Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]([S:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[S:21][CH2:22][CH2:23][C:24]([OH:26])=O)[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[C:49]([NH2:53])([CH3:52])([CH3:51])[CH3:50]>C(Cl)Cl.CC#N>[C:49]([NH:53][C:24]([CH2:23][CH2:22][S:21][CH:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH2:12][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)[CH:15]=1)[S:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])([CH3:52])([CH3:51])[CH3:50]
Reactant: O=C(O)CCSC(SCCC(=O)O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Reactant: CC(C)(C)N
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)NC(=O)CCSC(SCCC(=O)O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Reaction time: 1 h

Procedure:
To a solution of di-acid (Step 2) (55 g, 0.114 mol.), triethylamine (35 mL), in CH2Cl2 (2.8 l) and CH3CN (500 mL) at 0° was added 2-chloro-1-methylpyridinium iodide (32 g, 0.126 m). The suspension was stirred 1 hr at 0° to afford a yellow solution. To this solution was added t-butylamine (14 mL). The reaction was stirred at room temperature overnight. The mixture was then evaporated, and partitioned between ethyl acetate and H2O. The aqueous phase was adjusted to pH 3-4 before extraction. The organic phase was dried and evaporated. Flash chromatography of the residue using 15% acetone and 0.2% AcOH in toluene afforded the title compound as an oil. Trituration with ethanol afforded the title compound as a white solid which was further purified by swishing in ether.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11].O.[NH2:16][NH2:17]>CCOCC>[O:11]=[S:10]1(=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:2])[NH:17][NH:16]1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: NN
Solvent: CCOCC
Solvent: O
Product: O=C1NNS(=O)(=O)c2ccccc21
Reaction time: 8 h
Yield: 50.5 %

Procedure:
2-Chlorosulfonyl-benzoic acid methyl ester (7.04 g, 30 mmol) was added to hydrazine hydrate (66 mmol) stirring rapidly in 300 mL ether. The reaction was stirred overnight in an open flask and allowed to slowly concentrate. The remaining solvent was concentrated and the residue was treated with HOAc (3 mL) and DCM. The solution was washed with water, dried over MgSO4, and concentrated to give 3 g of a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([O:25]CC)=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][C:29]1=[O:34].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([OH:25])=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:31]1[CH2:32][CH2:33][NH:28][C:29](=[O:34])[CH2:30]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CNCCN1
Reactant: CCOC(=O)c1nc2cc(Br)ccc2cc1NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC(C)(C)O
Product: O=C1CN(c2ccc3cc(NC(=O)OCc4ccccc4)c(C(=O)O)nc3c2)CCN1
Temperature: 100 °C
Yield: 7 %

Procedure:
A mixture of ethyl 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylate (250 mg, 0.58 mmol), piperazin-2-one (120 mg, 1.2 mmol), Pd(OAc)2 (20 mg), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (41 mg, 0.087 mmol), and K3PO4 (490 mg, 2.3 mmol) in tert-butyl alcohol (8 mL) was deoxygenated and purged with nitrogen then heated at 100° C. in a sealed vial for 3 h. To the mixture resulting mixture, 20 mL of EtOAc and 20 mL of water were added. The precipitates collected by filtration and purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 60 mL/min.) to afford the sub-title compound (0.017 g, 6.9%). LCMS calc. for C22H21N4O5 [M+H]+: m/z=421.1. found: 421.2.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:18](=[O:28])[C:4]=2[N:5]2[CH2:14][CH2:13][C:12]3[CH:11]=[C:10]([O:15][CH3:16])[C:9]([F:17])=[CH:8][C:7]=3[C:6]=12.C([Sn](CCCC)(CCCC)[C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)CCC>C1(C)C=CC=CC=1.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:24]([N:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C:3]2[C:2]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)=[C:6]3[C:7]4[CH:8]=[C:9]([F:17])[C:10]([O:15][CH3:16])=[CH:11][C:12]=4[CH2:13][CH2:14][N:5]3[C:4]=2[C:18]1=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: COc1cc2c(cc1F)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1F)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Yield: 75.5 %

