Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:27])=[C:8](C(O)=O)[NH:9][C:10]=1[CH:11]=[C:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:23])([OH:3])=[O:2].[OH-].[K+].O.Cl>C(O)CO>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([C:12](=[CH:11][C:10]3[NH:9][CH:8]=[C:7]([CH3:27])[C:6]=3[CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:13](=[O:23])[NH:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2c(c1)NC(=O)C2=Cc1[nH]c(C(=O)O)c(C)c1CCC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COc1ccc2c(c1)NC(=O)C2=Cc1[nH]cc(C)c1CCC(=O)O
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
4-(2-carboxyethyl)-3-methyl-5-(6-methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid (501 mg) suspended in ethylene glycol (10 mL) was heated in a sealed tube in a pre-heated oil bath at 200° C. for 2 hours. The reaction mixture was cooled to 90° C. and potassium hydroxide (2 pellets) was added. The mixture was then stirred at 90° C. for 30 minutes, after which time it was cooled, poured into water, and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 221 mg (48%) of 3-[2-(6-methoxy-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4-methyl-1H-pyrrol-3-yl]-propionic acid.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:11][C:4]=12)[NH2:2].[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH:29]([CH:32]=O)[CH:30]=O.C1(C)C=CC=CC=1>>[CH3:17][Si:16]([CH3:19])([CH3:18])[CH2:15][CH2:14][O:13][CH2:12][N:9]1[C:5]2=[N:6][CH:7]=[CH:8][C:3]([N:1]3[CH:30]=[C:29]([C:21]4[O:20][C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=4)[CH:32]=[N:2]3)=[C:4]2[CH:11]=[CH:10]1
Reactant: O=CC(C=O)c1nc2ccccc2o1
Reactant: C[Si](C)(C)CCOCn1ccc2c(NN)ccnc21
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1ccc2c(-n3cc(-c4nc5ccccc5o4)cn3)ccnc21
Temperature: 70 °C
Yield: 69.5 %

Procedure:
To 4-hydrazino-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.083 g, 0.00030 mol) 3782-117-1 and 1,3-benzoxazol-2-ylmalonaldehyde (0.056 g, 0.00030 mol) in toluene (1.5 mL, 0.014 mol) was added molecular sieves. The mixture was heated in a sealed tube at 70° C. (an oil bath) with stilling for 2 h. The solvent was removed in vacuo and the crude product was purified by FCC on silica using ethyl acetate:hexanes 3:7 to give 2-[1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]-1,3-benzoxazole (0.090 gm) as an oil, LC/MS (M+H)+: 432.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([C:13]([F:16])([F:15])[F:14])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[F:17][C:18]([F:23])([F:22])[C:19]([NH2:21])=[NH:20]>CCO>[CH2:9]([O:8][C:6]([C:5]1[C:11]([C:13]([F:14])([F:15])[F:16])=[N:20][C:19]([C:18]([F:23])([F:22])[F:17])=[N:21][CH:4]=1)=[O:7])[CH3:10]
Reactant: N=C(N)C(F)(F)F
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)c1cnc(C(F)(F)F)nc1C(F)(F)F
Yield: 38.9 %

Procedure:
A solution of ethyl ethoxymethylene-4,4,4-trifluoroacetoacetate (15 g, 62.5 mmol) and trifluoroacetamidine (12.6 g, 112.5 mmol) in EtOH (50 mL) was heated at reflux for 24 h under N2. The reaction mixture was cooled and concentrated. Chromatography (SiO2, 20% EtOAc/hexane) afforded ethyl-2,4-bis (trifluoromethyl)pyrimidine-5-carboxylate as an oil (7.0 g, 39%), 1HNMR (CDCl3) δ 9.37 (s, 1H), 3.70 (q, 2H), 1.27 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Nc1cc(Cl)ccc1C(=O)c1ccncc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)ccc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-amino-4-chloro-phenyl)-pyridin-4-yl-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.30 (s, 9H), 7.04 (d, 1H, J=8.4 Hz), 7.25 (d, 1H, J=8.4 Hz), 7.45-7.52 (m, 4H), 7.74 (dd, 2H, J=8.8 Hz, 1.6 Hz), 7.52 (dd, 2H, J=4.4 Hz, 1.6 Hz), 7.78 (m, 2H), 7.84 (d, 1.6 Hz), 8.84 (d, 2H, J=5.6 Hz), 10.61 (s, 1H). MS: m/z 429.0 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[N:13]#[C:14]Br.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]1[O:5][C:14]([NH2:13])=[N:7][N:6]=1
