Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:14])[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.Br[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[C:3](=[O:14])[N:4]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1
Reactant: BrC1CCCC1
Reactant: O=c1[nH]cc(-c2ccccn2)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=c1c(Br)cc(-c2ccccn2)cn1C1CCCC1
Yield: 19.9 %

Procedure:
2.00 g of 3-bromo-5-(2-pyridyl)-1,2-dihydropyridin-2-one as the stock material was N-alkylated by the normal method with 5.94 g of bromocyclopentane and 5.50 g of potassium carbonate, to obtain 506 mg of 3-bromo-1-cyclopentyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one, 150 mg of which was treated in accordance with the method for Example 32, to obtain 120 mg of the subject compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6](Cl)[CH:5]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH2:27])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1>>[Cl:10][C:8]1[CH:9]=[C:4]([CH:5]=[C:6]([NH:27][C:17]2[CH:18]=[CH:19][C:20]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:15]([O:14][CH3:13])[CH:16]=2)[N:7]=1)[C:3]([O:2][CH3:1])=[O:12]
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Product: COC(=O)c1cc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)c1

Procedure:
The title compound was prepared in analogous manner as described in example 1e) from methyl-2,6-dichloroisonicotinate (64 mg, 0.3 mmol) and 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.3 mmol). The reaction mixture was heated for 16 h to reflux. Obtained as a yellow solid (40 mg, 36%) after column chromatography of the crude product on silica gel using dichloromethane/methanol (19:1 v/v) as eluent.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][NH:11]2)=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=2)[CH:6]=1)=[O:4].I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN[C@H]1CCCC[C@@H]1NC.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=2)[CH:6]=1)=[O:4]
Reactant: Ic1ccccc1
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)c2cn[nH]c2c1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc(C)cn2)c2cnn(-c3ccccc3)c2c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a solution of 4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid methyl ester (0.183 g, 0.684 mmol) in DMF (5 mL) was added iodobenzene (0.15 g, 0.753 mmol), CuI (0.028 g, 0.137 mmol), (1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (0.04 g, 0.274 mmol), and Cs2CO3 (0.15 g, 1.36 mmol). The reaction mixture was stirred at 110° C. overnight, then cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography gave 0.12 g (53%) of 4-(5-Methyl-pyridin-2-yl)-1-phenyl-1H-indazole-6-carboxylic acid methyl ester.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1COCC1.CCCCCC.Cl[Si:21]([CH3:24])([CH3:23])[CH3:22].[CH3:25][CH:26]([CH3:30])[C:27](=[O:29])[CH3:28]>CCCCC>[CH3:22][Si:21]([CH3:24])([CH3:23])[O:29][C:27](=[CH2:28])[CH:26]([CH3:30])[CH3:25]
Reactant: CC(=O)C(C)C
Reactant: C[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CCCCCC
Product: C=C(O[Si](C)(C)C)C(C)C

Procedure:
To freshly prepared LDA-solution in THF/hexane (1.05 eq.) was added slowly at −78° C. chloro-trimethyl-silane 7.59 mL, 60 mmol, 1.2 eq.), followed by 3-methyl-butan-2-one 5.32 mL, 50 mmol). The reaction vessel was kept for 30 Min. at −78° C. and then allowed to reach RT. The reaction mixture was diluted with 200 mL of pentane and filtered. All volatile solvents were then evaporated from the filtrate and the residue distilled in vacuo (50 mbar, bp. 40-45° C.) to give 4.38 g of regioisomerically pure title compound as colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=O)[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[S:27])[CH:3]=1
Reactant: Cc1cc(C)nc(NC(=O)c2cnccn2)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(NC(=S)c2cnccn2)c1

