Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:13]([NH:14][C:15](=[O:26])/[C:16](/[C:20]3[N:21]=[C:22]([NH2:25])[S:23][CH:24]=3)=[N:17]\[O:18][CH3:19])[C:12](=[O:27])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10].Cl[C:29]1[N:30]([CH3:50])[N:31]=[C:32]([O:36][CH:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:33](=[O:35])[N:34]=1.C(N(CC)CC)C.C(O)=O>CN(C=O)C>[NH2:25][C:22]1[S:23][CH:24]=[C:20](/[C:16](=[N:17]/[O:18][CH3:19])/[C:15]([NH:14][CH:13]2[C:12](=[O:27])[N:7]3[C:8]([C:9]([OH:11])=[O:10])=[C:3]([CH2:2][NH:1][C:29]4[N:30]([CH3:50])[N:31]=[C:32]([O:36][CH:37]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[C:33](=[O:35])[N:34]=4)[CH2:4][S:5][C@H:6]23)=[O:26])[N:21]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN)CS[C@H]12)c1csc(N)n1
Reactant: Cn1nc(OC(c2ccccc2)c2ccccc2)c(=O)nc1Cl
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CNc3nc(=O)c(OC(c4ccccc4)c4ccccc4)nn3C)CS[C@H]12)c1csc(N)n1
Reaction time: 3.5 h

Procedure:
A solution of 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-methoxyimino)acetamido]ceph-3-em-4-carboxylic acid (200 mg.), 2,5-dihydro-3-chloro-6-diphenylmethoxy-2-methyl-5-oxo-1,2,4-triazine (160 mg.) was triethylamine (200 ul.) in DMF (4 ml.) at 0° was allowed to stand for 3.5 hours. Formic acid (1 ml.) was added and the solvent was evaporated to give 7-[2-(2-aminothiazol-4-yl)-2-((Z)-methoxyimino)acetamido]-3-[(2,5-dihydro-6-diphenylmethoxy-2-methyl-5-oxo-1,2,4-triazin-3-yl)aminomethyl]ceph-3-em-4-carboxylic acid which was used without further purification. nmr in solvent B:--3.52 (s, 3 H); 3.6 (s, 2 H); 4.04 (s, 3 H); 4.4 (s, 2 H); 5.18 (d, 1 H); 5.84 (d, 1 H); 7.1 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:4][CH:3]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:16]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:4][CH:3]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(S(=O)(=O)O)c2ccccc12
Solvent: c1ccncc1
Product: O=C(Nc1ccc(S(=O)(=O)O)c2ccccc12)c1ccccc1
Reaction time: 8 h
Yield: 61.1 %

Procedure:
To a solution of 4-amino-naphthalene-1-sulfonic acid (2.3 g, 10.0 mmol) in pyridine (15 mL), was added benzoyl chloride (1.4 mL, 12.0 mmol) and the resultant solution was heated at 100° C. and stirred overnight. The solvent was removed in vacuo and the crude material was recrystallized from MeOH (2×) to give the pyridinium salt of 4-benzoylamino-naphthalene-1-sulfonic acid (2.0 g) as a gray colored solid. 1H NMR (300 MHz, DMSO) δ 8.92 (m, 3H), 8.60 (t, 1H), 8.00 (m, 6H), 7.55 (m, 6H); LC/MS m/z 327 (M−H)−.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]2[S:12][C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[CH:17][C:16]=4[N:22]([S:27]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)(=[O:29])=[O:28])CC(O)=O)=[N:10][CH2:9]2)[CH2:3][CH2:2]1.Cl.C[N:37](C)[CH2:38][CH2:39]CN=C=NCC.C(=O)([O-])[OH:48].[Na+]>CN(C)C=O>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]2[S:12][C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[CH:17][C:16]=4[N:22]([S:27]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)(=[O:28])=[O:29])[C:39](=[O:48])[CH2:38][NH2:37])=[N:10][CH2:9]2)[CH2:3][CH2:2]1
Reactant: O=C(O)CN(c1cccc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=C([O-])O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: NCC(=O)N(c1cccc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of N-{2-[5-(morpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-(2-thienylsulfonyl)glycine (60 mg) in N,N-dimethylformamide (5 mL) were added 1H-1,2,3-benzotriazol-1-ol-ammonia complex (30 mg) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (35 mg) under ice-cooling, and the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The residue was recrystallized from a mixed solvent of ethyl acetate-hexane to give the title compound (43 mg, yield 71%) as white crystals. MS: 520 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:20]([CH3:22])[CH3:21])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Reaction time: 18 h
Yield: 104.6 %

