Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]Cl.[NH2:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7].O>CC(O)=O>[NH2:3][C:4]1[CH:11]=[CH:10][C:9]([I:1])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: ClI
Reactant: N#Cc1ccccc1N
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cc(I)ccc1N
Reaction time: 3 h

Procedure:
A solution of iodine monochloride (16.7 g, 0.1 mol) in glacial AcOH (30 mL) as added dropwise over 15 min to a stirred solution of 2-aminobenzonitrile (11.8 g, 0.1 mol) in glacial AcOH (125 mL) at room temperature. The mixture was stirred for 3 h and then poured into H2O (1000 mL). The resulting pinkish-brown solid was filtered, washed with H2O, and dried in vacuo. Crystallization from cyclohexane-toluene (9:1) gave 2-amino-5-iodobenzonitrile (9) as translucent plates (14.9 g, 64%): mp 85-86° C. (lit. 85-86° C.); 1H NMR (CDCl3) δ 7.60 (d, J=1.6 Hz, 1H, H-6), 7.57 (dd, J=9.2 Hz, 1.6 Hz, 1H, H-4), 6.53 (d, J=9.2 Hz, 1H, H-3), 4.45 (br s; 2H, NH2). The product was used directly in the next reaction (Step 2).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:7][CH2:8][CH2:9][C:10]3[CH:16]=[C:15]([C:17]4[N:18]([C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=5[F:29])[N:19]=[CH:20][N:21]=4)[S:14][C:11]=3[C:12]=2[N:13]=1)#[N:2].OO.C(=O)([O-])[O-:33].[K+].[K+]>O.CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:7][CH2:8][CH2:9][C:10]3[CH:16]=[C:15]([C:17]4[N:18]([C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=5[F:29])[N:19]=[CH:20][N:21]=4)[S:14][C:11]=3[C:12]=2[N:13]=1)(=[O:33])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Yield: 38 %

Procedure:
Following the procedure to prepare 379, compound 366, hydrogen peroxide, potassium carbonate in water and DMSO were reacted to give 432. Yield 38% MS: (ESI+)=426.1
Reaction SMILES: CN(C)CCN(C)C.C([Li])(CC)C.[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[F:24])[C:18]([OH:20])=[O:19].[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>O.O1CCCC1>[Cl:25][C:16]1[C:15]([F:14])=[C:23]([F:24])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc(F)c(F)c1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(F)c(F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
To a mixture of N,N,N′,N′-tetramethylethylenediamine (8.40 mL) and tetrahydrofuran (75 mL) was added sec-butyllithium (1.0 mol/L cyclohexane solution, 55.7 mL) under an argon atmosphere at −78° C., and the mixture was stirred for 30 min. A mixture of 3,4-difluorobenzoic acid (4.00 g) and tetrahydrofuran (25 mL) was added dropwise to the reaction mixture at the same temperature over 30 min. After the reaction mixture was stirred for 30 min, a mixture of hexachloroethane (24.0 g) and tetrahydrofuran (40 mL) was added dropwise to the reaction mixture at the same temperature over 30 min. After stirring for 30 min while raising the temperature to room temperature, the reaction mixture was poured into water. The aqueous layer was washed with diisopropyl ether, acidified with 6 mol/L hydrochloric acid and extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was washed with diethyl ether to give the title product as a solid (yield: 2.95 g).
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](N(CC2C=CC=CC=2)CC2C=CC=CC=2)=[S:13])=[CH:7][CH:6]=1)=[O:2].[C:29](NNC1C=CC(N)=CC=1)(=O)C.C(N1C=CN=C1)(N1C=CN=C1)=S>>[C:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[S:13])=[CH:7][CH:6]=1)(=[O:2])[CH3:29]
Reactant: O=CNNc1ccc(NC(=S)N(Cc2ccccc2)Cc2ccccc2)cc1
Reactant: CC(=O)NNc1ccc(N)cc1
Agent: S=C(n1ccnc1)n1ccnc1
Product: CC(=O)NNc1ccc(N=C=S)cc1

Procedure:
4-(2-Acetylhydrazino)phenyl isothiocyanate was prepared as described for NA-11 in Example 4 with 1-acetyl-2-(4-aminophenyl)hydrazine (1.23 g, 0.0075 mole) and 1,1'-thiocarbonyldiimidazole (1.35 g, 0.0075 mole). Yield 1.20 g (77 percent), m.p. 172°-174° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][NH:9]1.[CH3:13][C:14]1([CH3:30])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[O:15]1>>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:25]([C:24]1[CH:23]=[CH:22][C:21]([B:16]2[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:30])([CH3:13])[O:15]2)=[CH:29][CH:28]=1)=[O:26]
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1

