Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:17]([C:20]4([C:23]5[CH:24]=[C:25]6[C:30](=[CH:31][CH:32]=5)[N:29]=[CH:28][CH:27]=[CH:26]6)[CH2:22][CH2:21]4)=[CH:18][N:19]=3)[CH:16]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:33][O:34][CH2:35][CH:36]([NH2:38])[CH3:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:17]([C:20]4([C:23]5[CH:24]=[C:25]6[C:30](=[CH:31][CH:32]=5)[N:29]=[CH:28][CH:27]=[CH:26]6)[CH2:22][CH2:21]4)=[CH:18][N:19]=3)[CH:16]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:38][CH:36]([CH3:37])[CH2:35][O:34][CH3:33])=[O:6]
Reactant: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F
Reactant: COCC(C)N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)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: COCC(C)NC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoic acid (19 mg, 0.045 mmol), 1-methoxypropan-2-amine (8 mg, 0.090 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (40 mg, 0.090 mmol), and N,N-diisopropylethylamine (31 μL, 0.18 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at RT for 2 h. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=496.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)O)[CH:11]=[N:12][C:13]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.COCCN(S(F)(F)[F:35])CCOC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[N:12][CH:11]=[C:10]([CH:16]([F:35])[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncc(C(O)c2ccc(F)cc2)cc1-c1cccc(Cl)c1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: COc1ncc(C(F)c2ccc(F)cc2)cc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of [5-(3-chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanol (Example 14, 70 mg, 0.18 mmol) in DCM (1 mL) was added Deoxo-Fluor® (79 mg, 0.36 mmol). The solution was stirred at room temperature for 1 h then concentrated under reduced pressure. Purification (FCC, SiO2, 0-10% EtOAc/hexanes) afforded the title compound (21 mg, 34%). 1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.52 (s, 1H), 7.47-7.31 (m, 5H), 7.15 (t, J=8.8 Hz, 2H), 6.70-6.52 (m, 1H), 3.96 (s, 3H). [M+H]=346.17.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:50][CH2:51][C:52]1[C:53]([OH:60])=[N:54][C:55]([CH3:59])=[CH:56][C:57]=1[CH3:58]>ClCCl>[OH:60][C:53]1[C:52]([CH2:51][NH:50][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])=[CH:18][CH:17]=2)=[C:57]([CH3:58])[CH:56]=[C:55]([CH3:59])[N:54]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: O=C(O)c1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(S(=O)(=O)c3ccccc3)cc2)c(O)n1
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
A solution of 4-(phenylsulfonyl)benzoic acid (80 mg, 0.3 mmol) in dichloromethane (15 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (171 mg, 0.45 mmol) and triethylamine (61 mg, 0.6 mmol), stirred for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (50 mg, 0.3 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was washed with water (10 mL), dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-TLC (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(phenylsulfonyl)benzamide as a light yellow solid (108 mg, 90.7%). LRMS (M+H+) m/z: calcd 396.11. found 396. HPLC purity (214 nm): 99%. 1H NMR (300 MHz, d6-DMSO): δ 11.50 (s, 1H), 8.63 (t, J=4.8 Hz, 1H), 8.03-7.98 (m, 6H), 7.76-7.63 (m, 3H), 5.88 (s, 1H), 4.31 (d, J=4.8 Hz, 2H), 2.17 (s, 3H), 2.13 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:29][C:30](=[O:31])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: O=C(CBr)c1ccccc1
Reactant: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(Cl)cnc2[nH]c1=O
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(Cl)cnc2n(CC(=O)c2ccccc2)c1=O

