Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([C:13]([NH2:15])=[O:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S(O[CH2:26][CH2:27][Cl:28])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:28][CH2:27][CH2:26][O:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([C:13]([NH2:15])=[O:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: NC(=O)c1ccc(-c2cccc(O)c2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1ccc(-c2cccc(OCCCl)c2)s1

Procedure:
5-(3-Hydroxyphenyl)-2-thiophenecarboxamide (0.31 g, 1.41 mmol), 2-chloroethyl p-toluenesulfonate (1.327 g, 5.65 mmol) and potassium carbonate (0.782 g, 5.65 mmol) in 20 ml of acetonitrile were heated to reflux for 15 h. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (50 to 80% ethyl acetate in hexanes) to give the title compound as a white solid.
Reaction SMILES: [O:1]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1[S:13](Cl)(=[O:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[Br:24]>>[Br:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[NH:17][S:13]([C:9]1[S:10][CH:11]=[CH:12][C:8]=1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:15])=[O:14]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1sccc1Oc1ccccc1
Product: Cc1noc(NS(=O)(=O)c2sccc2Oc2ccccc2)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenoxythiophene-2-sulfonamide was prepared from 3-phenoxythiophene-2-sulfonyl chloride and 5-amino-4-bromo-3-methylisoxazole using the method described in Example 1. The product was recrystallized from acetonitrile/H2O to give a solid m.p. 121°-123° C., 61% yield.
Reaction SMILES: [NH2:1][CH:2]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4].C(OC(C=C([NH:36][CH2:37][C:38]([O-])=[O:39])C)=O)C.[Na+].[K+].[Br-]>>[NH2:36][CH2:37][C:38]([NH:1][CH:2]([C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)[C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:12])([CH3:13])[S:11][C@H:7]12)=[O:4])=[O:39]
Reactant: CC1(C)S[C@@H]2C(NC(=O)C(N)c3ccc(O)cc3)C(=O)N2C1c1nnn[nH]1
Reactant: CCOC(=O)C=C(C)NCC(=O)[O-]
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Product: CC1(C)S[C@@H]2C(NC(=O)C(NC(=O)CN)c3ccc(O)cc3)C(=O)N2C1c1nnn[nH]1
Yield: 45 %

Procedure:
The title compound is prepared in 45% yield from 6-(2-amino-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam and sodium N-(2-ethoxycarbonyl-1-methylvinyl)-2-aminoacetate, using the procedure of Example XC. The product has m.p. 173°-188° C. (dec.). IR (KBr disc): 1785 cm-1 (β-lactam). NMR (DMSO-d6): 7.55-7.10 ppm (m, 2H), 7.00-6.00 ppm (m, 2H), 5.75-5.40 ppm (m, 3H), 5.10 ppm (s, 1H), 3.65 ppm (m, 2H), 1.55 ppm (s, 3H), 0.95 ppm (s, 3H).
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH:14]=[C:15]3[S:21][CH3:22])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:24])[CH:4]=[CH:5][C:6](=[O:23])[CH:7]=1.[C:25]1([CH3:33])[CH:30]=[CH:29][C:28]([S:31]Cl)=[CH:27][CH:26]=1>ClCCl>[F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][C:14]([S:31][C:28]4[CH:29]=[CH:30][C:25]([CH3:33])=[CH:26][CH:27]=4)=[C:15]3[S:21][CH3:22])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:24])[CH:4]=[CH:5][C:6](=[O:23])[CH:7]=1
Reactant: CSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Reactant: Cc1ccc(SCl)cc1
Solvent: ClCCl
Product: CSC1=C(Sc2ccc(C)cc2)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Yield: 106.9 %