Procedure:
The title intermediate is prepared in a manner substantially analogous General Procedure E using 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (CAS 180516-87-4). The crude product is confirmed by NMR and used without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:10]([C@@H:12]1[C@@H:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C@@H:15]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@H:14]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:34]2=[O:49])[O:13]1)[OH:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:50]([O:57][C:58]([NH:60][C@H:61]([C:73](=[O:79])[NH:74][CH2:75][CH2:76][CH:77]=O)[CH2:62][C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])=[O:59])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O1CCCC1>[CH2:66]([O:65][C:63](=[O:64])[CH2:62][C@@H:61]([C:73](=[O:79])[NH:74][CH2:75][CH2:76][CH2:77][NH:1][C@@H:2]([C@H:10]([CH:12]1[C@@H:16]([O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19])[C@@H:15]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[C@H:14]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:34]2=[O:49])[O:13]1)[OH:11])[C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])[NH:60][C:58](=[O:59])[O:57][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@H](O)[C@H](N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Reactant: O=CCCNC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](CC(=O)OCc4ccccc4)NC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 70.1 %

Procedure:
By using an analogous procedure to that described in Example 1, a solution of tert-butyl (2S,3R)-2-amino-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxypropanoate (100 mg, 0.139 mmol, obtained from Reference Example 6), benzyl (3S)-3-{[(benzyloxy)carbonyl]amino}-4-oxo-4-[(3-oxopropyl)amino]butanoate (71 mg, 0.173 mmol, obtained from Reference example 24), acetic acid (1 drop), and sodium triacetoxyborohydride (59 mg, 0.277 mmol) in anhydrous tetrahydrofuran (4 ml) was stirred under nitrogen at room temperature for 5 hours. The product was purified by chromatography (flash column, silica gel, 5% methanol in methylene chloride) to provide tert-butyl (5S,12S)-5-[2-(benzyloxy)-2-oxoethyl]-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (109 mg, 70%) as a white amorphous solid.
Reaction SMILES: C(O[C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[Cl:27])[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=O)[C@@H:18]4[CH2:28][C@@H:19]42)[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[C:6](=O)[CH3:7])(=O)C.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[Cl:27][C@@H:24]1[C@@:25]2([CH3:26])[C@@H:11]([CH2:10][CH:9]=[C:5]2[CH2:6][CH3:7])[C@H:12]2[C@@H:22]([C@:20]3([CH3:21])[C:15]([CH:14]=[CH:13]2)=[CH:16][CH2:17][C@@H:18]2[CH2:28][C@H:19]32)[CH2:23]1
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3C[C@H](Cl)[C@@]21C
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCC1=CC[C@H]2[C@@H]3C=CC4=CC[C@@H]5C[C@@H]5[C@]4(C)[C@H]3C[C@H](Cl)[C@]12C
Yield: 63.4 %

Procedure:
One gram of 17α-acetoxy-12α-chloro-1α,2α-methylene-4,6-pregnadiene-3,20-dione is treated analogously to Example 1 in "Dowtherm" for 1 hour at 280° C. and worked up. Recrystallization from isopropyl ether yields 500 mg of 12α-chloro-1α,2α-methylene-4,6,16-pregnatriene (61% of theory).
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][C:19]=2[O:30][CH3:31])=[N:15][N:14]=1.[C-:32]#[N:33].[Na+].O>CN(C=O)C>[CH3:31][O:30][C:19]1[CH:20]=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:22]=[CH:23][C:18]=1[C:16]1[O:17][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[C:32]#[N:33])=[N:14][N:15]=1
Reactant: [C-]#N
Reactant: COc1cc(N2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2Cl)o1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(N2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C#N)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a suspension of 4-{4-[5-(5-chloro-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3-methoxy-phenyl}-morpholine (145 mg, 0.33 mmol) in DMF (2 mL) was added sodium cyanide (18 mg, 0.36 mmol) and the mixture was stirred for 18 h at ambient temperature. The resulting yellow-green suspension was treated with water (15 ml) and cooled to 0° C. After stirring for 15 min at 0° C. the suspension was filtered off and washed twice with ice cold water (5 ml) affording the title compound (119 mg, 84%) which was obtained as a yellow solid. MS: m/e=430.3 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][S:5][C:6]1[CH:7]=[C:8]([N:13]2[C:21](=[O:22])[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]2=[O:23])[CH:9]=[CH:10][C:11]=1[Cl:12])([OH:3])=[O:2].[CH:24]1(O)[CH2:28][CH2:27][CH2:26][CH2:25]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH:24]1([O:2][C:1]([CH2:4][S:5][C:6]2[CH:7]=[C:8]([N:13]3[C:21](=[O:22])[C:20]4[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=4[C:14]3=[O:23])[CH:9]=[CH:10][C:11]=2[Cl:12])=[O:3])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: OC1CCCC1
Reactant: O=C(O)CSc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(CSc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl)OC1CCCC1
Yield: 44.3 %

