Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[C:4]([CH3:28])[CH:3]=1.[CH3:29][C:30]1[CH:31]=[C:32](B(O)O)[S:33][CH:34]=1.CC(C)([O-])C.[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:32]4[S:33][CH:34]=[C:30]([CH3:29])[CH:31]=4)=[CH:3][C:4]=3[CH3:28])(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1C
Reactant: Cc1csc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2cc(C)cs2)cc1C
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-2-methylbenzenesulfonamide (E102) (120 mg, 0.26 mmol) and (4-methyl-2-thienyl)boronic acid (73 mg, 0.51 mmol) in DME (3 ml) was added potassium tert-butoxide (263 mg, 2.34 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then evaporated in vacuo and purified using an SCX cartridge eluting with methanol followed by ammonia (2M in methanol). The appropriate fractions were combined and evaporated in vacuo and the residue purified further by mass directed autoprep HPLC to afford the title compound (E108). MS (ES+) m/e 486 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.[C:13]([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)(N1C=CN=C1)=O.[C:25]([C:28]1[CH:33]=[CH:32][C:31](N2CCNCC2)=[CH:30][CH:29]=1)(=[O:27])[CH3:26]>CN(C)C=O>[C:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:20]1[CH2:13][CH2:21][N:22]([C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])[CH2:23][CH2:24]1)(=[O:27])[CH3:26]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1N1CCN(C(=O)c2cccc3cc[nH]c23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution of indole-7-carboxylic acid (3.22 g; 20 mmoles) in 30 ml dimethylformamide was added 1,1'-carbonyldiimidazole (3.24 g; 20 mmoles). This was stirred for 50 minutes at ice bath temperature at which time 4-(4-acetylphenyl)piperazine was added to the reaction. This was stirred for 2 hours at ambient temperature. The solvent was then concentrated off and the resulting oil was triturated with water and filtered to give a solid. The solid was recrystallized from methanol:waterto give 5.31 g (76%) of 4-(4-(Acetylphenyl)-1-(1H-indol-7-ylcarbonyl)piperazine, m.p. 189°-191° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].Cl>>[CH2:24]([N:26]([CH2:27][CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)[CH3:25]
Reactant: CCNCC
Reactant: ClCCCCOc1ccccc1/C=C/c1nc2ccccc2o1
Agent: Cl
Product: CCN(CC)CCCCOc1ccccc1/C=C/c1nc2ccccc2o1
Yield: 12 %

Procedure:
The procedure of Example 18 was followed starting with (D) of Example 18 (2.5 g, 7.6 mmol) and using diethylamine in place of dibutylamine to produce 0.32 g (12% yield) of the named compound as the HCl salt, mp 219°-220° C. IR(KBr): 3400, 1600 cm-1. MS: 365(MH+). 1H NMR (CDCl3): δ 8.25-6.82 (m, 10H), 4.02 (t, J=5.4 Hz, 2H), 3.14 (m, 6H), 1.99 (m, 4H), 1.36 (m, 6H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([Cl:16])=[C:12]([CH:15]=1)[C:13]#[N:14].N1C=CC=CC=1.O>C(Cl)Cl>[Cl:16][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: N#Cc1cc(N)ccc1Cl
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc(Cl)c(C#N)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
A solution of ethyl chloroformate (3.68 g) in methylene chloride (5 ml) is added dropwise in about 20 minutes to a mixture of 5-amino-2-chlorobenzonitrile (5.2 g) and pyridine (2.77 g) in methylene chloride (75 ml), cooled to 0° C. and maintained in an inert atmosphere. At the end of the addition, the solution is stirred for 1 hour at 0° C. and is then brought to room temperature. At the end of the reaction, the mixture is poured into water (100 ml) and extracted with methylene chloride (2×80 ml); the organic phase is washed with water (2×80 ml), dried with sodium sulphate and concentrated under vacuum. 7.2 g of product are obtained.
Reaction SMILES: N1C=C[CH:4]=[CH:3][CH:2]=1.[C:7](Cl)(=O)[CH2:8][CH3:9].[CH2:12]([NH2:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19].C(N)(=O)CCCCCCCCCCCC(N)=O>C1C=CC=CC=1>[CH2:7]([NH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:20][CH2:2][CH2:3][CH3:4])[CH2:8][CH3:9]
Reactant: CCC(=O)Cl
Reactant: c1ccncc1
Reactant: NCCCCCCCN
Agent: NC(=O)CCCCCCCCCCCC(N)=O
Solvent: c1ccccc1
Product: CCCNCCCCCCCNCCC

