Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]2[NH:20][CH:21]=[CH:22][C:10]=12.[H-].[Na+].Cl[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31].O>CN(C)C=O.CCOC(C)=O>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]2[N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:21]=[CH:22][C:10]=12
Reactant: CCOC(=O)c1cnc2[nH]ccc2c1N[C@H]1CCCC[C@H]1C
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1N[C@H]1CCCC[C@H]1C
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-{[(1S,2R)-2-methylcyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (3.8 g) in N,N-dimethylformamide (76 mL) was added 60% sodium hydride (580 mg) at 4° C. The mixture was stirred at the same temperature for 1 hour. To the mixture was added [2-(chloromethoxy)ethyl](trimethyl)silane (2.55 mL) and the solution was stirred at ambient temperature for 1 hour. To the solution was added water and EtOAc. The mixture was extracted with EtOAc and washed with brine. The extract was dried over MgSO4, filtrated and evaporated. The residue was purified by column chromatography on silica gel with EtOAc and n-hexane (1:3 to 1:1) to give ethyl 4-{[(1S,2R)-2-methylcyclohexyl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (5.4 g) as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13](Br)[CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)C>[CH2:13]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCBr
Reactant: COc1cc(CC#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CCCCOc1ccc(CC#N)cc1OC
Temperature: 25 °C
Yield: 104.7 %

Procedure:
A mixture of 15 grams 4-hydroxy-3-methoxyphenylacetonitrile (91.91 mmol), 26.40 ml (33.59 grams) n-butyl bromide (245 mmol) and 21.17 grams potassium carbonate (153.2 mmol) in 150 ml acetone was heated to reflux under nitrogen for 18 hours. After cooling to room temperature, the mixture was diluted with diethyl ether and the inorganic salts were removed by filtration and were washed with diethyl ether. The filtrate and wash solutions were evaporated in vacuo to provide 21.11 grams of Compound 10c as a straw-colored viscous oil (99.9% yield) which was dried in vacuo at 50° C.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:15]([CH:16](Cl)[CH3:17])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:19])[N:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:5][C:6]1[C:15]([CH:16]([N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])[CH3:17])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:19])[N:7]=1
Reactant: CC(Cl)c1cc2c(Cl)cccc2nc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(c1cc2c(Cl)cccc2nc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 55 °C

Procedure:
Added thionyl chloride (301 μl, 4131 μmol). Obtained a clear colorless solution within minutes. Concentrated reaction mixture to dryness on the rotavap to obtain an oil, which was used without further purification. LC-MS (+esi, M+H+=260.0). Dissolved 2,5-dichloro-3-(1-chloroethyl)quinoline (215 mg, 825 μmol) in DMF (2 mL) and added phthalimide (127 mg, 866 μmol) and K2CO3 (228 mg, 1650 μmol). Submerged in oil bath and began heating to 55° C. After 10 min the temperature of the oil bath was raised to 80° C. After 30 more minutes the reaction mixture was partitioned between EtOAc:H2O. The organic layer was washed with water (3×), dried with sodium sulfate, filtered, and concentrated. The crude was solid was chromatographed on 12 g silica gel column with 0-20% EtOAc:Hex. The desired fractions were combined and concentrated to yield a white crystalline solid. 1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.99 (d, J=7.04 Hz, 3 H) 5.93 (q, J=7.17 Hz, 1 H) 7.64-7.70 (m, 2 H) 7.71-7.76 (m, 2 H) 7.77-7.83 (m, 2 H) 7.88-7.93 (m, 1 H) 8.95 (s, 1 H). LC-MS (+esi, M+H+=371.0)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40][C:41](=[O:47])OC(Cl)(Cl)Cl)Cl.[F:49][C:50]([F:61])([F:60])[C:51]1[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=1)[CH2:54]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:40][CH2:38][CH2:54][C:53]2[CH:57]=[CH:58][CH:59]=[C:51]([C:50]([F:49])([F:60])[F:61])[CH:52]=2)=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: OCCc1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCc4cccc(C(F)(F)F)c4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 81.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (72 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (125 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-trifluoromethylphenethyl alcohol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (101 mg, yield 76%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]([CH3:20])([CH3:19])[C:9]=2[CH:8]=1)[CH3:2].[C:21](Cl)(Cl)=[O:22].[NH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH2:4][CH2:5][N:6]([C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]([CH3:19])([CH3:20])[C:9]=2[CH:8]=1)[C:21](=[O:22])[NH:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=1)[CH3:2]
Reactant: CCOCCNc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=C(Cl)Cl
Reactant: COC(=O)c1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CCOCCN(C(=O)Nc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 44 %