Procedure:
2.5 g of product obtained in Example 21 and 5.31 g of Lawesson's reagent are dissolved in 50 ml of toluene, and the solutions maintained at reflux for 4 h. It is filtered and the solvent is evaporated off. The product is purified by chromatography on silica gel, eluting with dichloromethane.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].CC1C=CC(S(O[CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])(=O)=O)=CC=1>C1COCC1.C(OCC)(=O)C.O>[C:27]([O:26][C:24]([NH:23][CH2:22][CH2:21][S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)CS
Reactant: Cc1ccc(S(=O)(=O)OCCNC(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CSCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of ethyl 2-mercaptoacetate (0.593 mL, 5.25 mmol) in THF (10 ml) was added to a suspension of NaH (60% dispersion in mineral oil, 204 mg, 5.10 mmol) in THF (20 ml) at room temperature, followed by the addition of a solution of 2-((tert-butoxycarbonyl)amino)ethyl 4-methylbenzenesulfonate (intermediate 212, 1.71 g, 4.61 mmol) in THF (20 ml). The reaction mixture was stirred at room temperature for approximately 20 h and diluted with ethyl acetate and water. Layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried using MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography eluting with a gradient of EtOAc (0-40%) in hexane. Fractions containing the product were combined and evaporated to yield the title compound as colorless oil. (UPLC-MS 3) ESI-MS 264.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 4.93 (br s, 1H), 4.25-4.14 (m, 2H), 3.39-3.30 (m, 2H), 3.23 (s, 2H), 2.77 (t, 2H), 1.44 (s, 9H), 1.35-1.21 (t, 3H).
Reaction SMILES: C1([O:7][S:8](=O)(=[O:10])[NH2:9])C=CC=CC=1.[CH3:12][O:13][C:14]([C:16]1([OH:19])[CH2:18][CH2:17]1)=[O:15]>>[CH3:12][O:13][C:14]([C:16]1([O:19][S:8](=[O:10])(=[O:7])[NH2:9])[CH2:18][CH2:17]1)=[O:15]
Reactant: COC(=O)C1(O)CC1
Reactant: NS(=O)(=O)Oc1ccccc1
Product: COC(=O)C1(OS(N)(=O)=O)CC1

Procedure:
1-Sulfamoyloxy-cyclopropanecarboxylic acid methyl ester was synthesized according to the method presented in the synthesis of sulfamic acid phenyl ester in Example 1 with the exception of utilizing 1-hydroxy-cyclopropanecarboxylic acid methyl ester to obtain 1-Sulfamoyloxy-cyclopropanecarboxylic acid methyl ester.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:25])([F:24])[O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21](=[O:22])[CH:20]=[CH:19][C:18]2=[O:23])=[CH:13][CH:12]=1.CO[CH2:28][N:29]([CH2:37][Si](C)(C)C)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[CH2:30]([N:29]1[CH2:37][CH:19]2[C:18](=[O:23])[N:17]([C:14]3[CH:15]=[CH:16][C:11]([O:10][C:9]([F:8])([F:24])[F:25])=[CH:12][CH:13]=3)[C:21](=[O:22])[CH:20]2[CH2:28]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C1C=CC(=O)N1c1ccc(OC(F)(F)F)cc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C2CN(Cc3ccccc3)CC2C(=O)N1c1ccc(OC(F)(F)F)cc1
Reaction time: 3 h
Yield: 92 %

