Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26](I)=[CH:27][C:21]=4[S:20](=[O:30])(=[O:29])[N:19]=3)=[C:14]([OH:31])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:32][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:40]1[S:41](=[O:46])(=[O:45])[CH2:42][CH2:43][CH:44]=1)CCC>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:45]=[S:41]1(=[O:46])[CH2:42][CH2:43][CH:44]=[C:40]1[C:26]1[CH:25]=[CH:24][C:22]2[NH:23][C:18]([C:15]3[C:16](=[O:17])[N:7]([CH2:6][C:5]4[CH:33]=[CH:34][C:2]([F:1])=[CH:3][CH:4]=4)[C@@H:8]4[C@H:13]([C:14]=3[OH:31])[C@@H:12]3[CH2:32][C@H:9]4[CH2:10][CH2:11]3)=[N:19][S:20](=[O:30])(=[O:29])[C:21]=2[CH:27]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCS1(=O)=O
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C1C(C2=NS(=O)(=O)c3cc(C4=CCCS4(=O)=O)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 90 °C
Reaction time: 22 h
Yield: 19.1 %

Procedure:
To a solution of (1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 19, 200 mg, 0.34 mmol) and tributyl-(1,1-dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-stannane (prepared as described in US patent application US 2008/0031852, 180 mg, 0.44 mmol) in anhydrous N,N-dimethylformamide (7 mL) under a nitrogen atmosphere, Pd(PPh3)4 (20 mg, 0.017 mmol) was added. The resulting mixture was stirred at 90° C. for 22 h, and then allowed to cool to 25° C. The reaction mixture was concentrated in vacuo and the residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 30%-95% in 7 min @30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, (1R,2S,7R,8S)-5-[7-(1,1-dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (38 mg, 0.065 mmol, 20%), as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.19 (2H, m), 1.42-1.61 (4H, m), 2.50 (1H, m), 2.65 (1H, m), 2.97 (2H, m), 3.05 (1H, m), 3.53 (3H, m), 4.43 (1H, d, J=14.4 Hz), 4.96 (1H, d, J=15.6 Hz), 7.15 (2H, m), 7.33 (2H, m), 7.41 (1H, t, J=3.6 Hz), 7.66 (1H, d, J=9.2 Hz), 7.96 (1H, dd, J=8.8, 2.4 Hz), 8.10 (1H, d, J=2.4 Hz). LC-MS (ESI) calcd for C28H26FN3O6S2 583.12, found 584.2 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][NH2:10])=[C:6]([OH:8])[CH:7]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.[Cl:22][CH:23]([C:27](=O)[CH3:28])[C:24](=O)[CH3:25]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[C:27]([CH3:28])=[C:23]([Cl:22])[C:24]([CH3:25])=[N:10]2)=[C:6]([OH:8])[CH:7]=1
Reactant: NNc1ccc(Br)cc1O
Reactant: CC(=O)C(Cl)C(C)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: Cc1nn(-c2ccc(Br)cc2O)c(C)c1Cl
Yield: 76.9 %

