Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][N:12]=1.Br[C:20]1[N:24]2[N:25]=[CH:26][C:27]([C:29]([F:32])([CH3:31])[CH3:30])=[N:28][C:23]2=[N:22][CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].CN(C)C=O>[F:17][C:16]1[C:11]([C:3]2[CH:4]=[C:5]([C:20]3[N:24]4[N:25]=[CH:26][C:27]([C:29]([F:32])([CH3:30])[CH3:31])=[N:28][C:23]4=[N:22][CH:21]=3)[CH:6]=[CH:7][C:2]=2[F:1])=[N:12][CH:13]=[C:14]([F:18])[CH:15]=1
Reactant: CC(C)(F)c1cnn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2ncc(F)cc2F)c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(F)c1cnn2c(-c3ccc(F)c(-c4ncc(F)cc4F)c3)cnc2n1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To 4-fluoro-3-(3,5-difluoropyridin-2-yl)phenylboronic acid (0.08 g) and 7-bromo-3-(1-fluoro-1-methylethyl)imidazo[1,2-b][1,2,4]triazine (0.06 g, 0.23 mmol) was added dry potassium phosphate (0.3 g), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.04 g) and dry N,N-dimethylformamide (3 ml). The mixture was degassed, then stirred for 24 h at 80° C. under an atmosphere of dry nitrogen. The reaction was cooled to ambient temperature, and the solvent was stripped at reduced pressure. The residue was boiled with toluene (25 ml), and filtered hot. The filtrate was evaporated and the residue subjected to preparative thin layer chromatography (silica gel; 2.5% MeOH/CH2Cl2). The recovered product was crystallised from hot toluene/isohexane to afford the title compound as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 1.80 (6H, d, J 22.1 Hz), 7.60 (1H, dd, J 8.8, 9.8 Hz), 8.18 (1H, m), 8.32 (1H, m), 8.37 (1H, m), 8.59 (1H, s), 8.74 (1H, d, J 2.3 Hz), 9.03 (1H, s); MS (ES+) m/z 388 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:18]([C:19]#[C:20][C:21]([C:24]2[CH:28]=[C:27]([CH:29]=O)[O:26][N:25]=2)([OH:23])[CH3:22])=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[C:31](=O)([O-])[O-].[K+].[K+]>CO>[C:29]([C:27]1[O:26][N:25]=[C:24]([C:21]([OH:23])([CH3:22])[C:20]#[C:19][C:18]2[C:2]([F:1])=[CH:3][C:4]3[O:10][CH2:9][CH2:8][N:7]4[CH:11]=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=[C:6]4[C:5]=3[CH:17]=2)[CH:28]=1)#[CH:31]
Reactant: O=C([O-])[O-]
Reactant: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1cc(C=O)on1
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(C(C)(O)C#Cc2cc3c(cc2F)OCCn2cc(C(N)=O)nc2-3)no1
Temperature: 25 °C
Reaction time: 12 h
Yield: 20.8 %

