Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:24]([F:27])([F:26])[F:25])=[C:14]([N:17]3[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:28])[C:8]1=[O:29])=[O:5])[CH3:2].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:30]([NH:37][CH2:22][C:19]1[CH:20]=[CH:21][N:17]([C:14]2[CH:15]=[C:16]3[C:11]([NH:10][C:9](=[O:28])[C:8](=[O:29])[N:7]3[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:12][C:13]=2[C:24]([F:25])([F:27])[F:26])[CH:18]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=O)c3)cc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(CNCc4ccccc4)c3)cc21
Reaction time: 16 h
Yield: 59.9 %

Procedure:
1.2 g (2.9 mmol) of the compound of Example 70, 0.31 g (2.9 mmol) of benzylamine and 0.2 ml (2.9 mmol) of acetic acid were dissolved in 50 ml of ethanol and, at room temperature, 0.18 g (2.9 mmol) of sodium cyanoborohydride was added a little at a time. The mixture was stirred for 16 h and then concentrated under reduced pressure, and the organic phase was dried and finally concentrated again under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: methylene chloride/methanol=5:1) to yield 0.87 g (60%) of the product.
Reaction SMILES: CS(O[CH2:6][C@H:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=O)=O.[N-:22]=[N+:23]=[N-:24].[Na+].O>CN(C=O)C>[C:16]1([C@H:7]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][N:22]=[N+:23]=[N-:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])c1ccccc1
Temperature: 55 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
(S)-2-Phenyl-2-tert-butoxycarbonylaminoethyl methanesulfonate (15.77 g, 0.05 mol) was dissolved in 50 mL DMF followed by the addition of sodium azide (19.5 g, 0.3 mol). The mixture was stirred for 24 hrs at 55° C., cooled to room temperature, poured into cold water (500 mL) and stirred vigorously for 20 minutes. Precipitate was collected by filtration, washed with water and dried, affording 9.97 g of the title compound as a white solid. Yield: 76%; (MH)+=263; 1H NMR (DMSO-d6): 1.37 (s, 9H), 3.36-3.50 (m, 2H), 4.69-4.75 (m, 1H), 7.23-7.36 (m, 5H), 7.65-7.68 (d, J=9.2 Hz, 1H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([F:11])=[CH:4][CH:3]=1.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([F:29])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>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>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([F:11])=[CH:4][CH:3]=2)=[C:22]([F:29])[CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1nc(Br)ccc1F
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=C(O)c1nc(-c2ccc(OCc3ccccc3)cc2F)ccc1F
Yield: 41 %

Procedure:
Method 1 was followed using 6-bromo-3-fluoropicolinic acid (1.0 equiv.) and 4-(benzyloxy)-2-fluorophenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.15 equiv.) to give 6-(4-(benzyloxy)-2-fluorophenyl)-3-fluoropicolinic acid in 41% yield. LC/MS=342.1 (M+H), Rt=1.06 min.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[C:8](=O)[NH:9][CH:10]=[CH:11][CH:12]=1)=O.C1(C)C(C)=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>N1C=CC=CC=1>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]1[S:27][C:8]2[C:7]([N:6]=1)=[CH:12][CH:11]=[CH:10][N:9]=2
Reactant: O=C(Nc1ccc[nH]c1=O)c1ccccc1F
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1C
Solvent: c1ccncc1
Product: Fc1ccccc1-c1nc2cccnc2s1

