Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:15]=[CH:14][N:13]=3)[CH:9]=[C:8]([C:25](O)=[O:26])[C:5]2=[N:6][CH:7]=1.CN1C(=O)CCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:59]([CH2:61][NH2:62])[OH:60].C(N(CC)CC)C>>[OH:60][CH2:59][CH2:61][NH:62][C:25]([C:8]1[C:5]2=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]2[N:10]([CH2:11][C:12]2[C:17]([CH3:18])=[C:16]([O:19][CH2:20][C:21]([F:22])([F:24])[F:23])[CH:15]=[CH:14][N:13]=2)[CH:9]=1)=[O:26]
Reactant: Cc1cnc2c(C(=O)O)cn(Cc3nccc(OCC(F)(F)F)c3C)c2c1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1cnc2c(C(=O)NCCO)cn(Cc3nccc(OCC(F)(F)F)c3C)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 25.4 %

Procedure:
See FIG. 23(b). 6-methyl-1-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (55 mg, 0.14 mmol) and NMP (13.95 μl, 0.14 mmol) was taken in a 50 ml single necked flask equipped with an air condenser connected to nitrogen source. HATU (66.2 mg, 0.17 mmol) was added to get a suspension. Added ethanol amine (17.50 μl, 0.29 mmol) followed by the addition of triethyl amine (60.6 μl, 0.43 mmol). The reaction mass was stirred at RT for 5 minutes. LCMS showed completion of the reaction. The crude compound was purified by Gilson Prep HPLC to get pure N-(2-hydroxyethyl)-6-methyl-1-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (15.00 mg, 24.49%). ES+MS m/z: 423 (M+I). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.23 (s, 3 H ) 2.39 (s, 3 H ) 3.45 (br. s., 2 H ) 3.53 (br. s., 2 H ) 4.83 (s, 1 H ) 4.90 (d, J=9.04 Hz, 2 H ) 5.62 (s, 2 H ) 7.06 (d, J=5.65 Hz, 1 H ) 7.75 (s, 1 H ) 8.07 (s, 1 H ) 8.17 (d, J=5.09 Hz, 1 H ) 8.32 (s, 1H ) 8.79 (s, 1 H ).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:11][NH2:12])[OH:10])=[CH:4][C:3]=1[Cl:13].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1>CN(C=O)C>[NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([CH:9]([CH2:11][NH:12][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)[OH:10])=[CH:6][C:7]=1[Cl:8]
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Reactant: BrCCCCCCOCCCCCCc1cnccn1
Solvent: CN(C)C=O
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOCCCCCCc2cnccn2)cc1Cl
Yield: 56.3 %

Procedure:
A solution of 4-amino-α-(aminomethyl)-3,5-dichlorobenzenemethanol (1.2g), DEA (0.72 ml) and [6-[(6-bromohexyl)oxy]hexyl]pyrazine (1.16 g) in DMF (10 ml) was heated at 100°-110° for 3 h. The resulting dark solution was evaporated in vacuo and the residue purified by FCC eluting with System B (96:2:2→93:5:2) to give the title compound as pale yellow crystals (0.92 g), m.p. 60°-63°.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[CH2:8]([SH:12])[CH2:9][CH2:10][SH:11]>C(Cl)Cl>[CH2:2]([CH:1]1[S:12][CH2:8][CH2:9][CH2:10][S:11]1)[CH2:3][CH2:4][C:5]#[CH:6]
Reactant: C#CCCCC=O
Reactant: SCCCS
Solvent: ClCCl
Product: C#CCCCC1SCCCS1
Reaction time: 48 h
Yield: 72449.2 %

