Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:48])([CH3:47])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31][CH:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29][CH2:28]2)[CH:9]=1.[Br:49]N1C(=O)CCC1=O>C(#N)C>[CH3:44][Si:43]([CH3:46])([CH3:45])[CH2:42][CH2:41][O:40][CH2:39][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:47])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31][CH:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29][CH2:28]2)[C:9]=1[Br:49]
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)CC1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a 25 mL roundbottom flask was charged ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)-methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (198 mg, 287 μmol) and acetonitrile (10 mL). To this solution was added N-bromosuccinimide (56 mg, 316 μmol). The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the resulting oil was then purified via silica gel chromatography (0% to 30% ethyl acetate in hexanes gradient) to yield ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (205 mg, 266 μmol, 93% yield) as yellow oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:23])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20]Cl)[CH:7]=1.CO>C1COCC1>[CH3:3][O:4][C:5](=[O:23])[C:6]1[CH:7]=[C:8]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]2=[O:22])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1
Reactant: COC(=O)c1cc(NC(=O)CCCCCl)cc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N2CCCCC2=O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
NaH (60% w/w in mineral oil, 680 mg, 17 mmol, 0.9 equiv) was added portionwise to a solution of 3-(5-chloro-pentanoylamino)-5-nitro-benzoic acid methyl ester (D3) (6 g, 19 mmol, 1 equiv) in THF (40 ml) under nitrogen. The resulting mixture was stirred at room temperature for 1 h and then MeOH was added dropwise. The solution was concentrated in vacuo and the residue diluted with AcOEt. The organic phase was washed with H2O, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (AcOEt/iso-hexane: 1/2) gave 3-nitro-5-(2-oxo-piperidin-1-yl)-benzoic acid methyl ester (B82) (2.8 g, 53%) as a pale orange oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[C:7]=1[C:15]1[C:16]2[NH:23][CH:22]=[C:21]([C:24]([OH:26])=O)[C:17]=2[N:18]=[CH:19][N:20]=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH2:3][O:2][CH3:1])[C:16]=3[NH:23][CH:22]=2)=[O:26])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)O)c[nH]c13)OCO2
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A72) and commercially available 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11](=[O:12])[C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: O=C(CBr)c1ccsc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccsc1
Temperature: 25 °C
Yield: 45.2 %

Procedure:
A mixture of 5-chloropyrimidin-2-one (522 mg) and 3-bromoacetylthiophene (1.025 g) in triethylamine (0.84 ml) and ethanol (25 ml) was stirred at room temperature. After 1 h. the mixture was cooled to 3° C., the resulting precipitate was collected, then dried and recrystallised twice from ethanol to give the title pyrimidinone (460 mg), m.p. 227°-230° C., λmax (EtOH) 250 nm (ε 15,770), 333 nm (ε 2,690).
Reaction SMILES: [C:1]([C:4]1[C:13](=O)[C:12]2[C:7](=[C:8]([N+:15]([O-:17])=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:20])=O>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[Cl:20])=[CH:11][CH:10]=[CH:9][C:8]=2[N+:15]([O-:17])=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c[nH]c2c([N+](=O)[O-])cccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Temperature: 115 °C

Procedure:
A mixture of 3-acetyl-1,4-dihydro-8-nitro-4-oxoquinoline (500 mg) and phosphoryl chloride was heated at 115° C. for 15 minutes. After cooling, the mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo to give 3-acetyl-4-chloro-8-nitroquinoline (485 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([N-]C(C)C)(C)C.[Li+].[C:18]1([CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([CH:31]=[CH:32][CH:33]=[O:34])[CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.C1CCCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:33]([OH:34])[CH:32]=[CH:31][CH:28]1[CH2:27][CH2:26][N:25]([CH2:24][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:30][CH2:29]1
Reactant: c1ccc2scnc2c1
Reactant: O=CC=CC1CCN(Cc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: OC(C=CC1CCN(Cc2ccccc2)CC1)c1nc2ccccc2s1
Reaction time: 0.25 h

Procedure:
A solution of benzothiazole (0.243 g, 1.8 mmol) in 5 ml of dry THF was treated with 1.5M lithium diisopropylamide in cyclohexane (1.45 ml) at -78° C. and stirred at that temperature for 15 minutes. A solution of 3-[1-(phenylmethyl)-4-piperidinyl]propenal (452 mg, 1.97 mmol) in 3 ml of dry THF was added at -78 ° C. and stirred at that temperature for 30 minutes. The mixture was quenched with water and extracted with chloroform. The organic layer was dried and concentrated to give a thick yellow oil in a quantitative yield.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]([O:6][Si:7]([CH3:10])([CH3:9])[CH3:8])=[C:4]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1.C([Li])CCC.[C:26]1([P:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)Cl)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Cl-].[Li+]>O1CCCC1.CCCCCC>[C:17]([C:4]1[CH:3]=[C:2]([P:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=1[O:6][Si:7]([CH3:10])([CH3:9])[CH3:8])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1O[Si](C)(C)C
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1cc(P(c2ccccc2)c2ccccc2)cc(C(C)(C)C)c1O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 107.3 %