Procedure:
This compound was prepared from 6-chloro-2-oxo-4-[4-(furan-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (101) and 2-bromoacetophenone according to General Procedure B. Yield 233 mg (31%), MP 328° C.; 1H-NMR (DMSO-d6): δ 3.81 (m, 4H), 3.97 (m, 4H), 5.86 (s, 2H), 6.66 (dd, J=1.6, 3.2 Hz, 1H), 7.10 (d, J=3.2 Hz, 1H) 7.59 (m, 2H), 7.73 (m, 1H), 7.90 (d, J=1.6 Hz, 1H), 8.14 (m, 2H), 8.37 (d, J=2.0 Hz, 1H), 8.67 (d, J=2.0 Hz, 1H); EIMS: 502 (M+1). Anal. (C26H20ClN5O4) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=O)([O-])=O>C(O)C.C(OCC)(=O)C.[Pd]>[CH:14]1[N:10]2[C:5]3[C:4]([NH:1][CH2:15][C:11]2=[CH:12][CH:13]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: O=Cc1cccn1-c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: c1ccc2c(c1)NCc1cccn1-2
Reaction time: 2 h
Yield: 44.5 %

Procedure:
To a solution of 1.0 g of 1-(2-nitrophenyl)-1H-pyrrole-2-carboxaldehyde in 40 ml of ethyl alcohol and 40 ml of ethyl acetate, under argon, is added 40 mg of 10% Pd/C. The mixture is hydrogenated at 40 psi for 2 hours and filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a residue which is dissolved in ether and treated with hexanes to give 0.35 g of the desired product as a beige solid m.p. 108°-110° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:14]=[C:13]([CH3:33])[N:12]=1.O>COCCOCCOC>[CH3:33][C:13]1[N:12]=[C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:14]=1
Reactant: Oc1ccccc1
Reactant: Cc1cc(NCCOCCCc2cccnc2)c([N+](=O)[O-])c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: Cc1cc(NCCOCCCc2cccnc2)c([N+](=O)[O-])c(Oc2ccccc2)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 129.4 %

Procedure:
The general method described in Part E of Example 80 was used with the following modifications. A solution of phenol (1.45 g, 15.4 mmol) in diglyme (10 mL) was added to a cooled mixture of the sodium hydride dispersion (0.59 g, 14.7 mmol) in diglyme (15 mL), and the addition flask was rinsed twice with diglyme (5 mL), which was added to the reaction. A solution of (2-chloro-6-methyl-3-nitropyridin-4-yl)-{2-[3-(pyridin-3-yl)propoxy]ethyl}amine (4.9 g, 14 mmol) was added, and the reaction was heated at 60° C. for 20 hours. Additional reagent prepared from phenol (0.50 g, 5.3 mmol) and 60% sodium hydride (0.21 g, 5.3 mmol) in diglyme was added, and the reaction was heated at 60° C. for 2.5 hours. The reaction was allowed to cool to room temperature and slowly added to 800 mL of water and stirred for one hour to form a bright yellow solid. The solid was isolated by filtration and washed with hexane (50 mL) to provide 7.4 g of (6-methyl-3-nitro-2-phenoxypyridin-4-yl)-{2-[3-(pyridin-3-yl)propoxy]ethyl}amine as a yellow solid contaminated with water.
Reaction SMILES: CO/[CH:3]=[C:4]1/[C:5](=[O:15])[NH:6][C:7](=[O:14])[C:8]2[C:13]/1=[CH:12][CH:11]=[CH:10][CH:9]=2.CN(C=O)C.[N:21]1([CH2:28][C:29]2[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=2)[NH2:32])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CCCCCC>[N:21]1([CH2:28][C:29]2[CH:30]=[C:31]([NH:32]/[CH:3]=[C:4]3\[C:5](=[O:15])[NH:6][C:7](=[O:14])[C:8]4[C:13]\3=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:33]=[CH:34][CH:35]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccccc21
Reactant: Nc1cccc(CN2CCCCCC2)c1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C1NC(=O)c2ccccc2/C1=C/Nc1cccc(CN2CCCCCC2)c1
Temperature: 120 °C
Yield: 50.3 %

