Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C[C:16]1C=CC=[C:18](C)[C:17]=1[N+:23]([O-])=O.C(Cl)(=O)C(Cl)=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH2:8][C:9]([NH:23][CH:17]([CH3:18])[CH3:16])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C)c1[N+](=O)[O-]
Reactant: Cc1cccc(CC(=O)O)c1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc(CC(=O)NC(C)C)c1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
To a slurry of 3-methyl-2-nitrobenzeneacetic acid (prepared by the method of H. Rapoport et al., J. Org. Chem., 1954, 77, 670-675 from 1,3-dimethyl-2-nitrobenzene, 0.70 g, 3.6 mmol) in 10 mL of dichloromethane was added oxalyl chloride (0.41 mL, 4.7 mmol) and two drops of N,N-dimethylformamide. The reaction mixture was stirred for 20 minutes, resulting in a solution. The volatiles were removed with a rotary evaporator. The residue was dissolved in 10 mL of dichloromethane. Half of this material was added dropwise at 0° C. to isopropylamine (1 mL) in 5 mL of dichloromethane. The reaction mixture was stirred overnight at room temperature. Saturated sodium bicarbonate solution was added, and the reaction mixture was passed through a Celite® diatomaceous filter aid cartridge. The solvent was removed with a rotary evaporator to afford the title compound as an orange solid (0.40 g).
Reaction SMILES: C([O-])(=O)C.[Li+].FC(F)(F)S(O[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2)(=O)=O.[CH3:24][O:25]/[C:26](/[O:29][Si](C)(C)C)=[CH:27]\[CH3:28]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[N:17]1[C:18]2[C:13](=[C:12]([CH:27]([CH3:28])[C:26]([O:25][CH3:24])=[O:29])[CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: C/C=C(\OC)O[Si](C)(C)C
Reactant: O=S(=O)(Oc1cccc2ncccc12)C(F)(F)F
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: COC(=O)C(C)c1cccc2ncccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of tris(dibenzylideneacetone)-dipalladium (65 mg, 0.14 mmol), 1,1′-bis(diphenylphosphino)ferrocene(155 mg, 0.28 mmol) and lithium acetate(2.8 g, 27.6 mmol) in THF (50 mL) was stirred at room temperature for 5 minutes. To this mixture was added 5-quinolyl trifluoromethanesulfonate and [(E)-1-methoxy-1-propenyl]oxy(trimethyl)silane. The resulting mixture was heated at reflux for 24 hours and then allowed to cool to room temperature. The mixture was filtered, the residue was washed with THF(50 mL) and the solvent was removed under reduced pressure. Following a short silica column and aqueous workup, methyl 2-(5-quinolyl)propanoate was purified by HPLC yield 250 mg, 17%. HPLC (10% to 90% acetonitrile in 0.1N aqueous ammonium acetate over 10 min at 2 mL/min using a Waters Symmetry C18, 150×4.6 mm column) 6.89 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])/[CH:5]=[CH:6]/[CH:7]=[O:8])[CH3:2].[N+](C1C=CC=CC=1C(O)=O)([O-])=O.N1CCCC1.[OH:27][C:28]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]([O:38][CH3:39])[C:29]=1[CH:30]=O>CS(C)=O>[CH2:1]([O:3][C:4]([CH:5]1[C:6]([CH:7]=[O:8])=[CH:30][C:29]2[C:28](=[C:35]([O:36][CH3:37])[CH:34]=[CH:33][C:32]=2[O:38][CH3:39])[O:27]1)=[O:9])[CH3:2]
Reactant: CCOC(=O)/C=C/C=O
Reactant: COc1ccc(OC)c(C=O)c1O
Agent: O=C(O)c1ccccc1[N+](=O)[O-]
Solvent: C1CCNC1
Solvent: CS(C)=O
Product: CCOC(=O)C1Oc2c(OC)ccc(OC)c2C=C1C=O
Temperature: 25 °C
Reaction time: 78 h
Yield: 21.8 %

