Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:26][O:25][C:5]2([C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=3)[N:7]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:6]2=[O:24])[O:4][CH2:3]1.Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1([CH3:27])[CH2:3][O:4][C:5]2([C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N:14]([CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=3)[N:7]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:6]2=[O:24])[O:25][CH2:26]1
Reactant: COC(=O)CN1C(=O)C2(OCC(C)(C)CO2)c2cc(NS(C)(=O)=O)ccc21
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C2(OCC(C)(C)CO2)c2cc(N(CCN3CCOCC3)S(C)(=O)=O)ccc21
Temperature: 70 °C
Yield: 88.1 %

Procedure:
A mixture of methyl 2-(5,5-dimethyl-5′-(methylsulfonamido)-2′-oxospiro[[1,3]dioxane-2,3′-indoline]-1′-yl)acetate (0.400 g, 1.004 mmol), 4-(2-chloroethyl)morpholine hydrochloride (0.224 g, 1.204 mmol) (prepared in an analogous manner as described in Example 17, Scheme 17, Steps 1, 2, 3, 4) and K2CO3 (0.306 g, 2.208 mmol) in DMF (8 ml) was heated at 70° C. for 3 hours. The mixture was partitioned between ethyl acetate and water, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed several times with brine and dried over sodium sulfate; the solvent was removed and the crude was purified by chromatography on silica gel cartridge (DCM:MeOH=99:1 to 97:3) affording methyl 2-(5,5-dimethyl-5′-(N-(2-morpholinoethyl)-methylsulfonamido)-2′-oxospiro[[1,3]dioxane-2,3′-indoline]-1′-yl)acetate (0.453 g, 0.885 mmol, 88% yield, MS/ESI+ 512.1 [MH]+).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][O:23][C:22]2=[O:31])[CH2:17][CH2:16]1)=[O:14].Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:33][C:2]([F:1])([F:32])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:8]=[CH:7][C:6]=1[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][O:23][C:22]2=[O:31])[CH2:17][CH2:16]1)=[O:14]
Reactant: O=C(Cc1ccc(O)cc1OCC(F)(F)F)N1CCC(N2C(=O)OCc3ccccc32)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(CC(=O)N2CCC(N3C(=O)OCc4ccccc43)CC2)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-(1-(2-(2,2,2-trifluoro-ethoxy)-4-hydroxyphenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one (0.54 g, 1.2 mmol) from Example 32 in DMF (10 mL) was added tert-butyl bromoacetate (0.51 mL, 3.6 mmol) and Cs2CO3 (0.48 g, 1.5 mmol). The mixture was stirred at ambient temperature for 18 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (10 mL) and water (50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 1-(1-(2-(2,2,2-trifluoro-ethoxy)-4-(tert-butyloxycarbonylmethoxy)phenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one as a pale yellow oil (HPLC retention time=27.3 min (method D)).
Reaction SMILES: [C:1]([O:5][C@@H:6]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@H:8]([C@@H:9]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:10][C@@H:11]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C@H:16]([CH3:21])[CH:17]=[CH:18][CH:19]=O)[CH2:7]1)([CH3:4])([CH3:3])[CH3:2].O1C[CH2:39][CH2:38][CH2:37]1>>[C:1]([O:5][C@@H:6]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@H:8]([C@@H:9]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])[CH2:10][C@@H:11]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C@H:16]([CH3:21])[CH2:17][CH2:18][CH:19]=[C:38]([CH3:39])[CH3:37])[CH2:7]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: C1CCOC1
Reactant: C[C@H](C=CC=O)[C@H]1CC[C@H]2[C@@H]3C[C@H](OC(C)(C)C)[C@@H]4C[C@H](OC(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C)=CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](OC(C)(C)C)[C@@H]4C[C@H](OC(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 2 h

