Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([O:11][CH3:12])[CH:3]=1.Br[C:14]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3OC)[C:27]3[S:31][N:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[N:16]([CH3:43])[CH:15]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].FC(F)(F)C(O)=O>O1CCOCC1.O.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([S:23]([NH:26][C:27]4[S:31][N:30]=[CH:29][N:28]=4)(=[O:24])=[O:25])=[CH:20][CH:21]=3)[N:16]([CH3:43])[CH:15]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Reactant: COc1cc(F)ccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(F)ccc1-c1cn(C)c2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a vial containing 4-fluoro-2-methoxyphenylboronic acid (0.075 g, 0.450 mmol) was added a solution of 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (Intermediate D) (0.100 g, 0.191 mmol) and Pd(AmPhos)2Cl2 (0.014 g, 0.019 mmol) in 1 mL of dioxane. A solution of tripotassium phosphate (0.142 g, 0.669 mmol) in 318 μL of water was added, and the vial was sealed and placed in a heated shaker block. The vial was shaken for 2 hours at 100° C. The vial was uncapped and the reaction was concentrated. The resulting solid was dissolved in a solution of trifluoroacetic acid (0.293 mL, 3.82 mmol) in 1 mL of dichloromethane. The reaction was shaken at room temperature for 1 hour. The solution was filtered and the solids were washed with DCM and methanol. The filtrate was concentrated and purified via reverse phase HPLC (8 min gradient elution 15 to 75% ACN/H2O, 0.1% TFA modifier) to afford 3-(4-fluoro-2-methoxyphenyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.79 (s, 3 H) 3.87 (s, 3 H) 6.83 (td, J=8.42, 2.52 Hz, 1 H) 7.01 (d, J=2.52 Hz, 1 H) 6.99 (d, J=2.52 Hz, 1 H) 7.43-7.48 (m, 2 H) 7.56 (d, J=8.48 Hz, 1 H) 7.65 (s, 1 H) 7.84-7.90 (m, 2 H). m/z (ESI) 418.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:30])=[C:4]([NH:10][C@H:11]([C@@H:27]([OH:29])[CH3:28])[C:12]([NH:14][NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)=[O:17])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CN(C=O)C.N1C=CN=C1.[C:41]([Si:45](Cl)([CH3:47])[CH3:46])([CH3:44])([CH3:43])[CH3:42]>CCOC(C)=O.O>[Si:45]([O:29][C@@H:27]([CH3:28])[C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:30])[C:12]([NH:14][NH:15][C:16]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2)=[O:17])=[O:13])([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:47])[CH3:46]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc3[nH]ccc3c2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc3[nH]ccc3c2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 186 %

Procedure:
A 500 mL round bottomed flask was charged with N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-1H-indole-5-carbohydrazide (1.94 g, 4.56 mmol) and DMF (200 mL). Imidazole (1.55 g, 22.78 mmol) and tert-butyldimethyl silyl chloride (2.06 g, 13.68 mmol) were then added to the mixture which was stirred at room temperature for 18 h. Water (80 mL) was added to the mixture followed by EtOAc (150 mL). The phases were partitioned and the organic phase washed with water (70 mL) (×4), brine (50 mL), dried (Na2SO4) and concentrated to furnish a white solid. Purification by flash column chromatography [EtOAc-hexanes) as eluent] afforded the title compound as a colorless oil (4.58 g, 35% yield). 1H NMR (500 MHz, acetone d6, δ in ppm) δ 10.51 (br s, 1H), 9.5 (br s, 1H), 8.22 (br s, 1 H), 7.70 (d, J=8.41 Hz, 1H), 7.55-7.47 (m, 2 H), 7.44-7.42 (m, 1H), 6.77 (d, J=8.6 Hz, 1 H), 6.58-6.56 (m, 1H), 5.51 (d, J=7 Hz), 4.63-4.55 (m, 1H), 4.23-4.19 (m, 1H), 2.36 (s, 3H) and 1.36 (d, J=6.23 Hz, 3H), 0.95 (s, 9 H), 0.17 (s, 3 H) and 0.13 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:13][CH3:14].[NH:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[O:21]=[C:16]1[CH2:17][CH2:18][C:19](=[O:20])[N:15]1[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:13][CH3:14]
Reactant: O=C1CCC(=O)N1
Reactant: COc1cc(C=O)ccc1OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C=O)ccc1OCCN1C(=O)CCC1=O

