Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].N1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]3[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:23]=3[O:22][C:21]([CH3:31])([CH3:30])[N:20]=2)=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:24]3[CH:25]=[CH:26][C:27]([NH:29][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:28][C:23]=3[O:22][C:21]([CH3:31])([CH3:30])[N:20]=2)=[CH:17][CH:18]=1
Reactant: CC1(C)N=C(c2ccc(Cl)cc2)c2ccc(N)cc2O1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC1(C)N=C(c2ccc(Cl)cc2)c2ccc(NS(C)(=O)=O)cc2O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methanesulfonyl chloride (55 μL) and pyridine (85 μL) were added dropwise to a solution of 4-(4-chlorophenyl)-2.2-dimethyl-2H-1,3-benzoxazin-7-ylamine (a compound of Reference Example 1, 101 mg) in chloroform (8 mL) and said mixture was stirred at room temperature for 2 days. The reaction solution was purified by column chromatography on silica gel (Chromatorex NH-silica gel, FUJI SILYSIA CHEMICAL LTD., Solvent: chloroform/methanol=100/0 to 90/10) and the obtained powder was suspended in diisopropyl ether. The resultant precipitates were collected by filtration and washed with diisopropyl ether to give the titled compound (112 mg) as a colorless powder.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[O:9]=[C:10]1[NH:18][CH:17]=[N:16][C:15]2[N:14]([CH2:19][CH2:20][C:21](OCC)=[O:22])[CH:13]=[N:12][C:11]1=2>C(#N)C>[O:9]=[C:10]1[NH:18][CH:17]=[N:16][C:15]2[N:14]([CH2:19][CH2:20][C:21]([NH:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:22])[CH:13]=[N:12][C:11]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: CCN(CC)CCN
Solvent: CC#N
Product: CCN(CC)CCNC(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
0.500 g (4.30 mmol) of N,N-diethylethylenediamine was placed into a 10 ml round bottom flask equipped with a magnetic stirring bar. The amine was heated to 110° C. and 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was added to the stirring solution. The solution was heated for one hour at 110° C. and was allowed to cool to room temperature. 10 ml of acetonitrile was added and the solution was stirred for 15 minutes. The white precipitate was obtained by filtration and was washed with acetonitrile and then with ether. Upon drying, 195 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[2-(diethylamino)ethyl]propanamide (AIT-0064) as a white solid was obtained. Yield: 60%.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[N:11]1([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CCOC(=O)CCc1ccc(CCN2CCN(Cc3ccccc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(CCN2CCNCC2)cc1

Procedure:
A mixture of 57 g. (0.126 mole) ethyl 3-{4-[2-(1-benzylpiperazin-4-yl)-ethyl]-phenyl}-propionate and 200 ml. ethanol is hydrogenated, with the addition of 10% palladium-charcoal, at 50° C. and 50 bar hydrogen pressure in a shaking autoclave, then allowed to cool and filtered. After evaporation, the residue is dissolved in diethyl ether. The dihydrochloride is now precipitated out by adding hydrogen chloride-containing diethyl ether. The dihydrochloride is triturated with ethanol and filtered off with suction. Yield 31.0 g. (68% of theory) ethyl 3-{4-[2-(piperazin-1-yl)-ethyl]-phenyl}-propionate dihydrochloride; m.p. 243°-244° C.
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].O[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH3:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[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][CH:28]=[C:29]([CH3:32])[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: Cc1ccc2ncnc(O)c2c1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Product: Cc1ccc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2c1

Procedure:
The title compound was prepared using 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (83 mg, 0.3 mmol) and 4-hydroxy-6-methylquinazoline from the previous step (53 mg, 0.3 mmol) according to the procedure described in Example 1B Step 1 to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methylquinazolin-4-yloxy)phenyl)urea.
Reaction SMILES: [I:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)C=[CH:4][CH:3]=1.C=O.[ClH:14].P(=O)(O)(O)O.[C:20](O)(=O)[CH3:21]>O>[I:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:20]([CH2:21][Cl:14])=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Ic1cccc2ccccc12
Reactant: Cl
Agent: C=O
Agent: O=P(O)(O)O
Solvent: O
Product: ClCc1ccc(I)c2ccccc12