Procedure:
558 mg of the title compound was prepared in a manner similar to Example 54b) by using 5-bromo-2-hydrazinylphenol 4-methylbenzenesulfonate (0.9 g), which was prepared in a manner similar to Example 54a), and 3-chloropentane-2,4-dione (1.07 g).
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.[CH3:50][N:51]([CH3:57])[C@H:52]1[CH2:56][CH2:55][NH:54][CH2:53]1>CN(C)C=O>[CH3:50][N:51]([CH3:57])[C@H:52]1[CH2:56][CH2:55][N:54]([C:8]([NH:9][C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38]([NH:39][C:40]5[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=5)=[O:47])[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)=[O:7])[CH2:53]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CN(C)C=O
Product: CN(C)[C@H]1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)C1
Reaction time: 6 h
Yield: 81 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) was added (3S)-3-dimethylaminopyrrolidine (0.0508 ml) at room temperature, followed by stirring for 6 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (45.6 mg, 81%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Br[CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:24](=[O:25])[C:19]2[N:20]=[C:21]([CH3:23])[S:22][C:18]=2[C:17](=[O:26])[CH:16]=1.[I-].[Na+].[CH3:29][O:30][C:31]1[CH:54]=[CH:53][C:34]([CH2:35][NH:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]2[C:50](=[O:51])[C:45]3[N:46]=[C:47]([CH3:49])[S:48][C:44]=3[C:43](=[O:52])[CH:42]=2)=[CH:33][CH:32]=1>C(#N)C>[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:35][N:36]([CH2:37][CH2:38][CH2:39][NH:40][C:41]2[C:50](=[O:51])[C:45]3[N:46]=[C:47]([CH3:49])[S:48][C:44]=3[C:43](=[O:52])[CH:42]=2)[CH2:11][CH2:12][CH2:13][NH:14][C:15]2[C:24](=[O:25])[C:19]3[N:20]=[C:21]([CH3:23])[S:22][C:18]=3[C:17](=[O:26])[CH:16]=2)=[CH:53][CH:54]=1
Reactant: Cc1nc2c(s1)C(=O)C=C(NCCCBr)C2=O
Reactant: COc1ccc(CNCCCNC2=CC(=O)c3sc(C)nc3C2=O)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(CN(CCCNC2=CC(=O)c3sc(C)nc3C2=O)CCCNC2=CC(=O)c3sc(C)nc3C2=O)cc1
Temperature: 165 °C
Reaction time: 0.25 h

Procedure:
22 μl (128 μmol; 2 equivalents) of diisopropylethylamine, 21 mg (64 μmol; 1 equivalent) of 5-[(3-bromopropyl)amino]-2-methyl-1,3-benzothiazole-4,7-dione and a spatula tip's worth of sodium iodide are added to 23.6 mg (64 μmol) of 5-({3-[(4-methoxybenzyl)amino]propyl}amino)-2-methyl-1,3-benzothiazole-4,7-dione dissolved in 5 ml of acetonitrile. The reaction mixture is maintained under stirring under microwaves at 165° C. for 15 minutes, then the solvent is evaporated off under reduced pressure and the reaction residue is taken up in dichloromethane, followed by washing with 3 times 50 ml of water. The organic phases are combined, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure. The expected product is purified by chromatography on a silica column (eluent: dichloromethane/methanol: 93/7) and obtained in the form of a red oil.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]=[C:7]2[CH3:12].[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:7]1[C:8]2[C:3](=[C:2]([C:16]3[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][N:6]=1
Reactant: CC1=NCCc2c(I)cccc21
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC1=NCCc2c1cccc2-c1ccncc1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
A mixture of 5-iodo-1-methyl-3,4-dihydroisoquinoline (3.0 g, 11.1 mmol), pyridin-4-ylboronic acid (2.04 g, 16.6 mmol), Pd(PPh3)2Cl2 (3.88 g, 5.53 mmol) and Cs2CO3 (10.8 g, 33.2 mmol) in 1,4-dioxane (45 mL) was heated to reflux for 24 h. The mixture was allowed to cool to RT, and then filtered. The filter cake was washed with AcOEt, and the filtrate was then concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, DCM to DCM/MeOH 9:1) to afford the title compound (1.82 g) as a grey solid. UPLC-MS: MS 223.0 (M+H+); UPLC rt 0.38 min.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:38](=[O:39])[N:13]3[C:14]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[O:27])=[C:15](OS(C(F)(F)F)(=O)=O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:40][C:41]#[C:42][CH3:43].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:40][C:41]1[C:15]2[C@H:16]([C:42]=1[CH3:43])[S:17][C@H:12]1[N:13]([C:38](=[O:39])[C@H:11]1[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:14]=2[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)=[O:27]
Reactant: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reactant: CC#CC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C3C(C)=C(C)[C@@H]3S[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
A solution of p-methoxybenzyl (6R,7R)-7-phenylacetamido-3-(trifluoromethyl-sulphonyloxy)ceph-3-em-4-carboxylate (60 mg, 0.102 mmol) in dichloromethane (10 ml) was cooled to 0° C., 2-Butyne (1.2 ml, 15.3 mmol) was added followed by diisopropylethylamine (18 μl, 0.102 mmol). The mixture was stirred and allowed to warm to room temperature over 15 min. Chromatography gave the title compound (28.4 mg, 57%), (Found: M+, 490.1562. C27H26N2O5S requires M, 490.1562); νmax (CH2Cl2) 1783, 1716, 1684 cm-1 ; δH (CDCl3) 1.79 (3H, s), 1.97 (3H, s), 3.62 (2H, ABq, J 16.1), 3.79 (3H, s), 4.07 (1H, br s), 4.79 (1H, d, J 4.8), 5.21 (2H, ABq, J 11.8), 5.89 (1H, dd, J 8.6, 4.8), 6.06 (1H, d, J 8.6), 6.86 (2H, d, J 8.6), 7.30 (7H, m); δc (CDCl3) 12.5, 13.2, 43.3, 45.6, 55.3, 59.8, 62.3, 67.1, 111.8, 113.9 (2c), 127.4, 127.7, 129.2 (2c) 129.5 (2c), 130.8 (2c), 133.7, 135.4, 142.5, 149.1, 159.9, 161.4, 164.4, 171.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C[N:11](N=O)[C:12]([NH:14][N+:15]([O-:17])=[O:16])=N.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:12]([NH:14][N+:15]([O-:17])=[O:16])=[NH:11]
Reactant: NCc1cccc(F)c1
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C(NCc1cccc(F)c1)N[N+](=O)[O-]
Reaction time: 18 h
Yield: 89.2 %