Procedure:
A solution of 900 mg of 9-fluoro-11β-hydroxy-17-(methylthio)androsta-1,4,16-trien-3-one in 900 ml of dichloromethane is stirred with 500 mg of p-toluenesulfenyl chloride at room temperature under a nitrogen atmosphere for about 16 hours. The resulting solution is washed with water, dried over anhydrous Na2SO4 and evaporated in vacuo to give 1.3 g of a solid, which is dissolved in chloroform-hexane (3:2) and chromatographed on a 50 g-silica gel column. Elution with chloroform-hexane (3:2) gives 930 mg of a tlc-homogenous material. Two crystallizations from acetone-hexane give 400 mg of an analytical specimen of the title compound, melting point 205°-206° C.
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].C(N(CC)CC)C.C[Si](Cl)(C)C.[C:19](Cl)(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[C:19]([NH:1][CH:2]([CH3:3])[C:4]([OH:6])=[O:5])(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCC(=O)Cl
Reactant: CC(N)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: CCCCCC(=O)NC(C)C(=O)O

Procedure:
The preparation is carried out analogously to the procedure of Example 4A using 16.5 g (0.185 mol) of D,L-alanine, 41.23 g (0.407 mol) of triethylamine, 44.27 g (0.407 mol) of trimethylsilyl chloride and 24.93 g (0.185 mol) of hexanoyl chloride. The product crystallizes from toluene/n-hexane.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH:8]([CH3:15])[N:7]([CH:16]3[CH2:18][CH2:17]3)[C:6]=2[N:19]=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=1[O:30][CH3:31].C(O)C>Cl.O>[CH:16]1([N:7]2[CH:8]([CH3:15])[CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:6]2=3)[CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CC1C(=O)N(C)c2cnc(Cl)nc2N(C2CC2)C1C
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CC1)C(C)C(C)C(=O)N2C
Yield: 70.5 %

Procedure:
A mixture of 0.14 g (0.0005 mole) of (rac)-2-chloro-9-cyclopropyl-5,7,8-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-46), 0.10 g (0.0006 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.145 g of (rac)-4-(9-cyclopropyl-5,7,8-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-46a) as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:22])[CH:28]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2nc3cc(-c4cccc(Cl)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3-chlorophenylboronic acid (134 mg, 0.86 mmol) the subtitle compound was obtained, (72 mg, 33%). 1H NMR (DMSO) δ 8.71(d, 1H), 8.53(dd, 1H), 8.19(d, 1H), 7.95(d, 1H), 7.88(t, 1H), 7.83(dd, 1H), 7.79(d, 1H), 7.70(d, 1H), 7.58(t, 1H), 7.52(d, 1H), 4.12(s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[C:16]([Si:20]([CH3:45])([CH3:44])[O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1/[CH:32]=[C:33](/[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=1[F:43])\[C:34]#[N:35])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:32]([C:26]2[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=2[O:24][CH2:23][CH2:22][O:21][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:45])[CH3:44])[C:33]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=2[F:43])([C:34]#[N:35])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)cc1/C=C(\C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cc(Cl)ccc2OCCO[Si](C)(C)C(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Yield: 18.4 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl}-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (3.7 g, 8 mmol) prepared in Example 84a, AgF (1.0 g, 8 mmol), and triethylamine (2.8 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl}-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.0 g, 18%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:18]=3[N:14]2[CH2:13][CH2:12][C:11](=[O:28])[NH:10]1.[H-].[Na+].[CH3:31]I>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:18]=3[N:14]2[CH2:13][CH2:12][C:11](=[O:28])[N:10]1[CH3:31]
Reactant: CCN(CC)c1cccc2nc3n(c12)CCC(=O)NC3c1ccc(Cl)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)c1cccc2nc3n(c12)CCC(=O)N(C)C3c1ccc(Cl)cc1Cl
Reaction time: 0.25 h
Yield: 5.8 %

