Azzindani/Open_Reaction_Data huggingface dataset:
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]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:37]1([CH2:43][CH2:44][OH:45])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(N(C(C)C)CC)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[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]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:40]5[CH2:41][CH2:42][N:37]([CH2:43][CH2:44][OH:45])[CH2:38][CH2:39]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCN1CCNCC1
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCN(CCO)CC1
Temperature: 60 °C
Yield: 12.8 %

Procedure:
To the intermediate 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea (225 mg, 0.426 mmol) from Example 79A was added 2-piperazin-1-yl-ethanol (0.157 mL, 1.278 mmol) followed by diisopropyl ethylamine (1.3 mmol) and tetrabutyl ammonium iodide (0.43 mmol). The reaction mixture was heated at 60° C. for 3 days. Formation of product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (using phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea (34 mg, 13%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.05 (s, 1H), 8.65 (s, 1H), 7.85 (s, 1H), 7.60-7.20 (m, 5H), 6.45 (s, 1H), 4.45-4.25 (m, 3H), 4.00 (s, 3H), 3.45 (m, 2H), 2.80-2.30 (m, 12H), 1.25 (s, 9H); LC-MS (ESI)m/z 622 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[C:3]=1[CH:9]=O.[F:11][C:12]([F:22])([F:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][NH2:20]>CN(C1C=CN=CC=1)C.CN1C(=O)CCC1>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]([F:11])([F:21])[F:22])[N:20]=[CH:9][C:3]=12
Reactant: NNc1ccccc1C(F)(F)F
Reactant: O=Cc1c(I)ccnc1F
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccccc1-n1ncc2c(I)ccnc21
Temperature: 185 °C
Yield: 46 %

Procedure:
To a dry 15 mL ChemGlass pressure bottle under N2 was added 4-iodo-2-fluoro-3-formylpyridine (750 mg, 2.99 mmol), (2-(trifluoromethyl)phenyl)hydrazine (526 mg, 2.99 mmol), DMAP (200 mg, 1.637 mmol), and anhydrous NMP (4 mL). The reaction mixture was flushed with argon, securely capped and heated at 185° C. for 3.75 h. The reaction mixture was worked up according to the procedure described in Intermediate 69A to give 535 mg (44%) of the title compound (contains approximately 88% of the hydrazone intermediate) as a brown solid. LC/MS (Condition B): ret. T=4.19 min, (M+H)+ 389.90.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[C:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36]OS(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=4)([CH3:14])[C:4]([OH:3])=[O:23])=[CH:12][CH:11]=3)[N:34]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)cc1
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(4-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester using the procedure of Example 63. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, 2H, J=8.60 Hz), 6.95-6.85 (m, 4H), 6.79 (d, 2H, J=8.60 Hz), 4.12 (t, 2H, J=6.26 Hz), 3.20 (d, 1H, J=14.08 Hz), 3.11 (d, 1H, J=14.08 Hz), 2.95 (t, 2H, J=6.26 Hz) 2.85 (tt, 1H, J=11.73 Hz, J=3.52 Hz), 2.30 (s, 3H), 2.02-1.99 (m, 2H), 1.83-1.78 (m, 2H), 1.72-1.69 (m, 1H), 1.58-1.49 (m, 2H), 1.36 (s, 3H), 1.33-1.22 (m, 3H); HRMS (ES+) m/z exact mass calcd for C28H33NO5F 482.2343, found 482.2347.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:30]>C1(C)C=CC=CC=1>[Cl:30][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2ccc(-c3ccc(F)cc3)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Yield: 90.2 %

Procedure:
To a suspension of 4-hydroxy-6-(4-fluorophenyl)-quinazoline (720 mg, 3 mmol) in toluene (20 ml) was added diisopropylethylamine (1.5 ml, 9 mmol) and POCl3 (0.84 ml, 9 mmol). The mixture was refluxed for 1 hour. The solvents were evaporated in vacuo. The residue was redissolved in dichloromethane and the organic layer was washed with ice water till pH 6-7. The combined organic layers were dried over MgSO4 and concentrated to yield the title compound as a yellow solid (700 mg, yield: 90%) was characterized by its mass spectrum as follows: MS (m/z): 259 ([M+H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]=O.Cl.[CH3:16][C@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].BrC1C=CC(CN2CCN(C(OCC3C=CC=CC=3)=O)[C@@H](C)C2)=CC=1.C(N(CC)CC)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[CH2:8][N:21]1[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:17]([CH3:16])[CH2:22]1
Reactant: COC(=O)Cc1ccc(C=O)c(Cl)c1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: C[C@H]1CN(Cc2ccc(Br)cc2)CCN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c(Cl)c1

