Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Cl.[N:13]([O-])=O.[Na+].[Br:17][C:18]1[CH:22]=[CH:21][O:20][C:19]=1[C:23](=[O:28])[CH2:24][C:25](=[O:27])[CH3:26].C([O-])(=O)C.[Na+]>O.CO>[Br:17][C:18]1[CH:22]=[CH:21][O:20][C:19]=1[C:23](=[O:28])[C:24](=[N:13][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[C:25](=[O:27])[CH3:26]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC(=O)CC(=O)c1occc1Br
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)C(=NNc1cccc(C(F)(F)F)c1)C(=O)c1occc1Br
Reaction time: 0.25 h

Procedure:
To a mixture of 3-(trifluoromethyl)aniline (0.500 mL) and 6M hydrochloric acid (4 mL) was added dropwise a solution of sodium nitrite (0.345 g) in water (1 mL) at 0° C., and the mixture was stirred for 15 min. The obtained aqueous solution was added to a suspension, which was cooled to 0° C., of 1-(3-bromofuran-2-yl)butane-1,3-dione (0.924 g) and sodium acetate (1.97 g) in methanol (10 mL). The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.59 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.F[C:12]1[CH:13]=[CH:14][C:15]([N+:22]([O-:24])=[O:23])=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:10][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([Cl:8])[C:5]=1[O:9][C:12]1[CH:13]=[CH:14][C:15]([N+:22]([O-:24])=[O:23])=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Reactant: Oc1c(Cl)cc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2c(Cl)cc(Br)cc2Cl)cc1C(F)(F)F
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A mixture of 4-bromo-2,6-dichlorophenol (2.4 g), 5-fluoro-2-nitro-trifluoromethylbenzene (2.0 g), potassium carbonate (2.7 g) in dimethylformamide (30 mL) was heated at reflux for 2 hours. The reaction was cooled to room temperature and concentrated. The residue was partioned between ethyl acetate and hydrochloric acid (2 N), the organic phase concentrated and the residue purified on column (silica gel, ethyl acetate/petrolium ether, 5:95), to give 2.7 g of 3,5-dichloro-4-(4-nitro-3-trifluoromethylphenoxy)bromo-benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.C1(CN)CCCCC1.[O:19]=[C:20]1[C:28]2([CH2:32][O:31][C:30]3[CH:33]=[C:34]4[C:38](=[CH:39][C:29]2=3)[CH2:37][CH2:36][O:35]4)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]1[CH2:40][C:41]1[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=1[C:43](O)=[O:44].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:43](=[O:44])[C:42]2[CH:46]=[CH:47][CH:48]=[CH:49][C:41]=2[CH2:40][N:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]3([CH2:32][O:31][C:30]4[CH:33]=[C:34]5[C:38](=[CH:39][C:29]3=4)[CH2:37][CH2:36][O:35]5)[C:20]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: NCCc1ccc(Cl)cc1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(NCCc1ccc(Cl)cc1)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-(4-chlorophenyl)ethylamine to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-[2-(4-chlorophenyl)ethyl]-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (78%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.59 (br, 1H), 7.44-7.23 (m, 7H), 7.23-6.11 (m, 2H), 7.10-6.94 (m, 2H), 6.73 (d, J=7.7 Hz, 1H), 6.52 (s, 1H), 6.40 (s, 1H), 4.94-4.65 (m, 4H), 4.47 (t, J=8.6 Hz, 2H), 3.57-3.42 (m, 2H), 2.95 (t, J=8.3 Hz, 2H), 2.84 (t, J=6.7 Hz, 2H); MS (ES+) m/z 573.1 (M+23).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:23][O:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][O:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][N:37]([CH2:40][C:41](O)=[O:42])[C:36](=[O:44])[N:35]=2)=[O:32])=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:41](=[O:42])[CH2:40][N:37]1[CH:38]=[CH:39][C:34]([NH:33][C:31]([O:30][CH2:29][C:28]2[CH:45]=[CH:46][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[O:32])=[N:35][C:36]1=[O:44])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Reactant: COc1ccc(COC(=O)Nc2ccn(CC(=O)O)c(=O)n2)cc1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1ccc(NC(=O)OCc2ccc(OC)cc2)nc1=O
Yield: 86.8 %