Procedure:
Dimethyl [1-(methylidyneimino)-2-oxopropyl]phosphonate (27.9 mg, 0.15 mmol, 1.00 equiv) in methanol (0.2 mL) was added dropwise to a stirred mixture of 9-fluoro-10-(3-(5-formylisoxazol-3-yl)-3-hydroxybut-1-yn-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (60 mg, 0.15 mmol, 1.00 equiv) and potassium carbonate (39 mg, 0.28 mmol, 2.00 equiv) in methanol (1.5 mL) at room temperature. The resulting mixture was stirred for 12 h at room temperature and the solids were filtered out. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm, mobile phase, Water with 10 mmolNH4HCO3 and CH3CN (22% CH3CN up to 43% in 15 min, up to 95% in 2 min, down to 22% in 2 min); Detector, UV 254/220 nm to give 12.7 mg of the titled compound (21%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[C:7]([CH:12]3[CH2:14][CH2:13]3)[NH:8]2)=[CH:4][CH:3]=1.Br[C:16]1[CH:17]=[N:18][N:19]([CH2:21][CH3:22])[CH:20]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[C:7]([CH:12]3[CH2:14][CH2:13]3)[N:8]2[C:16]2[CH:17]=[N:18][N:19]([CH2:21][CH3:22])[CH:20]=2)=[CH:4][CH:3]=1
Reactant: CCn1cc(Br)cn1
Reactant: Fc1c(Cl)ccc2cc(C3CC3)[nH]c12
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCn1cc(-n2c(C3CC3)cc3ccc(Cl)c(F)c32)cn1
Temperature: 140 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a solution of compound 3 (4.3 g, 20.5 mmol) in toluene (50 mL) were added 4-bromo-1-ethyl-1H-pyrazole 4 (4.0 g, 22.8 mmol), potassium phosphate (11.0 g, 51.2 mmol), N,N′-dimethylethylenediamine (722 mg, 8.2 mmol) and Cu(I)I (390 mg, 2.0 mmol) at RT under inert atmosphere. The reaction solution was purged with argon for 15 min and then sealed the tube. The reaction mixture was heated to 140° C. and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was cooed to RT, diluted with EtOAc (50 mL) and filtered. The filtrate was washed with water (40 mL), brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel chromatography; 9% EtOAc/Hexanes) to afford compound 5 (3.9 g, 63%) as a pale brown solid. 1H NMR (400 MHz, CDCl3): δ 7.64 (s, 1H), 7.60 (s, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.01 (dd, J=8.4, 6.4 Hz, 1H), 6.12 (s, 1H), 4.25 (q, J=7.2 Hz, 2H), 1.69-1.62 (m, 1H), 1.56 (t, J=7.2 Hz, 3H), 0.92-0.87 (m, 2H), 0.76-0.72 (m, 2H); LC-MS (ESI): 98.6%; m/z 304.3 (M+H+); (column: X Select C-18, 50×3.0 mm, 3.5 μm); RT 4.23 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][N:3]=1.C1COCC1.[CH2:22]([O:24][CH:25]([O:34][CH2:35][CH3:36])[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27])[CH3:23]>CCCCCC.O>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:26]([OH:27])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]([O:24][CH2:22][CH3:23])[O:34][CH2:35][CH3:36])[C:5]([NH:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:15])[CH3:14])=[CH:4][N:3]=1
Reactant: Cc1c(NC(=O)C(C)(C)C)cnc(Cl)c1C
Reactant: CCOC(OCC)C(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCOC(OCC)C(O)(Cc1c(NC(=O)C(C)(C)C)cnc(Cl)c1C)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
144.3 g (0.6 mol) of 2-chloro-3,4-dimethyl-5-pivaloylaminopyridine are dissolved in 2.9 1 of abs. THF and the solution is treated under argon at -78° C. with 127 ml of a 10.4N solution of n-BuLl in n-hexane (1.32 mmol). The mixture is stirred at 0° C. for 3 h, 129.8 ml (0.6 mol) of 2,2-diethoxyacetophenone are slowly added at -78° C. and the mixture is stirred at room temperature overnight. It is then added to water and extracted 3 times with ethyl acetate, dried and concentrated on a rotary evaporator. The purity is sufficient for further reaction. After chromatography, 180.5 g (67%) of the title compound are obtained. M.p.: 133° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[O:4][Si:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7].ClC1C=CC=C(C(OO)=[O:28])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:19][C:2]([F:18])([F:1])[CH:3]([C:12]1[CH:17]=[CH:16][N+:15]([O-:28])=[CH:14][CH:13]=1)[O:4][Si:5]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH2:10][CH3:11]
Reactant: CC[Si](CC)(CC)OC(c1ccncc1)C(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC[Si](CC)(CC)OC(c1cc[n+]([O-])cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
To 40 ml of chloroform were added 5.5 g of 4-[2,2,2-trifluoro-1-(triethylsilyloxy)ethyl]pyridine, and 7.5 g of meta-chloroperbenzoic acid, and the mixture was stirred at 0° C. for 2 hours, and at room temperature for 3 hours. Thereafter, the reaction solution was poured into an aqueous saturated sodium sulfite solution, followed by extraction with chloroform three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 5 g of 4-[2,2,2-trifluoro-1-(triethylsilyloxy)ethyl]pyridine N-oxide.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].[CH2:17](O)[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][CH3:18])[CH:14]=2)[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCC1CCc2ccc(O)cc21
Reactant: CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1ccc2c(c1)C(CCNC(C)=O)CC2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1-[2-(acetylamino)ethyl]-6-hydroxyindan (1.00 g, 4.56 mmol), ethanol (0.32 ml, 5.47 mmol) and triphenylphosphine (1.32 g, 5.02 mmol) in THF (20 ml) was added dropwise, under ice-cooling, diethyl azodicarboxylate (0.87 g, 5.02 mmol). The mixture was stirred for 15 hours at room temperature. The reaction mixture was concentrated under reduced pressure. To the concentrate was added water, and the mixture was subjected to extraction with ethyl acetate. The extract solution was washed with brine, which was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography (ethyl acetate→ethyl acetate/methanol, 95:5) to give 1-[2-(acetylamino)ethyl]-6-ethoxyindan. To this compound was added hydrazine hydrate (20 ml). The mixture was heated under reflux for 15 hours under argon atmosphere. The reaction mixture was cooled, to which was added water. The mixture was subjected to extraction with ethyl acetate. The extract solution was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 0.34 g (yield 36%) of the above-titled compound as an oily product.
Reaction SMILES: [C:1](=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O.[OH:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[O:18][C:17](=[O:25])[CH:16]=1>CC(C)=O>[CH3:1][O:14][C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[O:18][C:17](=[O:25])[CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(O)cc(C(F)(F)F)o1
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1cc(C(F)(F)F)oc(=O)c1
Yield: 107.7 %

