Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([F:21])[CH:15]=1)[OH:13])[CH2:8][CH2:9]O)([CH3:4])([CH3:3])[CH3:2].O1CCCC1.CS(Cl)(=O)=O.CCC([O-])(C)C.[K+]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:7]1[CH2:8][CH2:9][O:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([F:21])[CH:15]=2)[CH2:11]1)=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCO)CC(O)c1ccc(Br)c(F)c1
Agent: CCC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)c(F)c2)C1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
[2-(4-Bromo-3-fluoro-phenyl)-2-hydroxy-ethyl]-(2-hydroxy-ethyl)-carbamic acid tert-butyl ester (25.3 g, 66.9 mmol) and triuethylamine (10.2 g, 14.0 ml, 100 mmol) were combined with tetrahydrofurane (270 ml) to give a light yellow solution. The reaction mixture was cooled to 0-5° C. and methanesulfonyl chloride (8.43 g, 5.73 ml, 73.6 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h to give a white suspension. The reaction mixture was filtered and washed with tetrahydrofurane (20 ml). Potassium 2-methyl-2-butoxide (1.7 M in toluene, 59 ml, 100 mmol) was added dropwise to the filtrate at 0-5° C. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was poured into ethyl acetate and extracted with dilute aqueous hydrochloric acid (pH 5), water and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give a yellow oil which was further purified by flash chromatography (silica gel, heptane/ethyl acetate 4:1): yellow solid (19.5 g, 81%), MS (ISP): 259.9 ([{79Br}M-BOC+H]+), 261.9 ([{81Br}M-BOC+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[N:20]=[C:19]3[N:14]([C:15](Cl)=[N:16][C:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])=[CH:18]3)[N:13]=2)[CH2:8][CH2:7]1)[CH3:2].Cl.[NH2:32][C:33]1[C:38]([C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])=[CH:37][CH:36]=[C:35]([NH:45][CH2:46][CH2:47][NH2:48])[N:34]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[N:20]=[C:19]3[N:14]([C:15]([NH:48][CH2:47][CH2:46][NH:45][C:35]4[CH:36]=[CH:37][C:38]([C:39](=[O:44])[C:40]([F:42])([F:43])[F:41])=[C:33]([NH2:32])[N:34]=4)=[N:16][C:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])=[CH:18]3)[N:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: NCCNc1ccc(C(=O)C(F)(F)F)c(N)n1
Reactant: CCOC(=O)CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C(=O)C(F)(F)F)c(N)n4)n3n2)CC1
Temperature: 130 °C

Procedure:
120 mg (0.23 mmol) of ethyl{4-[5-chlor-7-(2,4-dichlorophenyl)[1,2,4]triazolo[1,5-c]pyrimidin-2-yl]piperidin-1-yl}acetate (Example 55A), 78.7 mg (0.28 mmol) of 1-{2-amino-6-[(2-aminoethyl)-amino]pyridin-3-yl}-2,2,2-trifluoroethanone hydrochloride (Example 13A) and 0.24 ml (1.38 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 141 mg (90% of theory) of the product as a solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:22]([OH:24])=[O:23])[CH:14]([C:18]([F:21])([F:20])[F:19])[O:15]2)=[CH:10][C:9]=1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([C@H](N)C)C2C(=CC=CC=2)C=CC=1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:22]([OH:24])=[O:23])[C@H:14]([C:18]([F:19])([F:20])[F:21])[O:15]2)=[CH:10][C:9]=1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(cc1Cc1ccccc1)OC(C(F)(F)F)C(C(=O)O)=C2
Agent: C[C@@H](N)c1cccc2ccccc12
Product: Cc1cc2c(cc1Cc1ccccc1)O[C@@H](C(F)(F)F)C(C(=O)O)=C2

Procedure:
A racemic mixture of the compound prepared in Example 42a, Step 2 was chirally resolved using the same protocol as for Example 609e, Step 1, R-enantiomer was identified as peak 1 with retention time 5.45 min: ESHRMS m/z 347.0875 (M−H, C19H14F3O3 Calc'd 347.0890). 1HNMR (DMSO-d6/400 MHz) 13.19 (brs, 1H), 7.74 (s, 1H), 7.11-7.27 (m, 6H), 6.74 (q, 1H, J=7.1 Hz), 3.91 (s, 2H), 2.11 (s, 3H). R-isomer: 19FNMR (d6-benzene; 6 eq of (R)-(+)-1-(1-naphthyl)ethylamine) d −77.76 (d, 3F, J=6.8 Hz, R-enantiomer), −77.74 (d, 3F, J=6.8 Hz, S-enantiomer).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](B(O)O)[CH:7]=1.Br[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH:19]=[O:20])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C(OCC)(=O)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH:19]=[O:20])[CH:14]=2)[CH:7]=1
Reactant: O=Cc1cc(Br)ccn1
Reactant: OB(O)c1cc(Cl)ccc1O
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1cc(-c2cc(Cl)ccc2O)ccn1
Temperature: 100 °C
Yield: 22.1 %

