Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[C:3]([OH:7])(=[O:6])[CH2:4][SH:5].Cl[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=O)[CH3:16]>O.CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[CH3:16][C:15]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:5][C:4]=1[C:3]([OH:7])=[O:6]
Reactant: CC(=O)c1ccccc1Cl
Reactant: O=C(O)CS
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: Cc1c(C(=O)O)sc2ccccc12
Temperature: 122.77777777777777 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
Potassium hydroxide (12.5 g) was dissolved in water (105 ml) in a glass pressure bottle cooled in an ice bath. Then under a blanket of nitrogen, thioglycolic acid (7 ml) was added to the glass pressure bottle, to produce a reaction mixture. 2'-chloroacetophenone (12 g, 97%, 0.075 mol) and TBAB (0.5 g) were then added to the reaction mixture. The glass pressure bottle was then sealed and heated to 253° F. for 6 hours at 18 psi. The reaction was shut down and left overnight. Heating was then resumed at 270° F. at 30 psi for six hours and then cooled to ambient temperature. After the bottle was opened, the reaction mixture was washed with ether to remove organics, and acidified with hydrochloric acid to give 3.9 g of crude 3-methyl 2-benzo[b]thiophenecarboxylic acid (27% yield, mp>200° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:24]=1[NH2:25]>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[C:18]([NH:25][C:24]1[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:23]=1[O:22][CH3:21])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N)c(OC)c1
Reactant: O=C(O)C1CCc2c(OCc3ccccc3)cccc21
Product: COc1ccc(NC(=O)C2CCc3c(OCc4ccccc4)cccc32)c(OC)c1
Yield: 79.8 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 18 using 4-benzyloxyindan-1-carboxylic acid (0.8 g) and 2,4-dimethoxyaniline (0.5 g) as starting materials, 4-benzyloxy-N-(2,4-dimethoxyphenyl) indan-1-carboxamide (0.96 g) was obtained. melting point: 129.7° C.
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][C:50]([O:52][CH3:53])=[O:51])(C1C=CC(C)=CC=1)(=O)=O.[NH2:54][C:55]1[CH:56]=[C:57]([CH2:63][OH:64])[CH:58]=[C:59]([CH2:61][OH:62])[CH:60]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:62][CH2:61][C:59]1[CH:60]=[C:55]([NH:54][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][C:50]([O:52][CH3:53])=[O:51])[CH:56]=[C:57]([CH2:63][OH:64])[CH:58]=1
Reactant: COC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1cc(CO)cc(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNc1cc(CO)cc(CO)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a stirred mixture of methyl 1-(tosyloxy)-3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxanonatriacontan-39-oate (265b)(700 mg, 0.890 mmol) and (5-amino-1,3-phenylene)dimethanol (26) (150 mg, 0.978 mmol) in anhydrous DMF (2.0 ml) was added potassium carbonate (184 mg, 1.334 mmol). The reaction was stirred at 80° C. overnight. The mixture was cooled to room temperature, quenched with water and extracted with 10% Methanol/Methylene chloride. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluted with 5→15% MeOH/CH2Cl2) to give methyl 1-(3,5-bis(hydroxymethyl) phenylamino)-3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxanonatriacontan-39-oate (265c) (285 mg, 42%). 1H NMR (400 Hz, CDCl3): δ 6.62 (s, 1H), 6.51 (s, 2H), 4.52 (s, 4H), 3.72 (t, J=6.4 Hz, 2H), 3.65 (s, 3H), 3.61 (m, 48H), 2.94 (s, 2H), 2.63 (s, 1H), 2.57 (t, J=6.4 Hz, 2H); MS (m/z): found 790.4 (M+Na)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:8]=1.[CH3:21][NH:22][C:23](SC)=[CH:24][N+:25]([O-:27])=[O:26]>C(#N)C>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH:17][C:23]([NH:22][CH3:21])=[CH:24][N+:25]([O-:27])=[O:26])[N:8]=1
Reactant: NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: CNC(=C[N+](=O)[O-])SC
Solvent: CC#N
Product: CNC(=C[N+](=O)[O-])NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Yield: 26.8 %

