Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])(O)=O.[Na+]>C(N(CC)CC)C>[C:18]([CH2:17][CH2:16][NH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13])([O:20][CH2:21][CH3:22])=[O:19]
Reactant: COc1ccc(C(C)=O)c(N)c1OC
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNc1c(C(C)=O)ccc(OC)c1OC
Temperature: 135 °C
Reaction time: 5 h

Procedure:
Triethylamine (19.4 g, 192 mM) was added to a mixture of 2'-amino-3',4'-dimethoxyacetophenone (25 g, 128 mM) and ethyl 3-bromopropionate (139 g, 770 mM), in a 250 mL flask (equipped with a large stirring bar, reflux condenser and nitrogen inlet). The pale solid which formed was stirred at 135° C. for 5 hours. The brown homogeneous oil which formed was then cooled to 10° C. and 200 mL of 2% NaHCO3 was added. The solution was then extracted with CHCl3 (3×100 mL), the organic layer washed with H2O (100 mL) and dried over MgSO4. Following filtration, the CHCl3 and most of the bromopropionate were removed under reduced pressure. The oily residue was charged onto a 10×75 cm, SilicAR CC-7 column (800 g, hexane packed) and eluted with 5 to 20% ethyl acetate/hexane, collecting 1 L fractions. Evaporation of fractions 7-9 gave purified 2'-(N-2-carbethoxyethylamino)-3',4'-dimethoxyacetophenone as a yellow oil (5.86 g, 15%); UV (EtOH) nm: 244 (ε29110), 284 (ε11480); MS (Probe) 295 (M+).
Reaction SMILES: Cl.[CH:2]1([NH2:5])[CH2:4][CH2:3]1.[C:6]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:7][C:8]([CH3:10])=O.[F:15][C:16]([F:33])([F:32])[C:17]1[CH:31]=[CH:30][C:20]([CH:21]=[C:22]([C:27]([CH3:29])=O)[C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH:2]1([N:5]2[C:8]([CH3:10])=[C:7]([C:6]([O:12][CH2:13][CH3:14])=[O:11])[CH:21]([C:20]3[CH:30]=[CH:31][C:17]([C:16]([F:33])([F:32])[F:15])=[CH:18][CH:19]=3)[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:27]2[CH3:29])[CH2:4][CH2:3]1
Reactant: NC1CC1
Reactant: CCOC(=O)CC(C)=O
Reactant: COC(=O)C(=Cc1ccc(C(F)(F)F)cc1)C(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)N(C2CC2)C(C)=C(C(=O)OC)C1c1ccc(C(F)(F)F)cc1

Procedure:
3.6 g (0.039 mol) of cyclopropylamine hydrochloride are added to a solution of 3.9 g (0.03 mol) of ethyl acetoacetate and 8.16 g (0.03 mol) of methyl 2-(4-trifluoromethylbenzylidene)acetoacetate in 50 ml of pyridine and the mixture is heated under reflux for 5 hours. The reaction product is concentrated in vacuo, the residue is taken up in methylene chloride and water, the aqueous phase is separated off, and the methylene chloride solution is dried over sodium sulphate and evaporated. The residue is purified by chromatography on silica gel using methylene chloride as the solvent. After dissolving and crystallizing the product from n-heptane, 2.2 g (17.3% of theory) are obtained. Melting point: 110° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]2[S:18]C(=S)[NH:16][C:15]2=[O:20])=[CH:9][C:8]=1[O:21][CH3:22].IC.[CH3:35]N(C=O)C.[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>CCOC(C)=O>[F:1][C:2]([F:31])([F:32])[C:3]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]2[S:18][C:40]([N:41]3[CH2:46][CH2:45][N:44]([CH3:35])[CH2:43][CH2:42]3)=[N:16][C:15]2=[O:20])=[CH:9][C:8]=1[O:21][CH3:22]
Reactant: CN(C)C=O
Reactant: CN1CCNCC1
Reactant: COc1cc(C=C2SC(=S)NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1cc(C=C2SC(N3CCN(C)CC3)=NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 40 °C
Reaction time: 20 h
Yield: 37 %

Procedure:
