Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)O)[C:6]3[CH2:26][CH2:27][N:28]([CH3:30])[CH2:29][C:5]=3[C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[OH-].[Na+]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]3[CH2:26][CH2:27][N:28]([CH3:30])[CH2:29][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(O)(c2ccccc2)c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN1CCc2c(c3cc(Cl)ccc3n2C=C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
A solution of 2-(8-chloro-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1,1-diphenyl-ethanol (100 mg, 0.24 mmol) in DCM (5 mL) and DMF (2 drops) was stirred at 0-10° C. Thionyl chloride (1.5 mL, 20.67 mmol) was added and the reaction mixture was stirred at RT for 2 h. The solvent was removed under vacuum to obtain the crude yellow solid. 1N NaOH (10 mL) was added to the reaction mixture and the compound extracted with EtOAc (2×20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under vacuum to obtain the crude product (100 mg) which was purified by column chromatography on silica gel (100-200 mesh) [Eluent: 0-2.5% MeOH and DCM] to yield 35 mg product which was converted to HCL salt. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.46-7.40 (m, 6H), 7.25-7.16 (m, 5H), 7.10 (d, 1H), 6.98 (d, 2H), 4.62 (d, 1H), 4.30 (d, 1H), 3.70 (m, 1H), 3.40 (m, 1H), 3.0 (s, 3H), 2.90 (m, 2H).
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2C([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[CH:4][C:5]([Br:16])=[CH:6]3)[CH:2]=1)=O.[OH-].[Na+]>O.C(O)(=O)C.[Hg]=O>[Br:16][C:5]1[CH:6]=[C:7]([C:14]([OH:15])=[O:13])[C:8]2[C:3]([CH:4]=1)=[CH:2][CH:1]=[CH:10][CH:9]=2
Reactant: O=C1OC(=O)c2cc(Br)cc3cccc1c23
Agent: O=[Hg]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)cc2ccccc12
Temperature: 25 °C

Procedure:
To a mixture of 3-bromo-1,8-naphthalic anhydride (compound 74, 22.8 g, 82.4 mmol) and sodium hydroxide (13.2 g, 330 mmol) in water (500 mL) was added a solution of mercury(II) oxide (23.2 g, 107 mmol) in water (70 mL) and glacial acetic acid (24 mL). The reaction mixture was heated at reflux for 4 days and then cooled to room temperature. The resulting solid was filtered and dried in vacuo.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[C:4]([F:27])[CH:3]=1.[C:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)([OH:30])=[O:29].C(=O)([O-])[O-].[K+].[K+].Cl>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.O1CCOCC1>[C:20]([CH2:19][NH:18][C:16]([C:13]1[C:14](=[O:15])[N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH:35]=[CH:36][C:31]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:3][C:4]=2[F:27])[N:10]=[C:11]([CH:24]([CH3:26])[CH3:25])[C:12]=1[OH:23])=[O:17])([OH:22])=[O:21]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(C)c1nn(Cc2ccc(Br)cc2F)c(=O)c(C(=O)NCC(=O)O)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nn(Cc2ccc(-c3ccc(C(=O)O)cc3)cc2F)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 24.1 %

Procedure:
To a 5 ml microwave tube was added N-{[2-[(4-bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 46(b), 75 mg, 0.17 mmol), 4-carboxybenzeneboronic acid (34 mg, 0.20 mmol), potassium carbonate (70 mg, 0.51 mmol), and tetrakis(triphenylphosphine)palladium (0) (6 mg, 5 μmol), 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (5 ml), acidified with 1N HCl (2 ml), and extracted with ethyl acetate (20 ml). The organic phase was washed with brine, dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 15-95% acetonitrile/water (0.1% TFA)) to afford the title compound (20 mg, 0.041 mmol, 24% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.93 (s, 1H), 13.03 (br. s., 2H), 10.15 (t, J=5.43 Hz, 1H), 8.01 (d, J=8.34 Hz, 2H), 7.83 (d, J=8.59 Hz, 2H), 7.64 (dd, J=11.37, 1.77 Hz, 1H), 7.57 (dd, J=7.96, 1.64 Hz, 1H), 7.38 (t, J=7.96 Hz, 1H), 5.35 (s, 2H), 4.10 (d, J=5.81 Hz, 2H), 3.19 (sept, J=6.86 Hz, 1H), 1.19 (d, J=6.82 Hz, 6 H). MS (ES+) m/e 484 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:12]=[C:13]([O:17][CH2:18][C@@H:19]([NH:24]C(=O)OC(C)(C)C)[CH2:20][CH:21]([CH3:23])[CH3:22])[C:14]([CH3:16])=[CH:15][C:10]=2[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[C:3]1=[O:32].Cl.O1CCOCC1>CO>[NH2:24][C@@H:19]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:18][O:17][C:13]1[C:14]([CH3:16])=[CH:15][C:10]2[C:9]3[C:4](=[CH:5][N:6]=[CH:7][CH:8]=3)[C:3](=[O:32])[N:2]([CH3:1])[C:11]=2[CH:12]=1
Reactant: Cc1cc2c3ccncc3c(=O)n(C)c2cc1OC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc2c3ccncc3c(=O)n(C)c2cc1OC[C@@H](N)CC(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 49.5 %

