Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:26][CH2:25][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]4[CH2:24][CH2:23]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:27])[CH:3]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:52]1[CH:61]=[C:60]2[C:55]([CH:56]=[C:57]([C:62]#[N:63])[CH:58]=[N:59]2)=[CH:54][CH:53]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:62]([C:57]1[CH:58]=[N:59][C:60]2[C:55]([CH:56]=1)=[CH:54][CH:53]=[C:52]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]3[CH2:26][CH2:25][C:15]4([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]5[CH2:23][CH2:24]5)[CH2:16]4)[CH2:14][CH2:13]3)[C:9]([NH2:11])=[O:10])=[C:4]([F:27])[CH:3]=1)[CH:61]=2)#[N:63]
Reactant: N#Cc1cnc2cc(Br)ccc2c1
Reactant: NC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1cnc2cc(-c3ccc(C(C(N)=O)N4CCC5(CC4)CN(C4CC4)C(=O)CO5)c(F)c3)ccc2c1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (125 mg, 0.28 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (72 mg, 0.28 mmol) in 1,4-dioxane (2.0 mL) was added potassium acetate (61 mg, 0.63 mmol) and PdCl2(dppf)-CH2Cl2 adduct (23 mg, 0.03 mmol). The reaction mixture was purged with nitrogen and heated at 120° C. for 4 h. The reaction mixture was cooled and 7-bromoquinoline-3-carbonitrile (66.2 mg, 0.28 mmol) and 2M aq K2CO3 (0.3 mL, 0.6 mmol) were added. The reaction mixture was purged with nitrogen and heated with stirring at 100° C. for 1 h. The cooled reaction mixture was diluted with dichloromethane (60 mL) and salts were filtered away. The organic mixture was filtered through a plug of celite and sodium sulfate and the filtrate was treated with a small amount of Silicycle Si-thiol resin for 30 min. The mixture was filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (10-70% acetonitrile:water with 0.1% NH4OH) and the appropriate fractions were collected, combined and concentrated in vacuo to give expected product as a racemate (87 mg, 60%). Chiral HPLC was performed on this material in Example 63a. MS(ES)+ m/e 514 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 0.56-0.66 (m, 2 H) 0.75-0.87 (m, 2 H) 1.64-1.70 (m, 1 H) 1.72-1.77 (m, 1 H) 1.85-1.97 (m, 2 H) 2.31 (td, J=11.24, 2.53 Hz, 1 H) 2.56-2.61 (m, 1 H) 2.62-2.74 (m, 2 H) 2.77-2.86 (m, 1 H) 3.15 (s, 2 H) 4.00 (d, J=2.02 Hz, 2 H) 4.55 (s, 1 H) 5.65 (d, J=4.29 Hz, 1 H) 7.27 (d, J=4.04 Hz, 1 H) 7.49 (t, J=7.71 Hz, 1 H) 7.56 (d, J=1.77 Hz, 1 H) 7.65 (dd, J=7.96, 1.89 Hz, 1 H) 8.00 (dd, J=8.34, 1.77 Hz, 1 H) 8.06 (d, J=8.34 Hz, 1 H) 8.39-8.47 (m, 1 H) 8.63 (dd, J=2.02, 0.76 Hz, 1 H) 9.10 (d, J=2.27 Hz, 1 H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:6][C:7]([F:21])([F:20])[C:8]1[N:12]2[CH2:13][CH2:14][NH:15][CH2:16][C:11]2=[C:10]([C:17]([O-])=[O:18])[N:9]=1>O>[N:1]1([C:17]([C:10]2[N:9]=[C:8]([C:7]([F:20])([F:6])[F:21])[N:12]3[CH2:13][CH2:14][NH:15][CH2:16][C:11]=23)=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])c1nc(C(F)(F)F)n2c1CNCC2
Reactant: C1CCNC1
Solvent: O
Product: O=C(c1nc(C(F)(F)F)n2c1CNCC2)N1CCCC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
Pyrrolidine (560 mg, 8 mmol), methyl 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate 3b (400 mg, 1.60 mmol) and 0.4 mL of H2O were mixed in a sealed tube. After stirring at 50° C. for 4 hours, the reaction mixture was concentrated under reduced pressure to obtain crude pyrrolidin-1-yl-[3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanone 18a (460 mg) as a light yellow solid. The product was used directly in the next reaction without purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C:10]1[CH:15]=[C:14]([CH:16]=O)[CH:13]=[CH:12][C:11]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.NO.C[N:31]1CCCC1=O.Cl>O>[CH2:1]([O:8][C:9](=[O:26])[C:10]1[CH:15]=[C:14]([C:16]#[N:31])[CH:13]=[CH:12][C:11]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Reactant: CN1CCCC1=O
Agent: Cl
Agent: NO
Solvent: O
Product: N#Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Reaction time: 4 h
Yield: 76.7 %