Procedure:
A solution of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropylthio)pyrimidine (0.31 g.) in acetonitrile (5 ml.) was treated with 1-methylamino-1-methylthio-2-nitroethylene (0.15 g.) and the mixture heated under reflux for 18 hours. The hot solution was filtered and cooled and the solid which crystallised was collected and recrystallised from ethanol to give 1-[3-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimid-2-ylthio)propylamino]-1-methylamino-2-nitroethylene (0.11 g.), m.p. 189°-191°.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][N:27]=[CH:26][C:25]=2[CH2:29][CH2:30][C:31](O)=[O:32])=[CH:20][CH:19]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[CH2:30][CH2:29][C:25]2[CH:26]=[N:27][O:28][C:24]=2[C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: O=C(O)CCc1cnoc1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2cnoc2-c2ccc(Cl)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (0.37 g), 3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.35 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.25 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.33 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-diethylphosphonomethylphenyl)-3-[5-(4-chlorophenyl)-4-isoxazolyl]propionamide (0.61 g, yield 92%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 138–139° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[N:10]1[C:4]2[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([C:25]3[CH:26]=[C:27]([CH:31]=[CH:32][C:24]=3[CH3:23])[C:28]([OH:30])=[O:29])[C:3]=2[CH:13]=[CH:12][C:11]1=[O:14]
Reactant: CSc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CSc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
The solution of 4-chloro-8-(2,6-difluorophenyl)-2-(methylthio) pyrido[2,3-d]pyrimidin-7(8H)-one (1.70 g, 5.00 mmol) in DME (150 mL) and H2O (50 mL), in a pressure flask (500 mL, Chemglass), was added 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa borolan-2-yl)benzoic acid (1.97 g, 7.50 mmol) and K2CO3 (4.15 g, 30.0 mmol). The resulting mixture was degassed with Argon for 5 minutes, mixed with Pd(PPh3)4 (0.232 g, 0.20 mmol) and heated with a preheated oil bath (160° C.) under vigorous stirring for 30 minutes. The reaction mixture was filtered through celite, concentrated under vaccum to remove DME. It was then mixed with EtOAc (200 mL) and AcOH (2.5 mL), and shaked. The layers were separated. The organic layer was collected, further washed with brine (70 mL), dried over Na2SO4, filtered, concentrated and purified via a flash chromatography (load column with DCM, mobile phase EtOAc/Hexane) to afford the title compound as a white solid 2.15 g (98%). LC-MS (ES) m/z 440 (M+H)+; 1H-NMR (MeOD) δ 2.27 (s, 3 H), 2.31 (s, 3 H), 6.71 (d, J=9.6 Hz, 1 H), 7.28 (t, J=8.2 Hz, 2 H), 7.57 (d, J=8.4 Hz, 1 H), 7.64 (m, 2 H), 8.00 (d, J=1.6 Hz, 1 H), 8.14 (dd, J1=7.6 Hz, J2=1.6 Hz, 1 H).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12](#[N:16])[CH2:13][C:14]#[N:15].Br[C:18]([C:25]1[N:29]=[C:28]([CH3:30])[O:27][N:26]=1)([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1COCC1>[C:14]([CH:13]([C:12]#[N:16])[C:18]([CH3:24])([C:25]1[N:29]=[C:28]([CH3:30])[O:27][N:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:15]
Reactant: N#CCC#N
Reactant: CCOC(=O)C(C)(Br)c1noc(C)n1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(C)(c1noc(C)n1)C(C#N)C#N
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
DBU (2.56 mL, 8.1 mmol) was added dropwise to a −78° C. THF (20 mL) solution of malononitrile (1.12 g, 17 mmol) and the intermediate from Step C (1.49 g, 5.66 mmol). The reaction solution was stirred at −78° C. for 15 minutes and then at room temperature for 1 hour. The solution was then concentrated and the residue purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. 1H NMR δ (ppm) (CHCl3-d): 4.79 (1H, s), 4.30 (2H, dd, J=7.1, 2.6 Hz), 2.64 (3H, s), 2.02 (3H, s), 1.31-1.25 (3H, m).
