Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH:3]([CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH2:8]1)[CH2:4][OH:5].CCN(C(C)C)C(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[CH:3]([CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)[CH2:8]1)[CH2:4][O:5][S:35]([CH3:34])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(CN1CCOC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCC(CN1CCOC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
In a 50 mL round-bottomed flask, 3,3,3-trifluoro-2-((2-(3-(trifluoromethyl)phenyl)morpholino)-methyl)propan-1-ol (760 mg, 2.13 mmol) was combined with CH2Cl2 (10.0 ml) to give a colorless solution and then cooled to 0° C. DIPEA (412 mg, 557 μl, 3.19 mmol) and methanesulfonyl chloride (244 mg, 166 μl, 2.13 mmol) were added dropwise and the resulting reaction mixture was stirred for 30 min. The reaction was diluted with CH2Cl2 (30 ml), washed with sat. NaHCO3 solution followed by washing with H2O, dried over MgSO4, filtered and concentrated to give 880 mg (95%) of methanesulfonic acid 3,3,3-trifluoro-2-[2-(3-trifluoromethyl-phenyl)-morpholin-4-ylmethyl]-propyl ester as a colorless oil. MH+=436.
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:31])[C:5]([N:7]([CH3:30])[C@@H:8]1[CH2:14][CH2:13][CH2:12][C@@H:11]([CH3:15])[N:10]2[C:16](=[O:29])[C:17]([O:24]S(C)(=O)=O)=[C:18]([C:20](OC)=[O:21])[N:19]=[C:9]12)=[O:6])[CH3:3].[CH3:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][C:34]=1[F:41]>CS(C)=O>[F:41][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:33]=1[CH3:32])[CH2:37][NH:38][C:20]([C:18]1[N:19]=[C:9]2[C@H:8]([N:7]([CH3:30])[C:5](=[O:6])[C:4]([N:2]([CH3:3])[CH3:1])=[O:31])[CH2:14][CH2:13][CH2:12][C@@H:11]([CH3:15])[N:10]2[C:16](=[O:29])[C:17]=1[OH:24])=[O:21]
Reactant: Cc1ccc(CN)cc1F
Reactant: COC(=O)c1nc2n(c(=O)c1OS(C)(=O)=O)[C@H](C)CCC[C@H]2N(C)C(=O)C(=O)N(C)C
Solvent: CS(C)=O
Product: Cc1ccc(CNC(=O)c2nc3n(c(=O)c2O)[C@H](C)CCC[C@H]3N(C)C(=O)C(=O)N(C)C)cc1F
Temperature: 100 °C

Procedure:
The trans-rac-methyl 10-[[(dimethylamino)(oxo)acetyl](methyl)amino]-6-methyl-3-[(methylsulfonyl)oxy]-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepine-2-carboxylate from Step 10 (50 mg) was dissolved in DMSO (2 mL) and 4-methyl-3-fluorobenzylamine (0.1 mL) added. The resulting mixture was heated at 100° C. for 30 minutes. As determined by LC-MS, there was complete conversion to product which was purified by reverse phase Gilson chromatography: 1H NMR (400 MHz, CDCl3) δ 9.46 (br s, 1H), 7.05 (m, 3H), 5.96 (m, 1H), 5.56 (br s, 1H), 4.47 (qd, J=6.8, 14.5 Hz, 2H), 3.02 (s, 3H), 2.99 (s, 3H), 2.94 (s, 3H), 2.21 (s, 3H), 1.61-2.24 (m, 6H), 1.47 (d, J=7.5 Hz, 3H). ES MS M+1=487.8.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=2[OH:28])[CH2:12][N:13]([CH3:24])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:6]=[CH:7][CH:8]=1.[CH2:31]([O:38][C:39](=[O:43])[C@@H:40](O)[CH3:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:31]([O:38][C:39](=[O:43])[C@H:40]([O:28][C:27]1[CH:26]=[CH:25][C:11]([CH2:12][N:13]([CH3:24])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:10][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:29])[F:30])[CH:4]=1)[CH3:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Reactant: CN(Cc1ccc(O)c(-c2cccc(C(F)(F)F)c2)c1)S(=O)(=O)c1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1ccc(CN(C)S(=O)(=O)c2ccc(F)cc2)cc1-c1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 17.5 %

Procedure:
To a solution of N-(3-(3-trifluoromethylphenyl)-4-hydroxybenzyl)-4-fluoro-N-methylbenzenesulfonamide (36) (50.0 mg, 0.114 mmol, 1 eq) and (S)-benzyl-2-hydroxypropanoate (21 μL, 0.125 mmol, 1.1 eq, Aldrich, Milwaukee, Wis., USA) in THF (2 mL) at 0° C. was added diethyl azodicarboxylate (20 μL, 0.125 mmol, 1.1 eq) and triphenylphosphine (33 mg, 0.125 mmol, 1.1 eq). After stirring at 0° C. for 4 h, the mixture was extracted between saturated sodium bicarbonate and EtOAc, dried (Na2SO4), concentrated in vacuo, and purified on via silica gel chromatography (linear gradient of 5-10% EtOAc/hexane). The isolated material was further purified via reversed phase semi-preparative HPLC to give 12 mg of benzyl-(R)-2-(2-(3-trifluoromethylphenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)propanate. This intermediate was stirred in the presence of 10 mg of 10% Pd/C under a hydrogen atmosphere in EtOH. (5 mL) at room temperature for 16 h. The reaction mixture was then filtered through a celite pad and the filtrate was concentrated in vacuo. The crude residue was purified via reversed phase semi-preparative HPLC to give 7.8 mg of (R)-2-(2-(3-trifluoromethylphenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)propanoic acid (Example 35). 