Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][C:3](Cl)=[O:4].[CH:8]1([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([F:27])(=[O:26])=[O:25])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CO>C(Cl)(Cl)Cl>[CH:8]1([N:14]2[C:3](=[O:4])[CH2:2][C:1](=[O:6])[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24]([F:27])(=[O:26])=[O:25])[C:15]2=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: O=C(Nc1ccccc1S(=O)(=O)F)NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C1CC(=O)N(C2CCCCC2)C(=O)N1c1ccccc1S(=O)(=O)F
Yield: 76.3 %

Procedure:
Malonyldichloride (168 g, 1.2 mole) was added with stirring to N-cyclohexyl-N'-(2-fluorosulphonylphenyl)urea (270 g, 0.9 mole) in dry chloroform (1500 ml). This mixture was heated for 6 hours at 40°-50° C. and then cooled below 20° C., whereupon 300 ml of methanol were added cautiously. The reaction mixture was then evaporated under reduced pressure yielding 253 g of 1-cyclohexyl-3-(2-fluorosulphonylphenyl)barbituric acid. This sulphofluoride was converted into the sulphonamide as described under b) with a nearly quantitative yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([Br:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[O:14][CH3:15].[N+:16]([O-])([OH:18])=[O:17].ClCCl.O>ClCCl>[OH:1][C:2]1[C:7]([N+:16]([O-:18])=[O:17])=[CH:6][C:5]([C:8](=[O:13])[C:9]([Br:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)C(C)(C)Br)ccc1O
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(=O)C(C)(C)Br)cc([N+](=O)[O-])c1O

Procedure:
To a solution of 4'-hydroxy-3'-methoxy-2-bromoisobutyrophenone (10.0 g) in dichloromethane (80 ml) was gradually added 2M HNO3 -dichloromethane (19 ml). The mixture was stirred for 2 hours at 10° C. after which water (100 ml) was added. The organic phase was separated, dried over Na2SO4 and evaporated to dryness. Ether (20 ml) was added. The resulting crystals were filtered and washed with ether. Yield 3.3 g.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9]([O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)([CH3:11])[CH3:10]>>[CH:9]1([O:12][C:13]2[CH:14]=[C:15]([C:2]3[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:11][CH2:10]1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)Oc1cccc(B(O)O)c1
Product: Nc1ccc(-c2cccc(OC3CC3)c2)cc1
Yield: 7.5 %

Procedure:
The title compound (98 mg) was prepared from 4-bromoaniline (1 g, 5.81 mmol) and 3-isopropoxyphenylboronic acid (1.96 g, 7.55 mmol) as a yellow liquid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([NH:12][C:13]([CH3:15])=[O:14])=[CH:9][CH:10]=2)[C:5](=[O:19])[NH:4][C:3]1=[O:20].[C:22](=O)(O)[O-].[Na+]>C(OC(=O)CC)(=O)CC>[CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([NH:12][C:13](=[O:14])[CH2:15][CH3:22])=[CH:9][CH:10]=2)[C:5](=[O:19])[NH:4][C:3]1=[O:20]
Reactant: CC(=O)Nc1ccc2c(c1[N+](=O)[O-])C(=O)NC(=O)C2(C)C
Reactant: O=C([O-])O
Agent: CCC(=O)OC(=O)CC
Agent: [Na+]
Product: CCC(=O)Nc1ccc2c(c1[N+](=O)[O-])C(=O)NC(=O)C2(C)C
Temperature: 0 °C