To a flask purged with N2 was added ′5-[1-[4-(2,4-Bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-methylidene]-2-thioxo-thiazolidin-4-one, (1.12 g, 2.27 mmol), iodomethane (5.5 mL, 88 mmol) and DMF (35 mL). The solution was al lowed to stir at 40° C. for 20 h. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in MeCN (25 mL). To the mixture was added 1-methyl piperazine (0.76 mL, 6.8 mmol), and the solution was stirred at 65° C. for 2 h. The solution was then diluted with EtOAc (150 mL), washed with sat NH4Cl (70 mL×2), dried over Na2SO4, filtered and concentrated. The crude material was chromatographed (SiO2 DCM/MeOH 100:0 to 90:10) to provide the title product (470 mg, 37% yield). 1H NMR (DMSO-d6) δ 8.17 (1H, d, J=8.1 Hz), 8.11 (1H, s), 8.02 (1H, d, J=8.1 Hz), 7.61 (1H, s), 7.29 (1H, d, J=2.0 Hz), 7.20 (1H, dd, J=2.0 Hz, J2=8.4 Hz), 7.14 (1H, d, J=8.4 Hz), 5.41 (2H, s), 3.90 (2H, t, J=4.8 Hz), 3.86 (3H, s), 3.65 (2H, t, J=4.8 Hz), 2.43-2.50 (4H, m), 2.24 (3H, s); 19F NMR (DMSO-d6) d −59.5, −61.6; MS (ESI) 560 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21](C=O)[CH:20]=[CH:19][C:18]=3[N+:25]([O-:27])=[O:26])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.Cl.Cl.[CH3:30][NH:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[C:41](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH2:30][N:31]([CH3:41])[CH2:32][CH2:33][CH2:34][N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)[CH:20]=[CH:19][C:18]=3[N+:25]([O-:27])=[O:26])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CNCCCN1CCOCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CN(CCCN1CCOCC1)Cc1ccc([N+](=O)[O-])c(Nc2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)c1
Reaction time: 0.33 h
Yield: 68.3 %

Procedure:
A mixture of 0.900 g (2.23 mmole) of 4-(3-chloro-phenyl)-2-(5-formyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.2b), 1.03 g (4.46 mmole) of methyl-(3-morpholin-4-yl-propyl)-amine dihydrochloride and 60 mL of dichloromethane was stirred for 20 minutes, then 1.134 g (5.35 mmole) of sodium triacetoxyborohydride was added. The mixture was stirred for 4 days, then quenched by the addition of 50 mL of saturated sodium bicarbonate solution. The mixture was extracted three times with 50 mL of dichloromethane. The combined dichloromethane layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (90:10) to give 0.830 g of 4-(3-chloro-phenyl)-2-(5-{[methyl-(3-morpholin-4-yl-propyl)-amino]-methyl}-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.50a).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:7](=O)[NH:8][CH:9]=1)([O-:3])=[O:2].P(Br)(Br)([Br:17])=O.P(Br)(Br)Br.BrBr>>[Br:17][C:7]1[C:6]([C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1[nH]cc([N+](=O)[O-])cc1C(F)(F)F
Agent: BrBr
Agent: BrP(Br)Br
Product: O=[N+]([O-])c1cnc(Br)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 88 %

Procedure:
A mixture of 5-nitro-3-(trifluoromethyl)pyridin-2(1H)-one 3, POBr3 (1.5 equivalents), PBr3 (4 equivalents), and Br2 (2 equivalents) is heated to about 90-110° C. and is then poured into ice water. The mixture is neutralized and extracted. The combined organic phases are dried over Na2SO4 and all solvents removed under reduced pressure to obtain 2-bromo-5-nitro-3-(trifluoromethyl)pyridine 21 in a yield of 88%.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH2:25][CH2:26][N:27]3[CH:31]=[C:30]([N+:32]([O-])=O)[N:29]=[CH:28]3)=[CH:16][CH:15]=2)=[O:12])[N:7]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.CO.CC(O)=O.[H][H].[Pt]>[NH2:32][C:30]1[N:29]=[CH:28][N:27]([CH2:26][CH2:25][O:24][C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]([NH:13][C:11]([NH:10][C:8]3[N:7]([C:35]4[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=4)[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=3)=[O:12])=[CH:15][CH:16]=2)[CH:31]=1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCn3cnc([N+](=O)[O-])c3)c3ccccc23)cc1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCn3cnc(N)c3)c3ccccc23)cc1
