Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[N+]([O-])(O)=O.[N+:22]([O:25][CH2:26][CH2:27][NH2:28])([O-:24])=[O:23].[C:29]1([CH:39]2[S:43][C:42](=[O:44])[NH:41][CH:40]2[C:45](O)=[O:46])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>O1CCCC1>[N+:22]([O:25][CH2:26][CH2:27][NH:28][C:45]([CH:40]1[CH:39]([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)[S:43][C:42](=[O:44])[NH:41]1)=[O:46])([O-:24])=[O:23]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1NC(C(=O)O)C(c2cccc3ccccc23)S1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=[N+]([O-])O
Product: O=C1NC(C(=O)NCCO[N+](=O)[O-])C(c2cccc3ccccc23)S1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
1.23 ml of triethylamine and 0.36 ml of diethyl cyanophosphonate were added, whilst ice-cooling and stirring, to a suspension of 370 mg of N-(2-nitrooxyethyl)amine nitrate and 500 mg of 5-(1-naphthyl)-2-oxothiazolidine-4-carboxylic acid in 50 ml of dry tetrahydrofuran, and the resulting mixture was stirred at room temperature for 4 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was mixed with ethyl acetate. The resulting mixture was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the crystalline residue was recrystallized from ethanol, to give 367 mg of the title compound as colorless crystals, melting at 151°-153° C.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[C:7](=[O:23])[CH:6]3[CH2:24][O:25][CH2:26][CH2:27][N:5]3[C:4]=2[N:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][N:39]=[C:38]3[N:42]([S:45]([C:48]4[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=4)(=[O:47])=[O:46])[CH:43]=[CH:44][C:37]=23)O1.C([O-])(O)=O.[Na+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[C:7](=[O:23])[CH:6]3[CH2:24][O:25][CH2:26][CH2:27][N:5]3[C:4]3[N:3]=[C:2]([C:36]4[CH:41]=[CH:40][N:39]=[C:38]5[N:42]([S:45]([C:48]6[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=6)(=[O:46])=[O:47])[CH:43]=[CH:44][C:37]=45)[N:11]=[CH:10][C:9]2=3)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)ccnc32)cc1
Reactant: CS(=O)(=O)c1ccc(CN2C(=O)C3COCCN3c3nc(Cl)ncc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ncc5c(n4)N4CCOCC4C(=O)N5Cc4ccc(S(C)(=O)=O)cc4)ccnc32)cc1
Temperature: 100 °C
Yield: 52 %

Procedure:
2-Chloro-5-(4-(methylsulfonyl)benzyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (PREPARATION x38, 250 mg, 0.611 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (487 mg, 1.223 mmol), and PdCl2(dppf) (35.8 mg, 0.049 mmol) were suspended in dioxane (2.5 mL) and aqueous saturated NaHCO3 (0.5 mL). The reaction mixture was heated in a microwave at 100° C. on high absorbance for 1 hour and was subsequently diluted with ethyl acetate and washed with aqueous saturated NH4Cl (3×2 mL) and brine (3×2 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give a crude product which was loaded onto an ISCO® silica gel cartridge (4 g) and eluted using an ethyl acetatehexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow foam (205 mg, 52%). ESI-MS m/z [M+H]+ calc'd for C31H28N6O6S2, 645.15; found 645.5.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:36]=[CH:35][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([C@@H:20]3[CH2:24][CH2:23][CH2:22][N:21]3[S:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH2:62][CH:63]2[CH2:65][O:64]2)=[CH:57][CH:56]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:34][C:31]1[CH:30]=[CH:29][C:28]([S:25]([N:21]2[CH2:22][CH2:23][CH2:24][C@H:20]2[C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:10]3[CH:35]=[CH:36][C:7]([CH2:6][CH2:5][NH:4][CH2:65][C@H:63]([OH:64])[CH2:62][O:61][C:58]4[CH:59]=[CH:60][C:55]([OH:54])=[CH:56][CH:57]=4)=[CH:8][CH:9]=3)[CH2:13][CH2:14]2)=[O:19])(=[O:26])=[O:27])=[CH:33][CH:32]=1
Reactant: NCCc1ccc(NC2CCN(C(=O)[C@@H]3CCCN3S(=O)(=O)c3ccc(F)cc3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: O=C([C@@H]1CCCN1S(=O)(=O)c1ccc(F)cc1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 21.8 %

