Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2=[CH2:18].[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20]>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>[CH2:18]=[C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:25]3[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=3)[C:19]#[N:20])[CH:3]=2)[O:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: C=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=C1CC(c2ccccc2)Oc2ccc(-c3cccc(C#N)c3)cc21
Yield: 50.8 %

Procedure:
Pd(PPh3)2Cl2 (40 mg) in a 100 mL of flask under Ar2 was treated sequentially with 6-bromo-4-methylene-2-phenylchroman (200 mg, 0.67 mmol) in [1,4]dioxane (20 mL), Cs2CO3 (2 N, 3.33 mL) and 3-cyanophenylboronic acid (167 mg, 1.13 mmol). The mixture was heated under 120 at Ar2 under microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC to give 3-(4-methylene-2-phenyl-chroman-6-yl)-benzonitrile (110 mg, 51%). 1H-NMR (CDCl3): 2.81 (m, 2H), 4.96 (d, 1H), 5.10 (m, 1H), 5.61 (d, 1H), 7.98 (d, 1H), 7.29 (m, 1H), 7.35 (m, 3H), 7.41 (m, 2H), 7.46 (m, 1H), 7.52 (m, 1H), 7.72 (m, 2H), 7.79 (d, 1H).
Reaction SMILES: N([O-])=O.[Na+].[N+:5]([C:8]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:9]=1N)([O-:7])=[O:6].[BrH:16]>O>[N+:5]([C:8]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:9]=1[Br:16])([O-:7])=[O:6]
Reactant: Br
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 10 g of sodium nitrite in 30 ml of water were added with stirring at 0° C. to a suspension of 21.6 g of the product of Step B, 69 ml of 48% hydrobromic acid and 138 ml of water and the mixture was stirred at 0° C. for 10 minutes and then added with stirring to a solution of 30 g of cuprous bromide in 105 ml of 48% hydrobromic acid at 60° C. The mixture was stirred at 55°-60° C. for one hour and was poured into ice water. The mixture was extracted with isopropyl ether and the combined organic phases were dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with methylene chloride. The solution was evaporated to dryness and the residue was dried under reduced pressure to obtain 20.2 g of 2-nitro-4-fluoro-bromobenzene melting at 40°-41° C.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].[Li]CCCC.C[Si](C)(C)[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].C(I)C.Cl>C1COCC1.CCCCCC>[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([CH2:1][CH3:2])[C:23]([O:25][CH3:26])=[O:24]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)Cc1ccccc1O[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCI
Product: CCC(C(=O)OC)c1ccccc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (0.46 mL) in THF (3 mL) at 0° C. was added 1.6M BuLi in hexane (2.01 mL). After stirring for 30 minutes at 0° C., 2.74 mL of this solution was added to a solution of methyl (2-trimethylsilyloxyphenyl)acetate from Step 1, (357 mg) in THF (5 mL) at 0° C. After 20 minutes, ethyl iodide (0.144 mL) was added and the mixture was stirred for 18 hours at r.t. Then, 2 mL of 1N HCl was added and the resulting mixture was stirred for 30 minutes, extracted with EtOAc, washed twice with brine, dried over MgSO4, filtered, and evaporated to dryness, giving the title compound.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:20]([OH:22])=O)[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])[CH3:11])=[O:8])[CH3:6])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:38]([O:40][C:41](=[O:50])[C:42]([C:45](=[O:49])[N:46]([CH3:48])[NH2:47])([CH3:44])[OH:43])[CH3:39]>C(Cl)Cl.O1CCCC1>[CH2:38]([O:40][C:41](=[O:50])[C:42]([C:45](=[O:49])[N:46]([CH3:48])[NH:47][C:20](=[O:22])[C@H:15]([CH2:16][CH:17]([CH3:18])[CH3:19])[NH:14][C:12](=[O:13])[C@H:10]([CH3:11])[NH:9][C:7](=[O:8])[C@H:5]([CH3:6])[NH:4][C:1](=[O:3])[CH3:2])([CH3:44])[OH:43])[CH3:39]
Reactant: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)O
Reactant: CCOC(=O)C(C)(O)C(=O)N(C)N
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(O)C(=O)N(C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(C)=O
Temperature: 25 °C