Procedure:
The intermediate N,N'-di-n-propyl-1,7-heptanediamine was prepared as follows: To a solution containing 43.5 g. of pyridine in 600 ml. of benzene cooled in an ice bath was added dropwise over a period of 10 minutes 51.0 g. of propionyl chloride. To the resulting stirred and cooled solution was added dropwise over a period of 30 minutes 32.5 g. of 1,7-heptanediamine. After the ice bath was removed, the reaction mixture was stirred at room temperature for 20 hours and then filtered to remove a pale yellow solid. The filtrate was evaporated in vacuo. The residual material was combined with the pale yellow solid and the mixture was shaken well with a mixture of 500 ml. of chloroform, 500 ml. of water and 10 ml. of 12N hydrochloric acid. The layers were separated and the acidic aqueous layer was extracted with four 150 ml. portions of chloroform. The combined chloroform extracts were dried over anhydrous potassium carbonate. When the solid separated from the chloroform solution, an additional 750 ml. of chloroform was added. The mixture was heated to boiling and filtered through a sintered glass funnel. The chloroform solution was evaporated in vacuo and the solid residue was recrystallized from 250 ml. of acetonitrile and dried in a vacuum oven at 50° C. to yield 43.1 g. of heptamethylenebis(propionamide), m.p. 132°-133.5° C.
Reaction SMILES: C1(CCC(Cl)=O)CCCC1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[CH:33]1([CH2:38][CH2:39][C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH2:37][CH2:36][CH2:35][CH2:34]1>C1(C)C=CC=CC=1.C(O)C>[CH:33]1([CH2:38][CH2:39][C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37]1.[CH:33]1([CH2:38][CH2:39][C:40]([NH:42][C:43]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([O:25][C:16]3[C:15]4[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=4)[N:19]=[CH:18][N:17]=3)=[CH:27][CH:28]=2)=[S:44])=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(CCC1CCCC1)N=C=S
Agent: O=C(Cl)CCC1CCCC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)CCC4CCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
3-Cyclopentylpropanoyl isothiocyanate was prepared using commercially available 3-cyclopentylpropanoyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-cyclopentylpropanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (37 mg, yield 46%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.Br[CH2:34][CH2:35]Cl.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[F:32][C:2]([F:31])([F:1])[C:3]1[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[N:18]([CH2:39][CH2:38][N:37]4[CH2:35][CH2:34][CH2:40][CH2:41]4)[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: C1CCNC1
Reactant: ClCCBr
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C(=O)N1CCN1CCCC1

Procedure:
(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(2-pyrrolidin-1-ylethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[2,4-bis-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 6), 1-bromo-2-chloroethane and pyrrolidine following General Procedure G.
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][CH3:18])[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:16])[O:4]1)[CH3:2].[H-].[Na+].[CH3:21]I>CN(C=O)C>[CH2:17]([C:3]1([CH2:1][CH3:2])[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[N:6]([CH3:21])[C:5](=[O:16])[O:4]1)[CH3:18]
Reactant: CI
Reactant: CCC1(CC)OC(=O)Nc2ccc([N+](=O)[O-])cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1(CC)OC(=O)N(C)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 4,4-diethyl-6-nitro-1,4-dihydro-2H-3,1-benzoxazin-2-one (5.00 g, 19.98 mmol) in DMF (30 mL) at 0° C. was added sodium hydride (1.20 g-60%, 29.97 mmol). After 20 minutes, methyl iodide (3.8 mL, 61.00 mmol) was added and the reaction was warmed to room temperature. After stirring for one hour, the reaction was quenched with ammonium chloride (sat.) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine repeatedly and dried over magnesium sulfate. Solvent was removed and the residue was triturated with ether to give 4,4-diethyl-1-methyl-6-nitro-1,4-dihydro-2H-3,1-benzoxazin-2-one a yellowish-white solid (3.74 g, 71%). 1H NMR (DMSO-d6): δ 8.27 (dd, J=9.0, 2.6 Hz, 1H), 8.05 (d, J=2.6 Hz, 1H), 7.34 (d, J=9.0 Hz, 1H), 3.37 (s, 3H), 2.15 (m, 4H), 0.80 (t, J=7.3 Hz, 6H); MS (ESI) m/z 265 ([M+H]+); Anal. calcd for C13H16N2O4: C, 59.08; H, 6.10; N 10.60. Found: C, 59.62; H, 6.20; N, 10.48.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[C:9]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=1[CH3:26].[OH-].[Li+]>O1CCOCC1.O>[CH2:12]([CH:11]([NH:10][C:9]1[C:4]([C:3]([OH:27])=[O:2])=[C:5]([O:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[N:6]=[C:7]([CH3:16])[CH:8]=1)[CH2:14][CH3:15])[CH3:13]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)O
Temperature: 25 °C
Yield: 45.7 %

