Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][C:4]([CH3:14])([CH3:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=O.C(Cl)(=O)C(Cl)=O.Cl>ClCCl>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6]([CH2:5][C:4]([CH3:14])([CH3:13])[N:3]=[CH:1]2)=[CH:7][CH:8]=1
Reactant: CC(C)(Cc1ccc(Cl)cc1)NC=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC1(C)Cc2ccc(Cl)cc2C=N1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-formyl-1-(4-chlorophenyl)-2-amino-2-methyl propane (9.36 g, 44.2 mmol) in dichloromethane (400 mL) under nitrogen was added oxalyl chloride (4.25 mL, 48.6 mmol) over 10 minutes. After 1 hour, the reaction was cooled in an ice-salt bath (-5° C.) and then treated with anhydrous ferric chloride (8.62 g, 53.0 mmol). One hour later, the cold bath was removed and the reaction stirred an additional 16 h. The dark reaction was then treated with 2.0M aqueous hydrochloric acid and stirred vigorously for 1 h. The organic layer was removed, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo, to an oil. This oil was dissolved in 1:19 concentrated sulfuric acid:methanol (400 mL) and heated at reflux for 6 h. The reaction was stirred overnight at room temperature, then concentrated in vacuo to about 30 mL. This was transferred to a separatory funnel, diluted with water (300 mL), and washed with ethyl acetate (200 mL). The ethyl acetate layer was extracted with 2.0M aqueous hydrochloric acid (2×100 mL) and the three combined acid layers were made basic with concentrated ammonium hydroxide. This was extracted with dichloromethane (3×200 mL) and the combined extracts were dried (Na2SO4) and concentrated in vacuo to a clear, very slightly colored oil (5.27 g). Rapid chromatography with ethyl acetate gave the title compound with an Rf =0.45, SiO2, (ethyl acetate) as a slightly colored oil (5.22 g). 1H NMR (CDCl3): 8.18 (1H,s), 7.33 (1H, dd, J=2.0, 8.0 Hz), 7.27 (1H, d, J=2.0 Hz), 7.08 (1H, d, J=8.0 Hz), 2.69 (2H, s), 1.24 (6H, s) ppm. 13C NMR (CDCl3): 156.33, 134.03, 132.68, 131.07, 129.59, 128.75, 127.17, 54.94, 37.10, 27.74 ppm.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:25][C:26]1[CH:27]=[N:28][C:29]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]=O)[CH:34]=2)=[N:30][CH:31]=1>[Cl-]>[Cl:25][C:26]1[CH:31]=[N:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]=[C:1]([Br:5])[Br:2])[CH:34]=2)=[N:28][CH:27]=1
Reactant: O=Cc1cccc(Oc2ncc(Cl)cn2)c1
Reactant: BrC(Br)(Br)Br
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Clc1cnc(Oc2cccc(C=C(Br)Br)c2)nc1
Yield: 100.2 %

Procedure:
Carbon tetrabromide (3.32 g) was added with stirring to a solution of triphenylphosphine (5.24 g) in methylne chloride (20 ml) at 20° C. 5-Chloro-2-(3-formylphenoxy)-pyrimidine (1.8 g) was added immediately to the warm orange solution causing the colour to fade rapidly. After 2 hours at 20° C. the reaction mixture was washed with water and then the organic layer was dried and concentrated to a thick syrup. Extraction of this syrup with n-hexane (4×50 ml), followed by evaporation of the n-hexane gave a colourless oil (3 g). The oil was chromatographed on a column of silica gel (50 g) and elution with chloroform gave the title compound, in the first fractions, as a colourless crystalline solid (1.95 g), m.p. 68° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][CH:6]([O:8][CH:9]([CH:49]2[CH:53]([OH:54])[CH:52]([OH:55])[CH:51]([N:56]3[CH:61]=[CH:60][C:59](=[O:62])[NH:58][C:57]3=[O:63])[O:50]2)[CH:10]([C:46]([OH:48])=[O:47])[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:43])[CH3:42])[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])[CH:5]([O:64][CH3:65])[CH:4]1[OH:66].[CH:67](=O)[CH2:68][CH2:69][CH2:70][CH3:71].C([BH3-])#N.[Na+]>CO>[O:63]=[C:57]1[NH:58][C:59](=[O:62])[CH:60]=[CH:61][N:56]1[C@@H:51]1[O:50][C@H:49]([C@H:9]([O:8][CH:6]2[C@H:5]([O:64][CH3:65])[C@@H:4]([OH:66])[C@@H:3]([CH2:2][NH:1][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[O:7]2)[CH:10]([C:46]([OH:48])=[O:47])[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:42])[CH3:43])[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:29])[CH3:30])[C:25]([OH:27])=[O:26])[C@@H:53]([OH:54])[C@H:52]1[OH:55]
Reactant: COC1C(OC(C(NCCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C(=O)O)C2OC(n3ccc(=O)[nH]c3=O)C(O)C2O)OC(CN)C1O
