Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14](=[O:45])[NH:15][C@@:16]([C:31]2[CH:36]=[C:35]([O:37][C:38]([F:43])([F:42])[CH:39]([F:41])[F:40])[CH:34]=[C:33]([F:44])[CH:32]=2)([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3]1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:14]([NH:15][C@@:16]([C:31]2[CH:36]=[C:35]([O:37][C:38]([F:43])([F:42])[CH:39]([F:41])[F:40])[CH:34]=[C:33]([F:44])[CH:32]=2)([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:45])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1)[C@@H]1C[C@@H](F)CN1
Reaction time: 8 h
Yield: 80.2 %

Procedure:
(2S,4R)-tert-butyl 4-fluoro-2-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylcarbamoyl)pyrrolidine-1-carboxylate (18 mg, 0.03 mmol) was dissolved in a solution of CH2Cl2 (1 mL)/TFA (1 mL) at rt. The reaction mixture was stirred overnight and concentrated to dryness under a stream of argon. The resulting residue was dissolved in MeOH and purified by preparative HPLC (Phenoma Luna AXIA 10A, C18, eluting with 10%-90% MeCN/H2O containing 0.1% TFA, monitoring at 220 nm) to provide (2S,4R)-4-fluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)-phenyl)-1-(4-fluorophenyl)-2-phenylethyl)pyrrolidine-2-carboxamide (Example 276) as a white solid (13 mg, 83% yield). 1H NMR (500 MHz, MeOH-d4) δ ppm 7.22-7.13 (m, 7H), 7.07-6.96 (m, 7H), 6.68 (d, J=5 Hz, 2H), 6.40-6.18 (m, 1H, —CF2H), 5.43 (app d, J=50 Hz, 1H, —CFH), 4.55-4.51 (m, 1H), 4.01 (d, J=10 Hz, 1H), 3.92 (d, J=15 Hz, 1H), 3.65-3.49 (m, 2H), 2.72-2.64 (m, 1H), 2.10-1.96 (m, 1H); LC/MS: RT=3.310 min [M+H] 541.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeCN/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20](/[C:23](=[CH:29]\[CH:30]=[CH:31]\[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)/[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N+]=[N-]>C(OCC)C>[CH2:27]([O:26][C:24]([C:23](=[CH:29][CH:30]=[CH:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1)[N:20]=[P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)/C(=C/C=C/c1ccc(C)cc1)N=[N+]=[N-]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CCOC(=O)C(=CC=Cc1ccc(C)cc1)N=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Following General Procedure J, triphenylphosphine (1.5 g, 5.8 mmol) ethyl (2Z,4E)-2-azido-5-(4-methylphenyl)penta-2,4-dienoate (Compound 45, 1.5 g, 5.8 mmol) in diethyl ether (50 ml) were reacted to produce the title compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)=[CH:5][C:4]([C:27]2[CH:34]=[CH:33][CH:32]=[C:31]([N:35]3[C:47](=[O:48])[C:46]4[S:45][C:44]5[CH2:43][CH2:42][CH2:41][CH2:40][C:39]=5[C:38]=4[CH:37]=[N:36]3)[C:28]=2[CH:29]=[O:30])=[CH:3]1.[BH4-].[Na+]>CO>[OH:30][CH2:29][C:28]1[C:27]([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([CH:22]5[CH2:25][O:24][CH2:23]5)[CH2:18][C@@H:17]4[CH3:26])=[CH:12][N:11]=3)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[CH:34][CH:33]=[CH:32][C:31]=1[N:35]1[C:47](=[O:48])[C:46]2[S:45][C:44]3[CH2:43][CH2:42][CH2:41][CH2:40][C:39]=3[C:38]=2[CH:37]=[N:36]1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cccc(-n4ncc5c6c(sc5c4=O)CCCC6)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cccc(-n4ncc5c6c(sc5c4=O)CCCC6)c3CO)cn(C)c2=O)nc1