Procedure:
Methyl 3-chloro-4-hydroxybenzoate (50 g, 0.27 mole; available from Alfa Aesar), potassium carbonate (74 g, 0.54 mole) and 2-iodopropane (29.5 ml, 0.23 mole) were stirred at room temperature in DMF (100 ml). After 18 hours, the solvent was removed by evaporation under vacuum and the residue was chromatographed over a column of silica 60 eluting with ethyl acetate/hexane (1:1) to give the title compound as an oil (55 g). MS: m/z (API-ES) 229 [MH+]; 1H NMR (400 MHz, CDCl3) δ (inter alia) 8.05 (1H, d), 7.89 (1H, dd), 6.94 (1H, d), 4.60-4.72 (1H, m), 3.89 (3H, s), 1.41 (6H, d).
Reaction SMILES: CN(C(ON1N=N[C:11]2[CH:12]=[CH:13][CH:14]=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:34](O)(=[O:36])[CH3:35].[Cl:38][C:39]1[CH:40]=[C:41]([NH:53][C:54]2[C:63]3[C:58](=[CH:59][CH:60]=[CH:61][C:62]=3[O:64][CH2:65][CH2:66][NH:67][CH3:68])[N:57]=[CH:56][N:55]=2)[CH:42]=[CH:43][C:44]=1[O:45][CH2:46]C1C=CC=CN=1>C(Cl)Cl>[Cl:38][C:39]1[CH:40]=[C:41]([CH:42]=[CH:43][C:44]=1[O:45][CH2:46][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][N:15]=1)[NH:53][C:54]1[C:63]2[C:58](=[CH:59][CH:60]=[CH:61][C:62]=2[O:64][CH2:65][CH2:66][N:67]([CH3:68])[C:34](=[O:36])[CH3:35])[N:57]=[CH:56][N:55]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(=O)O
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reaction time: 2 h
Yield: 69 %

Procedure:
A mixture of HATU (197 mg), diisopropylethylamine (90 μl), acetic acid (22 μl) and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine (150 mg) in DCM (20 ml) was stirred for 2 hours. The solution washed with water, then brine and concentrated in vacuo. The residue was purified by chromatography using DCM—5% methanol as eluent to give the title compound as a white solid (114 mg, 69%); NMR spectrum (DMSO-d6) 1.95 (s, 3H), 3.00 (s, 3H), 3.89 (t, 2H), 4.48 (m, 2H), 5.29 (s, 2H), 7.18 (d, 1H), 7.24 (d, 1H), 7.35 (m, 2H), 7.59 (m, 2H), 7.72 (dd, 1H), 7.85 (dt, 1H), 7.96 (d, 1H), 8.46 (s, 1H), 8.58 (m, 1H), 9.70 (bs, 1H); Mass spectrum MH+ 478.5.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:5]=1[CH:6]=O.[CH:15](=[O:18])[CH2:16][CH3:17].C(O)(=O)C>O.CO>[Cl:3][C:4]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:5]=1[CH:6]=[C:16]([CH3:17])[CH:15]=[O:18]
Reactant: CCC=O
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(C=O)=Cc1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 78 %