Procedure:
A solution of 3α,6α-bis(t-butyloxy)-5β-cholen-24-al (prepared as described in my U.S. patent application Ser. No. 236,160) was dissolved in 5 ml of tetrahydrofuran and added dropwise to the ylid solution (described in Example I). The mixture was stirred for 2 hours and then the solution was refluxed for 2 hours. After evaporation of the solvent, the residue was dissolved in a 90% methanol-10% water mixture, extracted with petroleum ether and the petroleum ether extract evaporated. The residue was identified by NMR and IR data as the 3α,6α-bis(t-butyloxy)-5β-cholest-24-ene.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:16]=[N:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]2.Cl.O.[CH3:27]O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:16]=[N:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:27])=[O:12])=[CH:7]2
Reactant: CS(=O)(=O)c1ccc(Oc2cc(O)c3[nH]c(C(=O)O)cc3c2)cn1
Reactant: CO
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(O)c2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of 7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (4.7 g) in a mixture of methanol (30 mL) and toluene (90 mL) was added dropwise 2M trimethylsilyldiazomethane diethyl ether solution (7.4 mL) at 0° C. The mixture was stirred at 0° C. for 30 min, and 2M trimethylsilyldiazomethane diethyl ether solution (3.7 mL) was added dropwise to the mixture. After stirring at 0° C. for 30 min, 1M hydrochloric acid (2 mL) was added to the mixture to quench the reaction. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual yellow oil was solidified with ethyl acetate-diethyl ether. The resulting solid was washed with diethyl ether to give the title compound (3.6 g, 74%) as a pale orange solid. MS 363 (MH+).
Reaction SMILES: Br[C:2]1[N:6]([NH:7][C:8](=[O:18])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH3:17])[C:5]([CH2:19][CH2:20][CH3:21])=[N:4][C:3]=1[CH3:22].[Cu][C:24]#[N:25].N1C=CC=CC=1.[I-].[K+]>C(OCC)(=O)C>[C:24]([C:2]1[N:6]([NH:7][C:8](=[O:18])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH3:17])[C:5]([CH2:19][CH2:20][CH3:21])=[N:4][C:3]=1[CH3:22])#[N:25]
Reactant: CCCc1nc(C)c(Br)n1NC(=O)c1ccccc1OCC
Reactant: N#C[Cu]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCc1nc(C)c(C#N)n1NC(=O)c1ccccc1OCC
Temperature: 100 °C
Reaction time: 6 h

Procedure:
N-(5-Bromo-4-methyl-2-propylimidazol-1-yl)-2-ethoxybenzamide from Example 2a (0.5 g, 1.2 mmol) and copper(I) cyanide (0.3 g, 3.5 mmol) are introduced into 12.5 ml of pyridine and heated at 100° C. for 6 hours. Potassium iodide (23 mg, 0.56 mmol) is added to the mixture, which is then stirred for a further 6 hours at 100° C. The reaction mixture is cooled to room temperature and, after addition of 50 ml of ethyl acetate, washed with dilute alkaline H2O2 solution. The aqueous phase is re-extracted with ethyl acetate, and the combined ethyl acetate phase is concentrated, finally azeotroped with toluene and again concentrated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17](S(C3C=CC(C)=CC=3)(=O)=O)=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:13])[CH2:11][CH3:12].[OH-:30].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:30])=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:13])[CH2:11][CH3:12]
Reactant: [OH-]
Reactant: CCC(C)COc1ccc(-c2ccc(S(=O)(=O)c3ccc(C)cc3)cc2)cc1Br
Agent: [Na+]
Solvent: CCO
Product: CCC(C)COc1ccc(-c2ccc(O)cc2)cc1Br

