Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[CH3:16])=[O:4].O1CCCC1.C([Li])CCC.[CH3:29][N:30]=[CH:31][C:32]1[S:33][CH:34]=[CH:35][C:36]=1[CH3:37]>C1(C)C=CC=CC=1.O>[CH3:1][C:2]([CH3:18])([CH3:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:7]=1[CH2:16][CH:31]([NH:30][CH3:29])[C:32]1[S:33][CH:34]=[CH:35][C:36]=1[CH3:37])=[O:4]
Reactant: Cc1cc(C(F)(F)F)ccc1NC(=O)C(C)(C)C
Reactant: CN=Cc1sccc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CNC(Cc1cc(C(F)(F)F)ccc1NC(=O)C(C)(C)C)c1sccc1C

Procedure:
To a chilled (10° C.) solution of 12.81 g of 2,2-dimethyl-N-(2-methyl-4-trifluoromethylphenyl)propanamide and 200 ml of anhydrous tetrahydrofuran, was added dropwise over 20 min, 48 ml of a 2.5M solution of n-butyllithium in hexanes, with stirring. The solution was stirred, with cooling, for 1 hr, and 10.65 g of an 85% solution of 3-methyl-2-thiophenecarboxaldehyde methylimine in toluene, and 20 ml of tetrahydrofuran was added, dropwise over 10 min, with stirring. After stirring and cooling for 1.5 hr, 60 ml of water was added, and the mixture was evaporated. The residue was diluted with water and extracted with dichloromethane. The combined, organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by HPLC (Waters Associates Prep LC/System 500, silica gel, 200 ml/min flow rate; the residue was dissolved in sufficient ethyl acetate-hexane (1:1) to give 50 ml of solution, and the solution was applied in 25 ml portions to the columns, Gow Mac UV detector). The appropriate fractions were combined and concentrated. The residue was purified again by preparative HPLC under similar conditions, and finally, using a single recycle (elution with ethyl acetate-hexane (1:1)) to afford 9.53 g of product, mp 64°-69° C.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:13][CH3:14])[CH:11]=2)[C:6]([C:15]([OH:17])=O)=[CH:5]1)([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:54][C:55]1[S:56][CH:57]=[CH:58][N:59]=1>C(Cl)Cl>[S:56]1[CH:57]=[CH:58][N:59]=[C:55]1[NH:54][C:15]([C:6]1[C:7]2[C:12](=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:17]
Reactant: CSc1ccc2c(C(=O)O)cn(C(C)C)c2c1
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ccc2c(C(=O)Nc3nccs3)cn(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
A solution of 1-isopropyl-6-methylsulfanyl-1H-indole-3-carboxylic acid (275 mg, 1.10 mmol) and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (585 mg, 1.32 mmol) in methylene chloride (5 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.44 mL, 2.54 mmol). The reaction was stirred at 25° C. for 30 min. At this time, the reaction was treated with 2-aminothiazole (254 mg, 2.54 mmol) and then was stirred at 25° C. for 18 h. The reaction was then partitioned between water (40 mL) and ethyl acetate (40 mL) and was treated with a 1N aqueous hydrochloric acid solution (25 mL). The layers were shaken and separated. The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×25 mL), water (1×25 mL), and a saturated aqueous sodium chloride solution (1×25 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 1-isopropyl-6-methylsulfanyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (155 mg, 42%) as light yellow solid: mp 172-176° C.; (ES)+-HRMS m/e calcd for C16H17N3OS2 (M+Na)+354.0705, found 354.0709.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][S:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[CH3:11][CH:12]([C:18]1[CH:19]=C(O)[CH:21]=[C:22]([CH:24]=1)[OH:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH3:11][CH:12]([C:18]1[CH:24]=[C:22]([OH:23])[C:21]2[C:2]3[CH2:6][CH2:5][S:4][C:3]=3[C:7](=[O:8])[O:9][C:10]=2[CH:19]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC(C)c1cc(O)cc(O)c1
Reactant: COC(=O)C1SCCC1=O
Product: CCCCCC(C)c1cc(O)c2c3c(c(=O)oc2c1)SCC3

Procedure:
