Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31](=[O:43])[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[CH:26]=[CH:25]4)[N:18]=[CH:17][N:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[O:47][CH2:46][CH2:45]1>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([C:46](=[O:47])[CH3:45])[CH2:14][C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31](=[O:43])[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[CH:26]=[CH:25]4)[N:18]=[CH:17][N:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2cc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)ncn2)C1
Reactant: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1)C1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.5 h

Procedure:
To a solution of (±)-3-({6-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (60 mg, 0.10 mmol) in THF (5 mL) acetyl chloride (12 mg, 0.15 mmol) and TEA (20 mg, 0.2 mmol) are added at 0° C. After 30 min, the mixture is diluted with EtOAc, washed with water, brine, and the organic layer is dried over Na2SO4, filtered, and condensed. The residue is separated by FCC (0-10%, 2 M NH3 in MeOH/DCM) to provide the title compound. MS (ESI) m/z 638.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9](O)([CH2:15][N:16]1C=NC=N1)[C@@H:10](C)C(O)=O.[C:22]([N:29]1C=C[N:31]=[CH:30]1)([N:24]1[CH:28]=[CH:27]N=C1)=O.Cl.[O:35]1CCCC1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH3:10])([CH:27]([OH:35])[CH2:28][N:24]1[CH:22]=[N:29][CH:30]=[N:31]1)[C:15]#[N:16]
Reactant: C[C@@H](C(=O)O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: C1CCOC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Product: CC(C#N)(c1ccc(F)cc1F)C(O)Cn1cncn1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
165 mg (0.55 mmol) of (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-yl-butyric acid were dissolved in 3.3 ml of tetrahydrofuran and, after the addition of 120 mg (0.72 mmol) of 1,1′-carbonyldiimidazole, stirred for 2 hours at 60° C. The reaction mixture was poured onto 10 ml of aqueous 0.5N HCl, extracted twice with each 25 ml of ethyl acetate, dried and evaporated to dryness. The crude residue was dissolved in 6 ml of aqueous 25% ammonium hydroxide and, after the addition of 2 mg of dimethylaminopyridine, stirred at room temperature for 1 hour. After evaporation of the reaction mixture the resulting residue was treated with 200 mg of POCl3 at 40° C. for 3 hours. After evaporation of the excess POCl3 under reduced pressure the crude product was poured onto water and extracted twice with 15 ml of ethyl acetate. The organic phase was dried with Na2SO4 and evaporated. Column chromatography on silica gel (eluent ethyl acetate/n-hexane=1:1) gave 95 mg (74%) of (2R,3R)-3-(2,4-difluorophenyl-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-ylbutyronitrile.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:10]([O:17][CH3:18])[CH:9]=[C:8](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]=1[C:4](OC)=[O:5].[NH3:27]>>[OH:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:10]([O:17][CH3:18])[CH:9]=[C:8](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]=1[C:4]([NH2:27])=[O:5]
Reactant: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)OC)c1O
Reactant: N
Product: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(N)=O)c1O
Temperature: 0 °C
Yield: 92 %

Procedure:
Dissolve compound 8 (1.0 g, 2.84 mmol) in methanolic ammonia (10%, 10 ml), reflux to react for 4-6h, after completion, pour the solution into ice water, extract the solution with ethyl acetate, desiccate the organic layer over anhydrous magnesium sulfate. Filter and concentrate the solution, redissolve the residue, feed the solution into a chromatographic column, evaporate the solvent in the eluent to obtain a white solid as the target product (0.86 g, 92%). 1H NMR (400 MHz, DMSO-d6): 1.79 (s, 3H), 1.81 (s, 3H), 3.25 (d, J=7.6 Hz, 2H), 3.77 (s, 3H), 5.20 (t, J=7.6 Hz, 1H), 6.68 (s, 1H), 6.80 (d, J=16.0 Hz, 1H), 7.24 (d, J=16.0 Hz, 1H), 79 (t, J=7.6 Hz, 2H), 7.36 (s, 1H), 7.44 (t, J=7.6 Hz, 2H), 7.90 (s, 2H).