Procedure:
4 g of NaOH dissolved in 20 ml of water were added to a suspension of 185.5 g (1 mole) of 2-chloro-5-nitrobenzaldehyde in 500 ml of methanol, after which 70 g (1.2 moles) of propionaldehyde were added dropwise while cooling to 10°-15° C. The mixture was stirred for 2 days at room temperature and then neutralized with glacial acetic acid, and the precipitated solid was isolated by filtration under suction, washed with water and dried at 50° C. under reduced pressure to give the product of melting point 99°-102° C. in 78% yield.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[OH:11].[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>ClCCl>[OH:11][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[CH2:9][NH:8][C:20](=[O:23])[CH2:21][CH3:22]
Reactant: COc1cccc(C(O)CN)c1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NCC(O)c1cccc(OC)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (52 ml, 0.37 mol) was added to the amine from example 1 (31.3 g, 0.19 mol) in dichloromethane (400 ml) and reaction mixture stirred under an atmosphere of nitrogen gas at 0° C. for 10 minutes. Propionyl chloride (16.3 ml, 0.19 mol) was added and after stirring for 30 minutes, the reaction temperature was raised to room temperature for a further 5 hours. The reaction mixture was quenched 1 N HCl (aq) (100 ml) and then extracted with dichloromethane (2×50 ml). The organic fractions were combined, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a colourless oil that crystallised on standing to white crystals (28 g, 0.13 mol, 67%). 1H NMR (CDCl3, 400 MHz) δ: 1.18 (t, 3H), 2.22 (q, 2H), 2.51 (bs, 1H), 3.31 (m, 1H), 3.71 (dd, 1H), 3.80 (s, 3H), 4.81 (m, 1H), 5.95 (bs, 1H), 6.80 (d, 1H), 6.90 (d, 1H), 6.91 (s, 1H), 7.22 (t, 1H). LRMS: m/z 224. Mpt: 77-78° C. Analysis found C, 63.86; H, 7.82; N, 6.28%. C12H17NO3.0.1H2O requires C, 64.04; H, 7.70; N, 6.22%.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[N:7]12[CH2:13][CH:10]([CH2:11][CH2:12]1)[C:9](=O)[CH2:8]2.[C:15]([OH:18])(=[O:17])[CH3:16].[C:19]([OH:24])(=[O:23])[C:20]([OH:22])=[O:21]>CN(C=O)C.CCOCC.CO>[C:19]([OH:24])(=[O:23])[C:20]([OH:22])=[O:21].[CH2:1]([O:17][C:15](/[CH:16]=[C:9]1\[CH2:8][N:7]2[CH2:13][CH:10]\1[CH2:11][CH2:12]2)=[O:18])[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: O=C1CN2CCC1C2
Reactant: CC(=O)O
Agent: O=C(O)C(=O)O
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CO
Product: CCOC(=O)/C=C1\CN2CCC1C2
Temperature: 25 °C