Procedure:
An amount of (4E)-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione (1.0 g, 4.9 mmol) is added to N,N′-dimethylformamide, followed by 3-(azepan-1-ylmethyl)aniline (1.0 g, 4.9 mmol). The reaction mixture is heated at 120° C. under N2 for 40 minutes. After evaporating to dryness, the red oil is dissolved in warm ethyl acetate and filtered through a pad of celite to give a yellow solution. Addition of hexane into this organic solution yielded an orange precipitate, which is collected and recrystallized from EtOAc/Hex to give orange crystal (0.925 g, 50.05% yield): mp 116-117° C.; 1H NMR (DMSO-d6) δ 12.43 (d, J=9 Hz, 1H), 11.33 (s, 1H), 8.80 (d, J=9 Hz, 1H), 8.18 (d, J=9 Hz, 1H), 8.04 (d, J=9 Hz, 1H), 7.63 (t, J=6 Hz, 1H), 7.46 (s, 1H), 7.39 (m, 2H), 7.30 (t, J=3 Hz, 1H), 7.17 (d, J=6 Hz, 1H), 3.64 (s, 2H), 2.60 (s, 4H), 1.58 (m, 8H); MS (ESI) m/z 376.1 (M+H)+1; Analysis for C23H25N3O2; Calcd: C, 73.6; H, 6.71; N, 11.2. Found: C, 72.92; H, 6.45; N, 11.03.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][N:7]1[C:11]([C:12](=[O:29])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[N:18]([N:20]=[C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[N:22]=3)[CH:19]=2)=[C:10]([C:30](O)=[O:31])[CH:9]=[N:8]1>>[N:23]1([C:21]2[N:22]=[C:17]3[CH:16]=[CH:15][C:14]([NH:13][C:12]([C:11]4[N:7]([CH3:6])[N:8]=[CH:9][C:10]=4[C:30]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:31])=[O:29])=[CH:19][N:18]3[N:20]=2)[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: C1CCNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Product: Cn1ncc(C(=O)N2CCCC2)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1

Procedure:
Using pyrrolidine and 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. Brown solid (110 mg, 64%). MS: m/z=425 (M+H+).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C@@H:13]2[C@@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([OH:21])[C@H:15]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH2:29][C:30]4[S:31][C:32]([C:35]5[O:36][CH:37]=[CH:38][CH:39]=5)=[CH:33][N:34]=4)[CH:23]=3)[O:14]2)(=O)=O)=CC=1.[CH3:40][O-].[Na+]>CO>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C@H:15]2[C@H:16]([OH:21])[C@@H:17]([OH:20])[C@H:18]([OH:19])[C@@H:13]([CH2:12][O:11][CH3:40])[O:14]2)=[CH:23][C:24]=1[CH2:29][C:30]1[S:31][C:32]([C:35]2[O:36][CH:37]=[CH:38][CH:39]=2)=[CH:33][N:34]=1
Reactant: C[O-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](c3ccc(Cl)c(Cc4ncc(-c5ccco5)s4)c3)[C@H](O)[C@@H](O)[C@@H]2O)cc1
Agent: [Na+]
Solvent: CO
Product: COC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 56 %