Procedure:
Acetylalanylalanylleucine (1.5 mmole) and N-methylmorpholine (3 mmole) are dissolved in methylene chloride (10 ml) and diluted with dry tetrahydrofuran (250 ml) and cooled to -20° to -25°. Isobutyl chloroformate (1.5 mmole) is added with stirring and the mixture is stirred for 10 minutes. A solution of 2-azaalanyl-dl-lactic acid ethyl ester (1.5 mmole, Example 5, Step A) in tetrahydrofuran (3 ml) is added and the mixture is allowed to warm to room temperature over a period of 2 hours and stirred overnight. The precipitate is filtered off and the filtrate is evaporated to dryness. Chromatography on silica gel (25 gm) and elution with 12% methanol in chloroform gives acetylalanylalanylleucyl-2-azaalanyl-dl-lactic acid ethyl ester.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C@@H:11]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:27]([C:29]1[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=1)#[CH:28].C(N(CC)CC)C>C(OCC)(=O)C.O.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][N:24]([CH3:26])[CH2:23][C@H:11]([NH:10][S:7]([C:5]1[S:6][C:2]([C:28]#[C:27][C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[CH:3][CH:4]=1)(=[O:9])=[O:8])[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cccc(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cccc(C#Cc2ccc(S(=O)(=O)N[C@H](CC(=O)OCc3ccccc3)CN(C)C)s2)c1
Temperature: 60 °C
Yield: 100.7 %

Procedure:
A solution of (R)-benzyl 3-(5-bromothiophene-2-sulfonamido)-4-(dimethylamino)butanoate (25 mg, 0.05 mmol) and 3-ethynyltoluene (6 mg, 0.055 mmol) in ethyl acetate (0.5 mL) and H2O (50 μL) was purged with argon. Triethylamine (15 μL, 0.1 mmol), copper iodide (0.5 mg, 0.05 eq) and Bis(triphenylphosphine)palladium(II) dichloride (0.9 mg, 0.025 eq) were added and the solution was heated to 60° C. for 2 h. The mixture was cooled and purified by silica gel chromatography (CH2Cl2 to 2% MeOH in CH2Cl2) to give the title compound as a green oil (25 mg, 92%). MS ESI 497.3 [M+H]+, calcd for [C26H28N2O4S+H]+ 497.15.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[C:3]([N:5]=[C:6]=[O:7])=[O:4].[OH:10][CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[C@H:22]([NH:23][C:24](=[O:31])[CH2:25][C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)[C:21](=[O:32])[N:16]2[C:17]=1[C:18]([OH:20])=[O:19]>C(OCC)(=O)C>[S:27]1[CH:28]=[CH:29][CH:30]=[C:26]1[CH2:25][C:24]([NH:23][C@@H:22]1[C:21](=[O:32])[N:16]2[C:17]([C:18]([OH:20])=[O:19])=[C:12]([CH2:11][O:10][C:6](=[O:7])[NH:5][C:3](=[O:4])[C:2]([Cl:9])([Cl:8])[Cl:1])[CH2:13][S:14][C@H:15]12)=[O:31]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)NC(=O)C(Cl)(Cl)Cl)CS[C@H]12
Reaction time: 0.67 h

Procedure:
Trichloroacetylisocyanate (4.3 ml) was added rapidly to a stirred suspension of (6R,7R)-3-hydroxymethyl-7-(2-thienylacetamido)ceph-3-em-4-carboxylic acid (10.62 g) at 6° in ethyl acetate (70 ml). The reaction mixture was stirred at 5° for 40 min. Petroleum ether was added dropwise during 15 min. The mixture was stirred for 30 min, filtered and the solid was washed with petroleum ether and dried to give the title compound as a solid (16.48 g), [α]D22 +73° (c 1.2 in Me2SO).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:12]=[C:11]([NH:13][C:14]([NH:16][C:17]3[C:26]4[C:21](=[C:22]([F:27])[CH:23]=[CH:24][CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[O:15])[CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CN(C=O)C.[H][H]>[Pd].CO.CC(O)=O>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:21]=1[N:20]=[CH:19][CH:18]=[C:17]2[NH:16][C:14]([NH:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[N:12]=1)=[O:15]
Reactant: O=C(Nc1cccc(C2=CCOCC2)n1)Nc1ccnc2c(F)cccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(Nc1cccc(C2CCOCC2)n1)Nc1ccnc2c(F)cccc12
Yield: 98.8 %

Procedure:
A solution of (1-(6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-3-(8-fluoroquinolin-4-yl)urea (21 mg, 0.058 mmol) and 12.3 mg of palladium on charcoal in 20 mL of methanol together with 1 mL of DMF and 1 drop of AcOH was stirred under 1 atm of hydrogen for 18 h. Filtration and evaporation to dryness afforded 21 mg (99%) of the desired title product.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]([NH:12][C:13]([NH2:15])=[O:14])[CH2:5][CH2:4][CH2:3]1.C(O)C.[BH4-].[Na+]>O>[OH:1][C@H:2]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C@H:6]([NH:12][C:13]([NH2:15])=[O:14])[CH2:5][CH2:4][CH2:3]1
Reactant: NC(=O)NC1CCCC(=O)c2sccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)N[C@@H]1CCC[C@@H](O)c2sccc21
Reaction time: 5.5 h

