Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]1[C:10](=[O:11])[C:9]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[NH:8][C:7]1=[O:17].[H-].[Na+].I[CH2:21][CH2:22][CH3:23]>CN(C)C=O.O>[CH2:21]([N:8]1[C:9]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:10](=[O:11])[N:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[C:7]1=[O:17])[CH2:22][CH3:23]
Reactant: CCCI
Reactant: O=C1NC2(CCCCC2)C(=O)N1c1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1C(=O)N(c2nccs2)C(=O)C12CCCCC2
Reaction time: 1 h
Yield: 67 %

Procedure:
5.05 g of the product from Example 2, stage 2 were dissolved in 20 ml of dimethylformamide. 1.10 g of sodium hydride (50% suspension in mineral oil) were added in portions with stirring at 200C. After 1 hour's stirring, 4 ml of 1-iodopropane were added. Stirring was continued for a further 3 hours. The mixture was then diluted with 100 ml of distilled water, extracted three times with 30 ml portions of ethyl acetate, washed with saturated sodium chloride solution and dried over sodium sulphate. Once the solvent had been removed by distillation, the residue was purified by passage through a silica gel column with ethyl acetate/n-hexane=8/5. 3.95 g of l-propyl-3-thiazol-2-yl-1,3-diazaspiro[4.5]decane-2,4-dione (67% of th.) were obtained in the form of white crystals (mp 135-138° C.).
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C>C(O)C>[N:23]1([CH2:22][CH2:21][NH:20][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCCN1CCCCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NCCN4CCCCC4)ncnc32)[C@H](O)[C@@H]1O

Procedure:
The experiment of Example 1 was repeated in every essential detail except for the following. The suspension was prepared using 2.0 g (6.98 mmol) of the 6-chloropurine riboside in 30 ml of absolute ethanol. 1-(2-Aminoethyl) piperidine (commercially available) was added in an amount of 1.07 g (0.7 ml, 8.3 mmol). Also added to this suspension was 1.5 ml (10.5 mmol) of triethylamine. The reaction mixture was refluxed for 72 hours. The resulting residue was chromatographed on a silica gel column eluting with an eluent of 20 parts methanol, 79 parts dichloromethane and one part ammonium hydroxide. The title product was produced in a yield of 1.1 g (42%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5](/[CH:10]=[CH:11]/[C:12]([OH:14])=O)=[C:4]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:3]=1.[F:20][C:21]1[CH:35]=[CH:34][C:24]([CH2:25][N:26]2[CH2:31][C@H:30]([CH3:32])[NH:29][CH2:28][C@H:27]2[CH3:33])=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5](/[CH:10]=[CH:11]/[C:12]([N:29]2[CH2:28][C@H:27]([CH3:33])[N:26]([CH2:25][C:24]3[CH:34]=[CH:35][C:21]([F:20])=[CH:22][CH:23]=3)[CH2:31][C@H:30]2[CH3:32])=[O:14])=[C:4]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:3]=1
Reactant: C[C@@H]1CN[C@@H](C)CN1Cc1ccc(F)cc1
Reactant: COc1cc(/C=C/C(=O)O)c(NS(C)(=O)=O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)c(NS(C)(=O)=O)cc1Cl
Yield: 82.7 %

Procedure:
(E)-3-(4-Chloro-2-methanesulfonylamino-5-methoxyphenyl)-acrylic acid (100 mg; 0.32 mmol), (2R,5S)-1-(4-fluorobenzyl)-2,5-dimethylpiperazine (Mavunkel, Babu J. et al., WO 00171535) (73 mg; 0.32 mmol) and EDCl.HCl (75 mg, 0.39 mmol), HOBt (5 mg; 0.03 mmol) were dissolved in DMF (2 ml) and stirred over night. The reaction mixture was evaporated, taken up in 2N Na2CO3 and extracted with EtOAc three times. The combined organic phases were evaporated and purified via chromatography (SiO2 acetone/hexanes 3/7) to yield the title compound as yellow foam (135 mg; 81%)
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH2:13]([NH:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)c1ccccc1N
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ccccc1NCc1ccccc1