Procedure:
The compound m-fluorobenzylamine (7.5 g, 0.06 mol) is added to a slurry of N-methyl-N-nitroso-N'-nitroguanidine (8.33 g, 0.056 mol) in a 50% aqueous ethanol mixture. The thus-formed mixture is stirred for 18 hours, then treated with 1N NaOH (150 ml), and the mixture filtered. The filtrate is acidified with concentrated HCl, and the reaction mixture is then filtered to obtain the desired fluffy white solid product (10.6 g) having a melting point of 177° C.-179° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9]=O)=[N:6][C:7]=1[CH3:8].[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C=O)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: Cc1nc(CN2CCN(C(=O)OC(C)(C)C)CC2)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
A 250 mL round-bottom flask was charged with 5-bromo-6-methylpyridine-2-carbaldehyde (4.90 g, 24.6 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (4.60 g, 24.7 mmol, 1.01 equiv), 1,2-dichloroethane (150 mL). The resulting solution was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (15.6 g, 73.6 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and diluted with water (50 mL), extracted with dichloromethane (2×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (30/70) to provide 7.80 g (82% yield) of tert-butyl 4[(5-bromo-6-methylpyridin-2-yl)methyl]piperazine-1-carboxylate as a light yellow solid. LCMS (ESI, m/z): 370 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)([CH3:4])([CH3:3])[CH3:2].[NH2:24][NH:25][C:26]([NH2:28])=[S:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:8](=[N:24][NH:25][C:26]([NH2:28])=[S:27])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NNC(N)=S
Reactant: CC(C)(C)c1cc(C(=O)c2ccccc2)cc(C(C)(C)C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C(=NNC(N)=S)c2ccccc2)cc(C(C)(C)C)c1O