Procedure:
The title compound was prepared from methyl (3-chloro-4-formylphenyl)acetate (Epple, R. et al., PCT Int. Appl. WO2005116000) and 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate hydrochloride using a method similar to that described for D6 with the addition of triethylamine (1.1 eq) to the reaction mixture and a reaction time of ˜3 days.
Reaction SMILES: [NH2:1][C:2]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:38])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[CH:9]=2)[N:4]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:3]1=[O:31].[C:39](Cl)(=[O:41])[CH3:40]>>[C:39]([NH:1][C:2]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:38])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[CH:9]=2)[N:4]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:25])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C:3]1=[O:31])(=[O:41])[CH3:40]
Reactant: CCOc1ccc2c(c1)C(N)(c1ccccc1Cl)C(=O)N2S(=O)(=O)c1ccc(NC(=O)N(CC)CC)cc1
Reactant: CC(=O)Cl
Product: CCOc1ccc2c(c1)C(NC(C)=O)(c1ccccc1Cl)C(=O)N2S(=O)(=O)c1ccc(NC(=O)N(CC)CC)cc1

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 2 from the compound obtained in EXAMPLE 87 and acetyl chloride. Crystallization from a DCM/iso ether mixture gives the expected product, which crystallizes with 0.25 mol of iso ether.
Reaction SMILES: [Na].[CH3:2][CH:3]([C:6](=O)[CH3:7])[CH:4]=O.[CH2:9]([NH:11][C:12](=[O:16])[CH2:13][C:14]#[N:15])[CH3:10].C(O)(=O)C.N1CCCCC1>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:9]([N:11]1[C:6]([CH3:7])=[C:3]([CH3:4])[CH:2]=[C:13]([C:14]#[N:15])[C:12]1=[O:16])[CH3:10]
Reactant: CCNC(=O)CC#N
Reactant: CC(=O)C(C)C=O
Agent: [Na]
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCn1c(C)c(C)cc(C#N)c1=O
Temperature: 135 °C
Reaction time: 5 h
Yield: 95.9 %

Procedure:
To a suspension of 2-methyl-3-oxobutanal sodium salt (3.18 g) and N-ethylcyanoacetamide (3-0003-02) (2.243 g) in DMF (20 mL) were added acetic acid (1.49 mL) and piperidine (0.40 mL) at room temperature, and the reaction mixture was refluxed with stirring in an oil bath at 135° C. for 5 h. The reaction mixture was dissolved in chloroform and water, extracted three times with chloroform, dried over magnesium sulfate, and evaporated under reduced pressure. The obtained crystal residue (4.07 g) was washed three times with n-hexane (1 mL) to give 1-ethyl-3-cyano-5,6-dimethyl-2-pyridone (3-003-03) (3.38 g, 96%) as a brown crystal.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][CH2:9][CH2:10]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][CH2:9][CH2:10][N:18]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCOC(c1ccccc1)c1ccccc1
Reactant: C1CNCCNC1
Product: c1ccc(C(OCCN2CCCNCC2)c2ccccc2)cc1
Yield: 68 %

Procedure:
Following a procedure similar to that described in Preparation 1, but using 2-(diphenylmethoxy)ethyl chloride and homopiperazine, the title compound was obtained ina yield of 68%.
Reaction SMILES: C1(=O)CCCCC1.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:28]([OH:32])(=[O:31])[CH:29]=[CH2:30]>>[CH:20]([CH:30]=[CH:29][C:28]([OH:32])=[O:31])=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C=CC(=O)O
Reactant: C=Cc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O=C1CCCCC1
Product: O=C(O)C=CC=Cc1ccccc1
Reaction time: 2 h

