Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[N:11]([CH3:20])[C:10]=2[CH:21]=1.[C:25]([C:27]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34])([CH3:29])[CH3:28])#[N:26].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:25]([C:27]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([NH:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:13]=[C:12]([NH:14][C:15]([CH:17]4[CH2:19][CH2:18]4)=[O:16])[N:11]([CH3:20])[C:10]=3[CH:21]=2)[CH:3]=1)=[O:34])([CH3:29])[CH3:28])#[N:26]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: Cn1c(NC(=O)C2CC2)nc2ccc(Oc3cccc(N)c3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: Cn1c(NC(=O)C2CC2)nc2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)cc21
Yield: 38.3 %

Procedure:
Using N-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-yl]cyclopropanecarboxamide (166 mg, 514.3 μmol) produced in Example C4(vi), 3-(1-cyano-1-methylethyl)benzoic acid (316 mg, 1.67 mmol), pyridine (5 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (456 mg, 2.38 mmol) and N,N-dimethylpyridine-4-amine (38.9 mg, 318 μmol) as starting materials, and in the same manner as in Example C4(vii), the title compound (97.3 mg, 38%) was obtained as colorless crystals.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[C:9]([CH3:17])([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1.[CH2:19](Br)[CH:20]=[CH2:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:21]([S:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[C:9]([CH3:10])([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH3:17])=[CH:4][CH:3]=1)[CH:20]=[CH2:19]
Reactant: CC(C)(C(=O)c1ccc(S)cc1)N1CCOCC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCSc1ccc(C(=O)C(C)(C)N2CCOCC2)cc1

Procedure:
10 g (0.38 mol) of 1-(4-mercaptophenyl)-2-methyl-2-morpholinopropan-1-one, 5 g (0.041 mol) of freshly distilled allylbromide and 5.2 g (0.038 mol) of dry potassium carbonate are suspended in 50 ml of acetone and the mixture is heated to reflux temperature for 16 hours. After cooling, the solvent is removed by distillation, water and diethyl ether are added to the residue, and the water phase is extracted with ether. The organic phase is washed with 10% NaOH solution and water, dried over MgSO4 and concentrated. The oil which remains is distilled in a bulb tube at 180°-200° C./13 Pa. (Compound No. 23).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@@H:9]([C:25]([O-:27])=[O:26])[CH2:10][CH2:11][C@@H:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[F:24])[CH2:13][N+:14]([O-:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C(N(C)C)=N.[CH2:43]=[O:44]>C(#N)C.C([O-])(O)=O.[Na+]>[C:31]([O:30][C:28]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([CH2:10][CH2:11][C@@H:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[F:24])[CH:13]([N+:14]([O-:16])=[O:15])[CH2:43][OH:44])[C:25]([O:27][CH2:12][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:26])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: C=O
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@H](C[N+](=O)[O-])c1cccc(F)c1F)C(=O)[O-]
Agent: CN(C)C(=N)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@@H](c1cccc(F)c1F)C(CO)[N+](=O)[O-])C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of (5S)-N,N-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-6-nitro-D-norleucinate (2.30 g, 3.975 mmol) and 1,1,3,3-tetramethylguanidine (46 mg, 0.40 mmol) in acetonitrile (20 mL) was added formaldehyde (0.15 mL, 37% aqueous solution). After stirring for 60 min, more formaldehyde (0.050 mL, 37% aqueous solution) was added. After stirring for an additional 60 min the mixture was diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2 (3×). The combined organics were dried over magnesium sulfate, filtered and concentrated to give a residue that was purified by silica gel chromatography (25%→75% ethyl acetate/hexanes) to give the title compound (1.44 g,). MS 409.1 (M+1-2 Boc).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:6]=[CH:5]2.C[O-].[Na+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[CH3:16][CH:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:3]=2)[CH:8]=1)[C:13]([OH:15])=[O:14]
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Reactant: ClCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C(=O)O)c1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
To a solution of 6-hydroxy-α-methyl-2-naphthaleneacetic acid (6.48 g, 30 mmol) in methanol (100 ml) is added sodium methoxide (60 mm). After 10 minutes the solvent is removed and replaced with dimethylformamide (100 ml). Benzyl chloride (7.6 g, 60 mmol) is then added and the reaction mixture is stirred overnight at room temperature. The reaction is then heated at 150° C. for 1 hour. The solvent is then removed and the residue is partitioned between water and methylene chloride. The organic layer is washed with water, dried over magnesium sulfate and evaporated to 11.5 g of crude product. This crude product is extracted with 100 ml hot hexane which affords 3.5 g of white crystals. A final recrystallization from methanol affords 2.5 g of white crystals of the intermediate ethyl ester (21% yield, m.p. 76°-78° C.).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][C:10](=[O:12])[CH3:11].[CH3:13][O:14][CH:15](Cl)[CH3:16].[OH-].[Na+]>CCCCCC>[CH3:13][O:14][CH:15]([N:9]([CH3:8])[C:10](=[O:12])[CH3:11])[CH3:16]
Reactant: CNC(C)=O
Reactant: COC(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COC(C)N(C)C(C)=O
Reaction time: 2 h