Procedure:
{4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}{(2S)-1-[(4-fluorophenyl)sulfonyl]-pyrrolidinyl}methanone formate (0.30 g, 0.574 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.232 g, 0.574 mmol) according to Procedure G to give the title compound (0.11 g, 0.125 mmol).
Reaction SMILES: CC(C)([O-])C.[K+].Cl[CH2:8][C:9]1[N:10]([CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=1>C1COCC1>[CH:19]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[C:11]1[N:10]3[CH2:22][CH2:23][CH2:24][N:25]([C:26]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:32])[CH2:8][C:9]3=[N:21][C:12]=1[CH:13]=[N:14]2
Reactant: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2cnc3ccccc3c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCn2c(nc3cnc4ccccc4c32)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium tert-butoxide (77.2 mL of a 1 M solution in THF) was added to a solution of tert-butyl 3-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate (24.12 g, 64.34 mmol, prepared according to the methods described in Example 6 Parts A through C) in THF (250 mL), and the reaction was stirred overnight at ambient temperature. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluting with 2N ammonia in methanol/dichloromethane in a gradient from 0:100 to 15:85) to provide 9.1 g of tert-butyl 11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=3[N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:21]([OH:23])=O)=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:33])[CH:5]=1)(=[O:3])[CH3:2].[NH3:34]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=3[N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[C:21]([NH2:34])=[O:23])=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:33])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C(=O)O)ccc3N3CCOCC3)CC2)c(F)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C(N)=O)ccc3N3CCOCC3)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described for example K/step2 from 3-[4-(4-Acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-morpholin-4-yl-benzoic acid and ammonia (10%, white solid, MS (m/e): 455.2 (M+H, 100%)
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C@@H:11]([CH3:25])[CH2:10][C@H:9]2[N:26]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:27](=[O:30])[CH2:28][CH3:29].[NH3:39]>CO>[C:3]([CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16](=[O:24])[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[C@@H:11]([CH3:25])[CH2:10][C@H:9]2[N:26]([C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)[C:27](=[O:30])[CH2:28][CH3:29])(=[O:2])[NH2:39]
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(OCC(=O)OC)cc21
Reactant: N
Solvent: CO
Product: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(OCC(N)=O)cc21
Temperature: 25 °C

Procedure:
(±)-Cis-N-[6-carbamoylmethoxy-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-(4-chloro-phenyl)-propionamide was prepared from (±)-cis-4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yloxy]-acetic acid ester. To solid (±)-cis-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yloxy]-acetic acid methyl ester (76 mg, 0.14 mmol) was added a solution of ammonia in methanol (2 M, 10 mL). The resulting solution was stirred over night at room temperature and concentrated. The resulting crude amide was purified by silica gel chromatography (100% hexanes-100% ethyl acetate gradient) to afford pure product (59 mg, 76%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:10]1([C:16]2[CH:17]=[N:18][NH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:10]1([C:16]2[CH:17]=[N:18][N:19]([CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:20]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc(-c2cn[nH]c2)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.8 %

Procedure:
The mixture of ethyl 4-bromobutyrate (0.400 g, 2.05 mmole), 4-phenyl-1H-pyrazole (0.296 g, 2.05 mmole) and K2CO3 (0.567 g, 4.10 mmole) in DMF (10 ml) was stirred at room temperature overnight. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (2×). The combined organic phases were washed with water and then brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative to afford the desired product (73 mg, 52%) as colorless oil. LCMS calculated for C15H19N2O2 (M+H): 259. found: 259.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)#[N:2].[ClH:22]>C(OCC)(=O)C>[ClH:22].[NH:12]1[CH2:11][CH2:10][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=2)[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C2CCNCC2)nc1
Temperature: 7.5 °C
Reaction time: 0.67 h
Yield: 97 %

Procedure:
Through a solution of tert-butyl 4-(5-cyanopyridin-2-yl)piperidine-1-carboxylate (compound 50.2, 200 mg, 0.70 mmol, 1.00 equiv) in ethyl acetate (20 mL) was bubbled HCl gas. The resulting mixture was stirred for 40 min at 5-10° C. The resulting precipitate was collected by filtration and dried to yield 150 mg (97%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11](NC3C=C(C=CC=3F)C(O)=O)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[NH2:24][C:25]1[C:26]([CH3:35])=[N:27][CH:28]=[C:29]([CH:34]=1)[C:30]([O:32][CH3:33])=[O:31]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:24][C:25]3[C:26]([CH3:35])=[N:27][CH:28]=[C:29]([CH:34]=3)[C:30]([O:32][CH3:33])=[O:31])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: O=C(O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Reactant: COC(=O)c1cnc(C)c(N)c1
Product: COC(=O)c1cnc(C)c(NC(=O)c2cnc3cc(Br)ccn23)c1

Procedure:
The title compound was prepared from 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (Intermediate 1A, step 3) and methyl 5-amino-6-methylnicotinate (step 2) analogously to Intermediate 1A;
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Cl.[CH3:20]O>>[NH2:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([O:16][CH3:20])=[O:15])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: CO
Reactant: Cc1nc(N)ccc1-c1ccc(C(=O)O)cc1
Agent: Cl
Product: COC(=O)c1ccc(-c2ccc(N)nc2C)cc1
Yield: 70 %