Reactant: CCCCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCNC[C@H]1OC(O[C@H](C(NCCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C(=O)O)[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)[C@H](OC)[C@H]1O
Yield: 13 %

Procedure:
The title compound is prepared by the procedure of Example 17, using 50.0 mg (53 μmol) of 16-({[5-(aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid (λmax nm in water=259) in 0.4 ml of methanol, 4.7 mg (1.0 eq., 55 μmol) of valeraldehyde and 3.3 mg (1.0 eq., 53 μmol) of sodium cyanoborohydride to give 7.0 mg of the desired product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([O:17][CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=2)=[CH:2]1.Cl.[CH3:27][O:28][C:29](=[O:34])[CH:30]([CH2:32][OH:33])[NH2:31].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(N(CC)CC)C>[OH:33][CH2:32][CH:30]([NH:31][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([O:7][CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[CH:9][C:10]=1[O:17][CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:29]([O:28][CH3:27])=[O:34]
Reactant: COC(=O)C(N)CO
Reactant: C[Si](C)(C)CCOCOc1cc(OCc2ccsc2)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(CO)NC(=O)c1ccc(OCc2ccsc2)cc1OCOCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.6 %

Procedure:
A mixture of 4-(3-thienylmethoxy)-2-(2-trimethylsilylethoxymethoxy)benzoic acid (6 g), (RS) serine methyl ester hydrochloride (2.7 g), 1-hydroxybenzotriazole (2.6 g), triethylamine (2.4 mL), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (3.6 g) and DMF (100 mL) is stirred at ambient temperature for 16 hours. The reaction is concentrated in vacuo and the residue partitioned between ethyl acetate (150 mL) and 1N HCl (100 mL). The organic phase is washed with water (2×100 mL) then dried over magnesium sulphate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica eluting initially with a mixture of ethyl acetate and cyclohexane (3:7 v/v) then with a mixture of ethyl acetate and cyclohexane (1:1 v/v). Fractions homogeneous in the required product are combined and evaporated to give methyl (RS)-3-hydroxy-2-[4-(3-thienylmethoxy)-2-(2-trimethylsilylethoxymethoxy)benzoyl]aminopropionate (6.5 g) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[OH-].[Na+].Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>O1CCOCC1>[CH3:8][N:7]([CH3:9])[C:5]([C:4]1[CH:3]=[C:2]([NH:1][C:16](=[O:17])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: CN(C)C(=O)c1cccc(N)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(C)C(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3-amino-N,N-dimethylbenzamide (1.3 g) in 1,4-dioxane(20 ml) was added 1N sodium hydroxide (23.4 ml) and phenyl chloroformate (1.5 ml) successively in an ice-cooled bath. The bath was removed and the reaction mixture was stirred vigorously for 3 hours during which time, phenyl chloroformate (0.7 ml) was further added. The mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated sodium chloride solution. After dried over anhydrous magnesium sulfate and filtered, the solvent was removed in vacuo and the residual oil was purified by flash chromatography eluting with ethyl acetate-n-hexane (2:1, V/V) to give a solid, which was recrystallized from benzene-n-hexane (5:1, V/V) to afford phenyl 3-(dimethylcarbamoyl)phenylcarbamate (1.4 g) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH3:20])=[C:10]([C:21]([NH2:23])=[O:22])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[I:24]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH3:20])=[C:10]([C:21]([NH2:23])=[O:22])[C:9]=2[I:24])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(Cl)cc1-c1[nH]c(-c2ccnc(N)n2)cc1C(N)=O
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1-c1[nH]c(-c2ccnc(N)n2)c(I)c1C(N)=O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 42.9 %

Procedure:
5-(2-Amino-pyrimidin-4-yl)-2-(5-chloro-2-methyl-phenyl)-1H-pyrrole-3-carboxamide (1.1 g, 3.36 mmol) in dry DMF (6 mL) was treated with solid N-iodosuccinimide (830 mg, 3.69 mmol), stirred at room temperature for 4.5 h and poured into iced water (150 mL). The solid was then filtered with suction, washed thoroughly with water, dried in an oven under vacuum at 50° C. and purified by flash chromatography over silica gel (DCM/MeOH/7 N NH3 in MeOH 95/5/0.5) to afford the title compound (654 mg, 43%).