Reaction SMILES: CNCCNC.[CH3:7][S:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[N:10]=1.Br[C:17]1[CH:28]=[CH:27][C:20]([O:21][CH2:22][C:23]([CH3:26])([OH:25])[CH3:24])=[C:19]([O:29][CH3:30])[CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)Cl.[Cu]I.O1CCOCC1.CN(C=O)C>[OH:25][C:23]([CH3:26])([CH3:24])[CH2:22][O:21][C:20]1[CH:27]=[CH:28][C:17]([N:12]2[CH:13]=[CH:14][C:9]([S:8][CH3:7])=[N:10][C:11]2=[O:15])=[CH:18][C:19]=1[O:29][CH3:30]
Reactant: CSc1cc[nH]c(=O)n1
Reactant: COc1cc(Br)ccc1OCC(C)(C)O
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(-n2ccc(SC)nc2=O)ccc1OCC(C)(C)O
Temperature: 105 °C
Reaction time: 7 h
Yield: 37 %

Procedure:
After addition of N,N′-Dimethylethane-1,2-diamine (1.6 g, 18.15 mmol) to a stirred mixture of 4-(methylthio)pyrimidin-2(1H)-one Part A (430 mg, 3.02 mmol), 1-(4-bromo-2-methoxyphenoxy)-2-methylpropan-2-ol Part B (1.0 g, 3.63 mmol), copper(I)iodide (346 mg, 1.82 mmol) and potassium phosphate, tribasic (3.85 g, 18.15 mmol) in 3:1 dioxane-DMF (80 mL), the mixture was stirred at 105° C. for 7 h. The reaction mixture was diluted with CH2Cl2, washed with saturated NaHCO3, dried (MgSO4) and concentrated. The crude product was subjected to flash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient) to afford 1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-4-(methylthio)pyrimidin-2(1H)-one 1C (0.375 g, 37% yield). 1H NMR (400 MHz, chloroform-D) δ 7.37 (1H, d, J=7.03 Hz), 6.95 (1H, d, J=8.53 Hz), 6.92 (1H, d, J=2.51 Hz), 6.85 (1H, dd, J=8.53, 2.51 Hz), 6.28 (1H, d, J=7.03 Hz), 3.85 (3H, s), 3.84 (2H, s), 2.61 (3H, s), 2.59 (1H, s), 1.35 (6H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]([CH:14]2[CH2:17][N:16]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:31][N:32](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.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].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:25]1([CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:16]2[CH2:15][CH:14]([CH:9]([C:4]3[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[CH:5]=3)[C:31]#[N:32])[C:10]([F:13])([CH3:12])[CH3:11])[CH2:17]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN(C)C=O
Reactant: CC(C)(F)C(c1cc(F)cc(Br)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CC(C)(F)C(c1cc(F)cc(C#N)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 140 °C
Reaction time: 17 h

Procedure:
A solution of 16.19 g (34.42 mmol) of 3-[1-(3-bromo-5-fluorophenyl)-2-fluoro-2-methylpropyl]-1-(diphenylmethyl)azetidine, 3.23 g (27.53 mmol) of zinc cyanide, 1.10 g (1.2 mmol) of tris(dibenzylideneacetone)dipalladium, and 1.53 g (2.75 mmol) of DPPF in 99 mL of DMF and 1 mL of water was degassed for 1 h at rt. Then it was stirred at 140° C. After 17 h, it was concentrated to remove solvents. Then the mixture was poured into 300 mL of ether/ethyl acetate (1:1) and 100 mL aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound as a white solid; 1H-NMR(CDCl3) δ 1.22(d, 3H, J=21 Hz), 1.30(d, 6H, J=21 Hz), 2.30 (t, 1H, J=7.8 Hz), 2.86-2.96 (m, 2H), 3.08-3.18 (m, 2H), 3.65 (t, 1H, J=7 Hz), 4.25 (s, 1H), 7.13-7.43 (m, 13H); Mass Spectrum: m/e=417 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:11][CH2:12][C:13]1[NH:14][C:15](=[O:23])[C:16]2[CH2:22][O:21][CH2:20][CH2:19][C:17]=2[N:18]=1)[CH3:10].[F:24][C:25]1[CH:42]=[CH:41][C:28]([C:29]([CH:31]2[CH2:36][CH2:35][N:34]([CH2:37][C:38](O)=[O:39])[CH2:33][CH2:32]2)=[O:30])=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([N:11]([CH2:12][C:13]1[NH:14][C:15](=[O:23])[C:16]2[CH2:22][O:21][CH2:20][CH2:19][C:17]=2[N:18]=1)[C:38](=[O:39])[CH2:37][N:34]1[CH2:35][CH2:36][CH:31]([C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([F:24])=[CH:42][CH:41]=2)[CH2:32][CH2:33]1)[CH3:10]
Reactant: CC(NCc1nc2c(c(=O)[nH]1)COCC2)c1ccc(F)cc1F