Procedure:
A stirred suspension of 4-(6-amino-2-methylpyridin-3-yl)benzoic acid hydrochloride (D6, 1.9 g, 8.3 mmole) in methanol (120 ml) was treated with conc. HCl acid (1 ml) and heated under reflux for 2 h. The solution was concentrated in vacuo, the residue treated with excess 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound as a pale yellow solid (1.4 g, 70%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.C1COCC1>[F:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[C:2]1[N:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Reactant: COc1ccc(B(O)O)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1cnc(-c2ccc(OC)cc2F)cc1C(F)(F)F

Procedure:
Methyl 6-chloro-4-(trifluoromethyl)nicotinate (963.6 mg, 4.02 mmol), 2-fluoro-4-methoxybenzeneboronic acid (854 mg, 5.03 mmol), cesium carbonate (2883 mg, 8.85 mmol), PdCl2(dppf)-CH2Cl2 adduct (328 mg, 0.402 mmol) and THF (30 mL) were refluxed in a 80° C. oil bath overnight. LCMS trace of the reaction aliquot indicated completion of reaction. The reaction crude was filtered through a bed of Celite® 521. The filtrate was concentrated in vacuo and purified by flash chromatography (SiO2, Biotage SNAP Cartridge, silica gel, KP-Sil, 100 g cartridge). The column was eluted by an EtOAc/hexanes mixture (0% to 20%). Related fractions were pooled and evaporated to afford a colorless oil as the titled compound. LCMS calc.=329.07. found=330.17 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[OH:24])[N:8]=2)[CH2:3]1.C(N(CC)CC)C.Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>O.C(Cl)Cl>[CH2:36]([O:35][C:33](=[O:34])[NH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[OH:24])[N:8]=2)[CH2:3]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To (R)-2-[4-(3-amino-pyrrolidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol (50.8 mg, 0.16 mmol) was added 500 μL of CH2Cl2 and the solution was cooled to 0° C. To this solution was added sequentially triethylamine (33.2 μL, 0.24 mmol) and benzyl chloroformate (29.2 mg, 0.17 mmol). The reaction mixture was stirred from 0° C. to 5° C. over 45 min, then diluted with water and CH2Cl2 (10 mL). The organic layer was separated and dried over Na2SO4, and the solvent was removed under reduced pressure to give (R)-{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamic acid benzyl ester. LC/MS: m/z 455.2 (M+H)+ at 2.81 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([C:4]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[C:7]([OH:8])=[CH:6][C:5]=1[OH:14])(=[O:3])[CH3:2].[OH-].[Na+].I[CH2:18][CH2:19][CH2:20][CH3:21]>O>[CH2:18]([C:6]1[C:7]([OH:8])=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=[C:4]([C:1](=[O:3])[CH3:2])[C:5]=1[OH:14])[CH2:19][CH2:20][CH3:21]
Reactant: CC(=O)c1cc(C(C)=O)c(O)cc1O
Reactant: CCCCI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCc1c(O)c(C(C)=O)cc(C(C)=O)c1O

Procedure:
4,6-Diacetyl resorcinol (485 g, 2.5 m) sodium hydroxide (220 g, 5 m), 1-iodobutane (285 ml, 2.5 m) and water (2 l) were heated on a steam bath for 16 hours, cooled to 20° and the yellow-white precipitate filtered and washed with water. The solid was washed with dilute hydrochloric acid, extracted into chloroform (2×1.5 l) and the chloroform solution washed with water (2 l) and brine (1 l), then dried (anhyd. Na2SO4). Filtration and removal of solvent gave an oil (420 g) which crystallised on standing.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:22]#[N:23].[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])=[CH:27][CH:26]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:22]([C:3]1[N:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]2)=[N:7][C:2]=1[NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)=[O:32])=[CH:29][CH:30]=1)#[N:23]
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Cl)n2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Temperature: 115 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
A mixture of (R)-tert-butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate (400 mg, 1.19 mmol), (4-aminophenyl)(morpholino)methanone (490 mg, 2.38 mmol), Pd(OAc)2 (54 mg, 0.24 mmol), BINAP (150 mg, 0.24 mmol), fine powder Cs2CO3 (1.55 g, 4.76 mmol) in dioxane (40 mL) was degassed with nitrogen stream for 3 min. The mixture was stirred in a nitrogen atmosphere at 115° C. for 2.5 h. The mixture was cooled, diluted with 100 mL EtOAc, filtered through celite, and concentrated in vacuo. The residue was subjected to flash column chromatography with 0 to 65% EtOAc in DCM to give (R)-tert-butyl 1-(5-cyano-6-(4-(morpholine-4-carbonyl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate (88) (yield >85%).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9](N)=[O:10])=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([CH3:17])[S:15][CH:16]=1.[OH-:18].[Na+]>O>[CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]([OH:18])=[O:10])=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([CH3:17])[S:15][CH:16]=1
Reactant: [OH-]
Reactant: Cc1nc(-c2cc(C(N)=O)c(=O)[nH]c2C)cs1
Agent: [Na+]
Solvent: O
Product: Cc1nc(-c2cc(C(=O)O)c(=O)[nH]c2C)cs1