Reactant: Cc1ccc(C(=O)NN)c(C)c1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2nnc(N)o2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of 2,4-dimethylbenzohydrazide (example 16b) (2 g) in dry dioxane (12 mL) was added cyanic bromide (1.28 g, 12.2 mmol) followed by a solution of NaHCO3 (1.02 g, 12.2 mmol) in water (12 mL). The resulting mixture was stirred 2 hours at rt. The solution was concentrated to ½ volume on vacuum and diluted with water (20 mL). The resulting solid was collected and dried on vacuum to give 5-(2,4-Dimethylphenyl)-1,3,4-oxadiazol-2-amine (1.88 g, 82%) as a white solid. 1H NMR (300 MHz, dMSO): δ 2.29 (s, 3H), 2.52 (d, 3H), 7.13 (d, 1H), 7.16 (s, 3H), 7.54-7.56 (d, 1H); MS (M+H, 190).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[CH:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[O:12][CH2:13][CH2:14][CH2:15][N:7]21.[CH:26]1([Mg]Br)[CH2:28][CH2:27]1>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[CH:11]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=4[Cl:23])[O:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)c2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl)C1CC1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a stirred solution of 10-chloro-1-(2,4-dichlorophenyl)-4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-a]benzimidazole-7-carbaldehyde (88.1 mg, 0.223 mmol) in tetrahydrofuran (2 mL) was added a solution of cyclopropyl magnesium bromide in tetrahydrofuran (1.0 M, 357 μL, 0.357 mmol) at 0° C. After 0.5 h, the reaction mixture was quenched with aqueous ammonium chloride, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (81.4 mg, 0.186 mmol, 83%).
Reaction SMILES: Br[C:2]1[S:10][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[Br:11].[CH3:12][C:13]([OH:17])([C:15]#[CH:16])[CH3:14].CCN(C(C)C)C(C)C>O1CCOCC1.[Cu]I.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>[Br:11][C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:10][C:2]=1[C:16]#[C:15][C:13]([CH3:14])([OH:17])[CH3:12]
Reactant: C#CC(C)(C)O
Reactant: Brc1sc2cnccc2c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(O)C#Cc1sc2cnccc2c1Br
Temperature: 50 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a suspension of 2,3-dibromothieno[2,3-c]pyridine (400 mg, 1.37 mmol), 2-methyl-3-butyn-2-ol (121 μL, 1.24 mmol), copper (I) iodide (24 mg, 0.12 mmol) and DIPEA (2.16 mL, 12.41 mmol) in 1,4-dioxane (16 mL) was added Pd(PPh3)2Cl2 (174 mg, 0.25 mmol). The mixture was evacuated and refilled with nitrogen (3×), then stirred at 50° C. for 2 h. Solvent was evaporated and the resultant mixture was dissolved in EtOAc. The organic solution was washed with water and brine, dried over anhydrous sodium sulfate, and purified by ISCO column chromatography (0 to 5% MeOH:DCM) to afford 319 mg (87%) of the title compound as a light-yellow solid. MS (ESI): 296.38, 298.35 [M+H]+; HPLC tR=0.94 min (HPLC: Analytical—2 min).
Reaction SMILES: C[O:2][C:3]([C:5]1(/[CH:11]=[CH:12]/[C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][C:19]([C@H:23]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:24])=[N:20]3)=[CH:15][CH:14]=2)[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)=[O:4].O.[OH-].[Li+]>O1CCCC1.O>[C:29]([O:28][C:26]([NH:25][C@@H:23]([C:19]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][C:13](/[CH:12]=[CH:11]/[C:5]3([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][O:6]3)=[CH:14][CH:15]=2)[N:20]=1)[CH3:24])=[O:27])([CH3:30])([CH3:31])[CH3:32]
Reactant: COC(=O)C1(/C=C/c2ccc3ccc([C@@H](C)NC(=O)OC(C)(C)C)nc3c2)CCCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](NC(=O)OC(C)(C)C)c1ccc2ccc(/C=C/C3(C(=O)O)CCCCO3)cc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 2-{(E)-2-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-vinyl}-tetrahydro-pyran-2-carboxylic acid methyl ester (130 mg, 0.3 mmol) in tetrahydrofuran (6 mL) was stirred at 5° C. under nitrogen. A solution of lithium hydroxide monohydrate (25 mg, 0.6 mmol) in water (1.5 mL) was added and the reaction mixture was stirred at room temperature for 18 h. The majority of the organic solvent was evaporated. The solution was acidified to pH 2 with ice-cold hydrochloric acid (2 M) and the mixture was extracted with dichloromethane. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford 2-{(E)-2-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-vinyl}-tetrahydro-pyran-2-carboxylic acid (135 mg, 0.3 mmol) as a yellow gum which was used crude in the next step. LCMS (m/z) 427.1 [M+H], Tr=2.17 min.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)#N.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:22]([NH:24][CH2:25][CH2:26][NH2:27])[CH3:23].[O-]CC.[Na+]>C(O)C>[CH2:22]([N:24]1[CH2:25][CH2:26][N:27]=[C:1]1[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[CH3:23]