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
At 0° C., to a solution of 130b (120 mg, 0.18 mmol) in methanol (5 mL) was added sodium borohydride (20 mg, 0.54 mmol). The reaction was stirred for 30 minutes. It was then quenched with water (1 mL) and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 130 (70 mg, 59%). LCMS: [M+H]+ 666.3. 1H NMR (500 MHz, CDCl3) δ 8.62 (d, J=2.0 Hz, 1H), 8.26 (s, 1H), 7.98 (s, 1H), 7.84 (s, 1H), 7.56-7.54 (m, 2H), 7.42 (d, J=2.5 Hz, 1H), 7.37 (dd, J=2.0, 7.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 4.72-4.66 (m, 4H), 4.36 (d, J=5.0 Hz, 2H), 4.05 (t, J=5.5 Hz, 1H), 3.72 (s, 3H), 3.55-3.54 (m, 1H), 3.46-3.45 (m, 1H), 3.08-3.06 (m, 2H), 2.99 (t, J=5.0 Hz, 2H), 2.87 (t, J=5.0 Hz, 2H), 2.60-2.59 (m, 1H), 2.49-2.48 (m, 2H), 2.20-2.19 (m, 1H), 2.02-1.96 (m, 4H), 0.99 (d, J=6.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]3[CH2:15][CH2:16][C:17](=[N:18]O)[CH:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.N>CO.[Ni]>[F:21][C:2]([F:1])([F:20])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]3[CH2:15][CH2:16][CH:17]([NH2:18])[CH:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1
Reactant: ON=C1CCN2CCN(c3cccc(C(F)(F)F)n3)CC12
Agent: [Ni]
Agent: N
Solvent: CO
Product: NC1CCN2CCN(c3cccc(C(F)(F)F)n3)CC12

Procedure:
A mixture of Example 96A (265 mg, 0.883 mmol), 7 M ammonia in methanol (5.00 mL) and Raney®-nickel (2800, water slurry, 530 mg, 9.03 mmol) in a 50 mL pressure bottle was stirred for 16 hours under hydrogen (30 psi) at room temperature. The mixture was filtered through a nylon membrane, and the filtrate was concentrated to give the titled compound. LCMS (APCI) m/z 287 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([C:15]([CH2:26][CH3:27])([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=3)[CH2:16][CH3:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].Br[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:20]([CH3:25])[CH:19]=3)([CH2:26][CH3:27])[CH2:16][CH3:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C(CC)(CC)c3ccc(O)c(C)c3)cc2o1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2ccc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)cc2o1
Yield: 89.9 %

Procedure:
6-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-benzofuran-2-carboxylic acid ethyl ester (1.58 g, 4.31 mmol) and 1-bromopinacolone (1.16 g, 6.47 mmol) and K2CO3 (1.78 g, 12.9 mmol) in acetone (50 mL) are reacted analogous to Example 30-D to give the title compound (1.80 g, 90%).
