Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:6]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:38][C:39]1[N:44]=[C:43](Cl)[C:42]([Cl:46])=[CH:41][N:40]=1.O>CN(C=O)C>[C:28]([O:27][C:25]([NH:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:41]2[C:42]([Cl:46])=[CH:43][N:44]=[C:39]([Cl:38])[N:40]=2)=[CH:7][C:6]=1[CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(CCc2cc(Nc3nc(Cl)ncc3Cl)ccc2NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.3 %

Procedure:
A solution of tert-butyl [3-(2-{5-amino-2-[(tert-butoxycarbonyl)amino]phenyl}ethyl)phenyl]carbamate (8.15 g, 19.1 mmol) in DMF (19 mL) was treated with potassium carbonate (3.42 g, 24.8 mol) and stirred at 25° C. for 5 minutes. The reaction mixture was treated with 2,4,5-trichloropyrimidine (2.40 mL, 21.0 mmol) dropwise and stirred at 20° C. overnight. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (300 mL). The organic layer was separated and washed with brine (50 mL), dried with sodium sulfate, filtered, and concentrated to give a crude orange oil. The residue was purified with silica gel chromatography to give the desired product (10.9 g, 99.5%). LCMS calculated for C28H33Cl2N5O4Na (M+Na)+: m/z=596.0, 598.0.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[CH2:12]([OH:15])[C:13]#[CH:14]>C(N(CC)CC)C.[Cu]I.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>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:14]#[C:13][CH2:12][OH:15]
Reactant: C#CCO
Reactant: Brc1ccc2ccccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: OCC#Cc1ccc2ccccc2c1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
A mixture of 2-bromonaphthalene (19.83 g), CuI (1.59 g), 2-propyn-1-ol (10 ml) and dichlorobis(triphenylphosphine)palladium (II) (2.00 g) in triethylamine (300 ml) was stirred under argon atmosphere at 50° C. for 72 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was extracted with ethyl acetate and the extract was washed with water and brine, dried over Na2SO4and concentrated in vacuo. The residue was chromatographed on silica gel (hexane:ethyl acetate=5:2) followed by recrystallization from hexane-ethyl acetate to give the titled compound (14.92 g) as a colorless powder.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4]OS1(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-:37]>C1COCC1>[F:37][CH2:4][C:5]1([OH:1])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: [F-]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)COS(=O)(=O)O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(CF)CC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
1,1-dimethylethyl 1,3-dioxa-2-thia-8-azaspiro[4.5]decane-8-carboxylate 2,2-dioxide (500 mg, 1.7 mmol) was taken into THF (5 mL) followed by addition of TBAF (1M in THF, 1.8 mL) and the resulting solution was stirred for 3 h at 40° C. The mixture was then cooled and partitioned with ethyl acetate and 20% aqueous citric acid. The organic solution was washed with brine then dried over anhydrous sodium sulfate, filtered and concentrated to afford tert-butyl 4-(fluoromethyl)-4-hydroxypiperidine-1-carboxylate (350 mg, 88% yield). GC-MS (EI) for C11H20FNO3: 233 (M+). BOC-group deprotection was carried out in a manner well established in the literature (see, Greene and Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience) to give 4-(fluoromethyl)piperidin-4-ol hydrochloride salt as a colorless solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:26][CH:25]=5)[S:23][C:16]=34)=[C:10]([F:36])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:37][C:38](OC(C)=O)=[O:39]>N1C=CC=CC=1>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:32][CH2:33][O:34][CH3:35])[C:38](=[O:39])[CH3:37])=[CH:26][CH:25]=5)[S:23][C:16]=34)=[C:10]([F:36])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)cc1)C(C)=O
Yield: 89.7 %