Procedure:
3-(2-Fluorobenzoylamino)-2-pyridone (2 g.), 60 ml. of xylene and 15 ml of pyridine were heated until solution was complete. To this solution was added 6.5 grams of phosphorus pentasulfide and the mixture was heated at reflux for 16 hours. The reaction mixture was decanted from a gummy residue while hot, and the solvents were concentrated to dryness. The crystalline residue was recrystallized from ethanol to give 2-(2-fluorophenyl)thiazolo[ 5,4-b]pyridine, m.p. 119°-121° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:31]=[C:30]([C:32]([N:34]2[CH2:43][C:42]3[CH:41]=[N:40][N:39]([CH3:44])[C:38]=3[NH:37][C:36]3[CH:45]=[CH:46][CH:47]=[CH:48][C:35]2=3)=[O:33])[CH:29]=[CH:28][C:27]=1[CH2:49][CH2:50][C:51]([OH:53])=O.[O:54]1[CH:58]=[CH:57][CH:56]=[C:55]1[C:59]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)=[O:60]>CN(C=O)C.CCN(C(C)C)C(C)C>[O:54]1[CH:58]=[CH:57][CH:56]=[C:55]1[C:59]([N:61]1[CH2:62][CH2:63][N:64]([C:51](=[O:53])[CH2:50][CH2:49][C:27]2[CH:28]=[CH:29][C:30]([C:32]([N:34]3[CH2:43][C:42]4[CH:41]=[N:40][N:39]([CH3:44])[C:38]=4[NH:37][C:36]4[CH:45]=[CH:46][CH:47]=[CH:48][C:35]3=4)=[O:33])=[CH:31][C:26]=2[CH3:25])[CH2:65][CH2:66]1)=[O:60]
Reactant: O=C(c1ccco1)N1CCNCC1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCN(C(=O)c2ccco2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of HBTU (1.90 mg, 0.005 mmol) in DMF (0.05 ml) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid from Example E45 (1.95 mg, 0.005 mmol) in DMF (0.05 ml) and DIEA (0.0022 ml). The mixture was stirred at room temperature for 30 min then a solution of 1-(2-furoyl)piperazine (0.90 mg, 0.005 mmol) in DMF (0.05 ml) was added. The mixture was stirred for 18 h at room temperature then sol-vents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=553.4
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH:20]([CH3:22])[CH3:21]>CN(C)C=O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:11]=[CH:10][N:9]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:8]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2cc[nH]n2)s1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)Cn1ccc(-c2ccc(Cl)s2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
To a solution of 3-(5-chloro-2-thienyl)-1H-pyrazole (1 eq, 0.023 mol) and cesium carbonate (1.2 eq, 0.028 mol) in dry N,N-dimethylformamide (50 mL) was added 1-bromo-2-methylpropane (1.1 eq, 0.025 mol) slowly and the mixture was stirred at room temperature for 3 h. After completion of the reaction monitored by TLC, the reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude compound was purified by column-chromatography to afford 4.3 g of 3-(5-chloro-2-thienyl)-1-isobutyl-1H-pyrazole (76% yield).
Reaction SMILES: [C:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])(=[O:3])[CH3:2].[CH3:12][C:13](=[CH2:21])[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([C:4]1[C:5]([OH:6])=[C:7]([C:13]([CH3:21])([CH3:12])[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:8]=[CH:9][C:10]=1[OH:11])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(O)cccc1O
Reactant: C=C(C)CCCC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)CCCC(C)(C)c1ccc(O)c(C(C)=O)c1O
Temperature: 100 °C

Procedure:
1.5 Parts of 2-acetyl resorcinol, 1.4 parts of methyl 5-methyl-hex-5-enoate, and 0.1 parts of p-toluene sulphonic acid are sealed into a glass Carius tube and maintained at 100° C. for 48 hours. The reaction mixture is then washed free of the acid catalyst and chromatographed through silica to yield methyl 5-(3'-acetyl-2,4-dihydroxyphenyl)-5-methyl-hexanoate with m.p. 94°-7° after crystallisation from 40°-60° C. petroleum-ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][OH:18].C(=O)([O-])O.[Na+]>C(O)(C)(C)C.O>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:8]=[CH:9][C:10]([CH:13]=[N:14][O:18][NH2:17])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(C#N)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1ccc(C=NON)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
In a mixture of 21.2 ml of t-butanol and 2.1 ml of water were dissolved 4.3 g of 4-cyanobenzoic t-butyl ester, 1.84 g of hydroxylamine hydrochloride and 2.31 g of sodium hydrogencarbonate. The solution was stirred for 2 hours at 80° C. To the reaction mixture was added water, and the mixture was subjected to extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The concentrate was purified by means of a silica gel column chromatography (hexane/ethyl acetate=1/1), followed by crystallization from hexane to afford 4.41 g of the titled compound as colorless needles.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH2:14][OH:15].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(O)(O)=O>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:17]1[CH:22]=[C:21]([C:2]2[C:7](=[O:8])[N:6]3[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]3=[N:4][C:3]=2[CH2:14][OH:15])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc2nc(CO)c(Br)c(=O)n12
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)O
Solvent: O
Solvent: CC#N
Product: Cc1cccc2nc(CO)c(-c3cccc(F)c3)c(=O)n12
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-2-(hydroxymethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.09450 g, 0.3512 mmol), 3-fluorophenylboronic acid (0.09827 g, 0.7024 mmol), tetrakis(triphenylphosphine)palladium (0.02029 g, 0.01756 mmol), and sodium carbonate anhydrous (0.1861 g, 1.756 mmol) in acetonitrile-water (3:1) (4 mL) was stirred at 85° C. After 2 h, the mixture was cooled to rt and partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was washed with brine (50 mL×2), dried over Na2SO4, filtered, and concd under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 14 min and then 100% isocratic of EtOAc for 20 min as eluent to give 3-(3-fluorophenyl)-2-(hydroxymethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one as a yellow solid: Mass Spectrum (ESI) m/e=285.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[N:18]1([C:24]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:25]=2[C:26](Cl)=[O:27])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([C:26]([C:25]3[CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=[CH:32][C:24]=3[N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:27])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:11])[F:10]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: Fc1cc(N2CCNCC2)ccc1C(F)(F)F
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccc(C(F)(F)F)c(F)c2)CC1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 1-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine and 2-Morpholin-4-yl-5-nitro-benzoyl chloride (62%, yellow solid, MS (m/e): 483.2 (M+H, 100%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3[CH2:22][C:21](=O)[C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[S:18]3(=[O:29])=[O:28])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C([O-])(=O)C.[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3[CH2:22][C:21](=[N:31][OH:32])[C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[S:18]3(=[O:29])=[O:28])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CC(CCCN2CCN(c3ccc(F)cc3)CC2)S(=O)(=O)c2ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=S1(=O)c2ccccc2C(=NO)CC1CCCN1CCN(c2ccc(F)cc2)CC1
Yield: 88.3 %

