Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[C:13]([O:17][CH2:18]C)(=[O:16])[CH2:14][SH:15].C([O-])([O-])=O.[K+].[K+]>C(O)C>[NH2:5][C:4]1[C:3]2[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=2[S:15][C:14]=1[C:13]([O:17][CH3:18])=[O:16]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COC(=O)c1sc2ccc([N+](=O)[O-])cc2c1N
Yield: 54 %

Procedure:
2-Chloro-5-nitrobenzonitrile (25.0 g, 136.9 mmol), commercially available, was treated with 1 equivalent ethyl thioglycolate and 1 equivalent K2CO3 in ethanol by the procedure described in Example 41A to yield the title compound (19.68 g, 54%). m.p. 208°-210° C. 1H NMR(300MHz, DMSO) δ9.23 (d, 1H), 8.29 (d, 1H), 8.11 (dd, 1H), 7.45 (br s, 2H), 4.29 (q, 2H), 1.31 (t, 3H). MS (DCI/NH3) m/e 284 (M+NH4)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]3[C:15]([F:17])([F:16])[C:14]([F:19])([F:18])[C:13]([F:21])([F:20])[C:12]=3[C:22]3[C:23]4[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][C:24]=4[S:25][C:26]=3[CH3:27])=[C:9]([CH3:34])[S:8][C:7]=2[CH:35]=1.B(Br)(Br)Br.Cl>C(Cl)Cl>[OH:32][C:29]1[CH:30]=[CH:31][C:23]2[C:22]([C:12]3[C:13]([F:20])([F:21])[C:14]([F:18])([F:19])[C:15]([F:17])([F:16])[C:11]=3[C:10]3[C:6]4[CH:5]=[CH:4][C:3]([OH:2])=[CH:35][C:7]=4[S:8][C:9]=3[CH3:34])=[C:26]([CH3:27])[S:25][C:24]=2[CH:28]=1
Reactant: COc1ccc2c(C3=C(c4c(C)sc5cc(OC)ccc45)C(F)(F)C(F)(F)C3(F)F)c(C)sc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Cc1sc2cc(O)ccc2c1C1=C(c2c(C)sc3cc(O)ccc23)C(F)(F)C(F)(F)C1(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.9 %