Procedure:
29.1 gm of 4,4-dimethyl-7-acetamino-8-nitro-2H,4H-isoquinoline-1,3-dione were refluxed for 4 hours with 50 ml of propionic acid anhydride. The mixture was then poured into ice water and neutralized with sodium bicarbonate. The obtained precipitate was purified on a silicagel column (eluant: chloroform/acetone 19:1).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:15][C:14]3[C:9](=[C:10]([CH3:23])[CH:11]=[C:12]([C:16]4[O:20][N:19]=[C:18]([CH2:21]Cl)[N:17]=4)[CH:13]=3)[C:8]2=[O:24])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(OC([N:40]1[CH2:45][C@@H:44]2[CH2:46][C@H:41]1[CH2:42][NH:43]2)=O)(C)(C)C>CC#N.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:15][C:14]3[C:9](=[C:10]([CH3:23])[CH:11]=[C:12]([C:16]4[O:20][N:19]=[C:18]([CH2:21][N:40]5[CH2:45][CH:44]6[CH2:46][CH:41]5[CH2:42][NH:43]6)[N:17]=4)[CH:13]=3)[C:8]2=[O:24])=[CH:25][CH:26]=1
Reactant: Cc1cc(-c2nc(CCl)no2)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(-c2nc(CN3CC4CC3CN4)no2)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Temperature: 60 °C
Yield: 58.3 %

Procedure:
To a solution of 2-(4-chloro-benzyl)-5-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-7-methyl-2,3-dihydroisoindol-1-one (40 mg, 0.103 mmol) in MeCN (4 mL) was added K2CO3 (0.309 mmol) and (1s,4s)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (31 mg, 0.154 mmol). The mixture was heated at 60° C. overnight. The reaction was cooled and diluted with water, then extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. Column chromatography on silica (1% 2M NH3 in MeOH/CH2Cl2) provided 2-(4-chlorobenzyl)-5-[3-(2,5-diazabicyclo[2.2.1]hept-2-ylmethyl)-[1,2,4]oxadiazol-5-yl]-7-methyl-2,3-dihydroisoindol-1-one as a brown solid (27 mg). 1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H), 7.99 (s, 1H), 7.37 (d, 2H), 7.26 (d, 2H), 4.77 (s, 2H), 4.30 (s, 2H), 3.94 (dd, 2H), 3.58 (d, 2H), 3.26 (d, 1H), 3.11 (d, 1H), 2.89 (d, 1H), 2.84 (s, 3H), 2.63 (d, 1H), 1.88 (d, 1H), 1.66 (d, 1H).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([Cl:32])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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>[Cl:32][C:26]1[CH:25]=[C:24]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:7]=2)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
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: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2ccc(C#N)c(Cl)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 69 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.20 g, Example 33), 4-bromo-2-chlorobenzonitrile (0.288 g), 2M aqueous sodium carbonate (0.76 ml) and tetrakis(triphenylphosphine)palladium (0) (0.075 g) in ethanol (5 ml) with heating at 90° C. for 4 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil (0.18 g).
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[F:22])/[N:7]([CH2:24][CH2:25][OH:26])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C.C(=O)(OC(Cl)(Cl)Cl)[O:36][C:37](Cl)(Cl)[Cl:38]>CCOCC>[C:37]([Cl:38])(=[O:36])[O:26][CH2:25][CH2:24][N:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[S:9]/[C:8]/1=[N:10]\[C:11](=[O:23])[C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:15]=[CH:14][C:13]=1[F:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cn(CCO)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)c1cn(CCOC(=O)Cl)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Reaction time: 2 h
Yield: 195.6 %