Procedure:
To a stirred solution of 1-(2,4-dichlorophenyl)-7-(diethylamino)-1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,2-a]benzimidazol-3-one (83.5 mg, 0.200 mmol) in dimethylformamide (1 mL) was added sodium hydride (60%, 20.0 mg, 0.500 mmol) at room temperature. After 15 min, methyl iodide (62.3 μL, 1.00 mmol) was added. After 1 h, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-50% ethyl acetate/n-hexane gradient mixture and by preparative NH TLC eluting with a 33% ethyl acetate/n-hexane mixture to give the title compound as a colorless solid (5.0 mg, 0.0115 mmol, 5.7%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=2.[CH3:20][O:21][CH2:22][CH2:23]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.COCO>C1C=CC=CC=1.CCCCCC>[CH3:20][O:21][CH2:22][CH2:23][O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=2
Reactant: CC(C)(C)OC(=O)Cc1ccc2ncc(O)cc2c1
Reactant: COCCO
Agent: CCCCP(CCCC)CCCC
Agent: COCO
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COCCOc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of tert-butyl 2-(3-hydroxyquinolin-6-yl)acetate (0.1 g, 0.4 mmol) in benzene (5 mL) was added 2-methoxyethanol (0.09 ml, 1 mmol) and tri-n-butylphosphine (0.1 ml, 0.6 mmol). The resulting mixture was cooled to 0° C. followed by adding 1.1′-(azodicarbonyl)dipiperidine (0.1 g; 0.6 mmol). After 10 min, ice bath was removed; the reaction mixture was warmed up to rt. After 2 h, TLC showed there still existed 50% starting material. More methoxymethanol (2 eq, 0.06 mL) was added. The reaction mixture was continued to stir for 20 h. Hexane was added to the reaction mixture and dihydro-ADDP separated out was filtered off. The filtrate was concentrated. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-027, 40 g SiO2, hexane:acetone=85%:15%, Flow=40 mL/min) to afford the desired product as colorless liquid. MS m/z: 318.4 (M+H). Calc'd. for C18H23NO4−317.38.
Reaction SMILES: [CH3:1][O-].[Na+].[OH:4][CH2:5][CH2:6][C:7]1[C:8](=[O:15])[NH:9][C:10]([CH3:14])=[N:11][C:12]=1[CH3:13].IC>CO>[OH:4][CH2:5][CH2:6][C:7]1[C:8](=[O:15])[N:9]([CH3:1])[C:10]([CH3:14])=[N:11][C:12]=1[CH3:13]
Reactant: C[O-]
Reactant: Cc1nc(C)c(CCO)c(=O)[nH]1
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: Cc1nc(C)n(C)c(=O)c1CCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
Sodium methylate (1.9 g) was added to a mixture of intermediate 4 (6 g) in methanol (50 ml) while stirring at RT. Stirring was continued for 30 minutes and iodomethane (5 g) was added dropwise and the reaction mixture was stirred and refluxed for 4 hours. The solvent was evaporated, water was added to the residue and this mixture was extracted with CH2Cl2. The organic layer was separated, dried over MgSO4, filtered and the solvent was evaporated, yielding 6.0 g (94%) of 5-(2-hydroxyethyl)-2,3,6-trimethyl-4(3H)-pyrimidinone (intermediate 5).
Reaction SMILES: CC1C=CC(CNC2C(N)=CC=CC=2)=CC=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[C:30]3=[N:31][CH:32]=[CH:33][CH:34]=[C:29]3[N:28]=[C:27]2[CH2:35][CH:36]2[CH2:41][CH2:40][N:39](CC3C=CC=CC=3)[CH2:38][CH2:37]2)=[CH:21][CH:20]=1.[H][H]>[Pd].CO>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][N:26]2[C:30]3=[N:31][CH:32]=[CH:33][CH:34]=[C:29]3[N:28]=[C:27]2[CH2:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:23][CH:24]=1
Reactant: COc1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3cccnc32)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1ccc(CNc2ccccc2N)cc1
Solvent: CO
Product: COc1ccc(Cn2c(CC3CCNCC3)nc3cccnc32)cc1
Yield: 89 %