Procedure:
Triethylphosphonoacetate (2.69 g, 0.012 moles) in dry DMF (10 ml) was treated with potassium t-butoxide (1.59 g, 0.013 moles) at 0° C. with continuous stirring under an atmosphere of nitrogen. After 30 minutes (±)1-azabicyclo [2.2.1]heptan-3-one (D6, 1.11 g, 0.01 moles) in DMF (10 ml) was added at 0° C. and the stirred solution allowed to warm to room temperature over a period of 30 min. After standing at room temperature for lh the reaction was neutralised with acetic acid and concentrated in vacuo to a gum. The gum was then partitioned between aqueous potassium carbonate and chloroform. The chloroform solution was separated and concentrated in vacuo to a gum. Kugelrohr distillation in vacuo afforded a colourless oil b.pt 200° C. at 0.5 mm. The oil was dissolved in ether (20 ml) and treated with oxalic acid (900 mg) in methanol (2 ml). The title compound oxalate salt (D1) slowly crystallised out. Recrystallisation from methanol-ether afforded the pure title compound free from the E isomer as needles (D1) (2.13 g; 78%). m.p. 140°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[N:11]([CH3:12])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:17][C:6]1[C:7]2[N:11]([CH3:12])[C:10]([C:13]([F:16])([F:14])[F:15])=[N:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1cccc2c1nc(C(F)(F)F)n2C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)c2c1nc(C(F)(F)F)n2C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
To a solution of 7-methoxy-3-methyl-2-trifluoromethylbenzimidazole (1.4 g) in chloroform (50 ml) under nitrogen was added N-bromosuccinimide (1.2 g). The mixture was stirred for 20 minutes before the reaction was quenched by the addition of 5% sodium metabisulphite solution (50 ml) and the organic layer was separated. Washing with water (50 ml), drying over anhydrous magnesium sulphate and removal of the solvent in vacuo gave an orange oil. Purification by flash chromatography eluting with 50% ethyl acetate in hexane gave the title compound as an orange solid (1.73 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:15])[CH:10]=[N:9]2)=[C:5]([CH3:25])[O:4][N:3]=1.[C:26](=[O:31])=[N:27][C:28](Cl)=[O:29]>C1COCC1>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:28](=[O:29])[NH:27][C:26](=[O:31])[N:16]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:14]3=[O:15])[CH:10]=[N:9]2)=[C:5]([CH3:25])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(NC(=O)NCCc2ccccc2)cn1
Reactant: O=C=NC(=O)Cl
Solvent: C1CCOC1
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]c(=O)n(CCc3ccccc3)c2=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-3-phenethylurea (example 9-7a) (100 mg, 0.29 mmol) in THF (2 mL) was cooled to 0° C. and n-chlorocarbonyl isocyanate (93 mg, 0.88 mmol) was slowly added. After addition, the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was concentrated and the residue was purified by silica column chromotography (100% to 90% dichloromethane in methanol:30 minute gradient) to afford (1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-3-phenethyl-1,3,5-triazinane-2,4,6-trione (100 mg, 83%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.13 (s, 3H), 2.39 (s, 3H), 2.82 (t, J=5.8 Hz, 2H), 3.88 (t, J=8.0 Hz, 2H), 5.17 (s, 2H), 7.19-7.31 (m, 5H), 7.44 (s, 1H), 7.89 (s, 1H), 11.84 (s, 1H). LC/MS; [M+H] calculated for C20H20N6O4; expected 409.15; found 409.20. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 3.03 μM.
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][CH2:9][C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=2)[NH2:16])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:20]1([C:25]#[N:26])[CH2:24][CH2:23][CH2:22][CH2:21]1>ClC1C=CC=CC=1.CN(C)C1C=CN=CC=1>[ClH:1].[C:2]1([CH2:8][CH2:9][C:10]([NH:12][C:13]2[CH:14]=[C:15]([NH:16][C:25]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[NH:26])[CH:17]=[CH:18][CH:19]=2)=[O:11])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(NC(=O)CCc2ccccc2)c1
Reactant: N#CN1CCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Clc1ccccc1
Product: N=C(Nc1cccc(NC(=O)CCc2ccccc2)c1)N1CCCC1
Temperature: 25 °C

Procedure:
To a stirred suspension of the product of step (a), 2.0 g, 0.006 moles, in 35 ml of chlorobenzene was added 4-dimethylaminopyridine. To this was added 1-pyrrolidinecarbonitrile, 1.2 ml, 0.06 moles, and the reaction was heated to reflux for 4 hours. The reaction was cooled to room temperature and the solvent decanted. To the residue was added 25 ml of isopropanol and 150 ml of ethyl acetate. A solid crystallized and was collected by filtration. The above solid was then dried at 60° C. for 24 hours giving 700 mg of N-(3-(((2-phenylethyl)carbonyl)amino)phenyl)-1-pyrrolidinecarboximidamide hydrochloride, m.p. 220-221° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[F:27])[CH2:16][CH2:15]3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33]([NH:35][NH2:36])=[O:34]>CN1C(=O)CCC1>[NH2:8][C:6]1[N:7]=[C:2]([NH:36][NH:35][C:33]([C:29]2[O:28][CH:32]=[CH:31][CH:30]=2)=[O:34])[C:3]2[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[F:27])[CH2:16][CH2:15]3)[C:4]=2[N:5]=1
Reactant: Nc1nc(Cl)c2ccn(CCN3CCN(c4ccc(F)cc4F)CC3)c2n1
Reactant: NNC(=O)c1ccco1
Solvent: CN1CCCC1=O
Product: Nc1nc(NNC(=O)c2ccco2)c2ccn(CCN3CCN(c4ccc(F)cc4F)CC3)c2n1
Temperature: 25 °C