Procedure:
A solution of 417 mg (1 mmol) of the Compound 19, 139 mg (2 mmol) of hydroxylamine hydrochloride, and 164 mg (2 mmol) of sodium acetate in 15 ml of methanol was refluxed for 17 hours. After the post treatment in the same manner as in Example 8, the residue was recrystallized from acetonitrile to obtain 381 mg (yield: 88%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[C:18]([C:19]([O:21]C)=O)=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:7]=[CH:8][CH:9]=1.O.[NH4+:24]>C(O)C>[CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[C:18]([C:19]([NH2:24])=[O:21])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CNCc1cccc(-c2nc3cccc(C(=O)OC)c3o2)c1
Reactant: [NH4+]
Solvent: O
Solvent: CCO
Product: CNCc1cccc(-c2nc3cccc(C(N)=O)c3o2)c1
Temperature: 30 °C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
Methyl 2-(3-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (80 mg, 0.27 mmol) and ammonium water (75.7 mg, 2.16 mmol) were added to ethanol (30 mL) and the mixture was stirred at 30° C. for 1 hr. The resulting mixture was evaporated under reduced pressure and purified with Pre-HPLC to obtain 2-(3-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide (16 mg, yield 21%). 1H-NMR (400 MHz, DMSO-d6) δ 2.62 (s, 3H), 4.29 (s, 2H), 7.48-7.52 (t, J=8 Hz, 1H), 7.70-7.74 (m, 1H), 7.81-7.83 (d, J=8 Hz, 1H), 7.90-7.98 (m, 3H), 8.34-8.43 (m, 2H), 9.06 (s, 2H); LC-MS (ESI) m/z 282 [M+1]+.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:23].[H][H]>CO.O.[Pd]>[ClH:23].[ClH:23].[N:18]1([CH:16]2[CH2:17][NH:14][CH2:15]2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: [H][H]
Reactant: c1ccc(C(c2ccccc2)N2CC(n3ccnc3)C2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: c1cn(C2CNC2)cn1

Procedure:
3.20 g of 1-benzhydryl-3-(1-imidazolyl)azetidine [prepared as described in step (a) above] were dissolved in 30 ml of methanol, and 8.90 ml of a 10% w/v solution of hydrogen chloride in methanol were added to the resulting solution. 1.60 g of a 20% w/w palladium hydroxide-on-carbon catalyst were then added to the mixture, after which the mixture was hydrogenated at 50° C. for 40 minutes in an atmosphere of hydrogen. The catalyst was then removed by filtration and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was washed with diethyl ether and dried under reduced pressure, to obtain 2.03 mg of the title compound, as a powder.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: NC(=O)c1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cccc(NC(=O)CCl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
Chloroacetyl chloride (4 g, 35.4 mmol) was added to a stirred mixture of 3-aminobenzamide (4.0 g 25.9 mmol), K2CO3 (22 g, 159 mmol), water (40 ml), and dioxane (40 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and 25° C. for 16 hours, resulting in a solid precipitate. The precipitate was collected, washed, and dried to yield 4.1 g (75%) of the desired 3-chloroacetamidobenzamide, mp: 210 (D).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:12]C(OC(C)(C)C)=O)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@H:10]([NH2:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88.8 %

Procedure:
Dissolve (R)-3-benzyloxy-2-(tert-butoxycarbonylamino)-propane (800 mg, 3 mmol) in DCM (10 mL), add trifluoroacetic acid (5 mL), and stir at 0° C. for 20 min. Evaporate and purify by SCX chromatography to give the title compound as a colorless oil (440 mg, 89%). MS (ES+) m/z: 166 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[N:31]=[CH:30][C:29]([C:32]([O:34]C3C=CC=CC=3)=O)=[CH:28][N:27]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[N:27]=[CH:28][C:29]([C:32]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:34])=[CH:30][N:31]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncc(C(=O)Oc3ccccc3)cn2)CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncc(C(=O)N3CCCCC3)cn2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.3 %