Procedure:
A sample of 1.72 g. of 5,6,7,8-tetrahydro-8-oxo-4H-cyclohepta[b]thien-4-ylurea is stirred in 120 ml. of absolute ethanol and 0.5 g. of sodium borohydride is added. After 5.5 hours, 50 ml. of water is added to the mixture and the mixture is evaporated to dryness in vacuo. Acetone is added to the residue and the mixture is evaporated to dryness. The residue is then extracted with 3×75 ml. portions of boiling acetone, the acetone solution being decanted each time. The combined acetone solutions are filtered and evaporated to dryness. The residue is then washed with diethyl ether and the insoluble solid (contains some gum) is crystallized from methanol/ethyl acetate to afford 0.148 g. of yellow solid. The mother liquor is evaporated to dryness and chromatographed on preparative thin-layer silica-gel chromatographic plates with 15 parts methanol/85 parts chloroform. A fraction melting at 171°-175° C. is then obtained after separation and recrystallization from methanol/ethyl acetate. This material analyzes acceptably (carbon, hydrogen and nitrogen) for the title compound and the infrared spectrum also supports the structure. A second fraction melting at 169°-172° C. is also obtained and its infrared spectrum is virtually identical with that of the above-mentioned fraction.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][CH3:12].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1.CCOC(C)=O>[CH2:11]([S:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][OH:2])[CH3:12]
Reactant: CCSc1ccccc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCSc1ccccc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl-2-(ethylthio)benzoate (5.0 g, 25.5 mmol) in dry THF (67 mL) was added to a stirred solution of LAH (17.5 mL of a 1.0 M solution in THF) in an additional 50 mL dry THF at 0° C. under Ar. The reaction was allowed to warm to room temperature while stirring overnight. The resulting clear solution was diluted with EtOAc (140 mL). The mixture was poured into water (300 mL) and the resulting precipitate was filtered off. The filtrate was extracted with ether (3×200 mL) and the combined organic extracts were dried over MgSO4, filtered, concentrated in vacuo and dried overnight on a high vacuum line to yield the title compound as a pale yellow oil:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[I-].[Na+].CN(C)P(N(C)C)(N(C)C)=O>O.C(O)C.O>[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCCCCCCCc1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCCc2ccccc2)cc1

Procedure:
A mixture of 8.25 g. of ethyl p-aminobenzoate, 5.06 g. of 7-phenylheptylchloride, 3.6 g. of sodium iodide and 25 ml. of hexamethylphosphoramide is heated in an oil bath at 110° C. for 20 hours. The mixture is chilled, diluted with 30 ml. of ethanol-water (1:1) and with water to give crystals, m.p. 65°-67° C. Recrystallization from ethanol gives white crystals, m.p. 66.5°-68° C.
Reaction SMILES: C(O[CH:5]([C:28]1[N:40]=[C:31]2[N:32]=[C:33]([CH3:39])[C:34]3[CH2:38][CH2:37][CH2:36][C:35]=3[N:30]2[N:29]=1)[C:6]1(Br)[C:12](=[O:13])[N:11]2[C@@H:7]1[S:8][CH:9]=[C:10]2[C:14]([O:16]CC1C=CC([N+]([O-])=O)=CC=1)=[O:15])(=O)C.C(#N)C>C1COCC1.[Pd]>[CH3:39][C:33]1[C:34]2[CH2:38][CH2:37][CH2:36][C:35]=2[N:30]2[N:29]=[C:28](/[CH:5]=[C:6]3\[C@@H:7]4[N:11]([C:12]\3=[O:13])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][S:8]4)[N:40]=[C:31]2[N:32]=1
Reactant: CC(=O)OC(c1nc2nc(C)c3c(n2n1)CCC3)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1nc2nc(/C=C3/C(=O)N4C(C(=O)O)=CS[C@H]34)nn2c2c1CCC2
Temperature: 3 °C

