9])=[CH:18][C:17]=1[C:19]1[NH:20][C:21](=[O:32])[C:22]2[N:27]([CH3:28])[N:26]=[C:25]([CH2:29][CH2:30][CH3:31])[C:23]=2[N:24]=1)[CH3:35]
Reactant: CN1CCN(S(=O)(=O)Cl)CC1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(N)ccc3OCC)nc12
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(NS(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12

Procedure:
The title compound was prepared from 4-methyl-1-piperazinylsulphonyl chloride and 5-(5-amino-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, following the procedure of Example 91, and was obtained as an orange powder (13%), m.p. 152-153° C. Found: C,54.32; H,6.38; N,19.88. C22H31N7O4S requires C,53.97; H,6.38; N,20.03%.
Reaction SMILES: C(C1[CH:4]=[C:5]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:30])[NH:22][C:23]([CH3:29])=[CH:24][C:25]=2[CH2:26][CH2:27][CH3:28])=[O:17])[C:6]2[C:7]([CH3:15])=[CH:8][N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1)#N.[OH-].[K+].C(O)C.CC[O:38][C:39]([CH3:41])=[O:40]>>[CH3:15][C:7]1[C:6]2[C:10](=[CH:11][C:41]([C:39]([OH:38])=[O:40])=[CH:4][C:5]=2[C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:30])[NH:22][C:23]([CH3:29])=[CH:24][C:25]=2[CH2:26][CH2:27][CH3:28])=[O:17])[N:9]([CH:12]([CH3:13])[CH3:14])[CH:8]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(C#N)cc2c1c(C)cn2C(C)C
Reactant: CCOC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(C(=O)O)cc2c1c(C)cn2C(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 64.9 %

Procedure:
To a 5 ml microwave vial was added, 6-cyano-3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indole-4-carboxamide (100 mg, 0.247 mmol), KOH (41.6 mg, 0.742 mmol) was ground and added followed by Ethanol (8 mL) the reaction was microwaved at 145° C. for 22 hr. The reaction was poured onto acidic Ice water (20 mL) and was stirred for 20 min. EtOAc was added and the mix was stirred an additional 10 min. The layers were separated and the majority of the product was in the EtOAc which was evaporated. The residue was dissolved in MeOH (1 mL) and material was crashed out with ice and was filtered to give product 3-methyl-1-(1-methylethyl)-4-({[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]amino}carbonyl)-1H-indole-6-carboxylic acid (70 mg, 0.160 mmol, 64.9% yield) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.49 (br. s., 1H) 8.18 (s, 1H) 8.10 (s, 1H) 7.53 (d, J=7.58 Hz, 2H) 5.90 (s, 1H) 4.76-4.90 (m, 1H) 4.36 (d, J=4.80 Hz, 2H) 2.55 (br. s., 1H) 2.18 (s, 3H) 2.13 (s, 3H) 1.52-1.61 (m, 2H) 1.44 (d, J=6.57 Hz, 6H) 0.94 (t, J=7.33 Hz, 3H) MS(ES) [M+H]+ 423.8
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH3:16]>>[CH2:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH3:16]
Reactant: O=C1CCNCC1
Reactant: CCOCCCCCCl
Product: CCOCCCCCN1CCC(=O)CC1

Procedure:
1-(5-Ethoxypentyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-5-ethoxypentane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.CCCCCC.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.O>[C:24]([C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccccc2)c(C(=O)O)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromo-5-methoxybenzoic acid (5 g, 21.6 mmol) in 50 mL of THF is stirred under argon at −78° C., and a 1.6 M solution of n-butyllithium in hexane (29 mL, 45 mmol) is then added dropwise. The reaction mixture is stirred for 1 hour at −78° C. and benzoyl chloride (3.2 g, 22.7 mmol) is then added dropwise. The reaction mixture is stirred for 1 hour 30 minutes at −78° C. and then for 18 hours at room temperature. The mixture is hydrolysed with 100 mL water and then washed with ethyl acetate. The aqueous phase is acidified by addition of 5 N hydrochloric acid and then extracted with ethyl acetate. The organic phase obtained is washed with brine and then dried over anhydrous sodium sulfate. After filtration and evaporation under reduced pressure, 5.4 g of a colourless oil are obtained, and are used without purification.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[CH3:18][NH2:19]>CN(C=O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([NH:19][CH3:18])=[O:15]
Reactant: CN
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(-c2ccccc2)c1Cl
Temperature: 0 °C
Reaction time: 120 h
Yield: 70 %