Procedure:
Hex-5-ynal (20 g, 0.2M) and 1,3-propanedithiol (20 mL, 0.2 mmol) were stirred in 300 mL methylene chloride at 0°-5° C. and HCl(g) was bubbled into the solution for 10 minutes when it became cloudy. The mixture was stirred 2 days after which it was poured onto 100 mL of 10% KOH. The organics were washed again with 10% KOH (25 mL), then brine, and dried (MgSO4) before evaporation at reduced pressure. The residue was Kugelrohr distilled at 0.1 mm, oven 110° C. to give 27 g of product (72%). 1H NMR (CDCl3) δ 1.7-1.8 (m, 2H), 1.8-1.95 (m, 3H), 1.99 (t, J=2.6 Hz, 1H), 2.2-2.25 (m, 2H), 2.8-2.95 (m, 4H), 4.06 (t, J=6.9 Hz, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:25]=[CH:24][N:12]2[C:13](=[O:23])[CH:14]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:16]=[C:11]2[CH:10]=1)C1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.CO>ClCCl>[OH:8][C:9]1[CH:25]=[CH:24][N:12]2[C:13](=[O:23])[CH:14]=[C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[N:16]=[C:11]2[CH:10]=1
Reactant: O=c1cc(N2CCOCC2)nc2cc(OCc3ccccc3)ccn12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=c1cc(N2CCOCC2)nc2cc(O)ccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
A solution of 8-benzyloxy-2-morpholinyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.97 g, 2.9 mmol) in dichloromethane (50 ml) under nitrogen was treated dropwise with trifluoromethanesulfonic anhydride (1 ml, 6.0 mmol) and the mixture was stirred at RT overnight. Methanol (20 ml) was added and the solution stirred for a further 1 h, then the solution was evaporated to dryness. The residue was taken up in ethyl acetate, washed with brine, dried and then eluted through a silica column using a gradient of 0-5% methanol in ethyl acetate. The product was obtained as a brown powder (0.35 g)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH2:8][C@H:9]([OH:11])[CH3:10])[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:22][S:23]([O:11][C@H:9]([CH3:10])[CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:12])(=[O:25])=[O:24]
Reactant: Cc1ccc(F)cc1C[C@@H](C)O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C[C@@H](C)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (R)-1-(5-fluoro-2-methylphenyl)propan-2-ol (6.1 g, 36.3 mmol) and DIEA (12.6 mL, 72.6 mmol) in 200 mL anhydrous DCM was cooled in ice-water bath. Then methylsulfonyl chloride (3.4 mL, 43.5 mmol) was added slowly and the mixture was stirred for 30 min at rt. And then, saturated NaHCO3 solution (30 mL) was added to the solution and extracted with DCM, dried over anhydrous MgSO4, concentrated, passed through silicagel pad to give crude (R)-1-(5-fluoro-2-methylphenyl)propan-2-yl methanesulfonate (F-2).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:21](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:21][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:13])[F:14])[CH:7]=2)[C:2](=[O:1])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4]1
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2cc(C(F)(F)F)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 4-hydroxy-7-trifluoromethylquinoline-3-carboxylate (370.5 g), anhydrous potassium carbonate (179.4 g), iodomethane (202.4 g) and anhydrous dimethylformamide (2 liters) was stirred at room temperature overnight. More dimethylformamide (500 ml) was added and stirring was continued for 24 hours. The dimethylformamide was distilled off in vacuo and water (2 litres) was added to the residue. The resulting solid was collected, washed with water, dried and recrystallised from IMS to give the novel compound ethyl 1-methyl-4-oxo-7-trifluoromethyl-1,4-dihydroquinoline-3-carboxylate, m.p. 222°-224°.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[P:6]([O:11][CH2:12][CH3:13])(=[O:10])[O:7][CH2:8][CH3:9].[Li+].CC([N-]C(C)C)C.[CH:22](OC)=[O:23]>C1COCC1>[CH2:12]([O:11][P:6]([C:2]1[O:1][C:5]([CH:22]=[O:23])=[CH:4][CH:3]=1)([O:7][CH2:8][CH3:9])=[O:10])[CH3:13]
Reactant: COC=O
Reactant: CCOP(=O)(OCC)c1ccco1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1ccc(C=O)o1
Reaction time: 1 h