Procedure:
The title compound (2.86 g, 87%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [4-N-(4-methoxybenzyloxycarbonyl)-cytosin-1-yl]-acetic acid (1.67 g, 5 mmol) as per the procedure of Example 20. 1HNMR (500 MHz; DMSO-d6) δ 10.71 (s, 1H), 8.26 (dd, 1H), 8.16 (dd, 1H), 7.90 (d, 0.6H), 7.82 (d, 0.4H), 7.68˜7.60 (m, 2H), 7.34 (d, 2H), 7.00 (t, 1H), 6.93 (d, 2H), 5.10 (s, 2H), 4.82 (s, 1.2H), 4.61 (s, 0.8H), 4.34 (s, 0.8H), 4.13 (q, 0.8H), 4.05 (s, 1.2H), 4.03 (q, 1.2H), 3.74 (s, 3H), 3.56 (t, 1.2H), 3.40˜3.30 (m, 2H), 3.19 (t, 0.8H), 1.19 (t, 1.2H), 1.12 (t, 1.8H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C1COCC1>[Br-:15].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N+:10]2[CH:14]=[CH:13][N:12]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCCCCCCCBr
Reactant: O=[N+]([O-])c1ccc(-n2ccnc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCn1cc[n+](-c2ccc([N+](=O)[O-])cc2)c1
Product: [Br-]
Temperature: 25 °C

Procedure:
According to the general synthesis procedure, 5.3 mmol (1.00 g) 1-(4-nitrophenyl)imidazole and 6.3 mmol (1.76 g, 1.70 ml) 1-bromotetradecane are dissolved in 5 ml THF and heated for 45 h to 90° C. At the end of the reaction the reaction mixture is cooled down to room temperature and the precipitated product is washed with THF and diethylether.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](OC(=O)C(C)(C)C)[N:6]=[C:5]2[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[NH:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH:3]=2)[NH:7][N:6]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CC(C)(C)C(=O)On1nc(-c2ccc[nH]2)c2cc(N)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]nc(-c3ccc[nH]3)c2c1)c1ccncc1
Yield: 104.1 %

Procedure:
2,2-Dimethyl-propionic acid 5-amino-3-(1H-pyrrol-2-yl)-indazol-1-yl ester (0.38 mmol) was coupled with isonicotinoyl chloride (0.4 mmol) (Aldrich, Milwaukee, Wis.) and triethylamine in DCM at 0° C. to give 120 mg of the titled compound as a light yellow solid.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[N:8]1.[C:47](Cl)(=O)[C:48]1C=CC=[CH:50][CH:49]=1.C(N(CC)CC)C.[O:63]1[CH2:67][CH2:66][CH2:65][CH2:64]1>>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:67](=[O:63])[CH2:66][C:65]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:64]=3)=[CH:42][CH:41]=2)=[N:17]1
Reactant: C1CCOC1
Reactant: Nc1ccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)Nc1ccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)cc1
Yield: 5 %

Procedure:
The title compound was prepared as described in Example 376, using 4-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.303 g, 0.50 mmol) in tetrahydrofuran (4.5 mL) was added benzoyl chloride (0.10 mL, 0.76 mmol) and triethylamine (0.35 mL, 2.52 mmol). The final crude product was purified by preparative HPLC (30–80% acetonitrile to H2O, 30 min.) (0.010 g, 5% yield): 1H NMR (DMSO-d6) δ 10.37 (s, 1H), 8.68 (br s, 1H), 8.07 (d, 1H), 7.95 (br s, 2H), 7.80 (d, 2H), 7.69 (br s, 1H), 7.30 (m, 5H), 3.69 (s, 2H); ES-MS (m/z) 395 [M+1]+.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([CH3:13])[CH:6]=1)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)=O>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:13][C:7]1[CH:6]=[C:5]([OH:4])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: C=CCOc1ccc(C=O)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: CCOC(C)=O
Product: Cc1cc(O)ccc1C=O
Reaction time: 0 h
Yield: 35 %