Procedure:
(5-Chloro-2-hydroxyphenyl)boronic acid (1.58 g, 0.00914 mol) was combined with 4-bromopyridine-2-carbaldehyde (1.70 g, 0.0091 mol), bis(triphenylphosphine)palladium (II) chloride (0.321 g, 0.00046 mol) and potassium carbonate (3.16 g, 0.0228 mol) in a 5 mL microwave vial. 1,4-dioxane (3 mL) and water (0.2 mL) were added and heated to 100° C. for 50 minutes in the microwave. The reaction was diluted with ethyl acetate (30 mL) and water (20 mL), filtered, the organic phase was separated then dried over anhydrous sodium sulphate, concentrated in vacuo and purified by flash column chromatography, ISCO™ (80 g column, eluting with 100% heptane to 50% v/v ethyl acetate in heptane) to give the title compound as a beige solid (0.47 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7]/[C:8](/[NH:17]C(=O)OC(C)(C)C)=[N:9]\C(=O)OC(C)(C)C)[CH:4]=[N:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([NH2:17])=[NH:9])[CH:4]=[N:3]1
Reactant: Cn1cc(N/C(=N\C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(NC(=N)N)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 251.5 %

Procedure:
To a solution of di-tert-butyl {(E)-[(1-methyl-1H-pyrazol-4-yl)amino]methylylidene}biscarbamate (17.5 g, 50 mmol) in DCM (50 mL) was added TFA (50 mL) at 0° C. The reaction was allowed to warm to rt and stirred for 20 hrs. The reaction mixture was concentrated to dryness to afford the crude title compound (17.5 g, quant) as a yellow oil. 1H NMR (400 MHz, Methanol-d4) δ ppm 7.81-7.82 (d, 1H), 7.74 (s, 1H), 7.47 (s, 1H), 3.89 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1.Cl[O-].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClC1C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:6]=1
Reactant: OC(c1ccc(OCC(F)(F)F)nc1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Clc1ccccc1
Product: O=C(c1ccc(OCC(F)(F)F)nc1)C(F)(F)F

Procedure:
2.75 g (0.01 mol) of 2-(2,2,2-trifluoroethoxy)-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine and 0.17 g (0.0005 mol) of tetrabutylammonium bromide are dissolved in 30 ml of chlorobenzene at room temperature. 6.1 ml (0.012 mol) of an approximately 12% strength sodium hypochlorite solution are metered in within 5 minutes with vigorous stirring and the mixture is stirred for a further 4 hours at room temperature. The reaction mixture is added to 50 ml of water, the phases are separated, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product in a kugelrohr (0.3 mbar, 100°-120° C. bath temperature), 0.68 g (24.7% of theory) of 2-(2,2,2-trifluoroethoxy)-5-trifluoroacetylpyridine are obtained.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[N:11]([CH3:18])[C:10](=[O:19])[C:9]2([CH3:21])[CH3:20])C(=O)C>Cl>[CH3:18][N:11]1[C:12]2[C:8](=[CH:7][C:6]([NH:2][CH3:1])=[C:14]([N+:15]([O-:17])=[O:16])[CH:13]=2)[C:9]([CH3:20])([CH3:21])[C:10]1=[O:19]
Reactant: CC(=O)N(C)c1cc2c(cc1[N+](=O)[O-])N(C)C(=O)C2(C)C
Agent: Cl
Product: CNc1cc2c(cc1[N+](=O)[O-])N(C)C(=O)C2(C)C
Temperature: 0 °C

Procedure:
The crude N-methyl-N-(1,3,3-trimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide is dissolved in hydrochloric acid (6 N; 8 ml) and heated at reflux for 3 h. The mixture is poured into ice-water and the resulting precipitate collected by filtration. After drying the compound (176 mg) is obtained.
Reaction SMILES: CC([NH:9][S:10](/[CH:13]=[CH:14]/[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:12])=[O:11])(C)CC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[S:16]1[CH:17]=[CH:18][CH:19]=[C:15]1/[CH:14]=[CH:13]/[S:10]([NH2:9])(=[O:11])=[O:12]
Reactant: CC(C)(C)CC(C)(C)NS(=O)(=O)/C=C/c1cccs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)/C=C/c1cccs1
Yield: 88.8 %