Procedure:
A mixture of 17.8 g of 1-iodo-naphthalene, 4.4 g of paraformaldehyde, 10.4 ml of acetic acid, 14.6 ml of concentrated hydrochloric acid and 6.6 ml of phosphoric acid was stirred at 80° to 85° C. and thereto another 20 ml of concentrated hydrochloric acid was added with stirring 8 times at intervals of 1 hour. The reaction mixture was poured into water and was extracted with benzene. After distilling away benzene, 18.5 g of 4-iodo-1-chloromethylnaphthalene was obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[C:15]1=[O:37])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[C:15]1=[O:37])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=c1c2cc(F)c(Cl)nc2n(-c2cccc(C(F)(F)F)c2)c(=O)n1OCc1ccccc1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2cccc(C(F)(F)F)c2)c(=O)n1OCc1ccccc1
Yield: 76.1 %

Procedure:
Using the method of Example N-4, pyrrolidine (0.04 mL, 0.52 mmol), 3-benzyloxy-7-chloro-6-fluoro-1-(3-trifluoromethylphenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example V-2, 0.19 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) were combined in 20 mL of acetonitrile to give 0.16 g of the title compound as a solid, mp>250° C.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[CH2:15]([O:22][C:23]([NH:25][CH2:26][CH2:27][S:28][CH2:29][CH2:30][C@@H:31]([C:33]([N:35]1[CH2:42][CH2:41][CH2:40][C@H:36]1[C:37]([OH:39])=[O:38])=[O:34])[NH2:32])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:23]([NH:25][CH2:26][CH2:27][S:28][CH2:29][CH2:30][C@@H:31]([C:33]([N:35]1[CH2:42][CH2:41][CH2:40][C@H:36]1[C:37]([OH:39])=[O:38])=[O:34])[NH:32][CH:2]([C:3]([OH:5])=[O:4])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)C(=O)CCc1ccc(Cl)cc1
Reactant: N[C@@H](CCSCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Product: O=C(NCCSCC[C@H](NC(CCc1ccc(Cl)cc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O)OCc1ccccc1

Procedure:
In the manner described in Examples 3, 5 and 6, 2-oxo-4-(4-chlorophenyl)butyric acid and N-[S-(2-benzyloxycarbonylaminoethyl)-L-homocysteinyl]-L-proline were condensed to afford N-[S-(2-benzyloxycarbonylaminoethyl)-N-{1-carboxy-3-(4-chlorophenyl)propyl}-L-homocysteinyl]-L-proline. This reaction was followed by the removal of the carbobenzoxy group with 30-32% HBr in glacial acetic acid to give N-[S-(2-aminoethyl)-N-{1-carboxy-3-(4-chlorophenyl)propyl}-L-homocysteinyl]-L-proline in 67% yield; a white solid on freeze drying; ms (trimethylsilyl): 672 (M+3TMS-15), 600 (M+2TMS-15), 570 (M+2TMS-CO2H), 498 (M+1TMS-CO2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[S:11]1[CH:15]=[CH:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:19]([CH:20]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:21]([O:23][C@@H:24]3[CH:29]4[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]4)[CH2:25]3)=[O:22])[C:12]1=2>CCOC(C)=O>[Cl-:1].[S:11]1[CH:15]=[CH:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:19]([CH:20]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:21]([O:23][C@@H:24]3[CH:29]4[CH2:28][CH2:27][N+:26]([CH2:2][C:3](=[O:4])[C:5]5[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=5)([CH2:31][CH2:30]4)[CH2:25]3)=[O:22])[C:12]1=2
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1cccc2ccsc12
Reactant: O=C(CCl)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(Nc1ccccc1)c1cccc3ccsc13)C2)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.1 %

Procedure:
2-Chloro-1-phenylethanone (35.4 mg, 0.23 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-7-yl)-2-(phenylamino)acetate (C27) (90 mg, 0.23 mmol) in EtOAc (3 ml). The reaction was stirred at room temperature overnight. The solvent was removed under vacuum and the crude was triturated with Et2O. The compound was purified by preparative HPLC (Eluent: CH3CN/H2O) to obtain (3R)-3-(2-(benzo[b]thiophen-7-yl)-2-(phenylamino)acetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane chloride (26.6 mg, 21.2% yield).
Reaction SMILES: [Cl-:1].[C:2]([C:5]1[CH:10]=[CH:9][N+:8]([C:11]2[CH:16]=[CH:15][C:14]([N+]([O-])=O)=[CH:13][C:12]=2[N+]([O-])=O)=[CH:7][CH:6]=1)(=[O:4])[NH2:3].[Cl:23]C1C=CC=CC=1N>CO>[Cl-:23].[C:2]([C:5]1[CH:6]=[CH:7][N+:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[Cl:1])=[CH:9][CH:10]=1)(=[O:4])[NH2:3]
Reactant: Nc1ccccc1Cl
Reactant: NC(=O)c1cc[n+](-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: [Cl-]
Solvent: CO
Product: NC(=O)c1cc[n+](-c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.7 %

