Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8](=[NH:34])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C@H:19]2[N:23]3[C:24](=[O:33])[C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:26][N:27]=[C:22]3[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC([C:45]1[CH:50]=[CH:49]C(CNC([C@H]2N3C(=O)C(N)=CN=C3CC2)=O)=[CH:47][CH:46]=1)=N)(C)(C)C.C1(S(Cl)(=O)=O)C=CC=CC=1>>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8](=[NH:34])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C@H:19]2[N:23]3[C:24](=[O:33])[C:25]([NH:28][S:29]([C:32]4[CH:49]=[CH:50][CH:45]=[CH:46][CH:47]=4)(=[O:31])=[O:30])=[CH:26][N:27]=[C:22]3[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(N)c(=O)n32)cc1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(C)(=O)=O)c(=O)n32)cc1
Agent: O=S(=O)(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(=O)(=O)c4ccccc4)c(=O)n32)cc1
Yield: 80.1 %

Procedure:
Following a procedure similar to that for the preparation of intermediate 16a, intermediate 1j (50 mg, 0.117 mmol) and benzene sulfonyl chloride (22.8 mg, 0.129 mmol) yielded 53.6 mg (80.1%) of intermediate 17a. MS (ESI) 567.0 (M+H+).
Reaction SMILES: [C:1]([NH:4][C:5]([OH:7])=[O:6])([OH:3])=[O:2].[C:8]([O:12][C:13]([NH:15][C:16]1[C:17]([C:29]2[CH:37]=[CH:36][C:32]([C:33]([O-:35])=[O:34])=[C:31]([F:38])[CH:30]=2)=[N:18][C:19]([CH:22]2[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]2)=[CH:20][N:21]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:49]([Si:51]([CH2:55][CH3:56])([CH2:53][CH3:54])Cl)[CH3:50].C(=O)(O)[O-].[Na+]>C1COCC1>[C:1]([NH:4][C:5]([OH:7])=[O:6])([OH:3])=[O:2].[C:8]([O:12][C:13]([NH:15][C:16]1[C:17]([C:29]2[CH:37]=[CH:36][C:32]([C:33]([O-:35])=[O:34])=[C:31]([F:38])[CH:30]=2)=[N:18][C:19]([CH:22]2[CH2:23][CH2:24][C:25]([O:28][Si:51]([CH2:55][CH3:56])([CH2:53][CH3:54])[CH2:49][CH3:50])=[CH:26][CH2:27]2)=[CH:20][N:21]=1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)Nc1ncc(C2CCC(=O)CC2)nc1-c1ccc(C(=O)[O-])c(F)c1
Reactant: CC[Si](Cl)(CC)CC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)NC(=O)O
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC1=CCC(c2cnc(NC(=O)OC(C)(C)C)c(-c3ccc(C(=O)[O-])c(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of imidodicarbonic acid, 4-(3-((tert-butoxycarbonyl)amino)-6-(4-oxocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate, 1,3-bis(1,1-dimethylethyl) ester (12.1 g, 20.66 mmol) in THF (68.9 mL) was slowly added LiHMDS (1 M in THF) (22.73 mL, 22.73 mmol) at −78° C. After stirring for 30 min, triethylchlorosilane (3.67 mL, 21.69 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 h. Saturated sodium bicarbonate solution was added, and the mixture was extracted with EtOAc. The organic layer was washed well with water and brine, dried over anhydrous NaHCO3, filtered off, and concentrated in vacuo. The crude product was purified by flash chromatography eluting with 5% of EtOAc/heptane to provide imidodicarbonic acid, 4-(3-((tert-butoxycarbonyl)amino)-6-(4-((triethylsilyl)oxy)cyclohex-3-en-1-yl)pyrazin-2-yl)-2-fluorobenzoate, 1,3-bis(1,1-dimethylethyl) ester (12.1 g, 17.29 mmol). LCMS (m/z, neutral-nonpolar method): 701.8 (MH+), 1.14 min; 1H NMR (400 MHz, CDCl3) δ ppm 8.41 (s, 1H), 8.00-7.88 (m, 1H), 7.57-7.46 (m, 2H), 4.97 (br. s., 1H), 3.16-3.00 (m, 1H), 2.49-2.38 (m, 2H), 2.38-2.23 (m, 1H), 2.19-1.94 (m, 3H), 1.61 (s, 9H), 1.33 (s, 18H), 1.06-0.94 (m, 8H), 0.77-0.64 (m, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].