Yield: 113.2 %

Procedure:
A solution of 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(4-(2-(4-nitro-1H-imidazol-1-yl)ethoxy)naphthalen-1-yl)urea (30) (158 mg, 0.253 mmol) in DCM/MeOH/AcOH (1:1:2, 6.0 mL) was passed through a Thales H-cube (10% Pt/C Cat-Cart., 30 mm) at 1.0 ml·min−1 in full hydrogen mode at 50° C. The solvents were evaporated under reduced pressure to give 1-(4-(2-(4-amino-1H-imidazol-1-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate I) as a light brown oil (150 mg, 100%): m/z 524 (M+H)+ (ES+).
Reaction SMILES: C([Li])CCC.[I-].[CH3:7][C:8]1([CH2:13][CH2:14][CH2:15][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:12][CH2:11][CH2:10][O:9]1.[Cl:35][CH:36]=[C:37]1[CH:43]=[CH:42][C:41]2[CH:44]=[C:45]([CH:48]=O)[CH:46]=[CH:47][C:40]=2[O:39][CH2:38]1.O>O1CCCC1.ClCCl>[Cl:35][CH:36]=[C:37]1[CH:43]=[CH:42][C:41]2[CH:44]=[C:45]([CH:48]=[CH:15][CH2:14][CH2:13][C:8]3([CH3:7])[O:9][CH2:10][CH2:11][O:12]3)[CH:46]=[CH:47][C:40]=2[O:39][CH2:38]1
Reactant: O=Cc1ccc2c(c1)C=CC(=CCl)CO2
Reactant: CC1(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)OCCO1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC1(CCC=Cc2ccc3c(c2)C=CC(=CCl)CO3)OCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
0.206 ml (0.41 mmol) of a 1.9M n-butyllithium solution is added dropwise to 207 mg (0.435 mmol) of [3-(2-methyl-1,3-dioxolan-2-yl)propyl](triphenyl)phosphonium iodide in suspension in 3.2 ml of tetrahydrofuran cooled to 0° C. The medium is stirred for one hour and then the ylide is added at 0° C., via a hollow tube, to 48 mg (0.22 mmol) of 3-(chloromethylene)-2,3-dihydro-1-benzoxepin-7-carbaldehyde, prepared according to example 72, in solution in 3.6 ml of tetrahydrofuran. The medium is stirred at ambient temperature for 25 minutes and then water and dichloromethane are added. The phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are then washed with brine, are then dried and are then finally concentrated under vacuum. The crude reaction product is purified by chromatography on silica gel (ethyl acetate/heptane 10/90) to give 47 mg (71%) of 3-(chloromethylene)-7-[4-(2-methyl-1,3-dioxolan-2-yl)-1-butenyl]-2,3-dihydro-1-benzoxepin in the form of a mixture of four diastereoisomers in a Z/E (60/40) ratio for the unsaturated chain and a Z/E ratio (85/15) for the chloromethylene functional group; 1H NMR (300 MHz, CDCl3) ZZ isomer: 1.32 (s, 3H), 1.81 (m, 2H), 2.44 (m, 2H), 3.9 (m, 4H), 4.86 (s, 2H), 5.63 (m, 1H), 6.31 (m, 4H), 6.96 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[C:14]([Cl:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([CH2:18][CH:19]=O)[CH:10]=1.