Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[Na+].[I-]>CO>[ClH:1].[CH:14]([C:6]1[C:5]([C:3](=[O:4])[CH:2]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)[CH3:17])=[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:8]2[N:7]=1)([CH3:16])[CH3:15]
Reactant: CN1CCNCC1
Reactant: CC(Cl)C(=O)c1c(C(C)C)nn2ccccc12
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1nn2ccccc2c1C(=O)C(C)N1CCN(C)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 96 h
Yield: 21.4 %

Procedure:
A mixture of 500 mg (2 mmol) of 2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one, 272 μl (2.4 mmol) of N-methylpiperazine and 50 mg of NaI in 4 ml of MeOH was stirred at RT for 4 days. The solvent was removed and the crude residue was purified on an Al2O3 column. The fractions containing purified product were titrated with 4N HCl-dioxane to obtain a precipitate. Recrystallization from isopropanol/ether produced 150 mg of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-(4-methylpiperazin-1-yl)propan-1-one hydrochloride (shown in neutral form above). Compound 1035.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:14][NH2:15])=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1.[F:16][C:17]([F:32])([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[CH:25]2)[C:18](OC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C#N>C(Cl)Cl>[F:32][C:17]([F:16])([C:18]1[N:4]2[CH:5]=[C:6]([C:8]3[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=3)[CH:7]=[C:2]([F:1])[C:3]2=[N:14][N:15]=1)[C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[CH:25]2
Reactant: Cn1cc(-c2cnc(NN)c(F)c2)cn1
Reactant: COC(=O)C(F)(F)c1ccc2ncccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: N#CC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cc(-c2cc(F)c3nnc(C(F)(F)c4ccc5ncccc5c4)n3c2)cn1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a stirring suspension of 1-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)hydrazine (190 mg, 917 μmol), methyl 2,2-difluoro-2-(quinolin-6-yl)acetate (218 mg, 917 μmol), triphenylphosphine polymer supported (241 mg, 917 μmol), DIEA (200 μl, 1146 μmol) in DCM (4 mL) was added 2,2,2-trichloroacetonitrile (92 μl, 917 μmol). The reaction vessel was then appropriately sealed and heated to 150° C. with microwaves for 15 min. The reaction was then concentrated onto dry silica under reduced pressure and product purified on silica (40 g) eluting with 1-4% of 2 M NH3 in MeOH/DCM. The product was then further purified by RP-HPLC eluting with water/ACN (0.1% TFA). Collected fractions concentrated under reduced pressure, dissolved in MeOH/DCM (5 mL) and stirred with Si-Carbonated (300 mg; 0.2 mmol) for 30 min at 23° C. Solids were then removed by filtration, and washed with MeOH (3×1 mL). The filtrate was then concentrated under reduced pressure, and product isolated as an off white solid. MS (ESI pos. ion) m/z: 395 (MH+). Calc'd exact mass for C20H13F3N6: 394.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[CH:15]1[C:28]2[C:19](=[CH:20][C:21]3[C:26]([C:27]=2[CH:29]=O)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+].O>C(O)C>[CH:15]1[C:28]2[C:19](=[CH:20][C:21]3[C:26]([C:27]=2[CH2:29][NH:14][CH2:13][CH2:12][CH2:11][N:8]2[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:29][C:27]4[C:28]5[C:19]([CH:20]=[C:21]6[C:26]=4[CH:25]=[CH:24][CH:23]=[CH:22]6)=[CH:18][CH:17]=[CH:16][CH:15]=5)[CH2:10][CH2:9]2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:17][CH:16]=1
Reactant: NCCCN1CCN(CCCN)CC1
Reactant: O=Cc1c2ccccc2cc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc2c(CNCCCN3CCN(CCCNCc4c5ccccc5cc5ccccc45)CC3)c3ccccc3cc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.513 mL, 2.49 mmol) and 9-anthracenaldehyde (1.080 g, 5.24 mmol) in absolute ethanol (20 mL) was added 3 Å molecular sieves (5 g). After stirring the mixture for 12 h at room temperature, sodium borohydride (1.9 g, 49.9 mmol) was added and the mixture was stirred for 12 h at room temperature. Then the reaction mixture was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were extracted with HCl 1N (2×50 mL). The combined aqueous layers were neutralized with NaOH 1N (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over MgSO4, evaporated to dryness and the oily residue purified by flash chromatography (neutral aluminium oxide, CH2Cl2/MeOH: 90/10).
