Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C)C(=O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:4]2[CH:3]=[C:2]([C:27]3[CH:28]=[CH:29][C:24]([OH:23])=[CH:25][CH:26]=3)[CH:14]=[CH:13][C:5]=2[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:17][CH:18]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
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: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(O)cc2)cc1Nc1ccc(F)cc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To N,N-dimethylacetamide 2.5 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.10 g were added 4-hydroxyphenylboronic acid 75 mg, sodium carbonate 72 mg and tetrakis(triphenylphosphine)palladium(0) 3.2 mg, and it was stirred at 110° C. for 4 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 2-(4-fluoroanilino)-4-(4-hydroxyphenyl)benzoate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](SC)=[N:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Br:16])[CH:10]=2)=[N:4][S:5][N:6]=1.Cl.[NH2:20][OH:21].C(N(CC)C(C)C)(C)C>C(O)C>[NH2:1][C:2]1[C:3]([C:7](=[N:20][OH:21])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Br:16])[CH:10]=2)=[N:4][S:5][N:6]=1
Reactant: NO
Reactant: CSC(=Nc1ccc(F)c(Br)c1)c1nsnc1N
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nsnc1C(=NO)Nc1ccc(F)c(Br)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 79.4 %

Procedure:
A solution of methyl 4-amino-N-(3-bromo-4-fluorophenyl)-1,2,5-thiadiazole-3-carbimidothioate (78 mg, 0.22 mmol) in ethanol (2.3 mL) was treated with hydroxylamine hydrochloride (62 mg, 0.9 mmol) followed by N,N-diisopropylethylamine (180 μL, 1.0 mmol) and stirred at 90° C. for 16 h. The reaction mixture was purified by preparative HPLC to give the desired product (58 mg, 78%). LCMS for C9H8BrFN5OS (M+H)+: m/z=331.9, 333.9.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11](N(OC)C)=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[Mg][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH3:10])[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cccc([Mg]Br)c1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: COc1cccc(C(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of N2-(tert-butoxycarbonyl)-N-methoxy-N-methyl-L-alaninamide (777 mg, 3.3 mmol) in dry THF (50 ml) was added a solution of bromo(3-methoxyphenyl)magnesium (1M in THF, 10 ml, 10 mmol). The mixture was stirred at r.t. for 5 h, then quenched with saturated aqueous NH4Cl (50 ml). After stirring for 30 min, the layers were separated, the aqueous layer extracted with ethyl acetate (50 ml). The combined organic layers were dried with Na2SO4, and the solvent was removed in vacuo. The subtitle compound was isolated by flash chromatography on silica gel (n-heptane/ethyl acetate, gradient from 20 to 50% ethyl acetate). Yield 471 mg (94%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[CH3:21][C:22]1[C:31]2[C:26](=[C:27]([OH:32])[CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>O1CCCC1>[CH2:21]([C:22]1[C:31]2[C:26](=[C:27]([OH:32])[CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: Cc1ccnc2c(O)cccc12
Reactant: CCCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCCCCc1ccnc2c(O)cccc12
Temperature: 0 °C
Reaction time: 5 h
Yield: 98.8 %