Procedure:
To a suspension of 113 (100 mg, 0.197 mmol) in pyridine (3 mL) was added Ac2O (30.2 mg, 0.296 mmol) and the reaction mixture was stirred for an hour. The mixture was concentrated then re-dissolved in EtOAc and washed with saturated CuSO4 solution then water. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. The resultant solid was triturated with Et2O to afford title compound 114 (97 mg, 90% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.68 (s, 1H), 8.48 (m, 1H), 8.03 (s, 1H, rotamer), 7.83 (m, 2H, rotamer), 7.70 (m, 1H), 7.36 (m, 3H), 7.18 (m, 1H), 6.56 (m, 2H), 4.57 (s, 2H, rotamer) 3.43 (s, 3H), 3.29 (s, 2H), 3.20 (s, 2H, rotamer), 2.49 (m, 1H), 2.06 (s, 3H, rotamer), 0.63 (m, 2H), 0.41 (m, 2H). MS (m/z)=549.57 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8](Br)[CH:7]=1)[CH3:2].[F:15][C:16]1[CH:17]=[CH:18][C:19](B2OC(C)(C)C(C)(C)O2)=[C:20]([CH:23]=1)[CH:21]=[O:22]>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:7]=[C:8]([C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:23][C:20]=2[CH:21]=[O:22])[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(Cl)cc(Br)c1
Reactant: CC1(C)OB(c2ccc(F)cc2C=O)OC1(C)C
Product: CCOC(=O)Cc1cc(Cl)cc(-c2ccc(F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (3-bromo-5-chloro-phenyl)-acetic acid ethyl ester and 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([C:40]([OH:42])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([C:40]([N:50]4[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)N2CCN(C)CC2)CC1

Procedure:
In a manner analogous to the method described in example 163,1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidine-4-carboxylic acid (example 211) was reacted with N-methylpiperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H51Cl2N6O3 [(M+H)+] 733.3394, observed 733.3390.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[O:13].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=O)=[CH:15]1>>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=[C:7]2[C:6](=[O:13])[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[O:9][CH2:8]2)=[CH:15]1
Reactant: COc1ccc2c(c1)C(=O)CCO2
Reactant: O=Cc1c[nH]c2ccccc12
Product: COc1ccc2c(c1)C(=O)C(=Cc1c[nH]c3ccccc13)CO2

Procedure:
By the method of Example 1, 6-methoxy-4-chromanone (10.0 g) and 3-indolecarbaldehyde were converted to present title product recrystallized from CH3OH/CH2Cl2, 16.7 g (98%), m.p. 217-219° C.
Reaction SMILES: Cl.[NH:2]([C:9]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.N1(O)C2C=CC=CC=2N=N1.[NH:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH2:29].C(N(C(C)C)CC)C>CN(C=O)C>[NH:2]([C:9]1([C:14]([NH:29][NH:28][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)C1(Nc2ccccc2)CCCC1
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN(CC)C(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)C1(Nc2ccccc2)CCCC1

Procedure:
1-Anilinocyclopentanecarboxylic acid hydrochloride and N-[3-(dimethylaminopropyl)]-N′-ethylcarbodiimide hydrochloride, 1H-1,2,3-benzotriazol-1-ol hydrate, tert-butyl hydrazinecarboxylate, N,N-diethylisopropylamine were stirred in DMF at room temperature to obtain tert-butyl 2-[(1-anilinocyclopentyl)carbonyl]hydrazinecarboxylate.
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1.FC(F)(F)C(O)=O.[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:31])=[N:21]1.C(N(CC)CC)C.O>CN(C)C=O>[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([C:2]3[O:6][N:5]=[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:3]=3)[CH2:34][CH2:33]2)=[O:31])=[N:21]1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Reactant: Clc1nc(-c2ccccc2)no1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(-c3ccccc3)no2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.5 %