Procedure:
In a 25 mL round-bottomed flask, (S)-tert-butyl (1-((6,9-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (80 mg, 0.182 mmol) was taken in MeOH (6 mL). The reaction mixture was cooled to 0° C. and a 4M solution of HCl in 1,4-dioxane (3.75 mL, 12 mmol) was added and the mixture stirred at RT for 2 h. The MeOH was removed and the crude product was dissolved in ethyl acetate (20 mL). The ethyl acetate layer was washed with water (10 mL) and dried over sodium sulfate. Removal of the solvent gave crude product which was purified by silica-gel column (MeOH—CHCl3 mixture) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-6,9-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (0.03 g, 0.09 mmol, 49% yield) as yellow solid. LC/MS (ESI) m/e 340.2 [(M+H)+, calcd for C20H26N3O2, 340.4]; LC/MS retention time (method B): tR=1.33 min. HPLC retention time (method A): tR=8.58 min; HPLC retention time (method B): tR=8.12 min. 1H NMR (400 MHz, CD3OD) δ ppm 9.51 (s, 1H), 8.79 (d, J=6.02 Hz, 1H), 8.40 (d, J=5.77 Hz, 1H), 8.33 (s, 1H), 7.10 (s, 1H), 4.50 (dd, J=10.67, 3.14 Hz, 1H), 4.36 (dd, J=10.67, 5.90 Hz, 1H), 3.77-3.87 (m, 4H), 2.46 (s, 3H), 1.79-1.92 (m, 2H), 1.66-1.77 (m, 1H), 1.08 (dd, J=6.27, 4.02 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[N:23][C:5]2[N:6](COCC[Si](C)(C)C)[C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[C:3]=1[N:25]1[CH2:29][CH2:28][C@H:27]([N:30]([CH2:38][CH3:39])C(=O)OC(C)(C)C)[CH2:26]1.Br.[OH-].[Na+].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:24]=[N:23][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[C:3]=1[N:25]1[CH2:29][CH2:28][C@H:27]([NH:30][CH2:38][CH3:39])[CH2:26]1
Reactant: CCN(C(=O)OC(C)(C)C)[C@H]1CCN(c2c(Cl)cnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN[C@H]1CCN(c2c(Cl)cnc3[nH]c4cnc(C#N)cc4c23)C1
Temperature: 55 °C
Yield: 65.2 %

Procedure:
(S)-tert-butyl 1-(3-chloro-6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yl)pyrrolidin-3-yl(ethyl)carbamate (100 mg, 0.18 mmol) was dissolved in 1,4-dioxane (0.3 mL) and then treated with 48% HBr(aq) (0.3 mL) and heated at 55° C. for 20 minutes. The cooled reaction mixture was then basified to pH ˜12 by dropwise addition of 6N sodium hydroxide and then immediately acidified to pH ˜8-9 by dropwise addition of concentrated hydrochloric acid, producing a cloudy precipitate. The solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a pale yellow solid (40 mg, 60% over two steps). 1H NMR (500 MHz, d6-DMSO) δ 8.96 (s, 1H), 8.70 (s, 1H), 8.46 (s, 1H), 3.79 (m, 1H), 3.73 (m, 1H), 3.66-3.60 (m, 1H), 3.55-3.47 (m, 2H), 2.65 (m, 2H), 2.26 (m, 1H), 1.98-1.88 (m, 1H), 1.13 (t, J=7.1, 3H), NH signal not observed. LCMS (Method D): RT=7.287 min, M+H+=341.0.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:16])[C:5]([Cl:17])=[CH:4][N:3]=1.[O:18]1[CH2:23][CH2:22][CH:21](O)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]([O:16][CH:21]3[CH2:22][CH2:23][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[C:5]([Cl:17])=[CH:4][N:3]=1
Reactant: Oc1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: OC1CCOCC1
Product: Fc1cccc(OC2CCOCC2)c1Nc1nc(Cl)ncc1Cl