Procedure:
5.60 g (0.01 mol) of the compound obtained in step 3 and 100 mL of pre-distilled CH2Cl2 are introduced into a 3-necked round-bottomed flask under nitrogen. The resulting mixture is cooled by using a ice-water bath, then 4.91 mL (0.05 mol) of BBr3 is added dropwise. The solution is warmed to room temperature and stirred for 6 hours. Then, the mixture is cooled by using a ice-water bath and 100 mL of 10% HCl aqueous solution is added slowly. The chlorinated phase is separated from the aqueous phase. This latter is extracted several times with ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulfate and then are concentrated under reduced pressure. The crude product is purified by column chromatography on silica gel and eluted with mixtures consisting of CH2Cl2 and Et2O of increasing polarity (100:0 to 90:10) to give a white solid (4.7 g, 93% yield).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]3[N:18]=[C:17]([NH:19][C:20]([C:22]4[N:26]([CH3:27])[N:25]=[CH:24][C:23]=4[C:28]([O:30]CC)=[O:29])=[O:21])[CH:16]=[CH:15][N:14]3[CH:33]=2)[CH:8]=[CH:9][CH:10]=1.C(O)C.C1COCC1.Cl>O>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]3[N:18]=[C:17]([NH:19][C:20]([C:22]4[N:26]([CH3:27])[N:25]=[CH:24][C:23]=4[C:28]([OH:30])=[O:29])=[O:21])[CH:16]=[CH:15][N:14]3[CH:33]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2cc(-c3cccc(OCCF)c3)nc2n1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2cc(-c3cccc(OCCF)c3)nc2n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Ethyl 5-(2-(3-(2-fluoro ethoxy)phenyl)imidazo[1,2-a]pyrimidin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylate (100 mg, 221 μmol) was combined with Ethanol (0.570 ml) and THF (0.570) to give a yellow solution. The reaction was stirred at RT for 6 h. H2O was added to the suspension and then HCl 1N was added until the mixture was acidic (pH=3). The suspension was stirred for 30 min and then the reaction mixture was filtered. The residual solvent was removed under vacuum. The title compound was obtained as a light yellow solid (73 mg, 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9](C3C=CN=C(SC)N=3)[C:10]3[C:11]([N:17]=2)=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CC(O)=O.C1([C@@H](N)C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]3[C:11]([N:17]=2)=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[CH:6][CH:7]=1
Reactant: CSc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(N)ccc32)n1
Agent: C[C@H](N)c1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1ccc2[nH]c(-c3ccc(F)cc3)nc2n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
2-(4-Fluorophenyl)-1-(2-methylthio-4-pyrimidinyl)-5-aminoimidazo[4,5-b]pyridine (110 mg, 0.31 mmol) is dissolved in CH2Cl2/HOAc 1:1 (6.2 nm), combined at 0° C. with mCPBA (84 mg 70%, 0.34 mmol) and stirred for 30 min. The reaction mixture is poured on 2N Na2CO3 and extracted with ethyl acetate three times. The combined organic phases are dried over Na3SO4, filtered and evaporated to dryness to yield the crude sulfoxide (110 mg). 50 mg are dissolved in 1-(S)-phenylethylamine (0.5 ml) and heated to 120° C. for 1 h. Purification over RP18 (CH3CN/Water 70/30 to 10/90) yielded the title compound as light brown foam (30 mg 52%)
Reaction SMILES: N1C=CC=CC=1.[NH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1.[CH2:24]([S:28](Cl)(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[CH2:24]([S:28]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1)(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCS(=O)(=O)Cl
Reactant: c1cc(-c2noc(C3CCNCC3)n2)ccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCS(=O)(=O)N1CCC(c2nc(-c3ccncc3)no2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of pyridine (18 μl, 0.22 mmol) and 4-(5-piperidin-4-yl-[1,2,4]oxadiazol-3-yl)pyridine (Example 51, 50 mg, 0.22 mmol) in CH2Cl2 (4 ml) was treated with butane-1-sulfonyl chloride (56 μl, 0.43 mmol). The reaction was stirred at rt for 18 h then quenched with saturated aqueous NaHCO3 (1 ml). The organic phase was separated, dried (MgSO4) and evaporated. The residue was dissolved in EtOAc (5 ml) and extracted into 2M HCl (10 ml). The aqueous phase was then basified using 2M NaOH to pH=8 and extracted with CH2Cl2 (2×10 ml). The combined organic phases were dried (MgSO4) and evaporated to afford the title compound: RT=3.29 min, m/z (ES+)=351.2 [+H]+.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:35])/[C:23](/[F:34])=[C:24](\[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=2)/[CH3:25])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:42]([O:45][CH2:46]Br)(=[O:44])[CH3:43]>CN(C=O)C.C(OCC)(=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([N:21]([C:22](=[O:35])/[C:23](/[F:34])=[C:24](\[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=2)/[CH3:25])[CH2:43][C:42]([O:45][CH3:46])=[O:44])=[CH:17][CH:16]=1)(=[O:7])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OCBr
Reactant: C/C(=C(\F)C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)c1cccc(C#N)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CN(C(=O)/C(F)=C(/C)c1cccc(C#N)c1)c1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.8 %