Procedure:
A solution of trifluoroacetic acid (0.89 g, 0.78 mmol) in dichloromethane was added at 4° C. to a stirred solution of 1-(4-(trifluoromethoxy)phenyl)-1H-pyrrole-2,5-dione (2.0 g, 7.8 mmol) and N-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine (2.2 g, 9.3 mmol) in dichloromethane (100 mL). After 3 h at room temperature, the solution was washed with saturated sodium bicarbonate (80 mL) and brine (80 mL) and dried over Na2SO4. After removal of dichloromethane, the residue was purified by column chromatography on silica gel with petroleum ether:ethyl acetate (10:1 to 5:1) to yield the title compound (2.8 g, 90%). 1H NMR (300 MHz, CDCl3): δ 7.46-7.41 (m, 5H), 7.38-7.31 (m, 4H), 4.19 (s, 2H), 3.89-3.87 (m, 2H), 3.67-3.65 (m, 2H), 3.21 (bs, 2H), LC-MS: [M+1]+ 390.9.
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:7]([NH2:19])[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH2:3][CH2:4][CH3:5].[CH3:20][C:21]([CH3:23])=O>C(O)(C)C>[CH2:2]([C:6]1[N:7]([N:19]=[C:21]([CH3:23])[CH3:20])[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1nc2cnc3ccccc3c2n1N
Reactant: CC(C)=O
Agent: Cl
Solvent: CC(C)O
Product: CCCCc1nc2cnc3ccccc3c2n1N=C(C)C
Temperature: 55 °C

Procedure:
A solution of 2-butyl-1H-imidazo[4,5-c]quinolin-1-amine hydrochloride (520 mg, 2.17 mmol) in 10 mL of isopropanol was treated with 2 mL of acetone and 200 mg of DOWEX W50-X1 acid resin. The reaction mixture was heated to 55° C. overnight. The reaction mixture was treated with an additional 10 mL of isopropanol and 5 mL of acetone and heated to 70° C. for 2 h. The reaction mixture was filtered and the filtrate was treated with 0.5 mL of triethylamine and concentrated under reduced pressure. Chromatography (SiO2, 3% MeOH/CHCl3) gave N-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylideneamine (421 mg) as a brown oil.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[CH:6]1([C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:15](=[O:30])[N:14]([CH2:31][C:32]([NH:34][C:35]3[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=3)[C:38](O)=[O:39])=[O:33])[N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:6]1([C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:15](=[O:30])[N:14]([CH2:31][C:32]([NH:34][C:35]3[CH:43]=[CH:42][CH:41]=[C:37]([C:38]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:39])[CH:36]=3)=[O:33])[N:13]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)Nc2cccc(C(=O)O)c2)N=C(C2CCCCC2)c2ccccc21
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)Nc2cccc(C(=O)NS(C)(=O)=O)c2)N=C(C2CCCCC2)c2ccccc21
Reaction time: 17 h
Yield: 82.3 %

Procedure:
Methanesulfonamide (96 mg, 1.00 mmol) was added to a solution of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid (Example 2)(409 mg, 0.80 mmol), EDC (207 mg, 1.08 mmol) and DMAP (122 mg, 1.00 mmol) in DCM (20 ml) at room temperature. After stirring for 17 h, the mixture was washed with 5% KHSO4 (50 ml), brine (50 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by flash column chromatography (MeOH-DCM (1:10) to afford the title compound as a white crystalline solid (392 mg, 83%). 1H NMR (DMSO-d6) 9.99 (1H, s), 8.02 (1H, s), 7.63-7.36 (5H, m), 7.23 (1H, t), 7.13 (1H, d), 4.73 (2H, dd), 4.29 and 4.25 (2H, d×2), 3.24 (3H, s), 2.87 (1H, m), 1.80-1.48 (6H, m), 1.30-1.09 (13H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 53.93; H, 7.07; N, 10.17%; C30H37N5O6S.C7H17NO5.2.0H2O requires: C, 53.74; H, 7.07; N, 10.16%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[S:14][C:13]([CH2:15][NH:16][CH2:17][C:18]3[NH:19][C:20](=[O:28])[C:21]4[CH2:27][O:26][CH2:25][CH2:24][C:22]=4[N:23]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[F:29][C:30]1[CH:47]=[CH:46][C:33]([C:34]([CH:36]2[CH2:41][CH2:40][N:39]([CH2:42][C:43](O)=[O:44])[CH2:38][CH2:37]2)=[O:35])=[CH:32][CH:31]=1.CC#N.O>C(O)=O>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:34]([CH:36]2[CH2:37][CH2:38][N:39]([CH2:42][C:43]([N:16]([CH2:15][C:13]3[S:14][C:10]([S:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)(=[O:9])=[O:8])=[CH:11][CH:12]=3)[CH2:17][C:18]3[NH:19][C:20](=[O:28])[C:21]4[CH2:27][O:26][CH2:25][CH2:24][C:22]=4[N:23]=3)=[O:44])[CH2:40][CH2:41]2)=[O:35])=[CH:46][CH:47]=1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: O=c1[nH]c(CNCc2ccc(S(=O)(=O)N3CCOCC3)s2)nc2c1COCC2
Solvent: O=CO
Solvent: O
Solvent: CC#N
Product: O=C(c1ccc(F)cc1)C1CCN(CC(=O)N(Cc2nc3c(c(=O)[nH]2)COCC3)Cc2ccc(S(=O)(=O)N3CCOCC3)s2)CC1