Procedure:
The solution of toluenesulfonate 90 (104 mg, 0.18 mmol) and NaOMe (25 wt. % in MeOH, 5 mL) in methanol (3.5 mL) was stirred at room temperature for 15 h. After reaction complete, the resulting solution was quenched with H2O. Reaction mixture was evaporated under reduced pressure. The residue was purified by prep HPLC (C18) to afford the titled compound 91 (12 mg, 56%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][NH:10][CH:11]1[CH:15]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:14][N:13]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:12]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:43][CH2:44][C:45](Cl)=[O:46]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][N:10]([CH:11]1[CH:15]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])[CH2:14][N:13]([C:24](=[O:32])[C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[CH2:12]1)[C:45](=[O:46])[CH2:44][Cl:43])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCNC1CN(C(=O)c2ccc(Cl)cc2)CC1O[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCN(C(=O)CCl)C1CN(C(=O)c2ccc(Cl)cc2)CC1O[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of {2-[4-(tert-butyl-dimethyl-silanyloxy)-1-(4-chloro-benzoyl)-pyrrolidin-3-ylamino]-ethyl}-carbamic acid tert-butyl ester (389 mg, 0.78 mmol) at 0° C., was added DIPEA (0.150 mL, 0.85 mmol) and chloroacetyl chloride (62 uL, 0.78 mmol). The reaction mixture was stifled at RT for overnight. The organic phase was washed with Sat. NaHCO3, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (Ethyl acetate:Hexane: 1:2) to give the desired product (260 mg, 58% yield) as a colorless oil. MS: (ESI), M/Z, 574 (M+1). Retention time: 2.78 min (FA-polar).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[CH:9]2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[O:3]1.C(N1C=CN=C1)(N1[CH:27]=[CH:26]N=C1)=O.C(=O)=O.[O-]CC.[Na+]>CN(C)C=O.C(O)C>[CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([N:8]2[C:12]([C:13]([O:15][CH2:26][CH3:27])=[O:14])=[CH:11][N:10]=[CH:9]2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[O:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(C)CC(n2cncc2C(=O)O)c2ccccc2O1
Agent: CC[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1cncn1C1CC(C)(C)Oc2ccccc21
Yield: 63.5 %

Procedure:
A solution of 3.3 parts of 1-(2,3-dihydro-2,2-dimethyl-4H-1-benzopyran-4-yl)-1H-imidazole-5-carboxylic acid in 45 parts in warm N,N-dimethylformamide was cooled to room temperature and then 2 parts of 1,1'-carbonylbis[1H-imidazole] were added. The whole was stirred at room temperature till CO2 evolution had ceased (±30 minutes). The mixture was heated to ±70° C. and 2.4 parts of ethanol and 0.1 parts of sodium ethoxide were added. Stirring was continued over weekend at ±70° C. After evaporation, the residue was taken up in water and trichloromethane. The organic layer was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from hexane. The product was filtered off and dried, yielding 2.36 parts (63.5%) of ethyl 1-(2,3-dihydro-2,2-dimethyl-4H-1-benzopyran-4-yl)-1H-imidazole-5-carboxylate; mp. 80.9° C. (compound 1.138).
Reaction SMILES: Cl.NC1NC=C(CO)N=1.Cl.Cl.NCCS.[NH2:16][C:17]1[NH:18][CH:19]=[C:20]([CH2:22][S:23][CH2:24][CH2:25][NH2:26])[N:21]=1.[N+:27]([CH:30]=[C:31](SC)[S:32][CH3:33])([O-:29])=[O:28]>>[N+:27]([CH:30]=[C:31]([S:32][CH3:33])[NH:26][CH2:25][CH2:24][S:23][CH2:22][C:20]1[N:21]=[C:17]([NH2:16])[NH:18][CH:19]=1)([O-:29])=[O:28]
Reactant: NCCSCc1c[nH]c(N)n1
Reactant: CSC(=C[N+](=O)[O-])SC
Agent: Cl
Agent: NCCS
Agent: Nc1nc(CO)c[nH]1
Product: CSC(=C[N+](=O)[O-])NCCSCc1c[nH]c(N)n1