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Product: CC(c1ccc(F)cc1F)N(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (43.3 mg) from 2-((1-(2,4-difluorophenyl)ethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C30H31F2N4O4 568.6. found 569.4 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.80-8.00 (m, 2H) 7.23-7.41 (m, 1H) 7.11 (t, J=8.59 Hz, 3H) 6.81-6.95 (m, 2H) 6.67-6.81 (m, 2H) 6.41-6.61 (m, 1H) 4.32-4.58 (m, 4H) 4.17-4.32 (m, 1H) 3.70-3.96 (m, 4H) 3.47 (d, J=11.12 Hz, 1H) 3.15-3.37 (m, 1H) 3.09 (br. s., 1H) 2.62 (br. s., 1H) 2.50 (br. s., 1H) 2.36 (br. s., 1H) 2.14 (br. s., 2H) 2.04 (s, 1H) 1.60 (d, J=6.57 Hz, 1H) 1.39 (d, J=6.57 Hz, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:25]([CH3:27])[CH3:26])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:24][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:25]([CH3:26])[CH3:27])[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23]
Reactant: CCOC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1nc2ccc(Cl)cc2c(Cc2ccccc2Cl)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 6 step B from a mixture of 6-chloro-4-(2-chloro-benzyl)-2-isopropyl-quinoline-3-carboxylic acid ethyl ester (30 mg, 0.074 mmol) and 1N NaOH in ethanol. White solid (16 mg, 57%) LC-MS: 374 (M+H)+.
Reaction SMILES: [C:1]1([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH:15]([C:16]([OH:18])=[O:17])[C:11]3=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.Cl>C(O)CC(C)C>[C:1]1([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH:15]([C:16]([O:18][CH2:13][CH2:14][CH:15]([CH3:16])[CH3:11])=[O:17])[C:11]3=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1cccs1)c1ccc2n1CCC2C(=O)O
Agent: Cl
Solvent: CC(C)CCO
Product: CC(C)CCOC(=O)C1CCn2c(C(=O)c3cccs3)ccc21
Reaction time: 24 h

Procedure:
A solution of 300 mg. of 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 5 ml. of isoamyl alcohol is saturated with hydrogen chloride. After 24 hours, the excess alcohol is distilled off in vacuum and the residue purified by chromatography on alumina to yield isoamyl 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate.
Reaction SMILES: [N+]([C:4]1[C:5]([N+:11]([O-:13])=[O:12])=[C:6](C)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[C:14]1(C)C=CC=C(N)C=1N.S(=O)(=O)(O)O.[N+]([O-])(O)=O>C1(C)C=CC=CC=1>[N+:11]([C:5]1[CH:4]=[CH:9][C:8]([CH3:14])=[CH:7][CH:6]=1)([O-:13])=[O:12]
Reactant: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: Cc1cccc(N)c1N
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O=[N+]([O-])O
Product: Cc1ccc([N+](=O)[O-])cc1

Procedure:
Nitroaromatics, particularly dinitrotoluene, are widely used as intermediates in the manufacture of aromatic amines, e.g. toluene diamine which then can be converted to isocyanates for polyurethane manufacture. Commercially, dinitrotoluene, for example, is produced by the mixed acid nitration of toluene, the mixed acid being a mixture of concentrated sulfuric acid and nitric acid. In this process mononitrotoluene is formed in a first nitration stage and then separated from the aqueous phase. The crude mononitrotoluene is then dinitrated with fresh acid in a second nitration stage and the aqeuous phase is recycled to the mononitration stage. The dinitrotoluene then is recovered from the dinitration stage and the impurities removed.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][NH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:17][CH:16]=2)=[O:14])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.C(N(C(C)C)CC)(C)C.BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[NH2:1][C:2]1[C:3]([C:9]2[O:14][C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[CH:19][CH:20]=3)=[N:12][N:11]=2)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: CN(Cc1ccc(C(=O)NNC(=O)c2nc(Br)cnc2N)cc1)C(=O)OC(C)(C)C
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(Cc1ccc(-c2nnc(-c3nc(Br)cnc3N)o2)cc1)C(=O)OC(C)(C)C