Following a procedure similar to that described in Example 1B hereinabove, methyl 3-oxo-2,3,4,5-tetrahydrothiophene-2-carboxylate is reacted with 5-(2-heptyl)resorcinol to give 1,2-dihydro-7-(2-heptyl)-9-hydroxy-4-oxo-4H-thieno[2,3-c][1]benzopyran.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>COCCOC>[CH:22]([N:12]([C:10](=[O:11])[CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:36]1[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=1)[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:24])[CH3:23]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2ccccc2CCC(=O)N(NC(=O)c2ccccc2)C(C)C)cc1
Yield: 64.6 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 4-methoxy-phenylboronic acid (29 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (35 mg, 66%). LC-MS m/e 417.29 (M+H+)
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.[C:13]([C:16]1[CH:21]=[CH:20][C:19](F)=[C:18]([Cl:23])[CH:17]=1)(=[O:15])[NH2:14]>>[ClH:23].[Cl:23][C:18]1[CH:17]=[C:16]([C:13](=[O:15])[NH2:14])[CH:21]=[CH:20][C:19]=1[O:9][CH:6]1[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]2[O:12][CH:11]=[CH:10][C:5]1=2
Reactant: CN1CCC(O)c2ccoc2C1
Reactant: NC(=O)c1ccc(F)c(Cl)c1
Product: CN1CCC(Oc2ccc(C(N)=O)cc2Cl)c2ccoc2C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-carbamoyl-2-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[F:41][C:42]1[CH:43]=[CH:44][C:45]([S:48](F)(=[O:50])=[O:49])=[N:46][CH:47]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:48]([C:45]2[CH:44]=[CH:43][C:42]([F:41])=[CH:47][N:46]=2)(=[O:50])=[O:49])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(F)c1ccc(F)cn1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2ccc(F)cn2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 28 h
Yield: 28.5 %

Procedure:
To a suspension of sodium hydride (60% in oil, 40 mg) in tetrahydrofuran (2.5 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (162 mg), 15-crown-5 (220 mg) and 5-fluoropyridine-2-sulfonyl fluoride (120 mg) at room temperature, and the mixture was stirred at room temperature for 28 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→7:3) to give the title compound as a pale-yellow oil (yield 69 mg, 29%).
Reaction SMILES: [P:1]([O-])([O:11][CH2:12][C:13]1C=CC=CC=1)([O:3][CH2:4][C:5]1C=CC=CC=1)=[O:2].C(Cl)(=O)C(Cl)=O.[CH2:26]1[N:31]([CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]3[CH:43]=[CH:44][C:45]([NH:47][C:39]=3[CH:38]=2)=[O:46])[CH2:30][CH2:29][N:28]([C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=2[Cl:55])[CH2:27]1.CC(C)([O-])C.[K+]>ClCCl.CN(C)C=O.CC1CCCO1>[P:1]([O:11][CH2:12][CH3:13])([O:3][CH2:4][CH3:5])([O:46][C:45]1[CH:44]=[CH:43][C:40]2[C:39](=[CH:38][C:37]([O:36][CH2:35][CH2:34][CH2:33][CH2:32][N:31]3[CH2:30][CH2:29][N:28]([C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=4[Cl:55])[CH2:27][CH2:26]3)=[CH:42][CH:41]=2)[N:47]=1)=[O:2]
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: ClCCl
Solvent: CC1CCCO1
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)Oc1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of dibenzyl phosphate (2.48 g, 8.91 mmol) in dichloromethane (25 ml) was added N,N-dimethyl formamide (1 drop) followed by oxalyl chloride (0.75 mL, 8.91 mmol). After 2 hours the reaction mixture was concentrated in vacuo. The residue was dissolved in 2-methyltetrahydrofuran (5 mL) and added to a suspension of dehydro-aripiprazole (1.66 g, 3.71 mmol) and potassium t-butoxide (0.92 g, 8.17 mmol) in 2-methyltetrahydrofuran (35 mL) at 0° C. under argon gas, then allowed to gradually warm to room temperature. After stirring overnight the reaction was quenched with water (25 mL) and 28% aq NH3 (15 mL) and stirred for 10 minutes. The reaction mixture was then extracted with ethyl acetate (2×40 mL). The combined organics were washed with water (50 mL) and brine (50 mL) then dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by column chromatography eluting with 5% methanol (1:1 ethyl acetate/dichloromethane) to give the product. The 1H-NMR showed minor impurities still present (impurities not observed by LCMS). Various further purifications were attempted but failed to remove these impurities.