Procedure:
6.2 g of 3,5-di-t-butyl-4-hydroxybenzophenone and 2.2 g of thiosemicarbazide were dissolved in 20 ml of toluene, and 0.4 g of p-toluenesulfonic acid was added. The solution was refluxed for 16 hours while removing water. After the reaction, dilute hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was distilled off under reduced pressure. The residue was chromatographed on a silica gel column, and recrystallized from dichloromethane/n-hexane to give 3,5-di-t-butyl-4-hydroxybenzophenone thiosemicarbazone.
Reaction SMILES: [O-:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Na+].[Na+].Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[O:24]1[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:9]3)=[CH:4][CH:3]=2)[CH2:22][CH2:23]1
Reactant: O=S(=O)([O-])c1ccc2ccc([O-])cc2c1
Reactant: ClCCN1CCOCC1
Agent: [Na+]
Product: O=S(=O)(O)c1ccc2ccc(OCCN3CCOCC3)cc2c1
Yield: 44.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 26B, sodium 7-oxidonaphthalene-2-sulfonate (Pfaltz and Bauer, 200 mg, 0.75 mmol) and 4-(2-chloroethyl)morpholine (223 g, 1.49 mmol) were converted to the title compound (113 mg, 45%). 1H NMR (DMSO-d6) δ 9.90 (br s, 1H), 8.10 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.58 (dd, J=8.1, 1.3 Hz, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.24 (dd, J=8.7, 2.3 Hz, 1H), 4.48 (br s, 2H), 3.99 (br s, 2H), 3.65 (br s, 4H), 3.26 (br s, 4H); MS (ESI+) m/z 336.3 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=2[Br:22])=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2].[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([O:19][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][O:29]3)=[O:18])=[CH:15][C:14]=2[Br:22])=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2]
Reactant: C1=COCCC1
Reactant: CCCc1c(OCCCOc2ccc(C(=O)O)cc2Br)ccc(C(C)=O)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCCc1c(OCCCOc2ccc(C(=O)OC3CCCCO3)cc2Br)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In methylene chloride (30 ml) was dissolved 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-bromobenzoic acid (1.35 g). To the solution were added dihydropyran (0.9 ml) and p-toluene sulfonic acid.monohydrate (5 mg). The mixture was stirred at room temperature for 30 minutes, to which was further added methylene chloride (30 ml). The resulting solution was washed with an aqueous solution of sodium hydrogen carbonate and then with water, followed by drying with sodium sulfate. The solvent was evaporated off, and the residue was purified by means of a silica-gel column chromatography (Developing solvent: chloroform) to give 1.4 g of tetrahydropyranyl 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-bromobenzoate as colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([NH:21][O:22][CH2:23][CH:24]3[CH2:28][O:27]C(C)(C)[O:25]3)=[O:20])=[CH:11][C:12]3[O:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:31])[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([NH:21][O:22][CH2:23][CH:24]([OH:25])[CH2:28][OH:27])=[O:20])=[CH:11][C:12]3[O:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:31])[CH:3]=1
Reactant: CC1(C)OCC(CONC(=O)c2cc3ocnc3c(F)c2Nc2ccc(Br)cc2Cl)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NOCC(O)CO)c1cc2ocnc2c(F)c1Nc1ccc(Br)cc1Cl
Reaction time: 1 h
Yield: 58.4 %

Procedure:
To a solution of 5-((4-bromo-2-chlorophenyl)amino)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluorobenzo[d]oxazole-6-carboxamide (473 mg, 0.92 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (0.2 mL, 2.69 mmol). The mixture was stirred for 1 h and washed with saturated sodium bicarbonate (aq.). The aqueous layer was extracted by CH2Cl2 (10 mL×2). The combined organic layers were washed by water (10 mL) and brine (10 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 50:1, v/v) to afford the desired product (white solid, 255 mg, 44.7% yield for two steps). 1H NMR (400 MHz, DMSO-d6): δ 11.78 (s, 1H), 8.95 (s, 1H), 8.05 (s, 1H), 7.89 (s, 1H), 7.54 (d, 1H), 7.30 (d, 1H), 6.42 (m, 1H), 4.83 (d, 1H), 4.62 (m, 1H), 3.86 (m, 1H), 3.70 (m, 2H), 3.35 (m, 2H). MS APCI (+) m/z: 475.7, [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19].[OH-].[Na+]>>[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][N:11]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=[C:10]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([OH:29])=[O:28]
Reactant: CCOC(=O)CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2Cl)c1-c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2Cl)c1-c1ccccc1Cl
Yield: 72.8 %

