Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]([NH2:29])([CH3:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[C:30]([O:34][CH3:35])(=[O:33])[CH:31]=[CH2:32]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:26]([NH:29][CH2:32][CH2:31][C:30]([O:34][CH3:35])=[O:33])([CH3:27])[CH3:28])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: C=CC(=O)OC
Reactant: CC(C)(N)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Solvent: ClCCl
Product: COC(=O)CCNC(C)(C)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 100 °C

Procedure:
2-(3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-propan-2-amine (0.081 g, 0.20 mmol) and methyl acrylate (0.18 mL, 2.00 mmol) were combined in a sealed tube and heated neat at 100° C. for 1 day, during which LC-MS indicated completion of reaction. The cooled reaction mixture was diluted with CH2Cl2 and washed with aqueous saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. ISCO purification with 5% to 25% EtOAc/Hexanes afforded methyl 3-(2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)propan-2-ylamino)propanoate as a white amorphous solid. MS (ESI) m/z: Calculated: 489.2; Observed: 490.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[C:18](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-].C(=O)([O-])O.[Na+]>CO>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[C:14]#[CH:18])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1ncc(C=O)c1OCc1ccc(Cl)cc1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Product: C#Cc1cnn(C)c1OCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.8 %

Procedure:
A mixture of 5-[(4-chlorobenzyl)oxy]-1-methyl-1H-pyrazol-4-carbaldehyde (125 mg), potassium carbonate (173 mg), dimethyl (1-diazo-2-oxopropyl)phosphonate (192 mg) and methanol (2.5 mL) was stirred at a room temperature for 24 hours. Thereafter, a saturated sodium hydrogencarbonate aqueous solution was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was washed with a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=80:20 to 70:30), so as to obtain the title compound (76 mg) in the form of a light yellow oily substance.
Reaction SMILES: C(OC([C:6]1[N:16]([CH:17]([CH3:27])[CH2:18][NH:19][C:20](OC(C)(C)C)=[O:21])[C:9]2=[N:10][C:11]([Cl:15])=[C:12]([CH3:14])[CH:13]=[C:8]2[CH:7]=1)=O)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+].O>ClCCl.C(OCC)(=O)C>[Cl:15][C:11]1[N:10]=[C:9]2[C:8](=[CH:13][C:12]=1[CH3:14])[CH:7]=[C:6]1[N:16]2[CH:17]([CH3:27])[CH2:18][NH:19][C:20]1=[O:21]
Reactant: CCOC(=O)c1cc2cc(C)c(Cl)nc2n1C(C)CNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc2cc3n(c2nc1Cl)C(C)CNC3=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 73.7 %

Procedure:
To an ice-cold solution of 0.50 g (1.25 mmol) ®-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-6-chloro-5-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester in 6 mL dichloromethane was added 1.91 mL (2.85 g, 25.0 mmol) trifluoroacetic acid; the ice-bath was removed after complete addition. After 45 min., the volatile components were removed and the residue was dissolved in 3 mL methanol then treated cautiously with 0.70 g (5.0 mmol) potassium carbonate. After 2 h the reaction mixture was poured into water and ethyl acetate and the separated aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated. The residue was dissolved in dichloromethane and tert-butyl methyl ether, evaporated under vacuum until a suspension appeared, then cooled to 0° C. The ice-cold suspension was filtered and the filter cake was washed with tert-butyl methyl ether to give the product as a colourless solid (73.7%).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:8][C:6]=1[NH2:7])[CH2:2][CH3:3].[CH:21](=O)[CH3:22].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[C:9]1[CH:10]=[CH:11][C:5]2[N:4]([CH2:1][CH2:2][CH3:3])[C:21]([CH3:22])=[N:7][C:6]=2[CH:8]=1
Reactant: CC=O
Reactant: CCCNc1ccc(-c2nc3ccccc3o2)cc1N
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1c(C)nc2cc(-c3nc4ccccc4o3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.9 %

Procedure:
To a solution of 2-(2-n-propylaminoanilin-5-yl)benzoxazole (see Working Example 50-1) (148 mg, 0.554 mmol) in dimethylformamide (3 mL) was added an aqueous solution of acetaldehyde (approx. 90%, 104 μL, 1.66 mmol) and oxone (341 mg, 0.554 mmol), and this was stirred at room temperature for 3 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (46.6 mg, 29% yield) as gray crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][CH2:25][CH3:26])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])C.[OH-].[K+]>>[CH3:26][CH2:25][NH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=[C:9]2[N:12]([CH2:15][CH3:16])[N:13]=[CH:14][C:8]=12
Reactant: CCNc1ccccc1Nc1c(C(=O)OCC)cnc2c1cnn2CC
Agent: [K+]
Agent: [OH-]
Product: CCNc1ccccc1Nc1c(C(=O)O)cnc2c1cnn2CC