Procedure:
(E)-2-Thiophen-2-yl-ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (5.17 g, 17.2 mmol) was stirred for 15 minutes in a 1:1 mixture of trifluoroacetic acid and dichloromethane (40 mL). The mixture was concentrated in vacuo to afford a solid that was washed with dichloromethane (10 mL) in heptane (100 mL). The resultant solid was collected by suction filtration and dried under vacuum at ambient temperature to afford (E)-2-thiophen-2-yl-ethenesulfonic acid amide (2.89 g, 89%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:19]1[CH:24]=[C:23]([CH:25]=[O:26])[C:22]([CH:27]=O)=[CH:21][CH:20]=1.CCOCC>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[CH2:27][C:22]3[C:23](=[CH:24][CH:19]=[CH:20][CH:21]=3)[C:25]2=[O:26])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: O=Cc1ccccc1C=O
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(C)(=O)=O)N2Cc3ccccc3C2=O)ccc1OC
Yield: 69.4 %

Procedure:
A stirred mixture 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (100 mg, 0.37 mmol) and 1,2-phthalic dicarboxaldehyde (49 mg, 0.37 mmol) in acetic acid (2 mL) was heated to reflux for 15 min. Removal of solvent in vacuo and chromatography gave an oil which was stirred with ether (2 mL). The resulting suspension was filtered to yield 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindolin-1-one as a light yellow solid (100 mg, 70% yield): mp, 130.0-134.0° C.; 1H NMR (CDCl3) δ 1.45 (t, J s=7 Hz, 3H, CH3), 2.96 (s, 3H, CH3), 3.70 (dd, J=4.5, 14.7, Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.07 (q, J=6.9 Hz, 2H, CH2), 4.25 (d, J=16.5 Hz, 1H, CHH), 4.31 (dd, J=10.3, 14.5 Hz, 1H, CHH), 4.46 (d, J=16 HZ, 1H, CHH), 5.71 (dd, J=4.5, 10.3 Hz, 1H, NCH), 6.84-7.01 (m, 3H, Ar), 7.38-7.56 (m, 3H, Ar), 7.85 (d, J=6.9 Hz, 1H, Ar); 13C NMR (CDCl3) δ 14.65, 41.33, 46.27, 52.33, 55.95, 56.00, 65.56, 111.45, 112.28, 119.30, 122.85, 123.85, 128.13, 129.89, 131.80, 132.27, 141.26, 148.88, 149.62, 169.09; Anal Calcd for C20H23NO5S: C, 61.68; H, 5.95; N, 3.60. Found: C, 61.68, H, 6.06; N, 3.62.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>COCCOC.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>[N+:16]([C:4]1[CH:3]=[C:2]([C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])([O-:18])=[O:17]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 72.9 %

Procedure:
A mixture of tert-butyl (4-bromo-2-nitrophenyl)carbamate (6.0 g, 18.92 mmol, 1.0 eq.), thiophen-2-ylboronic acid (3.2 g, 24.6 mmol, 1.3 eq.), potassium carbonate (7.84 g, 56.8 mmol, 3.0 eq.) and tetrakis(triphenylphosphine)palladium(0) (1.53 g, 1.32 mmol, 0.07 eq.), tri-tolylphosphine in DME/H2O (105 mL) was first degassed then heated to 90° C. for 20 h. The reaction was then filtered through Celite. The product was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 2% EtOAc/hexanes) to obtain pure tert-butyl (2-nitro-4-(thiophen-2-yl)phenyl)carbamate (4.42 g, 73% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)([CH3:18])[CH3:17]>>[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:21][CH:20]=1)([CH3:18])[CH3:17]
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: COc1ccc(CNc2ccc(C(C)C)cc2)cc1
Product: COc1ccc(CN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(C(C)C)cc2)cc1
Yield: 56.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 4 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g) and (4-isopropylphenyl)[(4-methoxyphenyl)methyl]amine (0.38 g) as starting materials, N-(4-isopropylphenyl)-N-[(4-methoxyphenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.37 g) was obtained. melting point: 83-85° C.
Reaction SMILES: C([NH:4][C:5]1[NH:6][C:7](=[O:39])[C:8]([CH2:15][CH2:16][CH2:17][NH:18][C:19]2[CH:38]=[CH:37][C:22]([C:23]([NH:25][C@H:26]([C:33]([O:35]C)=[O:34])[CH2:27][CH2:28][C:29]([O:31]C)=[O:30])=[O:24])=[CH:21][CH:20]=2)=[C:9]([NH:11]C(=O)C)[N:10]=1)(=O)C.C=O.[C:42]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C.CN(C)C=O>[NH2:4][C:5]1[NH:6][C:7](=[O:39])[C:8]([CH2:15][CH2:16][CH2:17][N:18]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([NH:25][C@H:26]([C:33]([OH:35])=[O:34])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:24])=[CH:37][CH:38]=2)[CH3:42])=[C:9]([NH2:11])[N:10]=1
Reactant: [BH3-]C#N
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(NCCCc2c(NC(C)=O)nc(NC(C)=O)[nH]c2=O)cc1)C(=O)OC
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN(CCCc1c(N)nc(N)[nH]c1=O)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Yield: 130.7 %