Procedure:
432 g of cyclohexanone and 3 g of azobisisobutyronitrile were poured into a five-necked reaction vessel having a capacity of one litter. Then, while introducing nitrogen gas into the reaction vessel, the resultant mixture was heated to 80° C. Then, a mixed liquid constituted by 98.9 g of styrene and 9.1 g of acrylic acid was added drop-wise to the above mixture taking two hours. 30 minutes after finishing of the dropping of the mixed liquid, 3 g of azoisobutyronitrile was added to the resultant mixture and the mixture thus obtained was heated for 5 hours to obtain a styrene-acrylic acid copolymer. The weight average molecular weight of the styrene-acrylic acid copolymer thus obtained was 6900.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:22][CH2:21][C:20]3[N:19]4[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]4)=[C:13]([F:23])[C:12]=3[C:11]2=[O:24])[N:5]=[CH:4][CH:3]=1.[CH3:25][N:26]1[C:30]([CH3:31])=[CH:29][C:28]([NH:32][C:33]2[C:34](=[O:49])[N:35]([CH3:48])[CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=2)=[N:27]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[CH3:25][N:26]1[C:30]([CH3:31])=[CH:29][C:28]([NH:32][C:33]2[C:34](=[O:49])[N:35]([CH3:48])[CH:36]=[C:37]([C:2]3[CH:3]=[CH:4][N:5]=[C:6]([N:10]4[CH2:22][CH2:21][C:20]5[N:19]6[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]6)=[C:13]([F:23])[C:12]=5[C:11]4=[O:24])[C:7]=3[CH:8]=[O:9])[CH:38]=2)=[N:27]1
Reactant: O=Cc1c(Cl)ccnc1N1CCc2c(c(F)c3n2CCCC3)C1=O
Reactant: Cc1cc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nn1C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Nc2cc(-c3ccnc(N4CCc5c(c(F)c6n5CCCC6)C4=O)c3C=O)cn(C)c2=O)nn1C
Temperature: 110 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 4-chloro-2-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)nicotinaldehyde 134c (97 mg, 0.28 mmol), 3-[(1,5-dimethyl-1H-pyrazol-3-yl)amino]-1-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one 218a (192.6 mg, 0.56 mmol), Pd2(dba)3 (54.9 mg, 0.060 mmol), tri(cyclohexyl)phosphine (50.2 mg, 0.18 mmol), Cs2CO3 (182.6 mg, 0.56 mmol), dioxane (8 mL), and water (0.25 mL). After three cycles of vacuum/argon flush, the mixture was stirred at 110° C. for 2 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 35:1 ethyl acetate/methanol to afford 261a (90 mg, 61%) as a black solid. MS-ESI: [M+H]+ 530.2
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:5]=[C:4]([C:12]([O:14]C)=[O:13])[CH:3]=1.[OH-].[K+].CO.ClCCl>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[N:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(Br)cc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6.09 g of dimethyl 4-bromopyridine-2,6-dicarboxylate, 1.08 g of potassium hydroxide, 200 ml of methanol and 20 ml of dichloromethane was stirred at room temperature for 3 hours, and 200 ml of ether was added thereto. The resulting white solid was filtered, and then washed with ether. The obtained white solid was dissolved in water, and then 12 ml of hydrochloric acid (2 M) was added thereto. The resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo to give the title compound.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH2:20][CH3:21])(=O)=O)C=CC=CC=1.[OH-].[Na+]>CO>[Cl:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][C:11]([CH2:20][CH3:21])=[CH:12]2
Reactant: CCc1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc2cc(Cl)ccc2[nH]1

Procedure:
A mixture of 2 (1.3 g, 4.07 mmol), 2N NaOH (12 mL), and MeOH (62 mL) was refluxed for 40 h. The organic solvent was evaporated and the remaining residue was extracted with EtOAc. The combined extract were washed with brine, dried (Na2SO4) and evaporated in vacuo to give a residue which was purified by flash chromatography (silica gel, cyclohexane/ethyl acetate, 8:2) and crystallization from ether/cyclohexane.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[F:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:16][CH2:15][N:14]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=CCNCC2)cc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2=CCN(S(C)(=O)=O)CC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.4 %

