Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>C1COCC1>[F:8][C:7]1[C:2]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1cccnc1Br
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ncccc1F
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
Cool a solution of 2-bromo-3-fluoro-pyridine (542 mg, 3.08 mmol) in dry THF to −78° C. using a dry ice acetone bath. Add n-butyl-lithium (1.6 M in THF, 2.0 mL) to the reaction mixture dropwise via syringe over a 20 minute period. After stirring for 1.5 hours at −78° C., add tributyltin chloride slowly via syringe and remove the cooling bath. After 2 hours, partition the reaction mixture between EtOAc and brine, dry the EtOAc layer (Na2SO4) and remove the solvents under reduced pressure. Flash chromatography (ether/hexanes) yields 3-fluoro-2-tributylstannanyl-pyridine as a colorless oil.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([F:26])=[C:16]([CH:18]([O:21][Si](C)(C)C)C#N)[CH:17]=1.[CH3:27][O:28][CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.Cl>C(#N)C.C1COCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([F:26])=[C:16]([C:18]([C:32]2([OH:35])[CH2:33][CH2:34][CH:29]([O:28][CH3:27])[CH2:30][CH2:31]2)=[O:21])[CH:17]=1
Reactant: C[Si](C)(C)OC(C#N)c1cc(Br)ccc1F
Reactant: COC1CCC(=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COC1CCC(O)(C(=O)c2cc(Br)ccc2F)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 18.6 %

Procedure:
LiHMDS (1.0 M, 165 mL, 165 mmol) was added dropwise to a solution of 2-(5-bromo-2-fluorophenyl)-2-((trimethylsilyl)oxy)acetonitrile (Intermediate 12 Step 1, 45.80 g, 150 mmol) in acetonitrile (250 mL) at −78° C. The reaction mixture was stirred for 1.5 h and a solution of 4-methoxycyclohexanone (Lee, C. K.; Lee, I.-S. H.; Noland, W. E. Heterocycles, 2007, 71, 419-428) (20.3 g, 150 mmol) in THF (30 mL) was added slowly and the stirring at −78° C. was continued for 3 h. 1M HCl aq. (300 mL) was added at −78° C., and the mixture was allowed to warm slowly to r.t. and stirred overnight. The phases were separated and the aqueous layer was extracted with EtOAc (2×500 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford 57 g of the crude material. A portion of the crude product (30 g) was purified by flash chromatography using a gradient of 0 to 50% EtOAc in EtOAc in hexanes to afford 9.24 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>C(#N)C.C(Cl)(Cl)Cl>[Cl:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: ClCCCBr
Reactant: O=C1CCc2cc(O)ccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=C1CCc2cc(OCCCCl)ccc2N1
Temperature: 110 °C
Reaction time: 4 h
Yield: 57.2 %

Procedure:
A suspension of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (50 g), cesium carbonate (150 g) and 1-bromo-3-chloropropane (58 g) in acetonitrile (300 mL) was stirred at 110° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with chloroform and filtered to remove insoluble materials. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform→chloroform/methanol=4/1), and the resulting solid was subjected to recrystallization from ethanol to give the titled compound (42 g, 68%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH3:44])[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]=[CH:32][CH:31]=[CH:30]2)=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:9])[NH:10][N:11]([CH2:13][C:14]([NH:19][C@@H:20]([CH3:44])[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]=[CH:30]3)=[O:22])=[O:16])[CH3:12])=[CH:17][CH:18]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)N
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 113 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-11) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: C([O:3][C:4](=[O:46])[C@@H:5]([CH3:45])[CH2:6][N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:15]2[N:16]=[N:17][N:18]([CH3:20])[N:19]=2)[C:9]2[CH:36]=[C:37]([CH3:44])[C:38]([C:40]([F:43])([F:42])[F:41])=[CH:39][C:8]1=2)C.[OH-].[Na+]>CO.O>[F:30][C:28]([F:29])([F:31])[C:26]1[CH:27]=[C:22]([CH:23]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:25]=1)[CH2:21][N:14]([C:15]1[N:16]=[N:17][N:18]([CH3:20])[N:19]=1)[CH:10]1[CH2:11][CH2:12][CH2:13][N:7]([CH2:6][C@H:5]([CH3:45])[C:4]([OH:46])=[O:3])[C:8]2[CH:39]=[C:38]([C:40]([F:41])([F:42])[F:43])[C:37]([CH3:44])=[CH:36][C:9]1=2
Reactant: CCOC(=O)[C@@H](C)CN1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc(C)c(C(F)(F)F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc2c(cc1C(F)(F)F)N(C[C@H](C)C(=O)O)CCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 60 °C