1HNMR (CDCl3, 400 MHz): δ 7.78 (m, 3H), 7.64(d, 1H), 7.48 (m, 2H), 7.25 (m, 3H), 7.17 (d, 1H), 6.73 (d, 1H), 4.87 (m, 1H), 4.04 (s, 2H), 2.53 (s, 3H), 1.32 (d, 3H). MS (ESI): MH+=512.1. HPLC (Method B) tR=3.48 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:23]([O:22][CH3:21])[CH:24]=3)=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
In a 200 mL round-bottomed flask, 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (25 mg, 0.088 mmol) and 3,4-dimethoxybenzoyl chloride (17.6 mg, 0.088 mmol) were combined with methylene chloride (3 mL) to give a yellow suspension. The reaction mixture was cooled to 0° C. After 15 min. stirring at reduced temperature, N,N-diisopropylethylamine (56.7 mg, 76.6 μL, 0.439 mmol) was added. The reaction mixture quickly became a yellow solution, then was stirred at 0° C. for 1 hr. After this time, LC/MS indicated that the reaction was complete. The reaction mixture was warmed to room temperature, then stirred overnight. In the morning, the reaction mixture was concentrated over silica gel. Flash chromatography (25 gram Analogix column, 20% ethyl acetate-hexanes ramped to 100% ethyl acetate) was used to purify the product. N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3,4-dimethoxy-benzamide (26 mg, 59%) was obtained as a white solid. MS calcd. for C25H21ClN2O4 [(M+H)+] 448.9, obsd. 449.1.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:32])=[C:16]([NH:21][CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:34])[CH3:33])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:35](Cl)(=[O:37])[CH3:36].C(=O)([O-])O.[Na+]>CCCCCC.C(OCC)(=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:32])=[C:16]([N:21]([CH2:22][CH2:23][C:24]4[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=4)[C:35](=[O:37])[CH3:36])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:34])[CH3:33])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1ccc(CCNc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(CCN(C(C)=O)c2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
Sodium hydride (a 60% dispersion in liquid paraffin, 232.1 mg, 5.80 mmol) was washed twice with hexane and then suspended to N,N-dimethylformamide (25 ml). To this suspension was added under an argon atmosphere 3-(4-isopropylphenyl)-N-[2-(4-methoxyphenyl)ethyl]-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (537.9 mg, 1.18 mmol) and the reaction mixture was stirred at 60° C. for 20 minutes. Then, acetyl chloride (0.5 ml, 7.03 mmol) was added into the reaction mixture and stirred at the same temperature for 1 hour. After the reaction solution was cooled down to room temperature, an aqueous saturated solution of sodium hydrogen carbonate was added to the reaction mixture and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried on magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 3:1) to obtain the rotamer 1 (Rf=0.38; hexane-ethyl acetate 3:1) of the title compound (46% yield). Melting point: 134-136° C. (Ethyl acetate-hexane)
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[N:21][O:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:18]([OH:20])=[O:19])[N:16]=1>O1CCCC1>[CH:1]([NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[N:21][O:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:18]([OH:20])=[O:19])[N:16]=1)=[O:3]
Reactant: Nc1nc(C(=NOC2CCCC2)C(=O)O)cs1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CNc1nc(C(=NOC2CCCC2)C(=O)O)cs1
Yield: 40.7 %

Procedure:
To acetic anhydride (32 g.) was added formic acid (14.4 g.) under ice-cooling and stirred at 40° to 45° C. for an hour. 2-(2-Aminothiazol-4-yl)-2-cyclopentyloxyiminoacetic acid (syn isomer, 20 g.) and tetrahydrofuran (100 ml.) were added to the solution under ice-cooling and stirred at 35° C. for 3 hours. After the solution was concentrated in vacuo, the residue was pulverized with diisopropyl ether, and dried over phosphorus pentoxide to give 2-(2-formamidothiazol-4-yl)-2-cyclopentyloxyiminoacetic acid (syn isomer, 9.04 g.), mp. 158° C. (dec.).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C(O)(C)C.Cl>[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][N:27]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)[CH2:28][CH2:29]2)=[CH:20][CH:19]=1
Reactant: COC(=O)COc1ccc2nccc(Br)c2c1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)COc1ccc2nccc(N3CCN(c4ccncc4)CC3)c2c1
Yield: 34.3 %

Procedure:
To a solution of methyl 4-bromoquinolin-6-yloxyacetate (169 mg) in isopropanol(10 ml) was added 1-(4-pyridyl)piperazine (93 mg) followed by 2 drops of saturated ethereal HCl. The resulting mixture was refluxed for 18 hours. The mixture was filtered and concentrated. Purification by flash column chromatography on silica, eluting with methanol/dichloromethane (10% to 15% v/v in 1% increments) gave methyl 4-[4-(4-pyridyl)piperazin-1-yl]quinolin-6-yloxyacetate (74 mg) as a solid: NMR(d6DMSO) δ 3.2-3.4(m,4H), 3.6-3.7(m,4H), 3.75(s, 3H), 5.0(s,2H), 6.95(d,2H), 7.05(d,1H), 7.25(d,1H), 7.45(dd,1H), 7.9(d,1H), 8.25(d,2H), 8.6(d,1H); m/e 379(M+H)+.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.Cl[C:17]1[N:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]>O>[F:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:17]1[N:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: Oc1cccc(F)c1
Reactant: O=C(O)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cccnc1Oc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19.2 %

Procedure:
Sodium hydride dispersion, 50% by weight (3.05 grams, 63.47 mmol) is placed into a 125 ml round bottom equipped with a stir bar and condenser under nitrogen and is charged with 32 ml of dimethylformamide. 3-Fluorophenol (3.56 grams, 31.73 mmol) is added portionwise over five minutes. During this addition, an exotherm and vigorous gas evolution is observed. The reaction is allowed to stir for five minutes. 2-Chloronicotinic acid (5.00 grams, 31.73 mmol) is added portionwise over five minutes. Gas evolution is observed. When it subsides, the reaction is heated to reflux for 2 hours. The reaction is cooled to room temperature and 300 ml of water is added. The aqueous layer is extracted with diethyl ether (2×200 ml). The aqueous layer is then pH adjusted to acidic with glacial acetic acid and extracted with ethyl acetate (3×150 ml). The organics are combined and washed with water (2×150 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield a yellow oil. The oil is purified by trituration with diethyl ether/hexanes (3/1) to yield 1.42 grams (19.2%) of product as a yellow crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:26][C:25](=[O:27])[C:24]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][N:22]=5)[CH:17]=[CH:16][C:15]=4[N:14]=3)=[CH:11][C:10]([C:28]([F:31])([F:30])[F:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(#N)C.O.[CH:36]([NH2:39])([CH3:38])[CH3:37]>[Cl-].[Na+].O>[CH:36]([NH:39][C:25]([C:24]1[C:15]([NH:14][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([C:28]([F:31])([F:29])[F:30])[CH:11]=2)=[O:26])=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)=[O:27])([CH3:38])[CH3:37]
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ccc3cccnc3c12
Reactant: CC(C)N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)NC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)ccc2cccnc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