Procedure:
A mixture of 4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)nicotinic acid methyl ester (16 mg, 0.043 mmol) and lithium hydroxide (30 mg) in dioxane (1 ml) and water (1 ml) was stirred at rt over night. The mixture was quenched with water and adjusted to pH 7.0 and extracted with chloroform. The organic layer was dried and concentrated to give the crude material. The crude material was purified through silica gel column chromatography using 10% ethyl acetate in chloroform as eluent to give 7 mg of the title compound as white solid. 1H NMR (CDCl3) δ 9.12 (d, 11H), 6.87 (s, 2H), 6.16 (s, 1H), 3.35 (m, 11H), 2.29 (s, 3H), 2.10 (s, 3H), 2.07 (s, 6H), 1.4-1.6 (m, 4H), 0.94 (t, 6H) ppm.
Reaction SMILES: [C:1]1([N:11]2[C:15](=[S:16])[N:14]=[N:13][NH:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH:25]1[O:27][CH2:26]1.CCN(CC)CC>CO>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH:25]([OH:27])[CH2:26][S:16][C:15]1[N:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:12]=[N:13][N:14]=1
Reactant: S=c1nn[nH]n1-c1cccc2ccccc12
Reactant: Clc1ccccc1CC1CO1
Solvent: CO
Solvent: CCN(CC)CC
Product: OC(CSc1nnnn1-c1cccc2ccccc12)Cc1ccccc1Cl
Yield: 13.7 %

Procedure:
A solution of 1,2-dihydro-1-(1-naphthalenyl)-5H-tetrazole-5-thione (50.0 mg, 0.22 mmol), 2-chloro-1-(2,3-epoxypropyl)benzene (36.9 mg, 0.22 mmol) and Et3N (0.15 mL, 1.10 mmol) in MeOH (5 mL) was heated at reflux for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by HPLC using a gradient of MeCN/H2O containing TFA (0.1%) (CombiPrep ODS-AQ 50×20 mm, 5μ, 120 Å). The pure fractions were concentrated to give the title compound (12 mg, 14% yield) as a colorless solid.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][N:19]([C@@H](C3C=CC=CC=3)C)[CH2:18][C@@H:17]2[OH:30])=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>>[ClH:1].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]2[OH:30])=[CH:12][CH:11]=1
Reactant: [H][H]
Reactant: C[C@H](c1ccccc1)N1CC[C@H](c2ccc(OCc3ccccc3)cc2)[C@@H](O)C1
Agent: Cl
Product: Oc1ccc([C@H]2CCNC[C@@H]2O)cc1

Procedure:
reacting (3R,4R)-4-(4-benzyloxy-phenyl)-1-((R)-1-phenyl-ethyl)-piperidin-3-ol hydrochloride with hydrogen to yield (3R,4R)-4-(4-hydroxy-phenyl)-piperidin-3-ol hydrochloride;
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)#[CH:2].[N-:10]=[N+:11]=[N-:12].[Na+].IC.[Na].O=[C:18]1O[C@H]([C@H](CO)O)C(O)=C1O>O.ClCCl.[Cu]I>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]2[N:10]=[N:11][N:12]([CH3:18])[CH:2]=2)=[CH:4][CH:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C#Cc1ccc(F)cc1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: [Cu]I
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CI
Solvent: ClCCl
Product: Cn1cc(-c2ccc(F)cc2)nn1
Temperature: 75 °C
Yield: 286.4 %

Procedure:
The reaction mixture was splitted in 24 tubes of 1.00 g (8.32 mmol) each. A mixture of 1-ethynyl-4-fluorobenzene (24.0 g, 200 mmol), sodium azide (14.41 g, 222 mmol), iodomethane (14.93 mL, 240 mmol), copper(I) iodide (8.03 g, 42 mmol) and L-(+)-ascorbic acid sodium salt (7.84 g, 40 mmol) in water (240 mL) was heated at 75° C. for 10 h. The mixture was then diluted with dichloromethane (25 mL) and filtered off. The aqueous layer of the filtrate was extracted with dichloromethane and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 5% methanol in dichloromethane) afforded the title compound (20.3 g, 57%) as a white solid after recrystallisation from ethyl acetate-heptane. MS: m/e=178.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([OH:12])[CH3:11].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([O:12][S:22]([CH3:21])(=[O:24])=[O:23])[CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)C(=O)c1ccc(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)C(=O)c1ccc(F)cc1F
Reaction time: 0.25 h