Procedure:
A solution of 3.5 g of 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid, ethyl ester and 20 ml of 40% aqueous methylamine in 20 ml DMF was stirred at room temperature for about 45 hours. Thin layer chromatography showed mostly starting material so an additional 10 ml of 40% aqueous methylamine was added to the reaction mixture which was stirred for an additional 5 days. The reaction mixture was poured into ice water and the precipitated solid was collected by filtration. After drying, the solid was recrystallized from toluene to afford 2.3 g of 5-chloro-1-phenyl-N-methyl-1H-pyrazole-4-carboxamide. Yield 70%. mp=182°-183° C.
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][CH2:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]([CH3:22])[C:12](=[O:23])[CH2:11]1>ClCCl.[O-2].[O-2].[O-2].[Cr+6]>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:22])[C:12](=[O:23])[CH2:11][CH:10]2[CH2:9][CH:8]=[O:7]
Reactant: COc1ccc2c(c1)C(CCO)CC(=O)N2C
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C(CC=O)CC(=O)N2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a chilled (0° C.) solution of 69 ml of pyridine in 600 ml of dichloromethane was added 42.5 g of chromium trioxide. The resulting mixture was stirred at room temperature for 0.5 hour and a solution of 10.0 g of 3,4-dihydro-4-(2-hydroxyethyl)-6-methoxy-1-methyl-2(1H)-quinolinone in 100 ml of dichloromethane was added, dropwise. The reaction mixture was stirred for 0.5 hour, the solvent was decanted, and the resulting residue washed with dichloromethane. The combined organic layers were washed with 5% sodium hydroxide solution, 10% hydrochloric acid solution, water, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting oil was filtered through silica (elution with ethyl acetate) and concentrated to afford 1,2,3,4-tetrahydro-6-methoxy-1-methyl-2-oxo-4-quinolineacetaldehyde.
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[F:15][C:16]1[CH:17]=[C:18]([CH:28]=[C:29]([F:32])[C:30]=1[F:31])[CH2:19][N:20]1[CH2:25][CH2:24][O:23][C:22](=[O:26])[C:21]1=[O:27].[OH-].[Na+].OO.S(=O)(O)[O-].[Na+]>C1COCC1.[Cl-].[Na+].O.C(Cl)(Cl)Cl>[OH:26][CH:22]1[O:23][CH2:24][CH2:25][N:20]([CH2:19][C:18]2[CH:28]=[C:29]([F:32])[C:30]([F:31])=[C:16]([F:15])[CH:17]=2)[C:21]1=[O:27]
Reactant: O=C1OCCN(Cc2cc(F)c(F)c(F)c2)C1=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=S([O-])O
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C1C(O)OCCN1Cc1cc(F)c(F)c(F)c1
Reaction time: 2 h
Yield: 53 %