[CH3:33][C:34]1[C:38]([S:39](Cl)(=[O:41])=[O:40])=[C:37]([CH3:43])[O:36][N:35]=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11](/[CH:10]=[C:7]4/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][S:39]([C:38]5[C:34]([CH3:33])=[N:35][O:36][C:37]=5[CH3:43])(=[O:41])=[O:40])[C:5](=[O:32])[S:6]/4)=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:28]([F:30])([F:29])[F:31])[CH:23]=1
Reactant: NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Product: Cc1noc(C)c1S(=O)(=O)NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
N-{2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}-3,5-dimethylisoxazole-4-sulfonamide was prepared from 3-(2-aminoethyl)-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 49) and 3,5-dimethylisoxazole-4-sulfonyl chloride following General Procedure U.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[CH2:11][C:12]1[C:17]([CH3:18])=[N:16][N:15]2[C:19]([CH2:22][CH3:23])=[CH:20][CH:21]=[C:14]2[C:13]=1[C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Br:30])[CH:29]=1)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1>[Br:30][C:28]1[CH:29]=[C:24]([C:13]2[C:14]3[N:15]([C:19]([CH2:22][CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:17]([CH3:18])[C:12]=2[CH2:11][CH2:10][OH:9])[CH:25]=[N:26][CH:27]=1
Reactant: CCOC(=O)Cc1c(C)nn2c(CC)ccc2c1-c1cncc(Br)c1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCc1ccc2c(-c3cncc(Br)c3)c(CCO)c(C)nn12
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
To a suspension of LiAlH4 (113 mg) in THF (10 mL) was added ethyl[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate (600 mg) under ice-water cooling and the mixture was stirred at 0° C. for 2 hours. To the mixture was added potassium sodium tartrate solution and the insolubles were filterred off. After evaporation of solvent, the residue was partitioned between AcOEt and water. The organic layer was separated, washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (5:1-1:1) to give 2-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]ethanol as yellow oil (246 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[O:14][CH2:15][C@H:16]([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([NH2:20])=O)=[CH:6]3.C(N(CC)CC)C.O=P(Cl)(Cl)Cl.N#N>C(Cl)Cl>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[O:14][CH2:15][C@H:16]([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:21])[C:5]([C:18]#[N:20])=[CH:6]3
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C(N)=O)cn1c23
Agent: N#N
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Reaction time: 5 h
Yield: 82.2 %

Procedure:
To a solution of 4 (500 mg, 1.69 mmol) and triethylamine (1.2 mL, 8.5 mmol.) in DCM (20 mL) was added POCl3 (431 μL, 3.2 mmol.) dropwise under Ar (or N2) at 0° C. Stirring was continued for an additional 5 h. A dark colored mixture was formed. Upon completion of the reaction, DCM was removed under vacuo and the residue was washed several times with water. The solid was dried under vacuum to give 5 (385 mg, 82% yield). This product was not very soluble except in DMF or DMSO and was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][C:15]([Cl:35])=[C:16]([S:22]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)(=[O:24])=[O:23])[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.C1COCC1.