Procedure:
The compound of Step B, 13.54 g (76.9 mmole), 1.72 g (7.69 mmole) palladium acetate, and 12.09 g (46.2 mmole) triphenylphosphine were mixed in a 250 ml flask. Formic acid, 3.2 ml (84.6 mmole), was added and the reaction was swirled. Within 15 seconds, the reaction foamed, exothermed and formed a gum which was dissolved in ethyl acetate, washed once with sodium bicarbonate and once with brine. The organic layer was chromatographed on 350 ml silica, eluting with 20%, then 40% ethyl acetate/hexane. The fractions were combined and the product crystallized from methylene chloride/hexane to give 3.61 g (35%) of product which was used without further purification.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:11]1[C:16]2[NH:17][CH:18]=[CH:19][C:15]=2[C:14]([N:20]2[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]2)=[N:13][CH:12]=1.CN1CCOCC1>ClCCl.CN(C=O)C>[C:1]1([CH2:7][C:8]([NH:26][CH:23]2[CH2:22][CH2:21][N:20]([C:14]3[C:15]4[CH:19]=[CH:18][NH:17][C:16]=4[N:11]=[CH:12][N:13]=3)[CH2:25][CH2:24]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC1CCN(c2ncnc3[nH]ccc23)CC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC1CCN(c2ncnc3[nH]ccc23)CC1
Reaction time: 8 h