Procedure:
A solution of diethyl 2-furanphosphonate (1 mmole) in THF was treated with LDA (1.12 mmole, lithium N,N-diisopropylamide) at −78° C. for 20 min. Methyl formate (1.5 mmole) was added and the reaction was stirred for 1 h. Extraction and chromatography gave compound 1 as a clear yellow oil. Preferably this aldehyde can be prepared from 2-furaldehyde as described below.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([S:14]([OH:17])(=[O:16])=O)[CH:12]=2)[NH:7][C:6]1=[O:18])[CH3:3].[CH3:19][O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24]C=1N.CS(O)(=O)=O>C(O)C>[CH3:19][O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[NH:2][CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([S:14](=[O:16])(=[O:17])[NH:7][CH:8]([CH3:13])[CH3:9])[CH:12]=2)[NH:7][C:6]1=[O:18]
Reactant: CN(C)C=C1C(=O)Nc2ccc(S(=O)(=O)O)cc21
Reactant: COC(=O)c1ccccc1N
Agent: CS(=O)(=O)O
Solvent: CCO
Product: COC(=O)c1ccccc1NC=C1C(=O)Nc2ccc(S(=O)(=O)NC(C)C)cc21
Temperature: 150 °C

Procedure:
A mixture of rpm282 (0.260 g, 0.841 mmol) methyl-2-aminobenzoate (0.139 g, 0.925 mmol, 1.2 eq) and methansulfonic acid (0.088 g, 0.925 mmol, 1.1 eq) in ethanol (5 mL) was heated in the microwave at 150° C. for 5 min. The reaction mixture was cooled to 0° C., and the orange precipitate was collected by filtration and dried, to give pure rpm335 (0.207 g, 0.498 mmol, 59%). MS (API-ES): m/z 416 (M+H)+; HRMS (API-ES) m/z Found: 416.1276 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH:11]C=O)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:14][CH2:15][CH2:16][O:17][CH2:18][P:19]([O:24]CC)([O:21]CC)=[O:20].C[Si](Br)(C)C>CN(C)C=O>[NH2:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[O:14][CH2:15][CH2:16][O:17][CH2:18][P:19]([OH:24])([OH:21])=[O:20])=[C:2]([Cl:1])[N:10]=1
Reactant: CCOP(=O)(COCCOn1cnc2c(Cl)nc(NC=O)nc21)OCC
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Product: Nc1nc(Cl)c2ncn(OCCOCP(=O)(O)O)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.9 %

Procedure:
To a solution of 6-chloro-9-[2-(diethoxyphosphorylmethoxy)ethoxy]-2-formamidopurine (0.370 g, 0.91 mmol) in dry dimethylformamide (5 ml) was added trimethylsilyl bromide (1.3 ml, 9.6 mmol) and the solution stirred at ambient temperature for 3 hours. The solvent was removed under reduced pressure and the residue co-evaporated with acetone:water 1:1 (×2). The solid residue obtained was crystallised from hot water to give the title compound as a tan solid (0.15 g, 51%), m.p. 190°-195° C. IR: νmax (KBr) 3480, 3430, 3200, 3150, 2920, 1660, 1625, 1570, 1525, 1480, 1370, 1320, 1235, 1195, 1125, 1105, 1030, 995, 950, 920, 880, 780 cm-1. 1H NMR: δH [(CD3)2SO] 3.63 (2H, d, J=8.52 Hz, OCH2P), 3.81 (2H, m, CH2OCH2P), 4.45 (2H, m, N-OCH2), 2.75-5.25 (2H, broad, D2O exchangeable PO(OH)2), 7.11 (2H, br.s, D2O exchangeable NH2), 8.37 (1H, s, H-8). Found: C,28.89; H,3.51; N,21.15%. C8H11N5O5PCl. 0.5H2O requires: C,28.88; H,3.63; N,21.06%.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:10]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]2=[N:8][CH:7]=1)CCC.Br[C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:32][CH:33]=1>>[C:34]1([C:31]2[CH:30]=[CH:29][C:28]([C:6]3[N:10]4[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[N:14][C:9]4=[N:8][CH:7]=3)=[CH:33][N:32]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Brc1ccc(-c2ccccc2)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: FC(F)(F)c1ccn2c(-c3ccc(-c4ccccc4)nc3)cnc2n1