Procedure:
A stirred suspension of 20.0 g (56 mmol) of 4-bromo-2,6-di-tert-butylphenoxy(trimethyl)silane in 80 ml of dry tetrahydrofuran at -78° C. is admixed dropwise with 38 ml (56 mmol) of a 1.55M solution of n-butyllithium in hexane. The resulting homogeneous solution is stirred for 1 hour at -78° C. and then 12.36 g (56 mmol) of diphenylchlorophosphine is added dropwise. The reaction mixture is stirred for 24 hours at room temperature, and then the suspension of lithium chloride is removed by filtration. The solvent is removed in vacuo. The residue is dissolved in 250 ml of diethyl ether and extracted (3×250 ml) with water. The organic phase is dried over anhydrous sodium sulfate and evaporated in vacuo to give 27.8 grams of a yellow liquid. The crude product is purified by preparative HPLC (silica gel, 99:1 heptane:ethyl acetate eluent) to give 10.7 grams (41%) of a white solid, m.p. 76°-80° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[C:3](=[C:11]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)/[CH:4]=[CH:5]/[C:6]([O:8]CC)=[O:7].[OH-].[Na+].Cl>C1(C)C=CC=CC=1>[CH3:1][CH:2]([CH3:26])[C:3](=[C:11]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)/C=C/C(=C(c1ccc(F)cc1)c1ccc(F)cc1)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)C(/C=C/C(=O)O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 77.3 %