Reactant: CCNCCN
Reactant: N#CCCc1ccncc1
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCO
Product: CCN1CCN=C1CCc1ccncc1
Temperature: 190 °C
Yield: 59.1 %

Procedure:
A mixture of 4-(2-cyanoethyl)pyridine (1.32 g, 0.01 M) and N-ethyl-1,2-diaminoethane mono-p-toluenesulfonate (5.5 g, 0.02 M) were heated at 190° C. for 4 hrs under nitrogen. The reaction mixture was dissolved in ethanol (30 ml) and sodium ethoxide (0.02 M) in ethanol (50 ml) was added. The mixture was filtered and the filtrate was stripped to dryness and distilled at 130° C./0.2 mmHg to yield 4-[2-(1-ethyl-4,5-dihydro-imidazol-2-yl)ethyl]-pyridine (1.2 g, 60% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[C@H:29]([CH2:47][OH:48])[CH2:28]3)[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[C@H:29]([CH2:47][OH:48])[CH2:28]3)[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH3:17]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(N3CCN(C(=O)[C@H]4CCCN4C(=O)OC(C)(C)C)[C@H](CO)C3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(N3CCN(C(=O)[C@H]4CCCN4)[C@H](CO)C3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of (R)-t-butyl 2-((S)-4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d]imidazol-6-yl)-2-(hydroxymethyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.075 g, 0.12 mmol) in dichloromethane (2 mL) and the resulting solution was stirred at room temperature for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (10 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-20% methanol in dichloromethane) to give the title compound as a white solid (0.024 g, 0.048 mmol, 40%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1 H), 7.67 (d, J=8.8 Hz, 1 H), 7.45 (d, J=2.0 Hz, 1 H), 7.14 (dd, J=2.4, 8.4 Hz, 1 H), 6.94 (dd, J=2.4, 8.8 Hz, 1 H), 6.85 (d, J=8.4 Hz, 1 H), 6.55 (d, J=2.0 Hz, 1 H), 5.89 (q, J=6.8 Hz, 1H), 4.76-4.72 (m, 1 H), 3.97-3.87 (m, 3 H), 3.80-3.77 (m, 1 H), 3.65-3.60 (m, 2 H), 3.44-3.41 (m, 1 H), 3.21-3.15 (m, 2 H), 2.89-2.82 (m, 2 H), 2.77-1.65 (m, 2 H), 1.96 (d, J=7.5 Hz, 3 H), 1.89-1.71 (m, 3 H); MS: (ES) m/z calculated for C25H30Cl2N5O2 [M+H]+ 502.2, found 502.4.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:29]O)[C:5]([CH2:21][O:22]C2CCCCO2)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[OH:22][CH2:21][C:5]1[C:4]([CH2:29][N:35]2[C:31](=[O:41])[C:32]3[C:33](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:34]2=[O:36])=[CH:3][C:2]([CH3:1])=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2[S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(CO)cc(C)c32)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CO)c(CN4C(=O)c5ccccc5C4=O)cc(C)c32)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of (±)-(7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indol-5-yl)methanol (Example 52-C) (210 mg, 0.49 mmol), phthalimide (144 mg, 0.98 mmol), and PPh3 (385 mg, 1.47 mmol) in THF (5 mL) was added DIAD (0.29 mL, 1.48 mmol) at 0° C., and then the mixture was stirred at room temperature for 3.5 h. The reaction was then concentrated and partially purified by SiO2 column chromatography (heptane/EtOAc=1/0 to 6/4). A solution of the resulting residue and 4M HCl in dioxane (4 mL) in MeOH (10 mL) was stirred at room temperature for 0.5 h. The reaction mixture was poured into 5% aq. NaHCO3. The basic mixture was extracted with CH2Cl2. The organics extract was washed with H2O and brine, dried over Na2SO4, and then filtered. Concentration of the filtrate gave a residue which was purified by SiO2 column chromatography (heptane/EtOAc=6/4 to 3/7) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.76-7.95 (m, 5H), 7.59 (d, J=8.34 Hz, 2H), 7.38 (d, J=8.34 Hz, 2H), 7.06 (d, J=4.04 Hz, 1H), 6.90 (s, 1H), 5.08 (t, J=5.31 Hz, 1H), 4.91 (s, 2H), 4.85 (d, J=5.31 Hz, 2H), 2.38 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=3)=[C:15]([CH3:27])[CH:14]=1)=[N:5][CH:6]=[N:7]2.[CH3:28][NH:29][C@@H:30]([CH3:33])[CH2:31][OH:32]>>[CH3:28][NH:29][C@@H:30]([CH3:33])[CH2:31][O:32][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=3)=[C:15]([CH3:27])[CH:14]=1)=[N:5][CH:6]=[N:7]2