Reaction SMILES: [OH-:1].[Na+].Cl.[NH2:4]O.[CH2:6]([C:8]1([CH2:13][C:14]#[N:15])[O:12][CH2:11][CH2:10][O:9]1)[CH3:7]>O.CO>[CH2:6]([C:8]1([CH2:13][C:14]([NH:4][OH:1])=[NH:15])[O:12][CH2:11][CH2:10][O:9]1)[CH3:7]
Reactant: [OH-]
Reactant: NO
Reactant: CCC1(CC#N)OCCO1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC1(CC(=N)NO)OCCO1
Reaction time: 0.08 h

Procedure:
A solution of NaOH (1.17 g, 29.3 mmol) in water/methanol (1:1) (18 ml), cooled to 0° C. in an ice bath, is treated with hydroxylamine hydrochloride (1.58 g, 22.78 mmol), with stirring for 5 minutes. (2-Ethyl-[1,3]dioxolan-2-yl)-acetonitrile (1.42 g, 10.125 mmol) is added and the reaction mixture stirred at room temperature for 18 hours, then refluxed for a further 2 hours. The reaction mixture is cooled and partitioned between ethyl acetate and water. The organic phase is dried over MgSO4, filtered, and the solvent evaporated to yield 2-(2-Ethyl [1,3]dioxolan-2-yl)-N-hydroxy-acetamidine. [M+H] 175.21
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]([OH:9])[CH3:8].C(N(CC)C(C)C)(C)C.[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24]Cl>C(Cl)Cl>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]([O:9][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[CH3:8]
Reactant: COCCOCCl
Reactant: CC(O)c1ccsc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOC(C)c1ccsc1Br
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A solution of 2-bromo-3-(l-hydroxyethyl)thiophene (97.5 g, 0.47 mol) in dry methylene chloride (400 ml) was cooled in ice and N,N-diisopropylethylamine (68.2 g, 0.517 mol) was added followed by methoxyethoxymethYl chloride (64.4 g, 0.517 mol). The solution was stirred at room temperature over night. The dark solution was washed with water, 3N HCl, saturated NaHCO3 and finally with water. The solution was dried over anhydrous Na2SO4 filtered and concentrated in vacuo at room temperature. A dark amber oil was obtained (123.1 g). The impure product was distilled and the product was collected at 108-116° C. at 0.7 mm Hg. to give 91.1 g (66%) of colorless liquid. NMR supported the structure.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[C:35]2[CH:40]=[CH:39][C:38]([S:41][C:42]([F:45])([F:44])[F:43])=[CH:37][CH:36]=2)=[CH:19]\[CH2:20][O:21][C:22]2[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:24]([CH3:34])[CH:23]=2)=[CH:14][CH:13]=1.C(NC(C)C)(C)C>O1CCCC1.[Cu]I.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>[OH:10][CH:7]1[CH2:8][CH2:9][N:4]([CH2:1][C:2]#[C:3][C:12]2[CH:13]=[CH:14][C:15](/[C:18](/[C:35]3[CH:36]=[CH:37][C:38]([S:41][C:42]([F:44])([F:43])[F:45])=[CH:39][CH:40]=3)=[CH:19]\[CH2:20][O:21][C:22]3[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:24]([CH3:34])[CH:23]=3)=[CH:16][CH:17]=2)[CH2:5][CH2:6]1
Reactant: C#CCN1CCC(O)CC1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(SC(F)(F)F)cc2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCC(O)CC3)cc2)c2ccc(SC(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-Propargylpiperidin-4-ol (154 mg, 1.10 mmol) was added to a solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-[4-(trifluoromethyl-sulfanyl)phenyl]allyloxy]-2-methylphenoxy]-acetate (340 mg, 0.553 mmol; prepared as described in example 56) and diisopropylamine (0.35 mL, 2.49 mmol) in tetrahydrofuran (9 mL). The mixture was degassed and copper(I) iodide (8.4 mg, 0.044 mmol) and bis(triphenylphosphine)palladium(II) dichloride (19.3 mg, 0.027 mmol) were added. The reaction mixture was stirred under argon at ambient temperature for 20 h, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, chloroform/methanol 97:3) yielding methyl (E)-[4-[3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]phenyl]-3-[4-(trifluoromethylsulfanyl)phenyl]-allyloxy]-2-methylphenoxy]acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[CH:13]1([Mg]Cl)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Cl-].