[OH-].[K+].Cl>O>[Cl:35][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:21])[NH:20][C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)=[N:12]2)=[CH:17][C:16]=1[S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)(=[O:24])=[O:23]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(S(=O)(=O)c4ccc(OC)c(OC)c4)cc3c(=O)[nH]2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)c2cc3c(=O)[nH]c(-n4cc(C(=O)O)cn4)nc3cc2Cl)cc1OC
Reaction time: 16 h
Yield: 12 %

Procedure:
1-[7-Chloro-6-(3,4-dimethoxy-benzenesulfonyl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester was combined with THF (5 mL), followed by the addition of a solution of aqueous 1M KOH (2.7 mL, 2.7 mmol), and the mixture was stirred for 16 h. The reaction mixture was cooled in an ice bath, then 1M aqueous HCl (5 mL) and water (5 mL) was added. The resulting precipitate was collected and purified by HPLC to furnish the titled compound (16 mg, 12%). MS (Cl): mass calcd. for C20H15ClN4O7S, 490.0; m/z found, 489.0 [M−H]−. 1H NMR (500 MHz, DMSO-d6): 13.10 (s, 2H), 8.95 (s, 1H), 8.86 (s, 1H), 8.32 (s, 1H), 7.87 (s, 1H), 7.59 (dd, J=8.6, 1.8, 1H), 7.41 (d, J=2.0, 1H), 7.19 (d, J=8.6, 1H), 3.85 (s, 3H), 3.81 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([C:17]([O:19]CC)=[O:18])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1.[Li+].[OH-].Cl>C1COCC1.CO>[CH3:1][C:2]1([C:17]([OH:19])=[O:18])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH2:3]1
Reactant: CCOC(=O)C1(C)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C(=O)O)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 95.4 %

Procedure:
To a solution of ethyl 3-methyl-1-(4-nitrophenyl)piperidine-3-carboxylate (2.920 g, 9.99 mmol) in THF (12.50 mL) and MeOH (12.5 mL) was added 2 M aqueous solution of LiOH (25 mL, 50 mmol). The resulting yellow solution was stirred at rt for 22 hrs. The reaction was adjusted to pH=5 with 3N aqueous HCl. The solution was extracted with EtOAc (3×). The combined EtOAc extracts were washed with saturated aqueous NaCl (2×), dried over Na2SO4, filtered and concentrated. The obtained yellow solid was dried under high vacuum to give the desired product, 3-methyl-1-(4-nitrophenyl)piperidine-3-carboxylic acid (2.650 g, 9.53 mmol, 95% yield) as a yellow solid. Anal. Calcd. for C13H16N2O4 m/z 264.2, found: 265.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.08 (d, J=9.34 Hz, 2H), 6.89 (d, J=9.34 Hz, 2H), 4.13 (d, J=12.64 Hz, 1H), 3.64 (ddd, J=12.50, 4.53, 4.40 Hz, 1H), 3.10-2.99 (m, 1H), 2.94 (d, J=13.19 Hz, 1H), 2.33-2.18 (m, 1H), 1.88-1.69 (m, 2H), 1.53-1.37 (m, 1H), 1.25 (s, 3H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH2:7]1
Reactant: CCCc1ccc(Br)cc1
Reactant: C[C@@H]1CNCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CCCc1ccc(N2CCN[C@H](C)C2)cc1
Temperature: 25 °C
Yield: 35.9 %

Procedure:
A mixture of (R)-2-methylpiperazine (3.00 g, 30.0 mmol, 1.0 eq), 1-bromo-4-propylbenzene (627 g, 31.5 mmol, 1.05 eq.), (+/−)-BINAP (747 mg, 1.2 mmol, 0.04 eq.) and sodium tert-butoxide (4.32 g, 45.0 mmol, 1.5 eq.) in toluene (70 mL) was degassed for 15 min with N2. Palladium(II) acetate (337 mg, 1.5 mmol, 0.05 eq.) was then added at once. The reaction mixture was then heated to reflux for 16 h then cooled to RT. The mixture was then filtered on a bed of cellite and washed with Et2O. The combined organic layers were then washed with H2O (3×), dried over MgSO4, filtered and evaporated to give a dark to brown oil. This residue was purified by chromatography on silicagel (DCM/MeOH 80/20) to give the title product as yellow oil (2.35 g, 36%). M+(ESI): 2192.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O.[OH-].[K+]>C(Cl)Cl>[CH3:3][CH:2]([CH3:4])[C:1]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5]
Reactant: CC(C)C(=O)Nc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)Nc1ccc(C2CCNCC2)cc1
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 4-(4-aminophenyl)-1-piperidinecarboxylate (8.20 g, 29.7 mmol) and triethylamine (8.4 mL, 60 mmol) in dry THF (100 mL) at 0° C. was slowly added a solution of 2-methylpropanoyl chloride (3.84 g, 36.0 mmol) in THF (50 mL). The reaction mixture was then warmed up to room temperature and stirred for 2 h. After removing the solvent in vacuo, the crude product was purified by recrystallization (hexane/THF), affording the desired amide, tert-butyl 4-[4-(isobutyrylamino)phenyl]-1-piperidinecarboxylate, as a white solid (8.60 g, 84%). The tert-butyl 4-[4-(isobutyrylamino)phenyl]-1-piperidinecarboxylate was dissolved in CH2Cl2 (50 mL) at room temperature, TFA (13.68 g, 120 mmol, 5 equiv.) was added by syringe. The reaction mixture was stirred for 3 or 4 h and another 5 equivalents of TFA was added and the mixture was stirred for 2 or 3 more hours. The reaction solution was then basified to pH>14 by KOH (aq, 2 M). The solution was extracted with CH2Cl2 (8×200 mL). The combined organic layer was dried over K2CO3. Removal of solvent under reduced pressure gave the free amine, 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide, as a brownish solid (5.99 g, 98%). 1H NMR (400 MHz, CDCl3) δ 7.55–7.35 (m, 2H), 7.35–6.9 (m, 3H), 3.26–2.98 (m, 2H), 2.84–2.64 (m, 2H), 2.64–2.53 (m, 1H), 2.53–2.32 (m, 1H), 1.90–1.68 (m, 2H), 1.68–1.36 (m, 3H), 1.22 (d, 6H, J=6.0 Hz); ESMS m/e: 247.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[CH:15]([CH3:25])[C:16]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:17].O>CN(C)C=O>[CH2:12]([O:11][C:3]([CH:4]([CH:15]([C:16](=[O:17])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH3:25])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:10])[CH3:13]
Reactant: CC(Cl)C(=O)c1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)C(C)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (50% oil dispersion, 3.5 g) was added with caution to a cooled solution of diethyl malonate (11.85 ml) in dimethylformamide (10 ml). The reaction mixture was stirred at room temperature for 30 minutes before a solution of 2-chloro-1-(4-fluorophenyl)-1-propanone (12.13 g) in dimethylformamide (50 ml) was added in small aliquots. The resulting reaction mixture was stirred for 2 hours at room temperature and then water (35 ml) was added. The mixture was extracted with petroleum ether (b.p. 40°-60° C.) (3×50 ml) and the combined organic extracts were evaporated under reduced pressure to afford ethyl 2-ethoxycarbonyl-3-(4-fluorobenzoyl)butanoate (15.92 g).