Procedure:
A 1 M solution of lithium tri-sec-butylborohydride in THF (31.4 mL) was added dropwise to a solution of 4-(3,4,5-trifluorobenzyl)morpholine-2,3-dione (7.38 g) in THF at −15° C., and the reaction solution was stirred for two hours. A 5 N sodium hydroxide solution (2.85 mL) and 30% aqueous hydrogen peroxide (968 μL) were added dropwise to the reaction solution at 20° C. or less, which was then stirred at 10° C. for one hour. Sodium bisulfite (888 mg) was added to the reaction solution, which was then stirred for 30 minutes. Brine and chloroform were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography using a silica gel (heptane:ethyl acetate=1:1 to 0:100) to obtain 3.94 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][NH2:22])[CH2:15][CH2:14]1.C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:22][CH2:21][CH2:20][CH2:19][N:16]3[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CN1CCN(CCCN)CC1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(CCCNc2ccc3ncc(Br)n3n2)CC1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 3-(4-methylpiperazin-1-yl)propan-1-amine according to general procedure 1 providing the intermediate (200 mg, 85%) as a clear oil: Rf=0.25 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.54 (d, J=9.6 Hz, 1H), 7.39 (s, 1H), 6.67 (d, J=9.7 Hz, 1H), 3.42 (t, J=7.0 Hz, 2H), 2.53-2.50 (m, 10H), 2.29 (s, 3H), 1.91 (quin, J=6.6 Hz, 2H)
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=3)[C@@H:14]([CH2:34][N:35]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[S:36]([CH3:39])(=[O:38])=[O:37])[CH2:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-])=O.C([O-])(O)=O.[Na+]>[Fe].C(O)(=O)C>[NH2:1][C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([C:24]([OH:33])([C:25]([F:28])([F:26])[F:27])[C:29]([F:32])([F:31])[F:30])=[CH:20][N:19]=3)[C@@H:14]([CH2:34][N:35]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[S:36]([CH3:39])(=[O:38])=[O:37])[CH2:13]2)(=[O:10])=[O:11])=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)N(C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)c1ccccc1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CS(=O)(=O)N(C[C@H]1CN(S(=O)(=O)c2ccc(N)s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)c1ccccc1
Temperature: 50 °C
Yield: 72.7 %

Procedure:
A 20-mL vial was charged with N-(((2R)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-phenylmethanesulfonamide (0.131 g, 0.186 mmol, step 1), iron filings (0.052 g, 0.93 mmol) and acetic acid (2 mL). The reaction mixture was heated at 50° C. for 40 min and then allowed to cool to room temperature. Saturated aqueous NaHCO3 (20 mL) was then added slowly. The aqueous phase was extracted with EtOAc (2×20 mL) and the combined organic phases were washed with saturated aqueous NaCl (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (25 g of silica gel, 20 to 80% EtOAc in hexanes) to afford N-(((2R)-4-((5-amino-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-phenylmethanesulfonamide (0.0912 g) as a light-yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.[ClH:10]>O1CCOCC1>[ClH:10].[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][Cl:10])[CH:3]=1
Reactant: OCc1cncc(Br)c1
Agent: Cl
Solvent: C1COCCO1
Product: ClCc1cncc(Br)c1
Yield: 66 %

Procedure:
(5-Bromopyridin-3-yl)methanol (XLV) (1.54 g, 8.2 mmol) was treated with 4M HCl in dioxane (10 mL) at 0° C. and then evaporated. The residue was dissolved in SOCl2 (4 mL) and refluxed for 2 hrs. The SOCl2 was removed and the residue was triturated with hexane to produce HCl salt of 3-bromo-5-(chloromethyl)pyridine (XLVI) as a brown solid (1.30 g, 5.4 mmol, 66% yield). The product was used without further purification. ESIMS found for C6H5BrClN m/z 206 (M+H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:22][C:21]([Cl:32])=[N:20][C:19]=4[CH:18]=3)[CH2:13]2)[CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C[Si]([N:44]=C=O)(C)C>C(Cl)Cl>[Cl:32][C:21]1[N:22]=[C:23]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:24]2[S:25][C:17]([CH2:16][N:12]3[CH2:13][CH:14]4[CH2:15][N:8]([C:6]([NH2:44])=[O:7])[CH2:9][CH:10]4[CH2:11]3)=[CH:18][C:19]=2[N:20]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)N1CC2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of 5-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (250 mg, 0.52 mmol) in DCM (4.5 mL) was added TFA (0.5 mL). The reaction mixture stirred at RT for 1 h, then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH, and concentrated in vacuo. The resultant residue was dissolved in DCM (5 mL) and trimethylsilyl isocyanate (139 μL, 1.0 mmol) was added. The reaction mixture was stirred at RT for 1 h, then partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with brine, then dried (Na2SO4) and concentrated in vacuo to give the title compound as a colourless oil (185 mg, 84%).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]([OH:20])=O)[N:14]3[CH3:17])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1)[CH3:2].Cl.Cl.[CH3:33][C:34]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)([CH3:38])[C:35]([NH2:37])=[O:36]>>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]([N:42]4[CH2:41][CH2:40][N:39]([C:34]([CH3:38])([CH3:33])[C:35]([NH2:37])=[O:36])[CH2:44][CH2:43]4)=[O:20])[N:14]3[CH3:17])=[C:10]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)O)n(C)c2n1
Reactant: CC(C)(C(N)=O)N1CCNCC1
Agent: Cl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)N3CCN(C(C)(C)C(N)=O)CC3)n(C)c2n1