Procedure:
Sodium carbonate (1.35 g, 13 mmol) and dimethyl sulfate (2.17 g, 17 mmol) were added to a solution of 4-hydroxy-6-trifluoromethylpyran-2-one (3.0 g, 17 mmol) in acetone (50 mL). The mixture was heated under reflux for 3 hours and, after cooling, filtered. Concentration of the filtrate resulted in 2.9 g of crude product as a brown oil. It was possible to obtain 4-methoxy-6-trifluoromethylpyran-2-one (2.74 g, 14 mmol, 83%) as colorless needles with a melting point of 61° C. by crystallization from hexane.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[C:46]([F:47])=[CH:45][C:44]([F:48])=[CH:43][C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[CH:43]=[C:44]([F:48])[CH:45]=[C:46]([F:47])[C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: OB(O)c1cc(F)cc(F)c1F
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3cc(F)cc(F)c3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3,5-trifluorophenyl)boronic acid gave 261. 1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 7.80 (d, J=9.1 Hz, 1H), 7.67 (s, 1H), 7.60 (d, J=9.5 Hz, 3H), 5.05-4.71 (m, 2H), 4.20-3.90 (m, 2H), 3.77 (s, 3H), 3.31-3.26 (m, 1H), 2.19-2.09 (m, 1H), 1.91-1.78 (m, 2H), 1.69-1.64 (m, 1H). LCMS (ES+) m/z 485 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:15])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([CH3:16])[C:5]2=1.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.CCOC(C)=O>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=3)[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([CH3:16])[C:5]2=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Cc1cncc2[nH]c3c(N)cc(Cl)cc3c12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: Cc1cncc2[nH]c3c(NC(=O)c4cccnc4)cc(Cl)cc3c12
Reaction time: 12 h
Yield: 8.1 %

Procedure:
A solution of 6-chloro-4-methyl-9H-β-carbolin-8-ylamine (43 mg, 0.19 mmol) in pyridine (4 ml) was stirred at RT under an argon atmosphere. Nicotinoyl chloride hydrochloride (40 mg, 0.22 mmol) was added thereto and the reaction mixture was stirred for 12 hr. The solution was diluted with H2O (5 ml) and poured into a separatory funnel containing H2O (5 ml) and EtOAc (25 ml). The reaction mixture was shaken and the layers were separated. The aqueous layer was extracted with EtOAc (2×25 ml). The combined organic layers were washed with a saturated sodium bicarbonate solution (15 ml), followed by brine, then dried over MgSO4, filtered, and concentrated to yield N-(6-chloro-4-methyl-9H-β-carbolin-8-yl)-nicotinamide (5.2 mg) as an orange viscous oil. 1H-NMR (300 MHz, DMSO-d6): δ 11.67 (s, 1); 10.70 (s, 1); 9.27 (s, 1); 8.83 (s, 2); 8.45 (s, 1); 8.20-8.12 (m, 2); 7.83 (s, 1); 7.66 (s, 1); 2.80 (s, 3). NH4OAc standard conditions. DAD Rf=1.92 min. M+H=337.
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[C:5]#[N:6].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:33]>C1COCC1>[Br:33][CH2:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: COc1ccc(CO)c(C#N)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CBr)c(C#N)c1
Reaction time: 21 h