Reaction SMILES: [O:1]1CCOCC1.[CH2:7]([C:10]([CH2:17][CH2:18][CH3:19])([CH2:14][CH2:15][CH3:16])[C:11](N)=[O:12])[CH2:8][CH3:9].Cl.N(OCCCC)=O>[OH-].[K+]>[CH2:7]([C:10]([CH2:17][CH2:18][CH3:19])([CH2:14][CH2:15][CH3:16])[C:11]([OH:1])=[O:12])[CH2:8][CH3:9]
Reactant: CCCC(CCC)(CCC)C(N)=O
Reactant: C1COCCO1
Agent: CCCCON=O
Agent: Cl
Agent: [K+]
Product: CCCC(CCC)(CCC)C(=O)O
Yield: 76 %

Procedure:
In a flask equipped with a dropping-funnel were placed 480 g. of distilled dioxan followed by 80 g. (0.432 mol) of tri-n-propylacetamide which was dissolved by stirring. For a period of 20 minutes a current of dry hydrochloric acid gas was passed through the dioxan solution at room-temperature, which represented a total of 100 g of hydrochloric acid gas. At the end of this operation, 88 g (0.86 mol) of freshly distilled butyl nitrite was slowly added over a period of 2 hours through the dropping-funnel. The temperature of the reaction medium rose from 31° to 43°C which necessitated cooling in a water-bath. The solution was then maintained for 2 hours at 85°-90°C. The dioxan was distilled off under a reduced pressure of 20 mm. Hg and a pasty residue obtained at room-temperature. This residue was dissolved in 290 g of a 10% aqueous solution of potassium hydroxide. The aqueous layer was decanted out and extracted twice with 75 g of ethyl ether. The potassium solution was acidified with 118 g of a 36% solution of hydrochloric acid (at 10° /20°C) after which the oily phase was decanted out. The aqueous phase was extracted twice with 75 g of ethyl ether after which the oily phase and the ethereal extracts were placed together. The ethereal solution was washed twice with 100 g of water and dried for 24 hours over 100 g of anhydrous sodium sulphate. The sodium sulphate was then centrifuged out. The ethyl ether was distilled off under atmospheric pressure and the residue recuperated under 7 mm. Hg. The fraction obtained boiled at 126° to 128°C and crystallized rapidly. In this way, 61 g of crude tri-n-propylacetic acid were obtained, which represents a yield of 76%. The crude product was then dissolved by heating in 75 g of ethyl ether. The ethereal solution was filtered while hot and the filtrate left at a temperature of -30°C for 4 hours. The precipitate which formed was centrifuged out and dried in a desiccator under a reduced pressure of 20 mm. Hg for 6 hours. By this means, 46 g of pure tri-n-propylacetic acid were obtained which represents a yield in pure product of 75.4% and a total yield of 57.3% M.P. 67°C
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH2:15][C:16]1[C:21]([C:22]#[N:23])=[CH:20][C:19]([C:24](=[O:31])[CH2:25][NH:26][CH:27]([CH2:29][CH3:30])[CH3:28])=[CH:18][C:17]=1[Cl:32]>>[NH2:15][C:16]1[C:21]([C:22]#[N:23])=[CH:20][C:19]([CH:24]([OH:31])[CH2:25][NH:26][CH:27]([CH2:29][CH3:30])[CH3:28])=[CH:18][C:17]=1[Cl:32]
Reactant: CCC(C)NCC(=O)c1cc(Cl)c(N)c(C#N)c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CCC(C)NCC(O)c1cc(Cl)c(N)c(C#N)c1

Procedure:
m.p. of the dihydrochloride: 190°-191° C., was prepared from 4'-amino-2-sec.butylamino-3'-chloro-5'-cyano-acetophenone analogous to Example 48.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:26]=[CH:25][C:8]2[C:9]3[N:10]=[C:11]([C:17]4[N:18]([CH:22]([CH3:24])[CH3:23])[N:19]=[CH:20][N:21]=4)[S:12][C:13]=3[CH2:14][CH2:15][O:16][C:7]=2[CH:6]=1)=O.[H-].C([Al+]CC(C)C)C(C)C.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1>[CH:22]([N:18]1[C:17]([C:11]2[S:12][C:13]3[CH2:14][CH2:15][O:16][C:7]4[CH:6]=[C:5]([CH2:3][OH:2])[CH:26]=[CH:25][C:8]=4[C:9]=3[N:10]=2)=[N:21][CH:20]=[N:19]1)([CH3:24])[CH3:23]
Reactant: COC(=O)c1ccc2c(c1)OCCc1sc(-c3ncnn3C(C)C)nc1-2
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(CO)ccc1-2