Procedure:
(E)-4-oxo-but-2-enoic acid ethyl ester (7.30 mL, 60.37 mmol), 2-nitro benzoic acid (1.852 g, 10.98 mmol), and pyrrolidine (0.91 mL, 10.98 mmol) were added simultaneously to a solution of commercially available 2-hydroxy-3,6-dimethoxy-benzaldehyde (10.0 g, 54.89 mmol) in dimethysulfoxide (50 mL) at 25° C. and the solution was stirred for 78 hours at 25° C. The reaction was quenched by the addition of water. The reaction mixture was then partitioned between water and ethyl acetate. The combined organics were washed with a saturated brine solution, dried over anhydrous sodium sulfate, filtered, rinsed and concentrated in vacuo. The residue obtained was purified on a silica gel flash column chromatography using ethyl acetate-hexanes (1:1.2) as eluents, yielding 3-formyl-5,8-dimethoxy-2H-chromene-2-carboxylic acid ethyl ester (3.5 g, 62.3%).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][NH:4][C:3]1=[O:9].[CH2:10]=O.[BH4-].[Na+]>CO.ClCCl>[CH3:1][C@@H:2]1[N:7]([CH3:10])[C@@H:6]([CH3:8])[CH2:5][NH:4][C:3]1=[O:9]
Reactant: C=O
Reactant: C[C@@H]1N[C@@H](C)CNC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: C[C@H]1CNC(=O)[C@H](C)N1C
Reaction time: 2 h
Yield: 39 %

Procedure:
To a solution of (3S,5S)-3,5-dimethyl-2-piperazinone in methanol (12 mL) at room temperature was added formaldehyde (0.345 mL, 37% water solution, 4.6 mmol) followed by sodium borohydride (261 mg, 6.9 mmol). The reaction mixture was stirred for 2 h before being diluted with dichloromethane and washed with 1N NaOH solution. The aqueous layer was back extracted with CH2Cl2 three times, and the combined organic layers were washed with brine, dried (MgSO4) and evaporated to yield (3S,5S)-3,4,5-trimethyl-2-piperazinone (128 mg, 39%). LCMS: (M+H)+: 143.1.
Reaction SMILES: [H-].[Na+].[I-].C[S+](C)(C)=O.F[C:10](F)(F)C(O)=O.[CH3:16][N:17]([CH2:19][C:20]1[CH:49]=[CH:48][C:23]([CH:24]=[CH:25][C:26]2[C:34]3[C:29](=[CH:30][C:31](/[CH:35]=[C:36]4/[C:37](=[O:47])[NH:38][C:39]5[C:44]/4=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=5)=[CH:32][CH:33]=3)[NH:28][N:27]=2)=[CH:22][CH:21]=1)[CH3:18]>CN(C=O)C>[CH3:16][N:17]([CH2:19][C:20]1[CH:49]=[CH:48][C:23](/[CH:24]=[CH:25]/[C:26]2[C:34]3[C:29](=[CH:30][C:31]([C@H:35]4[C@@:36]5([C:44]6[C:39](=[CH:40][CH:41]=[C:42]([O:45][CH3:46])[CH:43]=6)[NH:38][C:37]5=[O:47])[CH2:10]4)=[CH:32][CH:33]=3)[NH:28][N:27]=2)=[CH:22][CH:21]=1)[CH3:18]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc2c(c1)/C(=C\c1ccc3c(C=Cc4ccc(CN(C)C)cc4)n[nH]c3c1)C(=O)N2
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(/C=C/c4ccc(CN(C)C)cc4)n[nH]c3c1)C(=O)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.8 %

Procedure:
A, DMF (3 mL) was added to a mixture of NaH (60%, 85.2 mg, 2.1 mmol) and trimethylsulfoxonium iodide (131.5 mg, 0.60 mmol). The resulting mixture was stirred at rt for 10 min followed by the addition of (E)-3-((3-(4-((dimethylamino)methyl)-styryl)-1H-indazol-6-yl)methylene)-5-methoxyindolin-2-one 2,2,2-trifluoroacetate (163 mg, 0.29 mmol) as a solution in DMF (6 mL, divided for transfer and vial rinse). The reaction mixture was not complete after stirring at rt for 24 h. The mixture was heated at 55° C. for 1 h but was still not complete. After cooling to rt, NaH (60%, 44 mg, 1.1 mmol) and trimethylsulfoxonium iodide (69.5 mg, 0.31 mmol) was added and the mixture was heated at 55° C. for 1 h prior to quenching by addition of water (25 mL) and brine (25 mL). The mixture was extracted with EtOAc (300 mL) and the organic layer was washed with brine (2×25 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography (5-7.5% 2M NH3-MeOH in DCM) to yield the title compound as a yellow solid (42.8 mg, 32%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (s, 1H), 10.43 (s, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.64 (d, J=7.6 Hz, 2H), 7.47 (m, 3H), 7.29 (d, J=8.0 Hz, 2H), 7.03 (d, J=8.8 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.57 (dd, J=8.4, 2.4 Hz, 1H), 5.65 (d, J=2.4 Hz, 1H), 3.38 (s, 2H), 3.28 (s, 3H), 3.20 (t, J=7.6 Hz, 1H), 2.34 (m, 1H), 2.14 (s, 6H), 1.99 (m, 1H); MS ESI [M+H]+ 465.2, calcd for [C29H28N4O2+H]+ 465.2.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[S:28])[CH2:15][CH2:14]2)=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].CI.[C:31](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[C:20]3[S:28][CH3:31])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C(=O)N2CCC(n3c(=S)[nH]c4ccccc43)CC2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCCCc1ccc(C(=O)N2CCC(n3c(SC)nc4ccccc43)CC2)cc1
Reaction time: 18 h
Yield: 94.9 %