Reaction SMILES: [F:1][C:2]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:3]=1[NH:4][C@H:5]([CH3:9])[C:6]([OH:8])=[O:7].Cl.[CH2:17](O)[CH3:18]>>[F:1][C:2]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:3]=1[NH:4][C@H:5]([CH3:9])[C:6]([O:8][CH2:17][CH3:18])=[O:7]
Reactant: C[C@@H](Nc1ccc(F)c(F)c1F)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@@H](C)Nc1ccc(F)c(F)c1F

Procedure:
(2R)-2-(2,3,4-trifluoroanilino)propionic acid (219 mg; 99% ee) was dissolved in ethanol (2 ml) and hydrochloric acid (5 mol/l; 0.2 ml) was added thereto at room temperature. The liquid reaction mixture was heated under reflux for 6 hours and then the solvent was evaporated. To the obtained residue was added chloroform (10 ml). Next, the organic layer was washed with a saturated aqueous solution of sodium chloride and water and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography (ethyl acetate-normal hexane=1:4) to give the title compound (245 mg) as a pale yellow oily substance. The optical purity of the product was 98% ee. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 7.
Reaction SMILES: [OH:1][N:2]=[CH:3]/[C:4](/[CH3:18])=[CH:5]/[C@@H:6]1[C@@H:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:7]1([CH3:17])[CH3:16].Cl[CH2:20][C:21]#[CH:22].[H-].[Na+].Cl>CN(C=O)C>[CH3:16][C:7]1([CH3:17])[C@H:6](/[CH:5]=[C:4](\[CH3:18])/[CH:3]=[N:2][O:1][CH2:22][C:21]#[CH:20])[C@H:8]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: C/C(C=NO)=C\[C@@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Reactant: C#CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCON=C/C(C)=C/[C@@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
Under nitrogen atmosphere, to a mixture of 0.58 g of t-butyl (1R)-trans-3-[(E)-3-hydroxyimino-2-methyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylate, 0.75 g of 3-chloropropyne and 10 ml of anhydrous DMF was added 88 mg of sodium hydride (60% dispersion in mineral oil), and the mixture was stirred at room temperature overnight. Then, 1 mol/L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, then, filtrated, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.46 g of t-butyl (1R)-trans-2,2-dimethyl-3-[(E)-2-methyl-3-(2-propynyloxyimino)-1-propenyl]cyclopropanecarboxylate:
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2].C1(C)C=CC=CC=1.[CH3:31][S-:32].[Na+]>C(OCC)(=O)C>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:32][CH3:31])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2]
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(F)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CSc1ccc(S(=O)(=O)C[C@@H]2CCCC[C@H]2C(=O)NCC#N)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
trans-N-Cyanomethyl-2-(4-fluorobenzenesulfonylmethyl)-cyclohexanecarboxamide (102 mg) was weighed into a 2.5 mL vial fitted with a stir vane and nitrogen inlet. Anhydrous toluene (1.5 mL) was added, followed by addition of sodium thiomethoxide (22 mg). The reaction mixture was heated to 70° C. and stirred overnight. After cooling to room temperature, the reaction mixture was stirred for two days. The reaction mixture was diluted with ethyl acetate (15 mL), washed with water and brine. The organic layer was removed, dried over magnesium sulfate and concentrated on a rotary evaporator. Chromatography of the crude product on C-18 reverse-phase HPLC provided the title compound as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][C:10]1[N:21](S(C2C=CC=CC=2)(=O)=O)[C:13]2=[N:14][CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=[C:12]2[CH:11]=1.C(OCC)(=O)C>CO.O>[CH3:7][O:8][CH2:9][C:10]1[NH:21][C:13]2=[N:14][CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=[C:12]2[CH:11]=1