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:14]([F:17])([F:16])[F:15])[NH:7][C:6]=1[CH3:18])(=[O:3])[CH3:2].[Na].C(O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([O:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:14]([F:17])([F:15])[F:16])[NH:7][C:6]=1[CH2:18][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: OCc1ccccc1
Reactant: CC(=O)Oc1c(C)[nH]c2cccc(C(F)(F)F)c12
Agent: [Na]
Product: CC(=O)Oc1c(Cc2ccccc2)[nH]c2cccc(C(F)(F)F)c12

Procedure:
A solution of 0.05 mole of methyl-(4-trifluoromethyl-3-indolyl) acetate and 0.01 mole of sodium in 60 ml. anhydrous benzyl alcohol is slowly fractioned over a period of 41/2 hours through a Vigreux column to remove methanol. The excess benzyl alcohol is removed by distillation at 60° and 2.5 mm. to give a residue of crude benzyl-(4-trifluoromethyl-3-indolyl) acetate.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[N:13]1C=CC=C[CH:14]=1.OC[CH2:21][CH2:22][C:23]1[CH:34]=[CH:33][C:26]2[O:27][CH:28]([CH3:32])[C:29](=[O:31])[NH:30][C:25]=2[CH:24]=1.Cl.CN.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:14][NH:13][C:5](=[O:11])[O:6][CH2:7][CH2:21][CH2:22][C:23]1[CH:34]=[CH:33][C:26]2[O:27][CH:28]([CH3:32])[C:29](=[O:31])[NH:30][C:25]=2[CH:24]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC1Oc2ccc(CCCO)cc2NC1=O
Reactant: c1ccncc1
Agent: CN
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)OCCCc1ccc2c(c1)NC(=O)C(C)O2
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a 20 mL screw cap vial equipped with a magnetic stir bar was added triphosgene (20 mg, 0.068 mmol) in toluene (0.85 mL). The mixture was cooled to 0° C. and pyridine (0.017 mL, 0.21 mmol) was added followed by 188 (38 mg, 0.17 mmol) in toluene (0.5 mL). The reaction was stirred at 0° C. for 1 h then room temperature overnight. The reaction was concentrated in vacuo then taken up in DCM (1.0 mL) and cooled to 0° C. Methylamine HCl (57 mg, 0.85 mmol) was added followed by triethylamine (0.237 mL, 1.7 mmol). The reaction was allowed to warm to room temperature and was stirred for 18 h. The reaction was concentrated in vacuo and the residue was purified by preparative HPLC-MS using 20-45% MeCN in water as the gradient. The appropriate fractions were collected and concentrated in vacuo to give the title compound as a white solid (14 mg, 29% yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (d, J=6.82 Hz, 3H) 1.72-1.83 (m, 2H) 2.51-2.55 (m, 2 H) 2.56 (d, J=4.80 Hz, 3H) 3.92 (t, J=6.57 Hz, 2H) 4.57-4.64 (m, 1H) 6.69 (d, J=1.77 Hz, 1 H) 6.74 (dd, J=8.08, 2.02 Hz, 1H) 6.86 (d, J=8.08 Hz, 1H) 6.94-7.03 (m, 1H) 10.60 (s, 1H). ESI-MS: m/z 279.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].[CH:23]1(CBr)[CH2:25][CH2:24]1>>[CH:19]1[C:14]2[CH2:13][C@H:12]3[N:2]([CH2:1][CH:23]4[CH2:25][CH2:24]4)[CH2:3][CH2:4][C@:5]45[C@H:6]([C:7]([CH2:9][CH2:10][C@@:11]34[OH:22])=[O:8])[O:21][C:16]([C:15]=25)=[C:17]([OH:20])[CH:18]=1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Reactant: BrCC1CC1
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Yield: 88.6 %

Procedure:
Naltrexone can be produced from noroxymorphone by various direct and indirect alkylation methods. One method is by direct alkylation of noroxymorphone with cyclopropylmethylbromide. This process has been disclosed in general terms by Rice in WO 91/05768. Sanofi-Avensis (WO 2008/034973) describes a process for obtaining naltrexone in 88.6% yield by reacting noroxymorphone hydrochloride with cyclopropylmethylbromide in dimethylacetamide in the presence of sodium hydrogen carbonate. Cilag (WO 2008/138605) describes N-alkylation of noroxymorphone with cyclopropylmethylbromide in N-methyl-pyrrolidone in the presence of sodium hydrogen carbonate. Mallinckrodt (WO 2010/039209) describes N-alkylation of noroxymorphone with cyclopropylmethylbromide in the presence of a protic solvent. Specific examples in WO 2010/039209 describe the addition of water, isopropanol or ethanol as the protic solvent.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[C:21]2[CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][C:17](=[O:26])[NH:16][C:15]=2[CH:14]=[CH:13][C:12]=1[O:27][CH3:28]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[C:21]3[CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][C:17](=[O:26])[NH:16][C:15]=3[CH:14]=[CH:13][C:12]=2[O:27][CH3:28])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COc1ccc2c(c1N)CN(S(C)(=O)=O)CC(=O)N2