Procedure:
To a solution of (S)-3-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-2-methyl-propionic acid ethyl ester (Example 112) (0.04 mmol) in methanol (5 mL), add 5.0 N sodium hydroxide (2 mL). After heating at 60° C. for 6 h cool to room temperature and dilute with water (20 mL). Extract the organics with ethyl acetate (3×10 mL). Dry the combined organic phases over sodium sulfate, filter, and remove solvent under vacuum, to afford the title compound as a mixture of diastereomers. MS (ES+): 639 (M+H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:13][C:14](=[O:27])[N:15]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[O:25][CH3:26])[CH3:16])([CH3:12])([CH3:11])[CH3:10]>ClCCl>[C:9]([O:13][C:14](=[O:27])[N:15]([C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([Br:1])=[C:19]([CH3:24])[C:18]=1[O:25][CH3:26])[CH3:16])([CH3:12])([CH3:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(C)cc(C)cc1N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: COc1c(N(C)C(=O)OC(C)(C)C)cc(C)c(Br)c1C
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 92 %

Procedure:
N-Bromosuccinimide (326 mg, 1.83 mmol) was added to a solution of (2-methoxy-3,5-dimethyl-phenyl)-methyl-carbamic acid tert-butyl ester (456 mg, 1.72 mmol) in dichloromethane (1.8 ml) at 0° C., and the mixture was stirred at room temperature for 50 minutes. The reaction mixture was diluted with dichloromethane and adjusted to pH 9 and washed with water and a 1 N aqueous NaOH solution (1 ml), and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give (4-bromo-2-methoxy-3,5-dimethyl-phenyl)-methyl-carbamic acid tert-butyl ester as a colorless solid (545 mg, 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][NH2:36])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C>CN(C)C=O>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][NH:36][C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(N[C@H](C(=O)O)C1CCCCC1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)[C@@H](NC(=O)OCc2ccccc2)C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (S)-benzyloxycarbonylamino-cyclohexyl-acetic acid (5.4 g, 18.66 mmol) and 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (4.0 g, 18.66 mmol) in dimethylformamide were added HATU (7.09 g, 18.66 mmol) and collidine (2.46 ml, 18.66 mmol) at 0° C. The mixture was stirred for 1 hour and then allowed to warm to room temperature. The mixture was evaporated and separated between ethyl acetate and sodium bicarbonate solution. The organic layer was washed with aqueous solution (pH 4), dried and evaporated. The resulting residue was taken up in ethyl acetate and washed with potassium hydrogen sulfate solution, dried and evaporated to give the desired product. Yield: 8.29 g (91%), MS m/z: 488.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([S:15][CH2:16][CH3:17])[N:12]=[C:11]([NH2:18])[CH:10]=1.CO[CH:21](OC)[CH2:22]Br.O1CCOCC1>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([S:15][CH2:16][CH3:17])[N:12]2[CH:21]=[CH:22][N:18]=[C:11]2[CH:10]=1
Reactant: CCSc1nc(N)cc(-c2ccc(Cl)cc2Cl)n1
Reactant: COC(CBr)OC
Solvent: O
Solvent: C1COCCO1
Product: CCSc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12