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(tetrahydro-pyran-4-yloxy)-phenyl]-amine was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-phenol and Tetrahydro-pyran-4-ol in an analogous manner to Example 1273c. Title compound was obtained as a white solid (274 mg, 84%). HPLC purity 97%, LCMS 360.09 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.22 (s, 1H), 7.25-7.21 (m, 1H), 6.87-6.77 (m 3H), 4.58-4.55 (m, 1H), 3.89-3.84 (m, 2H), 3.61-3.56 (m, 2H), 2.06-2.01 (m, 2H), 1.80-1.72 (m, 2H).
Reaction SMILES: [CH2:1]([S:4][C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([CH3:19])([CH3:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:11])[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C>[CH2:1]([S:4][C@H:5]1[N:8]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([CH3:19])([CH3:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:11])[CH:2]=[CH2:3]
Reactant: C=CCS[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCS[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1CC(=O)OC
Reaction time: 18 h

Procedure:
To a stirred solution of 1.76 g of 4(R)-allylthio-3(S)-[1(R)-{dimethyl-(2-methylprop-2-yl)silyloxy}ethyl]azetidin-2-one in 60 ml dry DMF were added 3.52 g of finely ground K2CO3 and 0.6 ml of methyl bromoacetate. After 18 hours, the mixture was filtered and then partitioned between ethyl acetate and water. The separated organic layer was washed with water and dried over MgSO4. Evaporation in vacuo afforded a crude product which was chromatographed on silica gel. Elution with ethyl acetate-hexane mixtures afforded 1.56 g of the title compound as a pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[N:17][C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>O1CCOCC1>[ClH:27].[ClH:27].[N:21]1([C:18]2[N:17]=[CH:16][C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:20][CH:19]=2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(N3CCOCC3)nc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1cc(N2CCOCC2)ncc1NC1CCNCC1

Procedure:
A solution of 4-(6-morpholin-4-yl-pyridin-3-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.31 g, 3.61 mmol) in dioxane (20 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 263.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:8]([C:10]2[CH:15]=[C:14]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:13]=[C:12]([F:22])[C:11]=2[O:23]COC)[OH:9])[CH:7]=1.C[N+]1([O-])CCOCC1.[Cl-].[NH4+].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:23][C:11]1[C:12]([F:22])=[N:13][C:14]([CH:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:15][C:10]=1[C:8]2=[O:9]
Reactant: COCOc1c(C(O)c2cc(Br)ccc2F)cc(C2CCOCC2)nc1F
Agent: O=[Ru](=O)(=O)[O-]
Agent: BrB(Br)Br
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: O
Solvent: ClCCl
Product: O=c1c2cc(Br)ccc2oc2c(F)nc(C3CCOCC3)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.7 %

Procedure:
(5-Bromo-2-fluorophenyl)(2-fluoro-3-(methoxymethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)methanol (0.84 g, 1.90 mmol) was dissolved in DCM (30 mL) and treated with 4-methylmorpholine 4-oxide (0.56 g, 4.74 mmol). Once the reagent had dissolved tetrapropylammonium perruthenate (0.033 g, 0.095 mmol) was added and the pale yellow solution stirred at RT. After 10 min the mixture had turned dark. Additional DCM (50 mL) was added followed by water (50 mL) and saturated ammonium chloride (50 mL). The phases were mixed and separated and the organic dried with magnesium sulfate before evaporating to dryness under reduced pressure. The crude was redissolved in dichloromethane (25 mL) and cooled in an ice bath under nitrogen. Boron tribromide (neat, 0.25 mL, 2.64 mmol) was added and the mixture turned orange yellow. After 10 min saturated sodium bicarbonate (70 mL) and DCM (100 mL) were added. The phases were mixed and separated and the organic dried with magnesium sulfate before evaporating to dryness under reduced pressure. The crude was treated with excess cesium carbonate (1.2 g) and ACN (50 mL) and stirred at room temperature for 10 min. The mixture was evaporated to dryness under reduced pressure. The crude product was partitioned between DCM (100 mL) and water (100 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure to give 7-bromo-1-fluoro-3-(tetrahydro-2H-pyran-4-yl)-5H-chromeno[2,3-c]pyridin-5-one (0.645 g, 1.705 mmol, 90% yield) as a white solid. It was used without purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10].[CH2:15]([NH2:18])[C:16]#[CH:17]>O1CCOCC1.Cl>[CH2:15]([NH:18][S:9]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[C:2]([F:14])([F:13])[F:1])(=[O:11])=[O:10])[C:16]#[CH:17]
Reactant: C#CCN
Reactant: O=S(=O)(Cl)c1cnccc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: C#CCNS(=O)(=O)c1cnccc1C(F)(F)F
Reaction time: 8 h