Procedure:
A mixture of 3'-bromo-4'-(2-methylbutyloxy)-4-p-toluenesulfonylbiphenyl (40 g) prepared in the above step (iii), a 50% aqueous solution (20 g) of NaOH and ethanol (350 ml) was heated under reflux for 4 hours, followed by distilling off ethanol, adding toluene, further adding 6N hydrochloric acid, separating the resulting liquid layer, washing with water to make the solution neutral, drying and distilling off toluene to obtain a raw product of oily 3'-bromo-4'-(2-methylbutyloxy)-4-hydroxybiphenyl, which was then dissolved in pyridine (200 ml), followed by adding benzoyl chloride (20 g), heating the mixture on a water bath, allowing to stand overnight, adding toluene, washing with 6N hydrochloric acid, washing with water, further washing with an aqueous solution of 2N NaOH, washing with water to make the solution neutral, drying and distilling off toluene to obtain 3'-bromo-4'-(2-methylbutyloxy)-4-biphenylylbenzoate (25 g). M.p.: 93.6° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br-:20].[C:21]([C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][CH2:31]O)[CH:26]=[CH:27][CH:28]=1)#[N:22].C1C=CC=CC=1>C(#N)C>[Br:20][CH2:31][CH2:30][CH2:29][C:25]1[CH:24]=[C:23]([C:21]#[N:22])[CH:28]=[CH:27][CH:26]=1
Reactant: N#Cc1cccc(CCCO)c1
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: c1ccccc1
Product: N#Cc1cccc(CCCBr)c1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a mixture of 21.8 g (0.083 moles) of triphenyl phosphine stirred in 30 ml acetonitrile, 13.2 g (4.26 ml) bromide in 75 ml acetonitrile was added dropwise with stirring in an ice bath. After the addition was complete, the ice bath was removed and the mixture warmed to room temperature. Then a mixture of 12.1 g (0.075 mole) of 3-(3-cyanophenyl)-1-propanol (the product of step (b)) in 30 ml acetonitrile was added dropwise. The resulting mixture was allowed to warm to about 45°-50° C., was stirred overnight and then stripped. Benzene (50 ml) was added to the residue; the mixture was evaporated. Then, additional benzene (50 ml) was added. The mixture was stirred, and then filtered to remove the triphenyl phosphine. The filtrate was stripped to give an oil. The oil was chromatographed using a column containing 3.5 inches of 200 mesh silica gel (Merck) eluting with benzene, until TLC showed that no further product was eluted from the column. The eluates were pooled and stripped to give 17 g of an oil. The oil was distilled in a Kugelrohr apparatus, the fraction bpt. 102°-103° C. was collected to give 15.7 g of the above-identified product as an oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH2:7])=[O:6])[CH3:4].O=[C:9]([CH3:17])[CH2:10][CH2:11][C:12](OCC)=[O:13]>O>[CH3:4][C@@H:3]1[N:2]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]2([CH3:17])[NH:7][C:5]1=[O:6]
Reactant: C[C@H](N)C(N)=O
Reactant: CCOC(=O)CCC(C)=O
Agent: Cl
Solvent: O
Product: C[C@H]1C(=O)NC2(C)CCC(=O)N12