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylic acid methyl ester (778 mg, 2.1 mmol) in THF (20 mL) at −78° C. under nitrogen was added dropwise diisobutyl aluminum hydride (1.5M in toluene, 4.2 mL, 6.3 mmol) and the reaction mixture was stirred at 0° C. for 2 hours. MeOH (10 mL) was added cautiously followed by an aqueous 1M potassium sodium tartrate solution (7 mL) at RT. The mixture was concentrated in vacuo to remove organic solvent and the aqueous phase was extracted with DCM (×3). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the title compound as an off-white solid (713 mg, 99%). LCMS: RT=4.14 min, [M+H]+=343
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.O1CCCC1.[F:16][C:17]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:18]=1[NH2:19]>O>[F:16][C:17]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:18]=1[NH:19][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1ccc(F)cc1F
Reactant: Clc1nc2ccccc2o1
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(Nc2nc3ccccc3o2)c(F)c1
Temperature: 25 °C

Procedure:
To a solution of 15.4 g. (0.1 mole) of 2-chlorobenzoxazole in 200 ml. of tetrahydrofuran was added dropwise a solution of 12.9 g. (0.1 mole) of 2,4-difluoroaniline in 100 ml. of tetrahydrofuran with vigorous agitation. Following the addition, the reaction mixture was heated on a steam bath under reflux for 16 hours. The reaction mixture was cooled to about 25° C., and about 500 ml. of water added thereto. The tetrahydrofuran solvent was removed by distillation under vacuum. The precipitate which formed in the aqueous medium was removed by filtration and dried. The dried precipitate was dissolved in a minimum amount of warm benzene. About 200 ml. of hexane was added to the benzene solution to effect crystallization of the reaction product. The precipitate was filtered off and dried, yielding 18.3 g. of 2-(2,4-difluoroaniline)benzoxazole having a melting point of 115°-117° C.
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][CH2:5][C@@H:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([C@@H:3]1[NH:7][C@H:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCC(CC)=N1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC[C@H](CC)N1

Procedure:
Ethyl (2S)-5-ethyl-3,4-dihydro-2H-pyrrole-2-carboxylate dissolved in ethanol (32 mL) was stirred with 0.30 g of 10% Pd/C and under hydrogen (60 psi) for 16 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to provide the titled compound. MS (CI) m/z 172 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.Cl.[C@@H:12]12[O:19][C@@H:16]([CH2:17][CH2:18]1)[CH2:15][NH:14][CH2:13]2.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[N+:8]([C:4]1[CH:3]=[C:2]([N:14]2[CH2:13][C@H:12]3[O:19][C@H:16]([CH2:17][CH2:18]3)[CH2:15]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: C1C[C@H]2CNC[C@@H]1O2
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccc(N2C[C@H]3CC[C@@H](C2)O3)c1
Temperature: 100 °C
Yield: 68.9 %

Procedure:
The mixture of 1-bromo-3-nitrobenzene (0.15 g, 0.743 mmol), (1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (0.122 g, 0.82 mmol), Pd2(dba)3 (0.043 g, 0.074 mmol), X-Phos (0.071 g, 0.15 mmol) and Cs2CO3 (0.727 g, 2.23 mmol) in dioxane (30 mL) was heated to 100° C. for 16 h under N2 atmosphere. Then it was concentrated to dryness. The residue was purified by column chromatography (silica gel, 200˜300 mesh, eluting with ethyl acetate:petroleum ether=1:8) to afford (1R,5S)-3-(3-nitrophenyl)-8-oxa-3-azabicyclo[3.2.1]octane (0.12 g, 69%) as a brown solid. LC-MS: 235 [M+H]+, tR=1.57 min.
Reaction SMILES: [CH3:1][C:2](=[O:10])[CH2:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][CH3:8].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH:16]=[C:3]([C:4](=[O:9])[CH2:5][CH2:6][CH2:7][CH3:8])[C:2](=[O:10])[CH3:1])[CH3:15]
Reactant: COC(OC)N(C)C
Reactant: CCCCC(=O)CC(C)=O
Product: CCCCC(=O)C(=CN(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,4-octanedione (7.11 g, 0.50 mole) and dimethylformamide dimethylacetal (7.15 g, 0.60 mole) was stirred overnight at room temperature under argon. The resulting red oil was concentrated on the rotary evaporation then distilled on the kugelrohr at -15 mm, 140°-155° C. to yield 8.60 g (87%) of 3-[(dimethylamino)methyleno]-2,4-octanodione.