Procedure:
Following general procedure of Example 5, the title compound was prepared (0.044 g) from 2-(((5-(morpholinosulfonyl)thiophen-2-yl)methylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. 1H NMR (400 MHz, MeOD) δ ppm 8.04-8.16 (m, 2H), 7.33-7.59 (m, 1H), 7.23-7.31 (m, 2H), 7.05-7.15 (m, 1H), 4.84-4.89 (m, 2H), 4.54-4.63 (m, 2H), 4.36-4.52 (m, 4H), 3.85-3.98 (m, 2H), 3.67-3.83 (m, 6H), 3.17-3.28 (m, 3H), 2.87-2.98 (m, 4H), 2.47-2.67 (m, 2H), 1.98-2.26 (m, 4H). HRMS calculated for C31H37F1N5O7S2 674.2118. found (ESI, [M+H]+) 674.2119. MS (ESI) m/z 674.2. (M+H)+. Retention time: 3.3 min (5-95% CH3CN/H2O over 7.75 min with 0.1% formic acid, Inertsil ODS3 100×3 mm C18 column with flow rate of 1.0 mL/min).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[CH:32]=[N:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:27]5[CH:32]=[N:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1cnc(Cl)cn1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCN(c4cnc(C(F)(F)F)cn4)CC2)C3)CC1

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 39, the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-trifluoromethyl-pyrazine following a procedure analogous to that described for Example 79. LC (method 7): tR=1.56 min; Mass spectrum (ESI+): m/z=510 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[C:3]=1[CH2:21][O:22][C:23](=[O:25])[CH3:24].[Br:26]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:26][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[C:3]=1[CH2:21][O:22][C:23](=[O:25])[CH3:24]
Reactant: COc1cc2cc(COC(C)=O)c(COC(C)=O)c(C)c2cc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc2cc(COC(C)=O)c(COC(C)=O)c(CBr)c2cc1OC
Yield: 83.1 %

Procedure:
To a solution of 1-methyl-2,3-bis(acetoxymethyl)-6,7-dimethoxynaphthalene (5.0 g) in carbon tetrachloride (100 ml) are added N-bromosuccinimide (2.8 g) and benzoyl peroxide (150 mg), and the mixture is refluxed for 2 hours. The mixture is allowed to cool, and the insoluble materials are separated by filtration, and the filtrate is concentrated under reduced pressure to give 1-bromomethyl-2,3-bis(acetoxymethyl)-6,7-dimethoxynaphthalene (5.1 g) as crystal.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[C:12]([CH2:21][CH3:22])=[CH:11][C:10]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:21]([C:12]1[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])=[CH:14][C:9]([OH:8])=[C:10]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:11]=1)[CH3:22]
Reactant: [H][H]
Reactant: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCN
Agent: [Pd]
Solvent: CCO
Product: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCCN
Reaction time: 3.5 h
Yield: 90.8 %