Procedure:
4-Trifluoromethyl-pyridine-3-sulfonyl chloride (0.45 g) was dissolved in dioxane (3 ml), and pro-pargylamine (0.63 ml) was added to the mixture and allowed to stand at ambient temperature overnight. The reaction was diluted with 0.5% HCl and 37% HCl was added drop-wise until the mixture became acidic. This was extracted three times with-ethyl acetate. The ethyl acetate portions were combined, washed with saturated sodium bicarbonate and dried with magnesium sulfate. The drying agent was filtered away and the solvent evaporated to give 0.13 g of crude 4-tri-fluoromethyl-pyridine-3-sulfonic acid prop-2-ynylamide, which was chromatographed an silica gel using ethyl acetate and methylene chloride to yield 0.08 g of purified 4-Trifluoromethyl-pyridine-3-sulfonic acid prop-2-ynylamide. LC/ms analysis with RT=1.36 min yielded a purity of 98% m+/m− of 264.8/262.9. Melting-point of the purified compound tested as 97-98° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]#[N:11].B>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][NH2:11]
Reactant: N#CCCc1ccccc1Br
Agent: B
Solvent: C1CCOC1
Product: NCCCc1ccccc1Br
Temperature: 0 °C

Procedure:
Into a 250-mL 3-necked round-bottom flask, was placed a solution of 3-(2-bromophenyl)propanenitrile (2.1 g, 10.00 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). This was followed by the addition of borane (1 mol/L in THF, 50 mL, 5.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for overnight at room temperature. The reaction was then quenched by the addition of 50 mL of water at 0° C. and extracted with 3×50 mL of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved in 30 mL of 6N aqueous hydrogen chloride. The aqueous solution was extracted with 30 mL of ethyl acetate and the aqueous layers were combined. The pH value of the aqueous solution was adjusted to 10 with 10% aqueous sodium hydroxide. The resulting solution was extracted with 3×50 mL of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate, concentrated under vacuum. This resulted in 1.3 g (58%) of 3-(2-bromophenyl)propan-1-amine as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:18]([NH:20][C@H:21]([C:25]([NH:27][CH:28]([CH:37]([OH:50])[CH2:38][O:39][C:40]1[C:45]([F:46])=[C:44]([F:47])[CH:43]=[C:42]([F:48])[C:41]=1[F:49])[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:18]([NH:20][C@H:21]([C:25]([NH:27][CH:28]([C:37](=[O:50])[CH2:38][O:39][C:40]1[C:45]([F:46])=[C:44]([F:47])[CH:43]=[C:42]([F:48])[C:41]=1[F:49])[CH2:29][C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[C@H](NC(=O)c1cc2ccccc2n1CC(=O)OC(C)(C)C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)COc1c(F)c(F)cc(F)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1CC(=O)OC(C)(C)C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc1c(F)c(F)cc(F)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
To a solution of N-{[1-(tert-butyl)oxycarbonylmethyl-indole-2-carbonyl]valinyl}-3-amino-4-hydroxy-5-(2,3,5,6-tetrafluorophenyloxy)-pentanoic acid, tert-butyl ester (290 mg, 0-42 mmol) in CH2Cl2 (5.0 ml) was added Dess-Martin periodinane (204 mg, 0.48 mmol) and the solution stirred for 10 min. at room temperature. The reaction was quenched with Na2S2O4, diluted with EtOAc, washed with NaHCO3, and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography (1:1 EtOAc/hexane) to give the titled product as a white solid (235 mg, 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([O:23][CH3:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:3]=1[NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].O.C>CS(C)=O.C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([C:17]3([O:23][CH3:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:3]=1[NH:25][C:26](=[O:31])[C:27]([CH3:29])([CH3:28])[CH3:30]
Reactant: COC1(c2ccc(C#Cc3cc(F)cc(F)c3NC(=O)C(C)(C)C)cc2)CCOCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: COC1(c2ccc(/C=C/c3cc(F)cc(F)c3NC(=O)C(C)(C)C)cc2)CCOCC1