Procedure:
3-Tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine was reacted with 5-bromo-2-phenylpyridine (prepared according to the procedure of Tilley and Zawoiski, J. Org. Chem., 1988, 53(2), 386-90) by the method of Example 1 to afford 3-(2-phenylpyridin-5-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine as a yellow solid: δH (400 MHz, CDCl3) 7.30 (1H, d, J 7), 7.47-7.56 (3H, m), 7.96 (2H, m), 8.09 (2H, dd, J 8 and 1), 8.19 (1H, s), 8.83 (1H, d, J 7), 8.93 (1H, d, J 2); m/z (ES+) 340 (M++H).
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:17])[C@H:3]2[CH2:18][CH2:19][CH2:20][CH2:21][C@@H:2]12.C(N1C=CN=C1)([N:25]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1>[C:1]1(=[O:22])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][C:8]([NH2:25])=[O:9])[C:4](=[O:17])[C@H:3]2[CH2:18][CH2:19][CH2:20][CH2:21][C@@H:2]12
Reactant: O=C(O)CC(c1ccccc1)N1C(=O)[C@H]2CCCC[C@H]2C1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)CC(c1ccccc1)N1C(=O)[C@H]2CCCC[C@H]2C1=O
Reaction time: 1 h
Yield: 23.3 %

Procedure:
A mixture of 3-(cis-hexahydrophthalimido)-3-phenylpropionic acid (0.903 g, 3.00 mmol) and carbonyldiimidazole (0.525 g, 3.75 mmol) in 13 mL of anhydrous tetrahydrofuran under nitrogen was stirred for 1 hour, then 0.25 mL of concentrated ammonium hydroxide was added to the reaction solution. After 20 minutes, the reaction mixture was concentrated in vacuo to an oil. The oil was diluted with 20 mL of water and the mixture extracted with ethyl acetate (20 mL). The organic layer was dried (sodium sulfate) and concentrated to afford an oil. The oil was then purified by flash chromatography (silica gel, 5/95 methanol/methylene chloride, Rf =0.3) to afford 210 mg of 3-(cis-hexahydrophthalimido)-3-phenylpropionamide as an oil which slowly crystallized to an ivory solid: 1H NMR (DMSO-d6) d7.49 (s, 1H, NH), 7.4-7.2 (m, 5H, Ar), 6.90 (s, 1H, NH), 5.54 (t, 1H, J=7.8 Hz, CH), 3.09 (d, 2H, J=7.8 Hz, CH2), 2.95-2.80 (m, 2H, CH2), 1.8-1.1 (m, 8H); 13C NMR (DMSO-d6) δ179.6, 179.5, 171.5, 139.5, 128.6, 127.7, 127.2, 55.2, 50.6, 38.8, 36.5, 23.4, 23.3, 21.5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[CH2:10]([O:12][C:13](=[O:15])C)C.C(Cl)(Cl)=O>C1C=CC=CC=1>[Cl:9][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[OH:8])[NH:1][C:13](=[O:15])[O:12][CH3:10]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: CCOC(C)=O
Agent: O=C(Cl)Cl
Solvent: c1ccccc1
Product: COC(=O)Nc1ccc(O)c(Cl)c1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
Powdered 4-amino-2-chlorophenol (210 grams, 1.46 moles) is added to a dry ethylacetate solution (2100 ml.) of phosgene (210 grams, 2.05 moles) and the mixture is stirred at 0°C. to 10°C. Slowly the reaction mixture is raised to reflux temperature after 1 hour. Further phosgene (20 grams) is passed through the solution during a one-half hour period, then the mixture is heated under reflux during another 30 minute period, cooled to 40°C., and rapidly filtered. The filtrate is evaporated under reduced pressure to a volume of 900 ml. An infrared spectrum of this oil has a peak at 2260 cm.-1 (N=C=O). The isocyanate solution is added to methanol (1.8 liters) with stirring, and the reaction is brought to reflux for 16 hours, then set aside at 20°C. for 48 hours. Evaporation of the reaction mixture affords a viscous oil. Addition of benzene (2 × 300 ml.) followed by evaporation causes the oil to solidify. The crude solid is vacuum dried, melting point 96°C. to 98°C., 250.5 grams (86%). Crystallization of a 5 gram sample from benzene (trace n-hexane) affords crystals, melting point 104°C. to 105°C., 2.76 grams (47%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH2:3][C:2]1=[O:10].[H-].[Na+].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][N:29]4[CH:33]=[CH:32][N:31]=[CH:30]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[C:2]1=[O:10]