Procedure:
To a solution of 1.10 ml (7.88 mmol) of diisopropylamine in 20 ml of tetrahydrofuran at 0° C. under argon was added 4.1 ml (6.23 mmol) of 1.52M n-butyl lithium in hexanes dropwise. To the lithium diisopropylamide solution was added 502.0 mg (3.15 mmol) of 4-methyl-8-quinolinol (see example 1A) in 10 ml of tetrahydrofuran over 15 minutes at 0° C. The dark solution, which contained some insoluble material, was allowed to stir for five hours at 0° C., cooled to -78° C. and 0.46 ml (3.31 mmol) of 1-bromohexane was added. After 30 minutes at -78° C., the reaction was allowed to warm gradually from -30° C. to room temperature over 1.5 hours. The solution was allowed to stir for 45 minutes at room temperature, quenched with pH 6.5 phosphate buffer and extracted with ether. The ether extract was washed with water and brine, dried (magnesium sulfate) and evaporated to afford 757 mg of a yellow-brown solid. This material was dissolved in hot hexane, filtered to remove an insoluble residue and the filtrate was evaporated. Recrystallization from heptane provided 511.7 mg of the title compound as yellow plates: melting point 92°-93.5° C.
Reaction SMILES: II.[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=O)[CH2:17][O:18]C)[CH2:11]2)=[N:8][CH:9]=1.[BH4-].[Na+]>O1CCCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][CH2:16][CH2:17][OH:18])[CH2:11]2)=[N:8][CH:9]=1
Reactant: COCC(=O)N[C@@H]1CCN(c2ccc(Br)cn2)C1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCN[C@@H]1CCN(c2ccc(Br)cn2)C1
Temperature: 25 °C
Yield: 26.4 %

Procedure:
Add dropwise via an addition funnel a solution of iodine (727 mg, 2.86 mmol) in tetrahydrofuran (5 mL) over 15 min to a mixture of N—[(R)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-yl]-2-methoxy-acetamide (500 mg, 1.59 mmol) and sodium borohydride (217 mg, 6.05 mmol) in tetrahydrofuran (5 mL). Heat the colorless mixture at reflux overnight, then cool to room temperature and slowly quench with MeOH until no foaming is observed. Concentrate the material in vacuo. Add 1N NaOH (20 mL) to the residue and extract the mixture with dichloromethane (3×20 mL). Dry the combined organics over Na2SO4, filter, and concentrate to dryness. Purify using chromatography (0 to 10% MeOH/CH2Cl2) to afford 120 mg (26%) of the title compound. LC-MS/ES m/z (79Br) 286.2 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([CH3:26])[CH2:3][C:4]1[N:8]2[C:9]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:10]=3[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])=[N:12][CH2:13][C:7]2=[N:6][N:5]=1.C=O.[C:29](O)(=O)C.C([BH3-])#N.[Na+]>C(#N)C>[CH3:29][NH:1][CH:2]([CH3:26])[CH2:3][C:4]1[N:8]2[C:9]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:10]=3[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])=[N:12][CH2:13][C:7]2=[N:6][N:5]=1
Reactant: CC(=O)O
Reactant: CC(N)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Product: CNC(C)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