Procedure:
A mixture of 2-benzyloxy-5-formylbenzoic acid benzyl ester (693 mg, 2 mmol), hydroxylamine hydrochloride (167 mg, 2.4 mmol), and N-methylpyrrolidone (3 mL) was stirred at 115□ for 4 hours. After the reaction mixture was cooled, 2N hydrochloric acid (5 mL) and water (30 mL) were added and the mixture was extracted with ethyl acetate. The organic layer was washed with 2N aqueous sodium hydroxide, water, and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was suspended and washed with isopropyl ether under heating at reflux to give the title compound (527 mg, 76.7%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]([CH2:14][CH3:15])([C:9]([O:11]CC)=[O:10])[C:4]([O:6]CC)=[O:5])[CH3:2].OS(O)(=O)=O>>[CH2:14]([C:3]([CH2:1][CH3:2])([C:9]([OH:11])=[O:10])[C:4]([OH:6])=[O:5])[CH3:15]
Reactant: CCOC(=O)C(CC)(CC)C(=O)OCC
Agent: O=S(=O)(O)O
Product: CCC(CC)(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The following are weighed into a 2 liter multinecked flask equipped with a stirrer, thermometer, dropping funnel and distilling section: 530 ml of aqueous saturated K2SO4 solution (10% strength, from previous batches), 206 g of KOH flakes (85%, 3.12 mol) and 500 ml of ethanol 95% strength (recovery from previous batches). The mixture is then heated to boiling until a clear solution is obtained. Over a period of 1 h, 270.5 g of diethyl diethylmalonate (1.25 mol) are added dropwise, and over a period of 5-6 hours from 160-180 ml of ethanol are removed by distillation. The batch is cooled. Then, with cooling (to about 25° C.), a 177 g amount of conc. H2SO4 (96% strength, 1.73 mol), which amount beforehand is diluted with about the same amount of H2 O, is added gradually until the pH has dropped to a level of from 1-2.
Reaction SMILES: C[O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH:8]([O:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:7]1=[O:26]>O>[OH:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[CH2:10][C:9]([CH3:11])([CH3:12])[CH:8]([O:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:23])[F:24])[CH:15]=2)[C:7]1=[O:26]
Reactant: COc1ccccc1CN1CC(C)(C)C(Oc2ccc(C#N)c(C(F)(F)F)c2)C1=O
Solvent: O
Product: CC1(C)CN(Cc2ccccc2O)C(=O)C1Oc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
The product of example 11 was produced by subjecting the product of example 10 to a demethylation reaction analogous to that described in example 8. MS (APCl, M+1) 405.2 LCMS: 50-2% H2O, 214 nm, 2.839 min, 100%
Reaction SMILES: [Mg].II.[F:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Cl.[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]=[O:27])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>C(OCC)C.C(OCC)(=O)C>[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]([OH:27])[CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[F:4])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Reactant: Fc1ccccc1CCl
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OC(Cc1ccccc1F)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.17 h
Yield: 62 %