Procedure:
Phenylacetyl chloride (0.037 g, 0.240 mmol, commercially available from e.g sigma-aldrich or fluka) in Dichloromethane (DCM) (1.5 ml) was added to a solution of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D2 (0.043 g) and POL-NMM (0.279 g, 0.600 mmol) in DMF (1.5 ml). The mixture was shaked overnight at room temperature on a mini block. The resulting mixture was washed using DCM DMF (1:1) and the acid chloride left was removed using an NH2 cartridge. Then the solvents were evaporated overnight using the genevac. The crude was finally purified via MDAP using a formic acid method to obtain the desired product E51 in 24 mg. LCMS [M+H]+336.06@0.62 min (2 min run)
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[C:9]1([NH:19][S:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][C:31](Cl)=[O:32])[CH:26]=[CH:27][CH:28]=2)(=[O:22])=[O:21])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>O1CCCC1>[OH:3][NH:2][C:31](=[O:32])[CH:30]=[CH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([S:20](=[O:22])(=[O:21])[NH:19][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[CH:24]=1
Reactant: NO
Reactant: O=C(Cl)C=Cc1cccc(S(=O)(=O)Nc2cccc3ccccc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=Cc1cccc(S(=O)(=O)Nc2cccc3ccccc23)c1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.215 g, 3.1 mmol) in tetrahydrofuran (3.5 ml) a saturated NaHCO3 solution (2.7 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-[3-(naphthalen-1-ylsulfamoyl)-phenyl]-acryloyl chloride (16d) (0.23 g) in tetrahydrofuran (2.5 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was crystallised from ethyl acetate affording the title compound (0.054 g, 24%). M.p. 180° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.45 (1H, d, J=16.0 Hz); 7.14 (1H, dd, J=7.0 and 1.4 Hz); 7.31-8.14 (11H, m); 9.09 (1H, br s); 10.27 (1H, s); 10.76 (1H, br s). HPLC analysis on Symmetry C18 column: impurities 4% (column size 3.9×150 mm; mobile phase acetonitrile-0.1M phosphate buffer (pH 2.5), 40:60; sample concentration 0.3 mg/ml; flow rate 1.2 ml/min; detector UV 220 nm). Anal. Calcd for C19H16N2O4S, %: C, 61.94; H, 4.38; N, 7.60. Found %: C, 61.18; H, 4.32; N, 7.54.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([OH:17])(=[O:16])[CH2:12][C:13]([CH3:15])=O.[NH2:18]/[C:19](/[CH3:27])=[CH:20]\[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]>C(O)(C)(C)C>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:20]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])=[C:19]([CH3:27])[NH:18][C:13]([CH3:15])=[C:12]1[C:11]([OH:17])=[O:16]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CC(=O)CC(=O)O
Reactant: C/C(N)=C/C(=O)OC(C)C
Solvent: CC(C)(C)O
Product: CC1=C(C(=O)O)C(c2cccc(Cl)c2Cl)C(C(=O)OC(C)C)=C(C)N1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
A solution of 2,3-dichlorobenzaldehyde (0.70 g), 3-nitrooxy-2,2-bis(nitrooxymethyl)propyl ester of acetoacetic acid (1.42 g) and isopropyl 3-aminocrotonate (0.57 g) in tert-butyl alcohol (3 ml) was refluxed for 5.5 hours. The resulting mixture was cooled to 25° C., and then concentrated under reduced pressure. The residue obtained was subjected to column chromatography on silica gel (60 g) and eluted with chloroform. The fractions containing the desired compound were collected and evaporated under reduced pressure to give white powders. The powders were recrystallized from a mixture of diethyl ether and diisopropyl ether to give white crystals of 3-nitrooxy-2,2-bis(nitrooxymethyl)propyl ester of 4-(2,3-dichlorophenyl)-5-isopropoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine-3-carboxylic acid (1.36 g), mp 155° to 156.5° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([CH:14]=[C:12]([OH:13])[CH:11]=[C:9]([OH:10])[CH:8]=1)[OH:7].CN1CCOCC1>O1CCCC1>[CH3:1][S:2]([O:7][C:6]1[CH:14]=[C:12]([O:13][S:2]([CH3:1])(=[O:4])=[O:3])[CH:11]=[C:9]([O:10][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=1)(=[O:4])=[O:3]
Reactant: Oc1cc(O)cc(O)c1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CS(=O)(=O)Oc1cc(OS(C)(=O)=O)cc(OS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
39.8 g (0.33 mol) of methanesulfonic acid chloride were added dropwise at 0° C. within the course of 30 minutes to a solution of 12.6 g (0.10 mol) of phloroglucinol and 101 g (1.0 mol) of N-methylmorpholine in 200 ml of dry tetrahydrofuran in such a way that the temperature did not rise above 10° C. After the dropwise addition, the ice bath was removed, and the mixture was warmed to room temperature and stirred for 2 hours at this temperature. The mixture was then slowly added dropwise with continuous stirring to 3 l of ice water, and the resulting precipitate was filtered off with suction and washed until neutral with water. After drying, this gave 32.9 g (91%) of a colorless powder of melting point 145 to 149° C. Recrystallization from an isopropanol/acetone solvent mixture gave colorless, highly light-refracting platelets of melting point 150° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.[F-].[K+]>C1(C)C=CC=CC=1>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Brc1ccc2c(c1)OCO2
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1ccc2c(c1)OCO2
Yield: 100.7 %