Procedure:
To a solution of Example 61A (300 mg, 0.768 mmol) and triethylamine (233 mg, 2.305 mmol) in Et2O (5 mL) was added activated charcoal (10 mg, 0.768 mmol), followed by addition of bis(trichloromethyl) carbonate (114 mg, 0.384 mmol) and the mixture was stirred for 2 hr. The reaction was filtered, and concentrated to give the title compound as an oil (340 mg, 0.751 mmol, 98%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.33 (s, 9H) 3.80 (t, J=5.43 Hz, 2 H) 4.27 (t, J=5.43 Hz, 2 H) 7.32 (s, 1 H) 7.46-7.56 (m, 1 H) 7.88-7.97 (m, 1 H) 8.24-8.33 (m, 1 H); MS (DCI) m/z 453 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:13])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH3:20][C:21]1[S:22][C:23]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][C:25]=1[CH3:26].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl.CN(C)C=O>[CH2:27]([C:23]1[S:22][C:21]([CH3:20])=[C:25]([CH3:26])[C:24]=1[C:5]([C:4]1[CH:8]=[C:9]([CH3:13])[C:10]([O:11][CH3:12])=[C:2]([CH3:1])[CH:3]=1)=[O:7])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1cc(Cc2ccccc2)sc1C
Reactant: COc1c(C)cc(C(=O)O)cc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C)cc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1C
Temperature: -78 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a suspension of 3,5-dimethyl-p-anisic acid (15.2 g, 84.4 mmol, RN-21553-46-8) in anhydrous methylene chloride (200 mL) at room temperature under nitrogen was added oxalyl chloride (9.6 mL, 110 mmol) and N,N-dimethylformamide (5 drops). After two hours the solvent was removed. The resulting residue was dissolved in anhydrous methylene chloride (200 mL), and added to 2,3-dimethyl-5-benzylthiophene (17.1 g, 84.4 mmol) under nitrogen. The resulting mixture was, cooled to −78° C., and tin(IV) chloride (10.8 mL, 92.8 mmol) was added quickly. The −78° C. bath was removed and the mixture was stirred at room temperature for 2 h. The reaction mixture was then poured onto ice water (1 L), and the resulting mixture was extracted once with diethyl ether (700 mL), and a second time with diethyl ether (400 mL). The combined diethyl ether extracts were washed with ice water(500 mL), dilute sodium bicarbonate (500 mL), water (500 mL), brine (mL), and then dried (Na2SO4). Concentration under reduced pressure gave the title compound as a yellow oil (25.2 g, 82%): NMR (DMSO-d6): δ 7.40 (s, 2H), 7.24-7.15 (m, 3H), 7.06 (d, 2H), 3.83 (s, 2H), 3.70 (s, 3H), 2.28 (s, 3H), 2.26 (s, 6H), 1.83 (s, 3H).
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([O-:13])=[O:12].C(O)(=O)C.[BH4-].[Na+]>CO>[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:6][C:5]2[CH:7]=[CH:8][C:9]3[O:10][CH2:1][O:2][C:3]=3[CH:4]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: Nc1ccc2c(c1)OCO2
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1ccc(CNc2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3,4-methylenedioxyaniline (10 mmol) and 4-nitrobenzaldehyde (10 mmol) in methanol is stirred at ambient temperature for 18 hours. The precipitate obtained is filtered off and washed and then dissolved in tetrahydrofuran. After the addition of acetic acid and sodium borohydride (25 mmol), the reaction mixture is stirred at ambient temperature for 1 hour, then the solvent is evaporated off and the crude residue is purified by chromatography on silica using dichloromethane as eluant.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([C@:15]12[CH2:23][CH2:22][C@@H:21]3[C@@H:24]4[C:29]([CH2:30][CH2:31][C@H:20]3[C@@H:19]1[CH2:18][CH2:17][C@@H:16]2[OH:33])=[CH:28][C:27](=[O:32])[CH2:26][CH2:25]4)[CH3:14]>N1C=CC=CC=1.Cl>[CH2:13]([C@:15]12[CH2:23][CH2:22][C@@H:21]3[C@@H:24]4[C:29]([CH2:30][CH2:31][C@H:20]3[C@@H:19]1[CH2:18][CH2:17][C@@H:16]2[O:33][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:28][C:27](=[O:32])[CH2:26][CH2:25]4)[CH3:14]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12CC
Reaction time: 8 h
Yield: 50.1 %