Procedure:
L-Alaninamide hydrochloride (20.7 g, 0.166 mol) and ethyl 4-oxopentanoate (20 g, 0.13 mol) were reacted together according to the procedure of Example 2 to give the title compound, 4.5 g (19.1%), m.p. 228°-230° (with decomposition), [alpha]D =+50.7° (c=3, H2O). NMR (CDCl3): deltaH =7.95 (bs, 1H, NH); 4.30 (q, J=8 Hz, 1H, CHCH3); 3.00-2.10 (c.a., 4H, CH2CH2); 1.60 (s, 3H, C-CH3 ; 1.45 (d, J=8 Hz, 3H, CH3CH). MS (E.I., 70 eV, 1.5 mA) m/z=168 (M+), 153 (M-CH3)+, 125 (M-CHNO)+, 112 (M-C3H4O)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]3[N:18]([CH:21]4[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]4)[N:19]=[CH:20][C:15]3=[C:14]([N:28]3[CH2:34][CH:33]4[O:35][CH:30]([CH2:31][CH2:32]4)[CH2:29]3)[N:13]=2)=[CH:8][CH:7]=1)=[O:4].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:17]=[C:16]3[N:18]([CH:21]4[CH2:22][CH2:23][CH:24]([N:40]5[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]5)[CH2:25][CH2:26]4)[N:19]=[CH:20][C:15]3=[C:14]([N:28]3[CH2:29][CH:30]4[O:35][CH:33]([CH2:32][CH2:31]4)[CH2:34]3)[N:13]=2)=[CH:10][CH:11]=1)=[O:4]
Reactant: CNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCC(=O)CC4)c3n2)cc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCC(N5CCN(C)CC5)CC4)c3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-(4-oxocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}urea (65 mg) in DCE (2.0 mL) was added excess N-methylpiperizine, acetic acid (0.012 mL) and excess sodium triacetoxyborohydride. The mixture was stirred at room temperature overnight. The reaction was quenched with water and the organics were separated and concentrated under nitrogen and purified by Gilson HPLC to give the desired product (56 mg) MS m/z=560.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=O)[C:7](=[CH:18]N(C)C)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[NH2:25][C:26]([NH2:28])=[S:27].C[O-].[Na+]>CO.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:28]=[C:26]([SH:27])[N:25]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: NC(N)=S
Reactant: CN(C)C=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2C1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Sc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2.8 g (7.8 mmole) of 8-chloro-1-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one, 2.8 g (37 mmole) of thiourea, and 8.0 ml (32 mmole) of a 4.0M methanol solution of sodium methoxide in 80 ml of methanol was stirred at room temperature for 18 hr. The mixture was diluted with water and extracted with ether. The aqueous layer was neutralized with acetic acid and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow solid, mp 238°-239° C. Recrystallization from tetrahydrofuran gave yellow crystals, mp 232°-234° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.O.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]3[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Preparation 30 from 6-chloroindole (4.0 g, 26 mmol) and 4-piperidone hydrochloride hydrate (8.0 g, 52 mmol). The product was isolated as a yellow solid. Yield 3.7 g (61%). mp 181°-185° C. FDMS m/e=234 (M+ of free base).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[Cl:15][C:16]1[C:17](F)=[C:18]2[C:24]([NH2:25])=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1.C(N(C(C)C)C(C)C)C>CN1C(=O)CCC1>[NH2:25][C:24]1[C:18]2[C:19](=[N:20][CH:21]=[C:16]([Cl:15])[C:17]=2[N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)[NH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Nc1c[nH]c2ncc(Cl)c(F)c12
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(N)c23)C1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
(R)-tert-Butyl piperidin-3-ylcarbamate (1619 mg, 8.08 mmol) was added to a mixture of 5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (500 mg, 2.69 mmol; Example 8, Step D) and N-ethyl-N-isopropylpropan-2-amine (1408 μL, 8.08 mmol) in NMP (6.75 mL). N2 was bubbled through the mixture for 5 minutes, and the reaction was stirred at 120° C. under N2 for 24 hours. The mixture was allowed to cool, was diluted with 20% EtOAc/Et2O (200 mL) and washed with water (5×50 mL). The organic layer was then dried over MgSO4, filtered, and concentrated in vacuo to provide the crude (R)-tert-butyl 1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate. LCMS (APCI+) m/z 366 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:20][CH2:19][CH2:18][C:17]2[N:16]([CH2:21][CH2:22]OS(C)(=O)=O)[N:15]=[CH:14][C:13]1=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:28]#[N:29].[Na+].O>CS(C)=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@@H:12]1[CH2:20][CH2:19][CH2:18][C:17]2[N:16]([CH2:21][CH2:22][C:28]#[N:29])[N:15]=[CH:14][C:13]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCn1ncc2c1CCC[C@H]2NC(=O)OCc1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCn1ncc2c1CCC[C@H]2NC(=O)OCc1ccccc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 85.6 %

Procedure:
To a solution of methanesulfonic acid 2-((R)-4-benzyloxycarbonylamino-4,5,6,7-tetrahydroindazol-1-yl)-ethyl ester (850 mg, 2.16 mmol) in dimethyl sulfoxide (20 mL) was added sodium cyanide (540 mg, 10.8 mmol). The mixture was stirred at 55° C. for 4 hours. After cooling, the mixture was poured into water, and the aqueous layer was extracted with ethyl acetate (20 mL×4). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (10% methanol in dichloromethane) to afford [(R)-1-(2-cyano-ethyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl]-carbamic acid benzyl ester (600 mg, 85%) as a white solid. MS calcd. for C18H20N4O2 324, obsd. (ESI+) [(M+H)+] 325.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[CH:6][N:5]=[CH:4][N:3]=1.CS(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[C:40]([C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1)=[O:41]>O>[NH:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[C:40]([C:42]1[CH:47]=[CH:46][C:45]([O:48][C:2]2[C:7]([C:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=3)=[CH:6][N:5]=[CH:4][N:3]=2)=[CH:44][CH:43]=1)=[O:41]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cncnc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cncnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 100 °C