[NH4+]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[OH:12]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: Cl[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C1(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 18.15 g of 5-chloroisatin in 45 ml of THF is cooled to +4° C., 200 ml of a 2M solution of cyclohexylmagnesium chloride in ether are added dropwise and the mixture is stirred for 3 hours at RT. 900 ml of a saturated solution of ammonium chloride are added and the solvents are concentrated under vacuum. The aqueous phase is extracted with AcOEt, the organic phase is washed with a saturated solution of NaCl and dried over sodium sulfate and the solvent is evaporated of f under vacuum to give 4 g of the expected product after crystallization from a THF/AcOEt mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[C:10](Cl)(Cl)=[O:11].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]([CH3:28])[CH2:23][C:24](=[O:27])[NH:25][N:26]=2)=[CH:17][CH:16]=1>CCOCC.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:6][C:10]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]([CH3:28])[CH2:23][C:24](=[O:27])[NH:25][N:26]=2)=[CH:17][CH:16]=1)=[O:11]
Reactant: OCc1cccc(Cl)c1
Reactant: O=C(Cl)Cl
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)OCc2cccc(Cl)c2)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
A solution of 7.1 g (49.8 millimoles) of m-chlorobenzyl alcohol in 50 ml of absolute ether is added dropwise to a stirred solution of 11.2 g (113 millimoles) of phosgene in 100 ml of absolute ether at -20° C. The reaction solution is then stirred for 1 hour at -10° C. and for a further hour at room temperature, and thereafter the excess phosgene is removed by means of a dry stream of nitrogen and the other is then removed under reduced pressure at room temperature. The m-chlorobenzyl chloroformate which remains (12.0 g) is dissolved in 50 ml of absolute tetrahydrofuran and the solution is added, at room temperature, to a solution, prepared by the method described in Example 31, of 5.0 g (24.6 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone in 100 ml of absolute tetrahydrofuran. The reaction mixture is then refluxed for 14 hours and is worked up by the method described in Example 31. After recrystallizing the product first from chloroform/petroleum ether, then from acetone/water and finally from propanol/water, 4.0 g (44% of theory) of 6-[p-(m-chlorobenzyloxycarbonylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone are obtained as colorless crystals of melting point 165°-166° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:20]=[C:19](SCC2C=CC=C(F)C=2F)[C:18]2[C:13](=[N:14][C:15]([NH2:31])=[CH:16][N:17]=2)[N:12]=1.[NH2:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35]>CN1C=CN=C1>[NH3:12].[NH2:31][C:15]1[N:14]=[C:13]2[C:18]([C:19]([NH:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35])=[N:20][C:11]([S:10][CH2:9][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])=[N:12]2)=[N:17][CH:16]=1
Reactant: NC(CO)CO
Reactant: Nc1cnc2c(SCc3cccc(F)c3F)nc(SCc3cccc(F)c3F)nc2n1
Agent: Cn1ccnc1
Product: N
Product: Nc1cnc2c(NC(CO)CO)nc(SCc3cccc(F)c3F)nc2n1
Yield: 39.2 %

Procedure:
A solution of the product from example 1, step (c) (0.12 g) and serinol (330 mg) in 1-methylimidazole (1 ml) was heated at 130° C. for 90 minutes. After cooling, the reaction mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic phase was dried over magnesium sulphate, filtered and evaporated to give a brown solid which was purified by silica gel flash column chromatography, eluting with 200:20:1 dichloromethane:methanol:880 ammonia solution, to give the title compound as a pale brown solid (0.02 g).