Procedure:
Add decanoyl chloride (1.9 g.) to 13β-ethyl-17β-hydroxy-gon-4-en-3-one (1.3 g.) in pyridine (12.5 cc.) and allow the mixture to stand at room temperature overnight. Pour the mixture in 2N hydrochloric acid and extract with ether. Wash, dry and evaporate the extracts and recrystallize the residue from benzene-hexane to give the title compound (1.0 g.), m.p. 97°-97.5°; ultraviolet absorption peak at 239 mμ (ε16,500); infrared absorption peaks at 5.74; 5.99, 6.17 μ.
Reaction SMILES: [CH2:1]([C:4](=[CH2:8])[C:5]([OH:7])=[O:6])[CH2:2][CH3:3].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](I)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](/[CH:8]=[C:4](\[CH2:1][CH2:2][CH3:3])/[C:5]([OH:7])=[O:6])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: C=C(CCC)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)I)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC/C(=C\S(=O)(=O)c1ccc(C)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
2-Propylacrylic acid (5.0 g, 43.80 mmol) was added to a solution of toluene-4-sulfonyl iodide (14.32 g, 65.70 mmol) in dichloromethane (100 ml). The solution was stirred overnight at room temperature and then cooled to 0° C. Triethylamine (12.2 ml, 87.6 mmol) was added and the solution was stirred for 1 hour then allowed to warm to room temperature over 2 hours. The organic solution was washed with water (100 ml), 1N hydrochloric acid ((100 ml) 10% aqueous sodium bisulfite (50 ml), then extracted with sodium hydroxide (5 g) in water (100 ml). The aqueous layer was washed with ethyl acetate (20 ml) and then acidifed with conc. sulfuric acid (3 ml). The product was extracted into ethyl acetate (2×50 ml) and the combined organic layers were washed with brine (20 ml), dried over magnesium sulfate, filtered and evaporated to give the title compound in 85% yield. This yellow solid was dissolved in methanol (100 ml ) and stirred with activated charcoal (1 g). Filtration and evaporation gave a pale yellow solid which was slurried in dichloromethane:heptane 20:80. Filtration gave the title compound as white crystals (8.3 g, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:18]([O:22][C:23]([N:25]1[C@@H:29]([CH3:30])[CH2:28]OS1(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:24])[NH:25][C@@H:29]([CH3:28])[CH2:30][N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH:17]=2)[CH:13]=[CH:14]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1ccc(-c2ccc3cc[nH]c3c2)cc1
Reactant: C[C@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C
Product: COc1ccc(-c2ccc3ccn(C[C@H](C)NC(=O)OC(C)(C)C)c3c2)cc1

Procedure:
This compound was synthesized from 6-(4-methoxy-phenyl)-indole (synthesized from 6-bromo-indole according to Carrera, G. M. et al. Synlett 1994, 1, 93-94) and (S)-4-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester as described in example 4, step A1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([OH:6])=O.[CH3:13][O:14][C:15]1[CH:43]=[CH:42][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([NH2:25])[C:22]([C:26]3[NH:30][C:29]4[CH:31]=[CH:32][C:33]([CH2:35][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[CH:34][C:28]=4[N:27]=3)=[N:21]2)=[CH:17][CH:16]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([NH:25][C:23]1[C:22]([C:26]2[NH:30][C:29]3[CH:31]=[CH:32][C:33]([CH2:35][N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[CH:34][C:28]=3[N:27]=2)=[N:21][N:20]([CH2:19][C:18]2[CH:42]=[CH:43][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH:24]=1)=[O:6]
Reactant: COc1cccc(F)c1C(=O)O
Reactant: COc1ccc(Cn2cc(N)c(-c3nc4cc(CN5CCOCC5)ccc4[nH]3)n2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(NC(=O)c3c(F)cccc3OC)c(-c3nc4cc(CN5CCOCC5)ccc4[nH]3)n2)cc1
Yield: 116.8 %