Procedure:
To a stirred solution of 1.99 g (3.6 mmol) of dimethyl N-[4-[3-(2,4-bis(acetamido)-1,6-dihydro-6-oxo-5-pyrimidinyl)propylamino]benzoyl]-L-glutamate in 50 ml of acetonitrile and 5 ml of dimethylformamide was added 2 ml of 37% aqueous formaldehyde followed by 0.50 g (8.0 mmol) of sodium cyanoborohydride and 2 ml of acetic acid. After 18 hours the mixture was filtered to remove the solids and the filtrate was spin evaporated in vacuo. The residue was diluted with 100 ml of ice water, and then extracted with four 25 ml portions of methylene dichloride. The combined extracts were filtered through glass wool and spin evaporated in vacuo to give 2.1 g of the title compound as an oil which was a single spot on TLC. The oil was dissolved in 50 ml of ethanol and 50 ml of 1N sodium hydroxide and stirred at 70° C. for 20 hours. The reaction was cooled and spin evaporated in vacuo to a syrup. The syrup was dissolved in 50 ml of water, cooled on ice, and acidified to pH 3-4 with concentrated hydrochloric acid. The white solids were collected, washed with water, and finally with ether; yield, 1.10 g (67%), mp 190°-200° C. (one spot on TLC). Recrystallization from ethanol gave the analytical sample; yield, 0.54 g (33%, mp (166°-1678° changes to hard foam) 198°-204°; TLC (pyridine:BuOH:H2O/1:1:1); NMR (DMSO-d6) δ 8.16 (d, 1H, ArCONH), 7.71 (d, 2H, Ar), 6.66 (d, 2H, Ar), 5.94 (s, 2H, NH2), 5.76 (s, 2H, NH2) 4.36 (m, 1H, CHCO2H), 3.34 (m, 2H, CH2N(CH3)Ar), 2.93 (s, 3H, NCH3).
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-])=O)=[N:11][CH:12]=2)[C@@H:4]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][C@H:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[CH2:3]1>C(O)C.[Ni]>[F:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[C@@H:4]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][C@H:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[CH2:3]1
Reactant: O=[N+]([O-])c1ccc(N2C[C@@H](F)C[C@@H]2c2cc(F)ccc2O[C@H]2CCOC2)cn1
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(N2C[C@@H](F)C[C@@H]2c2cc(F)ccc2O[C@H]2CCOC2)cn1
Reaction time: 0.08 h
Yield: 356.5 %

Procedure:
To a stirred solution of 5-((2R,4S)-4-fluoro-2-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)pyrrolidin-1-yl)-2-nitropyridine (5.1 g, 3.26 mmol) in ethanol (50 ml) was cooled to 10° C. and added Raney Ni (1.02 g, 20% w/w) portion wise and stirred for 5 min, then added N2H4.2H2O (3 ml) drop wise for the period of 5 min, then stirred for 20 min at room temperature. After completion of reaction, reaction mixture was filter through celite bed under N2 atmosphere and filtrate was concentration under reduced pressure, the residue was re-dissolved in DCM and washed with water, brine and dried over Na2SO4 and concentration to get desired product as brown solid (4.2 g, yield: 89%), MS (ESI): 362.1 (M+H).
Reaction SMILES: [OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=O)[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[C:17]([NH:25][NH2:26])(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>C(O)C.O.Cl>[OH:1][C@H:2]([C:9]1[N:10]=[C:11](/[C:14](=[N:26]/[NH:25][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)/[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6]
Reactant: CC(=O)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Reactant: NNC(=O)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: C/C(=N\NC(=O)c1ccncc1)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Temperature: 55 °C
Reaction time: 24 h