Procedure:
2-Hydroxymethyl-5-methoxy-benzonitrile from step 3 (1.12 g, 7.62 mmol) was dissolved in THF (38 ml) and treated with Ph3P (3 g, 11.4 mmol) followed by CBr4 (3.8 g, 11.4 mmol). The reaction mixture was stirred at room temp. for 21 hours. The solvent was removed in vacuo and the residue purified by flash chromatography (15% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:8]([F:11])([F:10])[F:9])[CH:4]([NH2:7])[CH2:5][OH:6].N1C=CC=CC=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[F:1][C:2]([F:12])([F:13])[CH:3]([C:8]([F:9])([F:10])[F:11])[CH:4]([NH:7][S:25]([C:21]1[S:20][CH:24]=[CH:23][CH:22]=1)(=[O:27])=[O:26])[CH2:5][OH:6]
Reactant: NC(CO)C(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(NC(CO)C(C(F)(F)F)C(F)(F)F)c1cccs1
Temperature: 25 °C

Procedure:
To a solution of 3,3,3-trifluoro-2-(trifluoromethyl)-1-(hydroxymethyl)propylamine (prepared according to the method of Example 28, Part A, 105 mg, 0.5 mmol) in CH2Cl2 (1 mL) was added pyridine (100 μL) and 2-thiophenesulfonyl chloride (90.5 mg, 0.5 mmol) in CH2Cl2 (1 mL). The solution was stirred for about 8 to about 16 h at 25° C. and then concentrated. EtOAc (1 mL) was added and the solution washed with 1M HCl (1 mL), brine (1 mL), dried over Na2SO4 and concentrated. The crude solid was purified by the Biotage Flash™ 12 chromatography system, eluting with EtOAc/hexanes (2:3), to give thiophene-2-sulfonic acid (3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-amide (26.5 mg) as a white solid.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([C:9]1[N:13]=[C:12]([NH:14][C:15]3[C:20]([O:21][C:22]4[C:23]([CH3:28])=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][C:18]([S:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:17][N:16]=3)[S:11][N:10]=1)[CH2:2]2.C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42].[ClH:48]>C1COCC1>[ClH:48].[CH3:33][O:32][CH2:31][CH2:30][S:29][C:18]1[CH:19]=[C:20]([O:21][C:22]2[C:23]([CH3:28])=[N:24][CH:25]=[CH:26][CH:27]=2)[C:15]([NH:14][C:12]2[S:11][N:10]=[C:9]([CH:3]3[CH2:2][CH:1]4[N:8]([C:41](=[O:43])[CH3:42])[CH:5]([CH2:6][CH2:7]4)[CH2:4]3)[N:13]=2)=[N:16][CH:17]=1
Reactant: COCCSc1cnc(Nc2nc(C3CC4CCC(C3)N4)ns2)c(Oc2cccnc2C)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCSc1cnc(Nc2nc(C3CC4CCC(C3)N4C(C)=O)ns2)c(Oc2cccnc2C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.1 %

Procedure:
3-(8-Azabicyclo[3.2.1]octan-3-yl)-N-(5-(2-methoxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-1,2,4-thiadiazol-5-amine (96 mg, 0.198 mmol) was dissolved in THF (4 mL) and triethylamine (55.2 μL, 0.396 mmol) and acetic anhydride (22.5 μL, 0.238 mmol) were added. The reaction was stirred at ambient temperature for 5 minutes. The reaction was partitioned between saturated aqueous NaHCO3 and CH2Cl2, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (20% methanol in EtOAc) to afford 1-(3-(5-(5-(2-methoxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octan-8-yl)ethanone hydrochloride (91.6 mg, 0.163 mmol, 82.1% yield) as a solid after HCl salt formation. Mass spectrum (apci) m/z=527.2 (M+H—HCl).
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH:16]1[C:33]2=[C:34]3[C:23]([C:24]4[C:35]5[C:28](=[CH:29][CH:30]=[CH:31][C:32]2=5)[CH:27]=[CH:26][CH:25]=4)=[CH:22][CH:21]=[CH:20][C:19]3=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+]>ClC1C=CC=CC=1Cl.O>[CH:31]1[C:32]2=[C:35]3[C:24]([C:23]4[C:34]5[C:19](=[CH:18][CH:17]=[CH:16][C:33]2=5)[CH:20]=[CH:21][CH:22]=4)=[CH:25][CH:26]=[CH:27][C:28]3=[C:29]([CH:9]=[O:10])[CH:30]=1
Reactant: c1cc2cccc3c4cccc5cccc(c(c1)c23)c54
Reactant: CN(C=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1ccc2c3cccc4cccc(c5cccc1c52)c43