Procedure:
4,5-Bis(2-chlorophenyl)-1-(7-ethoxycarbonylheptyl)-2-phenylimidazole (1.9 g) was reacted with 2N sodium hydroxide in a method similar to Example 10. The aqueous reaction mixture was evaporated to remove ethanol and acidified to pH 5 with 2N aqueous hydrochloric acid. The resulting white solid was collected and recrystallisation from ethanol gave 1L(7-carboxyheptyl)-4,5-bis(2-chloro-phenyl)-2-phenylimidazole (1.31 g, 73%) as a white solid, m.p. 198°. Found: C, 68.53; H, 5.60; N, 5.37; C1, 14.79 %; C29H28C12N2O2 0.2% w/w C2H5OH requires: C, 68.31; H, 5.70; N, 5.40, C1, 13.69 %.
Reaction SMILES: Cl.N[N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]#[N:9].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl.[C:19]([NH2:22])(=[NH:21])[CH3:20].C(O)CCC>>[CH3:20][C:19]1[N:22]=[C:8]([NH2:9])[C:4]2=[CH:5][CH:6]=[CH:7][N:3]2[N:21]=1
Reactant: CC(=N)N
Reactant: N#Cc1cccn1N
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Cc1nc(N)c2cccn2n1
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of 1-amino-1H-pyrrole-2-carbonitrile hydrochloride (2.77 g, 19.3 mmol), potassium phosphate (21.11 g, 96.5 mmol), acetamidine hydrochloride (9.6 g, 96.5 mmol) and 1-butanol (166 mmol) was refluxed under nitrogen atmosphere. After 166.5 h of reflux, the mixture was allowed to cool to rt, and was then partitioned between ethyl acetate and water. The phases were separated, and the organic phase was extracted with 1N aqueous hydrochloric acid. The acid extracts were made basic (pH>7) and extracted with ethyl acetate. After washing the organic layers with water and brine, drying (anhydrous sodium sulfate) and concentration afforded 1.63 g (57%) of solid. 1H-NMR (CD2Cl2): δ 7.51 (m, 1 H), 6.40 (m, 2 H), 6.72 (br s, 2 H), 2.32 (s, 3 H). MS: LC/MS (+esi), m/z=149 [M+H]. RT=1.12 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:14][C:15](=[O:17])[CH3:16])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[NH2:28].Cl.N1C=CC=CC=1>C(OCCO)C>[C:18]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:28][C:22]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=1[Cl:20])=[CH:10][C:9]([O:12][CH3:13])=[C:8]([NH:14][C:15](=[O:17])[CH3:16])[CH:7]=2)#[N:19]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1NC(C)=O
Reactant: Nc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc(Cl)cc3Cl)c(C#N)cnc2cc1NC(C)=O
Temperature: 135 °C
Yield: 91.8 %

Procedure:
An amount of 6 g .(0.022 mol) of N-(4-chloro-3-cyano-6-methoxy-7-quinolinyl)acetamide was stirred in 60 ml of 2-ethoxyethanol. To this were added 2,4-dichloro-phenylamine (3.9 g, 0.024 mol), and 2.8 g (0.024 mol) pyridine hydrochloride, and the mixture was heated at 135° C. for 3 hours. The solvent was evaporated and the solid was stirred in ethyl acetate and filtered to give the HCl salt (8.1 g, 84%). A small portion was stirred in ethyl acetate and sodium hydroxide (1M). After separation of the layers, the organic layer was washed with saturated brine solution, dried over sodium sulfate, and evaporated to dryness to give a yellowish solid (92 mg, 1% yield), mp 245-246° C.; 1H NMR (DMSO-d6) δ 9.65 (s, 1H), 9.56 (s, 1H), 8.72 (s, 1H), 8.43 (s, 1H), 7.90 (s, 1H), 7.80 (m, 1H), 7.53 (m, 2H), 4.04 (s, 3H), 2.22 (s, 3H); HRMS (EI) m/z 401.05647 (M+1). Analysis for C19H14Cl2N4O2.0.1H2O: Found: C, 56.35; H, 3.42; N, 13.67. Calcd: C, 56.57; H, 3.52; N, 13.89.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.FC(F)(F)S(O[CH2:36][C:37]([F:40])([F:39])[F:38])(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:14][C:11]1[C:12]([CH3:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH2:36][C:37]([F:40])([F:39])[F:38])[CH2:6]2)[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(CC(F)(F)F)C1
Temperature: 25 °C
Yield: 40 %

Procedure:
A mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (15 mg, 0.024 mmol, chiral intermediate from first peak of Example 1, step 7), 2,2,2-trifluoroethyl trifluoromethanesulfonate (6.8 mg, 0.029 mmol) and triethylamine (12 μL, 0.085 mmol) in methylene chloride (0.3 mL) was stirred over a weekend at room temperature. The solvents were evaporated and the crude purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 4.5 mg (39%) of the desired product. The product was isolated as a single enantiomer. LCMS calculated for C21H25ClF3N6O (M+H)+: m/z=469.2; Found: 469.1.