Procedure:
3.5 g. of 4-[[(2-ethylamino)phenyl]amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.01 mol.) are heated at 60° for 12 hours with a solution of 1.7 g. of potassium hydroxide in 50 ml. of alcohol. The solvent is distilled off and the residue is dissolved in about 100 ml. of water. On acidifying with acetic acid, 4-[[(2-ethylamino)phenyl]amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid crystallizes and is purified by recrystallization from acetic acid, yeild 2.8 g. (93%), m.p. 224°-226°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([NH2:18])[C:14]([CH3:20])([CH3:19])[CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CO.[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([N:12]2[CH2:17][CH2:16][CH:15]([NH2:18])[C:14]([CH3:19])([CH3:20])[CH2:13]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(N2CCC(N)C(C)(C)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(N2CCC(N)C(C)(C)C2)ccc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Pd/C (10% wet base, 20 mg) was added to a solution of 1-(3-methoxy-4-nitrophenyl)-3,3-dimethylpiperidin-4-amine (INTERMEDIATE 40) (0.2 g, 0.72 mmol) in methanol (4 mL). The reaction mixture was degassed and was stirred at RT under a hydrogen ballon for 4 h. The catalyst was removed by filtering the mixture through a pad of Celite®. The filtrate was concentrated to give the title product and it was used without further purification. m/z 250.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)[C:5]([F:21])=[CH:4][C:3]=1[F:22].ClC1[NH:28][C:27]2[CH:29]=[C:30]([C:42]([F:45])([F:44])[F:43])[CH:31]=[C:32]([C:33]3[CH:38]=[C:37]([F:39])[C:36]([F:40])=[C:35]([F:41])[CH:34]=3)[C:26]=2[N:25]=1>>[F:22][C:3]1[C:2]([NH2:1])=[N:7][C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[NH:25][C:26]4[C:32]([C:33]5[CH:34]=[C:35]([F:41])[C:36]([F:40])=[C:37]([F:39])[CH:38]=5)=[CH:31][C:30]([C:42]([F:43])([F:44])[F:45])=[CH:29][C:27]=4[N:28]=3)[CH2:12][CH2:13]2)=[C:5]([F:21])[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N)c(F)cc2F)CC1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Product: Nc1nc(N2CCN(c3nc4cc(C(F)(F)F)cc(-c5cc(F)c(F)c(F)c5)c4[nH]3)CC2)c(F)cc1F

Procedure:
The piperazine from step (a) above (74 mg, 0.35 mmol) reacted with 2-chloro-6-(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzoimidazole (87 mg, 0.25 mmol, Example 51b) under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 529 (M+1).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].C(=O)(O)[O-].[Na+].Br[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:31][CH2:30]1>C(#N)C>[CH2:1]([N:3]([CH2:26][CH2:27][CH2:28][CH:29]1[CH2:31][CH2:30]1)[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=1)[OH:8])[CH3:2]
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Reactant: BrCCCC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCN(CCCC1CC1)CCCC(O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
According to Procedure B (Example 17, Step IV), a stirred mixture of N-[4-[4-(ethylamino)-1-hydroxybutyl]phenyl]methanesulfonamide (Example 7, Step II) and sodium bicarbonate in acetonitrile was allowed to react will 1-bromo-3-cyclopropylpropane (Step IV) to give the titled product, a compound of Formula I'. The high resolution FAB mass spectrum had (M+H)+ at m/z 369. Theory for C19H33N2O3S: 369.2212; measured: 369.2207.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([O:14][CH3:15])[CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:30]([C:32]1[CH:45]=[CH:44][C:35]([CH2:36][N:37]2[C:41]([CH:42]=O)=[CH:40][N:39]=[CH:38]2)=[CH:34][CH:33]=1)#[N:31]>ClCCCl.C(O)(=O)C>[C:30]([C:32]1[CH:33]=[CH:34][C:35]([CH2:36][N:37]2[C:41]([CH2:42][NH:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)=[C:4]([O:14][CH3:15])[CH:3]=3)=[CH:40][N:39]=[CH:38]2)=[CH:44][CH:45]=1)#[N:31]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Reactant: COc1cc(N)ccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(NCc2cncn2Cc2ccc(C#N)cc2)ccc1-c1ccccc1
Reaction time: 15 h

Procedure:
To a solution of 1-amino-3-methoxy-4-phenylbenzene in 1,2-dichloroethane at 0° C. was added 4A powdered molecular sieves and sodium triacetoxyborohydride. 1-(4-Cyanobenzyl)-5-imidazole-carboxaldehyde was added, followed by 5 drops of acetic acid. The cooling bath was removed after 5 hours, and the reaction was stirred for another 15 hours. The reaction was poured into ethyl acetate and water. The organic layer was extracted with sat. aq. NaHCO3 solution and brine, then dried (Na2SO4) and concentrated in vacuo to provide the product.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:10](=[O:11])[N:9]([CH:12]2[CH2:14][CH2:13]2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[N:7]1)C.[OH-].[K+]>CO>[CH:12]1([N:9]2[C:10](=[O:11])[N:6]([CH2:5][C:4]([OH:23])=[O:3])[N:7]=[C:8]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH2:14][CH2:13]1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2OC)n(C2CC2)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1-c1nn(CC(=O)O)c(=O)n1C1CC1