Procedure:
2-(3-Carboxymethylthio-4-chlorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (3.61 g), cyclopentanol (1.24 g) and p-toluenesulfonic acid monohydrate (0.18 g) were suspended in toluene (10 ml), molecular sieve 3A (0.2 g) was added thereto, and the resultant mixture was heated under reflux for 6 hours. The reaction mixture was allowed to cool, admixed with water and extracted with toluene. The extract was washed with water, dried, and concentrated. The precipitated crystals were washed with methanol to give 1.91 g of 2-(3-cyclopentyloxycarbonylmethylthio-4-chlorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione. m.p., 57°-59° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[N:5][CH:4]=1.[F:23][C:24]1[CH:30]=[C:29]([CH3:31])[C:28]([OH:32])=[CH:27][C:25]=1[NH2:26]>CC(O)CCC>[ClH:2].[F:23][C:24]1[CH:30]=[C:29]([CH3:31])[C:28]([OH:32])=[CH:27][C:25]=1[NH:26][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[N:5][CH:4]=1
Reactant: COc1cc2c(Cl)cnnc2cc1OCc1ccncc1
Reactant: Cc1cc(F)c(N)cc1O
Agent: Cl
Solvent: CCCC(C)O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)cnnc2cc1OCc1ccncc1
Yield: 29.3 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(4-pyridylmethoxy)cinnoline hydrochloride (268 mg, 0.71 mmol), (prepared as described for the starting material in Example 10), and 2-fluoro-5-hydroxy-4-methylaniline, (109 mg, 0.77 mmol), (prepared as described for the starting material in Example 11), in 2-pentanol (6 ml) was heated at reflux for 4 hours. After dilution with isopropanol the solid was filtered off, washed with isopropanol followed by ether to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylmethoxy)cinnoline hydrochloride (92 mg, 29%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH2:19]([O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO.C(Cl)Cl>[CH2:19]([O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:29][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
Following General Procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylalanine benzyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=170-171 ° C.). The reaction was monitored by tlc (Rf=0.7 in 5% MeOH/methylene chloride) and the product was purified by recrystallization from MeOH.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[CH:9]=O.[CH3:14][C:15]([CH3:17])=[O:16]>O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:9]=[CH:14][C:15](=[O:16])[CH3:17])[CH:11]=1
Reactant: COc1ccc(Cl)cc1C=O
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(Cl)cc1C=CC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In water (100 ml) was dissolved sodium hydroxide (3.0 g), and to the solution was added acetone (80 ml) and then was added dropwise a solution of 5-chloro-2-methoxybenzaldehyde (11.8 g) in acetone (30 ml). The reaction solution was stirred at room temperature for 2 hours, and acetone was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to give 4-(5-chloro-2-methoxyphenyl)-3-buten-2-one (6.8 g).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)=[N:5]2.C(N(CC)CC)C.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])=[CH:13][CH:12]=1)=[N:5]2
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(Oc2ccc3nccn3n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)Nc1ccc(Oc2ccc3nccn3n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
To a solution of 4-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (181 mg, 0.80 mmol) and triethylamine (0.011 mL, 0.08 mmol) in tetrahydrofuran (10 mL) was added phenyl isocyanate (0.104 mL, 0.96 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/methanol=100/0→90/10) and precipitated from ethyl acetate to give the title compound (223 mg, 81%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C@@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19]>>[C:18]([C@@H:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Br:1])=[CH:7][N:6]=1)=[O:10])[CH2:21][CH:22]([CH3:24])[CH3:23])(=[O:19])[NH2:20]
Reactant: O=C(O)c1cc(OCC2CC2)c(Br)cn1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1cc(OCC2CC2)c(Br)cn1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-bromo-4-(cyclopropylmethoxy)picolinic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials and isolated (16 mg, 47%) as yellow oil; MS (ESI, m/z): 385.9 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:8][N:7]=1)=[O:5])[CH3:2].[C:25]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]([CH3:25])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccccc2OCc2ccccc2)[nH]n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccccc2OCc2ccccc2)n(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of 5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (0.25 g, 0.00078 mole) in DMF (5 mL) was added K2CO3 (0.225 g, 0.00163 mole) followed by methyl iodide (0.116 g, 0.00081 mole) and at the resulting mixture was stirred at ambient temperature for 1 hour. The mixture was then quenched with iced water and the resulting precipitate was isolated by filtration. The solid was recrystallized from ethyl acetate to afford 0.251 g (96%) of 5-(2-benzyloxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 337.15 (M+1)+, 90.13%. To a stirred solution of 5-(2-benzyloxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (0.251 g, 0.00075 mole) in methanol (40 mL) was added 10% Pd/C (0.05 g) and the resulting mixture was stirred under an atmosphere of hydrogen for 1 hour. The mixture was then filtered through celite and the celite was washed with methanol. The combined filtrate was concentrated under reduced pressure to afford 0.169 g (92%) of 5-(2-hydroxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 247.1 (M+1)+, 99%. To a stirred solution of 5-(2-hydroxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (0.169 g, 0.00069 mol) in a mixture of THF (10 mL), methanol (5 mL) and H2O (5 mL), was added LiOH.H2O (0.087 g, 0.00206 mol) at ambient temperature and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and acidified with 10% HCl. The product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford 0.13 g (87%) of 5-(2-hydroxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid. LCMS: 219.07 (M+1)+, 81.5%
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:60][CH2:61][C:62]1[CH:63]=[C:64]([CH:69]=[C:70]([O:72][CH3:73])[CH:71]=1)[C:65]([O:67][CH3:68])=[O:66]>ClCCl>[CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([NH:60][CH2:61][C:62]3[CH:63]=[C:64]([CH:69]=[C:70]([O:72][CH3:73])[CH:71]=3)[C:65]([O:67][CH3:68])=[O:66])=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2]
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Reactant: COC(=O)c1cc(CN)cc(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cc(OC)cc(C(=O)OC)c3)cn2)C1
Reaction time: 0.17 h
Yield: 87 %