Procedure:
A mixture of 4-carbamoyl-1-(2,4-dinitrophenyl)-pyridinium chloride (41 g) and 2-chloroaniline (20 g) in methanol (500 ml) was stirred at ambient temperature for 24 hours. The mixture was then heated under reflux for 24 hours and then a further portion of 2-chloroaniline (10 g) was added. Heating under reflux was continued for a further 48 hours then another portion of 2-chloroaniline (10 g) was added. The mixture was heated for a further 48 hours, then cooled and the solvent removed in vacuo. The residue was triturated with hot acetone (2×11), cooled and the solid collected by filtration. The solid was dissolved in hot methanol (100 ml), treated with charcoal and hot filtered. Hot ethyl acetate (500 ml) was added to the filtrate and the solution was allowed to cool. The resulting solid was collected by filtration, washed with ethyl acetate and dried to give crude 4-carbamoyl-1-(2-chlorophenyl)-pyridinium chloride (23.69 g) which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9](O)=O)=[CH:5][CH:4]=1)#[N:2].[NH2:14][C:15]1[C:20]([NH:21][CH3:22])=[CH:19][CH:18]=[C:17]([CH3:23])[N:16]=1>O1CCCC1>[CH3:22][N:21]1[C:20]2[C:15](=[N:16][C:17]([CH3:23])=[CH:18][CH:19]=2)[N:14]=[C:9]1[CH2:8][O:7][C:6]1[CH:12]=[CH:13][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(OCC(=O)O)cc1
Reactant: CNc1ccc(C)nc1N
Solvent: C1CCOC1
Product: Cc1ccc2c(n1)nc(COc1ccc(C#N)cc1)n2C
Reaction time: 0.25 h

Procedure:
11.4 g (63 mmol) of 4-cyanophenoxyacetic acid were dissolved in 200 mL of absolute tetrahydrofuran and mixed at room temperature with 10.2 g (63 mmol) of N,N′-carbonyldiimidazole. After 15 minutes at 60° C., 5.70 g (41.5 mmol) of 2-amino-3-methylamino-6-methylpyridine were added. After 2 hours at 60° C., the solvent was distilled off and the crystalline residue was mixed with water, washed with water, and dried. After crystallization from ethanol, 9.95 g (91% of theory) were obtained in the form of white crystals. C16H14N4O (278.32). Mass spectrum: M+=278.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[C:8]([O:12][C:13]([NH:15][OH:16])=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([O:16][NH:15][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])=[O:4]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)OC(=O)NOC(=O)C(C)(C)C

Procedure:
[(tert-Butoxy)carbonyl]amino 2,2-dimethylpropanoate is prepared from trimethyl acetyl chloride and N-tert-butoxycarbonyl hydroxylamine according to Scheme 1 described by Carpino et al. J. Am. Chem. Soc. 1959, 955-957. (6.4 g, 78%), 1H NMR (250 MHz, DMSO-d6) δ ppm 10.46 (1H, br. s.), 1.40 (9H, s), 1.20 (9H, s).
Reaction SMILES: O[C:2]1([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.S(Cl)(C)(=O)=O>C(Cl)Cl>[O:6]1[C:5]2([CH2:10][CH2:11][C:2]([C:12]3[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=3)=[CH:3][CH2:4]2)[O:9][CH2:8][CH2:7]1
Reactant: N#Cc1ccc(C2(O)CCC3(CC2)OCCO3)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C2=CCC3(CC2)OCCO3)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To a solution of 4-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)benzonitrile (7.8 g) in methylene chloride (100 mL) was added triethylamine (21 mL) at room temperature. The solution was cooled down to −40° C. and then mesyl chloride (4.7 mL) was added dropwise. The reaction mixture was stirred at −40° C. for 30 min, then warmed up to room temperature gradually and continuously stirred overnight. The reaction was quenched with sat. aqueous NaHCO3 solution. The aqueous layer was extracted with methylene chloride. The combined organic extracts were washed with brine, dried with Na2SO4, then evaporated. The residue was purified by column (Hex/EtOAc=5/1) to give the product 5.2 g as a white solid (yield: 71%): 1H NMR (CDCl3) δ 7.62-7.55 (2H, m), 7.50-7.45 (2H, m), 6.17-6.13 (1H, m), 4.02 (4H, s), 2.68-2.62 (2H, m), 2.53-2.47 (2H, m), 1.96-1,92 (2H, m); MS: 242 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([NH:29][C:30]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[O:31])[C:24]=4[Cl:28])[CH:19]=3)(=[O:17])=[O:16])[C:10]2=[O:40])[CH:4]=1)#[N:2].Br[CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>>[C:46]([O:45][C:43](=[O:44])[CH2:42][N:14]([C@H:11]1[CH2:12][CH2:13][N:9]([CH2:8][C:5]2[CH:4]=[C:3]([C:1]#[N:2])[S:7][CH:6]=2)[C:10]1=[O:40])[S:15]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:29][C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[C:24]=2[Cl:28])[CH:19]=1)(=[O:17])=[O:16])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1cc(CN2CC[C@H](NS(=O)(=O)c3ccc4c(Cl)c(NC(=O)OCc5ccccc5)ccc4c3)C2=O)cs1
Product: CC(C)(C)OC(=O)CN([C@H]1CCN(Cc2csc(C#N)c2)C1=O)S(=O)(=O)c1ccc2c(Cl)c(NC(=O)OCc3ccccc3)ccc2c1