Procedure:
First 20 g of triethylamine and then a mixture of 91 g of triethylamine (1.1 moles in total) and 36.5 g (0.5 mole) of N-methylacetamide are added dropwise, at 0° C., to a solution of 94.5 g (1 mole) of α-chloroethyl methyl ether in 200 ml of hexane. After 2 hours, 44 g (1.1 moles) of technical-grade sodium hydroxide flakes are added and 20 ml of 50% strength sodium hydroxide solution are added dropwise, whilst cooling with ice, and the mixture is stirred for a further half an hour. The hexane solution is decanted, the flask is rinsed with hexane and the reaction solution is concentrated, the triethylamine employed being completely recovered in the distillate. The residue is subjected to flash distillation in vacuo. This yields 61 g (93% of theory) of N-α-methoxyethyl-N-methyl-acetamide. Boiling point (23 mm Hg): 84° C. 1H-NMR (CDCl3): 1.2-1.4 ppm (dd); 2.1 ppm (d); 2.8 ppm (d); 3.2 ppm (d); 4.95-5.15 ppm (q); 5.6-5.9 ppm (q).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH2:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[C:8](=[O:27])[NH:7][C:6]=2[CH:28]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH2:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[C:8](=[O:27])[NH:7][C:6]=2[CH:28]=1)(=[O:31])[CH3:30]
Reactant: Nc1ccc2c(c1)NC(=O)C(CCCN1CCN(c3ccc(F)cc3)CC1)O2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)NC(=O)C(CCCN1CCN(c3ccc(F)cc3)CC1)O2
Temperature: 0 °C
Yield: 71.5 %