To a suspension of 140 mg (0.28 mmol) of the above 2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-3-oxa-1,5-diaza-phenanthren-4-one in 5.60 mL of a mixture acetonitrile: H2O 4:1 (v/v) is added 73 μL (0.85 mmol) of isopropylamine. The reaction mixture is stirred for 6 hours at ambient temperature. Brine is then added to the mixture and the product is extracted with ethyl acetate (3 times). The regrouped organic phases are dried on Na2SO4, filtrated and evaporated. The purification of the residue by flash chromatography (SiO2, heptane and ethyl acetate as eluants) affords 100 mg (70%) of a white solid; LC/MS: 503/505 (M+H)+, m.p.: 225-226° C.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10](P(=O)(OCC)OCC)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+]>O1CCCC1>[C:11]1(/[CH:10]=[CH:4]/[C:3]2[C:2]([NH2:1])=[N:9][CH:8]=[CH:7][CH:6]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ncccc1C=O
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ncccc1/C=C/c1ccccc1
Temperature: 80 °C
Yield: 40.4 %

Procedure:
In 35 ml of tetrahydrofuran (THF) was dissolved 1.28 g of 2-aminonicotinaldehyde, followed by addition of 2.50 g of diethyl benzylphosphonate and 2.08 g of potassium hydroxide, and the mixture was refluxed at 80° C. for 4.5 hours. This reaction mixture was filtered to remove insoluble matter and the filtrate was evaporated under reduced pressure. The residue was dissolved in 2N-hydrochloric acid and the solution was washed with ether, made basic bv adding 15% aqueous sodium hydroxide solution, and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated off. The residue was recrystallized from acetonitrile to provide 0.83 g of the title compound as yellow prisms. This product was used as a starting material without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[CH:7]2.[Li]C(C)(C)C.C(=O)=O.[C:27](OC)(=[O:32])[C:28]([O:30][CH3:31])=[O:29]>C1COCC1.CCOC(C)=O>[CH3:31][O:30][C:28](=[O:29])[C:27]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[CH:7]2)=[O:32]
Reactant: COC(=O)C(=O)OC
Reactant: C[Si](C)(C)CCOCn1ccc2cccc(Br)c21
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(=O)c1cccc2ccn(COCC[Si](C)(C)C)c12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 84.5 %

Procedure:
A solution of 7-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole (3.0 g, 9.19 mmol) in THF (100 mL) was cooled to −78° C. and a 1.7 M solution of tBuLi in pentanes (15 mL, 25.5 mmol) added dropwise over 15 min. After 15 min, the resultant bright yellow suspension was transferred over 15 min via a cannula cooled with dry ice to a solution of dimethyl oxalate (3.61 g, 30.6 mmol) in THF (40 mL) maintained at −78° C. After 15 min, the mixture was allowed to warm to room temperature and stirred 3 h. The cloudy yellow mixture was treated with pH 7.0 buffer, poured into-EtOAc and the EtOAc washed with pH 7.0 buffer (brine was added to clarify the layers), brine, dried (MgSO4) and concentrated to a cloudy oil. Flash chromatography (10% EtOAc/hexanes) afforded the title compound (2.59 g, 84%) as a bright yellow oil. 1H NMR (400 MHz, DMSO-d6) 7.97 (dd, J=8, 1 Hz, 1H), 7.64 (d, J=3 Hz, 1H), 7.57 (dd, J=8, 1 Hz, 1H), 7.24 (dd, J=8, 8 Hz, 1H), 6.68 (d, J=3 Hz, 1H), 5.59 (s, 2H), 3.91 (s, 3H), 3.04 (t, J=8 Hz, 2H), 0.62 (t, J=8 Hz, 2H), −0.17 (s, 9H). 13C NMR (75.5 MHz, DMSO-d6) 185.17, 163.31, 132.59, 131.60, 130.87, 127.19, 126.15, 120.09, 118.95, 102.40, 77.05, 63.92, 52.83, 16.74, −1.69. IR (CHCl3, cm−1) 1740, 1683. HRMS 334.1481 (M++1, calcd for C17H24NO4Si 334.1475).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][N:8]=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([N:58]1[CH:62]=[C:61]([CH2:63][C:64]2[CH:69]=[CH:68][C:67]([C:70]#[N:71])=[CH:66][CH:65]=2)[N:60]=[CH:59]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:60]2[C:61]([CH2:63][C:64]3[CH:69]=[CH:68][C:67]([C:70]#[N:71])=[CH:66][CH:65]=3)=[CH:62][N:58]=[CH:59]2)=[CH:9][N:8]=1
Reactant: OCc1ccc(-c2ccccn2)nc1