Procedure:
After suspending 1.84 g of magnesium in 20 ml of diethyl ether, a catalytic amount of iodine was added, a portion of a diethyl ether solution (70 ml) containing 9.97 g of 2-fluorobenzyl chloride was added dropwise while stirring, and the mixture was heated to initiate the reaction. The remaining solution was then added dropwise at a rate to maintain reflux. After 10 minutes, the mixture was cooled on ice, a diethyl ether solution (70 ml) containing 15.4 g of 1-benzyl-4-piperidinecarboxaldehyde [CAS No.22065-85-6] was added dropwise, and stirring was continued for 20 minutes. Saturated aqueous ammonium chloride solution was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (13.4 g, 62% yield).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:38])[N:6]([CH2:11][C:12]2[N:16]([CH3:17])[C:15]([C:18]3[S:26][C:25]4[C:20](=[N:21][CH:22]=[CH:23][C:24]=4[O:27][C:28]4[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][C:29]=4[F:37])[CH:19]=3)=[N:14][CH:13]=2)[CH2:7][CH2:8][O:9][CH3:10])[CH2:3][CH2:2]1.[Cl-].[NH4+]>CO.[Zn]>[NH2:34][C:31]1[CH:32]=[CH:33][C:28]([O:27][C:24]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:19]=[C:18]([C:15]4[N:16]([CH3:17])[C:12]([CH2:11][N:6]([CH2:7][CH2:8][O:9][CH3:10])[C:5]([NH:4][CH:1]5[CH2:2][CH2:3]5)=[O:38])=[CH:13][N:14]=4)[S:26][C:25]=23)=[C:29]([F:37])[CH:30]=1
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)n1C)C(=O)NC1CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)NC1CC1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a solution of 159 (300 mg, 0.555 mmol) in MeOH (10 mL) was added zinc powder (145 mg, 2.22 mmol) and ammonium chloride (59.4 mg, 1.11 mmol) and the reaction mixture was heated to reflux for 3 hours. The mixture was cooled to RT and filtered. The solvent was evaporated and the residue was extracted with DCM. The extract was dried over anhydrous Na2SO4, filtered and concentrated. The crude title compound 160 (283 mg, 100% yield) was used in the next step with no additional purification. MS (m/z)=511.2 (M+H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.N([O-])=O.[Na+].[BrH:15]>[Cu]Br>[Br:15][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: Br
Reactant: Nc1ccc2c(c1)CCC2
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Product: Brc1ccc2c(c1)CCC2
Temperature: -5 °C
Reaction time: 0.33 h

Procedure:
5-Aminoindane was treated with concentrated hydrobromic acid. The suspension was cooled to −5° C., and 5M sodium nitrite solution was added at a temperature between 0° C. to 5° C. in period of 30 minutes through an addition funnel. Stirring was continued for 20 minutes at 0° C. to 5° C. The reaction mixture was now very dark fluid slurry. In a second reaction vessel, a solution of copper (I) bromide in concentrated hydrobromic acid had been prepared and preheated to 40° C. When the diazonium salt slurry was added in portions, a very slow gas evolution was observed which became vehement when heating to 60° C. After stirring at 60° C. for 40 min, the gas evolution ceased. The mixture was poured onto water. The product was extracted twice with ethyl acetate. Some of the precipitated copper bromide was removed by filtration to facilitate phase separation. The organic extracts were washed twice with water and one time with brine. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. After flash chromatography, the title compound was obtained as pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([NH:20][C:21]([C:23]2[C:31]3[CH:30]=[C:29]([C:32]4[C:37]([Br:38])=[CH:36][N:35]=[C:34](Cl)[N:33]=4)[S:28][C:27]=3[CH:26]=[CH:25][CH:24]=2)=[O:22])[CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:34]2[N:33]=[C:32]([C:29]3[S:28][C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([C:21](=[O:22])[NH:20][CH:17]5[CH2:18][CH2:19]5)[C:31]=4[CH:30]=3)[C:37]([Br:38])=[CH:36][N:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Br)cc12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CCNc2ncc(Br)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1

Procedure:
4-(2-Aminoethyl)-piperidine-1-carboxylic acid tert-butyl ester (1.41 g, 6.18 mmol) is added to a stirred suspension of 2-(5-bromo-2-chloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (0.75 g, 2.1 mmol) and diisopropylethylamine (0.80 g, 6.2 mmol) in anhydrous 1,4-dioxane (15 mL) at room temperature under nitrogen. The resultant mixture is heated in an oil bath at 90° C. for 12 hours. At room temperature the mixture is concentrated and chromatographed on silica gel, eluting with 2 M NH3/CH3OH in dichloromethane: 1-10%, to give 4-{2-[5-bromo-4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:17]O>>[NH2:1][C:2]1[C:10]([OH:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: Nc1c(C(=O)O)ccc(F)c1O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)c(O)c1N
Temperature: -78 °C
Reaction time: 17 h
Yield: 44 %