Procedure:
Reaction of 2-amino-4-hydroxymethylimidazole hydrochloride (which is obtained by treating the pierate salt with hydrochloric acid) with cysteamine hydrochloride and reaction of the resulting 2-amino-4-[(2-aminoethyl)thiomethyl]imidazole with 1-nitro-2,2-bis-methylthioethylene according to the procedure of Example 8(i) gives 1-nitro-2-methylthio-2-[2-((2-amino-4-imidazolyl)methylthio)ethylamino]ethylene. Finally, reaction with methylamine by the procedure of Example 8(ii)produces the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[NH3:15]>CO.CCOC(C)=O>[NH2:15][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: N
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(SC)nc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a stirred solution of ethyl 4-chloro-2-methylsulfanyl-5-pyrimidinecarboxylate (4.50 g, 19.4 mmol) in MeOH is added 7 N NH3 (13.9 mL) in MeOH at 0° C. and the mixture is stirred for 2 h at room temperature. The reaction mixture is diluted with EtOAc and washed with saturated NaHCO3 solution. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is crystrallized from the mixed solvent of EtOAc and hexanes to give 2.90 g (66%) of ethyl 4-amino-2-methylsulfanyl-5-pyrimidinecarboxylate as a white solid.
Reaction SMILES: C[Mg]Br.[C:4]1(C)C=CC=CC=1.C1COCC1.[Cl:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23](N(OC)C)=[O:24])[CH:18]=1>C1COCC1>[Cl:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23](=[O:24])[CH3:4])[CH:18]=1
Reactant: Cc1ccccc1
Reactant: CON(C)C(=O)c1cc(Cl)ccn1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 79.7 %

Procedure:
To a 0° C. solution of 1.4 M methyl magnesium bromide in toluene/THF (6.89 mL, 9.65 mmol) in anhydrous THF (8.77 mL) was added a solution of 4-chloro-N-methoxy-N-methylpyridine-2-carboxamide (1.06 g, 5.26 mmol) in anhydrous THF (8.77 mL). The reaction mixture was stirred at RT under N2 for 17 h. The volatile solvent was removed under reduced pressure, and partitioned between EtOAc and water. The organic layer was washed with H2O, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by MPLC (biotage) eluted with 10% EtOAc/Hex to afford 652 mg of 1-(4-chloropyridin-2-yl)ethanone (95.5%) as a white crystalline solid. 1H-NMR (Acetone-d6) δ 8.69 (d, J=5.4 Hz, 1H), 7.95 (dd, J=2.1, 1.0 Hz, 1H), 7.71 (dd, J=5.4, 2.1 Hz, 1H), 2.65 (s, 3H); TLC (10% EtOAc/Hex), Rf=0.26.
Reaction SMILES: N#N.[C:3]([NH:7][C:8]1[N:13]=[C:12]([C:14]#[CH:15])[CH:11]=[CH:10][N:9]=1)([CH3:6])([CH3:5])[CH3:4].I[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1>CCN(CC)CC.C1COCC1.[Cu]I>[C:3]([NH:7][C:8]1[N:13]=[C:12]([C:14]#[C:15][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:11]=[CH:10][N:9]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: C#Cc1ccnc(NC(C)(C)C)n1
Reactant: Fc1ccc(I)cc1
Agent: [Cu]I
Agent: N#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)Nc1nccc(C#Cc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.4 %

Procedure:
To a mixture of Pd(PPh3)Cl2 (0.4 g) in Et3N (150 mL) and THF (150 mL) under a stream of N2, was added tert-butylamino-4-ethynylpyrimidine (18.6 g, 0.11 mol). After bubbling N2 into the solution for 15 min, 4-iodo-fluorobenzene (23.6 g, 0.11 mol) and CuI (0.22 g) were added sequentially. The mixture was stirred at rt for 2.5 h. The precipitate was filtered and washed with EtOAc. The filtrate was concentrated and the residue was diluted with EtOAc and loaded directly onto a short pad of silica gel. The product was eluted with 10% EtOAc in hexanes to afford the crude product, which was recrystallized from EtOAc/hexanes to give the title compound as a light yellow solid (25 g, 84%). TLC: Rf=0.30. mp 97-99° C. IR: 3287 (w), 2964 (w), 2222 (w), 1566 (s). 1H NMR: 8.26 (d, J=4.2 Hz, 1H), 7.60-7.55 (m, 2H), 7.10-7.00 (m, 2H), 6.65 (d, J=4.9 Hz, 1H), 5.22 (s, 1H), 1.45 (s, 9H). 13C NMR: 164.19, (162.19, 162.03), 157.77, 150.83, (134.35, 134.29), (117.84, 117.81), (115.94, 115.76), 112.37, 89.91, 87.24, 51.07, 28.86. Anal. Calcd for C16H16FN3: C, 71.36; H, 5.99; N, 15.60. Found: C, 71.25; H, 5.95; N, 15.66.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:8][C:7](=[O:27])[CH2:6][CH2:5]1.[C:28](OC(=O)C)(=[O:30])[CH3:29].O>N1C=CC=CC=1>[C:28]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C@@H:11]1[CH2:10][C:9]2[C@H:4]([CH2:5][CH2:6][C:7](=[O:27])[CH:8]=2)[C@@H:3]2[C@@H:12]1[C@H:13]1[C@@:17]([CH2:19][C@@H:2]2[F:1])([CH3:18])[C:16](=[O:20])[CH2:15][CH2:14]1)(=[O:30])[CH3:29]
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCO)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Reaction time: 0.75 h