Procedure:
4-nitrobenzyl (5R)-6-[(acetyloxy)(5-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (200 mg, 0.31 mmol) was dissolved in THF (20 mL) and acetonitrile (20 mL) and phophate buffer (6.5 pH) (20 ml) and hydrogenated over Pd/C (10%) (200 mg) under 40 psi pressure. At the end, reaction mixture was filtered, cooled to 3° C., and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate was washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was concentrated under high vacuum at 35° C. to give a yellow precipitate. The product was purified by HP21 resin reverse phase column chromatography. Initially the column was eluted with deionized water (2 L) and latter with 10% acetonitrile:water. The fractions containing the product were collected and concentrated under reduced pressure at room temperature. The yellow solid was washed with acetone, filtered and dried. Yield: 15 mg, 13%; as yellow crystals; mp 250° C. (Dec); (M+H+Na) 378. 1H NMR (DMSO-d6) δ 6.80 (s, 1H), 6.76 (s, 1H), 6.25(s, 1H), 3.24(m, 2H), 2.96 (m, 2H), 2.49 (s, 3H), 2.25(m, 2H).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[CH2:10]([NH:17][CH:18]1[CH2:24][CH2:23][CH2:22][C:21]2[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:20]=2[CH2:19]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[CH2:10]([N:17]([CH2:3][CH:2]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[OH:1])[CH:18]1[CH2:24][CH2:23][CH2:22][C:21]2[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:20]=2[CH2:19]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1cncc(C2CO2)c1
Reactant: COc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Solvent: CCO
Product: COc1ccc2c(c1)CC(N(Cc1ccccc1)CC(O)c1cccnc1)CCC2
Yield: 11 %

Procedure:
Under nitrogen, a solution of 3-oxiranylpyridine (1.9 g) and N-benzyl-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (3.3 g) in ethanol (15 ml) was refluxed for 5 hours. After removal of ethanol in vacuo, the residue was dissolved into a mixture of aqueous sodium hydrogencarbonate and ethyl acetate. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol=20:1) to give 2-[N-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-1-(pyridin-3-yl)ethanol (520 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>CN(C)C=O>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[CH:11][CH:10]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: OC1CCNCC1
Solvent: CN(C)C=O
Product: OC1CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
0.202 g (0.002 mol) of 4-hydroxypiperidine and 0.55 g (0.0022 mol) of 4-bromobenzyl bromide were dissolved in 5 ml of dimethylformamide and stirred at room temperature for 2 hrs. The solvent was distilled off and the residue was taken up in dichloromethane and washed with sat. bicarbonate solution and sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated. 0.54 g (100%) of 1-(4-bromo-benzyl)-piperidin-4-ol was obtained as a colorless oil. MS: me/e (% basic peak)=271, 269 (C12H16BrNO30 , 73, 76), 270, 268 (79, 70), 171, 169 (99, 100), 114 (64), 100 (60).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:10][C:11]([CH:13]2[CH2:17][CH:16]([O:18][C:19]3[C:28]4[C:23](=[C:24]([Cl:38])[C:25]([O:29][CH2:30][CH2:31][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:26][CH:27]=4)[N:22]=[C:21]([C:39]4[N:40]=[C:41]([NH:44][CH:45]([CH3:47])[CH3:46])[S:42][CH:43]=4)[CH:20]=3)[CH2:15][N:14]2[C:48](=[O:64])[CH:49]([NH:54][C:55]([O:57][CH:58]2[CH2:63][CH:62]3[CH:60]([CH2:61]3)[CH2:59]2)=[O:56])[C:50]([CH3:53])([CH3:52])[CH3:51])=[O:12])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:4].[Li+].[OH-].CO.Cl>C1COCC1.O>[CH:60]12[CH2:61][CH:62]1[CH2:63][CH:58]([O:57][C:55]([NH:54][CH:49]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:48]([N:14]1[CH2:15][CH:16]([O:18][C:19]3[C:28]4[C:23](=[C:24]([Cl:38])[C:25]([O:29][CH2:30][CH2:31][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:26][CH:27]=4)[N:22]=[C:21]([C:39]4[N:40]=[C:41]([NH:44][CH:45]([CH3:46])[CH3:47])[S:42][CH:43]=4)[CH:20]=3)[CH2:17][CH:13]1[C:11]([NH:10][C:5]1([C:3]([OH:4])=[O:2])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:12])=[O:64])=[O:56])[CH2:59]2
Reactant: CCC1CC1(NC(=O)C1CC(Oc2cc(-c3csc(NC(C)C)n3)nc3c(Cl)c(OCCN4CCOCC4)ccc23)CN1C(=O)C(NC(=O)OC1CC2CC2C1)C(C)(C)C)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCC1CC1(NC(=O)C1CC(Oc2cc(-c3csc(NC(C)C)n3)nc3c(Cl)c(OCCN4CCOCC4)ccc23)CN1C(=O)C(NC(=O)OC1CC2CC2C1)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.9 %