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[C:14]([Cl:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([CH2:18][CH2:19][N:24]2[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(Cl)c(-c2cc(Cl)ccc2Cl)cc1CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: COc1cc(Cl)c(-c2cc(Cl)ccc2Cl)cc1CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a stirred solution of 2-(2′,5′,6-trichloro-4-methoxybiphenyl-3-yl)acetaldehyde (300 mg, 0.92 mmol) in DCM (20 mL) at room temperature, tert-butyl piperazine-1-carboxylate (205 mg, 1.1 mmol) was added followed by drops of AcOH. The reaction mixture was stirred at room temperature for 1 h, and then NaBH(OAc)3 (1.95 g, 9.2 mmol) was added. The resulting mixture was stirred at reflux for 16 h. The mixture was allowed to cool to room temperature, diluted with water and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (1-33% ethyl acetate/petroleum ether) to afford the desired product (350 mg, 77% yield) as a white solid.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][Si](C)(C)C)=[N:6][CH:7]=1.[Br:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=1.[CH3:22]CN(CC)CC.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>[Cu]I.O.CN(C)C=O>[CH3:22][C:7]1[N:6]=[C:5]([C:8]#[C:9][C:19]2[CH:18]=[N:17][CH:16]=[C:15]([Br:14])[CH:20]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(C#C[Si](C)(C)C)nc1
Reactant: Brc1cncc(Br)c1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C#Cc2cncc(Br)c2)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
To a solution of 5-methyl-2-trimethylsilanylethynylpyridine (5.32 mmol) in 25 mL degassed N,N-dimethylformamide was added successively 3,5-dibromopyridine (6.96 mmol), CuI (0.57 mmol), Et3N (21.2 mmol) and trans-dichlorobis(triphenylphosphine) palladium (29 mmol). The resulting mixture was warmed to 70° C., Bu4NF (5.85 mmol) was added drop-wise, and the reaction was stirred at this temperature 2 h. After cooling, 20 mL of H2O was added and the resulting solution was extracted with EtOAc (4×20 mL). The organic layer was washed with saturated NaCl (3×20 mL), dried over Na2SO4 and evaporated to dryness. Purification of the residue by column chromatography provided Br-5MPEPy in 41% yield as a clear oil. HCl salt was prepared by adding 2 M HCl/Et2O to a solution of free base in EtOAc and isolated by suction filtration. 1H NMR (CDCh) δ ppm: 2.24 (s, 3H, CH3); 7.32 (d, 1H, J=7.5 Hz, CHAr); 7.38 (dd, 1H, J=7.5, 2.5 Hz, CHAr); 7.86 (t, 1H, J=2.5 Hz, CHAr); 8.34 (s, IH, CHAr); 8.50 (d, 1H, J=2.5 Hz, CHAr); 8.59 (d, IH, J=2.5 Hz, CHAT) 13c NMR (CDCh) δ ppm: 18.9 (1C, CH3); 83.6 (1C, C═C); 93.3 (1C, C═C); 120.3 (1C, Cq); 121.4 (1C, Cq); 127.2 (1C, CHAr); 133.9 (1C, Cq); 137.0 (1C, CHAr); 139.6 (1C, Cq); 141.2 (1C, CHAr); 150.4 (1C, CHAT); 150.7 (1C, CHAr); 151.1 (1C, CHAr). HCl salt mp 166-168° C. Anal. (C13H9N2-HCl-0.6H20) C, H, N.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[CH3:22][Si:23]([C:26]#C)([CH3:25])[CH3:24]>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.O1CCCC1>[CH3:22][Si:23]([CH3:26])([CH3:25])[C:24]#[C:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][CH:2]=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(I)c([N+](=O)[O-])c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#COC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
25 g (0.08 mol) Methyl 4-iodo-3-nitrobenzoate (compound IV), 20 ml (0.14 mol) triethylamine and 200 ml tetrahydrofuran were added into a reaction flask, protected by nitrogen gas, and stirred to dissolve, then 2.4 g (0.0034 mol) bis(triphenylphosphine)palladium dichloride, 0.65 g (0.0034 mol) cuprous iodide and 13.7 ml (0.096 mol) trimethylsilylethyne were added, the mixture was reacted at room temperature for 1 hour, concentrated under reduced pressure to evaporated most of the tetrahydrofuran. After extracting with 300 ml ethyl acetate, the organic layer was washed with water for three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and separated by column chromatography to obtain methyl 4-(2-(trimethylsilyl)ethynyl-3-nitrobenzoate (Compound III), 15.1 g (0.055 mol), yield 66.9%.