Product: COc1ccc2c(c1Nc1nc(Cl)ncc1Cl)CN(S(C)(=O)=O)CC(=O)N2
Temperature: 120 °C

Procedure:
A mixture of 2,4,5-Trichloro-pyrimidine (1.5 g, 0.0084 mol), 6-Amino-4-methanesulfonyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.400 g, 0.00140 mol) was heated at 120° C. for 48 hrs. The reaction was triturated with ethyl acetate and then with methanol giving 6-(2,5-Dichloro-pyrimidin-4-ylamino)-4-methanesulfonyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one the product as a gray solid (0.338 g, 51%). Mp 280-300d; LCMS (m/e)-432 (M); 1H-NMR (DMSO, 400 MHz) δ 10.23 (s, 1H), 9.34 (s, 1H), 8.34 (s, 1H), 7.20-7.17 (d, 1H, J=9.10 Hz), 7.14-7.11 (d, 1H, J=8.84 Hz), 4.40-4.30 (m, 1H), 4.25-4.10 (m, 1H), 3.83 (s, 3H), 2.88 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C=O.[C:36]([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]([CH3:36])[CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:26][CH2:27][CH3:28])[CH2:29][CH2:30][CH3:31])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: CCCN(CCC)CCCCNCc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCN(C)Cc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The compound (150.7 mg) obtained in Example 25-5 was dissolved in methanol (3.0 ml). Then, a 36% formaldehyde aqueous solution (manufactured by Kanto Kagaku) (50 μl) and sodium cyanoborohydride (36.2 mg) were added to the solution in this order. After the reaction solution was adjusted to pH 5 with acetic acid, the solution was stirred at room temperature for 17 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then extracted with chloroform. Subsequently, the organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After the solvent had been distilled off, the residue obtained was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated with hydrochloric acid, thereby obtaining hydrochloride (126.2 mg) of the subjected compound as a white solid.
Reaction SMILES: [OH-].[Na+].[C:3]1([S:9]([N:12]([C:22]2[C:26]([Br:27])=[C:25]([CH3:28])[O:24][N:23]=2)S(C2C=CC=CC=2)(=O)=O)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[Br:27][C:26]1[C:22]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)(=[O:11])=[O:10])=[N:23][O:24][C:25]=1[CH3:28]
Reactant: Cc1onc(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1onc(NS(=O)(=O)c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Sodium hydroxide (1.3 g, 30.6 mmol) was added to a solution of N-(benzenesulfonyl)-N-(4-bromo-5-methyl-3-isoxazolyl)benzene-sulfonamide (7g, 15.3 mmol, prepared as described in (a)) in methanol (100 ml). The resulting solution was stirred at 25° C. for 30 h. Excess methanol was removed under reduced pressure. The residue was dissolved in water (50 ml) and acidified (pH 3-4)by the addition of concentrated HCl with cooling. The mixture was extracted with dichloromethane (2×100 ml) and the combined organic layer was dried over anhydrous magnesium sulfate. Removal of the solvent gave N-(4-bromo-5-methyl-3-isoxazolyl)benzenesulfonamide which was purified by crystallization from ethyl acetate/hexanes (4.5 g, 92% yield). The compound is identical to the one isolated in step (b).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Br:19])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])[CH3:2].[CH3:20][Mg]Br>CCOCC.[Cl-].[NH4+].[Cu](Br)Br>[Br:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]([CH3:20])[CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)C(=Cc1ccccc1Br)C(=O)OCC
Reactant: C[Mg]Br
Agent: Br[Cu]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)OCC)C(C)c1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution in 500 ml of ether of 50.98 g of ethyl α-ethoxycarbonyl-o-bromo-cinnamate (170.5 mmole) and 1.0 g of copper bromide was added dropwise 56.7 ml of an ethereal solution of methylmagnesium bromide (175.6 mmole) at -20° C. The mixture was stirred overnight at room temperature, diluted with an aqueous ammonium chloride solution to separate the phases. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to give ethyl 3-(2-bromophenyl)-2-ethoxycarbonyl-3-methylpropionate.