Procedure:
To a hot solution of 20 g NaOH in 1250 ml water was added 68 g 2-aminobenzamide followed by 58 ml benzyl chloride. The mixture was refluxed 20 minutes, cooled and the solid filtered and washed with water. The product was recrystallized from 95% alcohol to give 62 g, m.169-73.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[CH:21][C:20]=1C)=[O:18].BrC1C=CC(OC)=C([C:39](C2C=CC(NC3C=CC(F)=CC=3F)=CC=2Cl)=[O:40])C=1.C([Si](C)(C)C)#C>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[CH:21][C:20]=1[O:40][CH3:39])=[O:18]
Reactant: COc1ccc(Br)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: Cc1ccc(C#C[Si](C)(C)C)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: C#C[Si](C)(C)C
Product: COc1ccc(C#C[Si](C)(C)C)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 406, using compound 425 (0.99 mmol) and ethynyltrimethylsilane (0.99 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 10:90 as the eluent to afford the title compound as light orange syrup.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:19])=[C:8]([C:12]([O:14]C(C)(C)C)=[O:13])[NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].FC(F)(F)C(O)=O>O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:19])=[C:8]([C:12]([OH:14])=[O:13])[NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)[nH]c(C(=O)OC(C)(C)C)c1C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(C)[nH]c(C(=O)O)c1C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
3,5-Dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 6b (5.34 g, 20 mmol) was dissolved in trifluoroacetic acid (7.4 mL, 100 mmol) and the mixture was stirred for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. Then 40 mL of water was added. The mixture was filtered and the filter cake was washed with dichloromethane and dried to obtain the title compound 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid 4-ethyl ester 6c (3.65 g, yield 86.5%) as a pink solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][N:6]([S:24]([CH3:27])(=[O:26])=[O:25])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:23])[CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH3:16])=[CH:9][CH:8]=1)[CH3:2].C(OCC)C.[C:35]1([Mg]Br)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].[NH4+]>O>[CH2:28]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]([S:24]([CH3:27])(=[O:26])=[O:25])[C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:23])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH3:16])=[CH:11][CH:12]=1)[CH3:29]
Reactant: CCC(C(=O)c1ccc(N(CCN(CC)CC)S(C)(=O)=O)cc1)c1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CCC(c1ccccc1)C(O)(c1ccccc1)c1ccc(N(CCN(CC)CC)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
N-(2-Diethylaminoethyl)-4'-(1-oxo-2-phenylbutyl)methanesulfonanilide (24.0 g., 0.0576 mole) is dissolved in 500 ml. ethyl ether and added dropwise during 1/2 hr. to a solution of phenylmagnesium bromide (0.145 mole) in 500 ml. ethyl ether. The mixture is heated at reflux for 16 hrs. After cooling to room temperature, 100 g. of ammonium chloride in 400 ml. water is added and the solution is stirred for 15 min. The ether layer is separated and the aqueous layer is extracted with ethyl ether and the combined ether solutions are washed with water followed by 1N HCl. The acidic aqueous wash is washed with ethyl ether and basified with 50% NaOH to pH 11. The product is extracted with ethyl ether and the ether solution is washed with water and dried (MgSO4). Evaporation of the ethyl ether yields 28 g. of product as an oil (100% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]3[C:20]4[C:15](=[CH:16][C:17]([N:21]([CH3:29])[C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=5)=[CH:18][CH:19]=4)[NH:14][N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:30](N)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]3[C:20]4[C:15](=[CH:16][C:17]([N:21]([CH3:29])[C:22]5[CH:23]=[C:24]([NH:28][C:30](=[O:37])[C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)[CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:19]=4)[NH:14][N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN(c1cccc(N)c1)c1ccc2c(C=Cc3ccc4c(c3)OCO4)n[nH]c2c1
Reactant: NC(=O)c1ccccc1
Product: CN(c1cccc(NC(=O)c2ccccc2)c1)c1ccc2c(C=Cc3ccc4c(c3)OCO4)n[nH]c2c1