Procedure:
A flask was charged with 10% palladium on carbon (200 mg), ethanol (20 mL), and 1-benzyloxy-2-(4-fluorophenyl)-4-ethyl-5-[(4-aminobutyl)oxy]-benzene (500 mg). The flask was fitted with a balloon and pressurized with hydrogen to fully inflate the balloon. The reaction was stirred 3.5 hours, filtered through Celite, and the filtrate concentrated under vacuum to afford 4-ethyl-2-(4-fluorophenyl)-5-[(4-aminobutyl)oxy]phenol as a white powder (350 mg). HPLC showed that ˜25% starting material remained. It was not purified but carried directly into the next step. Mass Spec (EI), m/e=304.1 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Br-:18].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1>[Br:18][CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:10][CH:11]=1)=[O:17]
Reactant: CCCCCCCOc1ccc(C(C)=O)cc1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 137.7 %

Procedure:
To a stirring solution of 1-(4-(heptyloxy)phenyl)ethanone (500 mg, 2.13 mmol) in THF (8.5 mL) under nitrogen was added phenyltrimethylammonium tribromide (842 mg, 2.24 mmol). The reaction mixture was stirred at RT for 2 h, filtered under vacuum and the captured solid washed with THF. The combined liquors were concentrated to afford 919 mg (100%) of 2-bromo-1-(4-(heptyloxy)phenyl)ethanone INT-4 as a yellow oil. LCMS-ESI (m/z) calculated for C15H21BrO2: 313.2; found 313.0 [M+H]+, tR=2.12 min. (Method 4).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[C:27]([CH3:36])[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[C:27]([CH3:36])[CH:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Cc1cc(O)ccc1NS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)ccc1NS(C)(=O)=O
Temperature: 160 °C
Yield: 31.8 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 25 mg, 0.075 mmol), N-(4-hydroxy-2-methyl-phenyl)methanesulfonamide (ChemBridge Corporation, San Diego, Calif., USA; 15 mg, 0.075 mmol), and potassium carbonate (27 mg, 0.2 mmol) in dimethylformamide was heated in the microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture and the precipitate was filtered through a silica plug, washing with methanol. The solvent was removed and the residue was purified by HPLC to afford 4-[4-(4-methanesulfonylamino-3-methyl-phenoxy)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (12 mg, 33%) as an off white solid. Mass Spec MH+=503.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[NH:9][N:10]=[C:11]([C:12]([O:14]CC)=[O:13])[C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].Cl>CCO>[O:1]=[C:2]1[C:8]2[NH:9][N:10]=[C:11]([C:12]([OH:14])=[O:13])[C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1n[nH]c2c1CCCCC2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1n[nH]c2c1CCCCC2=O
Yield: 85.8 %

Procedure:
Ethyl 8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxylate (2.67 g, 12.01 mmol) was suspended in EtOH (80 mL) and treated with a 2 M solution of NaOH (24 mL, 48.0 mmol) at reflux temperature for 1 h. After cooling the mixture is neutralized with 2 N HCl (24 mL) and the resulting precipitate was collected by filtration to give 2.0 g of the title compound (90% yield) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][OH:10])[CH:4]=1)#[N:2].P(=O)(O)(O)O>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=[O:10])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccnc(CO)c1
Agent: O=P(O)(O)O
Solvent: CS(C)=O
Product: N#Cc1ccnc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-cyano-2-hydroxymethylpyridine (1.1 g, 8.2 mmol) from stage A in dry DMSO (18 mL) was added N,N-dicyclohexylcarbodiimide (5.08 g, 24.6 mmol) and phosphoric acid (0.4 g, 4.1 mmol). The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with ether and water. The filtrate and washings were combined, and the organic layer separated. The aqueous layer was further extracted 4 times with ether, the organics combined, dried over magnesium sulphate and evaporated. The residue was purified by SPE silica column chromatography, eluting with dichloromethane, then chloroform, then diethyl ether. Evaporation of the appropriate fractions afforded 4-cyanopyridine-2-carboxaldehyde as a solid.
Reaction SMILES: [F:1][C:2]1[N:3]=[N:4][C:5]([F:8])=[CH:6][CH:7]=1.[F:9][B-:10]([F:13])([F:12])[F:11].[CH3:14][O+](C)C>CO.O.CC(O)=O>[F:9][B-:10]([F:13])([F:12])[F:11].[F:1][C:2]1[N:3]=[N+:4]([CH3:14])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: C[O+](C)C
Reactant: Fc1ccc(F)nn1
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: C[n+]1nc(F)ccc1F