Procedure:
4-(3-Fluoro-4-methoxy-phenyl)-1,2,3,6-tetrahydro-pyridine hydrochloride salt (462.00 mg, 1.90 mmol) is suspended in dichloromethane (10 mL). Triethylamine (479.58 mg, 660.57 μL, 4.74 mmol) and methanesulfonyl chloride (260.59 mg, 176.07 μL, 2.27 mmol) are added and the reaction is capped and stirred at room temperature for 16 h. The reaction is partitioned between dichloromethane and water. The aqueous layer is extracted with dichloromethane. The combined organic layers are washed with brine, dried over magnesium sulfate, filtered, and concentrated to dryness. The crude material is purified by chromatography using a 5 g silica gel cartridge eluting with dichloromethane to provide 349 mg of the title compound as a white solid. MS (m/z) 286 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.[Zn]>[O:17]=[S:13]1(=[O:16])[CH2:12][CH2:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(N2CCS(=O)(=O)CC2)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc(N2CCS(=O)(=O)CC2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
Zinc powder (0.47 g, 7.2 mmol) was added to a solution of 4-(4-nitro-phenyl)-thiomorpholine 1,1-dioxide (155 mg, 0.60 mmol) in acetic acid (3 mL) and the mixture was stirred at 60° C. for 2 h. The reaction mixture was concentrated to dryness, diluted with ethyl acetate and washed with sodium bicarbonate solution and water then dried over sodium sulfate. The organic layer was concentrated to dryness to afford 4-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-phenylamine (70 mg, 51%).
Reaction SMILES: C([Li])CCC.CCCCCC.[Cl-].[CH3:13][O:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:35]1[C:40]([C:41]([C:43]([F:46])([F:45])[F:44])=O)=[CH:39][CH:38]=[C:37]([Cl:47])[CH:36]=1.CCCCCC>C1COCC1>[CH3:13][O:14][CH:15]=[C:41]([C:40]1[CH:39]=[CH:38][C:37]([Cl:47])=[CH:36][CH:35]=1)[C:43]([F:46])([F:45])[F:44]
Reactant: O=C(c1ccc(Cl)cc1)C(F)(F)F
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC=C(c1ccc(Cl)cc1)C(F)(F)F
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
Under a nitrogen atmosphere, 33.6 ml of n-butyllithium/hexane solution (1.2M solution) was added to a solution of 17.3 g of methoxymethyltriphenylphosphonium chloride in 150 ml of dry THF at -60° C. The reaction solution was stirred at -60° C. for 30 minutes and at -20° C. for 30 minutes. A solution of 7.0 g of 4-chloro-α,α,α-trifluoroacetophenone in 10 ml of dry THF was slowly added to the reaction solution at -60° C. The reaction solution was stirred at -60° C. for 1 hour and at room temperature for 12 hours. Thereafter, 200 ml of n-hexane was added to the reaction mixture and insoluble materials were filtered out. The filtrate was washed with dilute HCl-ice water and saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residues was subjected to column chromatography on silica gel [eluted with n-hexane/ethyl acetate (40:1) mixture] to obtain 4.17 g of the desired compound (E/Z=ca. 1/1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([C:17]3=[CH:18][C:19]4[O:23][CH2:22][O:21][C:20]=4[CH:24]=[C:16]3[O:15][CH2:14]2)[C:6]1=[O:25].C(N(CC)CC)C.[Cl:33][C:34]1[CH:38]=[CH:37][S:36][C:35]=1[C:39](Cl)=[O:40]>ClCCl>[Cl:33][C:34]1[CH:38]=[CH:37][S:36][C:35]=1[C:39]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([C:17]3=[CH:18][C:19]4[O:23][CH2:22][O:21][C:20]=4[CH:24]=[C:16]3[O:15][CH2:14]2)[C:6]1=[O:25])=[O:40]
Reactant: NCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Reactant: O=C(Cl)c1sccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21)c1sccc1Cl
Reaction time: 2 h
Yield: 69 %