Reaction SMILES: CO[C:3](=O)[CH:4]([N+:15]([O-:17])=[O:16])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:6].[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=C.Cl>C(O)(C)(C)C.C(OCC)C>[CH3:24][O:23][C:19](=[O:22])[CH2:6][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH:4]([N+:15]([O-:17])=[O:16])[CH2:3][CH2:20][C:19]([O:23][CH3:24])=[O:22]
Reactant: C=CC(=O)OC
Reactant: COC(=O)C(C(C)c1ccc(Cl)c(Cl)c1)[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: COC(=O)CCC(C(CC(=O)OC)c1ccc(Cl)c(Cl)c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of 350 g of nitro-3-(3,4-dichlorophenyl)butanoic acid methyl ester, 118 g of methyl acrylate and 25 ml of Triton B in 500 ml of t-butanol is allowed to stir at room temperature for 94 hours. Excess aqueous hydrochloric acid (1 N) is added and the solution is diluted with diethyl ether. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated to give 4-nitro-3-(3,4-dichlorophenyl)heptanedioic acid dimethyl ester.
Reaction SMILES: [CH:1]([C:3]1[C@H:8]([C:9]([OH:11])=[O:10])[N:7]2[C:12](=[O:24])[C@@H:13]([NH:14][C:15](=[O:23])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:6]2[S:5][CH:4]=1)=[O:2].O1CCOCC1.CO.[C:33]1([C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[N+]=[N-])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1CCCCC1>[C:33]1([CH:39]([O:10][C:9]([C@@H:8]2[N:7]3[C:12](=[O:24])[C@@H:13]([NH:14][C:15](=[O:23])[CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C@H:6]3[S:5][CH:4]=[C:3]2[CH:1]=[O:2])=[O:11])[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=CC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: C1CCCCC1
Solvent: C1COCCO1
Solvent: CO
Product: O=CC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of 10 g of 3-formyl-7β-phenylacetylamino-ceph-2-em-4α-carboxylic acid in 250 ml of a 4:1 mixture of dioxane and methanol is treated with a solution of 1.5 mol equivalents of diphenyldiazomethane in cyclohexane. After 2 hours at room temperature, the red-violet solution is evaporated to dryness under reduced pressure. The residue is dissolved in hot methylene chloride; the solution is diluted with cyclohexane whilst warm, and 3-formyl-7βphenylacetylamino-ceph-2-em-4α-carboxylic acid diphenylmethyl ester is obtained in practically quantitative yield in the form of fine colourless felted needles, melting point 175.5°-176° C. (uncorrected, decomposition); [α]D20 =+513°±1° (c=1,084 in chloroform); thin layer chromatogram (silica gel): Rf=0.35 (system: toluene/acetone, 80:20) and Rf=0.58 (system: toluene/acetone 65:35); ultraviolet absorption spectrum (in 95% ethanol): λmax =289 mμ (ε=20,200) and λmin =245 mμ (ε= 2,100); infrared absorption spectrum: characteristic bands at 2.92μ, 3.53μ, 5.59μ, 5.72μ, 5.91μ, 6.34μ, 6.61μ and 6.67μ (in methylene chloride) and at 3.00μ, 5.63μ, 5.76μ, 5.95μ (double band), 5.99μ, 6.07μ and 6.58μ (in mineral oil).