Procedure:
140 mg (0.44 mmol) of ethyl[4-cyclopropyl-3-(2-methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetate from Example 72A are placed in 0.3 ml methanol and stirred overnight at room temperature with 0.12 ml of 20% aqueous potassium hydroxide. This is then concentrated and adjusted to about pH 1 with 1 N hydrochloric acid. The precipitated solid is filtered off, washed with diethyl ether and then dried in vacuo. 81 mg (63% of theory) of the target compound are thus obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][N:17]([CH3:22])[CH:18]3[CH2:21][O:20][CH2:19]3)[N:13]([CH3:23])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:30]([N:44]2[CH2:55][CH2:54][N:53]3[C:46](=[CH:47][C:48]4[CH2:49][C:50]([CH3:57])([CH3:56])[CH2:51][C:52]=43)[C:45]2=[O:58])=[N:31][CH:32]=[CH:33][C:34]=1B1OC(C)(C)C(C)(C)O1)(=[O:26])[CH3:25].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:24]([O:27][CH2:28][C:29]1[C:30]([N:44]2[CH2:55][CH2:54][N:53]3[C:46](=[CH:47][C:48]4[CH2:49][C:50]([CH3:57])([CH3:56])[CH2:51][C:52]=43)[C:45]2=[O:58])=[N:31][CH:32]=[CH:33][C:34]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][N:17]([CH3:22])[CH:18]3[CH2:21][O:20][CH2:19]3)[N:13]([CH3:23])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:26])[CH3:25]
Reactant: CN(Cc1cc(Nc2cc(Br)cn(C)c2=O)nn1C)C1COC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc(CN(C)C4COC4)n(C)n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 44.1 %

Procedure:
A 25-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 302d (200 mg, 0.52 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (210 mg, 0.53 mmol), PdCl2(dppf) (37 mg, 0.050 mmol), K3PO4 (250 mg, 1.2 mmol), sodium acetate (100 mg, 1.20 mmol), acetonitrile (8 mL), and water (0.5 mL). The system was evacuated and then refilled with N2. The mixture was heated at 100° C. for 1 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford 302e as a yellow solid (150 mg, 44%). MS-ESI: [M+H]+ 655.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc(Cl)nc1
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)nc1
Reaction time: 48 h
Yield: 67.9 %

Procedure:
To a solution of 6-chloropyridin-3-ol (40 g, 309 mmol, Eq: 1.00) and ethyl 2-bromo-2-methylpropanoate (63.2 g, 48.1 ml, 324 mmol, Eq: 1.05) in 300 ml of CH3 CN was added Cs2 CO3 (216 g, 664 mmol, 309 mmol, Eq: 2.15) and the resulting reaction mixture was stirred under argon atmosphere for 48 h. The reaction mixture was filtered and the filtercake was washed well with EtOAc. The combined filtrate and washes were diluted with water (300 ml) and shaken and the organic phase was collected. The aqueous phase was back-extracted with EtOAc (2×150 ml). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by passing through a plug of 200 g of silica and elution with 30% EtOAc/Hexanes afforded the desired product (51.1 g) as a light yellow oil. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J=7.18 Hz, 3 H) 1.61 (s, 6 H) 4.24 (q, J=7.18 Hz, 2 H) 7.12-7.25 (m, 2 H) 8.01 (d, J=2.64 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=2[N:3]=1.[H-].[Na+].[CH:34]([S:37](Cl)(=[O:39])=[O:38])([CH3:36])[CH3:35]>C1COCC1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=3[N:3]=[C:2]2[NH:1][S:37]([CH:34]([CH3:36])[CH3:35])(=[O:39])=[O:38])=[CH:17][CH:16]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(N)n2Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)Nc1nc2c(c(=O)n(CCCOC3CCCCO3)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To a solution of 8-amino-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (95 mg, 0.21 mmol, intermediate 53) in THF (5 mL) was added sodium hydride (10 mg, 0.23 mmol) at 0° C. The reaction was stirred at room temperature for 1 h; then Isopropylsulphonyl chloride (29 mg, 0.21 mmol) was added dropwise at 0° C. The mixture was stirred at room temperature 1 h. The reaction was quenched with aqueous ammonium chloride (2 mL) at 0° C. and then was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give the product as a yellow syrup (60 mg) which was used without purification. LCMS retention time 1.519 min; LCMS MH+-THP 470.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[C:13]([C:15]2[CH2:19][C:18]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[O:17][N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:45]2[CH2:46][CH2:47][N:48]([CH2:51][CH2:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][CH:50]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:47][CH:46]=2)=[C:13]([C:15]2[CH2:19][C:18]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([CH2:20][C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[O:17][N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CCN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cc(OCc3ccccc3)ccc2Br)=NO1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)CCN1CC=C(c2ccc(OCc3ccccc3)cc2C2=NOC(CC(=O)OC(C)(C)C)(CC(=O)OC(C)(C)C)C2)CC1
Yield: 99.4 %