A solution of 0.001 mole of 1-(2-aminopropyl)-8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in acetonitrile is successively treated with 0.001 mole each of formaldehyde, acetic acid and sodium cyanoborohydride at room temperature. The mixture is concentrated in vacuo and the residue treated with 25% aqueous ethylene diamine (5 ml.) and methanol (10 ml.) and refluxed under nitrogen for 2 hours. This mixture is concentrated and the residue mixed with water and extracted with chloroform. The chloroform extracts were filtered, evaporated, and crystallized to give 1-[2-(methylamino)propyl]-8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[C:23]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)(=[O:25])[NH2:24]>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:12]([O:11][N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:30]3[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=3)[C:23]([NH2:24])=[O:25])[CH:3]=2)[CH:8]=[CH:9]1)[CH3:13]
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Product: CC(On1ccc2ncc(-c3cccc(C(N)=O)c3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and (3-carbamoylphenyl)boronic acid according to the procedure described in example 4.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][CH2:6][N:7]1[CH2:14][CH:13]2[O:15][CH:9]([CH2:10][N:11]([CH2:16][CH2:17][O:18][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[CH2:12]2)[CH2:8]1.[CH3:27][C:28]1[C:32]([S:33](Cl)(=[O:35])=[O:34])=[C:31]([CH3:37])[O:30][N:29]=1.C(N(CC)CC)C>C(Cl)Cl>[C:23]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][N:11]2[CH2:10][CH:9]3[O:15][CH:13]([CH2:14][N:7]([CH2:6][CH2:5][NH:4][S:33]([C:32]4[C:28]([CH3:27])=[N:29][O:30][C:31]=4[CH3:37])(=[O:35])=[O:34])[CH2:8]3)[CH2:12]2)=[CH:26][CH:25]=1)#[N:24]
Reactant: N#Cc1ccc(OCCN2CC3CN(CCN)CC(C2)O3)cc1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1S(=O)(=O)NCCN1CC2CN(CCOc3ccc(C#N)cc3)CC(C1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
4-{2-[7-(2-Amino-ethyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-ethoxy}benzonitrile tri hydrochloride salt (1 g, 2.35 mmol; Prep F) and 3,5-dimethylisoxazole-4-sulfonyl chloride (0.597 g, 3 mmol) were dissolved in DCM (25 mL). Triethylamine (1.95 mL, 3 mmol) was added and the reaction mixture was stirred at room temperature overnight under a nitrogen amosphere. The reaction mixture was concentrated and then redissolved in DCM (25 mL) and transferred to a phase separator. The DCM layer was washed with water (30 mL) and the layers were separated. The retained water was extracted with DCM (25 mL) and the layers were separated. The combined DCM fractions were concentrated under reduced pressure. Purification was performed by precipitation from a mixture of DCM, EtOAc and IPA to give a solid material (0.2 g, 17%).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:29]([C:30]4[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[C:33]([F:39])=[CH:32][C:31]=4[O:40][CH3:41])=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[N+:42]([O-])=O)[CH:21]=3)[C@H:14]2[CH3:45])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>[Pd].CCOC(C)=O>[NH2:42][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[CH:28]=[C:29]([C:30]1[CH:35]=[C:34]([CH:36]([CH3:37])[CH3:38])[C:33]([F:39])=[CH:32][C:31]=1[O:40][CH3:41])[C:20]([CH2:19][N:15]1[C@@H:14]([CH3:45])[C@@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:47])([F:1])[F:46])[CH:4]=3)[O:17][C:16]1=[O:18])=[CH:21]2
Reactant: COc1cc(F)c(C(C)C)cc1-c1cc2c([N+](=O)[O-])cccc2cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(F)c(C(C)C)cc1-c1cc2c(N)cccc2cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 8 h