Procedure:
4-Bromo-1,2-(methylenedioxy)benzene (201 mg, 1.02 mmol) reacted with 2-methylphenylboronic acid (150 mg, 1.10 mmol) using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (116 mg, 2.00 mmol) in toluene at room temperature for 3 h to give the title compound (218 mg, 99%): 1H-NMR (300 MHz, CDCl3): δ 7.31-7.27 (m, 4H), 6.94-6.82 (m, 3H), 6.04 (s, 2H), 2.35 (s, 3H). 13C{1H}-NMR (125 MHz, CDCl3): δ 147.24, 146.39, 141.52, 135.84, 135.42, 130.26, 129.79, 127.10, 125.69, 122.44, 109.76, 107.98, 100.95, 20.45. GC/MS(EI): m/z 212 (M+), 181, 153. Anal. Calcd for C14H12O2: C, 79.23; H, 5.70. Found: C, 79.36; H, 5.73.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[S:14](=O)(=O)[CH2:15][CH2:16][C:12]=3[N:11](C(OC(C)(C)C)=O)[C:10]3[CH2:26][O:27][CH2:28][C:29](=[O:30])[C:9]2=3)=[CH:4][C:3]=1[Sn](C)(C)C.ClN1C(=O)CCC1=O.[I-:43].[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[S:14][CH2:15][CH2:16][C:12]=3[NH:11][C:10]3[CH2:26][O:27][CH2:28][C:29](=[O:30])[C:9]2=3)=[CH:4][C:3]=1[I:43]
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)N1C2=C(C(=O)COC2)C(c2ccc(F)c([Sn](C)(C)C)c2)C2=C1CCS2(=O)=O
Agent: O=C1CCC(=O)N1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: O=C1COCC2=C1C(c1ccc(F)c(I)c1)C1=C(CCS1)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.6 %

Procedure:
A mixture of the product from Example 37B (0.023 g, 0.038 mmol) in 1% acetic acid in methanol (25 mL) was treated with N-chlorosuccinimide (0.010 g, 0.077 mmol), then treated with sodium iodide (0.011 g, 0.077 mmol), stirred for 10 minutes, treated with pulverized sodium thiosulfate pentahydrate (0.020 g, 0.080 mmol), stirred for 10 minutes and concentrated to dryness. The residue was treated with trifluoroacetic acid (3 mL), stirred at ambient temperature for 15 minutes and concentrated to dryness. The residue was treated with trifluoroacetic acid (3 mL), heated gently on a steam bath for 1 minute, cooled to ambient temperature and concentrated to dryness. The residue was purified by chromatography on silica gel (2% methanol and then 5% methanol in methylene chloride) to provide the title compound (0.0156 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][CH2:10][Cl:11]>[OH-].[Na+]>[ClH:11].[ClH:11].[Cl:11][CH2:10][CH2:9][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: ClCCBr
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(CCCl)CC1
Product: Cl
Temperature: 50 °C
Yield: 30.4 %

Procedure:
10 ml of 25% NaOH and 1 ml (9 mmol) of 4-methyl piperazine were added successively into a reaction flask. The mixture was heated up to 50° C., and 1.8 ml (18 mmol) 1-bromo-2-chloroethane was added dropwise. The mixture was reacted at 50° C. for 6 h, then cooled to room temperature. The reaction solution was extracted with ethyl acetate, and the extraction was washed with saturated saline solution and dried over anhydrous sodium sulfate, then filtered. The filtrate was concentrated to dry in a reduced pressure and a small amount of ethanol/NaOH solution was added dropwise into the residue. The mixture was shaken and placed in a refrigerator for standing, then concentrated to dry in a reduced pressure to obtain 0.43 g white solid with the yield of 23%. m.p. 227-230° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:16](Cl)(=[O:18])=[O:17])=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[N:8]([CH2:11][CH2:12][CH2:13][N:14]=3)[C:9]=2[CH:10]=1.[CH3:20][O:21][CH2:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][NH:24]1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([S:16]([N:24]2[CH2:25][CH2:26][CH2:27][C@H:23]2[CH2:22][O:21][CH3:20])(=[O:18])=[O:17])=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[N:8]([CH2:11][CH2:12][CH2:13][N:14]=3)[C:9]=2[CH:10]=1
Reactant: COC[C@@H]1CCCN1
Reactant: O=C1C2=NCCCN2c2cc(Cl)c(S(=O)(=O)Cl)cc21
Solvent: ClCCl
Product: COC[C@@H]1CCCN1S(=O)(=O)c1cc2c(cc1Cl)N1CCCN=C1C2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.5 %