Procedure:
B method: 11.66 g (45 mmol) of 4-(2-bromo-ethoxy)-3-methoxy-benzaldehyde (6.2) and 4.46 g (45 mmol) pyrrolidine-2,5-dione (7.2) is heated with 8.28 g (60 mmol) K2CO3 in 200 ml of acetonitrile for 8 h. After same isolation procedure as in A method 4.1 is given with same purity.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[CH2:5][C:4](=[O:16])[C:3]=1[C:17](=O)[CH2:18][CH3:19].[CH2:21]([O:23][NH2:24])[CH3:22]>C(O)C>[CH2:21]([O:23][N:24]=[C:17]([C:3]1[C:4](=[O:16])[CH2:5][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[CH2:7][C:2]=1[OH:1])[CH2:18][CH3:19])[CH3:22]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc(SC)cc2)CC1=O
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2ccc(SC)cc2)CC1=O
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Into 20 ml of ethanol was dissolved 2.9 g of 3-hydroxy-5-(4-methylthiophenyl)-2-propionyl-2-cyclohexen-1-one and to the solution was added 0.8 g of ethoxyamine. The mixture was kept for 15 hours at room temperature and it was poured into ice water. The crystal sedimented was collected with a filtering step and recrystallized with methanol. Thus, 3.1 g of colorless objective crystals having a melting point of 83°-84° C. was obtained.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[OH2:20].[OH-].[Na+]>Cl>[NH2:14][C:11]1[N:10]=[C:9]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[C:8]([C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:20])[CH:7]=2)=[CH:13][N:12]=1
Reactant: Nc1ncc(-c2ccnc(F)c2)c(-c2ccco2)n1
Reactant: O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncc(-c2cc[nH]c(=O)c2)c(-c2ccco2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A suspension of 5-(2-fluoro-4-pyridyl)-4-(2-furyl)-2-pyrimidinylamine (3.00 g, 11.70 mmol) in concentrated hydrochloric acid (15 ml)-water (15 ml) was stirred at 100° C. for 2 hours. After cooling as it was, the reaction mixture was neutralized with a 5N aqueous sodium hydroxide solution. The resulting solid was collected by filtration, washed with water and dried at 60° C. for 22 hours, to give the title compound (2.19 g, 70%) as a pale brown solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][CH:11]=[C:12]([CH2:13][CH3:14])[C:5]=12.Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[C:12]([CH2:13][CH3:14])[C:5]=12
Reactant: CCc1c[nH]c2nccc(Cl)c12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cn(COCC[Si](C)(C)C)c2nccc(Cl)c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
Sodium hydride (0.877 g, a 55% dispersion in paraffin liquid) was added to a solution of compound (41c) (3.3 g) in DMF (61 mL) at 0° C., followed by stirring for 10 min. Then, [2-(chloromethoxy)ethyl]trimethylsilane (3.53 mL) was added to the reaction solution, followed by stirring at room temperature for 1 hr. After cooling, ice water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline in this order and was then dried over anhydrous sodium sulfate. After distillation of the solvent, the residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain compound (41d) (4.30 g, 76%) as a colorless oily substance.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(OCC)C>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: OCCCCCCCCCCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCCCCBr
Reaction time: 2 h
Yield: 200.2 %