Procedure:
N-[3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1H-indazol-6-yl]-N-methyl-benzene-1,3-diamine (prepared as described in Example 15) was converted to N-(3-{[32-benzo[1,3]dioxol-5-yl-vinyl)1H-indazol-6-yl]-methyl-amino}-phenyl)-benzamide in the manner described in Example 12(a). LCMS (ESI) [M+H]/z Calc'd 489, Found 489. Anal. Calc'd: C, 73.76; H, 4.95; N, 11.47. Found: C, 73.19; H, 5.09; N, 11.20.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.O.[O:12]1[C@H:14]2[CH2:15][C@H:16]3[C@:29]([CH3:31])([CH2:30][C@@H:13]12)[C@@H:28]1[C@H:19]([C@H:20]2[C@@:24]([CH2:26][CH2:27]1)([CH3:25])[C@@H:23]([OH:32])[C@@H:22]([N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:21]2)[CH2:18][CH2:17]3>C(#N)C>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C@H:13]3[CH2:30][C@@:29]4([CH3:31])[C@@H:16]([CH2:17][CH2:18][C@@H:19]5[C@@H:28]4[CH2:27][CH2:26][C@@:24]4([CH3:25])[C@H:20]5[CH2:21][C@H:22]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[C@@H:23]4[OH:32])[CH2:15][C@@H:14]3[OH:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Reactant: C1CC2(CCN1)OCCO2
Solvent: O
Solvent: CC#N
Product: C[C@]12C[C@H](N3CCC4(CC3)OCCO4)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12

Procedure:
After adding 63 g of 1,4-dioxa-8-azaspiro[4.5]decane and 13 ml of water to 17 g of 2α,3α-epoxy-16β-(1-pyrrolidinyl)-5α-androstane-17β-ol, the reaction mixture is maintained at 100° to 105° C. for 80 hours while introducing nitrogen. After completion of the reaction, the solution containing a precipitate is diluted with 200 ml of acetonitrile and after filtering, the precipitate is thoroughly washed with water and then with acetonitrile, dried and recrystallized from methanol to give the title product in a yield of 18.2 g (76.5%), m.p.: 184°-187° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].C(N(CC)C(C)C)(C)C.[I-].[Na+].[NH2:37][CH2:38][CH2:39][CH2:40][OH:41]>C(O)CCC>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:37][CH2:38][CH2:39][CH2:40][OH:41])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][CH:10]([CH2:16]3)[CH2:9]1)[CH2:17]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCCl)ccc1Cl
Reactant: NCCCO
Agent: [I-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCNCCCO)ccc1Cl
Temperature: 110 °C