Reaction SMILES: [Br:1][C:2]1[N:10](S(C2C=CC=CC=2)(=O)=O)[C:9]2[C:4](=[N:5][C:6]([Cl:20])=[CH:7][CH:8]=2)[CH:3]=1.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([Cl:20])=[CH:7][CH:8]=2)[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1c(Br)cc2nc(Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Clc1ccc2[nH]c(Br)cc2n1

Procedure:
2-Bromo-5-chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine (20.7 g, 44.6 mmol, prepared as in Example 62, Step 1, but isolated as the free base) in THF (300 mL) was stirred with 1N NaOH (300 mL, 300 mmol) overnight. The reaction mixture was extracted with EtOAc three times. The combined extracts were dried over sodium sulfate, filtered, and concentrated to afford 2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine in theoretical yield. LCMS (M+H)+: 233.0 (most abundant).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:11]=[C:12]([C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[O:17])[CH:13]=[CH:14][CH:15]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1.C1C(=O)N([I:31])C(=O)C1>CC(C)=O>[I:31][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[C:8]([C:10]3[CH:11]=[C:12]([C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[O:17])[CH:13]=[CH:14][CH:15]=3)[CH:9]=2)[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(c1cccc(-c2cnc3[nH]ccc3c2)c1)N1CCOCC1
Solvent: CC(C)=O
Product: O=C(c1cccc(-c2cnc3[nH]cc(I)c3c2)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.4 %

Procedure:
To a solution of (3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (550 mg, 1.79 mmol) in acetone (10 mL) was added NIS (604 mg, 2.68 mmol) and the mixture was stirred at room temperature for 20 minutes. Acetone was removed by reduced pressure and the crude product was purified by silica gel chromatography to afforded (3-(3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (600 mg, 77% yield). MS: m/z 434.2 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([C:12](O)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C=O.O1CCOCC1>[C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1c[nH]c(-c2ccccc2)n1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OCc1c[nH]c(-c2ccccc2)n1
Reaction time: 2 h

Procedure:
To a suspension of 1.88 g (0.01 mol) of 2-phenylimidazole-4-carboxylic acid in a mixture of 3 ml of ~37% formaldehyde and 3 ml of 1,4-dioxane is added 2.1 g (0.02 mol) of sodium carbonate, and the resultant mixture is heated at 60°-70° C. for 5 hours, with stirring. After completion of the reaction, 5 ml of water is added, and the mixture is allowed to stand for 2 hours, on cooling. The resultant solid is recovered by filtration and recrystallized from ethyl acetate and filtered to afford 2-phenyl-4-hydroxymethylimidazole as a solid, m.p.168°-170° C.
Reaction SMILES: I[C:2]1[S:3][C:4]2[NH:5][C:6](=[O:15])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1.[CH2:16](C([SnH3])=C(CCCC)CCCC)[CH2:17]CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH:16]([C:2]1[S:3][C:4]2[NH:5][C:6](=[O:15])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1)=[CH2:17]
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Reactant: O=c1[nH]c2sc(I)nc2c2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: C=Cc1nc2c([nH]c(=O)c3ccccc32)s1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