Procedure:
To a solution of 5-chloro-3-phenyl-1,2,4-oxadiazole (99.9 mg, 0.555 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) in N,N-dimethylformamide (2 ml) was added triethylamine (0.389 ml, 2.78 mmol) at room temperature, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was poured to water, and the desired product as a solid was separated by filtration. The resulting solid was recrystallized from a mixed solvent of ethyl acetate and tetrahydrofuran to give 157 mg (72.4%) of the desired product. mp 215-216° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][C@@H:6]1[C@H:8](/[CH:9]=[CH:10]/[C:11](/[CH3:18])=[CH:12]/[C:13]([O:15]CC)=[O:14])[C@@:7]1([CH3:33])[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1.Cl>C1COCC1.CO.C(OCC)(=O)C>[CH3:3][O:4][CH2:5][C@@H:6]1[C@H:8](/[CH:9]=[CH:10]/[C:11](/[CH3:18])=[CH:12]/[C:13]([OH:15])=[O:14])[C@@:7]1([CH3:33])[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1
Reactant: CCOC(=O)/C=C(C)/C=C/[C@H]1[C@@H](COC)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@@H]1[C@H](/C=C/C(C)=C/C(=O)O)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 50 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
Sodium hydroxide solution (1N, 1 mL) was added to a solution of Compound 16a (59 mg, 0.13 mmol) in 4 mL of THF/MeOH (1:1) at 50° C. After stirring at 50° C. for 16 h, the mixture was diluted with ethyl acetate (10 mL) ad acidified with 1 mL of 1 HCl at 0° C. The organic layer was then washed with brine (1×5 mL), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography using 30% EtOAc in hexane to give the title compound (43 mg, 79% yield) as a white solid:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[Br:29])[N:25](COCC[Si](C)(C)C)[N:24]=[C:23]2[NH:38][C:39](=[O:43])[CH2:40][CH2:41][CH3:42].C(OCC)(=O)C>O1CCCC1>[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[Br:29])[NH:25][N:24]=[C:23]2[NH:38][C:39](=[O:43])[CH2:40][CH2:41][CH3:42]
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Br)c(Br)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(Br)c(Br)cc12
Yield: 62.6 %

Procedure:
12.2 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1 g of N-[5,6-dibromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 60 cm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours; after cooling, 75 cm3 of ethyl acetate are added and the organic phase is washed successively with 100 cm3 of saturated sodium hydrogen carbonate solution and then with 75 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.) to give 1.6 g of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (50/50 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 20 cm3 of diisopropyl ether, filtered off, washed with 2×10 cm3 of diisopropyl ether and dried (90 Pa; 45° C.) to give 460 mg of N-[5,6-dibromo-1H-indazol-3-yl]butanamide in the form of bluish crystals melting at 250° C.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.[Cl:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH2:22]Cl)[C:17]=1[CH3:24].[OH-].[Na+]>C(O)C>[Cl:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH2:22][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:17]=1[CH3:24]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(OCCCl)ccnc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(OCCCl)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