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[S:22][N:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][C:18]3[S:22][N:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:23])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ncns3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2ncns2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40.3 %

Procedure:
To a solution of [1-hydroxy-4-methyl-6-([1,2,4]thiadiazol-5-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (100 mg, 0.30 mmol) in THF (2.5 mL) and H2O (1 mL) was added LiOH (0.063 g, 1.50 mmol) at 0° C. The resulting solution was stirred at room temperature for 20 minutes. The mixture was diluted with H2O and acidified to pH 3 with 1N HCl at 0° C. The resulting mixture was purified by prep HPLC to give the title compound (37 mg, 45%) as a white solid. 1H NMR (CD3OD) δ7.06 (d, 1H), 6.84 (d, 1H), 5.44 (dd, 1H), 3.04 (dd, 1H), 2.30 (s, 3H), 2.18 (dd, 1H). MS found: (M+H)+: 307.
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][CH2:7]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Br:23]Br>ClCCl.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>[Br:23][C:13]1[CH:14]=[C:9]2[CH2:8][CH2:7][N:6]([Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:16])[CH3:15])[C:10]2=[N:11][CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)N1CCc2cccnc21
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)N1CCc2cc(Br)cnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a 0° C. solution of 1-(tert-butyl-dimethyl-silanyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (20 g, 85.6 mmol) and pyridine (8.4 mL) in dichloromethane (500 mL) was added dropwise to a solution of bromine (5.6 mL, 111.4 mmol) in dichloromethane (400 mL) over a period of 1 h. After stirring for 1 h at 0° C., the mixture was diluted with a mixture of saturated solutions of sodium thiosulfate-sodium bicarbonate (1:1 v/v) and stirred vigorously for 30 min. The resulting mixture was partitioned and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 2% ethyl acetate/hexanes) to afford 5-bromo-1-(tert-butyl-dimethyl-silanyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (22.5 g, 84%) as a light yellow oil: LC/MS m/e calcd for C13H22BrN2Si [M+H]+ 314.32, observed 313.1, 315.1; 1H NMR (400 MHz, CDCl3) δ ppm 0.32 (s, 6H), 0.96 (s, 9H, 3×CH3), 3.01 (t, J=8.7 Hz, 2H), 3.68 (t, J=8.7 Hz, 2H), 7.21 (br. s., 1H), 7.81 (br. s., 1H).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)([CH3:10])[C:8]#[CH:9].[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].[NH4+].[Cl-]>CCCCCC.CCOCC.CCCCCC.CCOC(C)=O>[CH3:10][C:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)([CH3:6])[C:8]#[C:9][C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(=O)OCC