Bis(triphenylphosphine)palladium dichloride (0.005 g, 0.007 mmol) was added to a solution of 2-iodo-4H-1,3-thiazolo[5,4-c]isoquinolin-5-one (0.115 g, 0.35 mmol) and DMF (5 ml) at 23° C. After 30 minutes, tributylvinylstannane (0.11 ml, 0.37 mmol) was added, and the reaction mixture was stirred overnight at 45° C. All volatiles were evaporated, and the resulting oil was purified by flash-chromatography (CH2Cl2/methanol, 99/1) to afford the title compound as a yellow solid (a quantitative yield). m.p 235-239° C. (dec.); 1H NMR (200 MHz, DMSO) δ 5.55 (d, 1H, CHH, J=11 Hz), 5.95 (d, 1H, CHH, J=17 Hz), 6.85-7.00 (m, 1H, CH), 7.47-7.54 (m, 1H, Ar), 7.74-7.82 (m, 1H, Ar), 8.09-8.20 (m, 2H, Ar), 12.43 (bs, 1H, NH).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:35])=[C:4]([N:22]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]2)[CH:5]=[C:6]([N:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:9]([O:11][CH3:12])=[O:10])[CH:7]=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>C(Cl)CCl>[NH2:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:9](=[O:10])[O:11][CH3:12])[CH:5]=[C:4]([N:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]2)[C:3]=1[F:35].[C:38]([OH:40])([C:37]([F:42])([F:41])[F:36])=[O:39]
Reactant: COC(=O)N(Cc1ccc(OC)cc1)c1cc(N)c(F)c(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N(Cc1ccc(OC)cc1)c1cc(N)c(F)c(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-butyl 4-(3-amino-2-fluoro-5-((4-methoxybenzyl)(methoxycarbonyl)amino)phenyl)piperazine-1-carboxylate (317 mg, 0.474 mmol) was dissolved in ClCH2CH2Cl (4 ml): Trifluoroacetic acid (1 ml; 12.98 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours, then evaporated to dryness. 470.1 mg crude methyl (3-amino-4-fluoro-5-(piperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate, TFA (470.1 mg) were isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]([CH:31]=1)[CH2:7][C@@H:8]([CH2:16][NH:17][CH2:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([O:27][CH3:28])=[CH:21][C:20]=1[O:29][CH3:30])[C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]([CH:31]=1)[CH2:7][C@H:8]1[CH2:16][N:17]([CH2:18][C:19]2[C:24]([O:25][CH3:26])=[CH:23][C:22]([O:27][CH3:28])=[CH:21][C:20]=2[O:29][CH3:30])[C:13](=[O:15])[CH2:12][NH:11][C:9]1=[O:10]
Reactant: COc1cc(OC)c(CNC[C@H](Cc2cc(Cl)ccc2OC)C(=O)NCC(=O)O)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: COc1cc(OC)c(CN2C[C@H](Cc3cc(Cl)ccc3OC)C(=O)NCC2=O)c(OC)c1
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-{(2S)-2-(5-chloro-2-methoxybenzyl)-3-[(2,4,6-trimethoxybenzyl)amino]propanoyl}glycine (1g) in acetonitrile (30 ml), 1-hydroxy benzotriazole (421 mg) was added at room temperature. The mixture was stirred at 40° C. for 20 minutes, then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (598 mg) was added to the reaction solution, and the mixture was stirred for 2 hours. After the reaction solution was concentrated in vacuo, toluene was added to the obtained residue, and the resulting mixture was washed with 6% aqueous sodium bicarbonate and saturated brine. The organic layer was concentrated in vacuo, then the obtained residue was purified by silica gel column chromatography to obtain the title compound (894 mg) as a colorless crystal.
Reaction SMILES: Cl.CC1C=CC=C(C)C=1NC(NC(NCC(F)(F)F)=N)=O.CN(C(OC)OC)C.[CH3:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:32]=1[N:38]1[CH:43]=[N:42][CH:41]([NH:44][CH2:45][C:46]([F:49])([F:48])[F:47])[NH:40][C:39]1=[O:50]>CC#N>[CH3:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([CH3:30])[C:32]=1[N:38]1[CH:43]=[N:42][C:41]([NH:44][CH2:45][C:46]([F:47])([F:49])[F:48])=[N:40][C:39]1=[O:50]
Reactant: Cc1cccc(C)c1N1C=NC(NCC(F)(F)F)NC1=O
Agent: COC(OC)N(C)C
Agent: Cc1cccc(C)c1NC(=O)NC(=N)NCC(F)(F)F
Agent: Cl
Solvent: CC#N
Product: Cc1cccc(C)c1-n1cnc(NCC(F)(F)F)nc1=O
Temperature: 100 °C

Procedure:
To a suspension of 130 g (40.0 mmol) of 1-(2,6-dimethylphenylcarbamoyl)-3-(2,2,2-trifluoroethyl) guanidine hydrochloride in CH3CN (50 ml) were added 95 g (80.0 mmol) of DMF-DMA and the mixture heated at reflux for two hours. The solvent was removed under vacuum, and the residue partitioned between CHCl3 and H2O. The layers were separated and the aqueous layer was extracted with CHCl3 (1×100 ml). The extracts were dried (MgSO4) and concentrated to give a white solid which was crystallized from absolute EtOH to give after heating under vacuum at 100° C. for one hour; 9.5 g (80%) of 1-(2,6-dimethylphenyl)-4-(2,2,2-trifluoroethylamino)dihydro-1,3,5-triazin-2-one; melting point 212°-3° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.O>CS(C)=O>[N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[CH:10]=[CH:11][C:12]([CH:13]=[O:14])=[CH:15][CH:16]=2)=[CH:3][CH:2]=1
Reactant: OCc1ccc(/C=C/c2ccncc2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1ccc(/C=C/c2ccncc2)cc1
Reaction time: 4 h
Yield: 70.7 %

Procedure:
To a solution of 4-[(E)-2-(4-pyridyl)vinyl]benzyl alcohol (740 mg) and triethylamine (1.77 g) in dimethyl sulfoxide (3 ml) was added sulfur trioxide-pyridine complex (1.11 g) at ambient temperature, and after stirring for 4 hours, water was added thereto. The mixture was extracted with ethyl acetate, and the extract was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (chloroform-ethyl acetate) and crystallized with diisopropyl ether to give 4-[(E)-2-(4-pyridyl)vinyl]-benzaldehyde (518 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][NH:7][C:6]1=[S:15].Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](Cl)=[O:24])[CH:18]=1>CN(C)C=O>[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[NH:5][C:6](=[S:15])[NH:7][CH2:8]3)=[O:24])[CH:18]=1
Reactant: S=C1NCc2ccccc2N1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C(c1cccnc1)c1ccc2c(c1)CNC(=S)N2
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
106 Parts of N,N-dimethylformamide were added dropwise to 650 parts of aluminum chloride and the solution was stirred for 15 min at 75° C. There were added portionwise 112 parts of 3,4-dihydro-2(1H)-quinazolinethione and, after stirring for 15 min at 75° C., 136 parts of 3-pyridinylcarbonyl chloride hydrochloride. Stirring at 75° C. was continued overnight and then the mixture was poured into 2500 parts of ice-water. The precipitate was filtered off and stirred for 13 hours in a mixture of ice-water and 1530 parts of a sodium hydroxide solution 50%. The product was filtered off, washed with water and dried, yielding 150 parts (82%) of (3-pyridinyl) (1,2,3,4-tetrahydro-2-thioxo-6-quinazolinyl)methanone; (decomp.) (interm. 54).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O.[CH3:44][O:45][C:46]1[CH:47]=[C:48]([CH:51]=[C:52]([O:54][CH3:55])[CH:53]=1)[CH2:49]Br.BrCC1CCCCO1>>[CH3:55][O:54][C:52]1[CH:51]=[C:48]([CH:47]=[C:46]([O:45][CH3:44])[CH:53]=1)[CH2:49][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: COc1cc(CBr)cc(OC)c1
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: COc1cc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc(OC)c1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 3,5-dimethoxybenzyl bromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′(3,5-dimethoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (97%) as a colorless solid: mp 192-195° C. (diethyl ether/hexanes); 1F1 NMR (300 MHz, CDCl3) δ7.23-7.15 (m, 2H), 7.02 (dd, J=7.5, 7.5 Hz, 1H), 6.81 (d, J=7.5 Hz, 1H), 6.51 (s, 1H), 6.47 (d, J=1.8 Hz, 2H), 6.37 (t, J=1.8 Hz, 1H), 6.25 (s, 1H), 5.04 (d, J=15.5 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.72 (d, J=15.5 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.22-4.16 (m, 2H), 4.14-4.09 (m, 2H), 3.76 (s, 6H); 13C NMR (75 MHz, CDCl3) δ177.7, 161.3, 155.4, 144.7, 142.2, 138.5, 138.2, 132.3, 129.0, 123.9, 123.5, 121.2, 111.6, 109.5, 105.4, 99.8, 99.6, 80.2, 64.6, 64.0, 58.2, 55.5, 44.3; MS (ES+) m/z 446.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH:7]=1.[C:24]([NH2:32])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu]I>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][CH2:9][CH2:8][N:6]3[C:5](=[O:23])[CH:4]=[CH:3][C:2]([NH:32][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:7]3)=[CH:12][CH:13]=[N:14]2)=[CH:19][CH:18]=1