12.3 g of crude 2-mercaptobenzimidazole, 20 g of 4-(2-chloroethoxy-2-chloromethyl-3-methylpyridine hydrochloride and 11 g of sodium hydroxide were dissolved in 300 ml of ethanol to obtain a solution. This solution was stirred at 60° C. for 2 hours and distilled under a reduced pressure to remove the ethanol. The obtained residue was chromatographed over a silica gel column and eluted with 40% ethyl acetate in hexane and then with ethyl acetate to obtain 15.5 g of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][CH2:10][OH:11])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH2:19]Cl)[CH:18]=1>CN(C=O)C>[Br:12][C:13]1[CH:18]=[C:17]([CH2:19][O:11][CH2:10][CH2:9][N:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH:16]=[N:15][CH:14]=1
Reactant: OCCN1CCOCC1
Reactant: ClCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cncc(COCCN2CCOCC2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
To the NaH (484 mg, 60% in mineral oil, 12.1 mmol) in DMF (dry, 1 mL) at 0° C., is slowly added 2-morpholin-4-yl-ethanol (1.47 ml, 12.1 mmol). Then the mixture is stirred at 0° C. for 30 min. 3-bromo-5-chloromethyl-pyridine (500 mg, 2.42 mmol) is added at 0° C. The mixture is then stirred at room temperature overnight and is quenched by adding water dropwise. The mixture is partitioned between DCM and water. The DCM phase is separated and then washed with water twice. The DCM phase is evaporated under high vacuum. The residue is separated by silica gel flash column (MeOH/DCM 0 to 5% gradient, then 5%) to obtain 370 mg of 4-[2-[(5-bromo-3-pyridyl)methoxy]ethyl]morpholine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:67]=[C:66]([O:68][CH3:69])[CH:65]=[C:64]([O:70][CH3:71])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:27]([CH:30](/[CH:50]=[CH:51]/[C:52]1[C:57]([O:58][CH3:59])=[CH:56][C:55]([O:60][CH3:61])=[CH:54][C:53]=1[O:62][CH3:63])[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39]S(C2C=CC(C)=CC=2)(=O)=O)[CH:32]=1)(=[O:29])=[O:28])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16]S(C2C=CC(C)=CC=2)(=O)=O)[CH:9]=1.[OH-].[Na+].Cl>CO>[CH3:71][O:70][C:64]1[CH:65]=[C:66]([O:68][CH3:69])[CH:67]=[C:3]([O:2][CH3:1])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:27]([CH:30](/[CH:50]=[CH:51]/[C:52]1[C:53]([O:62][CH3:63])=[CH:54][C:55]([O:60][CH3:61])=[CH:56][C:57]=1[O:58][CH3:59])[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([OH:39])[CH:32]=1)(=[O:29])=[O:28])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([OH:16])[CH:9]=1
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(OS(=O)(=O)c3ccc(C)cc3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(OS(=O)(=O)c3ccc(C)cc3)c2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(O)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(O)c2)c(OC)c1
Yield: 95 %