Reaction time: 0.75 h

Procedure:
tert-butyl N-[[4-[[(3-amino-6-bromo-pyrazine-2-carbonyl)amino]carbamoyl]phenyl]methyl]-N-methyl-carbamate (7.66 g, 15.98 mmol) was dissolved in dry acetonitrile (114.9 mL) and cooled in an ice bath and put under a nitrogen atmosphere. Diisopropylethylamine (6.196 g. 8.350 mL, 47.94 mmol) was added via a syringe followed by dibromo(triphenyl)phosphorane (8.767 g, 20.77 mmol) portion wise. Reaction mixture started to precipitate out therefore left to stir for 45 minutes in an ice bath and isolated precipitated product by filtration as a beige powder (4.5 g). This material was then sonicated, triturated in acetonitrile, filtered and dried to give the sub-titled compound as yellow solid. (3.17 g, 40.9%). 1H NMR (400 MHz, DMSO-d6) δ 1.38-1.45 (br d, 9H), 2.80 (s, 3H), 4.45 (s, 2H), 7.48-7.51 (br s, 2H), 7.80 (br s, 2H), 8.10-8.20 (m, 2H), 8.45 (s, 1H) ppm; LC/MS m/z 463.1, 464.2 [M+H]+.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](OS(C)(=O)=O)([CH2:18][CH2:19][CH3:20])[CH2:15]1)([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.[NH3:26]>C(O)C>[NH2:26][C:16]1([CH2:18][CH2:19][CH3:20])[CH2:17][N:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:15]1
Reactant: CCCC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: N
Solvent: CCO
Product: CCCC1(N)CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 16 h

Procedure:
7.5 g of 1-benzhydryl-3-methanesulphonyloxy-3-propyl-azetidine are added to a solution at approximately 5° C. of 100 cm3 of a solution of ammonia in ethanol (prepared from 15 g of ammonia in 100 cm3 of ethanol at 5° C., the temperature is allowed to rise to approximately 20° C. and the mixture is stirred for 16 hours at the same temperature. After concentration to dryness under reduced pressure (20 kPa) at approximately 40° C., the residue is taken up with 25 cm3 of water and 2.22 g of methanesulphonic acid. The aqueous phase is washed with twice 25 cm3 of ethyl ether, treated with 10 cm3 of 40% aqueous sodium hydroxide and extracted with 3 times 50 cm3 of dichloromethane; the combined organic extracts are washed with 10 cm3 of water saturated with sodium chloride, dried over magnesium sulphate and concentrated to dryness under the above conditions. 5.2 g of 3-amino-1-benzhydryl-3-propylazetidine are obtained in the form of an oily product, which is used without further purification for the subsequent steps.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH:13]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]1[CH2:19][CH2:20][CH2:21][C:22]1[S:26][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:23]=1.CCN(CC)CC>C(Cl)Cl>[CH:12]([CH:13]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]1[CH2:19][CH2:20][CH2:21][C:22]1[S:26][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:23]=1)=[O:11]
Reactant: COC(=O)c1ccc(CCCN2C(=O)CCC2CO)s1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CCCN2C(=O)CCC2C=O)s1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 98.1 %

Procedure:
A DCM solution of oxalyl chloride (4.38 mL, 2.0 M 8.76 mmol) was diluted with dry DCM (50 mL) and cooled to −78° C. then a solution of DMSO (0.76 mL, 10.77 mmol) in DCM (5 mL) was added dropwise. After 15 min., a solution of methyl 5-[3-(2-(hydroxymethyl)-5-oxopyrrolidin-1-yl)propyl]thiophene-2-carboxylate (2.0 g, 6.73 mmol) in DCM (10 mL) was added dropwise to this solution. The resulting solution was stirred at −78° C. for 2 hours. Et3N (4.7 mL, 33.65 mmol) was added and the solution warmed to RT. After 15 min. the solution was diluted with DCM (100 mL) and washed with a saturated solution of NH4Cl (2×100 mL), brine (100 mL), dried over sodium sulfate and concentrated in vacuo to afford the aldehyde intermediate (1.95 g, 98%) used in the next step without further purification.