Procedure:
48.5 g (161.55 mmol) of 6-(2,4-dichlorophenyl)-2-(ethylthio)pyrimidine-4-amine (Example 3A) and 163.84 g (969.32 mmol) of bromoacetaldehyde dimethyl acetal are introduced into a mixture of 1164 ml of dioxane and 291 ml of water and heated under reflux for 16 h. The dioxane is substantially removed in vacuo, and 1000 ml of ethyl acetate and 1000 ml of saturated aqueous sodium bicarbonate solution are cautiously added. The phases are separated and a further extraction with ethyl acetate is carried out. The combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and then freed of solvent. The residue is purified by silica gel chromatography. 16.6 g (27% of theory) of the product are obtained and are reacted further in this form.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([O:16][CH3:17])=[O:15].C([O-])(=O)C.[K+].O>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][C:9]1[CH:13]=[C:12]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:11][C:10]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1sccc1C
Reactant: Ic1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1sc(-c2ccccc2)cc1C
Temperature: 150 °C
Yield: 4.5 %

Procedure:
At room temperature, a solution of 4-iodobenzene (9.6 mmol) and methyl 3-methylthiophene-2-carboxylate (19.2 mmol) in dimethylacetamide (20 ml) were degassed with nitrogen for 15 minutes. Potassium acetate (0.87 mmol) and palladium acetate (0.02 mmol) were added, the reaction vessel was sealed and heated at 150° C. for 1 hour. Then, the reaction mixture was cooled down to room temperature and poured into water, extracted with dichloromethane, washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by chromatography on silica gel (eluent: gradient of 3% diethyl ether in petroleum ether) to give 100 mg of Intermediate V.1 (22%) as a yellow solid, which was characterized by the following spectroscopic data: 1H NMR (CDCl3, 400 MHz) δ (ppm) 2.57 (s, 3H), 3.88 (s, 3H), 7.13 (s, 1H), 7.32-7.34 (m, 3H), 7.59-7.64 (m, 2H); and MS (ESI, EI+) m/z=233 (MH+).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21].IC>C1COCC1>[CH3:1][C:16]1[C:15]([F:21])=[C:14]([Br:13])[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(F)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Diisopropylamine (11.9 ml, 85 mmol) is dissolved in 50 ml of anhydrous THF and cooled in a dry ice/acetone bath. n-Butyllithium (34 ml of a 2.5 M solution in hexanes, 85 mmol) is added dropwise. After 15 minutes, a solution of 1-bromo-2,4-difluorobenzene (16 g, 83 mmol) in 8 ml of THF is added at a rate to keep the temperature below −65° C. The reaction is stirred for 2.5 hours then a solution of iodomethane (10.3 ml, 166 mmol) in 8 ml of THF is added to the reaction. The ice bath is removed and the reaction is allowed to warm to room temperature. After 2 hours the reaction is quenched with water and 1N HCl. The aqueous layer is extracted twice with ether. The combined organics are washed with brine and dried over Na2SO4. Removal of the solvent affords the desired product.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([OH:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][CH2:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([O:12][CH2:21][CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(O)ccc(Br)c1C
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(OCCOC2CCCCO2)ccc(Br)c1C
Temperature: 55 °C
Yield: 71.6 %