Procedure:
175 g of 11-bromoundecanol (Fluka) is dissolved in 420 ml of tetrahydrofuran and combined at 25° with 101 g of imidazole as well as 130.1 g of tert-butyldimethylsilyl chloride in 140 ml of tetrahydrofuran, and agitated for 2 hours at 25°. For the working up step, 1.2 1 of diethyl ether is added, the thus-precipitated hydrochloride is filtered off, the mixture concentrated to dryness under vacuum and chromatographed on silica gel with hexane/ethyl acetate, yielding 509.6 g of 11-bromoundecyl-tert-butyldimethylsilyl ether as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:38])[CH3:37])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[C:36]([NH:35][C:31]1[CH:30]=[C:29]([CH:26]2[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][CH2:20][NH:19][C:9](=[O:11])[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH2:24][CH2:25]2)[CH:34]=[CH:33][CH:32]=1)(=[O:38])[CH3:37]
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 55 was prepared from bis(4-chlorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.39 (br s, 1H), 7.31–7.22 (m, 11H), 6.94–6.92 (m, 1H), 4.76 (s, 1H), 3.39 (dd, 2H, J=6.4, 12.0 Hz), 2.97 (d, 2H, J=10.0 Hz), 2.49 (m, 1H), 2.44 (t, 2H, J=6.4 Hz), 2.17 (s, 3H), 2.05–1.99 (m, 2H), 1.83 (d, 2H, J=13.2 Hz), 1.71 (m, 2H), 1.61 (m, 2H); ESMS m/e: 538.3 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](Cl)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[N:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27]([N:50]5[CH2:51][CH2:52][N:47]([C:42]6[CH:43]=[CH:44][CH:45]=[CH:46][N:41]=6)[CH2:48][CH2:49]5)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude 10-(4-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carbonyl chloride prepared in the manner of Example 23 (0.5 g) was added to a stirred mixture of N,N-diisopropylethyl amine (0.32 g), 4-(2-pyridyl)piperazine (0.39 g) and 4-(dimethylamino)pyridine (0.05 g) in dichloromethane (25 mL). After stirring overnight at room temperature the reaction mixture was washed with water and saturated aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate. The solution was filtered through a short column of Magnesol®. and the eluate evaporated to dryness to provide the desired title compound (0.30 g) as a pale yellow amorphous solid.
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]([CH3:38])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:17]=[N:18][C:19]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)=[CH:20][C:21]=2[C:22]([F:25])([F:24])[F:23])=[CH:10][C:9]=1[CH3:37])[CH3:6])C.[Li+].[OH-]>>[CH3:38][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:17]=[N:18][C:19]([C:26]3[CH:27]=[CH:28][C:29]([O:32][C:33]([F:35])([F:36])[F:34])=[CH:30][CH:31]=3)=[CH:20][C:21]=2[C:22]([F:23])([F:24])[F:25])=[CH:10][C:9]=1[CH3:37])([CH3:6])[C:4]([OH:39])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(OC(F)(F)F)cc3)cc2C(F)(F)F)cc1C
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(OCc2cnc(-c3ccc(OC(F)(F)F)cc3)cc2C(F)(F)F)ccc1OC(C)(C)C(=O)O

Procedure:
In analogy to the procedure described in example 26C], 2-methyl-2-{2-methyl-4-[6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-ylmethoxy]-phenoxy}-propionic acid ethyl ester was treated with 1 N aqueous LiOH solution to give the title compound as yellow crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH:6]=[CH:7][CH:8]=[N:9][NH:10][C:11]([NH2:13])=[S:12].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=O>>[F:28][C:27]([F:29])([F:30])[C:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:13]=[C:11]([NH:10][N:9]=[CH:8]/[CH:7]=[CH:6]/[C:5]3[CH:4]=[C:3]([CH2:2][OH:1])[CH:16]=[CH:15][CH:14]=3)[S:12][CH:18]=2)=[CH:26][CH:25]=1
Reactant: NC(=S)NN=CC=Cc1cccc(CO)c1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Product: OCc1cccc(/C=C/C=NNc2nc(-c3ccc(C(F)(F)F)cc3)cs2)c1
Yield: 37 %

Procedure:
The compound is prepared according to the method described in example 1B from 3-hydroxymethylcinnamaldehyde thiosemicarbazone (0.4 mmoles) prepared in step 28A and from 2-bromo-4′-trifluoromethylacetophenone (0.4 mmoles). Yield 37%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:20])C(=O)C1>ClCCl.C(Cl)(Cl)Cl.[Cl-].[Zr+4].[Cl-].[Cl-].[Cl-]>[Cl:20][C:11]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[N:9]=[C:8]([CH3:12])[CH:7]=[CH:6]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc2ccc(O)cc2n1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc2ccc(O)c(Cl)c2n1
Reaction time: 23 h
Yield: 55 %