Procedure:
To a solution of (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)-2-fluorobut-2-enamide (230 mg, 0.47 mmol) in 15 ml DMF was added cesium carbonate (460 mg, 1.41 mmol) and bromomethyl acetate (355 mg, 2.35 mmol). The reaction mixture was stirred at room temperature for 4 hours then diluted with 25 ml of ethyl acetate. Organic was washed with 3×25 ml water, 3×25 ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated in vacuo to give methyl 2-{(2E)-N-[4-(2-{[(tert-butyl)amino]-sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)-2-fluorobut-2-enoylamino}acetate (230 mg, 86%) as yellow foam. ES-MS (M+H+): 563.2.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].F[P-](F)(F)(F)(F)F.S1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=C1.C(N(CC)CC)C.[Br:43][C:44]1[C:45]([CH3:63])=[C:46]([CH:60]=[CH:61][CH:62]=1)[C:47]([NH:49][CH2:50][C:51]1[CH:59]=[CH:58][C:54]([C:55]([O-])=[O:56])=[CH:53][CH:52]=1)=[O:48]>CN(C=O)C>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][C:55](=[O:56])[C:54]1[CH:58]=[CH:59][C:51]([CH2:50][NH:49][C:47](=[O:48])[C:46]2[CH:60]=[CH:61][CH:62]=[C:44]([Br:43])[C:45]=2[CH3:63])=[CH:52][CH:53]=1
Reactant: Cc1c(Br)cccc1C(=O)NCc1ccc(C(=O)[O-])cc1
Reactant: Nc1ccccc1N
Agent: CN(C)[P+](O[SH]1C=Nc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(Br)cccc1C(=O)NCc1ccc(C(=O)Nc2ccccc2N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
Phenylenediamine (217 mg, 2.01 mmol), 1H-benzothiazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate (BOP; 667 mg, 1.51 mmol) and triethyl amine (203 mg, 2.01 mmol) were dissolved in 3 mL of DMF. 350 mg of the 4-((3-bromo-2-methylbenzamido)methyl)benzoate obtained in step 2 (1.01 mmol) was added thereto and stirred at room temperature overnight. The resulting mixture was subjected to thin layer chromatography to monitor the amount of 4-((3-bromo-2-methylbenzamido)methyl)benzoate consumed, and DMF was removed under a reduced pressure. 50 mL of saturated sodium bicarbonate was added to the resulting mixture, extracted with methylene chloride (3×75 mL) and the separated organic layer was dried over anhydrous magnesium sulfate. The residue was dissolved in methylene chloride and n-pentane was added thereto. The resulting solid thus obtained was filtered and washed with ethanol to obtain the title compound (231 mg, 52%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[F:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]34)[CH:10]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: OB(O)c1cccc(F)c1
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3cccc(F)c3)cc3c1N2CC3

Procedure:
The title compound was prepared by the method of Example 90 tert-butyl (±)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (125 mg, 0.28 mmol) and corresponding 3-fluorophenylboronic acid (77 mg, 0.56 mmol), to afford after chromatographic purification the title compound (48 mg, 44%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ7.20-7.40 (m, 2H), 7.10-7.20 (m, 3H), 6.80-7.00 (m, 1H), 3.80-3.90 (m, 1H), 3.60-3.80 (m, 1H), 3.10-3.50 (m, 7H), 2.80-3.00 (m, 1H), 1.70-1.90 (m, 2H), 1.48 (s, 9H) ppm. MS (CI, NH3): 395 (base, M+H).
Reaction SMILES: [Li+].[OH-].[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]2[NH:21][CH:20]([CH2:22][C:23]([O:25]C)=[O:24])[C:19](=[O:27])[N:18]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:17][C:16]=2[CH:36]=1)=[O:11]>O1CCOCC1.O>[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]2[NH:21][CH:20]([CH2:22][C:23]([OH:25])=[O:24])[C:19](=[O:27])[N:18]([CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:17][C:16]=2[CH:36]=1)=[O:11]
Reactant: COC(=O)CC1Nc2ccc(C(=O)NCc3ncc[nH]3)cc2CN(CCc2ccccc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CC1Nc2ccc(C(=O)NCc3ncc[nH]3)cc2CN(CCc2ccccc2)C1=O
Temperature: 65 °C
Yield: 76.6 %