Procedure:
The title compound is prepared from N-Cbz-6-amino-5-chloro-naphthalene-2-sulfonic acid-[1-(5-cyanothiophen-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide as described in EXAMPLE 141, Part D using tert-butyl bromoacetate in place of benzyl bromide. The crude product is purified by column chromatography eluting with a gradient of 5% EtOAc/CH2Cl2 to 10% EtOAc/CH2Cl2 to provide the title compound as a solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][C:5]([C:13]#[C:14][Si](C)(C)C)=[N:4]1)[CH3:2]>CO.[OH-].[Na+].C(OCC)(=O)C>[CH2:1]([N:3]1[C:7]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][C:5]([C:13]#[CH:14])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C#C[Si](C)(C)C)nc1N1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1nc(N2CCCC2)n(CC)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
A mixture of 1-ethyl-5-(pyrrolidin-1-yl)-3-((trimethylsilyl)ethynyl)-1H-1,2,4-triazole (122 mg, 465 μmol, Eq: 1.00) in methanol (3 ml) and 1N NaOH aq. (0.1 ml) was stirred for 18 hours at 25° C. under argon atmosphere. The mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated affording 1-ethyl-3-ethynyl-5-pyrrolidin-1-yl-1H-[1,2,4]triazole (79 mg, 89.3%) as an orange oil. MS: m/z=191.2 (M+H+)
Reaction SMILES: [CH3:1][C:2]([CH3:21])([S:4]([NH:6][C:7]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17]C(=O)C)=[CH:13][CH:12]=2)[CH2:10][O:9][CH2:8]1)=[O:5])[CH3:3].O>C(OCC)(=O)C>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([C:7]2([NH:6][S:4]([C:2]([CH3:21])([CH3:3])[CH3:1])=[O:5])[CH2:8][O:9][CH2:10]2)=[CH:16][CH:15]=1
Reactant: CC(=O)Nc1ccc(C2(NS(=O)C(C)(C)C)COC2)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)S(=O)NC1(c2ccc(N)cc2)COC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Claisen's alkali (potassium hydroxide, 12.7 g in 9 ml water and 33 ml methanol) was added to N-(4-(3-(1,1-dimethylethylsulfinamido)oxetan-3-yl)phenyl)acetamide (300 mg, 0.966 mmol) and the reaction was stirred at 90° C. for 2 hours. The mixture was cooled to room temperature when water and ethyl acetate were added. The aqueous layer was extracted twice with ethyl acetate and the combined organics were dried with magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by regular phase flash column chromatography to give the title compound.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[N:3]1.[CH3:8][N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11]>>[Br:7][C:4]1[CH:5]=[CH:6][N:2]([O:1][C:10](=[O:11])[N:9]([CH3:8])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: On1ccc(Br)n1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)On1ccc(Br)n1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-3-bromopyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (63%, oil).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[N:27]3[CH2:30][C:29](C(OCC)=O)([C:31]([O:33]CC)=[O:32])[CH2:28]3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]>CO.[OH-].[Na+]>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[N:27]3[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CN([C@@H]2CCc3c(-c4noc(-c5ccc(OC(C)C)c(C#N)c5)n4)cccc32)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N3CC(C(=O)O)C3)no2)cc1C#N
Temperature: 50 °C
Reaction time: 15 h
Yield: 33.1 %