Procedure:
A solution of methyl 3-bromo-6-hydroxy-2-methylbenzoate (Cpd GG, 1.94 g, 7.90 mmol) in DMF (25 mL) was treated with cesium carbonate (3.45 g, 10.0 mmol) and then 2-(2-bromoethoxy)tetrahydro-2H-pyran (2.06 g, 9.84 mmol). The reaction mixture was heated at 55° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water (2×) and brine. The organic layer was concentrated under vacuum to give a brown oil which was purified by column chromatography (0-25%, ethyl acetate/heptane) to give the title compound (Cpd HH, 2.11 g, 67% yield) as a clear oil. 1H NMR (400 MHz, chloroform-d) δ 7.50 (d, J=8.80 Hz, 1H), 6.72 (d, J=8.80 Hz, 1H), 4.68 (t, J=3.36 Hz, 1H), 4.13-4.18 (m, 2H), 4.00 (td, J=4.77, 11.37 Hz, 1H), 3.91 (s, 3H), 3.86 (ddd, J=3.06, 8.59, 11.34 Hz, 1H), 3.74-3.80 (m, 1H), 3.49-3.56 (m, 1H), 2.32 (s, 3H), 1.78-1.89 (m, 1H), 1.67-1.77 (m, 1H), 1.58-1.66 (m, 2H), 1.49-1.55 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:29]=[CH:28][C:18]([O:19][CH:20]([CH2:25][O:26][CH3:27])[C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1)([O-])=O.[H][H]>O1CCCC1>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH:20]([CH2:25][O:26][CH3:27])[C:21]([O:23][CH3:24])=[O:22])=[CH:28][CH:29]=1
Reactant: COCC(Oc1ccc(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1)C(=O)OC
Reactant: [H][H]
Solvent: C1CCOC1
Product: COCC(Oc1ccc(Nc2ccc(C(F)(F)F)cc2N)cc1)C(=O)OC

Procedure:
A solution of 17 g of 10B in 100 ml of tetrahydrofuran was treated with hydrogen (40 psi hydrogen pressure, Parr-shaker, 10% palladium-on-charcoal catalyst) to give methyl 2-(4-(2-amino-4-(trifluoromethyl)phenylamino)phenoxy)-3-methoxypropionate (10C), as an oil.
Reaction SMILES: CS([Cl:5])(=O)=O.CCN(CC)CC.[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([CH:22]=1)[CH2:20]O>ClCl>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([CH:22]=1)[CH2:20][Cl:5]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc([N+](=O)[O-])c(CO)c1
Agent: ClCl
Solvent: CCN(CC)CC
Product: COc1ccc([N+](=O)[O-])c(CCl)c1
Yield: 94.9 %

Procedure:
MsCl (1.9 mL, 24 mmol) was added to Et3N (4.5 mL, 32 mmol) and 5-methoxy-2-nitrobenzyl alcohol (1.48 g, 8.1 mmol) in CH2 Cl2 (80 mL) and the mixture kept at reflux for 12 h. The solution was cooled, washed with dilute HCl (2N, 2×50 mL), dried (Na2 SO4), concentrated, and filtered through a short column of silica (eluting with 9:1 petroleum ether:EtOAc) to give 5-methoxy-2-nitrobenzyl chloride as a yellow liquid (1.55 g, 95%). 1H NMR (CDCl3) δ 8.17 (d, J=9.1 Hz, 1H, H-3), 7.20 (d, J=2.8 Hz, 1H, H-6), 6.93 (dd, J=9.1, 2.8 Hz, 1H, H-4), 5.03 (s, 2H, ArCH2Cl), 3.93 (s, 3H, ArOCH3); 13C NMR (CDCl3) δ 163.7 (C-2), 140.7, 135.5, 128.2, 116.5, 113.7 (C-1,3,4,5,6), 56.1 (OCH3), 43.7 (CH2Cl); MS (EI) m/z 201 [70%, M+ (35Cl)], 184 (100%), 166 (60%, M--Cl), 156 (50%), 106 (70%); HRMS (EI) Calcd. for C8H8 ClNO3 203.0163 (35Cl). Found 203.0165.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.Br[CH:13]([CH2:19][CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: Nc1ccc2ccccc2c1
Reactant: CCOC(=O)C(Br)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(CC)Nc1ccc2ccccc2c1