Procedure:
A solution of (4-butyl-phenyl)-[4-(2-thioxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-methanone (0.167 g, 0.424 mmol) in acetonitrile (5 mL) was treated with methyl iodide (0.120 g, 0.848 mmol) and potassium carbonate (0.117 g, 0.848 mmol). The reaction mixture was stirred 18 h then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate as the eluent to give (4-butyl-phenyl)-[4-(2-methylsulfanyl-benzoimidazol-1-yl)-piperidin-1-yl]-methanone (0.164 g; 95%).
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([OH:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[CH:30].N1C=CN=C1>ClCCl>[Si:1]([O:31][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[CH:30])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C#CCCCCCCCCCCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C#CCCCCCCCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
tert-Butyldiphenylsilyl chloride (TBDPSCl, 8.70 g, 31.65 mmol) was slowly added to a 0° C. solution of dodec-11-yn-1-ol (4.80 g, 26.37 mmol) and imidazole (3.23 g, 47.47 mmol) in anhydrous dichloromethane (100 mL). After stirring at room temperature for 3 h, the reaction mixture was washed with water (75 mL), brine (50 mL), and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography using 3% EtOAc/hexanes as eluent to give 12-(tert-butyldiphenylsilyloxy)dodec-1-yne (9.75 g, 88%) as a colorless oil. TLC: 6% EtOAc/hexanes, Rf≈0.7; 1H NMR (CDCl3, 300 MHz) δ 7.65-7.68 (m, 4H), 7.34-7.42 (m, 6H), 3.65 (t, J=7.3 Hz, 2H), 2.18 (dt, J=7.0, 2.4 Hz, 2H), 1.94 (t, J=1.9 Hz, 1H), 1.20-1.60 (m, 16H), 1.04 (s, 9H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([NH:16][C:17](=[O:25])OC3C=CC=CC=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[S:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[S:40][C:41]1[CH:42]=[C:43]([NH:44][C:17]([NH:16][C:9]2[CH:10]=[C:11]([C:12]([F:13])([F:14])[F:15])[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[O:25])[CH:45]=[CH:46][CH:47]=1
Reactant: O=C(Nc1cc(C(F)(F)F)n(-c2ccccc2)n1)Oc1ccccc1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(F)(F)F)n(-c5ccccc5)n4)c3)c2cc1OC
Yield: 45 %

Procedure:
The title compound was prepared as described in Example 169C, using phenyl 1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate described in Example 169B (0.115 g, 0.33 mmol), 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.103 g, 0.33 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL), to afford 1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]urea as solid (0.084 g, 45%). 1H NMR (300 MHz, DMSO-d6) δ 9.47 (s, 1H), 9.01 (s, 1H), 8.70 (s, 1H), 7.86 (s, 1H), 7.55 (m, 6H), 7.45 (t, 1H), 7.36 (s, 1H), 7.35 (s, 1H), 7.28 (s, 1H), 7.14 (s, 1H), 4.00 (s, 6H); LC-MS (ESI) m/z 567 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[NH:12][N:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=1)=[O:7].C(N(CC)C(C)C)(C)C>C(#N)C>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:9]=[C:8]2[C:6](=[O:7])[NH:5][CH2:4][CH2:3][CH2:2][N:12]2[N:11]=1
Reactant: O=C(NCCCBr)c1cc(C(F)(F)F)n[nH]1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCCCn2nc(C(F)(F)F)cc21

Procedure:
A mixture of 400 mg (1.33 mmol) of N-(3-bromopropyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide, 350 mL (2 mmol) of N,N-diisopropylethylamine, and 8 mL of acetonitrile was stirred at reflux for 4.5 h. The cooled reaction mixture was concentrated, and the residue was flash chromatographed on silica gel [0-10% of (9:1 methanol:concentrated ammonium hydroxide) in dichloromethane]. Further purification by preparative HPLC (C18 reverse phase column, 10-50% acetonitrile in water containing 0.05% trifluoroacetic acid) separated the product from a major by-product, 2-[3-(trifluoromethyl)-1H-pyrazol-5-yl]-1,3-oxazinane, to give the title compound.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11](I)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:16][CH:17]([CH:22]=[CH2:23])[C:18]([O:20][CH3:21])=[O:19]>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:22][C:17](=[O:16])[C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=CC(O)C(=O)OC
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(I)c1
Product: COC(=O)C(=O)CCc1cccc(O[Si](C)(C)C(C)(C)C)c1