Procedure:
A mixture of 41 parts of 3-[(4-methoxyphenyl)methyl]-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-3H-imidazo[4,5-b]-pyridine and 480 parts of methanol was hydrogenated at normal pressure and at 50° C. with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 30 parts (89%) of 3-[(4-methoxyphenyl)methyl]-2-(4-piperidinylmethyl)-3H-imidazo[4,5-b]pyridine (37). In a similar manner there were also prepared:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[Cl:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:34])[F:33])[O:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:33])[F:34])[O:22][CH:23]1[CH2:24][CH2:25][N:26]([CH2:2][C:3]([NH:5][C@@H:6]2[CH2:11][O:10][C:9]3=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]3[CH2:7]2)=[O:4])[CH2:27][CH2:28]1
Reactant: FC(F)(F)c1ccc(OC2CCNCC2)cc1Cl
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Product: O=C(CN1CCC(Oc2ccc(C(F)(F)F)c(Cl)c2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 64.3 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(3-chloro-4-(trifluoromethyl)phenoxy)piperidine (279 mg, 1.0 mmol) as crude materials, 162 mg title compound was generated and yield was 65%.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C(=O)([O-])O.[Na+].[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH2:24][C:25]3[N:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][CH:26]=3)=[C:16]([C:20]3([CH3:23])[CH2:22][CH2:21]3)[NH:17]2)=[CH:13][CH:12]=1>CS(C)=O.O>[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH2:24][C:25]3[N:30]=[C:29]([C:31](=[N:3][OH:2])[NH2:32])[CH:28]=[CH:27][CH:26]=3)=[C:16]([C:20]3([CH3:23])[CH2:22][CH2:21]3)[NH:17]2)=[CH:13][CH:12]=1
Reactant: COc1ccc2c(Cc3cccc(C#N)n3)c(C3(C)CC3)[nH]c2c1
Reactant: [NH3+]O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(Cc3cccc(C(N)=NO)n3)c(C3(C)CC3)[nH]c2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 106.3 %

Procedure:
To a solution of hydroxylammonium chloride (117 mg) in dimethylsulfoxide (1.7 mL) was added sodium hydrogen carbonate (170 mg), and the mixture was stirred at 50° C. for 1 hour. Then, a solution of 6-[6-methoxy-2-(1-methylcyclopropyl)-1H-indol-3-ylmethyl]pyridine-2-carbonitrile (53.6 mg) in dimethylsulfoxide (1.7 mL) was added dropwise thereto, followed by stirring at 80° C. for 2.5 hours. The reaction mixture was left to be cooled and diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (62.9 mg). 1H-NMR (CDCl3) δ ppm: 0.68-0.76 (2H, m), 0.84-0.92 (2H, m), 1.34 (3H, s), 3.82 (3H, s), 4.35 (2H, s), 5.68 (2H, br s), 6.69 (1H, dd, J=2.3, 8.8 Hz), 6.82 (1H, d, J=2.3 Hz), 6.98-7.05 (1H, m), 7.23 (1H, d, J=8.8 Hz), 7.50 (1H, t, J=7.8 Hz), 7.66-7.73 (1H, m), 7.82 (1H, br s). ESI-MS (m/z): 351 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:7]=[CH:6]2)#[N:2].Cl.[NH2:20][OH:21].C(=O)(O)[O-].[Na+]>C(O)C>[OH:21][NH:20][C:1](=[NH:2])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:7]=[CH:6]2
Reactant: CCOC(=O)CCn1ncc2cc(C#N)ccc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCn1ncc2cc(C(=N)NO)ccc21
Temperature: 60 °C