Procedure:
Referring to FIG. 19, under a nitrogen atmosphere, 7-hydroxyquinaldine (4, 0.39 g, 2.452 mmol) was added to a solution of NCS (0.3283 g, 2.459 mmol) and zirconium chloride (0.0285 g, 0.122 mmol) in dichloromethane (35 mL). After stirring for 23 h, the solution was diluted with chloroform and washed successively with saturated sodium carbonate solution, water, and brine. The solvent was evaporated to give a brown residue, which was purified by column chromatography (1:3 EtOAc/hexane) to yield 5c (0.2612 g, 1.349 mmol, 55%) as an oily yellow residue: 1H NMR (CDCl3) δ 8.00 (1H, d, J=8.0 Hz), 7.64 (1H, d, J=9.2 Hz), 7.28 (1H, d, J=8.0 Hz), 7.23, (1H, d, J=8.4 Hz), 2.80 (3H, s); 13C NMR (CDCl3) δ 160.6, 152.8, 144.9, 136.6, 127.5, 122.7, 120.7, 117.0, 114.6, 25.9; FTIR (neat) 2926, 1619, 1509, 1437, 1343, 1267, 1215, 1141, 1002, 835, 750 cm−1; MS (ESI) m/z calculated for (C10H8ClNO+H)+ 194 (35Cl) and 196 (37Cl), found 194 (35Cl) and 196 (37Cl); HRMS (ESI) m/z calculated for (C10H8ClNO+H)+ 194.0373 (35Cl) and 196.0343 (37Cl), found 194.0362 (35Cl) and 196.0333 (37Cl).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39](O)=[O:40])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:52])([CH2:50][OH:51])[CH2:48][OH:49].[Cl-].[NH4+]>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39](=[O:40])[NH:46][C:47]([CH2:50][OH:51])([CH3:52])[CH2:48][OH:49])=[CH:33][C:32]=3[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(N)(CO)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1cc(/C=C/C(=O)NC(C)(CO)CO)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 26 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-2-carboxyvinyl]-2-methyl-phenyl}methyl)-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1,3-propanediol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and ammonium chloride, respectively.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[NH2:10][C:11]1[C:12]([F:19])=[CH:13][C:14]([F:18])=[C:15]([OH:17])[CH:16]=1>>[CH3:9][C:4]1[N:5]=[C:6]([NH:10][C:11]2[C:12]([F:19])=[CH:13][C:14]([F:18])=[C:15]([OH:17])[CH:16]=2)[CH:7]=[C:2]([NH:10][C:11]2[C:12]([F:19])=[CH:13][C:14]([F:18])=[C:15]([OH:17])[CH:16]=2)[N:3]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: Nc1cc(O)c(F)cc1F
Product: Cc1nc(Nc2cc(O)c(F)cc2F)cc(Nc2cc(O)c(F)cc2F)n1
Yield: 57 %

Procedure:
This compound was obtained (yield 57%) based on the method described in Production Example 2B using 4,6-dichloro-2-methylpyrimidine instead of the 4,6-dichloro-2-ethylpyrimidine, and using 5-amino-2,4-difluorophenol instead of the 3-aminophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][CH:7]=[C:8]([CH2:9][P:10]([CH3:15])(=[O:14])[O:11][CH2:12][CH3:13])[C:4]=2[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:28](=[O:30])=[O:29].CC(OC)(C)C>C1COCC1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][CH:7]=[C:8]([CH:9]([P:10]([O:11][CH2:12][CH3:13])([CH3:15])=[O:14])[C:28]([OH:30])=[O:29])[C:4]=2[CH:3]=1
Reactant: CCOP(C)(=O)Cc1csc2ccc(Cl)cc12
Reactant: O=C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCOP(C)(=O)C(C(=O)O)c1csc2ccc(Cl)cc12
Temperature: -20 °C