Reaction SMILES: [N:1]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=CC=C[CH:15]=2)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][C@H:2]1C(O)=O.[CH2:20](Cl)[Cl:21]>>[CH2:13]([O:12][C:10]([Cl:21])=[O:11])[CH:14]([CH3:19])[CH3:15].[CH3:20][CH:7]1[CH2:6][CH2:2][NH:1][CH2:9][CH2:8]1
Reactant: O=C(O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Reactant: ClCCl
Product: CC(C)COC(=O)Cl
Product: CC1CCNCC1

Procedure:
A suspension of 1.300 g (4.94 mmoles) of N-benzyloxycarbonyl-(L)-pipecoline-2-carboxylic acid (abbreviation Z-(L)-PipOH, prepared from (L)-pipecholine-2carboxylic acid (Aldrich) according to the method of Wunsch) in 60 ml of dry methylene chloride (CH2Cl2) was brought under argon atmosphere to a temperature of approximately -20° C. On stabilization of the temperature, the following were added in quick succession: 0. 670 ml (5.13 mmoles) of isobutylchloroformate (IBCF) and 0.630 ml (5.18 mmoles) of 4-methylpiperidine (NMP), leaving the system under stirring for approximately 2 minutes. A solution, pre-cooled to approximately -15 ° C. for 30 minutes, of 1.730 g (4.70 mmoles) of (L) -Leu-(L) TrpOMe. HCl (Novabiochem) and 0.580 ml (4.77 mmoles) of NMP in 25 ml of anhydrous N,N-dimethylformamide (DMF) was then added, leaving, under stirring and static argon, the temperature free to rise to room temperature. After approximately 3,5 hours of reaction, the white precipitate was filtered away and washed with a little CH 2 Cl2. The latter was put back into the pale yellow coloured organic solution, which was extracted in succession using 5% NaHCO3 (3×30 ml); saturated aqueous NaCl (2×30 ml); 4% KHSO4 (3×30 ml) and finally saturated aqueous NaCl (3×30 ml), discarding the aqueous phases. The organic phase extracted, of a pale yellow colour, was left in a cold chamber under argon and on anhydrous Na2SO4 for 12 hours. The desiccant was then filtered away and the organic solution, concentrated to a small volume, was added dropwise under stirring to 200 ml of dry petroleum ether (30/50), obtaining an abundant milk-white precipitate which, after several hours at rest in a cold chamber, was filtered and left for 24 hours under vacuum on P2O5 2.300 g (84.8%) of an analytically pure white solid were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]=C2CCCCI2C2C=CC=CC=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11]>C(#N)C.CC#N.CC#N.CC#N.CC#N.F[P-](F)(F)(F)(F)F.[Cu+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][N:22]2[S:19]([C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][CH:17]=2)(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N=C2CCCCI2c2ccccc2)cc1
Reactant: C=Cc1ccc(Cl)cc1
Agent: [Cu+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CC2c2ccc(Cl)cc2)cc1
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a suspension of 1-chloro-4-vinylbenzene (0.1195 ml, 0.9957 mmol), tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.01856 g, 0.04979 mmol), and 4 angstrom molecular sieves (300 mg) in dry acetonitrile (2.5 ml) degassed with argon was added [N-[(p-nitrophenyl)sulfonyl]imino]phenyliodinane (0.6037 g, 1.494 mmol) portion-wise over 2 hours as a solid. It was stirred overnight under argon, then was loaded directly onto a Biotage SP1 system eluting with a 2-30% linear gradient of EtOAc in hexanes to yield 276 mg of the title compound (81.8% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1>>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:35]2[CH:34]=[N:33][C:32]([Cl:31])=[CH:37][CH:36]=2)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccc(Cl)nc2)sc1C(=O)OCC

Procedure:
Prepared from 2-bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethy ester, example 81(b), and 2-chloropyridine-5-boronic acid under conditions analogous to experimental example 81(c). MS: (+) m/z 534.3 (M+1).