Procedure:
To a solution of 6-amino-2-{3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}-2H-1,4-benzoxazin-3(4H)-one (500 mg) in pyridine (5 ml) was added acetic anhydride (0.18 ml) while stirring. The mixture was stirred at room temperature for further 4 hours, which was then poured into ice-water. Precipitated crystals were collected by filtration, followed by recrystallization from dichloromethane-ethyl acetate to give 397 mg (71.5%) of 6-acetamido-2-{3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}-2H-1,4-benzoxazin-3(4H)-one, m.p. 111°-112° C.
Reaction SMILES: O[CH:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[C@H:5]([CH3:14])[CH2:4][CH:3]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].CS(Cl)(=O)=O.C(N(CC)CC)C.Cl>ClCCl>[CH3:14][C@@H:5]1[CH2:4][C:3]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[CH:2][CH2:7][N:6]1[C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9]
Reactant: C=CCOC(=O)N1CC(O)C(C(=O)OC(C)(C)C)C[C@H]1C
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)N1CC=C(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a solution of 1-allyl 4-tert-butyl (2R)-5-hydroxy-2-methyl-1,4-piperidinedicarboxylate (1.85 g, 6.2 mmol) in dichloromethane (40 ml) were added at −30° C. methanesulfonyl chloride and triethylamine, and the mixture was stirred 0° C. for 2 hours. The reaction mixture was poured into diluted hydrochloric-acid and the mixture was extracted three times with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was dissolved in a mixture of toluene (5 ml) and dichloromethane (10 ml). The solution was cooled to 0° C. and thereto was added DBU. The mixture was stirred for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted three times with ethyl acetate. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel (30 g) chromatography to give 1-allyl 4-tert-butyl (2R)-2-methyl-3,6-dihydro-1,4(2 H)-pyridinedicarboxylate (1.33 g, 76%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]4[S:33][CH:34]=[CH:35][N:36]=4)(=[O:30])=[O:29])=[CH:24][C:23]=3[C:37]#[N:38])=[C:17]([C:39]3[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(C)(C)C.[ClH:46]>ClCCl.O1CCOCC1>[ClH:46].[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]4[S:33][CH:34]=[CH:35][N:36]=4)(=[O:29])=[O:30])=[CH:24][C:23]=3[C:37]#[N:38])=[C:17]([C:39]3[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cn1nccc1-c1cc(-c2cccc(CNC(=O)OC(C)(C)C)c2)ccc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1nccc1-c1cc(-c2cccc(CN)c2)ccc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
tert-Butyl-{[4′-{2-cyano-4-[(1,3-thiazol-2-ylamino)sulfonyl]phenoxy}-3′(1-methyl-1H-pyrazol-5-yl)biphenyl-3-yl]methyl}carbamate (Preparation 77, 380 mg, 0.59 mmol) was dissolved in dichloromethane (20 mL), 4M HCl in 1,4-dioxane (4 mL) was added and the reaction was stirred for 18 hours at room temperature. The reaction mixture was concentrated in vacuo, slurried in cold diethyl ether (20 ml) then filtered to afford the title compound (342 mg, 99%) as a yellow solid as the hydrochloride salt.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][CH:23]([CH:26]([CH3:28])[CH3:27])[CH2:24][OH:25]>>[OH:25][CH2:24][CH:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[CH:26]([CH3:28])[CH3:27]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: CC(C)C(N)CO
Product: CC(C)C(CO)Nc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Yield: 45 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 2-amino-3-methyl-butan-1-ol according to the GPA affording 17 mg (45%) of a red powder. Rt=4.00 min.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:20][CH2:21][CH2:22]Cl)[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]2[CH2:16][CH2:17][CH2:18][CH3:19].[H-].[Na+]>CN(C=O)C>[CH2:16]([N:6]1[C:5]2=[N:4][N:3]3[CH2:20][CH2:21][CH2:22][NH:1][C:2]3=[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7]1=[O:15])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCn1c(=O)n(CCC)c(=O)c2c(N)n(CCCCl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCC)c(=O)c2c3n(nc21)CCCN3
Temperature: 25 °C
Reaction time: 5 h
Yield: 32 %

Procedure:
To a stirred solution of 3-amino-7-butyl-2-(3-chloropropyl)-5-propyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione(2.1 g) in DMF(30 ml) was added sodium hydride(60% oil, 0.7 g) in portions under ice-cooling. The mixture was stirred at room temperature for further 5 hours. The reaction mixture was concentrated to dryness and the concentrate was added to ice-water. The mixture was stirred for a while, whereupon crystals precipitated out. The crystals were collected by filtration and recrystallized from aqueous alcohol to afford colorless crystals(0.6 g, 32%), m.p. 147°-150° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([NH2:9])=[O:8].C(=O)([O-])O.[Na+].[CH:15](I)([CH3:17])[CH3:16]>C(#N)C.ClCCl>[CH3:16][CH:15]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([NH2:9])=[O:8])[CH3:17]
Reactant: CC(C)I
Reactant: NC(=O)C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)N1CCOCC1C(N)=O
Temperature: 150 °C
Yield: 97 %