Reaction SMILES: [CH2:1]([NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-])=O)[C:12]=1[OH:21])(=[O:10])=[O:9])[C@H:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[H][H]>[Pd]>[CH2:1]([NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([NH2:18])[C:12]=1[OH:21])(=[O:9])=[O:10])[C@H:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC[C@@H]2CCCO2)c1O
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)NC[C@@H]2CCCO2)c1O
Yield: 92.1 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, N-((2S)-tetrahydrofurfuryl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (270 mg, 0.80 mmol) was reduced with hydrogen and Pd/C (140 mg) to form the desired product (226 mg, 94%). EI-MS m/z 305(M-H)−.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:8]([N:9]([CH2:18][CH3:19])[C:10](=[O:17])[CH2:11][CH:12]2[CH2:15][NH:14][C:13]2=[O:16])=[CH:7][N:6]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:5]=1.[CH3:26]I>CN(C=O)C>[Cl:3][C:4]1[C:8]([N:9]([CH2:18][CH3:19])[C:10](=[O:17])[CH2:11][CH:12]2[CH2:15][N:14]([CH3:26])[C:13]2=[O:16])=[CH:7][N:6]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:5]=1
Reactant: CCN(C(=O)CC1CNC1=O)c1cn(-c2cccnc2)nc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)CC1CN(C)C1=O)c1cn(-c2cccnc2)nc1Cl
Reaction time: 0.02 h

Procedure:
To a suspension of NaH (60% dispersion in oil, 0.029 g, 0.72 mmol) in DMF (2 mL) was added N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-(2- oxoazetidin-3-yl)acetamide (0.20 g, 0.60 mmol) in DMF (0.5 mL), dropwise, at a temperature of about −10° C. over one minute. The reaction mixture was charged with methyl iodide (0.093 g, 0.66 mmol) in DMF (0.5 mL), dropwise, and stirred for 5 minutes. The reaction mixture was quenched with ice water (10 mL) and extracted with EtOAc (3×15 mL). The organic layers were combined and washed with water (3×10 mL) and brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 1%-8% MeOH/CH2Cl2 to afford the title compound F32 as a gum (0.065 g, 31%).
Reaction SMILES: C([N:5]1[C:9]2[N:10]([CH3:15])[C:11](=[O:14])[CH:12]=[CH:13][C:8]=2[CH:7]=[N:6]1)(C)(C)C.[Br:16]Br.[OH2:18].[OH-].[Na+]>CC(O)=O>[C:11]([OH:14])(=[O:18])[CH3:12].[Br:16][C:12]1[C:11](=[O:14])[N:10]([CH3:15])[C:9]2[NH:5][N:6]=[CH:7][C:8]=2[CH:13]=1
Reactant: O
Reactant: BrBr
Reactant: Cn1c(=O)ccc2cnn(C(C)(C)C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cn1c(=O)c(Br)cc2cn[nH]c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-tert-butyl-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (240 mg, 1.17 mmol) in glacial AcOH (5.5 mL) at RT was added bromine (0.060 mL, 1169 μmol) slowly. An orange suspension resulted and it was allowed to stir at RT for 1 h. 5.0 mL water was added, and the pH was adjusted to pH 6 using 5 N NaOH, It was extracted with 2×50 mL EtOAc, dried over MgSO4, filtered and concentrated in vacuo (rotovap) affording 5-bromo-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one acetic acid adduct (305 mg) as a beige solid. MS (ESI, pos.ion) m/z: 227.9 (M+1) and 229.9 (M+1). This crude product was used in the next step.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:18]3[N:19]([C:24]([C:27]([NH:29][C:30]4[CH:35]=[CH:34][N:33]=[CH:32][C:31]=4[F:36])=[O:28])=[CH:25][N:26]=3)[N:20]=[C:21](Cl)[CH:22]=2)=[N:12]1)(C(C)(C)C)(C)C.[C@H:37]1([NH2:44])[CH2:42][CH2:41][C@H:40]([NH2:43])[CH2:39][CH2:38]1>CN1C(=O)CCC1>[NH2:43][C@H:40]1[CH2:41][CH2:42][C@H:37]([NH:44][C:21]2[CH:22]=[C:17]([NH:16][C:13]3[CH:14]=[CH:15][N:11]([CH2:10][CH2:9][OH:8])[N:12]=3)[C:18]3[N:19]([C:24]([C:27]([NH:29][C:30]4[CH:35]=[CH:34][N:33]=[CH:32][C:31]=4[F:36])=[O:28])=[CH:25][N:26]=3)[N:20]=2)[CH2:38][CH2:39]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(Nc2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Solvent: CN1CCCC1=O
Product: N[C@H]1CC[C@H](Nc2cc(Nc3ccn(CCO)n3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 110 °C

Procedure:
A mixture of 50A (40 mg, 0.075 mmol) and trans-cyclohexane-1,4-diamine (86 mg, 0.753 mmol) in NMP (0.5 mL) was heated at 110° C. overnight. The reaction mixture was cooled to room temperature and purified by reversed-phase preparative HPLC. The desired fractions were concentrated and dried to give 50B (19.3 mg, 51%) as a beige solid. HPLC Rt=2.037 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+H]=495.