Procedure:
A solution of the title A compound, 4-chloro-7-(2-(4-(2,4-difluorophenyl)piperazin-1-yl)ethyl) -7H-pyrrolo[2,3-d]pyrimidin-2-amine (75 mg, 0.19 mmol) and 2-furoic acid hydrazide (49 mg, 0.39 mmol) in 1 mL of NMP is heated at 150° C. for 3 h. After cooling to RT, the crude reaction is purified by column chromatography on silica gel, eluting with a gradient of 5% to 10% of MeOH in EtOAc. Fractions containing the product are combined and evaporated to dryness to afford N′-(2-amino-7-(2-(4-(2,4-difluorophenyl)piperazin-1-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)furan-2-carbohydrazide yellow solid: LC/MS (M+1=483.2).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[CH3:19][C:20]1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O.Cl[C:35]1[N:40]=[C:39]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:44][C:43]=2OC)[C:38]([Cl:56])=[CH:37][N:36]=1.C(O)(C(F)(F)F)=O>>[Cl:56][C:38]1[C:39]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:44][C:43]=2[CH2:19][CH3:20])=[N:40][C:35]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][C:2]([F:17])([F:18])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:36][CH:37]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(NCC(F)(F)F)CC2
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)(F)F)CC3)ncc1Cl
Yield: 8.3 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2,2-Trifluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine (75 mg, 0.290 mmol) was combined with DL-10-camphorsulfonic acid (101 mg, 0.436 mmol) and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (103 mg, 0.290 mmol) to prepare 5-Chloro-N*4*-(2-ethyl-4-morpholin-4-yl-phenyl)-N*2*-[7-(2,2,2-trifluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]-pyrimidine-2,4-diamine (13.82 mg, 8.4% yield) as a yellow TFA salt. 1H-NMR (CDCl3) δ 8.24 (dd, J=26.9, 8.81 Hz, 1H), 8.00 (m, 1H), 7.87 (br s, 1H), 7.47 (m, 1H), 6.95 (m, 1H), 6.53 (m, 3H), 3.89 (m, 7H), 3.16 (m, 4H), 2.84 (m, 2H), 2.69 (m, 2H), 2.04 (m, 2H), 1.29 (m, 2H). LC/MS (ESI+)=571 (M+H). MP=155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[SH:23].CN(C=O)C>CS(C)=O>[Cl:9][C:6]1[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=[C:2]([Cl:1])[C:7]=1[S:23][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1
Reactant: Sc1ccc2ccccc2c1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1

Procedure:
2-(2,6-Dichloro-4-nitro-phenylsulfanyl)-napthalene was synthesized (100%) from 3,4,5-trichloronitrobenzene (Acros) and napthalene-2-thiol (Avocado) in a similar manner as described in example 1 using DMSO as solvent instead of DMF.
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[C:11](#[N:24])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>C(O)C.O.C(O)C>[OH:3][NH:2][C:11](=[NH:24])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCC#N
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCC(=N)NO
Reaction time: 0.03 h
Yield: 26.5 %