Procedure:
To a solution of 1.1 g (6.3 mmol) of morpholine-3-carboxamide (a synthesis of which is described in WO-2005/026 156, Hennequin L. F. A. et al.) in acetonitrile (16 ml) are successively added 1.86 g (22.2 mmol) of sodium hydrogen carbonate powder and 0.7 ml (7.0 mmol) of isopropyl iodide, and the mixture is then heated at 150° C. by microwave for 30 minutes. The reaction mixture is cooled to room temperature, diluted with dichloromethane (30 ml) and filtered through Celite. The filtrate is concentrated under reduced pressure and 1.1 g of compound are obtained in the form of a beige-coloured powder, which is used without further purification in the following step. Yield: 97%. MH+: 173.2 (tr: 0.72 min., condition 1).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][S:2](=[O:1])(=[O:30])[CH2:3][CH2:4]2)=[O:9])=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2ccc(Cl)cc2)CC1
Yield: 34 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 4-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless solid (34%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10]([CH3:15])([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:10]([CH3:15])([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C)(C)C1
Temperature: 25 °C

Procedure:
To a solution of 18.5 g (82.0 mmol) 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester in 150 mL DCM at RT was added 30.0 mL (174 mmol) DIPEA. The mixture was cooled with ice and a solution of 14.0 mL (93.2 mmol) benzyl chloroformate in 60 mL DCM was added dropwise. The reaction mixture was stirred at RT over night and quenched with saturated aqueous sodium bicarbonate solution. The product was extracted with DCM. The organic layers were combined, dried over sodium sulfate and concentrated in vacuo.
Reaction SMILES: [C:1](O)(=O)[C:2]1C=CC=CC=1.[C:10]1([NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].C(OC(=O)C)(=O)C>>[CH3:1][C:2]1[NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:17]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1ccccc1N
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2ccccc2[nH]1