Procedure:
To a solution of 7-chloro-10-oxo-2,3,4,10-tetrahydropyrimido[1,2-a]indole-8-sulfonyl chloride (0.140 g, 0.439 mmol) in CH2Cl2 (10 mL) was added (S)-(+)-2-(methoxymethyl)pyrrolidine (0.119 g, 0.965 mmol, 2.2 eq) drop-wise with cooling in an ice bath under a dry N2 atmosphere. After stirring at room temperature for 1.5 hr, the mixture was quenched with H2O (10 mL) and extracted with EtOAc (3×). The combined organic extracts were dried over MgSO4, filtered, and concentrated to give a film on glass. The film was combined with the product of an earlier run and purified on Biotage KP silica gel eluting with a step gradient of 20/80 petroleum ether/EtOAc, followed by 100% EtOAc to give the title compound as a bright yellow solid (0.104 g, 52.3% yield). Anal. Calc'd. for C17H20ClN3O4S.0.2H2O: C, 50.86; H, 5.12; N, 10.47. Found, C, 50.82; H, 5.00; N, 10.31. NMR (400 MHz, DMSO-d6): consistent. MS: (ES−) m/z 396/398 [M−H] 1 chlorine pattern observed. m.p.: 127-130° C. HRMS: consistent ESI Adduct [M+H] Exact 398.09358, Expt'l 398.09411, mmu 0.53, ppm 1.34, RI % 100.
Reaction SMILES: C(OC([N:8]1[C:12]2=[C:13]([Cl:26])[N:14]=[CH:15][C:16]([C:17](=[O:25])[NH:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:11]2[C:10]([CH3:27])=[CH:9]1)=O)(C)(C)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CO>[ClH:26].[O:22]1[CH2:21][CH2:20][CH:19]([NH:18][C:17]([C:16]2[C:11]3[C:10]([CH3:27])=[CH:9][NH:8][C:12]=3[C:13]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:14][CH:15]=2)=[O:25])[CH2:24][CH2:23]1
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)NC3CCOCC3)c12
Reactant: C1COCCN1
Solvent: CO
Product: Cc1c[nH]c2c(N3CCOCC3)ncc(C(=O)NC3CCOCC3)c12
Product: Cl

Procedure:
Prepared in a similar manner to Example 11 (c) from 7-chloro-3-methyl-4-(tetrahydro-pyran-4-ylcarbamoyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester and morpholine (71 mg) except that the hydrochloride salt was formed using methanol instead of dichloromethane as solvent to give the title compound (40 mg).
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH2:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=2)[CH2:11][CH2:10]1)[CH:7]=[CH2:8]>CO>[CH2:6]([N:9]1[CH2:10][CH2:11][N:12]([C:15]2[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=2)[CH2:13][CH2:14]1)[CH:7]=[CH2:8]
Reactant: C=CCN1CCN(c2ncc([N+](=O)[O-])cn2)CC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: C=CCN1CCN(c2ncc(N)cn2)CC1

Procedure:
3.84 g (17.0 mmol) of tin(II) chloride dihydrate were added to a solution of 530 mg (2.13 mmol) of 2-(4-allylpiperazin-1-yl)-5-nitropyrimidine from Example 16.1 in 20 ml of methanol and, after that, the reaction mixture was heated at reflux for 1 hour. After the solvent had been evaporated to dryness, the residue was treated with saturated aqueous sodium chloride solution and then made alkaline using dilute aqueous sodium hydroxide solution. After that, the aqueous reaction mixture was extracted with ethyl acetate. The solid which had precipitated out was filtered off with suction. The phases were then separated and the aqueous phase was extracted in each case twice with ethyl acetate and dichloromethane. After the combined organic phases had been dried over sodium sulfate, the drying agent had been filtered off and the solvent had been evaporated down to dryness, 220 mg (46% of theory) of the title compound were obtained.