Procedure:
To a solution of 2-chloro-5-[2-chloroethoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 11a, 0.15 g) and N,N-diisopropylethylamine (0.50 ml) in 1-butanol (4 ml) was added sodium iodide (0.06 g) and 3-aminopropan-1-ol (0.09 ml). The reaction vessel was sealed and the mixture heated at 110° C. for 24 h. The reaction mixture was partitioned between ethyl acetate and sodium hydrogencarbonate solution, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by RPHPLC (eluting with 25-95% MeCN/0.1% AcONH4 aqueous) to give 2-chloro-5-[2-[(3-hydroxypropyl)amino]ethoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide as the acetate salt. This was converted to the hydrochloride salt by stirring with 4M HCl in dioxane and concentration under reduced pressure. Recrystalisation from isohexane/isopropanol gave the title compound as a white solid (0.1 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH:12]([NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29])[CH:13]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:8][CH:7]=1.[CH3:31][N:32]1[CH:36]=[C:35]([S:37](Cl)(=[O:39])=[O:38])[N:34]=[CH:33]1.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[Cl:23])[CH2:16][CH:13]1[C:14]2[C:9](=[CH:8][CH:7]=[C:6]([O:5][CH2:4][CH2:3][NH:2][S:37]([C:35]3[N:34]=[CH:33][N:32]([CH3:31])[CH:36]=3)(=[O:39])=[O:38])[CH:15]=2)[CH2:10][CH2:11][CH:12]1[NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29]
Reactant: CCOC(=O)NC1CCc2ccc(OCCN)cc2C1Cc1ccc(Cl)c(Cl)c1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)NC1CCc2ccc(OCCNS(=O)(=O)c3cn(C)cn3)cc2C1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
Ethyl 7-(2-aminoethoxy)-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate hydrochloride (100 mg, 0.229 mmol) and DMAP (27.9 mg, 0.229 mmol) were dissolved in CH2Cl2 (15 ml) and 1-methyl-1H-imidazole-4-sulfonyl chloride (41.3 mg, 0.229 mmol) dissolved in CH2Cl2 (15 ml) was added. The reaction mixture was stirred over night at RT. After addition of H2O the phases were separated and the aqueous phase was extracted with CH2Cl2. The organic layer was washed with HCl (1N), NaHCO3 solution and NaCl solution, then dried on MgSO4 and the solvent was removed. To the residue EtOAc/diethylether (1:1) was added, stirred, and the precipitate was separated by filtration to obtain a brown solid of product (100 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[C:55]([C:57]1[CH:58]=[C:59]([S:63](Cl)(=[O:65])=[O:64])[CH:60]=[CH:61][CH:62]=1)#[N:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:63]([C:59]2[CH:60]=[CH:61][CH:62]=[C:57]([C:55]#[N:56])[CH:58]=2)(=[O:65])=[O:64])[CH2:49][CH2:48]1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(S(=O)(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)c1
Yield: 25 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 3-cyanobenzenesulfonyl chloride as starting materials in 25% yield. LCMS for C31H30ClN8O3S (M+H)+: m/z=629.2.
Reaction SMILES: [CH:1]([C@@H:3]1[C@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[O:4]1)=O.[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17]>ClCCl>[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][N:17]=[CH:1][C@H:3]1[C@H:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:4]1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=C[C@H]1O[C@H]1c1ccccc1
Solvent: ClCCl
Product: COc1ccc(CN=C[C@@H]2O[C@H]2c2ccccc2)c(OC)c1
Reaction time: 12 h

Procedure:
To a solution of (2S,3S)-2-formyl-3-phenyloxirane (430 mg, 2.90 mmol) in 8.0 mL of dichloromethane under nitrogen was added a solution of 2,4-dimethoxybenzylamine (461 mg, 2.75 mmol) in 1.0 mL of dichloromethane via cannula. Residual amine was washed into the reaction flask with 1.0 mL of dichloromethane. Molecular sieves (2.3 g of pellets, 4 Å, activated) were added and the mixture was allowed to stand for 12 hours. This solution was used directly in the cycloaddition after removing and concentrating a small aliquot for spectral analysis: IR (CHCl3) 3016, 1615, 1510 cm-1 ; 1H NMR (CDCl3, 250 MHz) δ 7.40-7.24 (6H, N=CH, ArH), 7.14 (d, 1H, J=8.8 Hz, ArH), 6.52-6.43 (2H, ArH), 4.62 (s, 2H, NCH2Ar), 3.69 (d, 1H, J=1.9 Hz, oxirane CHCHPh), 3.82 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 3.62 (dd, 1H, J=1.9, 7.0 Hz, oxirane CHCHPh).
Reaction SMILES: [Cl:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:6]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: FC(F)(F)c1cc(Cl)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1nc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of 5-chloro-3-(trifluoromethyl)-1H-pyrazole (i.e. the product of Example 10, Step C) (2.1 g, 12.3 mmol) and potassium carbonate (3.6 g, 26.0 mmol) in 20 mL of N,N-dimethylformamide was added ethyl bromoacetate (2.1 mL, 18.8 mmol), and the resulting mixture was stirred at room temperature for 12 h. The resulting mixture was diluted with ethyl acetate, washed with water, and dried (MgSO4). The reaction mixture was concentrated in vacuo and further purified by medium-pressure liquid chromatography using 0-50% of ethyl acetate in hexanes as eluant to give 940 mg of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[CH:7]=[CH:6]2.[Br:14]N1C(=O)CCC1=O>C(#N)C>[Br:14][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH3:13])=[N:9]2
Reactant: COc1ccc2nc(C)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ccc2nc(C)ccc2c1Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.4 %