Procedure:
Following General Procedure AJ above and using 2-aminonaphthalene (Aldrich) and ethyl 2-bromobutyrate (Aldrich), the title compound was prepared as a solid, m.p. 81-83° C. The reaction was monitored by silica gel tlc (Rf=0.5 in CHCl3). Purification was by chromatography (silica gel using chloroform as the eluant).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:32][CH3:33])[CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:21]>C(#N)C>[CH2:32]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7](=[O:15])[C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:27]1)[CH3:33]
Reactant: CCN(CC)CCCC1CCCNC1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Solvent: CC#N
Product: CCN(CC)CCCC1CCCN(C(=O)N2c3ccccc3NC(=O)c3cccnc32)C1
Yield: 38 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 3-[3-(diethylamino)propyl]piperidine in a yield of 38% of theory. Colourless crystals, m.p. 123°-125° C. (acetonitrile).
Reaction SMILES: C(OC(=O)[N:7]([CH3:25])[C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)(C)(C)C.[NH2:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH3:25][NH:7][C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:27][CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1
Reactant: NC1CCOCC1
Reactant: CSc1nccc(-c2cnc3c(N(C)C(=O)OC(C)(C)C)nccn23)n1
Product: CNc1nccn2c(-c3ccnc(NC4CCOCC4)n3)cnc12

Procedure:
Methyl-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-amine was prepared by a process analogous to that described in Example 12 starting from methyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (from Example 8 supra), and 4-amino-tetrahydropyran.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]([F:34])([F:33])[C:6]1[CH:7]=[C:8]([NH:12][C:13]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][C:25]4[CH:30]=[C:29]([CH:31]=[O:32])[N:28]=[CH:27][N:26]=4)=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)=[O:14])[CH:9]=[CH:10][CH:11]=1>C1COCC1>[F:34][C:5]([F:33])([F:4])[C:6]1[CH:7]=[C:8]([NH:12][C:13]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][C:25]4[CH:30]=[C:29]([CH:31]([OH:32])[CH3:1])[N:28]=[CH:27][N:26]=4)=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Solvent: C1CCOC1
Product: CC(O)c1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Reaction time: 3 h

Procedure:
Methylmagnesium bromide solution (3 M in ether, 20 mL) is added to a solution of 5-(6-formyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (5.0 g 11.7 mmol) in THF (400 mL) at 0° C. The mixture is stirred at that temperature for 3 h before the reaction is then quenched with saturated aqueous NH4Cl. The product is extracted with EtOAc (3×40 mL) and the combined organic layers are washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue is purified semi-prep HPLC (C18; 30-100% I/H2O with 0.1% TFA) to give the title compound as a racemate. MS (ESI) m/z 441.1 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.62 (s, 1 H), 8.36 (d, J=8.84 Hz, 1 H), 8.06 (s, 1 H), 7.95 (d, J=3.79 Hz, 1 H), 7.90 (d, J=8.08 Hz, 1 H), 7.58 (t, J=7.83 Hz, 1 H), 7.43 (d, J=2.27 Hz, 2 H), 7.12 (dd, J=8.97, 2.40 Hz, 1 H), 7.09 (s, 1 H), 6.75 (d, J=3.79 Hz, 1 H), 4.75 (d, J=6.57 Hz, 1 H), 1.45 (d, J=6.57 Hz, 3 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH3:23])[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:27])[CH2:25][CH3:26]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH3:23])[C:20]([NH:27][CH2:24][CH2:25][CH3:26])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)OC1=O
Reactant: CCCN
Solvent: CO
Product: CCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 293 mg (0.9 mmole) of (3R, 5S)-5-[(1S)-1-(t-butoxycarbonyl)amino-2-cyclohexylethyl]-3-methyldihydrofuran-2(3H)-one (prepared as described in Preparation 2) in 3 ml of methanol was mixed with 3 ml of propylamine, whilst ice-cooling, and the mixture was allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was concentrated by distillation under reduced pressure, and the residue was triturated with hexane to afford 315 mg of the title compound as white crystals, melting at 115°-116° C.