Procedure:
Hydroxylamine hydrochloride (0.90 g, 12.9 mmol) was added to a solution of triethylamine (1.79 mL, 12.9 mmol) in 50% ethanol/water (4 mL) and the mixture was stirred for 2 minutes. Tridecane nitrile (2.02 g, 10.4 mmol) in ethanol (10 mL) was added and the mixture refluxed for 2 hours, allowed to cool, and poured into water (50 mL). The precipitate was collected, stirred with hexanes, and filtered to yield a white solid (0.63 g, 26%). EI+ 229, 196, 85, 74.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]2[N:15]=[C:16]([CH3:18])[CH:17]=[C:4]2[N:3]=1.[I:19]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]2[N:15]=[C:16]([CH3:18])[C:17]([I:19])=[C:4]2[N:3]=1
Reactant: Cc1cc2nc(Cl)cc(-c3cccc(Cl)c3)n2n1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: Cc1nn2c(-c3cccc(Cl)c3)cc(Cl)nc2c1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
5-Chloro-7-(3-chlorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine (186 mg) is dissolved in CH2Cl2 (40 mL) and N-iodosuccinimide (NIS, 323 mg) is added to the reaction solution. The reaction mixture is stirred at room temperature for 16 hours. The reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with 1 M NaHCO3 aqueous solution and brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield the target compound (237 mg). 1H NMR (CDCl3, 300 MHz) δ 7.99 (s, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.53 (m, 3H), 6.85 (s, 1H), 2.51 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@H:10]2[N:15]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:14](=[O:21])[C:13]3([CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22]3)[NH:12][CH2:11]2)[CH:6]=[C:7]([F:9])[CH:8]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[F:9][C:7]1[CH:6]=[C:5]([C@H:10]2[N:15]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:14](=[O:21])[C:13]3([CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27]3)[N:12]([CH3:28])[CH2:11]2)[CH:4]=[C:3]([F:2])[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CN1C(=O)C2(COCCOC2)NC[C@H]1c1cc(F)cc(F)c1
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)CN1C(=O)C2(COCCOC2)N(C)C[C@H]1c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
0.10 g (0.25 mmol) (R)-methyl 2-(3-(3,5-difluorophenyl)-5-oxo-8,11-dioxa-1,4-diazaspiro[5.6]dodecan-4-yl)acetate hydrochloride in 20 ml acetonitrile were combined with 83 mg (0.60 mmol) potassium carbonate and with 0.04 ml (0.60 mmol) methyl iodide. The reaction mixture was stirred for 5 days at RT. Then the reaction was evaporated down and reacted without any further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[O:17]=[C:18]1[NH:23][CH:22]=[C:21]([CH2:24][C:25]#[N:26])[CH:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:16][C:12]1[CH:11]=[C:10]([C:4]2[N:3]=[C:2]([O:17][C:18]3[N:23]=[CH:22][C:21]([CH2:24][C:25]#[N:26])=[CH:20][CH:19]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: N#CCc1ccc(=O)[nH]c1
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(Oc2ccc(CC#N)cn2)nc(-c2cccc(Cl)c2)n1
Yield: 15.8 %

Procedure:
A solution of 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.300 g, 1.19 mmol), 2-(6-oxo-1,6-dihydropyridin-3-yl)acetonitrile (0.239 g, 1.78 mmol), and potassium carbonate (0.246 g, 1.78 mmol) in DMF (3 mL) was heated with microwave irradiation to 120° C. for 1 h. After this time, the reaction was cooled and concentrated. The residue was purified by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford the title compound (0.066 g, 22%). MW=350.80. 1H NMR (CD3OD, 300 MHz) δ 8.51-8.41 (m, 2H), 8.32-8.28 (m, 1H), 7.89 (s, 1H), 7.64 (dd, J1=12.1 Hz, J2=2.6 Hz, 1H), 7.56-7.47 (m, 2H), 6.70 (d, J=9.5 Hz, 1H), 3.87-3.82 (m, 2H), 2.98 (q, J=7.6 Hz, 2H), 1.46-1.8 (m, 3H); APCI MS m/z 351 [M+H]+.