Reactant: C#CC(C)(C)OC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)C(=O)C#CC(C)(C)OC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (18 mL, of a 1.6 M solution in hexane, 28 mmol) was added to a solution of 3-methyl-3tetrahydropyranyloxy-butyne (3.3 g, 19 mmol) in Et2O, previously cooled at 0° C. The resulting solution was stirred for 30 min at 0° C., then cooled to −78° C. and diethyl oxalate (4.3 mL, 29.4 mmol) was added. The reaction was followed by TLC (hexane/AcOEt 90:10). After ca. 2 h the reaction mixture was poured in a cold aqueous solution of NH4Cl. The aqueous layer was extracted with of Et2O (3×25 mL). The organics were dried over MgSO4, the solvent was removed under reduced pressure and the resulting pale yellow oil was purified by chromatography (silica gel, hexane/AcOEt 90:10) to give ethyl 5-methyl-2-oxo-5-(tetrahydro-2H-pyran-2-yloxy)hex-3-ynoate (2) as a pale yellow liquid. Yield: 2.04 g (40%). 1H-NMR spectrum in CDCl3 (ppm): 5.10 (m, 1H), 4.38 (q, 2H), 4.36 (m, 2H), 3.96 (m, 2H), 3.54 (m, 2H), 1.85 (m, 2H), 1.75 (m, 2H), 1.64 (s, 3H), 1.59 (s, 3H), 1.40 (t, 3H). 13C-NMR spectrum in CDCl3 (ppm): 169.3, 158.7, 101.4, 96.2, 81.6, 70.5, 63.1, 31.5, 29.2, 28.9, 25.2, 19.9, 13.8, 13.8. Selected IR (neat, cm−): 2209, 1741, 1689. MS-APCI calculated for C14H20O5 [M]− 268.13. found 267.96.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[OH-:34].[NH4+:35]>C(O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([NH2:35])=[N:25][OH:34])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [OH-]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)NCC1CCN(S(=O)(=O)c2ccc(C#N)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC1CCN(S(=O)(=O)c2ccc(C(N)=NO)cc2)CC1

Procedure:
{1-[(4-cyanophenyl)sulfonyl]-4-piperidinyl}methylcarbamic acid t-butyl ester (1 g, 2.6 mmol), potassium carbonate (1.8 g, 13 mmol), and ammonium hydroxide hydrochloride (0.916 g, 13 mmol) were heated in ethanol (5 ml) at reflux for 2.5 days. The reaction was cooled in an ice-water bath, and filtered. The solid was washed with cold ethanol, and evaporated to a white solid (0.870 g, 2.10 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=C[C:26]2N(O)N=[N:29][C:27]=2[CH:28]=1.CCN(C(C)C)C(C)C.C1(N)CC1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH:27]1([NH:29][C:16](=[O:18])[CH2:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:14][CH:13]=2)[CH2:28][CH2:26]1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)O)cc1
Agent: NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)Nc1ccc(CC(=O)NC2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{4-[(tert-butoxycarbonyl)amino]phenyl}acetic acid (300 mg, 1.2 mmol) was dissolved in DMF (3 ml). EDC (275 mg, 1.4 mmol), HOBt (256 mg, 1.7 mmol), DIEA (450 mg, 3.6 mmol) and cyclopropyl amine (82 mg, 1.4) were added and the mixture stirred at RT for 2 hours. The mixture was diluted into a 10% solution of sodium bicarbonate (aq, 50 ml), extracted with EtOAc (3×30 ml), the organic fractions combined, dried over Na2SO4, filtered and the volatiles removed in vacuum to give the titled compound. LRMS calc: 290.16; obs: 397.27 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:17][CH2:18][CH3:19])=[CH:8][C:9]2[O:14][C:13](=[O:15])[CH:12]=[CH:11][C:10]=2[CH:16]=1.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CO.C([O-])(=O)/C=C/C([O-])=O>C(O)C>[CH2:18]([O:17][C:7]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]2)=[CH:16][C:10]2[CH:11]=[CH:12][C:13](=[O:15])[O:14][C:9]=2[CH:8]=1)[CH3:19]
Reactant: CCOc1cc2oc(=O)ccc2cc1OCCCCl
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CO
Solvent: CCO
Product: CCOc1cc2oc(=O)ccc2cc1OCCCN1CCN(c2ccccc2)CC1
Yield: 57 %

Procedure:
Method A (26 h at 60° C.); starting materials: 6-(3-chloropropoxy)-7-ethoxy-2H-1-benzopyran-2-one (see example 70) and 1-phenylpiperazine; yield 57%; fusion point 151° to 153° (from methanol and ethanol). Fumarate: method E; yield 78%; fusion point 170° to 173° C. (from ethanol).