Procedure:
Preparation of the intermediate benzoic acid 2 is shown in Scheme 2. 1,2-phenylenediamine is condensed with acetic anhydride to form 2-methylbenzimidazole which is then reacted with benzyl halide 5 (where X is Br, Cl, I, methansulfonyl, or p-toluenesulfonyl), in the presence of base to form 6. Hydrolysis of ester 6 gives benzoic acid 2. Condensation of 3,4-diaminopyridine with acetic anhydride followed by reaction with benzyl halide 5 as described above gives a mixture of 1-, 3-, and 5-substituted imidazo[4,5-c]pyridines (compounds 8, 9, and 10) which are separated by chromatography on silica gel and convened to 2 as described above. Similarly, imidazo[4,5-b]pyridines 12, 13, and 14 are prepared from 2,3-diaminopyridine. ##STR10##
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:29])([F:28])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:26][CH2:25][C:15]3([CH2:24][CH2:23][C:18]4([O:22][CH2:21][CH2:20][O:19]4)[CH2:17][CH2:16]3)[C:14]2=[O:27])=[CH:9][CH:8]=1)[OH:6].I[CH3:31]>CN(C=O)C>[F:29][C:4]([F:3])([F:28])[C@@H:5]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:26][CH2:25][C:15]3([CH2:16][CH2:17][C:18]4([O:22][CH2:21][CH2:20][O:19]4)[CH2:23][CH2:24]3)[C:14]2=[O:27])=[CH:11][CH:12]=1)[O:6][CH3:31]
Reactant: O=C1N(c2ccc([C@@H](O)C(F)(F)F)cc2)CCC12CCC1(CC2)OCCO1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@H](c1ccc(N2CCC3(CCC4(CC3)OCCO4)C2=O)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 91.3 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 311 mg) was combined with DMF (10 mL) under argon. The suspension was cooled down to 0° C. and a solution of 10-[(R)-4-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (1.50 g) in DMF (15 mL) was added dropwise over a period of 10 minutes. The mixture was stirred for 45 minutes at 0° C., then, iodomethane (663 mg) was added dropwise over a period of 10 minutes. The mixture was stirred at 0° C. for 15 minutes and then warmed up to RT for 1.5 hours. The reaction mixture was poured into ice/water and was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was once again evaporated with toluene (200 mL). The crude material was purified by flash chromatography (gradient of ethyl acetate in heptane) to give the title compound as a colorless solid (1.42 g). MS (ESI): 400.2 (MH+).
Reaction SMILES: N[C:2]1[C:11]([Cl:12])=[CH:10][C:9]([N:13]([C:18]2[C:37]([CH:38]3[CH2:40][CH2:39]3)=[CH:36][C:21]3[C:22]([C:32](=[O:35])[NH:33][CH3:34])=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[O:24][C:20]=3[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CC#N.[BrH:44].N([O-])=O.[Na+]>O>[Br:44][C:2]1[C:11]([Cl:12])=[CH:10][C:9]([N:13]([C:18]2[C:37]([CH:38]3[CH2:40][CH2:39]3)=[CH:36][C:21]3[C:22]([C:32](=[O:35])[NH:33][CH3:34])=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[O:24][C:20]=3[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Br
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(Br)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 1 L 3-necked flask equipped with a magnetic stirrer was added 58.0 g (99.0 mmol) of methyl 2-amino-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate followed by 500 mL of MeCN and then 500 mL of 48% aqueous HBr. The dark brown solution was cooled to 0° C. in an ice water/brine bath and treated with a solution of 8.20 g (119 mmol) of sodium nitrite in 50 mL of water over a 5 minute period. After 30 minutes LCMS indicated complete consumption of the starting material. The solution was treated with 18.5 g (129 mmol) of CuBr over 2 minutes and then warmed to 50° C. After 30 minutes at 50° C. LCMS indicated complete reaction. The solution was cooled to RT and partitioned between 1 L of EtOAc and 1.5 L of water. The phases were separated and the aqueous solution extracted with EtOAc (2×200 mL). The combined EtOAc solutions were washed with 5% aqueous NaCl (1×1 L), 5% aqueous sodium bisulfite (2×300 mL), saturated aqueous sodium bicarbonate (2×300 mL), saturated aqueous brine (1×300 mL), and dried over sodium sulfate. The drying agent was removed by filtration through a pad of silica gel and the filtrate concentrated to dryness at reduced pressure to give 64.3 g of crude methyl 2-bromo-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate as a reddish-brown foam. The crude product was carried forward without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.50 (q, J=4.29 Hz, 1H) 8.16 (s, 1H) 7.92-8.03 (m, 2H) 7.79 (d, J=2.73 Hz, 1H) 7.65 (d, J=2.73 Hz, 1H) 7.41 (t, J=8.93 Hz, 2H) 7.24 (s, 1H) 3.81-3.89 (m, 3H) 3.45-3.53 (m, 3H) 2.85 (d, J=4.59 Hz, 3H) 2.04-2.16 (m, 1H) 0.71-1.07 (m, 3H) 0.40 (br. s., 1H). LCMS (ESI): 649 (M+H+).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[S:10][C:9]([C:11]([OH:13])=[O:12])=[C:8]([CH3:14])[CH:7]=1.[CH3:15]O>>[Br:5][C:6]1[S:10][C:9]([C:11]([O:13][CH3:15])=[O:12])=[C:8]([CH3:14])[CH:7]=1
Reactant: Cc1cc(Br)sc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1sc(Br)cc1C

Procedure:
After thionyl chloride was added to methanol, 5-bromo-3-methylthiophene-2-carboxylic acid was added thereto and the resulting solution was heated and refluxed to obtain methyl 5-bromo-3-methylthiophene-2-carboxylate. EI: 234, 236.