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH:16]([C:17]([O:19]C(C)C)=[O:18])[C:12]3=[CH:11][C:10]=2[CH3:23])=[O:8])=[CH:3][CH:2]=1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]1([CH3:24])[CH:2]=[CH:3][C:4]([C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]3=[CH:11][C:10]=2[CH3:23])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(=O)c2c(C)cc3n2CCC3C(=O)OC(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)c2c(C)cc3n2CCC3C(=O)O)cc1

Procedure:
A solution of 500 mg. of isopropyl 5-p-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate in 15 ml. of methanol is treated with a solution of 1.05 g. of potassium carbonate in 8 ml. of water. The reaction mixture is refluxed under nitrogen atmosphere for 30 minutes, cooled, and evaporated to dryness. The residue is taken up in 10 ml. of 10% aqueous hydrochloric acid and 50 ml. of water and the resultant mixture extracted with ethyl acetate (3 × 50 ml.). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure, to give 5-p-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid [(A), R = CH3, R1 = p-CH3 ].
Reaction SMILES: Cl.C(O[C:5](=[NH:21])[C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:20])(=[O:19])[NH:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[CH:8][CH:7]=1)C.[NH3:22]>>[S:15]1[CH:16]=[CH:17][N:18]=[C:14]1[NH:13][S:12]([C:9]1[CH:8]=[CH:7][C:6]([C:5]([NH2:21])=[NH:22])=[CH:11][CH:10]=1)(=[O:19])=[O:20]
Reactant: N
Reactant: CCOC(=N)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Agent: Cl
Product: N=C(N)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-(thiazol-2-ylsulfamoyl)-benzimidic acid ethyl ester hydrochloride (100 mmol) in 7 N NH3 (120 mL in methanol) was stirred at 60° C. for 2 h. After reaction mixture was cooled to room temperature, the precipitate was filtered, washed with methanol, and dried in vacuo to give a quantitative yield of 4-(thiazol-2-ylsulfamoyl)-benzamidine.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18]OCl.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:26][C:27]#[N:28]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25](/[C:26](=[CH:4]/[C:3]2[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=2[O:1][CH2:18][O:17][CH2:16][CH2:15][O:14][CH3:13])/[C:27]#[N:28])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: COCCOCOCl
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Product: COCCOCOc1ccc([N+](=O)[O-])cc1/C=C(\C#N)c1ccc(OC)c(OC)c1
Yield: 39.9 %

Procedure:
The hydroxyl group of 2-hydroxy-5-nitrobenzaldehyde (1.00 g) was protected by use of 2-methoxyethoxymethoxyl chloride (0.75 g) in accordance with (production process 1), to thereby produce an MEM form (1.10 g, yield: 65%). The resultant MEM form (510 mg) and 3,4-dimethoxybenzyl cyanide (354 mg) were subjected to condensation in accordance with process B of (production process 2), to thereby produce (Z)-2-(3,4-dimethoxy-phenyl)-3-[2-(2-methoxy-ethoxymethoxy)-5-nitro-phenyl]-acrylonitrile (330 mg, yield: 40%). The thus-produced (Z)-2-(3,4-dimethoxy-phenyl)-3-[2-(2-methoxy-ethoxymethoxy)-5-nitro-phenyl]-acrylonitrile (200 mg) was subjected to deprotection in accordance with (production process 3), to thereby produce the target product (87 mg, yield: 55%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[CH3:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:31][CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:32][CH2:31][C:21]2[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:24][C:20]=2[CH3:19])=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Reactant: Cc1sc(-c2ccccc2)nc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)sc2C)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 2-(5-methyl-2-phenyl-thiazol-4-yl)-ethanol [PCT Int. Appl. (2002), WO 02/18355 A1] in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-{3-fluoro-4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-3-fluoro-4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid as an off-white solid.