Procedure:
To a vial was added tert-butyl 4-(4-chloropyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (320 mg, 1.082 mmol), DMSO (5.4 mL), cesium carbonate (370 mg, 1.136 mmol), and (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (258 mg, 1.082 mmol) before sealing and heating to 100° C. for 45 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate before drying over magnesium sulfate, filtering, and concentrating under reduced pressure. The crude material was taken after purifying by column chromatography (10% methanol/dichloromethane), affording tert-butyl 4-(4-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate. MS (ESI, pos. ion) m/z: 498.3 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[NH:3]1.[H-].[Na+].Br[CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.Cl>O1CCCC1.CN(C)C=O>[CH3:1][C@@H:2]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[N:3]1[CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2[C@H](C)CCS2(=O)=O)cc1
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
Under a nitrogen stream, (R)-3-methylisothiazolidine 1,1-dioxide (149 mg) described in Preparation Example 2 was dissolved in a solution of tetrahydrofuran (5 mL) and N,N-dimethylformamide (4 mL), sodium hydride (44 mg) was added under ice-cooling, and the mixture was stirred at the same temperature for 15 min. Then, a solution of methyl 4-bromomethylbenzoate (229 mg) in tetrahydrofuran (5 mL) was added, and the mixture was stirred under ice-cooling for 1.5 hr, and at room temperature for 2 hr. To the reaction mixture was added 0.5N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (159 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([O:25]CC)=O)[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[O:25])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:28])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: CCO
Product: CN1CCN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)CC1
Temperature: 60 °C
Yield: 91.5 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (300 mg, 0.76 mmol) in ethanol (4 ml) was treated with 1-methylpiperazine (0.84 ml, 7.60 mmol) and the resulting mixture was heated at 60° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (98:2) gradually changing to dichloromethane methanol (95:5) to afford the title compound (312 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[C:6]=2[CH:21]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)([CH3:13])[C:6]=3[CH:21]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CN1C(=O)OC(C)(c2ccc(Cl)cc2)c2cc(N)ccc21
Product: CN1C(=O)OC(C)(c2ccc(Cl)cc2)c2cc(Nc3ccc(Br)cc3)ccc21

Procedure:
Prepared from 6-amino-4-(4-chlorophenyl)-1,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 4-bromophenyl boronic acid according to the coupling procedure described in example 1. MS (ESI) m/z [M+H]+ (457/459/461); MS (ESI) m/z [M−H]−(455/457/459); Anal. calcd for C22H18BrClN2O2: C, 57.73; H,3.96; N6.12. Found: C, 56.88; H, 3.90; N, 5.70.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.[CH3:10][Sn:11](Cl)([CH3:13])[CH3:12].[Cl-].[NH4+].O>O1CCCC1>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Sn:11]([CH3:13])([CH3:12])[CH3:10])=[CH:3][CH:2]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc([Sn](C)(C)C)cc1
Temperature: 25 °C

Procedure:
p-Tolylmagnesium bromide solution (Aldrich) (1.0M solution in diethyl ether) (53 ml, 0.0530 mol) was added dropwise to trimethyltin chloride (6.92 g, 0.0347 mol) in tetrahydrofuran (50 ml) under nitrogen at -10° C. The suspension was allowed to warm slowly to room temperature over 3 h then saturated ammonium chloride solution (10 ml) was added followed by sufficient water to dissolve the precipitate. The solution was extracted three times with diethyl ether-hexane (1:1). The combined organic phase was washed with brine, dried (magnesium sulfate) and the solvents removed in vacuo. Vacuum distillation of the residue afforded a colorless liquid (39°-40° C., 0.1 mm Hg) which was further purified by flash chromatography (silica gel, hexane) to give p-tolyltrimethyltin as a colorless liquid; 1H NMR (300 MHz, CDCl3) δ7.40 (d, J=7.7 Hz, 2H), 7.19 (d, J=7.7 Hz, 2H), 2.34 (s, 3H), 0.30 (s, 9H).