Procedure:
A suspension of 10% palladium on carbon (4.0 mg) in a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)-5-nitro-2-naphthyl]methyl}-4-methyl-1,3-oxazolidin-2-one (21.3 mg, 0.0321 mmol) in EtOAc (2.5 mL) was stirred under H2 (double balloon pressure) overnight. The reaction mixture was filtered through a plug of Celite and the filtrate was concentrated in vacuo to afford (4S,5R)-3-{[5-amino-3-(4-fluoro-5-isopropyl-2-methoxyphenyl)-2-naphthyl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=635.2; found=634.8 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([NH2:30])[CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[S:42](Cl)(=[O:44])=[O:43]>O>[CH2:1]([O:8][C:9]([N:11]1[C:15]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([NH:30][S:42]([C:38]2[S:37][CH:41]=[CH:40][CH:39]=2)(=[O:44])=[O:43])[CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc3cc(Cl)c(Cl)cc3n2C(=O)OCc2ccccc2)cc1N
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-c2nc3cc(Cl)c(Cl)cc3n2C(=O)OCc2ccccc2)cc1NS(=O)(=O)c1cccs1
Reaction time: 8 h

Procedure:
2-(3-Amino-4-methoxy-phenyl)-5,6-dichloro-benzoimidazole-1-carboxylic acid benzyl ester from Step C was mixed with pyridine (5 mL) and 2-thienylsulfonyl chloride (0.1283 g, 0.7 mmol) was added. The mixture was allowed to stand overnight. Water (100 mL) was added to the reaction mixture and the product crystallized within 5 hours. The solid was then collected by filtration and triturated with 1/1, hexanes/ethyl acetate (0.2 g), mp 195-198° C.
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:26])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][SH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1.[C:29]([NH:32][C@H:33]([C:38](O)=[O:39])[CH2:34][CH2:35][S:36][CH3:37])(=[O:31])[CH3:30]>>[C:29]([NH:32][CH:33]([CH2:34][CH2:35][S:36][CH3:37])[C:38](=[O:39])[S:18][CH2:17][C:16](=[O:19])[C@:15]1([OH:25])[C@:20]2([CH3:24])[C@H:12]([C@H:11]3[C@:2]([F:1])([CH:22]([OH:23])[CH2:21]2)[C@:3]2([CH3:28])[C:8](=[CH:7][C:6](=[O:27])[CH:5]=[CH:4]2)[CH2:9][CH2:10]3)[CH2:13][C@@H:14]1[CH3:26])(=[O:31])[CH3:30]
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CS
Reactant: CSCC[C@H](NC(C)=O)C(=O)O
Product: CSCCC(NC(C)=O)C(=O)SCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)C(O)C[C@@]21C
Yield: 53.4 %

Procedure:
The title compound (0.38 gm) was prepared from 9-fluoro-11β,17-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione-21-thiol (0.50 gm) and N-acetyl-L-methionine (0.70 gm) in the same manner as in Synthetic Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:20])[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1Br)[CH3:9].[OH:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:20])[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[C:25]1[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=1)[CH3:9]
Reactant: CC(OC(=O)Nc1ccncc1Br)c1ccccc1Cl
Reactant: OB(O)c1ccc(O)cc1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(OC(=O)Nc1ccncc1-c1ccc(O)cc1)c1ccccc1Cl
Temperature: 80 °C

Procedure:
(3-Bromo-pyridin-4-yl)-carbamic acid 1-(2-chloro-phenyl)-ethyl ester (0.180 g, 0.51 mmol), 4-hydroxyphenylboronic acid (0.104 g, 0.76 mmol) and potassium carbonate (0.245 g, 1.78 mmol) were suspended in DME:H2O (2:1, 3 mL). The suspension was purged with N2 (g) for 5 minutes then tetrakis(triphenylphosphine)palladium(0) (0.058 g, 0.051 mmol) was added and the N2 (g) purge continued for 5 additional minutes. The reaction vessel was sealed and heated to 80° C. for 1 hour then allowed to cool. The reaction mixture was submitted to EtOAc/H2O workup then purified on silica gel to yield the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH:33][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-dimethylamino-ethyl)-amide (42 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), N,N-dimethyl-ethylenediamine (0.29 ml), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 480. 1H NMR (DMSO-d6, 400 MHz): δ 8.16 (t, 1H), 7.81 (s, 1H), 7.61 (d, 1H), 7.49 (d, 1H), 7.29 (d, 1H), 7.15 (d, 1H), 7.07 (d, 1H), 3.56 (s, 3H), 3.32 (m, 2H), 2.85 (m, 2H), 2.41 (t, 1H), 2.17 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([S:12][CH3:13])=[N:7][C:6]=1Cl)[CH3:2].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([S:12][CH3:13])=[N:7][C:6]=1[NH:19][CH:16]1[CH2:18][CH2:17]1)[CH3:2]
Reactant: CCOC(=O)c1cc(F)c(SC)nc1Cl
Reactant: NC1CC1
Solvent: CC#N
Product: CCOC(=O)c1cc(F)c(SC)nc1NC1CC1
Yield: 69.1 %