Procedure:
2',4'-Difluoro-2-hydroxypropiophenone (2.8 g) was dissolved in methylene chloride (28 ml), to which were added triethylamine (2.5 ml) and methanesulfonyl chloride (1.3 ml) at 0° C. After stirring for 15 minutes, the mixture was washed with water (30 ml), and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (3 cm×10 cm) and eluted with methylene chloride. The desired fraction was concentrated, to give 2',4'-difluoro-2-methanesulfonyloxypropiophenone (3.0 g) as a colorless oil. This compound (3.0 g) was dissolved in 30 ml of N,N-dimethylformamide, to which were added 1H-1,2,4-triazole (0.94 g) and then 60% sodium hydride suspension in oil (0.5 g) at -10° C. After stirring at 0° C. for 50 minutes, the reaction mixture was added to a mixture of ethyl acetate (100 ml) and water (200 ml) for extraction. The water layer was extracted with ethyl acetate (100 ml) and the ethyl acetate layers were combined, washed with saturated aqueous solution of sodium chloride (30 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (3 cm×10 cm) and eluted with ethyl acetate. The desired fraction was concentrated, to give 2',4'-difluoro-2-(1H-1,2,4-triazol-1-yl)propiophenone (1.5 g) as a colorless oil. This compound (1.24 g) was added to a mixture of dimethyl sulfoxide (30 ml), 60% sodium hydride suspension in oil (0.25 g) and trimethylsulfoxonium iodide (1.38 g) at 10° C. and then the temperature was raised to 25° C. Two hours later, the reaction mixture was added to a mixture of diethyl ether (100 ml) and water (150 ml), diethyl ether layer was separated, and the water layer was extracted with diethyl ether (100 ml×2). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (3 cm×10 cm) and eluted with ethyl acetate-hexane (3:1), to give 2-(2,4-difluorophenyl)-2-[1-(1H-1,2,4-triazol-1-yl)ethyl]oxirane as a colorless oil (0.87 g).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]([NH2:11])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[Si](C)(C)C.CC([Mg]Cl)C.[CH2:22]([O:24][C:25]([CH:27]1[CH2:29][CH:28]1[CH:30]=[O:31])=[O:26])[CH3:23]>C1COCC1>[CH2:22]([O:24][C:25]([CH:27]1[CH2:29][CH:28]1[CH:30]([C:2]1[N:10]2[C:5]([C:6]([NH2:11])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[OH:31])=[O:26])[CH3:23]
Reactant: CCOC(=O)C1CC1C=O
Reactant: Nc1ncnn2c(Br)ccc12
Agent: CC(C)[Mg]Cl
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1CC1C(O)c1ccc2c(N)ncnn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.3 %