Reaction SMILES: [OH-].[K+].C1(C)C=CC=CC=1.[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:12]=1[C:13]([OH:15])=[O:14].Cl[CH2:22][C:23]([NH2:25])=[O:24]>C(OCC)(=O)C.O>[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:12]=1[C:13]([O:15][CH2:22][C:23]([NH2:25])=[O:24])=[O:14]
Reactant: NC(=O)CCl
Reactant: O=C(O)c1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: NC(=O)COC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 48.4 %

Procedure:
A sample of 5.9 grams (0.105 mole) of potassium hydroxide was ground to a powder and placed in the reaction vessel. To this was added 270 ml of dry toluene, followed by 20.0 grams (0.105 mole) of 2,6-dichlorobenzoic acid. The stirred reaction mixture was heated under reflux while the water by-product was collected by azeotropic distillation using a Dean-Stark trap. A total of 2.8 ml of water was collected during a 30-minute period. At the end of this time the reaction mixture was cooled slightly and 2.0 grams of 1,4,7,10,13,16-hexaoxacyclooctadecane, followed by 9.8 grams (0.105 mole) of chloroacetamide were added. Upon completion of the addition the reaction mixture was heated under reflux for 18 hours. the reaction mixture was cooled to ambient temperature and the toluene layer was separated from the two-phase system and washed with one portion of 100 ml of water. An emulsion formed but was broken up by the addition of 100 ml of ethyl acetate. The organic layer was separated and dried with sodium sulfate. The mixture was filtered, and the filtrate evaporated under reduced pressure to a residual semi-solid. The solid was recrystallized twice from high-boiling petroleum ether-ethyl acetate using decolorizing carbon to give 12.6 grams of (aminocarbonyl)methyl 2,6-dichlorobenzoate; mp 113.5°-115.5°. The ir and the nmr spectra were consistent with the proposed structure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:18][C:19](=[O:26])[C:20](=[CH:24][CH:25]=2)[C:21](O)=O)=[CH:13][CH:12]=1)(=[O:10])=[O:9].S(Cl)([Cl:29])=O.NS(C1C=CC(C2NC(=O)C(=CC=2)C[Cl:46])=CC=1)(=O)=O>CN(C)C=O>[ClH:29].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:18][C:19](=[O:26])[C:20](=[CH:24][CH:25]=2)[CH2:21][Cl:46])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: O=C(O)c1ccc(-c2ccc(S(=O)(=O)Nc3ccccn3)cc2)[nH]c1=O
Reactant: O=S(Cl)Cl
Reactant: NS(=O)(=O)c1ccc(-c2ccc(CCl)c(=O)[nH]2)cc1
Solvent: CN(C)C=O
Product: Cl
Product: O=c1[nH]c(-c2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1CCl

Procedure:
From 7.0 g. of 6-[4-(2-pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 200 ml. of thionyl chloride, and 1.5 ml. of dimethylformamide, following the procedure of (c) above, there is obtained 6-[4-(2-pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride hydrochloride.