Procedure:
20 g of 11β-fluoro-7α-(5-hydroxypentyl)-estr-4-ene-3,17-dione in 100 ml of pyridine can be reacted over a period of 2 hours with 50 ml of acetic anhydride at 25° C. Then, 5 ml of water is added at 0° C., and it is stirred for 45 minutes. It is extracted with diethyl ether, washed with 2N sulfuric acid, pyridine-free, and the solution is neutralized in succession with saturated sodium bicarbonate solution and water. After drying and concentration by evaporation in a vacuum, the crude product is chromatographed on silica gel with a hexane-ethyl acetate-gradient. 17 g of 7α-(5-acetoxypentyl)-11β-fluoro-estr-4-ene-3,17-dione with a melting point of 78.4° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=O)=[N:9]2)=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][NH:19][CH2:18][C:17]3[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:16]=3[O:15][CH3:14])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=Cc1ccc2ccc(Br)cc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(CNCc2ccc3ccc(Br)cc3n2)c(OC)c1
Reaction time: 3.5 h
Yield: 98.3 %

Procedure:
7-Bromo-quinoline-2-carbaldehyde (354 mg, 1.50 mmol, prepared as described in EP 239746) was dissolved in 1,2-dichloroethane (15 mL) and 2,4-dimethoxybenzylamine (251 mg, 225 μL, 1.50 mmol) was added and the reaction mixture stirred for 5 minutes before sodium triacetoxyborohydride (477 mg, 2.25 mmol) was added. After 3.5 h stirring the reaction mixture was quenched with saturated sodium hydrogen carbonate solution and ethyl acetate was added. The organic layer was separated and washed with sodium hydrogen carbonate and the combined aqueous layers were extracted with ethyl acetate. The organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to give the crude, title compound as a yellow gum (571 mg) which was used without further purification. LCMS (m/z) 387.0, 389.0 [M+H], Tr=1.57 min.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:23][CH2:24][N:25]([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27]>C(#N)C>[CH3:15][O:14][C:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:2]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:3]([OH:5])=[O:4])=[CH:7][CH:8]=1)=[O:13].[CH2:24]([N:25]([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH3:23]
Reactant: COC(=O)c1ccc(C(Br)C(=O)O)cc1
Reactant: Nc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C(Nc2ccccc2)C(=O)O)cc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 35.9 %

Procedure:
2-Bromo-2-(4-(methoxycarbonyl)phenyl)acetic acid (700 mg, 2.56 mmol), aniline (0.23 mL, 2.56 mmol), and DIPEA (0.94 mL, 5.38 mmol) are dissolved in acetonitrile (5 mL). The reaction is stirred at 100° C. under microwave irradiation for 15 minutes. Acetonitrile is evaporated and the residue is dissolved in DCM and washed with water and brine. The organic layer is dried (Na2SO4), filtered and evaporated. The crude compound is purified by flash chromatography (DCM/MeOH=9/1) to obtain intermediate I142 as a white solid (381 mg, 37% yield).