Procedure:
LiOH (16 mg, 0.38 mmol) was added at RT to a solution of methyl (±)-7-[[[(2-imidazolyl)methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (98 mg, 0.21 mmol) in dioxane (3 mL) and H2O (3 mL). The reaction mixture was heated at 65° C. for 3 h then the organic solvent was removed in vacuo. The aqueous residue was acidified with 1M HCl solution (0.38 mL) to obtain a white solid which was filtered, dissolved in hot methanol, and precipitated with ether. The thus obtained white solid was collected to yield the title compound (72 mg, 78%). 1H NMR (DMSO-d6, 400 MHz) δ 2.59 (dd, J=16.2, 5.0 Hz, 1H), 2.77 (dd, J=7.7, 6.8 Hz, 2H), 2.92 (dd, J=16.5, 8.8 Hz, 1H), 3.63-3.75 (m, 2H), 3.79 (d, J=16.5 Hz, 1H), 4.61 (s, 2H), 5.13 (dd, J=8.8, 5.0 Hz, 1H), 5.45 (d, J=16.5 Hz, 1H), 6.57 (d, J=8.6 Hz, 1H), 7.07 (s, 2H), 7.10-7.19 (m, 5H), 7.41 (s, 1H), 7.54 (d, J=8.4 Hz, 1H). MS (ES) m/e 448 (M+H)+. Anal. Calcd. for C24H25N5O4.H2O: C, 61.92; H, 5.85; N, 15.04. Found: C, 61.69; H, 5.60; N, 14.86.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]([CH2:11][C:12]#[CH:13])[C:4](=[O:14])[CH:3]=1.[N:15]([O-])=[O:16].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]([CH2:11][C:12]#[CH:13])[C:4](=[O:14])[C:3]=1[N:15]=[O:16]
Reactant: O=N[O-]
Reactant: C#CCn1c(=O)cc(N)n(CC)c1=O
Agent: [Na+]
Solvent: CC(=O)O
Product: C#CCn1c(=O)c(N=O)c(N)n(CC)c1=O
Temperature: 4 °C

Procedure:
A solution of 6-amino-1-ethyl-3-propargyluracil (5 g, 26 mmol) in 75 ml of 50% acetic acid was heated at 50-60° C. Subsequently sodium nitrite (2.5 g, 36 mmol) was added in small portions over a period of 5 min. The end of the reaction was indicated by the formation of brown nitric gases. The deep violet solution was highly concentrated under reduced pressure. The remaining violet crystals were was suspended in a minimum of water, cooled to 4° C., filtered under reduced pressure, washed with methanol and dried at 70° C. Yield: 5 g (87%).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:4]=1[C:5]([O:7][CH3:8])=[O:6])#[N:2].[Br:14]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)Cl>[Br:14][CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)cccc1C#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(C#N)cccc1CBr

Procedure:
To a solution of EXAMPLE 6B (2.37 g) in chloroform (30 mL) was added N-bromosuccinimide (2.41 g) and AIBN (4 mg), and the mixture was heated at reflux for 18 hours. After cooling, the solvent was removed, and the concentrate was partitioned between ethyl acetate and water. The extract was washed with brine and concentrated, and the concentrate was purified by flash chromatography on silica gel with 20% ethyl acetate in hexanes.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][C:11]1[N:15]([CH2:16][CH2:17][C:18]#[N:19])[C:14]2[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=2[N:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][CH2:8][CH2:9][CH2:10][C:11]1[N:15]([CH2:16][CH2:17][C:18]#[N:19])[C:14]2[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=2[N:12]=1
Reactant: N#CCCn1c(CCCOC2CCCCO2)nc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: N#CCCn1c(CCCO)nc2ccccc21
Reaction time: 8 h

Procedure:
The crude 3-{2-[3-(tetrahydro-pyran-2-yloxy)-propyl]-benzimidazol-1-yl }-propionitrile was stirred in 250 mL of methanol with sufficient p-toluenesulfonic acid monohydrate to make the solution acidic (pH=1-2). After stirring overnight, the solution was concentrated under reduced pressure, made basic (pH=8) with 1N sodium hydroxide and extracted into 8×50 mL of ethyl acetate. The aqueous layer was saturated with NaCl to aid in extraction of the product. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. Chromatography using a gradient of ethyl acetate then 10% methanol in ethyl acetate followed by trituration with ether-hexane gave 4.8 g of 3-[2-(3-hydroxy-propyl)-benzimidazol-1-yl]-propionitrile as a solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:40]1[C:47]([F:48])=[CH:46][C:43]([C:44]#[N:45])=[CH:42][N:41]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[C:47]([F:48])=[CH:46][C:43]([C:44]#[N:45])=[CH:42][N:41]=5)=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: N#Cc1cnc(Cl)c(F)c1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ncc(C#N)cc5F)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 6-chloro-5-fluoronicotinonitrile (187 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 120° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (451 mg, 82%) as a brown solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][CH2:37][Cl:38])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C(OCC)(=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][CH2:37][Cl:38])=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCCl
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Temperature: 50 °C
Yield: 61 %