Procedure:
A solution of 6-methoxy-2-methylquinoline (177 g, 1.02 mol) in acetonitrile (1.77 L) was cooled to 0-3° C. followed by portion-wise addition of N-bromosuccinimide (200 g, 1.12 mol) over a period of 30 min while maintaining the same temperature. The resulted brown slurry was warmed to ambient temperature and stirred for an additional 6 h. The reaction was then quenched by a 10% NaHSO3 solution (211 mL). The reaction mixture was concentrated to a volume of 600 mL then slowly poured into 0.1 N NaOH (2.5 L). The slurry (pH=9) was stirred at room temperature for 1 h then filtered, washed with water (2×1 L) and dried in a vacuum oven to give 253 g (98.6%) of the title compound as a brown solid.
Reaction SMILES: CS(C)=O.[CH2:5]([C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:12]([CH2:51]OS(C)(=O)=O)=[C:11]([Cl:57])[N:10]=1)[CH2:6][CH2:7][CH3:8].[N-:58]=[N+:59]=[N-:60].[Na+].[Na+].[Cl-]>CCOC(C)=O>[N:58]([CH2:51][C:12]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:9]([CH2:5][CH2:6][CH2:7][CH3:8])=[N:10][C:11]=1[Cl:57])=[N+:59]=[N-:60]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1nc(Cl)c(COS(C)(=O)=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(Cl)c(CN=[N+]=[N-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.9 %

Procedure:
To a dimethyl sulfoxide (100 mL) solution of intermediate (11c) (15 g, 20 mmol) was added sodium azide (3.9 g, 60 mmol). The mixture was stirred at room temperature for 20 minutes. EtOAc (500 mL) and saturated aqueous NaCl (100 mL) were added and the layers were separated, retaining the organic layer. The organic was washed an additional three times with saturated aqueous NaCl (100 mL). After drying over sodium sulfate and filtration, the removal of solvent provided intermediate (11d) as a yellow solid (12 g), which was used directly in the next step. MS m/z: [M+H+] calcd for C41H36ClN9, 690.29. found 690.5.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Sc2ccc(Cl)cc2)cc1
Temperature: 90 °C
Yield: 63.8 %

Procedure:
A mixture of 4-fluorobenzaldehyde (12.6 mmol, 1.57 g), 4-chlorobenzenethiol (12.6 mmol, 1.81 g), K2CO3 (15.1 mmol, 2.09 g) in DMF (5.00 mL) was heated at 90° C. for 10 h. After cooling to room temperature, the reaction mixture was poured into a separatory funnel with water (100 mL). The phases were separated and the aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with water (2×100 mL), brine (50 mL) and dried over MgSO4. Removal of the solvents in vacuo gave a light yellow liquid. Purification by flash column chromatography (eluent: 5% EtOAc in Hexane) provided 4-(4-chlorophenylthio)benzaldehyde (2.00 g, 76.0% yield) as a light yellow liquid. 1H NMR (CDCl3) δ 9.93 (s, 1H), 7.72 (d, J=8.3 Hz, 2H), 7.46-7.39 (m, 4H), 7.25 (d, J=8.3 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:30]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4([NH:41]C(=O)OC(C)(C)C)[CH2:40][CH2:39][CH2:38]4)=[CH:33][CH:32]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:22]5[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]5)[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:49].O1CCOCC1>C(Cl)Cl>[ClH:49].[ClH:49].[ClH:49].[NH2:41][C:37]1([C:34]2[CH:33]=[CH:32][C:31]([N:30]3[C:11]4=[N:12][C:13]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([N:22]6[CH2:27][CH2:26][S:25](=[O:28])(=[O:29])[CH2:24][CH2:23]6)[CH:17]=5)=[CH:14][CH:15]=[C:10]4[N:9]=[C:8]3[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:36][CH:35]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(N6CCS(=O)(=O)CC6)c5)nc43)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1ncccc1-c1nc2ccc(-c3cccc(N4CCS(=O)(=O)CC4)c3)nc2n1-c1ccc(C2(N)CCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
tert-Butyl [1-(4-{2-(2-aminopyridin-3-yl)-5-[3-(1,1-dioxidothiomorpholin-4-yl)phenyl]-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)cyclobutyl]carbamate (29.0 mg, 0.0449 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 2 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (33.2 mg, 85.1%) as pale yellow solid.