Procedure:
To a stirred suspension of Raney nickel (16 g.) in MeOH (13 ml.) at 0° was added a solution of 3-azidomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-methoxy-imino)acetamido]ceph-3-em-4-carboxylic acid (2.96 g.) in MeOH/TFA (14 ml., 1.13 ml.). After effervescence ceased the mixture was diluted with MeOH and filtered through paper. The filtrate was evaporated, the residue purified by HPLC using water/HOAc/MeOH 79:1:20 v/v/v as eluant and the product dried over P2O5 to give 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxy-imino)acetamido]ceph-3-em-4-carboxylic acid trifluoroacetate (yield 45%) having the following n.m.r. in solvent A:- 3.5-4.2 (m, 4H); 3.9 (s, 3H); 5.15 (d, 1H); 5.85 (d, 1H); 6.75 (s, 1H). 12. HPLC eluant MeOH/water/HOAc 10:89:1 v/v/v. 13. n.m.r. in solvent B: 3.46 (d,1H), 3.72 (d,1H); 3.97 (s,3H); 4.25 (s,3H); 4.11 (d,1H); 4.63 (d,1H); 5.13 (d,1H); 5.73 (d,1H); 6.97 (s,1H); 7.57 (d,1H); 7.98 (dd,1H); 8.93 (d,1H). 14. HPLC eluant MeOH/water/HOAc 15:84:1 v/v/v. 15. n.m.r. in solvent B: 3.43 (d,1H); 3.69 (d,1H); 3.97 (s,3H); 4.19 (s,3H); 4.23 (d,1H); 4.66 (d,1H); 5.12 (d,1H); 5.69 (d,1H); 7.0 (s,1H); 7.98 (d,1H); 8.2 (s,1H); 8.6 (d,1H). 16. The starting material was prepared by reaction of 3,6-difluoropyridazine and trimethyloxonium tetrafluoroborate in CH2C 12 for 15 hours at ambient temperature to give 3,6-difluoro-1-methylpyridazinium tetrafluoroborate. This compound in acetonitrile was treated with a solution of ammonia in chloroform in the presence of 1 equivalent of NaHCO3 for 0.5 hours at ambient temperature to give 3-amino-6-fluoro-2-methyl pyridazinium tetrafluoroborate. 17. HPLC eluant MeOH/water/HOAc 25:74:1 v/v/v. 18. n.m.r. in solvent B: 1.53 (s,6H); 3.5 (m,2H); 3.7 (s,3H); 3.95 (d,1H); 4.5 (d,1H); 5.15 (d,1H); 5.8 (d,1H); 7.0 (s,1H); 7.3 (s,2H). 19. The starting material was prepared by reaction of 2,5-dimethyl-3-fluoropyrazine and trimethyloxonium tetrafluoroborate in CH2Cl2 at ambient temperature for 5 hours to give 3-fluoro-1,2,5-trimethylpyrazinium tetrafluoroborate. 20. n.m.r. in solvent B: 1.53 (s,6H); 2.38 (s,3H); 2.53 (s,3H); 3.5 (m,2H); 4.1 (s,3H); 4.2 (d,1H); 4.85 (d,1H); 5.1 (d,1H); 5.85 (d,1H); 7.05 (s,1H); 7.9 (s,1H).