Procedure:
To a stirred solution of crude (R)-diethyl 1-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3,3-dicarboxylate (93 mg, 0.17 mmol) in MeOH (2 mL) was added 6 N NaOH (5 drops). The resulting solution was heated to 50° C. in a closed vial. After 24 h the solution was concentrated, dissolved in water, neutralized with 1N HCl, and heated at 100° C. After 15 h, additional 1N HCl was added, and the mixture was stirred at 105° C. for 24 h. The mixture was diluted with water and extracted with DCM and EA. The organic layers were combined, dried over Na2SO4, and purified by preparative HPLC to provide 25 mg (33%) of (R)-1-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid 202. LCMS-ESI (m/z) calculated for C25H24N4O4: 444.5; found 445.2 [M+H]+, tR=2.55 min. Compound 203 was made in an analogous fashion.
Reaction SMILES: C([Sn](CCCC)=O)CCC.[Cl:11][C:12]1[CH:13]=[C:14]2[C:20]([C:21]3[N:26]=[C:25]([NH:27][C@H:28]4[CH2:33][CH2:32][CH2:31][C@@H:30]([C:34]#[N:35])[CH2:29]4)[C:24]([F:36])=[CH:23][N:22]=3)=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1.[N:37]([Si](C)(C)C)=[N+:38]=[N-:39]>C1(C)C=CC=CC=1>[NH:37]1[C:34]([C@@H:30]2[CH2:31][CH2:32][CH2:33][C@H:28]([NH:27][C:25]3[C:24]([F:36])=[CH:23][N:22]=[C:21]([C:20]4[C:14]5[C:15](=[N:16][CH:17]=[C:12]([Cl:11])[CH:13]=5)[NH:18][CH:19]=4)[N:26]=3)[CH2:29]2)=[N:35][N:39]=[N:38]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#C[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1N[C@H]1CCC[C@@H](c2nnn[nH]2)C1
Temperature: 120 °C
Yield: 99.4 %

Procedure:
A suspension of dibutyl(oxo)tin (0.016 g, 0.064 mmol) and (1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexane-carbonitrile (54c) (0.043 g, 0.107 mmol) in toluene (3 mL) was treated with azido(trimethyl)silane (0.200 mL, 1.507 mmol). The mixture was heated in a sealed tube at 120° C. overnight. The mixture was absorbed onto silica-gel and purified by silica gel chromatography (25-50% gradient of 20% MeOH:DCM containing 0.5% AcOH modifier). The combined fractions were concentrated to dryness to give a residue that was triturated with ether then dried under vacuum at 45° C. to afford 44 mg of a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([CH2:16][CH2:17][OH:18])[C:8]=23)=[C:4]([F:21])[CH:3]=1.Cl[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:26]=[C:25]([NH2:33])[N:24]=1.Cl.[OH-].[Na+]>O>[NH2:33][C:25]1[N:24]=[C:23]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[NH:13][CH:14]=[C:15]([CH2:16][CH2:17][OH:18])[C:8]=34)=[C:4]([F:21])[CH:3]=2)[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[N:26]=1
Reactant: Nc1ccc(Oc2ccnc3[nH]cc(CCO)c23)c(F)c1
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(Nc2ccc(Oc3ccnc4[nH]cc(CCO)c34)c(F)c2)cc(C(F)(F)F)n1

Procedure:
130 mg (0.45 mmol) of 2-[4-(4-amino-2-fluorophenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]ethanol and 107 mg (0.54 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are suspended in 6 ml of water. 0.6 ml (0.6 mmol) of 1N hydrochloric acid is added and the mixture is heated at reflux overnight. Using 1N aqueous sodium hydroxide solution, the suspension is adjusted to pH 10, resulting in the precipitation of crystals. The crystals are filtered off with suction, washed with water and purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol (7N ammonia) 100:1 to 100:3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@@H:14]([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[O:19]1[CH2:24][CH2:23][CH2:22][C:21](=O)[CH2:20]1>>[F:15][C@H:14]1[CH2:13][O:12][CH2:11][C:10]([NH2:16])=[N:9][C@@:8]1([C:6]1[CH:7]=[C:2]([NH:1][CH:21]2[CH2:22][CH2:23][CH2:24][O:19][CH2:20]2)[CH:3]=[CH:4][C:5]=1[F:18])[CH3:17]
Reactant: O=C1CCCOC1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COC[C@@H]1F
Product: C[C@]1(c2cc(NC3CCCOC3)ccc2F)N=C(N)COC[C@@H]1F
Yield: 49.6 %

Procedure:
In an analogous manner as described for example 1 the reductive amination of (5R,6R)-5-(5-amino-2-fluoro-phenyl)-6-fluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-ylamine (intermediate A10B) (20 mg, 78.4 μmol) and dihydro-2H-pyran-3(4H)-one (CAS [23462-75-1]) (8.63 mg, 86.2 μmol) yielded the title compound (13.2 mg, 49.6%) as a colorless solid. MS (ISP): m/z=340.2 [M+H]+.