Procedure:
A solution of (2-ethoxy-ethyl)-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine (37) (484 mg, 1.76 mmole) in 5 mL toluene was treated with 0.96 mL of a 20% phosgene solution in toluene, stirred at room temperature for 12 hours and then concentrated in vacuo. The residue was diluted with 7.2 mL of pyridine and treated with 530 mg of methyl p-aminobenzoate (2 eq.), heated at 40° C. for 15 hours, then concentrated in vacuo to give an orange oil. The product was purified by flash chromatography (SiO2, 15% ethyl acetate/hexanes, dry pack) to provide 520 mg (44%) of methyl 4-[3-(2-ethoxy-ethyl)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoate (39) as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH2:18][CH2:19][S:20][CH2:21][CH2:22][CH3:23])[CH2:4][C@@H:5]([OH:16])[CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:32])C=1>CO>[CH2:1]([N:3]([CH2:17][CH2:18][CH2:19][S:20]([CH2:21][CH2:22][CH3:23])=[O:32])[CH2:4][C@@H:5]([OH:16])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=1)[CH3:2]
Reactant: CCCSCCCN(CC)C[C@@H](O)COc1ccc(C#N)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Product: CCCS(=O)CCCN(CC)C[C@@H](O)COc1ccc(C#N)cc1

Procedure:
Oxidation of 4-[3-[ethyl[3-(propylthio)propyl]amino]-2(R)-hydroxypropoxy]benzonitrile with m-chloroperbenzoic acid was carried out as described for the stereoisomeric mixture in example 3. [α]D20 -18.6° (C 1.0, CH3OH).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[C:32]([CH2:34][CH3:35])[CH:31]=[CH:30][C:29]=3[S:36](=[O:39])(=[O:38])[NH2:37])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:40][C:41]1[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=1[C:43](O)=[O:44].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[C:32]([CH2:34][CH3:35])[CH:31]=[CH:30][C:29]=3[S:36](=[O:39])(=[O:38])[NH:37][C:43](=[O:44])[C:42]3[CH:46]=[CH:47][CH:48]=[CH:49][C:41]=3[Cl:40])=[CH:26][CH:27]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2cc(CC)ccc2S(N)(=O)=O)cc1
Reactant: O=C(O)c1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2cc(CC)ccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Yield: 80 %

Procedure:
The reaction of 5-n-butyl-2-[2-chloro-5-nitrophenyl]-2,4-dihydro-4-[(2'-sulfamoyl-5'-ethylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Step B) with 2-chlorobenzoic acid (3 equivalents), CDI (3 equiv), and DBU (3 equiv) was carried out according to the procedure of Example 51 to give an 80% yield of the title compound as a yellow solid; minor impurity by TLC in 95:5 CH2Cl2 --MeOH but suitable for use without further purification; mass spectrum (FAB) m/e 708 (M+1)+.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2C=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]([F:14])=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1.CC1(C)S[C@@H]2[C@H](N)C(=O)[N:27]2[C@H]1C(O)=O>>[CH3:1][CH2:2][N:3]1[C:9]2[N:27]=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]([F:14])=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)nc21
Yield: 25 %