Procedure:
The product from Example 6 (3.0 g) was dissolved in dimethylsulphoxide and Pd(dba)2 (200 mg) was added. The mixture was treated with H2 at atmospheric pressure until gas uptake ceased. On completion, the reaction was added to water (500 ml) and extracted with ethyl acetate (2×400 ml). The combined organic extracts were washed with water (2×300 ml) and then dried on MgSO4, and filtered. Removal of the solvent in vacuo gave a yellow oil which was dissolved in diethyl ether, treated with charcoal, then filtered through. Hyflo. Removal of the solvent from the filtrate gave the crude title product. Precipitation from ethyl acetate/40-60° petroleum ether afforded the title product as a white solid; mp 150-151° C.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17]CC=C)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)C=C>C(OCC)(=O)C>[CH2:10]([C:9]1[CH:10]=[C:5]([OH:4])[CH:6]=[CH:7][C:8]=1[C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][C:16]=1[CH2:9][CH:8]=[CH2:7])[CH:5]=[CH2:6]
Reactant: C=CCOc1ccc(-c2ccc(OCC=C)cc2)cc1
Solvent: CCOC(C)=O
Product: C=CCc1cc(O)ccc1-c1ccc(O)cc1CC=C
Temperature: 190 °C
Yield: 196 %

Procedure:
Into a 50 ml round bottom flask was added 6.03 g of 7 (22.6 mmol). The flask was purged with N2 and sealed by a septum. The reactant was heated to 190° C. overnight. A light yellow solid was obtained after the reaction was cooled down. This crude product was subjected to a flash column (15% ethyl acetate in hexanes). A white crystaline solid (5.9 g, 97.8%) was obtained. 1H NMR (CDCl3) δ7.3-7.25 (m, 4H), 6.83 (m, 2H), 6.04 (m, 2H), 5.22-5.17 (m, 4H), 5.01 (s, 2H), 3.46 (d, 4H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[C:38]([F:46])=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH:47]([C:50]1[S:54][C:53]([C:55](O)=[O:56])=[CH:52][CH:51]=1)([CH3:49])[CH3:48].C(N(CC)CC)C>CN(C=O)C>[F:46][C:38]1[C:39]([CH2:43][CH2:44][OH:45])=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:33]1[CH2:34][CH2:35][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:55]([C:53]3[S:54][C:50]([CH:47]([CH3:49])[CH3:48])=[CH:51][CH:52]=3)=[O:56])[CH2:29]2)[CH2:31][CH2:32]1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Reactant: CC(C)c1ccc(C(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.2 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.13 g), 5-isopropylthiophene-2-carboxylic acid (0.07 g) and triethylamine (0.23 mL) in DMF (7 mL) at 0° C. The resulting yellow solution was allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL), the organic phase was washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added, and the solvent evaporated to give the subtitled compound as a clear gum. Yield 0.23 g.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[C:6](Cl)[CH:5]=1)[CH3:2].C[O-].[Na+].[CH3:21][O:22]NC1C=CC=CC=1>CO>[CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[C:6]([O:22][CH3:21])[CH:5]=1)[CH3:2]
Reactant: CCNc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CONc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCNc1cc(OC)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 119 °C

Procedure:
A solution of 14.0 g. (0.052 mole) of N-ethyl-3-chloro-6-nitro-4-trifluoromethylaniline and 16.98 g. (0.057 mole) of 18.23% methanolic sodium methoxide in 25 ml. of anhydrous methanol was sealed in a glass tube and heated at 119°C. for 88 hours. Removal of the solvent by distillation left a yellow solid residue which was triturated with hot chloroform. Filtration and evaporation of chloroform from the filtrate gave a crude solid residue. Crystallization of the residue from ethanol gave 12.4 g. of yellow crystalline product, m.p. 140.5° - 141.5°C. shown by its NMR spectrum to be the desired methoxyaniline.