Reactant: CN[C@@H](C)CO
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(F)c34)cc2C)cn1
Product: CN[C@@H](C)COc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Yield: 71 %

Procedure:
The procedure described in Example 103, preparation of starting materials, was repeated using 5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (obtained as described in Example 103, preparation of starting materials) and (2S)-2-(methylamino)propan-1-ol (obtained as described in Chacchio et al., Tetrahedron, 1995, 51, 5689) to give 5-{[(2S)-2-(methylamino)propyl]oxy}-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine in 71% yield; NMR Spectrum: (CDCl3) 1.30 (d, 3H), 2.28 (s, 3H), 2.52 (s, 3H), 2.53 (s, 3H), 3.20 (m, 1H), 4.09 (m, 1H), 4.21 (m, 1H), 6.89 (m, 2H), 7.14-7.07 (m, 2H), 7.45 (d, 1H), 7.63 (m, 2H), 8.26 (s, 1H), 8.63 (s, 1H); Mass spectrum: MH+ 430.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[N:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[CH2:22]([O:25][NH2:26])[CH:23]=[CH2:24]>>[CH2:22]([O:25][NH:26][C:16]([C:14]1[N:13]=[CH:12][C:11]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:20][CH:19]=3)[CH:8]=[N:9][C:10]=2[CH:15]=1)=[O:18])[CH:23]=[CH2:24]
Reactant: O=C(O)c1cc2ncn(Cc3ccc(F)cc3)c2cn1
Reactant: C=CCON
Agent: Cl
Product: C=CCONC(=O)c1cc2ncn(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound was prepared by coupling of 3-(4-fluorobenzyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid and N-allyloxyamine hydrochloride under the same conditions as those in step (c) of example 1. 1H NMR (300 MHz, MeOH-d4) δ: 8.71 (s, 1H), 8.53 (s, 1H), 8.31 (s, 1H), 7.40-7.33 (m, 2H), 7.09-7.01 (m, 2H), 6.01-5.99 (m, 1H), 5.57 (s, 2H), 5.40-5.20 (m, 2H), 4.41 (d, 2H, J=6.0 Hz). LCMS (API-ES, M+H+): 327.0.1. HRMS calcd for C17H16FN4O2 (M+H) 327.1257, found 327.1248. HPLC: 100% purity.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([NH:12][CH:13]=[C:14]([C:20]([O:22]CC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][CH:11]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>CCO>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:7]=[C:8]2[C:9]([C:20](=[O:22])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][NH:12]2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(=CNc1cccc(C2OCCO2)c1)C(=O)OCC
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2cc(C3OCCO3)ccc2c1=O
Temperature: 257.5 °C
Yield: 84 %

Procedure:
Compound 7 was added to 300 mL diphenyl ether (Aldrich) that had been preheated to 250° C. in a 1 L 3-neck round bottom flask. The temperature dropped to ca 240° C. for a brief time (1-2 min), after which it was brought up to 257° C. and maintained at 255-260° C. for 15 min, as the color darkened and evolution of EtOH vapor was observed. Upon cooling to room temperature, some ppt separated, but the mixture was extremely thick. The mixture was diluted 1:4 with hexane, and more ppt separated. The ppt was filtered, washed 3× hexane, and dried to afford 19.02 g product (84%) 8. Analysis (1H NMR) showed that the product was of high enough purity to be used as such in the next step.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[NH2:13][C:14]1[N:18]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[N:17]=[C:16]([NH:28][C:29]2[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=2)[N:15]=1.N>CN(C=O)C>[NH2:13][C:14]1[N:18]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([NH2:3])=[O:24])=[CH:26][CH:27]=2)[N:17]=[C:16]([NH:28][C:29]2[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=2)[N:15]=1