Procedure:
The tetrabutyl ammonium salt of enoxacin [J. Med. Chem., 27, 292 (1984)] was prepared and converted into the corresponding dimethylacetal, using the procedure described for the corresponding norfloxacin analog in Example 15 (but done on a 0.112 mmol scale). This was coupled to 6-aminopenicillanic acid (24.2mg, 0.112 mmol) by following the procedure as described for the preparation of the product in Example 33. The product, which was very unstable, was purified by preparative liquid chromatography (C-18 reverse phase, 0-100% aqueous acetonitrile gradient) to give an amorphous, pale yellow powder after lyophilization (16.4 mg, 25% yield).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH3:5])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:46][CH2:47][C:48]1[C:49]([OH:56])=[N:50][C:51]([CH3:55])=[CH:52][C:53]=1[CH3:54]>ClCCl.O>[CH2:1]([O:3][CH:4]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:46][CH2:47][C:48]2[C:49]([OH:56])=[N:50][C:51]([CH3:55])=[CH:52][C:53]=2[CH3:54])=[O:12])=[CH:13][CH:14]=1)[CH3:5])[CH3:2]
Reactant: CCOC(C)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(C)c1ccc(C(=O)NCc2c(C)cc(C)nc2O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.7 %

Procedure:
To the solution of 4-(1-ethoxyethyl)benzoic acid (167 mg, 0.86 mmol) in dichloromethane (80 mL) was added o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (490 mg, 1.3 mmol) and triethylamine (260 mg, 2.6 mmol). then the 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (131 mg, 0.86 mmol) was added, the solution was stirred at room temperature for 12 hours, water was added and washed 3 times, the organic layer was evaporated and purified by column chromatography (silica gel, dichloromethane/meth anol=20:1) to give 4-(1-ethoxyethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (67 mg, 24%). LRMS (M+H+) m/z: calcd: 390.19. found 390. 1H-NMR (300 MHz, CD3OD) δ 7.73 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 5.96 (s, 1H), 4.58 (d, 2H), 4.43-4.41 (m, 1H), 3.35-3.31 (m, 1H), 2.39 (s, 3H), 2.28 (s, 3H), 1.42-1.40 (d, J=6.6 Hz, 3H), 1.176 (m, 3H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:22]([NH2:24])=[O:23])[CH:13]=[C:14]([C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26].C(N(CC)CC)C>C(Cl)Cl>[CH2:25]([S:27]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:22]([NH2:24])=[O:23])[CH:13]=[C:14]([C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1)(=[O:29])=[O:28])[CH3:26]
Reactant: NC(=O)c1cc(-c2cccs2)cc2c(C3CCNCC3)n[nH]c12
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccs4)cc23)CC1

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 3-(4-piperidinyl)-5-(2-thienyl)-1H-indazole-7-carboxamide hydrochloride (Intermediate 17) (0.117 mmol) was reacted with ethane sulfonyl chloride (0.02 mL, 0.234 mmol) in the presence of triethylamine (0.04 mL, 0.468 mmol) in methylene chloride (10 mL) to give the title compound (4.9 mg, 10% for the last two steps)
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[CH2:9][C@@H:10]([C:12]1[C:13]([CH3:22])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]2)[OH:11].[CH3:23][C:24]1[CH:25]=[C:26]([S:35](Cl)(=[O:37])=[O:36])[CH:27]=[CH:28][C:29]=1[N:30]1[CH:34]=[N:33][N:32]=[N:31]1>>[OH:11][C@H:10]([C:12]1[C:13]([CH3:22])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]2)[CH2:9][N:3]1[CH2:4][C@@H:5]2[CH2:8][C@H:2]1[CH2:7][N:6]2[S:35]([C:26]1[CH:27]=[CH:28][C:29]([N:30]2[CH:34]=[N:33][N:32]=[N:31]2)=[C:24]([CH3:23])[CH:25]=1)(=[O:37])=[O:36]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1-n1cnnn1
Reactant: Cc1c([C@@H](O)CN2C[C@@H]3C[C@H]2CN3)ccc2c1COC2=O
Agent: Cl
Product: Cc1cc(S(=O)(=O)N2C[C@@H]3C[C@H]2CN3C[C@H](O)c2ccc3c(c2C)COC3=O)ccc1-n1cnnn1