Procedure:
Ethyl 3-(5-cyano-1H-indazol-1-yl)propanoate D47 (3.6 g, 14.80 mmol) was dissolved in ethanol (40 ml), hydroxylamine hydrochloride (2.057 g, 29.6 mmol) and sodium bicarbonate (6.22 g, 74.0 mmol) were added. The mixture was heated at 60° C. overnight. Cooled, filtered and the filtrate was evaporated, dissolved in EtOAc, washed with water (3×20 ml), dried over MgSO4 and evaporated again to give (1.75 g) of product. A further 0.290 g of white crystals were recovered from the rotary evaporater. MS (ES+): C13H16N4O3 requires 276; found (MH+) 277.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:12][CH3:13])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C[O:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([N:24]2[CH:28]=[C:27]([C:29]3[CH:30]=[N:31][N:32]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:33]=3[CH2:34][CH3:35])[N:26]=[CH:25]2)[CH:18]=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:12][CH3:13])=[C:9]([NH:11][C:16](=[O:15])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([N:24]3[CH:28]=[C:27]([C:29]4[CH:30]=[N:31][N:32]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:33]=4[CH2:34][CH3:35])[N:26]=[CH:25]3)[CH:18]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(C)(C)C)cc1N
Reactant: CCc1c(-c2cn(-c3cc(C(=O)OC)ccc3C)cn2)cnn1-c1ccccc1
Product: CCc1c(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)ccc4OC)ccc3C)cn2)cnn1-c1ccccc1

Procedure:
Example 153 was prepared from 5-tert-butyl-2-methoxy-phenylamine and 3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoic acid methyl ester (Example 151) in the same manner as Example 151. ESI MS m/z 534 [C33H35N5O2+H]1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[C:4]([C:18]2[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=2)[CH:3]=1.[NH2:24][C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[CH:5]=[C:4]([C:18]3[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=3)[CH:3]=[C:2]([NH:24][C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1cc(-c2cnn(C)c2)cc(Cl)n1)c1ccc(F)cc1
Reactant: Nc1cnccn1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cc(-c2cnn(C)c2)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 73.7 %

Procedure:
235 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2-amine, 74 mg of 2-aminopyrazine, 68 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 95 mg of sodium t-butoxide and 37 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 100° C. for 1.5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 204 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N6-(pyrazin-2-yl)pyridine-2,6-diamine as pale yellow powder. The obtained compound was dissolved in ethanol, and an equivalent of 1N hydrochloric acid was added thereto, and then the solvent was removed to obtain the objective compound as pale yellow powder.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([N:14]=[C:15]2[NH:19][C@@H:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:17][S:16]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:24](Br)[CH:25]([CH3:27])[CH3:26]>>[N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([N:14]=[C:15]2[N:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[C@@H:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:17][S:16]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)CBr
Reactant: CC(C)C[C@H]1CSC(=Nc2ccc([N+](=O)[O-])c3ccccc23)N1
Product: CC(C)C[C@H]1CSC(=Nc2ccc([N+](=O)[O-])c3ccccc23)N1CC(C)C

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. 4-Nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to Method A2b. 4-Nitro-1-naphthyl isothiocyanate was reacted with (1S)-1-(hydroxymethyl)-3-methylbutylamine to Method C2a to give (4S)-2-(4-nitro-1-naphthylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-nitro-1-naphthylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:12]([Mg]Cl)[CH:13]([CH3:15])[CH3:14].S(=O)(=O)(O)O>O1CCCC1.O>[CH3:12][CH:13]([CH3:15])/[CH:14]=[CH:8]/[C:7]1[CH:10]=[CH:11][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CC(C)C[Mg]Cl
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)/C=C/c1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
4-Carboxybenzaldehyde (1.0 g, 6.66 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) and cooled to 0° C. To the mixture was added isobutylmagnesium chloride (16 mL, 32 mmol, 2.0 M solution in THF). The reaction mixture was warmed to room temperature and stirred for 2 hours. The solution was acidified with 50% sulfuric acid in water and the THF was removed under vacuum. The aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to give the desired compound (950 mg) as grey powder.