Reaction SMILES: [CH:1]1([C:4]2[S:5][C:6]3[CH:12]=[C:11]([O:13]C)[C:10]([CH3:15])=[CH:9][C:7]=3[N:8]=2)[CH2:3][CH2:2]1.[Br:16]C1C2SC=NC=2C=C(C)C=1O.COC1C(C)=CC2N=CSC=2C=1>>[Br:16][C:12]1[C:6]2[S:5][C:4]([CH:1]3[CH2:3][CH2:2]3)=[N:8][C:7]=2[CH:9]=[C:10]([CH3:15])[C:11]=1[OH:13]
Reactant: COc1cc2sc(C3CC3)nc2cc1C
Reactant: Cc1cc2ncsc2c(Br)c1O
Agent: COc1cc2scnc2cc1C
Product: Cc1cc2nc(C3CC3)sc2c(Br)c1O

Procedure:
Compound 15 was prepared from compound 6B by the method used to prepare compound 5D from compound 5B as outlined in Example 1. LCMS-ESI+: calc'd for C141H10BrNOS: 284.0 (M+H+). Found: 284.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CC[N:15](C(C)C)C(C)C.N.CO.CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cccc(C(=O)O)c1N
Agent: CCN=C=NCCCN(C)C
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COc1cccc(C(N)=O)c1N
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To 2-amino-3-methoxybenzoic acid (8.11 g, 48.52 mmol) in DMF (150 mL) at rt were added DIEA (13.2 mL, 58.22 mmol), 2 N ammonia in MeOH (33.96 mL, 67.92 mmol), EDCI (11.16 g, 58.22 mmol), and 1-hydroxybenzotriazole (7.87 g, 58.22 mmol). The solution was stirred at rt under argon. After 20 h the solution was diluted with water and extracted ten times with EtOAc. The EtOAc volume was reduced and washed with brine. The EtOAc fraction was concentrated and diluted with diethyl ether. The resulting tan solid was collected and dried in vacuo to give 2-amino-3-methoxybenzamide (6.08 g, 76%). 1H NMR (300 MHz, DMSO-d6) δ 3.79 (s, 3H), 6.26 (bs, 2H), 6.48 (m, 1H), 6.88 (d, J=7.9 hz, 1H), 7.12 (bs, 1H), 7.19 (dd, J=8.2, 1.0 Hz, 1H), 7.70 (bs, 1H) LC-MS (ESI) m/z 167 (M+H)+.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[O:24][CH:25]=[CH:26][C:27]=4[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:29].[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:33][CH:32]=1>C1COCC1>[CH3:28][C:27]1[CH:26]=[CH:25][O:24][C:23]=1[C:21]([NH:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:3](=[CH:2][NH:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:35][CH:36]=3)[C:4](=[O:29])[NH:5]2)=[CH:10][CH:9]=1)=[O:13])=[O:22]
Reactant: Nc1ccc(CCC(=O)O)cc1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(CCC(=O)O)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
A small screw cap test tube was charged with 3-Methyl-furan-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 354, 200 mg, 0.515 mmol) and THF (5.0 mL). To the resulting solution was added 3-(4-Amino-phenyl)-propionic acid (85.1 mg, 0.515 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified by flash silica gel chromatography (EtOAc:MeOH mix eluant with gradient of 1% MeOH to 10% MeOH) to afford the title compound in 57% yield (0.157 g, 0.293 mmol).
Reaction SMILES: [N:1]1([CH2:6][CH:7]([P:16]([O:21]CC)(=[O:20])[O:17]CC)[P:8]([O:13]CC)(=[O:12])[O:9]CC)[CH:5]=[CH:4][CH:3]=[N:2]1.[N:24]1([CH2:29][CH:30]([P:39]([O:44]CC)(=[O:43])[O:40]CC)[P:31]([O:36]CC)(=[O:35])[O:32]CC)[CH:28]=[CH:27][N:26]=[CH:25]1.C[Si](C)(C)Br>CO>[N:1]1([CH2:6][CH:7]([P:8]([OH:13])(=[O:9])[OH:12])[P:16]([OH:20])(=[O:17])[OH:21])[CH:5]=[CH:4][CH:3]=[N:2]1.[N:24]1([CH2:29][CH:30]([P:31]([OH:36])(=[O:32])[OH:35])[P:39]([OH:43])(=[O:40])[OH:44])[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: CCOP(=O)(OCC)C(Cn1cccn1)P(=O)(OCC)OCC