Procedure:
To a suspension of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (50 mg, 0.14 mmol) and HATU (63 mg, 0.17 mmol) in dry dichloromethane (3 mL) was added N,N-diisopropylethylamine (0.075 mL, 0.42 mmol) at 20-25° C. The mixture was stirred for 10 min, then methyl 3-(aminomethyl)-5-methoxybenzoate hydrochloride was added (33 mg, 0.14 mmol) at 20-25° C. The reaction mixture was stirred at 20-25° C. for 1 hour. The mixture was concentrated under reduced pressure and the resulting residue was dissolved in ethyl acetate (10 mL), washed with water (2 times with 10 mL), and dried over NaSO4. The organics were concentrated under reduced pressure to obtain methyl (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-5-methoxybenzoate (65 mg, 87%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4cccc(F)c4)C3)nc(N)n2)cc1F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC[C@H](C(=O)Nc3cccc(F)c3)C2)n1
Temperature: 150 °C
Yield: 70.3 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(3-fluorophenyl)-3-piperidinecarboxamide (90 mg, 0.207 mmol), 3 mL of EtOH, Hunig's base (0.109 mL, 0.621 mmol), and hydrazine anhydrous (0.026 mL, 0.829 mmol) were added, and the yellow mixture was heated at 150° C. for 150 minutes under microwave conditions. The solution turned into black. LCMS showed mainly product. The black solids were filtered and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH, and purified by HPLC (CH3CN/H2O w/0.1% HCO2H) to afford a formic acid salt of the title compound (65 mg) as a light yellow solid. LC-MS (ES) m/z=447 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.35-1.44 (m, 1H), 1.69 (m, 1H), 1.91-2.11 (m, 2H), 2.12-2.27 (m, 1H), 2.61-2.78 (m, 1H), 3.39-3.80 (m, 1H), 4.24-4.41 (m, 1H), 4.68-5.17 (m, 1H), 6.85 (m, 2H), 7.22-7.47 (m, 3H), 7.51-7.60 (m, 1H), 7.79 (m, 1H), 7.89-8.01 (m, 1H).
Reaction SMILES: C(S)C.[H-].[Na+].[OH:6][C:7]1[C:12]2[C:13]([CH3:25])=[C:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=3)[O:15][C:11]=2[CH:10]=[CH:9][C:8]=1[CH2:26][CH2:27][CH3:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[OH:6][C:7]1[C:12]2[C:13]([CH3:25])=[C:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[O:15][C:11]=2[CH:10]=[CH:9][C:8]=1[CH2:26][CH2:27][CH3:28]
Reactant: CCCc1ccc2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: CCCc1ccc2oc(Cc3ccc(O)cc3)c(C)c2c1O
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
Under nitrogen atmosphere, ethanethiol (4.9 g; 80 mmoles) was added dropwise over 5 minutes to a mixture of 99% sodium hydride (1.9 g; 80 mmoles) in dimethylformamide (100 ml). After stirring for 15 minutes, a solution of 4-hydroxy-2-(4-methoxybenzyl)-3-methyl-5-propylbenzofuran (2.4 g; 8 mmoles) in dimethylformamide (5 ml) was added in one portion. The mixture was refluxed for 2 hours, cooled, acidified with 20% citric acid solution and extracted with ether. The ether solution was washed with water, dried (Na2SO4), filtered, concentrated, and chromatographed to obtain 2.2 g of the title compound as an oil which crystallized from an ether-hexane mixture.