Reactant: COc1cc(Nc2nc(N)n(-c3ccc(C(=O)O)cc3)n2)cc(OC)c1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc(N)n(-c3ccc(C(N)=O)cc3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0° C., 1,1′-carbonyldiimidazole (83 mg, 0.5 mmol) was added to a solution of 4-[5-amino-3-(3,4,5-trimethoxy-phenylamino)-[1,2,4]triazol-1-yl]-benzoic acid (100 mg, 0.25 mmol) in DMF (3 mL). The reaction mixture was stirred at rt. for 1 h, and ammonia (7.0M in MeOH, 1 mL) was added. The reaction mixture was stirred at rt. for 2 days. The mixture was then purified by semi-prep HPLC. FIA-MS: m/e=385.1 (M+H), 383.1 (ES−). Rt=3.60 min (method A). 1H-NMR (500 MHz, DMSO(d6)): 8.87 (s, 1H), 8.02 (br.s, 1H), 7.99 (d, 2H), 7.67 (d, 2H), 7.39 (br.s, 1H), 7.00 (s, 2H), 6.62 (s, 2H), 3.78 (s, 6H), 3.65 (s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH2:22][CH2:21][CH2:20][N:12]3[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]3[CH2:22][CH2:21][CH2:20][N:12]3[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:7][CH:8]=1)=[O:31]
Reactant: CSc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5.0 g (16.3 mmoles) of 2-(4-methylthiophenyl)-3-(4-pyridyl)-6,7-dihydro [5H]-pyrrolo[1,2 a]imidazole of Example 3 dissolved in 75 ml of chloroform, chilled in an ice bath, was added dropwise a solution of 3.30 g (16.3 mmoles) of 85% 3-chloroperbenzoic acid in chloroform. After stirring at 25° C. overnight, the reaction mixture was washed with 5% sodium carbonate, dried over anhydrous potassium carbonate, and stripped in vacuo. The residue was flash chromatographed on silica eluting with 5 to 10% methanol in methylene chloride: 2-propanol (9:1). The solvent was removed in vacuo and the residue recrystallized from ethyl acetate to give the desired titled compound, mp 163.5-165.5° C. 1H NMR (360 MHz, CDCl3) δ8.62 (2H,d), 7.68 (2H,d), 7.57 (2H,d), 7 25 (2H,d), 4.05 (2H,t), 3.02 (2H,t), 2.72 (s) superimposed upon 2.69 (m) (5H total). Mass Spec. (CI) (M+H) 324 (MW=323).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]([CH2:14][OH:15])[CH2:8]1.[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.O>[CH2:16]([O:23][C:24]([N:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]([CH2:14][OH:15])[CH2:8]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCC1CCCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCCCC(CO)C1
Temperature: 0 °C
Yield: 94 %

Procedure:
Potassium carbonate was added to a mixture of azepan-3-yl-methanol (145) (0.032 g, 0.2485 mmol) in THF/H2O (2:1, 0.31 mL). The suspension was cooled to 0° C., and (benzyloxy)carbonyl chloride (0.071 mL, 0.497 mmol) was added dropwise. The reaction was allowed to warm to room temperature overnight, and was then concentrated in vacuo. CH2Cl2 and H2O were added. The organics were extracted, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by automated silica gel chromatography with 75:25 Hexanes:EtOAc to obtain 3-Hydroxymethyl-azepan-1-carboxylic acid benzyl ester (146) in approximately 94% yield.
Reaction SMILES: OC(C)(C)CNC(=O)C[N:7]1[CH2:10][CH:9]([C:11]2[CH:32]=[CH:31][C:14]3[C:15]4[N:16]=[C:17]([C:23]5[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=5)[S:18][C:19]=4[CH2:20][CH2:21][O:22][C:13]=3[CH:12]=2)[CH2:8]1.[NH:36]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:37]([C:40]([OH:42])=O)([CH3:39])[CH3:38]>>[C:46]([O:45][C:43](=[O:44])[NH:36][C:37]([CH3:38])([CH3:39])[C:40]([N:7]1[CH2:10][CH:9]([C:11]2[CH:32]=[CH:31][C:14]3[C:15]4[N:16]=[C:17]([C:23]5[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=5)[S:18][C:19]=4[CH2:20][CH2:21][O:22][C:13]=3[CH:12]=2)[CH2:8]1)=[O:42])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(=O)NCC(C)(C)O)C3)ccc1-2
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)C(C)(C)NC(=O)OC(C)(C)C)C3)ccc1-2

Procedure:
Following a similar method to N-(2-hydroxy-2-methyl-propyl)-2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamide using Boc-Aib-OH, (2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester was isolated as a colourless oil (203 mg, 59%). LCMS: RT=4.77 min, [M+H]+=553