Reactant: CCOP(=O)(OCC)C(Cn1ccnc1)P(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Solvent: CO
Product: O=P(O)(O)C(Cn1cccn1)P(=O)(O)O
Product: O=P(O)(O)C(Cn1ccnc1)P(=O)(O)O

Procedure:
The procedure of Example 9 is repeated, starting from tetraethyl 2-(pyrazol-1-yl)ethane-1,1-diphosphonate and tetraethyl 2-(imidazol-1-yl)ethane-1,1-diphosphonate. Treatment with trimethylbromosilane and working up with aqueous methanol gives 2-(pyrazol-1-yl)ethane-1,1-diphosphonic acid, m.p. 227° C. (dec.), and 2-(imidazol-1-yl)ethane-1,1-diphosphonic acid, m.p. 255° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:18])([CH3:17])[CH:15]=O)[CH:11]=[CH:10][C:9]=2[NH:19][C:20]([C:22]2[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])=[CH:4][CH2:3]1.[CH3:30][C:31]1([CH3:39])[O:38][CH:34]2[CH2:35][NH:36][CH2:37][CH:33]2[O:32]1>CO.C(Cl)Cl>[CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:15])([CH3:17])[CH2:18][N:36]3[CH2:37][CH:33]4[O:32][C:31]([CH3:39])([CH3:30])[O:38][CH:34]4[CH2:35]3)[CH:11]=[CH:10][C:9]=2[NH:19][C:20]([C:22]2[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)C=O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: CC1(C)OC2CNCC2O1
Solvent: ClCCl
Solvent: CO
Product: CC1(C)CC=C(c2cc(C(C)(C)CN3CC4OC(C)(C)OC4C3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Yield: 61.8 %

Procedure:
The title compound was prepared by the procedure of Example 138, step (i) using 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1,1-dimethyl-2-oxo-ethyl)-phenyl]-amide (as prepared in Example 138, step (h), 60.0 mg, 0.154 mmol) and 2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole (Couturier, M. et at, Organic Process Research & Development, 2002, 6, 42-48, 132 mg, 0.924 mmol). Silica gel chromatography (1-3% MeOH/DCM) afforded the title compound (49.3 mg, 63%) as a white solid. 1H-NMR (1:1 CD3OD; 400 MHz): 8.13 (d, 1H, J=8.6 Hz), 7.98 (s, 1H), 7.32 (dd, 1H, J=8.6, 2.3 Hz), 7.21 (d, 1H, J=2.3 Hz), 5.73 (m, 1H), 4.48 (m, 2H), 2.70 (d, 2H, J=11.4 Hz), 2.59 (s, 2H), 2.31 (m, 2H), 2.08 (m, 2H), 1.98-2.04 (m, 2H), 1.59 (t, 2H, J=6.3 Hz), 1.44 (s, 3H), 1.34 (s, 6H), 1.23 (s, 3H), 1.09 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C30H39N5O3, 518.3 (M+H). found 518.3.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9]CC)=[O:8])=[CH:5][N:6]=1.[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[N:12]1[CH:17]=[CH:16][C:15]([C:2]2[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: OB(O)c1ccncc1
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: C1COCCO1
Solvent: O
Product: O=C(O)c1cnc(-c2ccncc2)s1
Reaction time: 0.33 h

Procedure:
A mixture of ethyl 2-bromo-1,3-thiazole-5-carboxylate (0.095 mL, 0.64 mmol), pyridine-4-ylboronic acid (0.094 g, 0.76 mmol), tetrakis(triphenylphosphine)palladium(0) (0.007 g, 0.006 mmol), and potassium carbonate (0.263 g, 1.91 mmol) in 1,4-dioxane (10 mL) and water (0.5 mL) was subjected to MWI at 160° C. for 20 min. The reaction mixture was diluted with water and extracted with EtOAc. The organic solutions were combined, acidified and concentrated. The residue was dissolved in EtOAc and brine was added. The organic solution was separated, dried over Na2SO4, filtered and concentrated to give 2-pyridin-4-yl-1,3-thiazole-5-carboxylic acid which was used without further purification. LCMS: (FA) ES+ 207.