Procedure:
A toluene (8 ml) solution of the above ester (2.38 g, 6.7 mmol) was added to powdery sodium hydroxide (0.34 g, 8.5 mmol) under argon atmosphere, and the whole was stirred at 60° C. for 5 hours. The reaction mixture was neutralized with 1M hydrochloric acid (10 ml) and extracted with ethyl acetate (25 ml×3 times). The organic layer was washed with water, saturated sodium chloride aq solution and then dried over anhydrous magnesium sulfate. Concentration of the organic layer in vacuo followed by recrystallization from a mixed solvent (hexane:ethyl acetate=4:1) gave 1.70 g (78% yield) of (E)-5-methyl-4-bis(4-fluorophenyl)methylidene-2-hexenoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:4]=1[C:5]([C:7]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:8]=1[C:9](O)=[O:10])=O.O.[NH2:25][NH2:26]>>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:4]=1[C:5]1[C:7]2[C:8](=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:9](=[O:10])[NH:26][N:25]=1
Reactant: NN
Reactant: COc1ccc(OC)c(C(=O)c2ccc(OC)cc2C(=O)O)c1
Solvent: O
Product: COc1ccc(OC)c(-c2n[nH]c(=O)c3cc(OC)ccc23)c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 2-(2,5-dimethoxybenzoyl)-5-methoxybenzoic acid with hydrazine hydrate.
Reaction SMILES: C[Si]([N-:5][Si](C)(C)C)(C)C.[Li+].Cl[CH:12]([B:15]1[O:19][C:18]([CH3:21])([CH3:20])[C:17]([CH3:23])([CH3:22])[O:16]1)[CH2:13][CH3:14].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>O1CCCC1>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[CH2:13]([CH:12]([B:15]1[O:19][C:18]([CH3:21])([CH3:20])[C:17]([CH3:23])([CH3:22])[O:16]1)[NH2:5])[CH3:14]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCC(Cl)B1OC(C)(C)C(C)(C)O1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCC(N)B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
10 ml (10 mmol) of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran were added dropwise to a solution of 2.03 g (9.9 mmol) of 2-[1(RS)-chloropropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 20 ml tetrahydrofuran under a nitrogen atmosphere at -78° C. The solution was then stirred overnight at room temperature. The solvent was removed by evaporation and the residue was taken up in diethyl ether. Insoluble material was removed by filtration and the filtrate was cooled to 0° C. 2.3 ml (30 mmol) of trifluoroacetic acid were added and the solution was stirred at 0° C. for 30 minutes. The resulting precipitate was filtered off and dried to give 0.5 g of a-(RS)-ethyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-methylamine trifluoroacetate as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([C@@H:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:25])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][Mg]Cl.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([C:18]2[CH:19]=[CH:20][C:21]([C@@H:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:25])=[CH:22][CH:23]=2)([OH:34])[CH3:35])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(C)(O)C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
112 mg of the compound [22-1] was dissolved in 5 mL of tetrahydrofuran, and cooled to 0° C. Thereafter, 320 μL of methylmagnesium chloride (3.0M tetrahydrofuran solution) was added thereto, and the mixture was stirred for 1.5 hours while heating back to room temperature. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the solution was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0-30/70), to obtain 53 mg of benzyl-4-[1-(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)-1-hydroxyethyl]piperidine-1-carboxylate [22-2] (hereinafter, referred to as the compound [22-2]).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH:5]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])C.[OH-].[Na+]>C(O)C>[C:20]1([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:4]([OH:26])=[O:3])=[CH:19][CH:18]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1
Reactant: CCCCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 38 g of α-[p-(1-cyclohexenyl)-phenoxy]-nonanoic acid ethyl ester in 150 ml of ethanol are added 150 ml of 2N sodium hydroxide solution and the mixture is stirred at room temperature for 2 hours. The ethanol is stripped off in vacuo and the residue partitioned between 2N hydrochloric acid and ether. The organic phase is washed until neutral, dried over sodium sulphate and evaporated to dryness. Distilation of the residue at 0.04 mm yields in the fraction boiling at 173°-176° C the α-[p-(1-cyclohexenyl)-phenoxy]-nonanoic acid of the formula ##STR16## (m.p. 61°-63° C).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].ClC(Cl)(Cl)[C:28]([N:30]=C=O)=[O:29]>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([NH:23][C:28]([NH2:30])=[O:29])[CH3:22])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3ccc(C(C)N)cc3)s2)cc1
Solvent: ClCCl
Product: CC(C)Oc1ccc(Oc2ncc(-c3ccc(C(C)NC(N)=O)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
To a solution of Example 1F (0.15 g, 0.0004 mol) in methylene chloride (5 mL) was added trichloroacetyl isocyanate (0.08 mL, 0.0006 mol) and the mixture was stirred at room temperature for 15 minutes, and concentrated. The residue was dissolved in methanol (10 mL) and refluxed with a few drops of saturated sodium carbonate solution for 0.5 hours. The mixture was cooled to room temperature, concentrated to dryness and triturated with methanol (15 mL) and water (2 mL) to give 0.15 g of the title compound (88% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.23-1.34 (m, 9 H) 4.55-4.75 (m, 2 H) 5.42 (s, 2 H) 6.44 (d, J=8.09 Hz, 1 H) 6.97-7.05 (m, 2 H) 7.25-7.36 (m, 4 H) 7.49 (d, J=8.09 Hz, 2 H) 7.65 (s, 1 H). MS (ESI), m/z 397.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8](=[O:16])[C:9]=1[NH:10]2.[F-].[Cs+].[C:19]([Si](C)(C)C)([F:22])([F:21])[F:20]>C1COCC1>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:3]=1[C:4]1[CH:5]([C:19]([F:22])([F:21])[F:20])[CH2:6][CH2:7][CH:8]([OH:16])[C:9]=1[NH:10]2
Reactant: O=C1CCCc2c1[nH]c1c(Cl)ccc(Cl)c21
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: OC1CCC(C(F)(F)F)c2c1[nH]c1c(Cl)ccc(Cl)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.5 %

Procedure:
To a solution of 5,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.1 g, 0.39 mmol) in anhydrous THF (8 mL) at 0° C., CsF (59 mg, 0.39 mmol) and CF3TMS (0.56 g, 3.93 mmol) were added. The reaction mixture was slowly warmed to room temperature and stirred for 18 h. After the volatiles were removed in vacuo, the residue was diluted with water and extracted with EtOAc (2×15 mL) to give the crude compound which was purified by silica gel chromatography [EtOAc-hexane (1:4) as eluant] to give the title compound (0.127 g, 16%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 11.07 (s, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 6.62 (s, 1H), 3.01-3.0 (m, 2H), 2.22-2.19 (m, 1H), 1.97-1.92 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([CH3:21])[C:15]([F:20])=[C:16](F)[CH:17]=2)[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.C([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])C>C(#N)C>[NH2:9][C:3]([C@@H:32]1[CH2:30][CH2:29][N:28]([C:16]2[CH:17]=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[C:14]([CH3:21])[C:15]=2[F:20])[CH2:31]1)([CH3:4])[CH3:2]
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Reactant: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(F)c(N2CC[C@@H](C(C)(C)N)C2)cc2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Temperature: 25 °C
Yield: 244.2 %