Procedure:
C-4. 1,2-Dihydro-6-methyl-5-(2-methyl-4-thiazolyl)-2-oxo-3-pyridinecarboxylic acid--A mixture containing 32 g of 1,2-dihydro-6-methyl-5-(2-methyl-4-thiazolyl)-2-oxo-3-pyridinecarboxamide, 50 ml of 35% aqueous sodium hydroxide solution and 300 ml of water was heated on a steam bath for 15 hours and cooled. The reaction mixture was filtered to remove a small quantity of insoluble material and the filtrate was acidified with concentrated hydrochloric acid. The resulting precipitate was collected, washed with water and dried in an oven at 80° C. to produce 30.2 g of 1,2-dihydro-6-methyl-5-(2-methyl-4-thiazolyl)-2-oxo-3-pyridinecarboxylic acid, m.p. 297°-299° C. with decomposition.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([OH:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CS(O[CH2:30][CH2:31][CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=O)=O>>[C:33]1([CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:31][CH2:30][O:21][C:16]2[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]3[O:12][C:11]([CH3:24])([CH3:23])[CH:10]([C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)[C:14]=3[C:15]=2[CH3:22])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Product: Cc1c(C)c2c(c(C)c1OCCC(c1ccccc1)c1ccccc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 55 %

Procedure:
Using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and 3,3-diphenylpropyl methanesulfonate, the title compound was obtained in the same manner as in Example 1. This was oily.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[OH-].[Na+].Cl.[NH2:25]O>C(O)C>[NH2:25][CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([N:3]([CH2:20][CH3:21])[CH2:1][CH3:2])=[O:19])=[CH:6][CH:7]=2)[CH2:13][CH2:14]1
Reactant: NO
Reactant: CCN(CC)C(=O)c1ccc(CN2CCC(=O)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(CN2CCC(N)CC2)cc1
Reaction time: 8 h
Yield: 66.2 %

Procedure:
N,N-Diethyl-4-[(4-oxo-1-piperidinyl)methyl]benzamide (58.74 g, 193 mmol) is dissolved in 580 mL of ethanol and treated with 290 mL of 30% NaOH followed by hydroxylamine hydrochloride (26.82 g, 386 mmol). The mixture is refluxed for 45 minutes, the heating mantle removed and the reaction mixture stirred with an overhead stirrer as 38.4 g of 50/50 aluminum-nickel alloy (powder) are added in small portions with ice cooling. After the addition, the mixture is refluxed for 1.75 hours, then allowed to stand at room temperature overnight, filtered through Solka Floc and most of the ethanol is evaporated in vacuo from the filtrate. The resulting aqueous phase is extracted with 3×100 mL of ether. The pooled extracts are concentrated in vacuo and the oily residue is poured into 500 mL of brine and continuously extracted with ether overnight. Concentration of the extract affords 37 g of product which is purified by flash chromatography on silica gel (110 mm column, 5% ammonia saturated methanol in methylene chloride eluent) affording 7.08 g (24.4 mmol, 13% yield) of product: 1H NMR (Me2SO-d6, 300 MHz) δ7.33 (d,J=8.2 Hz, 2H), 7.27 (d,J=8.2 Hz, 2H), 1.0-3.5 (m, 21H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH:36][CH2:37][C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])(=[O:35])=[O:34]>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[C:28]([S:33]([NH:36][CH2:37][C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])(=[O:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1
Reactant: CC(C)(CO)CNS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3ncc(N)nc3C#N)c(F)c2)OC1(C)C
Product: CC(C)(CO)CNS(=O)(=O)c1ccccc1-c1ccc(-c2ncc(N)nc2C#N)c(F)c1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile and 2-bromo-N-(3-hydroxy-2,2-dimethylpropyl)benzenesulfonamide. MS (ESI): mass calcd. for C22H22FN5OS, 455.14; m/z found, 456.0 [M+H]+. 1H NMR (600 MHz, DMSO-δ6) δ 8.26 (s, 1H), 7.93 (dd, J=7.8, 1.5, 1H), 7.72-7.60 (m, 3H), 7.47 (dd, J=7.4, 1.5, 1H), 7.43-7.34 (m, 5H), 4.49 (t, J=5.4, 1H), 3.08 (d, J=5.4, 2H), 2.62 (d, J=6.5, 2H), 0.73 (s, 6H).