Reactant: O=C1Cc2cccnc2N1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCn1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(C3C(=O)Nc4ncccc43)ncnc2cc1OCCn1ccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
A solution of 7-azaoxindole (165 mg, 1.23 mmol), (prepared as described for the starting material in Example 2), in DMF (3 ml) was added dropwise to a suspension of sodium hydride (50 mg, 1.23 mmol, prewashed with hexane) in DMF (3 ml). After stirring for 30 minutes at ambient temperature, 4-chloro-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (125 mg, 0.41 mmol) in DMF (3 ml) was added. The mixture was heated at 65° C. for 30 minutes. After cooling the mixture was partitioned between saturated aqueous ammonium chloride and methylene chloride. The precipitate was collected by filtration, dried and purified by flash chromatography eluting with methylene chloride/methanol (8/2). After evaporation of the solvent, the solid was dissolved in methylene chloride/methanol and 2.2 M hydrogen chloride in ether was added. After stirring for 10 minutes at ambient temperature, the volatiles were removed by evaporation. The residue was triturated with ether, collected by filtration and dried under vacuum to give 4-(7-azaoxindol-3-yl)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (110 mg, 53%).
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH2:16][N:17]3C(=O)C4=CC=CC=C4C3=O)[CH:15]=2)[N:9]=1)[NH2:3].O.NN.[ClH:31]>CO>[ClH:31].[ClH:31].[ClH:31].[NH2:17][CH2:16][C:14]1[CH:15]=[C:10]([C:8]2[N:9]=[C:5]([N:4]=[C:2]([NH2:3])[NH2:1])[S:6][CH:7]=2)[CH:11]=[N:12][CH:13]=1
Reactant: NC(N)=Nc1nc(-c2cncc(CN3C(=O)c4ccccc4C3=O)c2)cs1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CO
Product: NCc1cncc(-c2csc(N=C(N)N)n2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of 2-(diaminomethyleneamino)-4-(5-phthalimidomethylpyridin-3-yl)thiazole (2.47 g) and hydrazine hydrate (0.4 g) in methanol was stirred at room temperature for 5 hours. 3N hydrochloride solution (40 ml) was added slowly and then the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was suspended in water (30 ml) and then the resulting precipitate was removed by filtration. The solvent was removed under reduced pressure to afford 4-(5-aminomethylpyridin-3-yl)-2-(diaminomethyleneamino)thiazole trihydrochloride. NMR (DMSO-d6, δ): 4.31 (2H, q, J=5.2 Hz ), 8.27 (1H, s), 8.44 (4H, s), 8.99 (1H, br), 9.08 (2H, br), 9.52 (1H, br), 9.50 (1H, br)
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:13]2[NH:14][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][C:12]=2[C:11]([CH3:23])([CH3:22])[CH2:10][NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2].[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28](Cl)=[O:29]>>[CH:1]([O:4][C:5]([C:7]1[C:13]2[NH:14][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][C:12]=2[C:11]([CH3:23])([CH3:22])[CH2:10][N:9]([C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:33]([F:34])=[C:25]([F:24])[CH:26]=2)[CH:8]=1)=[O:6])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CCOC(=O)c1cc2c([nH]1)C(C(=O)OC(C)C)=CNCC2(C)C
Product: CCOC(=O)c1cc2c([nH]1)C(C(=O)OC(C)C)=CN(C(=O)c1ccc(F)c(F)c1)CC2(C)C