Procedure:
A mixture of di-tert-butyl 2,2′-(3-(5-(benzyloxy)-2-bromophenyl)-4,5-dihydro-1,2-oxazole-5,5-diyl)diacetate (200 mg), tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)propanoate (144 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (26.1 mg), a 2 M aqueous cesium carbonate solution (0.5 mL), and DME (2 mL) was stirred at 90 C for 2 hours under microwave irradiation under an argon atmosphere. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (245 mg).
Reaction SMILES: C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[NH:22][CH:23]=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1/[CH:30]=[CH:31]/[CH2:32]O>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[N:22]([CH2:32][CH:31]=[CH:30][C:26]2[S:25][CH:29]=[CH:28][CH:27]=2)[CH:23]=1
Reactant: OC/C=C/c1cccs1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CN(C)C=O
Product: O=c1ncc(Cl)cn1CC=Cc1cccs1
Yield: 8.8 %

Procedure:
N,N-Dimethylformamide dineopentyl acetal (6.2 ml) was added to a stirred suspension of 5-chloropyrimidin-2-one (1.802 g) and (E)-3-(thien-2-yl)prop-2-en-1-ol (2.710 g) in dry N,N-dimethylformamide (34 ml) under nitrogen and then stirring was continued at room temperature. After 3 h the reaction mixture was evaporated to dryness. The residue was dissolved in ethyl acetate (500 ml) and washed with water (3×100 ml), dried (MgSO4) and evaporated to a brown gum. The gum was subjected to column chromatography on silica developing and eluting with chloroform-ethanol, 29:1. The resulting orange solid was triturated with diethyl ether to give a buff solid which was crystallised from ethyl acetate to give off white crystals of the title pyrimidinone (306 mg), m.p. 159°-161° C., λmax (EtOH) 230 nm (ε 10,710).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17]([Sn](C)(C)C)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][N:14]3S(C2C=CC=CC=2)(=O)=O)=[O:8])[N:6]=1.Br[C:33]1[CH:34]=[C:35]([S:39]([NH:42][CH3:43])(=[O:41])=[O:40])[CH:36]=[N:37][CH:38]=1>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.CN(C=O)C>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17]([C:33]3[CH:38]=[N:37][CH:36]=[C:35]([S:39]([NH:42][CH3:43])(=[O:40])=[O:41])[CH:34]=3)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][NH:14]3)=[O:8])[N:6]=1
Reactant: Cc1nc(C(=O)Nc2cc([Sn](C)(C)C)cc3c2cnn3S(=O)(=O)c2ccccc2)cs1
Reactant: CNS(=O)(=O)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1cncc(-c2cc(NC(=O)c3csc(C)n3)c3cn[nH]c3c2)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 3.9 %

Procedure:
2-Methyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg) was placed in microwave vial with Pd(PPh3)4 (10 mg) and 5-bromo-N-methyl-3-pyridinesulfonamide (24.6 mg) was added. DMF (2 ml) was added and the reaction was heated under microwave irradiation for 15 min at 120° C. The reaction was evaporated to dryness and the residue was dissolved in IPA (2 ml) and 2M NaOH (aq) (1 ml). The reaction was stirred at RT for 3 h then evaporated to dryness. The residue was purified by MDAP (method E) to give the title compound (1.5 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N+:13]([O-])=O)[CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:1]([N:8]1[CH2:9][CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[CH:11]([NH2:13])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1cccc(Cl)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: NC1CN(Cc2ccccc2)CC1c1cccc(Cl)c1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
To a stirred solution of (3SR,4RS)-1-benzyl-3-(3-chloro-phenyl)-4-nitro-pyrrolidine (6.30 g, 19.8 mmol) in EtOAc (150 ml) was added portion wise SnCl2.2H2O (22.43 g, 99 mmol). The reaction mixture was then heated at reflux for 4 hours, cooled down to RT and a saturated aqueous solution of NaHCO3 (500 ml) was added. The salts were filtered off and the product extracted with EtOAc. The organic phases were then dried over Na2SO4, and concentration under vacuum. A column chromatography (CH2Cl2/MeOH 95/5) gave 4.47 g (78%) of the title compound as a light yellow oil. ES-MS m/e: 287.0 (M+H+).