Procedure:
Methyl 4-[3-(tert-butyldimethylsilyloxy)phenyl]-2-oxo-butyrate was prepared as a yellow oil from 3-(tert-butyldimethylsilyloxy) iodobenzene and methyl 2-hydroxy-3-butenoate.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:10]([NH:12][NH2:13])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:24](O)(=[O:26])[CH3:25]>C1COCC1>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:10]([NH:12][NH:13][C:24]([CH3:25])=[O:26])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)O
Reactant: NNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 50 ml of THF is dissolved 2.0 g of Z-Phe-NHNH2, followed by adding 1.4 ml of anhydrous acetic acid and 0.9 ml of TEA under ice-cooling, and the mixture is stirred for 2 hours at room temperature. The precipitated crystals are collected by filtration, washed well with diethyl ether and recrystallized from ethyl acetate to give 1.9 g of crystals, m.p. 205°-206° C., [α]D23 -16.4° (c=0.50, DMF), Rf1 =0.60.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][Si](C)(C)C)=[CH:13][N:12]=2)[CH2:7]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[CH:18])=[CH:13][N:12]=2)[CH2:7]1
Reactant: C[Si](C)(C)C#Cc1ccc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
Dissolve (S)-(2,4-dichlorbenzyl)-[1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-3-yl]-amine (190 mg, 0.45 mmol) in THF (10 mL). Add tetrabutylammonium fluoride (1 mL, 1.0 M in THF) dropwise. Stir for 2 h at room temperature. Add water. Extract with ethyl acetate (3×), wash the organic layers with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and chromatograph on silica gel, eluting with a 20:80 to 1:1 ethyl acetate:hexanes, to give the title compound as a yellow oil (141 mg, 90%). Dissolve the oil in methanol and add fumaric acid (47 mg, 0.41 mmol) in methanol. Concentrate most of the solvent, add acetonitrile and stir overnight. Filter the solid and dry in a vacuum oven at 60° C. overnight to give the title compound as its fumarate salt (139 mg, 74%). 1H NMR (400 MHz, MeOH-d4) 8.15 (d, 1H, J=2.4 Hz), 7.59-7.54 (m, 3H), 7.39 (dd, 1H, J=8.0, 2.0 Hz), 6.72 (s, 2H), 6.50 (d, 1H, J=8.8 Hz), 4.20-4.12 (m, 2H), 3.83-3.76 (m, 2H), 3.70-3.64 (m, 1H), 3.59-3.47 (m, 2H), 3.44 (s, 1H), 2.46-2.38 (m, 1H), 2.18-2.09 (m, 1H), MS (ES): m/z=346 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[CH:14][C:9]=2S[CH:7]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[O-:37][S:38]([O-:40])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:10]2[CH:9]=[CH:14][C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[CH:12][C:11]=2[S:38](=[O:40])(=[O:37])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Reactant: O=S([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC1=CS(=O)(=O)c2cc(OCc3ccc(Cl)cc3Cl)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.6 %

Procedure:
To a mixture of ethyl(6-((2,4-dichlorobenzyl)oxy)-1-benzothiophen-3-yl)acetate (10.0 g) in anhydrous DCM (400 mL) was added mCPBA (85%, 15.7 g), and the resulting solution was stirred at 25° C. for 3 d. To the reaction mixture was added Na2SO3 (30.0 g), and the mixture was stirred at 25° C. for 0.5 h. The reaction mixture was washed successively with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. The residue was washed with EtOAc to give the title compound (8.50 g).
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].Cl.[F:23][C:24]1([F:28])[CH2:27][NH:26][CH2:25]1.ON1C(=O)CCC1=O.C(N(CC)CC)C>CN(C=O)C.O>[CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([N:26]3[CH2:27][C:24]([F:28])([F:23])[CH2:25]3)=[O:20])=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: FC1(F)CNC1
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)N2CC(F)(F)C2)s1
Reaction time: 20 h
Yield: 29.4 %