Procedure:
A mixture of 2-fluoro-6-methoxy-benzoic acid (20 mg, 0.12 mmol), 1-(4-methoxy-benzyl)-3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (50 mg, 0.12 mmol), EDC (116 mg, 0.14 mmol) and HOBt (81 mg, 0.14 mmol) was stirred at room temperature in DMF (2 ml) for 20 h. The mixture was reduced in vacuo and the residue partitioned between EtOAc (5 ml) and water (2 ml) and the organic portion washed with saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and reduced in vacuo. The residue was purified by flash column chromatography [SiO2, EtOAc] to give 2-fluoro-6-methoxy-N-[1-(4-methoxy-benzyl)-3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide as a white solid (80 mg, 61%).
Reaction SMILES: CC(CC(O)=O)=O.[CH3:8][C:9]1[N:10](C(OCC(C)C)=O)[C:11]2[C:12]([N:28]=1)=[N:13][CH:14]=[C:15]([C:17]1[CH:18]=[CH:19][C:20]3[O:26][CH2:25][CH2:24][NH:23][CH2:22][C:21]=3[CH:27]=1)[CH:16]=2.Cl[C:37]1[C:42]([CH2:43][CH3:44])=[C:41]([CH3:45])[N:40]=[C:39]([CH2:46][N:47]([CH3:49])[CH3:48])[N:38]=1>>[CH2:43]([C:42]1[C:41]([CH3:45])=[N:40][C:39]([CH2:46][N:47]([CH3:49])[CH3:48])=[N:38][C:37]=1[N:23]1[CH2:22][C:21]2[CH:27]=[C:17]([C:15]3[CH:16]=[C:11]4[N:10]=[C:9]([CH3:8])[NH:28][C:12]4=[N:13][CH:14]=3)[CH:18]=[CH:19][C:20]=2[O:26][CH2:25][CH2:24]1)[CH3:44]
Reactant: Cc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2n1C(=O)OCC(C)C
Reactant: CCc1c(C)nc(CN(C)C)nc1Cl
Agent: CC(=O)CC(=O)O
Product: CCc1c(C)nc(CN(C)C)nc1N1CCOc2ccc(-c3cnc4[nH]c(C)nc4c3)cc2C1

Procedure:
Prepared as a diacetate salt by the method of example 6 using 2-methylpropyl 2-methyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate and 1-(4-chloro-5-ethyl-6-methylpyrimidin-2-yl)-N,N-dimethylmethanamine (reagent preparation 17) in step 3. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (br s, 1H), 8.03 (br s, 1H), 7.67 (d, 1H), 7.52 (dd, 1H), 7.02 (d, 1H), 4.63 (s, 2H), 4.35-4.30 (m, 2H), 3.83-3.78 (m, 2H), 3.32 (s, 2H), 2.65-2.57 (m, 1H), 2.54 (s, 3H), 2.52-2.45 (m, 1H (buried)), 2.36 (s, 3H), 2.10 (s, 6H), 1.86 (s, 8H), 1.15 (t, 3H); MS (EI) for C28H31N7O: 458 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[H-].[Na+].[CH3:11][OH:12]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:12][CH3:11])[CH:5]=[N:4][CH:3]=1
Reactant: CO
Reactant: Brc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cncc(Br)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a suspension of 12 g of 3,5-dibromopyridine and 40 g of 60% NaH in DMF was added 4.05 mL of methanol, and the reaction mixture was stirred for 4 hours at room temperature and 1 hour at 60° C. The DMF was removed under reduced pressure, and the residue was taken directly to the next step. MS (DCI/NH3) m/e 188/190 (M+H)+, 205/207 (M+NH4)+. 1H NMR (CDCl3, 300 MHz) δ: 8.32 (d, J=1.8 Hz, 1H, 8.27 (d, J=2.6 Hz, 1H), 7.42 (dd, J=1.8, 2.6 Hz, 1H), 3.88 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([S:11][CH2:12][CH2:13][CH:14]=[C:15]([F:17])[F:16])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:18](Cl)(=[O:21])[CH2:19][CH3:20].C(N(CC)CC)C>ClCCl>[O:21]=[C:18]([NH:1][C:2]1[C:7]2[N:8]=[C:9]([S:11][CH2:12][CH2:13][CH:14]=[C:15]([F:17])[F:16])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:19][CH3:20]
Reactant: Nc1cccc2oc(SCCC=C(F)F)nc12
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1cccc2oc(SCCC=C(F)F)nc12
Reaction time: 2 h