Procedure:
To a solution of 1′-(3-aminopropyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.05 g, 0.13 mmol) in dichloromethane (4.00 mL) was added triethylamine (0.03 g, 0.26 mmol) and 3-chlorothiophene-2-carbonyl chloride (0.02 g, 0.12 mmol) at 0° C. The mixture was stirred for 2 h, washed with 15% HCl solution and water. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was dissolved in ethyl acetate, and the product was precipitated with the addition of hexane. The white solid was collected by filtration and dried in vacuo to yield the title compound (0.04 g) in 67% yield: 1H NMR (300 MHz, CDCl3) δ 7.60 (t, 1H), 7.41 (d, 1H), 7.33-7.27-(m, 1H), 7.17 (d, 1H), 7.08-7.03-(m, 1H), 6.93 (t, 1H), 6.49 (s, 1H), 6.11 (s, 1H), 5.95 (m, 2H), 4.90 (d, 1H), 4.65 (d, 1H), 3.96-3.79-(m, 2H), 3.53-3.36-(m, 2H), 2.04-1.93-(m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.3, 160.6, 156.0, 149.0, 142.4, 141.8, 132.5, 129.4, 129.2, 129.1, 124.2, 123.7, 123.6, 119.2, 108.5, 102.9, 101.6, 93.7, 80.5, 58.3, 37.4, 36.5, 27.3; MS (ES+) m/z 483 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][O:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([F:35])=[CH:30][C:29]=1B(O)O>>[F:34][C:33]1[C:28]([O:27][CH3:26])=[C:29]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[CH:30]=[C:31]([F:35])[CH:32]=1
Reactant: COc1c(F)cc(F)cc1B(O)O
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Product: COc1c(F)cc(F)cc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 58, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-methoxy-3,5-difluorophenylboronic acid (CAS RN 737000-76-9) and using preparative HPLC for the chromatographic purification. Off-white solid (49%). MS (ESI): m/z=491.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:28][CH2:27][N:26]([C:29]([CH3:34])([CH2:32][OH:33])[CH2:30][OH:31])[CH2:25][CH2:24]3)[N:18]2[CH3:21])=[C:14]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:13]=1>>[CH3:34][C:29]([N:26]1[CH2:25][CH2:24][N:23]([CH2:22][C:17]2[N:18]([CH3:21])[C:19]3[C:15]([N:16]=2)=[C:14]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)[N:13]=[C:12]([N:3]2[C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=[C:2]2[CH3:1])[N:20]=3)[CH2:28][CH2:27]1)([CH2:32][OH:33])[CH2:30][OH:31]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCN(C(C)(CO)CO)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(CO)CO)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and 2-(4-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-1-yl)-2-methylpropane-1,3-diol were reacted to give 356. LCMS m/z: 536.3 (MH+)
Reaction SMILES: Cl.[CH:2]1([NH:5][CH3:6])[CH2:4][CH2:3]1.CCN(CC)CC.[CH2:14]([O:16][C:17](=[O:34])[CH2:18][C:19]1[N:32]=[C:31](Cl)[C:22]2[C:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]=3[S:30][C:21]=2[N:20]=1)[CH3:15]>CO>[CH2:14]([O:16][C:17](=[O:34])[CH2:18][C:19]1[N:32]=[C:31]([N:5]([CH:2]2[CH2:4][CH2:3]2)[CH3:6])[C:22]2[C:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]=3[S:30][C:21]=2[N:20]=1)[CH3:15]
Reactant: CNC1CC1
Reactant: CCOC(=O)Cc1nc(Cl)c2c3c(sc2n1)CCCCC3
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)Cc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCCC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.4 %

Procedure:
Cyclopropyl-methyl amine HCl (1.32 g, 0.0123 mol) and Et3N (2.4 g, 0.0246 mol) were added to a solution of (4-chloro-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benz[a]azulen-2-yl)-acetic acid ethyl ester (2 g, 0.00615 mol) in 20 ml of methanol and the mixture was stirred for 18 h at ambient temperature. The methanol was removed under vacuum and the crude was purified by chromatography on silica gel using 10% ethyl acetate in hexanes to give [4-(cyclopropyl-methyl-amino)-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benz[a]azulen-2-yl]-acetic acid ethyl ester (1.8 g, 81%) as a pale yellow liquid. 1H NMR (400 MHz, CDCl3): δ 4.18 (q, 2H), 3.89 (s, 2H), 2.92-3.00 (m, 5H), 2.78-2.90 (m, 3H), 1.85-1.92 (m, 2H), 1.68-1.77 (m, 2H), 1.60-1.67 (m, 2H), 1.25 (t, 3H), 0.68-0.75 (m, 2H), 0.40-0.47 (m, 2H); LC-MS: [M+H]: =359.9 m/z.