Reactant: COCc1cc2cc([N+](=O)[O-])cnc2n1S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COCc1cc2cc([N+](=O)[O-])cnc2[nH]1
Temperature: 60 °C
Yield: 106.6 %

Procedure:
Potassium carbonate (0.306 g, 2.22 mmol) was added to a solution of 2-(methoxymethyl)-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.11 g, 0.317 mmol) in methanol (3.3 mL) and water (0.9 mL). The reaction mixture was heated at 60° C. for 90 minutes. The reaction mixture was then cooled down. The mixture was treated with water and ethyl acetate, and the layers were separated. The organic layers were washed twice with water, dried over sodium sulfate, filtered, and evaporated to afford 2-(methoxymethyl)-5-nitro-1H-pyrrolo[2,3-b]pyridine (70 mg, quantitative yield).
Reaction SMILES: [Br-].[C:2]1([CH2:8][CH2:9][CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=1>C1COCC1.O>[C:2]1([CH2:8][CH2:9][CH:10]=[CH:39][C:36]2[CH:37]=[CH:38][C:33]([C:32]([O:31][CH3:30])=[O:41])=[CH:34][CH:35]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: c1ccc(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C=CCCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° solution of phenylpropyl triphenylphosphonium bromide (3.55 g, 1.25 eq) in 30 ml of dry THF under argon was added K-t-amylate (3.9 ml, 1.1 eq). After stirring for 30 minutes at 0° C. then allowing to warm to room temperature, a solution of 4-formylbenzoic acid methyl ester (1.0 g, 6.1 mmol) in ~8 ml of dry THF was added dropwise. This solution was stirred for 3 hours at room temperature, then diluted with ~1 ml of H2O, and concentrated to remove most of the THF. EtOAc (~200 ml) was added and the mixture was washed with H2O, 1N HCl (2×) and brine. After drying over anhydrous MgSO4, the solvent was removed in vacuo to yield a yellow oil which solidified soon after. Column purification of this crude product was done on a 50 mm column on silica gel eluted with 95:5 hexane/EtOAc. Product containing fractions were combined to yield after concentration title compound, 1.5 g (93%) as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[C:12](=O)[NH:11][N:10]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:10][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2n[nH]c(=O)c3cc(C)ccc23)cc1
Product: COc1ccc(-c2nnc(Cl)c3cc(C)ccc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-(4-methoxyphenyl)-7-methyl-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]#[N:13])[CH2:11][CH2:10]1.C(=O)([O-])[O-:15].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([NH2:13])=[O:15])[CH2:10][CH2:11]1
Reactant: O=C([O-])[O-]
Reactant: N#CC1(c2ccc(Cl)cc2Cl)CC1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)C1(c2ccc(Cl)cc2Cl)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(2,4-Dichloro-phenyl)-cyclopropanecarbonitrile (2.1 g, 10 mmol) was dissolved in DMSO (10 ml) and the solution cooled to 0° C. using an ice bath. Potassium carbonate (0.2 g, 1.5 mmol) was then added, followed by commercial 30% aqueous hydrogen peroxide (2 mL). The reaction was then allowed to warm to room temperature with stirring over 1 h. Water (20 mL) was added and the 1-(2,4-dichloro-phenyl)-cyclopropanecarboxylic acid amide collected as a white solid. Yield: 2.1 g (90%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:26][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:27]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:26])=[O:13])[CH2:8]2
Reactant: CNCc1ccccc1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: CN(Cc1ccccc1)c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccccc1

Procedure:
5-(Benzyl-methyl-amino)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and N-methylbenzylamine. Mass spectrum (ES) MH+=441.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:9]=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>CO>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:4]([OH:5])=[O:3])[N:11]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)n2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
To a solution of 3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-6,1′-dicarboxylic acid 1′-tert-butyl ester 6-ethyl ester (100 mg, 0.3 mmol) in methanol (5 mL) was added aq. solution of sodium hydroxide (2 M, 0.23 mL, 0.5 mmol) at RT. After stirring for 4 h at RT, the solvent was removed, and the residue was dissolved in THF (5 mL), and aq. solution of lithium hydroxide (7 mg in 1 mL of water) was added at RT. After stirring overnight at RT, the solvent was removed and the residue was dissolved in ethylacetate (10 mL) and the reaction mixture was acidified with 2M aq. solution of HCl until pH 2-3. After separation of phases, the aq. layer was re-extracted with ethylacetate (10 mL), and the combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and evaporated under reduce pressure to give 3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-6,1′-dicarboxylic acid 1′-tert-butyl ester (45 mg, 49%), which can be used in the next step without further purification. 1H-NMR (400 MHz, d6-DMSO): δ=1.43 (s, 9H), 1.58-1.68 (m, 2H), 1.81-1.84 (m, 2H), 2.84-2.96 (m, 2H), 3.27-3.39 (m, 1H), 4.07-4.10 (m, 2H), 7.52-7.54 (d, 1H), 7.86-7.92 (m, 2H). MS: m/z=329 (M+23).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:15](=[O:30])[C:16]1[CH:21]=[C:20]([C:22](F)(F)F)N=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1.[CH3:36][S:37](C1C=C(C=C(C(F)(F)F)C=1)C(N(C)C1C=NC=CC=1C1C=CC=CC=1C)=O)(=[O:39])=[O:38].F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:31][C:32]([F:34])([F:33])[F:35])[C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:28])([F:27])[F:29])[CH:22]=[C:20]([S:37]([CH3:36])(=[O:39])=[O:38])[CH:21]=1
Reactant: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reactant: O=C(c1cc(C(F)(F)F)nc(C(F)(F)F)c1)N(CC(F)(F)F)c1cnccc1-c1ccccc1F
Agent: CC[n+]1ccccc1Br
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(C(=O)N(CC(F)(F)F)c2cnccc2-c2ccccc2F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 4-(2-fluorophenyl)-N-(2,2,2-trifluoroethyl)pyridin-3-amine (79 mg, 292 μmol, example 151, intermediate) in CH2Cl2 (2 mL) was added 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (78.4 mg, 292 μmol, example 114, intermediate) and 2-bromo-1-ethylpyridinium tetrafluoroborate (96.1 mg, 351 μmol) and N,N-diisopropylethylamine (75.6 mg, 102 μL, 585 μmol). The reaction mixture was stirred at room temperature for 23 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in 30 mL 1N aqueous HCl and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed with 30 mL 1M aqueous HCl and 30 mL 10% aqueous NaHCO3 and 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography on a 10 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow solid (37 mg, 24%). MS (ESI): m/z=521.076 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].C(N(C(C)C)CC)(C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:8]([C:9]#[N:10])[CH:7]=1)(=[O:26])=[O:25]
Reactant: N#Cc1cccc(COCCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCOCc1cccc(C#N)c1
Reaction time: 2 h

Procedure:
To a solution of 3-[(2-hydroxyethoxy)methyl]benzonitrile (example 28vi) (6.00 g) and diisopropylethylamine (11.8 ml) in dichloromethane (100 ml) at 0° C. was added methanesulphonyl chloride (3.14 ml) dropwise and the mixture allowed to stir for 2 h. The resultant mixture was partitioned between dichloromethane and saturated sodium hydrogen carbonate. The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (8.5 g). LCMS RT=2.58 min.