Procedure:
A solution of 0.92 g (2.62 mmol) of 1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.90 g (3.9 mmol) of (3R)-(1,-methyl-1'-t-butoxycarbonylaminoethyl)pyrrolidine (9a), 0.80 g (7.9 mmol) of triethylamine, and 50 mL of acetonitrile was heated at reflux for 18 hours. The solution was cooled to room temperature and concentrated in vacuo to an orange solid. The residue was chromatographed on E. Merck silica gel (230-400 mesh), eluting with 90:10 CHCl3:MeOH to give 1.47 g of (R) 7-[3-(1-t-butoxycarbonylamino-1-methylethyl)-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid; NMR (CDCl3) δ8.47 (s, 1 H), 7.44 (m, 1 H), 7.15 (m, 2 H), 5.64 (d, J=7 HZ, 1 H), 4.47 (bs, 1 H), 3.50- 3.20 (m, 4 H), 2.85 (d, J=3.5 HZ, 3 H), 1.91 (m, 1 H), 1.74 (m, 2 H), 1.42 (s, 9 H), 1.29 (d, J=11 HZ, 6 H).
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16](I)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].C1(C)C=CC=CC=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>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.C(O)C>[C:1]([C:3]1[CH:17]=[C:16]([C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: OB(O)c1ccncc1
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
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: Cc1ccccc1
Solvent: CCO
Product: N#Cc1cc(-c2ccncc2)c2c(c1)ncn2-c1ccccc1
Yield: 32.4 %

Procedure:
5-Cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), pyridin-4-yl boronic acid (62 mg, 0.5 mmol), ethanol (3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) were combined and the mixture was stirred at reflux overnight. The solvent was removed under reduced pressure and the crude product was purified on a 2 g silica Isolute® SPE column, eluting with dichloromethane/methanol (95:5). The eluent was concentrated under reduced pressure and the crude product was suspended in acetonitrile then treated with diethyl ether to precipitate the product. The mother liquors were removed by filtration and the residual solid was further purified on a Biotage silica gel cartridge, eluting with dichloromethane/methanol (98:2). Recrystallisation from dichloromethane/diethyl ether afforded the title compound (48 mg, 32%) m/z, 297.4 (M+H)+.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH3:28])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[N:20]=[N:21][NH:22][C:23]=3[Si](C)(C)C)[CH:14]=2)[C:8]1=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F-].[K+]>C(O)C.Cl>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH3:28])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[NH:20][N:21]=[N:22][CH:23]=3)[CH:14]=2)[C:8]1=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2nn[nH]c2[Si](C)(C)C)c1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2cnn[nH]2)c1
Temperature: 25 °C

Procedure:
To a solution of 3-hexyl-6-methyl-6-{3-[5-(trimethylsilyl)-1H-1,2,3-triazol-4-yl]phenyl}-3-azabicyclo[3.1.0]hexan-2-one (Preparation 39, 1.2 g, 2.88 mmol) in ethanol (15 ml) was added potassium fluoride (183 mg, 3.17 mmol) and a few drops of concentrated hydrochloric acid. The mixture was heated at reflux for 1.5 hours and then cooled to room temperature. The solvent was removed in vacuo and the crude residue was dissolved in dichloromethane (40 ml) and washed with 10% potassium carbonate solution. The extract was dried (MgSO4), filtered and concentrated in vacuo to give the crude product which was used directly in the next step.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[C:32]2=[C:33](Br)[CH:34]=[C:35]([CH:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)[N:31]2[N:30]=[CH:29][N:28]=1>>[NH2:26][C:27]1[C:32]2=[C:33]([C:14]3[CH:15]=[CH:16][C:10]4[S:9][C:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[N:12][C:11]=4[CH:13]=3)[CH:34]=[C:35]([CH:36]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]3)[N:31]2[N:30]=[CH:29][N:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Br)c3c(N)ncnn23)CC1
Reactant: CC1(C)OB(c2ccc3sc(Cc4ccccc4)nc3c2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc4sc(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 95.6 %

Procedure:
In a manner similar to the procedure described for step 7 of the preparation of Example 330 and using 2-benzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazole and tert-butyl 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate as starting material, 411 mg (95.6%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 8.06 (s, 1H), 8.94 (s, 1H), 8.92 (d, 1 H), 7.49 (d, 1H), 7.37-7.45 (m, 5 H), 6.59 (s, 1H), 4.49 (s, 2 H), 4.25 (m, 2 H), 3.42 (m, 1H), 2.94 (m, 2H), 2.11 (m, 2H), 1.76-1.64 (m, 2 H), 1.48 (s, 9H); LC-MS m/z [M+H]+541.2, RT 3.37 min.