Procedure:
To a solution of 2-amino-4-fluoro-3-hydroxybenzoic acid (2.44 g, 9.7 mmol) in methanol (200 mL) was added thionyl chloride (3.8 mL, 50 mmol) at −78° C. The mixture was stirred in the boiling solvent for 17 h. The solvent was removed under reduced pressure; the residue was dissolved in methanol (200 mL). The solution was cooled to −78° C. and treated with thionyl chloride (8 mL, 100 mmol). The mixture was stirred in boiling solvent for 48 h. The solvent was removed under reduced pressure and the crude material was purified by column chromatography (silica gel, 0 to 70% ethyl acetate in hexanes) to afford methyl 2-amino-4-fluoro-3-hydroxybenzoate (1.5 g, 44%) as off-white solid. 1H NMR (300 MHz, CDCl3) δ 7.48-7.43 (m, 1H), 6.40 (t, J=9.3 Hz, 1H), 3.87 (s, 3H); MS (ESI+) m/z 186 (M+H).
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C@@H:15]([CH3:23])[C@H:16]([OH:22])[C:17](OCC)=[O:18])=[CH:9][NH:10]2.Br.[CH3:25][NH:26][C:27](NC)=[NH:28]>O>[Cl:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH:15]([CH:16]1[O:22][C:27]([NH:26][CH3:25])=[N:28][C:17]1=[O:18])[CH3:23])=[CH:9][NH:10]2
Reactant: CNC(=N)NC
Reactant: CCOC(=O)[C@@H](O)[C@H](C)c1c[nH]c2cccc(Cl)c12
Agent: Br
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CNC1=NC(=O)C(C(C)c2c[nH]c3cccc(Cl)c23)O1
Yield: 12.1 %

Procedure:
Sodium (100 mg) was dissolved into ethanol (5 ml). Ethyl (2S*,3R*)-3-(4-chloroindol-3-yl)-2-hydroxybutyrate (200 mg) and N,N′-dimethyl guanidine hydrogen bromide (143 mg) were added. The whole was refluxed for 16 hours. To the reaction mixture was added water and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. Concentration of the solution gave a residue, which was subjected to silica gel chromatography. Elution with hexane-acetone (1:1) provided the titled compound (25 mg).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[OH-].[Na+].[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]([N:22]([CH:27]([CH3:29])[CH3:28])[C:23](=[O:26])[CH2:24]Cl)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(C)(C)C>[CH2:9]([N:16]1[CH2:17][CH2:18][CH:19]([N:22]([CH:27]([CH3:29])[CH3:28])[C:23](=[O:26])[CH2:24][O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])[CH2:20][CH2:21]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)N(C(=O)CCl)C1CCN(Cc2ccccc2)CC1
Reactant: OCCCCO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC(C)N(C(=O)COCCCCO)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
1,4-Butanediol (16 mL, 178 mmol) was refluxed with sodium hydroxide (970 mg, 24.3 mmol) in tert-butanol (8 mL) for 2 h at which time the solid sodium hydroxide had dissolved. The solution was then cooled to room temperature and a solution of N-(1-benzylpiperidin-4-yl)-N-isopropyl 2-chloroacetamide (5.0 g, 16.2 mmol) in tert-butanol (8 mL) was added dropwise. The reaction mixture was then stirred at room temperature overnight. After removal of tert-butanol under reduced pressure, the residue was dissolved in dichloromethane and this solution washed with sodium bicarbonate, water and brine. The organic layer was then dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (dichloromethane/methanol/ammonium hydroxide: 90/9/1) to give 4.73 g of the title intermediate as a viscous oil (81% yield).
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:36][C:37]1[CH:42]=[C:41]([CH2:43]O)[CH:40]=[CH:39][N:38]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:43][C:41]4[CH:40]=[CH:39][N:38]=[C:37]([F:36])[CH:42]=4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(O)cc3c2C)C2CCCCC2)cc1
Reactant: OCc1ccnc(F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OCc4ccnc(F)c4)cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52 %

Procedure:
Ethyl 3-{[(4-{[cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (0.36 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (5 mL), and 2-fluoro-4-pyridinemethanol (114 mg), tributylphosphine (0.35 mL) and 1,1′-(azodicarbonyl)dipiperidine (0.34 g) were added to the solution under ice-cooling. The ice bath was removed, the reaction mixture was stirred at room temperature for 12 hr, then hexane (5 mL) was added to the mixture, and the precipitate was filtered off through celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.23 g, 54%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]3[CH:35]=[CH:34][NH:33][C:30]3=[N:31][CH:32]=2)O1>>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:27]3[CH:28]=[C:29]4[CH:35]=[CH:34][NH:33][C:30]4=[N:31][CH:32]=3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]=2[C:6]([CH3:14])=[N:7]1)([CH3:13])[CH3:12]
Reactant: COC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Product: COC(=O)c1cc(-c2cnc3[nH]ccc3c2)cc2c1c(C)nn2C(C)C