Procedure:
5-((R)-1-Hydroxy-2-((1S,4S)-5-(3-methyl-4-(1H-tetrazol-1-yl)phenylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)-4-methylisobenzofuran-1 (3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 3 starting from 5-((R)-2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1 (3H)-one hydrochloride (INTERMEDIATE 14) and commercially available 3-methyl-4-(1H-tetrazol-1-yl)benzene-1-sulfonyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH2:13])=[N:9]2)=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH:13][C:27]([CH:24]3[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:22][CH2:23]3)=[O:28])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NNc1cnc2ccc(Br)cc2n1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NNc2cnc3ccc(Br)cc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
A mixture of 7-bromo-2-hydrazinylquinoxaline (3 g, 12.55 mmol), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (3.16 g, 13.81 mmol), EDCI (2.89 g, 15.06 mmol), HOBt (2.03 g, 15.06 mmol), and TEA (1.9 g, 18.83 mmol) in DMF (100 mL) was stirred at r.t. overnight. The mixture was diluted with water (10 mL), and extracted with EtOAc (3×100 mL). The combined layers were dried over Na2SO4, and concentrated in vacuo to afford tert-butyl 4-(2-(7-bromoquinoxalin-2-yl)hydrazinecarbonyl)piperidine-1-carboxylate as pale yellow solid (3.5 g, yield 62%).
Reaction SMILES: C(O[C:4]1(OCC)[CH2:8][CH2:7][CH2:6]O1)C.[CH3:12][O:13][C:14](=[O:26])[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH2:23])=[C:17]([O:24][CH3:25])[CH:16]=1>C(O)(=O)C>[CH3:12][O:13][C:14](=[O:26])[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([N:23]2[CH:4]=[CH:8][CH:7]=[CH:6]2)=[C:17]([O:24][CH3:25])[CH:16]=1
Reactant: CCOC1(OCC)CCCO1
Reactant: COC(=O)c1cc(OC)c(N)c(OC)c1
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC)c(-n2cccc2)c(OC)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 9 g. of diethoxy-tetrahydrofuran and 5 ml. of glacial acetic acid was added dropwise at room temperature to a solution of 10.5 g of 4-amino-3,5-dimethoxy-benzoic acid methyl ester in 50 ml. of glacial acetic acid with stirring. The mixture was stirred at 100° C. for an additional 30 minutes, cooled with ice, filtered under vacuum, dried and recrystallized from cyclohexane, whereby there was obtained 3,5-dimethoxy-4-(pyrrol-1-yl)-benzoic acid methyl ester having a melting point of 145°-146° C.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:51][C:52]1[CH:64]=[CH:63][C:62]([F:65])=[CH:61][C:53]=1[O:54][CH:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>CN(C=O)C.O>[F:51][C:52]1[CH:64]=[CH:63][C:62]([F:65])=[CH:61][C:53]=1[O:54][CH:55]1[CH2:56][CH2:57][N:58]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:59][CH2:60]1
Reactant: Fc1ccc(F)c(OC2CCNCC2)c1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)ccc2F)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 0.03 h
Yield: 49.2 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.075 g, 0.0003 mol) in DMF (2 mL) was added DIPEA (0.135 g, 0.0012 mol), HOBt (0.061 g, 0.00045 mol) and EDCI.HCl (0.086 g, 0.00045 mol) at ambient temperature. After 2 minutes, 4-(2,5-difluoro-phenoxy)-piperidine hydrochloride (0.076 g, 0.0003 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was collected and washed with brine solution, dried over sodium sulfate and concentrated. The resulting residue was purified by column chromatography using neutral aluminum oxide (5% methanol in chloroform) to afford 0.065 g (49%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2,5-difluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 441.17 (M+1)+, 91.07%, 1H NMR (DMSO-d6): δ 13.8 (bs, 1H), 8.0 (bs, 1H), 7.8 (m, 2H), 7.4 (m, 5H), 7.2 (m, 1H), 6.8 (m, 1H), 4.6 (m, 1H), 4.2 (m, 2H), 3.9 (m, 1H), 3.8 (m, 1H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][C@@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:40])([F:39])[F:38])[CH3:30])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:41]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([NH2:41])=[O:26])=[C:21]([O:28][C@@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:40])([F:39])[F:38])[CH3:30])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1O[C@H](C)c1ccccc1C(F)(F)F
Reactant: N
Solvent: CO
Product: C[C@@H](Oc1cc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 12 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxylate and 1.3 l of a 7 N solution of ammonia in methanol is stirred in an autoclave at 125° C. for 4 hours. The reaction mixture is concentrated to dryness and the resulting residue is purified by flash chromatography [silica gel, eluent: toluol/dioxane, elution gradient of 7/3 (v/v) to 1/1 (v/v)] to yield the title product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[N:3]=1.[OH-:10].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([OH:10])[N:3]=1
Reactant: [OH-]
Reactant: Nc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Solvent: O
Product: Nc1nc(O)nc(Cl)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-Amino-4,6-dichloro-s-triazine 16.5 g, 0.1 mol) was suspended in 250 mL of water containing sodium hydroxide (4.4 g,0.11 mol), and the mixture was stirred at room temperature for 15 h. The mixture was filtered to remove 5.0 g of unreacted starting material before the cooled (0°-5° C.), clear, colorless filtrate was neutralized (pH 6.8-7.0) with glacial acetic acid. The white solid that separated was collected, washed with cold water (5×25 mL), and dried. It was crystallized from hot water to yield 7.5 g (73.4%, based on the recovery of the starting material): mp>320° C. (lit. mp 300° C.); UVλmax (pH 1)225 nm (ε=7400); UVλmax (pH 7) 250 nm (ε=4600); UVλmax (pH 11) 247 nm (ε=3600). Anal. (C3H3CIN4O, 146.54) C, H, N.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][OH:10])[CH2:4][CH2:3]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl>ClCCl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:10][CH2:9][CH2:8][CH:5]2[CH2:4][CH2:3][C:2]([CH3:11])([CH3:1])[CH2:7][CH2:6]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC1(C)CCC(CCO)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CCC(CCOS(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 13.3 %