Procedure:
2-(2-Ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purine-8-carboxylic acid was coupled with 2-methyl-2-(piperazin-1-yl)propanamide dihydrochloride according to General Procedure K to give 566. LCMS m/z: 281.3 (2M+H+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][C:5]=1[N+:18]([O-])=O.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][C:5]=1[NH2:18]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(Cc2ccccc2)C(=O)OC(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.5 %

Procedure:
To a suspension of CsCO3 (4.9 g, 15 mmoles) and (4-tert-Butoxycarbonylamino-2-nitro-benzoic acid methyl ester (2.96 g, 10 mmoles) in anhydrous DMF (100 mL) was added benzyl bromide (2.57 g, 15 mmoles) and the resulting mixture was stirred at room temperature for 12 hrs. The reaction mixture was filtered, concentrated, diluted with ethyl acetate, and washed with 5% citric acid, saturated NaHCO3 solution and water. The organic phase was hydrogenated over 10% Pd/C in EtOAc. After 12 hr, the mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo to give a crude oil which was purified by column chromatography to furnish the desired product as an off-white solid (2.05 g, 57% yield). ES+ MS showed 357 m/z, the correct mass for the product. 1H NMR (400 MHz, DMSO-d6) showed β=1.34 (s, 9H), 3.71 (s, 3H), 4.74 (s, 2H), 6.39 (d, J=9 Hz, 1H), 6.62 (s, 1+2H), 7.19 (d, J=7 Hz, 2H), 7.24 (d, J=7 Hz, 1H), 7.32 (dd, J1=J2=7 Hz, 2H),.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:14]=[CH:15][C:16]([F:20])=[C:17]([CH:19]=3)[NH2:18])[C:8]([CH3:12])=[N:9]2)=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][NH:28][CH3:29])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[NH2:18][C:17]1[CH:19]=[C:13]([C:7]2[C:8]([CH3:12])=[N:9][C:10]3[C:5]([CH:6]=2)=[CH:4][N:3]=[C:2]([N:28]([CH2:27][C:26]2[CH:30]=[CH:31][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH3:29])[CH:11]=3)[CH:14]=[CH:15][C:16]=1[F:20]
Reactant: CNCc1ccc(OC)cc1
Reactant: Cc1nc2cc(Cl)ncc2cc1-c1ccc(F)c(N)c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(CN(C)c2cc3nc(C)c(-c4ccc(F)c(N)c4)cc3cn2)cc1
Temperature: 170 °C
Yield: 67.6 %

Procedure:
Treat a solution of 5-(7-chloro-2-methyl-1,6-naphthyridin-3-yl)-2-fluoroaniline (0.353 g, 1.227 mmol) and 4-methoxy-N-methylbenzylamine (0.371 g, 2.454 mmol) in NMP (6 mL) in a sealed tube with N,N-diispropylethylamine (DIEA) (0.429 mL, 2.454 mmol), sparge with argon and heat at 170° C. overnight. Add additional 4-methoxy-N-methylbenzylamine (0.371 g, 2.454 mmol) and heat at 185° C. for 24 h. Add more 4-methoxy-N-methylbenzylamine (0.15 g, 1 mmol) and heat the mixture overnight at 185° C. Cool to RT, dilute with EtOAc and wash with satd. NaHCO3, water, and then brine. Dry the organics over MgSO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (334 mg, 68%). 1H NMR (400 MHz, DMSO-d6): δ 8.95 (s, 1H), 7.95 (s, 1H), 7.15 (d, J=8.4 Hz, 2H), 7.05 (dd, J=11.5, 8.2 Hz, 1H), 6.85 (m, 2H), 6.78 (dd, J=8.8, 2.3 Hz, 1H), 6.71 (s, 1H), 6.54 (ddd, J=8.2, 4.4, 2.2 Hz, 1H), 5.24 (s, 2H), 4.85 (s, 2H), 3.69 (s, 3H), 3.08 (s, 3H), 2.47 (s, 3H); MS (ESI) m/z: 403.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]1=[O:23].[CH2:24]([O:26]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:25]>>[C:24]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]1=[O:23])(=[O:26])[CH3:25]
Reactant: COc1cc2c(cc1OC)C(=O)C(Cc1ccncc1Br)CC2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Product: COc1cc2c(cc1OC)C(=O)C(Cc1ccncc1C(C)=O)CC2