Procedure:
A mixture of (E)-2,4,6-Trimethoxystyryl-3-[(p-Toluenesulfonyl)oxy]-4-methoxy-benzyl sulfones 26, (5.0 g, 9.1 mmol), 50 mL (20%) sodium hydroxide solution and methanol (50 mL) were taken in a round bottomed flask and refluxed until the reaction mixture is clear without any turbidity (3-4 h). The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature and neutralized with cold dilute HCl solution. The precipitate separated after neutralization was filtered, washed with water and dried to get the crude product which on recrystallization from 2-propanol resulted analytically pure sample 6aa. Yield: 95%; white solid mp 124-127° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[N:16]=[C:15]([CH:26]([F:28])[F:27])[CH:14]=2)=[CH:9][CH:8]=1)(=O)C>C1COCC1.CO>[F:28][CH:26]([F:27])[C:15]1[CH:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][OH:4])=[CH:8][CH:9]=2)[N:17]([C:18]2[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[N:16]=1
Reactant: COc1ccc(-n2nc(C(F)F)cc2-c2ccc(CCOC(C)=O)cc2)cn1
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-n2nc(C(F)F)cc2-c2ccc(CCO)cc2)cn1
Reaction time: 4 h
Yield: 33.7 %

Procedure:
To a solution of 2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenyl}ethyl acetate (10 g) in THF (120 ml) and MeOH (30 ml) was added 1NNaOH (60 ml) at room temperature. The reaction mixture was stirred at the same temperature for 4 hrs, and then neutralized with 1NHCl (60 ml), evaporated, and extracted twice with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered and evaporated to give crude product. The residue was column chromatographed on silica gel and crystalized from IPE and filtered to give 3.0 g of 2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethanol. The filtrate was evaporated and filtered to give 4.65 g of second crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([NH:22][CH2:23][C:24](O)=[O:25])=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:29][CH:30]1[CH2:35][CH2:34][N:33]([C:24](=[O:25])[CH2:23][NH:22][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:28]=[CH:27][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:19]=2)=[O:21])[CH2:32][CH2:31]1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Reactant: OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC(=O)N3CCC(O)CC3)ccc21
Yield: 64.2 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]amide (77 mg) was prepared by following General Procedure F starting from {[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (100 mg), 4-hydroxypiperidine (27 mg), HBTU (109 mg), and DIEA (63 uL), with a modification of General Procedure F where DIEA was slowly added to the reaction mixture as the last reagent. LC/MS: m/z 499.8. 1H NMR (DMSO-d6, 400 MHz): δ 8.48 (t, 1H), 8.11 (s, 1H), 7.92 (s, 1H), 7.81 (d, 1H), 7.67 (d, 1H), 7.51 (d, 1H), 7.39 (d, 1H), 4.80 (d, 1H), 4.15 (d, 2H), 3.98-3.88 (m, 1H), 3.76-3.68 (m, 2H), 3.63 (s, 3H), 3.20 (t, 1H), 3.05 (t, 1H), 1.85-1.65 (m, 2H), 1.46-1.20 (m, 2H), —NH proton signal was not observed.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH3:38])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1.[C:39]([N:46]1[CH2:53][CH2:52][CH2:51][C@H:47]1[C:48](O)=[O:49])([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].C(N(CC)CC)C>C(#N)C>[C:39]([N:46]1[CH2:53][CH2:52][CH2:51][C@H:47]1[C:48]([NH:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH3:38])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1)=[O:49])([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]
Reactant: COc1cc2ncnc(N3CCC(CCN)CC3)c2cc1OC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(N3CCC(CCNC(=O)[C@@H]4CCCN4C(=O)OC(C)(C)C)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
N,N'-dicyclohexylcarbodiimide (0.53 g) was added to a mixture of 4-(2-aminoethyl)-1-(6,7-dimethoxyquinazolin-4-yl)piperidine.2HCl (1.2 g), Boc-L-proline (1.1 g), triethylamine (0.72 ml) and acetonitrile (20 ml). The mixture was stirred at room temperature for 12 hours and filtered. The filtrate was dried and concentrated under reduced pressure. The residue was partitioned between an aqueous solution of 10% NaHCO3 and chloroform. The organic layer was dried over anhydrous magnesium sulfate, concentrated and purified by using a 40 g silica gel column to give 4-{2-(Boc-L-prolylamino)ethyl}-1-(6,7-dimethoxyquinazolin-4-yl)piperidine (1.23 g; 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][N:6]1[CH:20]=[C:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:18]2[N:11]3[CH2:12][CH2:13][N:14]([CH3:17])[C:15](=[O:16])[C:10]3=[C:9]([O:29][CH3:30])[C:8]=2[C:7]1=[O:31].[H-].[Na+].I[CH3:39]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][N:6]1[CH:20]=[C:19]([N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:39])[C:18]2[N:11]3[CH2:12][CH2:13][N:14]([CH3:17])[C:15](=[O:16])[C:10]3=[C:9]([O:29][CH3:30])[C:8]=2[C:7]1=[O:31]
Reactant: CI
Reactant: COc1c2n(c3c(NC(=O)OC(C)(C)C)cn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c2n(c3c(N(C)C(=O)OC(C)(C)C)cn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A cold (0° C.) solution of 2-(3-chloro-4-fluorobenzyl)-10-methoxy-4-(N-tert-butoxylcarbonyl-amino)8-methyl-7,8-dihydropyrido-[3′,4′:4,5]pyrrolo[1,2-a]pyrazine-1,9(2H,6H)-dione (0.54 g, 1.07 mmol) in anhydrous DMF (6 mL) was treated with sodium hydride (38 mg, 1.60 mmol). The resultant mixture was stirred at the same temperature for 30 minutes, and treated with iodomethane (0.23 g, 1.60 mmol). After stirring at 0° C. for 1 hour, the product mixture was concentrated under vacuum. The residue was partitioned between chloroform and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the titled compound.