Procedure:
A solution of 8.7 g (34.8 mmol) of 2-chloro-5-fluoro-6-methylsulfanylnicotinic acid ethyl ester (J. Med. Chem., 1993; 36:2676) and 5.7 g (100 mmol) of cyclopropylamine in 100 mL of acetonitrile is heated at reflux for 18 hours. After TLC showed the presence of unreacted starting material, 4.12 g (72 mmol) of cyclopropylamine is added and the reaction mixture is refluxed for 48 hours. The solvent is removed in vacuo and the residue is partitioned between dichloromethane (250 mL) and water (100 mL). The organic layer is washed with water, dried (MgSO4), filtered, and concentrated in vacuo. The residue is chromatographed over flash grade silica gel (230–400 mesh) eluting with dichloromethane to give 6.5 g of the title compound, mp 67–69° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]23[CH2:16][CH2:15][C:12]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH2:13][CH2:14]2)[CH2:11][CH2:10]3)=[CH:5][C:4]=1[N+]([O-])=O)#[N:2].[F-:25].[Cs+]>CN1CCCN(C)C1=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]23[CH2:16][CH2:15][C:12]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH2:13][CH2:14]2)[CH2:11][CH2:10]3)=[CH:5][C:4]=1[F:25])#[N:2]
Reactant: CCCCCC12CCC(c3ccc(C#N)c([N+](=O)[O-])c3)(CC1)CC2
Reactant: [F-]
Agent: [Cs+]
Solvent: CN1CCCN(C)C1=O
Product: CCCCCC12CCC(c3ccc(C#N)c(F)c3)(CC1)CC2
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
0 85 g of 1-(4-cyano-3-nitrophenyl)-4-n-pentylbicyclo[2.2.2]octane is dissolved in 8 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone, 2.16 g of caesium fluoride are added and the mixture is heated, with stirring, at 120° C. for 2.5 hours. Dilution with water and workingup after extraction gives 1-(4-cyano-3-fluorophenyl)-4-n-pentylbicyclo[2.2.2]octane, which is purified by chromatography and crystallization. m.p. 63°; c.p. 53.3°
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:8][C@H:6]1[N:7]([C:23](=[O:24])[CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:5]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cc1ccccc1

Procedure:
Prepared by the method of example 67 part (a) using (3R,5S)-3,5-dimethyl-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester and phenyl acetyl chloride to give the sub-title compound.
Reaction SMILES: [CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:29]=[CH:28][C:23]4[N:24]=[C:25]([NH2:27])[NH:26][C:22]=4[CH:21]=3)=[CH:18][CH:19]=2)=[O:14])[C:8](=[O:11])[NH:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:29]=[CH:28][C:23]4[N:24]=[C:25]([NH:27][C:30](=[O:32])[CH3:31])[NH:26][C:22]=4[CH:21]=3)=[CH:18][CH:19]=2)=[O:14])[C:8](=[O:11])[NH:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC(=O)[C@@H](NC(=O)c1ccc(-c2ccc3nc(N)[nH]c3c2)o1)C1CCCCC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CNC(=O)[C@@H](NC(=O)c1ccc(-c2ccc3nc(NC(C)=O)[nH]c3c2)o1)C1CCCCC1
Temperature: 100 °C

Procedure:
To a solution of 5-(2-amino-3H-benzimidazol-5-yl)-furan-2-carboxylic acid ((S)-cyclohexyl-methylcarbamoyl-methyl)-amide (10 mg, 0.025 mmol) in anhydrous pyridine (1 mL) is added acetic anhydride. The mixture is heated at 100° C. for 2 h. After cooling to room temperature the mixture is purified by reversed phase (HPLC). 4.6 mg, 42%, LC/MS ESI m/z (M+H)+=438.47.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:24]C2CCCCC2)[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:31]([CH2:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)#[N:32]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:38]4[CH:39]=[C:34]([CH2:33][C:31]#[N:32])[CH:35]=[CH:36][CH:37]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: NC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1CC1CCCCC1
Reactant: N#CCc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(CC#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 23.9 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.014 mmol) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-(cyclohexylmethyl)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(cyanomethyl)phenylboronic acid (16.7 mg, 0.104 mmol). The mixture was heated at 120° C. in a microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC followed by preparative HPLC to give pure 2-(3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)phenyl)acetonitrile (5.25 mg, 24%). 1H-NMR (MeOD): 2.04 (m, 1H), 2.21 (m, 1H), 3.08 (d, 3H), 3.85 (s, 2H), 5.21 (d, 0.2H), 5.81 (d, 0.8H), 6.94 (d, 1H), 7.11 (m, 1H), 7.24 (m, 2H), 7.35 (m, 3H), 7.39 (m, 5H).