Procedure:
To a dry 4N 300 ml flask equipped with magnetic stirrer, nitrogen inlet, temperature probe and addition port was added ethyl (5-chlorobenzo[b]thiophen-3-yl)methyl(methyl)phosphinate (12.7, 43.99 mmol) and dry THF (15 mL) under nitrogen. The resulting solution was cooled to −20° C. To the mixture was then added a 40% (2.2 M) NaHMDS solution in THF (25 mL), maintaining the temperature below 10° C. Following the base addition, CO2 was bubbled cautiously until no exotherm was observed, while maintaining the temperature of the reaction mixture below 15° C. The resulting mixture was then degassed with nitrogen and NaHMDS (10 mL) was added, followed by additional CO2 bubbling. The addition of NaHMDS ad CO2 was repeated 3 more times. The resulting solution was cooled to 0° C. and MTBE (80 mL) was added. To the resulting mixture was then added, slowly, 2N HCl (20 mL), followed by 6N HCl (40 mL), at which point the pH of the mixture was measured to be about 2. Throughout the addition of the acid, the temperature of the mixture was maintained between 0 and 15° C. Initial precipitation was observed upon acidification, while on completion of the acid addition, the mixture resolved in two clear layers. The layers were split, and the organic layer evaporated to yield an oil. The oil was digested overnight with MTBE (20 mL) to yield the title compound as a filterable solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[N:5]=[C:4]([C:12]([OH:15])([CH3:14])[CH3:13])[CH:3]=1.[C:16]([Cu])#[N:17].O.CCOC(C)=O>CN(C=O)C>[OH:15][C:12]([C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[N:5]=1)[C:16]#[N:17])([CH3:14])[CH3:13]
Reactant: N#C[Cu]
Reactant: CC(C)(O)c1cc(Br)cc(C(C)(C)O)n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(O)c1cc(C#N)cc(C(C)(C)O)n1
Reaction time: 20.5 h
Yield: 32.1 %

Procedure:
A solution of 1.45 g (5.28 mmol) of 2,2′-(4-bromopyridine-2,6-diyl)dipropan-2-ol and 585 mg (6.53 mmol) of CuCN in 20 mL of DMF was heated at 150° C. After about 20.5 h, 40 mL of H2O and EtOAc was added, and the mixture was filtered through a Buchner funnel. The layers were separated, and the organic layer was washed with water (3×30 mL) and brine (30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (1% MeOH/CHCl3) provided 373 mg of 2,6-bis(2-hydroxypropan-2-yl)isonicotinonitrile as a pale orange solid in 32% yield.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(O[K])(C)(C)C>CN1C(=O)CCC1.C(OCC)(=O)C>[C:23]([O:22][C:20]([N:27]1[CH2:32][CH2:31][N:30]([C:2]2[C:3]3[CH2:10][CH2:9][N:8]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:29][CH2:28]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(CN2CCc3c(Cl)ncnc32)cc1
Agent: CC(C)(C)O[K]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN2CCc3c(N4CCN(C(=O)OC(C)(C)C)CC4)ncnc32)cc1
Yield: 57.4 %

Procedure:
A solution of 4-Chloro-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (0.36 g, 1.31 mmol), 1-Boc-piperazine (1.0 g, 5.37 mmol) and tBuOK (0.18 g, 1.60 mmol) in NMP (20 mL) was heated to 128° C. for 20 hours. After cooling, the mixture was diluted with ethyl acetate (500 mL) and washed with water (5×150 mL). The organic phase was dried and concentrated. The residue was subject to column chromatography, eluted by hexane/ethyl acetate (1:1) to give 4-[7-(4-Methoxy-benzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.32 g, 57%). 1H NMR (CDCl3, 400 MHz) δ 8.17 (s, 1H), 7.20 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 4.50 (s, 2H), 3.79 (s, 3H), 3.59 (m, 4H), 3.48 (m, 4H), 3.35 (m, 2H), 3.30 (m, 2H), 1.49 (s, 9H). MS (APCI+) [M+H]+426.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[OH:9]
Reactant: Oc1cc(F)ccc1Cl
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)c(O)cc1F

Procedure:
A solution of 2-chloro-5-fluorophenol (1.5 g) in dichloromethane (50 ml) at 0° C. was treated with nitric acid (70%, 0.7 ml). The cooling bath was removed and after 15 min at room temperature the solution washed with water then dried over MgSO4, filtered and evaporated. The product was crystallised from diethyl ether to yield the title compound, 500 mg.
Reaction SMILES: Cl[CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11].[NH3:12]>C1(C)C=CC=CC=1>[NH2:12][CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11]
Reactant: N
Reactant: CCCC1CC(=O)N(CCl)C1
Solvent: Cc1ccccc1
Product: CCCC1CC(=O)N(CN)C1
Temperature: 25 °C

Procedure:
A solution of 1-chloromethyl-4-propyl-pyrrolidin-2-one (41.34 g, 0.235 mol) in toluene (350 ml) was added dropwise at −78° C. to liquid ammonia (300 ml). At the end of the addition, the temperature was raised slowly to room temperature and ammonia of the crude mixture was allowed to distilled at room temperature overnight. Filtration of the crude solution and subsequent evaporation lead to 55 g of the crude product a27 which was used without further purification.