Reactant: NC(=O)c1ccccc1
Reactant: COc1ccc2c(OCCn3cc(Br)ccc3=O)ccnc2c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COc1ccc2c(OCCn3cc(NC(=O)c4ccccc4)ccc3=O)ccnc2c1
Temperature: 120 °C

Procedure:
A suspension of 5-bromo-1-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridin-2(1 H)-one (220 mg, 586 μmol), benzamide (213 mg, 1759 μmol), n,n′-dimethylethylenediamine (189 μl, 1759 μmol), copper(I) iodide (167 mg, 879 μmol), and cesium carbonate (573 mg, 1759 μmol) in toluene (3 mL) was sparged with argon then heated to 120° C. for 90 min. The mixture was partioned between CH2Cl2 and 5% NaHCO3 and the hazy organic was washed with 30% NH4OH, dried over MgSO4, and concentrated onto silica (10 g) and purified on silica (12 g) eluting with 0 to 6% of 2M NH3 in MeOH/CH2Cl2. A solid crystallized upon evaporation of selected fractions as a white solid. MS (ESI pos. ion) m/z (MH+): 416. Calc'd exact mass for C24H21N3O4: 415. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.07 (s, 1 H) 8.62 (d, J=4.5 Hz, 1 H) 8.19 (d, J=9.0 Hz, 1 H) 7.96 (d, J=7.5 Hz, 2 H) 7.51-7.66 (m, 4 H) 7.28 (d, J=2.5 Hz, 1 H) 7.03 (dd, J=9.0, 2.5 Hz, 1 H) 6.92 (d, J=5.5 Hz, 1 H) 6.48 (d, J=10.0 Hz, 1 H), 4.48 (s, 4 H), 3.86 (s, 3 H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[S:15][C:14]=1[NH2:22].C1(O)C=CC=CC=1>C(OCC)(=O)C>[Cl:12][C:10]1[CH:9]=[CH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:22][C:14]3[S:15][C:16]4[C:21]([N:13]=3)=[CH:20][CH:19]=[CH:18][N:17]=4)[C:3]=2[N:11]=1
Reactant: Nc1nc2cccnc2s1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Solvent: CCOC(C)=O
Solvent: Oc1ccccc1
Product: Clc1ccc2ncnc(Nc3nc4cccnc4s3)c2n1
Yield: 49.3 %

Procedure:
4,6-Dichloro-pyrido[3,2-d]pyrimidine (100 mg; 0.503 mmol) and 76 mg (0.503 mmol) of thiazolo[5,4-b]pyridin-2-yl-amine in 0.3 mol of phenol were heated at 140° C. for 2 hours with stirring. Ethyl acetate was added to the reaction solution and the resulting solid was purified by a thin layer silica gel column chromatography (chloroform:methanol=10:1) to give 78 mg (yield: 45%) of (6-chloro-pyrido[3,2-d]pyrimidin-4-yl)-thiazolo[5,4-b]pyridin-2-yl-amine as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[NH2:8][C:9]1[CH:32]=[CH:31][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[CH:20]=[C:21]([C:23]4[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=4)[S:22][C:15]=23)=[C:11]([F:33])[CH:10]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[F:33][C:11]1[CH:10]=[C:9]([CH:32]=[CH:31][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23]3[CH:30]=[CH:29][C:26]([CH2:27][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:25][CH:24]=3)[S:22][C:15]=12)[NH2:8]
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C=O)cc4)sc23)c(F)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(N)cc5F)c4s3)cc2)CC1
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
A 20 mL vial was charged with 1-methylpiperazine (0.0457 mL, 0.412 mmol), 4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)benzaldehyde (Example 94, Step A; 0.150 g, 0.329 mmol) and CH2Cl2 (5 mL). The reaction mixture was stirred for 30 minutes and sodium triacetoxyborohydride (0.0977 g, 0.461 mmol) was added slowly over five minutes, and then the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into Na2CO3 (100 mL) and extracted with CH2Cl2 (2×100 mL). The organic layers were over sodium sulfate, filtered and concentrated to provide the product (103 mg, 64%) as a brown solid. LRMS (APCI+) 449 (M+1H).