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 by using 4,4-dimethyl-1,4,5,6-tetrahydro-pyrrolo[2,3-d]azepine-2,8-dicarboxylic acid 2-ethyl ester 8-isopropyl ester and 3,4-difluoro-benzoyl chloride. 1H-NMR(CDCl3): δ 11.11 (1H, s), 7.83 (1H, s), 7.48 (1H, m), 7.27 (1H, m), 6.87 (1H, d), 5.10 (1H, m), 4.33 (2H, q), 3.92 (2H, s), 1.37 (3H, t), 1.33 (6H, s), 1.21 (6H, d). MS (ES): 461 (MH+).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[Br:7][C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:14]=1)[NH2:11].N1C=CC=CC=1.Cl>C(Cl)Cl>[Br:7][C:8]1[CH:9]=[C:10]([NH:11][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:14]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cc(Br)cc(Oc2ccc(F)cc2F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cc(Br)cc(Oc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.6 %

Procedure:
Ethylsulfonyl chloride (15 uL, 0.16 mmol) was added dropwise to a stirred solution of 3-bromo-5-(2,4-difluorophenoxy)aniline (48 mg, 0.16 mmol) and pyridine (40 uL, 0.48 mmol) in DCM (320 uL) at 0° C. under nitrogen. After the mixture was allowed to warm to rt and stir for 12 h, it was treated with 1N HCl (1 mL) and extracted with DCM (3×5 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The crude solid was purified by silica gel column chromatography using a gradient of EtOAc (5 to 60%) in hexanes to afford the title compound (60 mg, 95%) as a tan solid. LCMS (M+H)+=393.
Reaction SMILES: C([N:4]1[C@:8]2([C@H:12]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH2:11][N:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:9]2)[C:7](=[O:28])[N:6]([C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[CH:30]=2)[C:5]1=[O:37])(=O)C.N1CCCC1>C1COCC1>[CH2:21]([N:10]1[CH2:11][C@@H:12]([C:13]2[CH:14]=[CH:15][C:16]([C:17]#[N:18])=[CH:19][CH:20]=2)[C@:8]2([NH:4][C:5](=[O:37])[N:6]([C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[CH:30]=3)[C:7]2=[O:28])[CH2:9]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(=O)N1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(Cc1ccccc1)C[C@H]2c1ccc(C#N)cc1
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: N#Cc1ccc([C@@H]2CN(Cc3ccccc3)C[C@@]23NC(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Yield: 113.3 %

Procedure:
A mixture of Example 11 (8.9 g, 16.7 mmol), TEA (3.8 ml) and pyrrolidine (2.2 ml) in THF (270 ml) was refluxed for 2 h 30 min. The mixture was concentrated in vacuo and taken into DCM, then washed with water. The organic layer was dried over MgSO4 and concentrated. The resulting solid was chromatographed over silica gel (eluent: DCM/MeOH 95/5) to yield the above-titled compound (9.3 g) as a white solid (mp=200° C.). 1H NMR (DMSO-d6): 9.32 (1H, br s), 7.84 (2H, d, J=8.2 Hz), 7.60 (1H, m), 7.25–7.45 (7H, m), 6.74 (2H, d, J=1.9 Hz), 3.65–3.9 (3H, m), 3–3.3 (4H, m).
Reaction SMILES: C1(C[O:8][C:9](=[O:44])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:13]=[C:12]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:11]=2)C=CC=CC=1.[H][H]>[Pd].C1COCC1>[CH2:26]([O:25][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:13]=1)[C:9]([OH:44])=[O:8])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCC(=O)OC)cc(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCC(=O)OC)cc(C(=O)O)c1
Yield: 97.3 %

Procedure:
A mixture of 11.3 g of 3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]benzoic acid phenylmethyl ester and 1.5 g of 10% palladium on carbon in 250 ml of THF was stirred in a hydrogen atmosphere at room temperature for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was triturated with hexane and filtered to give 9.37 g (98% yield, mp 68°-70°) of 3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]benzoic acid.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]([CH3:22])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Sn](Cl)(Cl)(Cl)Cl.[CH3:28][O:29]C(Cl)Cl>ClCCCl.ClCCl>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([O:11][C:12]2[CH:21]=[C:20]3[C:15](=[C:14]([CH3:22])[CH:13]=2)[CH:16]=[C:17]([CH:28]=[O:29])[CH:18]=[CH:19]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(OC2CCC(C(C)(C)C)CC2)cc2ccccc12
Reactant: COC(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(OC2CCC(C(C)(C)C)CC2)cc2ccc(C=O)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
To a mixture of 3-(4-tert-butyl-cyclohexyloxy)-1-methyl-naphthalene (450 mg, 1.5 mmol) in 1,2-dichloroethane (9 mL) was added tin tetrachloride (236 uL, 2 mmol) at 0° C. After stirred at 0° C. for 1 hr, dichloromethyl methyl ether (183 uL, 2 mmol) was added. The solution was stirred at 0° C. for 1 hr and then warmed to room temperature. The mixture was added ice water and stirred for 1 hr, then the dark solution was diluted with dichloromethane and washed with water. The organic phase was washed with sodium bicarbonate aqueous, and dried over MgSO4. The driving agent was filtered off and the solvent was concentrated to dryness to give dark solid product (0.48 g, yield: 97%). ESI-MS: 325.20 (M+H)+.