Procedure:
1-[4-((1R,2S,3R)-1,2,3,4-Tetrahydroxy-butyl)-1H-imidazol-2-yl]-ethanone (168 mg, 0.73 mmol) was suspended in ethanol (4 ml) and water (1 ml). Isonicotinic hydrazide (110 mg, 0.80 mmol, 1.1 eq.) and hydrochloric acid (one drop, 12 N) were added, and the suspension was stirred at 55° C. for 24 hours. LCMS analysis indicated the formation of the product and the absence of starting material. The reaction mixture was cooled to room temperature, and partially concentrated in vacuo. The resulting white precipitate was collected and washed with ethanol to yield the product, as one apparent isomer, as a white solid: 136 mg (75%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(#N)C>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CBr
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of 40 (1.33 g, 10.0 mmol) in acetonitrile (50 mL) were sequentially added potassium carbonate (5.53 g, 40.0 mmol) and ethyl bromoacetate (1.67 g, 10.0 mmol). The reaction mixture was stirred at room temperature overnight, then partitioned between EtOAc (200 mL) and water (150 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to give 90 (2.1 g, 99%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]1[Cl:11].[NH3:13]>CCOCC>[Cl:11][C:6]1[N:5]([CH2:4][C:3]([NH2:13])=[O:2])[C:9]([Cl:10])=[CH:8][CH:7]=1
Reactant: COC(=O)Cn1c(Cl)ccc1Cl
Reactant: N
Solvent: CCOCC
Product: NC(=O)Cn1c(Cl)ccc1Cl

Procedure:
A mixture of methyl(2,5-dichloro-1H-pyrrol-1-yl)acetate (0.5 g), in ether (3 cm3), and concentrated aqueous ammonia solution (3 cm3) was stirred at room temperature overnight in a stoppered flask. The precipitated crystalline product was collected by filtration and washed with ether to give 0.07 g of title compound. The ethereal washings were dried and evaporated. The crystalline residue was triturated with diisopropyl ether to give a further 0.13 g of title compound, m.p. 183°-4° C.
Reaction SMILES: COC[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:11]=1.ClC1N=CN=C(NC2C=C(CS(N)(=O)=O)C=CC=2)N=1.N1CCCCC1[CH2:53][NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58]>>[C:57]([O:56][C:55](=[O:61])[NH:54][CH2:53][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[N:11]=[C:12]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][S:24](=[O:26])(=[O:25])[NH2:27])[CH:18]=2)[N:13]=[CH:14][N:15]=1)([CH3:60])([CH3:59])[CH3:58]
Reactant: CC(C)(C)OC(=O)NCC1CCCCN1
Reactant: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Agent: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: CC(C)(C)OC(=O)NCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1

Procedure:
B7 was prepared following the procedure reported for B4 using A1 and rac-tert-butyl (piperidin-2-yl)methylcarbamate and obtained as a white crystalline solid; yield: 280 mg (65%). MS (ES) C21H31N7O4S requires: 477. found: 478 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[CH:16]=[C:15]([CH2:17][O:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([NH:29][C:30]([NH:32][C:33]3[N:37]([C:38]4[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=4)[N:36]=[C:35]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH:34]=3)=[O:31])=[CH:21][CH:20]=2)[CH:14]=[CH:13][N:12]=1.[Cl:49][CH2:50][C:51](Cl)=[O:52]>C(Cl)Cl.CN(C=O)C>[C:45]([C:35]1[CH:34]=[C:33]([NH:32][C:30](=[O:31])[NH:29][C:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]([O:18][CH2:17][C:15]3[CH:14]=[CH:13][N:12]=[C:11]([NH:10][C:51](=[O:52])[CH2:50][Cl:49])[CH:16]=3)=[CH:20][CH:21]=2)[N:37]([C:38]2[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[N:36]=1)([CH3:48])([CH3:47])[CH3:46]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(N)c3)c3ccccc23)cc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CCl)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
To a solution of DIPEA (1.37 ml, 7.68 mmol) and 1-(4-((2-aminopyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate A) (2.00 g, 3.84 mmol) in DCM (40 mL) and DMF (8.0 mL) was added chloroacetyl chloride (0.61 mL, 7.68 mmol). The reaction mixture was stirred at RT for 1 hr. LC-MS indicated nearly complete consumption of the starting material. A further portion of chloracetyl chloride (100 μl, 1.25 mmol) was added. After stirring for 1 hr at RT, the reaction mixture was partitioned between DCM (40 mL) and saturated aq NaHCO3 solution (40 mL). The organic phase was concentrated in vacuo and purified by column chromatography (80 g, 0-10% MeOH in DCM, gradient elution). Product fractions were concentrated in vacuo and the residue triturated with diethyl ether (20 mL) and iso-hexane (20 mL). The solid was collected by filtration to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) as a light purple solid (1.07 g, 42%): m/z 597, 599 (M+H)+ (ES+).