Procedure:
To a solution of 2-(4,4-dimethylcyclohexyl)-1-ethanol (Preparation 15, 1.45 g, 9 mmol) and 4-bromobenzenesulfonyl chloride (2.53 g, 10 mmol) in dichloromethane (30 ml) was added triethylamine (1.9 ml, 13.5 mmol), and the reaction mixture was allowed to stir at room temperature for 24 h. After a further addition of 4-bromobenzenesulfonyl chloride (2.53 g, 10 mmol) and triethylamine (1.9 ml, 13.5 mmol), the reaction mixture was heated under reflux for 1 h. After allowing the reaction mixture to cool to room temperature, the mixture was treated with 2N aqueous hydrochloric acid (100 ml) and the phases were separated. The organic extract was dried (MgSO4), filtered and concentrated in vacuo to afford the crude product. The residue was purified by silica (80 g) column chromatography eluting with diethyl ether:hexane (1:20) to give the title compound as a colourless oil (450 mg, 13%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15](S(C)(=O)=O)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[C:28]([C:30]1[CH:31]=[N:32][CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1)#[N:29]>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:34]3[CH:35]=[C:30]([C:28]#[N:29])[CH:31]=[N:32][CH:33]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: N#Cc1cncc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)c1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 3-cyanopyridine-5-boronic acid pinacol ester via General Procedure A. Purification on silica yielded 170. (400 MHz CDCl3): 2.68-2.71 (4H, m, CH2), 2.81 (3H, s, CH3), 3.30-3.32 (4H, m, CH2), 3.90-3.92 (6H, m, CH2), 4.06-4.08 (4H, m, CH2), 7.35 (1H, s, ar), 8.92 (1H, d (J=2.09), ar), 8.96-8.97 (1H, m, ar), 9.81 (1H, d (J=2.03), ar). MH+500.20