Procedure:
To a solution of (1-(5-tert-butyl-isoxazol-3-yl)-3-(3-hydroxy-phenyl)-urea, 300 mg, 1.089 mmol) from Example 1A and (4-chloro-7-(3-chloro-propoxy)-6-methoxy-quinazoline (343.96 mg, 1.119 mmol), from the previous step in THF, was added Cs2CO3 (532.2 mg, 1.63 mmol) and the mixture was heated at 50° C. for 12 hours. Completion of the reaction was monitored by LCMS. The reaction mixture was diluted with ethyl acetate and the ethyl acetate layer was washed with water and brine successively. The organic layer was dried (Na2SO4) and concentrated to dryness. The crude compound was purified by column chromatography to afford the pure compound 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea, (310 mg, 61%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.00 (s, 1H), 8.55 (s, 1H), 7.55 (m, 2H), 7.40 (m, 2H), 7.25 (d, 1H), 6.95 (d, 1H), 6.45 (s, 1H), 4.35 (t, 2H), 4.00 (s, 3H), 3.85 (2, 2H), 1.30 (s, 9H); LC-MS (ESI)m/z 526 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH2:10])=[S:9])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[OH:1][C:2]1[C:3]([C:8]2[S:9][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)c1ncccc1O
Solvent: CCO
Product: CCOC(=O)c1csc(-c2ncccc2O)n1
Yield: 32 %

Procedure:
A solution of 3-hydroxythiopicolinamide (500 mg) in dry ethanol (25 ml) was added dropwise to a solution of ethyl bromopyruvate (0.542 ml) in dry ethanol (20 ml) under nitrogen atmosphere and the mixture was refluxed for 2 hours. The solvent was removed from the reaction mixture, and the residue was treated with water, neutralized with 4% aqueous sodium carbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl, dried (anhydrous Na2SO4) and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:benzene=1:9). The second fraction was concentrated. The produced solids were recrystallized from methanol-water to give yellowish crystals of ethyl 2-(3-hydroxy-2-pyridyl)-4-thiazole carboxylate (260 mg, 32%), m.p. 131°-134° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[N:12]([Sn](C)(C)C)=[N+:13]=[N-:14]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]1[N:12]=[N:13][NH:14][N:5]=1
Reactant: N#Cc1c(F)cc(Cl)cc1Br
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: Fc1cc(Cl)cc(Br)c1-c1nn[nH]n1
Temperature: 120 °C
Yield: 88.7 %

Procedure:
A mixture of 2-bromo-4-chloro-6-fluoro-benzonitrile (4 g, 17.06 mmol) and azidotrimethyltin (3.86 g, 18.77 mmol) in toluene (100 ml) was heated to 120° C. for 72 h. After completion of the reaction, the mixture was partitioned between EtOAc (50 ml) and aqueous 0.5N HCl solution (40 ml). The organic layer was separated, washed with water and brine, dried with Na2SO4 and concentrated under reduced pressure to afford the title compound as red solid (4.2 g, 87%).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:10]2[C:5](=[N:6][C:7]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=34)=[N:8][CH:9]=2)[N:4]1[C@H:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C=O)C>[C:29]([N:25]1[CH2:26][CH2:27][CH2:28][C@H:23]([N:4]2[C:3](=[O:2])[NH:11][C:10]3[C:5]2=[N:6][C:7]([C:12]2[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=24)=[N:8][CH:9]=3)[CH2:24]1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n([C@H]5CCCNC5)c4n3)c2c1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)N1CCC[C@H](n2c(=O)[nH]c3cnc(-c4cnn5ccc(C#N)cc45)nc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.2 %

Procedure:
To a solution of the compound obtained in example 6 (31 mg, 0.063 mmol) in anhydrous DMF (3 mL), acetic anhydride (0.007 mL, 0.08 mmol) and anhydrous TEA (0.02 mL, 0.127 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, and the solvent was concentrated off. It was quenched with saturated NaHCO3 aqueous solution (15 mL) and extracted with EtOAc (3×15 mL). The combined organic phases were dried over anhydrous Mg2SO4, filtered and concentrated. The crude residue was flash chromatographed on a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 14.5 mg of the desired compound (57% yield).