Procedure:
1-({1-[2-(Bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-[8-chloro-2-(2-isopropylaminothiazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)quinolin-4-yloxy]pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acid methyl ester (12 g, 13 mmol) was dissolved in THF (200 ml), LiOH (11 g, 260 mmol) in H2O (200 ml) was added, followed by MeOH (200 ml). The mixture was kept stirring at room temperature for 20 h. Upon completion of the reaction, 4 N HCl in H2O was added to adjust pH to 7 at 0° C. The mixture was extracted with EtOAc (2×400 ml). The combined organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to give 1-({1-[2-(bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethyl-butyryl]-4-[8-chloro-2-(2-isopropylamino-thiazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acid as a yellow solid (11 g, 93% yield). LCMS found 911.52[M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:5]2=[N:6][CH:7]=1.[Cu](C#N)[C:21]#[N:22].N.O>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:21]#[N:22])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:5]2=[N:6][CH:7]=1
Reactant: N#C[Cu]C#N
Reactant: Fc1cnc2c(c1)c(I)nn2Cc1ccccc1F
Agent: N
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1nn(Cc2ccccc2F)c2ncc(F)cc12
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A suspension of 16.03 g (43.19 mmol) of 5-fluoro-1-(2-fluorobenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridine (Example 6A) and 4.25 g (47.51 mmol) of copper cyanide was initially charged in DMSO (120 ml) and stirred at 150° C. for 2 h. After cooling, the contents of the flask were cooled to about 40° C. and poured into a solution of conc. aqueous ammonia (90 ml) and water (500 ml), ethyl acetate (200 ml) was added and the mixture was subjected to brief extractive stirring. The aqueous phase was separated off and extracted two more times with ethyl acetate (200 ml each time). The combined organic phases were washed twice with 10% strength aqueous sodium chloride solution (100 ml each time), dried and concentrated under reduced pressure. The crude product was reacted without further purification.
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:32]=[C:31]2[C:27]([CH2:28][N:29]([S:33]([C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH2:30]2)=[CH:26][C:25]=1[Sn](CCCC)(CCCC)CCCC>>[CH:14]1([N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][C:24]=4[F:23])[CH2:30][N:29]([S:33]([C:36]4[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=4)(=[O:34])=[O:35])[CH2:28]5)[C:11]=3[O:12][CH3:13])[C:6](=[O:22])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2)[CH2:16][CH2:15]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC)c(Br)ccc2c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(cc1F)CN(S(=O)(=O)c1ccc(C)cc1)C2
Product: CCOC(=O)c1cn(C2CC2)c2c(OC)c(-c3cc4c(cc3F)CN(S(=O)(=O)c3ccc(C)cc3)C4)ccc2c1=O
Yield: 69 %

Procedure:
In the same manner as in Example 1, 0.23 g of ethyl 7-bromo-1-cyclopropyl-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate was reacted with 0.63 g of 6-fluoro-2-(p-toluenesulfonyl)-5-tributylstannyliso-indoline to obtain 0.25 g of ethyl 1-cyclopropyl-7-[6-fluoro-2-(p-toluenesulfonyl)isoindolin-5-yl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[NH:11][C:12]([NH:14][C:15]2[C:19]([CH3:20])=[CH:18][S:17][CH:16]=2)=[S:13])[O:4][CH2:3][CH2:2]1.CI.[C:23](OCC)(=O)C>O1CCCC1>[O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[NH:11][C:12](=[N:14][C:15]2[C:19]([CH3:20])=[CH:18][S:17][CH:16]=2)[S:13][CH3:23])[O:4][CH2:3][CH2:2]1
Reactant: Cc1cscc1NC(=S)NC1CCCCC12OCCO2
Reactant: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: CSC(=Nc1cscc1C)NC1CCCCC12OCCO2
Temperature: 70 °C
Reaction time: 48 h

Procedure:
1-(1,4-Dioxaspiro[4.5]dec-6-yl)-3-(4-methylthiophen-3-yl)thiourea (393 mg) was dissolved in absolute tetrahydrofuran (8.5 ml), and a solution of methyl iodide (179 mg) in absolute tetrahydrofuran (0.5 ml) was added. The mixture was then stirred at 70° C. in sand bath for 2 days. Ethyl acetate was then added to the reaction mixture, and the mixture was washed twice with water. The organic phase was dried over magnesium sulfate and the solvent was removed after filtration. The residue was purified by preparative chromatography and the product-containing fractions were combined, freed from acetonitrile, made basic and extracted three times with ethyl acetate. The organic phases were combined, dried (MgSO4) and filtered. This gave 59 mg of the desired product which was used directly for the next step.