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cc2cncn2Cc2ccc(-c3ccccn3)nc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(pyrid-2-yl)-5-hydroxymethyl-pyridine (269 mg, 1.33 mmol) and diisopropylethylamine (0.464 mL, 2.66 mmol) in dichloromethane (7 mL) at -78° C. is added trifluoromethanesulfonic anhydride (0.224 mL, 1.33 mmol) and the mixture stirred at -78° C. for 1 hour. To this mixture is added a solution of 1-trityl-4-(4-cyanobenzyl)-imidazole (566 mg, 1.33 mmol) in dichloromethane (5 mL). The mixture is allowed to warm to ambient temperature and stirred for 2 hours. The solvent is evaporated in vacuo. The residue is dissolved in methanol (50 mL), heated at reflux for 1 hour, and the solvent is evaporated in vacuo. The residue is partitioned between dichloromethane and sat. aq. NaHCO3 solution. The organic layer is dried, (Na2SO4) and the solvent evaporated in vacuo. The residue is chromatographed to afford the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[C:12]2[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27].[CH2:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]([CH3:31])[CH3:30]>>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[CH2:19][NH:18][C:12]1[C:11]2[C:16](=[C:7]([O:6][CH2:5][CH2:4][NH:3][S:32]([CH2:28][CH:29]([CH3:31])[CH3:30])(=[O:34])=[O:33])[CH:8]=[CH:9][CH:10]=2)[N:15]=[C:14]([CH3:17])[CH:13]=1
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: Cc1cc(NCc2ccc(Cl)cc2Cl)c2cccc(OCCN)c2n1
Agent: Cl
Product: Cc1cc(NCc2ccc(Cl)cc2Cl)c2cccc(OCCNS(=O)(=O)CC(C)C)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 21. Starting materials were [8-(2-aminoethoxy)-2-methylquinolin-4-yl]-(2,4-dichlorobenzyl)-amine dihydrochloride (example 36) and isobutanesulfonyl chloride.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[N+:18]([O-])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.C(OCC)(=O)C>[C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[NH2:18])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
To a solution of 2-phenylsulfonylamino-5-chloro-1-nitrobenzene (172 mg; prepared in Reference Example 11.) in acetic acid (4 ml), reduced iron powder (154 mg) was added at room temperature under an atmosphere of argon. The suspension was stirred for 2 hours at 120° C. The reaction suspension was diluted with ethyl acetate and filtered. The filtrate was concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (AcOEt-hexane) to give the title compound (92 mg) having the following physical data.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:20](=[O:22])[NH2:21])([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.O>[Pd].C1(C)C=CC=CC=1>[O:22]=[C:20]1[C:11]2([CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[N:21]1
Reactant: NC(=O)C1(N2CCCCC2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1N=C2CCCCN2C12CCNCC2
Yield: 70 %

Procedure:
A mixture of 10 g of 1-benzyl-4-carbamoyl-4-piperidino-piperidine, 3 g of 5% palladium-on-charcoal catalyst and 100 ml of water is boiled under reflux for 8 hours, while the toluene formed is removed. The reaction mixture is then cooled, and the catalyst is removed by filtration. The filtrate is concentrated to 10 ml under reduced pressure and is allowed to stand. The precipitated crystals are collected by filtration, dried and recrystallized from chloroform to give 2,3,5,6,7,8-hexahydro-2-oxoimidazo[1,2-a]pyridine-3-spiro-4'-piperidine as colorless crystals, m.p. 220° C., 70% yield.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:31][C@H:30]([CH2:32][O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C@@H:21]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:12]3[O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:41][NH2:42]>>[NH:41]([C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:31][C@H:30]([CH2:32][O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C@@H:21]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:12]3[O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[N:5]=[CH:6][N:7]=1)[NH2:42]
Reactant: Clc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: NN
Product: NNc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 10 g of 4-chloro-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine and 100 ml of anhydrous hydrazine is heated under reflux and a nitrogen atmosphere for one hour, evaporated in vacuo, and coevaporated with xylenes. The residue is distributed between a mixture of ethyl acetate and water. The aqueous layer is reextracted with ethyl acetate and the dried ethyl acetate solution is evaporated in vacuo to provide 9.0 of crude product. Purification of this material by silica gel chromatography (ethyl acetate) provides pure 4-hydrazino-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine as a yellow syrup.