Reaction SMILES: F[C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N)C1C=CC=CC=1>CN(C=O)C>[CH2:4]([NH:5][C:6]([C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:12][CH2:13]1)=[O:7])[C:3]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:2]=1
Reactant: O=C(NCc1ccccc1F)[C@H]1CC[C@@H](Cc2nc3ccccc3[nH]2)CC1
Agent: On1nnc2cccnc21
Solvent: NCc1ccccc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)[C@H]1CC[C@H](Cc2nc3ccccc3[nH]2)CC1
Reaction time: 15 h

Procedure:
Example 8 was prepared by the following procedure. To a solution of trans-4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic acid (F) (444 mg, 1.72 mmol), EDC (328 mg, 1.72 mmol) and HOAt (234 mg, 1.72 mmol) in anhydrous DMF (4 mL) was added benzylamine (184 mg, 1.72 mmol). The resulting reaction mixture was stirred for 15 h. The reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc and the organic layer washed 2× with water, and dried with MgSO4. Concentration gave trans-4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic acid benzylamide (400 mg, 67%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.49 (br s, 2H), 7.30-7.17 (m, 7H), 4.34 (s, 2H), 2.78 (d, 2H), 2.21 (m, 1H), 1.84 (m, 5H), 1.55 (q, 2H), 1.16 (q, 2H); mass spectrum m/z 348 [(M+H)+; calcd for C22H26N3O: 348].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[NH:22][CH3:23].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[N:32]=[C:33]=[O:34]>C(Cl)(Cl)Cl.CO>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[NH:32][C:33]([N:22]([C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1)[CH3:23])=[O:34]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: CNc1ncnc2cc(OCC3CCN(C)CC3)c(OC)cc12
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc2c(N(C)C(=O)Nc3c(Cl)cccc3Cl)ncnc2cc1OCC1CCN(C)CC1
Temperature: 85 °C
Yield: 5.1 %

Procedure:
6-Methoxy-4-methylamino-7-(N-methylpiperidin-4-ylmethoxy)quinazoline (0.195 g) was added to 2,6-dichlorophenyl isocyanate (0.3 g) under argon and the solids were mixed together using a spatula. The mixture was heated to 85° C. with gentle mixing for 40 minutes. The mixture was cooled to ambient temperature, dissolved in a mixture of chloroform (15 ml) and methanol (5 ml) and purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a 1% aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound (0.016 g); NMR Spectrum: (CDCl3) 1.5 (m, 2H), 1.98 (m, 5H), 2.3 (s, 3H), 2.91 (d, 2H), 3.6 (s, 3H), 4.02 (s, 3H), 4.03 (d, 2H), 7.1 (t, 1H), 7.28 (s, 2H), 7.37 (d, 2H), 8.61 (s, 1H), 8.96 (s, 1H); Mass Spectrum: M+H+ 504.
Reaction SMILES: CO[C:3](=[O:18])[CH:4]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=O.[CH3:19][O:20][C:21]([C:23]1[CH:27]=[C:26]([NH2:28])[NH:25][N:24]=1)=[O:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[CH3:19][O:20][C:21]([C:23]1[CH:27]=[C:26]2[NH:28][C:5]([C:7]3[O:8][CH:9]=[CH:10][CH:11]=3)=[C:4]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)[C:3](=[O:18])[N:25]2[N:24]=1)=[O:22]
Reactant: COC(=O)c1cc(N)[nH]n1
Reactant: COC(=O)C(C(=O)c1ccco1)C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Solvent: O
Product: COC(=O)c1cc2[nH]c(-c3ccco3)c(C3CCCCC3)c(=O)n2n1
Temperature: 120 °C
Yield: 32.1 %

Procedure:
A mixture of 1.1 g (4.4 mmol) of 2-cyclohexyl-3-furan-2-yl-3-oxo-propionic acid methyl ester, 0.592 g (4.2 mmol) of 5-amino-1H-pyrazole-3-carboxylic acid methyl ester, 76 mg (0.4 mmol, 10 mol %) of p-toluenesulfonic acid monohydrate (PTSA), and 50 mL of chlorobenzene was heated at 120° C. overnight. The reaction mixture was then concentrated to a residue which was chromatographed on silica gel (7% methanol in dichloromethane) to afford 0.46 g (32% yield) of desired 6-cyclohexyl-5-furan-2-yl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester as indicated by 1H NMR; LC-MS—calcd for C18H19N3O4 [M++H]+: 342.14, found: 342.3.