Procedure:
Piperidine (0.02 ml, 0.20 mmol) was added to a dimethylformamide solution (1.0 ml) of 2-(1-t-butoxycarbonylpiperidin-4-yloxy)-5-(phenoxycarbonyl)pyrimidine (40 mg, 0.100 mmol), and stirred at room temperature for 12 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through partitioning thin-layer chromatography (hexane:ethyl acetate=3:7) to obtain the entitled compound (38 mg, 97%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[N:2]1.CC[N:15]=C=NCCCN(C)C.Cl.Cl.C1C=CC2N(O)N=NC=2C=1.N>CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH2:15])=[O:12])=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc2[nH]nnc2c1
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2[nH]nnc2c1
Yield: 99.6 %

Procedure:
To a solution of 1H-1,2,3-benzotriazole-5-carboxylic acid (2 g), EDCl/HCl (2.82 g), and HOBt in DMF (70 ml) was added an aqueous NH3 solution (5.1 ml), followed by reaction at room temperature for 2 hours. It was concentrated, and the residue was washed with a saturated NaHCO3 solution, collected by filtration, and dried to obtain 1H-1,2,3-benzotriazole-5-carboxamide (1.98 g) as a black solid.
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[N:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]I>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:1]([O:8][N:9]1[CH2:13][CH2:12][N:11]([CH3:25])[C:10]1=[N:14][C:15]1[C:16]([Cl:22])=[CH:17][CH:18]=[CH:19][C:20]=1[Cl:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Clc1cccc(Cl)c1N=C1NCCN1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN1CCN(OCc2ccccc2)C1=Nc1c(Cl)cccc1Cl
Reaction time: 1 h

Procedure:
16.8 g of 1-(benzyloxy)-2-[(2,6-dichlorophenyl)imino]-imidazolidine are dissolved in 80 ml of dimethylformamide and treated while stirring at room temperature with 1.44 g of sodium hydride. After 1 hour, there is added dropwise thereto a solution of 4 ml of methyl iodide in 20 ml of toluene. The temperature rises to 48°. After 16 hours, the mixture is poured into ice and extracted with ether. The organic phase is washed successively with water, 15 percent tartaric acid solution and water, dried over magnesium sulfate and evaporated in vacuo. The 1-(benzyloxy)-2-[(2,6-dichlorophenyl)imino]-3-methylimidazolidine obtained is used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH:27]([CH3:31])[C:28]([NH2:30])=[O:29])[C:16]([C:32]([F:35])([F:34])[F:33])=[CH:15][N:14]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:38][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH:27]([CH3:31])[C:28]([NH2:30])=[O:29])[C:16]([C:32]([F:34])([F:33])[F:35])=[CH:15][N:14]=3)[CH:9]=[N:8]2)[CH2:5][CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCNCC3)c2)ncc1C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCN(C)CC3)c2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a solution of 2-(2-(2-(2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)propanamide 56 (1.14 g, 2.33 mmol) in MeOH (40 mL) was added formaldehyde solution (37% in water, 0.52 mL, 7.0 mmol) and sodium triacetoxyborohydride (1.98 g, 9.33 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature for 4 hours before concentrating under reduced pressure. The mixture was diluted with sat. aq. NaHCO3 (75 mL) and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organics were washed with brine and dried (MgSO4) before the solvent was removed in vacuo to give the product as a white solid (1.05 g, 90%). 1H NMR (400 MHz, d6-DMSO) δ 10.22-10.09 (m, 1H), 8.69-8.55 (m, 1H), 8.04-7.95 (m, 1H), 7.58 (s, 1H), 7.43-7.35 (m, 1H), 7.29-7.12 (m, 4H), 6.96-6.84 (m, 1H), 4.13-4.01 (m, 1H), 3.90-3.79 (m, 1H), 3.27-2.88 (m, 4H), 2.83 (d, J=10.0 Hz, 2H), 2.19 (s, 3H), 2.07-1.87 (m, 6H), 1.33 (d, J=6.8 Hz, 3H). LCMS-D: rt 3.03 min; m/z 502 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[NH2:37]C1C=CC(C(=O)C)=CC=1.[OH-].[K+]>C(O)C>[NH2:37][C:3]1[CH:2]=[CH:7][C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)c1ccc(N)cc1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)cc1
Yield: 10 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(4-amino-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (14 mg, 10% yield). MS: 463.23 (M+H+); HPLC Procedure A, retention time=8.62 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:26])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:25])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:24])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:23])[C:20](O)=[O:21])=[O:5])[CH3:2].[CH3:27][NH:28][CH3:29]>>[CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:26])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:25])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:24])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:23])[C:20]([N:28]([CH3:29])[CH3:27])=[O:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: CNC
Product: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N(C)C

Procedure:
Starting materials: 15-ethoxycarbonyl-2,6,10,14-tetramethyl-2,6,10,14-pentadecatetraenoic acid and aqueous dimethylamine solution.