Procedure:
To a stirred solution of 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (200 mg, 0.65 mmol), 3,3-difluoroazetidine hydrochloride (93 mg, 0.72 mmol) and N-hydroxysuccinimide (86 mg, 0.74 mmol) in DMF (1 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarboiimide (144 mg, 0.75 mmol) and DMF (1 mL) followed by triethylamine (0.29 mL, 2.1 mmol) and DMF (2 mL). The resulting mixture was stirred under argon for 20 h and then water added and the mixture extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated. Purification by chromatography (silica, 40% ethyl acetate in heptane) gave the title compound (73 mg, 29%) as pale yellow oil. MS: m/e=382.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[CH3:22][C:23]1([CH3:30])[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1.O>CC#N>[CH3:22][C:23]1([CH3:30])[CH2:28][CH2:27][CH:26]([NH:29][C:2]2[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:25][CH2:24]1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Reactant: CC1(C)CCC(N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC1(C)CCC(Nc2ncnc3c([N+](=O)[O-])cccc23)CC1
Yield: 69.4 %

Procedure:
To a solution of 4-chloro-8-nitroquinazoline (Intermediate-7, step-2, 150 mg, 0.72 mmol) in CH3CN (3 mL) were added K2CO3 (300 mg, 2.15 mmol) and 4,4-dimethylcyclohexanamine hydrochloride (352 mg, 2.15 mmol) and the reaction mixture was heated at reflux for 3 h. Then water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 150 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.58-8.55 (d, J=8.4 Hz, 1H), 8.50 (s, 1H), 8.38-8.35 (d, J=7.2 Hz, 1H), 8.25-8.22 (d, J=7.8 Hz, 1H), 7.67-7.61 (t, J=7.8 Hz, 1H), 4.17 (m, 1H), 1.75-1.56 (m, 4H), 1.46-1.18 (m, 4H), 0.98 (s, 3H), 0.95 (s, 3H); MS [M+H]+: 301.20.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH:19]=[O:20])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CCO>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6](=[CH:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][OH:20])[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1C=C1c2ccccc2CCc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccccc1C=C1c2ccccc2CCc2ccccc21
Reaction time: 4 h
Yield: 72 %

Procedure:
Treat a solution of 2-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-benzaldehyde (125 mg, 0.4 mmol) in EtOH (4 mL) with NaBH4 (30 mg, 0.8 mmol). After 4 h at room temperature, quench the reaction with 1N HCl and concentrate. Shake the residue en with water/EtOAc. Dry the organic layer (MgSO4) and concentrate to give 130 mg crude product. Purify on silica gel (EtOAc/hexane) to give 90 mg (72%) colorless oil which slowly crystallized, mp 121.8° C. 1H NMR (CDCl3) δ 3.28 (br s, 4H), 4.85 (s, 2H), 6.77-7.60 (m, 13H; MS (EI) 312. HPLC shows 98% purity.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:6].[OH-].[K+]>C(O)CCC>[F:28][C:27]([F:30])([F:29])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:10]=[N:9][C:8]([N:7]3[CH2:2][CH2:3][NH:4][C:5]3=[O:6])=[CH:13][CH:12]=2)[CH2:15][CH2:16]1)=[O:31]
Reactant: O=C(NCCCl)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(N3CCNC3=O)nn2)CC1
Yield: 71 %

Procedure:
A mixture of 1-(2-chloroethyl)-3-{6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]-pyridazin-3-yl}urea (0.296 g, 0.650 mmol), potassium hydroxide (0.364 g, 0.650 mmol), in BuOH (20 mL) was refluxed overnight. The reaction mixture was concentrated and purified by column chromatography. The title compound was obtained as a light yellow powder in 71% yield (0.213 g). 1H NMR (300 MHz, CDCl3) δ 8.43 (d, J=9.9 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.48-1.64 (m, 2H), 7.34 (d, J=7.5 Hz, 1H), 7.01 (d, J=9.9 Hz, 1H), 4.91-5.12 (br., 1H), 4.22 (t, J=7.8 Hz, 1H), 3.82-4.03 (m, 2H), 3.43-3.65 (m, 6H), 3.31 (t, J=5.7 Hz, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.CC(C)=O.Br[CH2:18][CH2:19][CH2:20][Cl:21].[OH-].[Na+]>O>[Cl:21][CH2:20][CH2:19][CH2:18][N:10]1[CH2:11][CH2:12][N:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8][CH2:9]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: ClCCCN1CCN(c2ncccn2)CC1

Procedure:
A mixture of 1-(2-pyrimidinyl)piperazine (2 g; 12.2 mmol), acetone (2 ml), 1-bromo-3-chloropropane (2.5 g; 15.9 mmol) and a 25% aqueous sodium hydroxide solution (1.9 ml) was stirred at room temperature for 6 hours. After completion of the reaction, the resultant mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 1-(3-chloropropyl)-4-(2-pyrimidinyl)piperazine. IR νmaxFilm (cm-1): 1595, 1550, 1500.