Procedure:
The title compound was prepared from methyl 6-bromo-1-isopropyl-3-methyl-1H-indazole-4-carboxylate, (0.7 g, 2.25 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.65 g, 2.70 mmol) in the same manner as described for example 80 (step a). The product was collected as an off-white solid (600 mg, 82.5%). 1H NMR (DMSO-d6, 400 MHz): δ 1.489 (d, J=6.4 Hz, 6H), 2.603 (s, 3H), 3.949 (s, 3H), 5.140-5.172 (m, 1H), 6.547 (s, 1H), 7.545 (s, 1H), 7.935 (s, 1H), 8.253 (s, 1H), 8.377 (s, 1H), 8.667 (s, 1H), 11.774 (s, 1H). LCMS (ES+) m/z: 349.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:35])[C:13]([NH:23][C:24](=[O:34])[CH2:25][C@@H:26]4[C:30](=[O:31])[O:29]C(C)(C)[O:27]4)=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[OH-].[Na+]>C1COCC1>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:35])[C:13]([NH:23][C:24](=[O:34])[CH2:25][C@@H:26]([OH:27])[C:30]([OH:31])=[O:29])=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)[C@@H](CC(=O)Nc2cn(C3CCCC3)c3cc(NC4CCCCC4)c(F)cc3c2=O)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(C[C@@H](O)C(=O)O)Nc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
To a 1.0 ml THF-1.0 ml methanol mixed solution of 130 mg of N-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]-2-[(4R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetamide was added 0.3 ml of 1 M hydrochloric acid, followed by overnight stirring at room temperature. Then, 0.8 ml of aqueous 1M sodium hydroxide solution was added, followed by overnight stirring at room temperature. The resulting reaction mixture was neutralized with 1 M hydrochloric acid, and then the insoluble materials were collected by filtration and purified by silica gel column chromatography to obtain 11 mg of (2R)-4-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]amino}-2-hydroxy-4-oxobutanoic acid.
Reaction SMILES: [CH:1]1([N:6]([C@@H:11]2[CH2:16][C:15]3[C:17]([O:22]C)=[CH:18][CH:19]=[C:20]([F:21])[C:14]=3[O:13][CH2:12]2)[CH:7]2[CH2:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N>Br>[CH:1]1([N:6]([C@@H:11]2[CH2:16][C:15]3[C:17]([OH:22])=[CH:18][CH:19]=[C:20]([F:21])[C:14]=3[O:13][CH2:12]2)[CH:7]2[CH2:10][CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(F)c2c1C[C@@H](N(C1CCCC1)C1CCC1)CO2
Agent: Br
Agent: N
Product: Oc1ccc(F)c2c1C[C@@H](N(C1CCCC1)C1CCC1)CO2
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 102.3 %

Procedure:
(R)-3-(N-Cyclopentyl-N-cyclobutylamino)-8-fluoro-5-methoxy-3,4dihydro-2H-1-benzopyran (0.53 g, 1.6 mmol) was dissolved in 47% HBr (15 mL) and stirred at 120° C. for 1.5 h. The solution was cooled by adding ice and alkalised by 14M ammonia. Extractive work-up gave 0.5 g of the title compound as a slightly brown oil. IR contained a typical OH-band at 3654 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][N:9]([S:13](Cl)(=[O:15])=[O:14])[CH2:8][C:7]=2[CH:17]=1.[NH2:18][C:19]1[C:24]2[CH:25]=[C:26]([CH2:28][CH:29]([NH:39]S(C3C=CC(OC4CCOCC4)=CC=3)(=O)=O)[C:30]([N:32]3[CH2:37][CH2:36][CH:35]([CH3:38])[CH2:34][CH2:33]3)=[O:31])[S:27][C:23]=2[CH:22]=[CH:21][N:20]=1>>[NH2:18][C:19]1[C:24]2[CH:25]=[C:26]([CH2:28][CH:29]([NH:39][S:13]([N:9]3[CH2:8][C:7]4[CH:17]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[O:12][CH2:11][CH2:10]3)(=[O:15])=[O:14])[C:30]([N:32]3[CH2:33][CH2:34][CH:35]([CH3:38])[CH2:36][CH2:37]3)=[O:31])[S:27][C:23]=2[CH:22]=[CH:21][N:20]=1
Reactant: CC1CCN(C(=O)C(Cc2cc3c(N)nccc3s2)NS(=O)(=O)c2ccc(OC3CCOCC3)cc2)CC1
Reactant: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CCO2
Product: COc1ccc2c(c1)CN(S(=O)(=O)NC(Cc1cc3c(N)nccc3s1)C(=O)N1CCC(C)CC1)CCO2

Procedure:
This compound was prepared from 210 mg of 7-methoxy-2,3-dihydro-5H-benzo[f][1,4]-oxazepine-4-sulfonyl chloride and 210 mg of 30a using the procedure described for 58c. Yield: 70 mg (oil), (+)-FAB-MS: 560 (MH+).