Procedure:
About 22 grams N-methylformanilide is initially dissolved in 40 milliliters o-dichlorobenzene, the vessel containing the above solution partially immersed in a water bath (bath temperature less than 25° C) and 22 grams phosphorous oxychloride introduced into the flask by dropewise addition. About 20 grams of perylene is stirred into the above solution and the resulting mixture heated on a steam bath for twelve hours (temperature of contents of vessel 90°-95° C). The contents of the flask are thereafter poured into a second vessel containing 100 grams sodium acetate dissolved in 250 milliliters water. The organic liquid phase of the mixture is separated from the aqueous phase by steam distillation. Crude aldehyde is thereafter precipitated from aqueous solution and the solids recystalized from acetic acid and from benzene. The solids thus obtained are further extracted in a soxhlet extractor with 30-60 pet ether. The material remaining in the extraction thimble is 3-perylenecarboxaldehyde, mp 230° C; yield 9.5 grams.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][C:30]1([OH:37])[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:29][C:30]1([OH:37])[CH2:36][CH2:35][CH2:34][N:33]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:32][CH2:31]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CC1(O)CCCNCC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCCC(C)(O)CC3)n(C)c2n1

Procedure:
Following General Procedure E for Displacement of alkyl bromide with amines, 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 4-methylazepan-4-ol were reacted to give 429. [M+H]+ 491.6
Reaction SMILES: O.O.[I-].[Li+].[Li+].[I-].C(C[C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:13][C:12]=1[NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(O)=O.Cl>N1C(C)=CC(C)=CC=1C.C(Cl)(Cl)Cl.O>[C:16]1([C:14]2[S:13][C:12]([NH:22][C:23](=[O:30])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:11][CH:15]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)Cc1cc(-c2ccccc2)sc1NC(=O)c1ccccc1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Product: O=C(Nc1ccc(-c2ccccc2)s1)c1ccccc1
Yield: 53 %

Procedure:
Lithium iodide dihydrate (25.5 g, 0.168 mole) in collidine (50 ml) under nitrogen were stirred and refluxed until the LiI dissolved. The amido-ester of Example 52 (17 g, 0.053 mole) in warm collidine (400 ml) was added and the solution stirred and refluxed for 48 hours. The cooled solution was poured into a mixture of 5 N. HCl (800 ml., 4 mole) and ice, extracted with chloroform, which was washed with saturated sodium hydrogen carbonate solution, dried (Na2SO4), and evaporated to leave a semisolid. This was heated in vacuo with water to remove residual collidine, stirred with saturated sodium hydrogen carbonate solution, the solid filtered, washed with water and dried to give the title compound (7.85 g) (m.p. 202°-203° C.).
Reaction SMILES: [Cl-].C[SiH](C)C.[F:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=1[CH2:9]Br.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1.O>O1CCCC1.BrC(Br)C.[Zn]>[Cl:16][C:17]1[CH:22]=[C:21]([CH2:9][C:8]2[C:7]([F:6])=[CH:14][CH:13]=[CH:12][C:11]=2[F:15])[N:20]=[CH:19][N:18]=1
Reactant: Fc1cccc(F)c1CBr
Reactant: Clc1cc(Cl)ncn1
Agent: CC(Br)Br
Agent: C[SiH](C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(F)c1Cc1cc(Cl)ncn1
Reaction time: 0.33 h
Yield: 28.5 %

Procedure:
In 10 ml of tetrahydrofuran was suspended 1.3 g of zinc (powder), to which dibromoethane (2 drops) was added. The mixture was heated under reflux for 5 minutes, to which trimethylsilane chloride was added. The mixture was further heated under reflux for 5 minutes, to which a solution of 2.5 g of 2,6-difluorobenzyl bromide dissolved in 20 ml of tetrahydrofuran was slowly added with heating under reflux, followed by stirring for 20 minutes. (The solution thus obtained is referred to as solution E). In 10 ml of tetrahydrofuran were suspended 1.5 g of 4,6-dichloropyrimidine and 0.1 g of dichlorobistriphenylphosphine palladium, to which the above solution D was added, followed by heating under reflux for 3 hours and further stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.69 g of 4-chloro-6-(2,6-difluorobenzyl)pyrimidine.