Procedure:
The title compound 104 is prepared according to the procedure reported in Example 36.5 with compound 100 (175 mg, 0.47 mmol) and (l-ethoxyvinyl)tri(n-butyl)stannane (0.16 mL, 0.47 mmol) as reactants. White solid. (Yield 93.2 g, 58%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][C:24]([F:27])([F:26])[F:25])=[C:19]([CH:22]=1)[CH:20]=O>COCCOC.CCOCC>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][C:24]([F:25])([F:26])[F:27])=[C:19]([CH:20]=[C:5]2[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]2=[O:7])[CH:22]=1
Reactant: O=Cc1cc(Br)ccc1OC(F)(F)F
Reactant: CC1(C)CC(=O)C(C)(C)O1
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: CC1(C)OC(C)(C)C(=Cc2cc(Br)ccc2OC(F)(F)F)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To an ice-cold solution of 2,2,5,5-tetramethyldihydrofuran-3-one (2.84 g, 20.00 mmol) in anhydrous 1,2-dimethoxyethane (6 ml) is added sodium methoxide (1.19 g, 22.04 mmol) in one portion. After stirring at this temperature for 5 minutes a solution of 5-bromo-2-trifluoromethoxybenzaldehyde (4.84 g, 18.00 mmol) in 1,2-dimethoxyethane (6 ml) is added dropwise over 10 mins, followed by stirring at 0° C. for a further 1hour. After warming to room temperature the reaction mixture is diluted with ether and washed with 2M hydrochloric acid (×2). Organic fractions are combined, dried over magnesium sulphate, filtered and the filtrate evaporated in vacuo to afford 4-[1-(5-bromo-2-trifluoromethoxyphenyl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (7.06 g) as an orange liquid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[SH:7][C:8]1[N:22]=[CH:21][CH:20]=[CH:19][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:11].Cl[CH2:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27]>CN(C=O)C>[O:27]=[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25][CH2:24][S:7][C:8]1[C:9]([C:10]([NH:12][CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[O:11])=[CH:19][CH:20]=[CH:21][N:22]=1
Reactant: O=C(CCCl)c1ccccc1
Reactant: O=C(NCc1cccs1)c1cccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCSc1ncccc1C(=O)NCc1cccs1)c1ccccc1
Reaction time: 0.5 h
Yield: 13.3 %

Procedure:
227 mg (1.65 mmol) of K2CO3 were added to a solution of 375 mg (1.5 mmol) of 2-mercapto-N-(thiophen-2-ylmethyl)nicotinamide in DMF (3.5 ml), and stirring was carried out for 30 min at RT. 252 mg (1.5 mmol) of 3-chloro-1-phenylpropan-1-one were then added and stirring was carried out for a further 2 d at RT. The mixture was then concentrated in vacuo and the residue was taken up in a mixture of EA and a 1N aq. NaHCO3 sol. The organic phase was separated off and the aqueous phase was extracted again with EA. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by means of CC (EA/hex 1:1), and subsequent crystallization (EA/hexane) yielded 73 mg (0.2 mmol, 13%) of 2-[(3-oxo-3-phenyl-propyl)sulfanyl]-N-(thiophen-2-yl-methyl)-pyridine-3-carboxylic acid amide. MS: m/z 383.1 [M+H]+.