Procedure:
To a stirred solution of 4-amino-2-(4,4-difluorobut-3-enylthio)benzoxazole (Compound No 80, Example 4B(iv), 255 mg) in dichloromethane (2 cm3) and propionyl chloride (102 mg) at the ambient temperature was added dropwise triethylamine (120 mg) and the reaction stirred for 31/2 hours, after which gc analysis indicated complete consumption of starting material. The reaction mixture was poured into ethyl acetate and water and the phases separated. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers washed with water and brine and then dried (MgSO4). Filtration and evaporation under reduced pressure gave a brown oil. Purification by silica gel chromatography using 30% t-butyl methyl ether in hexane as the eluent gave 4-(1-oxopropylamino)-2-(4,4-difluorobut-3-enylthio)benzoxazole as a pale yellow oil (124 mg). 1H NMR (DMSO): δ8.28(1H,d); 7.97(1H, b); 7.24(1H,t); 7.16(1H,d); 4.32(1H, ddt); 3.33(2H,t); 2.55(4H,m); 1.29(3H,t).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[NH:22][CH:23]=[CH:24]4)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(Br)cnc32)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a stirred suspension of 5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.35 g, 0.73 mmol) and 1H-indol-5-ylboronic acid (0.14 mg, 0.88 mmol) in CH3CN (10 mL) was added 1 M Na2CO3 (10 mL) followed by bis(triphenylphosphine)palladium(II) dichloride (0.050 g, 0.071 mmol). The resulting mixture was stirred overnight at 60° C. After the mixture was evaporated to dryness in vacuo, it was dissolved in DMF (3 mL), absorbed onto Celite, and dried. The residue was purified via silica gel chromatography using CH2Cl2 as the eluent to obtain the title compound (0.26 g, 76%). 1H NMR (CDCl3, 300 MHz): δ 8.48 (d, J=2.1 Hz, 1H), 8.27 (bs, 1H), 8.26 (d, J=2.4 Hz, 1H), 8.08 (d, J=8.1 Hz), 7.85 (s, 1H), 7.81 (m, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.37 (dd, J=1.8, 8.4 Hz), 7.30 (m, 3H), 6.63 (m, 1H), 2.39 (s, 3H); MS ESI (m/z): 466.2/468.2 (M+1)+, calc. 465.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([O:14][CH3:15])=[C:7](I)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:3])[CH3:2].[C:16]([C:18]1[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=1)#[CH:17]>CC#N.CCN(CC)CC.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>[CH3:15][O:14][C:6]1[C:7]([C:17]#[C:16][C:18]2[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=2)=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]=1[O:4][C:1](=[O:3])[CH3:2]
Reactant: COc1ccc(I)c(OC)c1OC(C)=O
Reactant: C#Cc1cncn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2cncn2C)c(OC)c1OC(C)=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
To a stirred solution of 3-acetoxy-2,4-dimethoxy-iodobenzene (250 mg, 0.776 mmol) and 5-ethynyl-1-methyl-1H-imidazole (100 mg, 1.09 mmol) in dry MeCN (3 ml) and dry NEt3 (1 ml) was added Pd(Ph3P)2Cl2 (20 mg, 3.7 mol %) and the reaction vessel was evacuated and backfilled with N2 (g) three times. Copper (I) iodide (15 mg) was added and the reaction was heated to 60° C. and stirred overnight. The resulting dark solution was cooled, diluted with EtOAc and filtered through celite. The filtrate was concentrated onto silica-gel under reduced pressure and the solid residue was purified by flash chromatography (silica-gel, eluted with EtOAc) to give the product as a tan solid (130 mg, 56%). 1H-NMR (300 MHz, CDCl3) δ 7.45 (br s, 1H), 7.30 (d, J=8.7 Hz, 1H), 7.30 (br s, 1H), 6.68 (d, J=8.7 Hz, 1H), 3.94 (s, 3H), 3.83 (s, 3H), 3.71 (s, 3H), 2.33 (s, 3H).