Procedure:
To a stirred solution of 7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (5.27 g, 24.7 mmol) in anhydrous THF (40 mL) was added chlorotrimethylsilane (5.9 g, 54.4 mmol) at rt. The reaction mixture was stirred at rt for 2 hours and cooled in an ice water bath. 2-propylmagnesium chloride in THF (52 mL, 104 mmol, 2.0 M) was added dropwise, and the reaction mixture was allowed stirred at rt for 2 hours. The reaction was cooled to 0° C. with an ice bath, and 2-formyl-cyclopropanecarboxylic acid ethyl ester (4.6 g, 32 mmol) was added. The reaction mixture was stirred at rt for 1 hour. The mixture was quenched with saturated, aqueous ammonium chloride (20 mL) In ice water bath. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with water, brine, dried by Na2SO4, filtered and concentrated. The crude product was separated by column (30% EtOAc/70% Hexane) to give 2.0 g (30%) of product. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.75 (bs, 2 H), 6.80 (s, 1 H), 6.60 (m, 1 H), 5.40 (s, 1 H), 5.0-4.8 (m, 1 H), 4.0 (m, 2 H), 1.9-1.8 (m, 2 H), 1.2 (t, 3 H), 1.0 (m, 2 H); ES-MS m/z 277.34 [M+H]+, HPLC RT (min) 1.51.
Reaction SMILES: [Li+].[Cl-].C(COC)OC.Br[C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].[C:18]1([CH3:26])[CH:23]=[CH:22][C:21]([Mg]Cl)=[CH:20][CH:19]=1>O1CCCC1>[C:18]1([CH3:26])[CH:23]=[CH:22][C:21]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:20][CH:19]=1
Reactant: N#Cc1ccccc1Br
Reactant: Cc1ccc([Mg]Cl)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of MnCl2 (0.25 g, 1.98 mmol) and LiCl (0.17 g, 3.955 mmol) in a mixture of 2 ml of anhydrous tetrahydrofuran and 0.38 ml of dimethoxyethane (3.955 mol) is stirred at room temperature until, after approximately 30 minutes, a homogeneous medium is obtained. The PdCl2/dppp complex (0.0023 g, 0.1 mol %) and the o-bromobenzonitrile (0.72 g, 3 955 mmol) are then added and then a solution of p-tolylmagnesium chloride in tetrahydrofuran (1.80N, 2.86 ml, 5.14 mmol) is added over 30 minutes. After stirring for 30 minutes, the reaction mixture is treated as described in Example 4. The o-(p-tolyl)benzonitrile is thus obtained with a yield of isolated product of 95%.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([C:18]3[CH:19]=[C:20]([N:24]([CH3:29])[C:25](=[O:28])[CH2:26]Br)[CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:15]=[N:14][C:13]=12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][NH:31][CH3:32].C.CCCCCC>C(O)C>[C:1]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([C:18]3[CH:19]=[C:20]([N:24]([CH3:29])[C:25](=[O:28])[CH2:26][N:31]([CH3:32])[CH3:30])[CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:15]=[N:14][C:13]=12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C(=O)CBr)c1cccc(-c2ccnc3c(C(=O)c4ccccc4)cnn23)c1
Reactant: CNC
Solvent: CCO
Solvent: CCCCCC
Product: CN(C)CC(=O)N(C)c1cccc(-c2ccnc3c(C(=O)c4ccccc4)cnn23)c1
Temperature: -10 °C
Reaction time: 16 h

Procedure:
A suspension of 1.7 g of N-[3-(3-benzoylpyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-2-bromo-N-methylacetamide in 100 ml of ethanol was treated with gaseous dimethylamine until a solution resulted. This was then placed in a pressure bottle and kept at room temperature for 16 hours. The ethanol was removed in vacuo and the residue partitioned between 50 ml of saturated aqueous sodium bicarbonate solution and 100 ml of methylene chloride. The methylene chloride layer was separated, dried over magnesium sulfate, and the methylene chloride removed in vacuo. The residue was dissolved in 50 ml of methylene chloride, the solution then treated with hexane at the boiling point until turbidity was present. Cooling at -10° C. gave a low yield of tacky solid. The cold mixture was treated with activated charcoal, clarified and the filtrate again treated at the boiling point with hexane until turbidity occurred. Cooling at -10° C. gave 0.3 g of the desired compound as a bright yellow solid, mp 166°-168° C.
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4]([C:6]1[CH:11]=[C:10](Cl)[N:9]=[C:8]([Cl:13])[N:7]=1)=[O:5]>CS(C)=O>[CH3:2][O:3][C:4]([C:6]1[CH:11]=[C:10]([NH2:1])[N:9]=[C:8]([Cl:13])[N:7]=1)=[O:5]
Reactant: N
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Solvent: CS(C)=O
Product: COC(=O)c1cc(N)nc(Cl)n1
Yield: 79 %

Procedure:
Ammonia was slowly bubbled through a solution of 2,6-dichloro-pyrimidine-4-carboxylic acid methyl ester (20.0 g, 97 mmol, see H. Gershon, J. Org. Chem. 1962, 27, 3507-3510 for preparation) in DMSO (100 mL) cooled with an ice bath to maintain the temperature below 70° C. When the temperature of the reaction solution began to decline, no additional ammonia was added. When the temperature of the reaction solution reached 44° C., the ice bath was removed. When the temperature of the reaction solution reached 32° C., the reaction mixture was diluted with 200 mL of water and filtered. The filtered product was washed with water, washed with ethyl acetate, and dried under vacuum to provide the title compound (14.4 g, 79% yield) that was used without further purification. Flash chromatography on silica gel yielded an analytically pure sample of the title compound: 1H NMR (DMSO-d6) δ 7.7 (br s, 2H), 7.00 (s, 1H), 3.84 (s, 3H).