Procedure:
To a degassed solution of 50 mg 27b and 62.3 mg 2-(tributylstannyl)thiophene in 3 mL toluene was added 12.9 mg tetrakis(triphenylphosphine)palladium(0). The mixture was stirred at reflux for 16 h. The crude reaction mixture purified by column chromatography over silica and was then triturated with diisopropyl ethyl ether/pentane (1:1) to give 38 mg 27c as a yellow solid.
Reaction SMILES: [CH2:1]([S:9][C:10]1[CH:11]=[C:12]([C:15]([O:17]C)=[O:16])[NH:13][CH:14]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[K+].Cl>CO.O>[CH2:1]([S:9][C:10]1[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[NH:13][CH:14]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cc(SCCc2ccccc2)c[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(SCCc2ccccc2)c[nH]1
Temperature: 0 °C
Yield: 36.8 %

Procedure:
A solution of methyl 4-(phenethylthio)-1H-pyrrole-2-carboxylate (233 mg, 0.890 mmol) and KOH (250 mg, 4.46 mmol) in MeOH (1.2 mL) and H2O (0.6 mL) was stirred at 60° C. for 1.5 h, cooled to 0° C., acidified with concentrated HCl and diluted with H2O. The solid precipitate was filtered, washed with H2O and air dried under vacuum to afford the title compound (81.0 mg) as a colorless solid that was used in the next step without purification: 1H NMR (400 MHz, CDCl3) δ 2.84-2.90 (m, 2H), 2.91-2.98 (m, 2H), 7.03-7.07 (m, 1H), 7.07-7.10 (m, 1H), 7.13-7.32 (m, 5H), 9.22 (br. s., 1 H); HPLC a) column: Phenomenex Luna 5μ 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% H3PO4 to 90% MeOH/10% H2O/0.1% H3PO4; 1 min hold, 4 mL/min UV detection at 220 nm, 3.293 min retention time, (95%); HPLC b) column: Phenomenex Luna C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 3.258 min retention time; MS (ES): m/z 248.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:22][CH2:21][C:20]3[N:19]4[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]4)=[CH:13][C:12]=3[C:11]2=[O:23])[N:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]([N:10]2[CH2:22][CH2:21][C:20]3[N:19]4[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]4)=[CH:13][C:12]=3[C:11]2=[O:23])[C:7]=1[CH2:8][OH:9]
Reactant: O=Cc1c(Cl)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1c2cc3n(c2CCN1c1nccc(Cl)c1CO)CCCC3
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a solution of 4-chloro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)nicotinaldehyde 139a (1.0 g, 3.0 mmol) in methanol (30 mL) was added sodium borohydride (380 mg, 9.0 mmol) at 30° C. The reaction mixture was stirred for another 1 h and quenched with water (10 mL). It was then concentrated under reduced pressure and the residue was extracted with dichloromethane (3×20 mL). The combined organic extract was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford 244a as a yellow solid (920 mg, 92%). MS-ESI: [M+H]+ 332.3
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:3].[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:35]2[C:34]([CH3:36])=[C:33]([CH3:37])[N:32]=[C:31]([NH2:38])[C:30]=2[N:29]=[CH:28]1>>[NH2:38][C:31]1[C:30]2[N:29]=[CH:28][N:27]([CH2:26][CH2:25][CH2:24][CH2:23][NH:22][S:18]([C:15]3[CH:16]=[CH:17][C:12](/[N:11]=[N:10]/[C:7]4[CH:8]=[CH:9][C:4]([N:2]([CH3:3])[CH3:1])=[CH:5][CH:6]=4)=[CH:13][CH:14]=3)(=[O:20])=[O:19])[C:35]=2[C:34]([CH3:36])=[C:33]([CH3:37])[N:32]=1
Reactant: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: Cc1nc(N)c2ncn(CCCCN)c2c1C
Product: Cc1nc(N)c2ncn(CCCCNS(=O)(=O)c3ccc(/N=N/c4ccc(N(C)C)cc4)cc3)c2c1C

Procedure:
Using the method of Examples 15-29 4-dimethylaminoazobenzene-4′-sulfonyl chloride was reacted with of 1-(4-aminobutyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired product. The observed accurate mass was 521.2452.
Reaction SMILES: Br[C:2]1[C:3]([F:12])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[C:22]([O:21][C:19]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[C:3]([F:12])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])[CH2:15][CH2:14]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1c(F)ccc(Br)c1F
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(F)c(C(=O)O)c2F)CC1

Procedure:
3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,6-difluorobenzoic acid was prepared as in Example 162 (Step ii) using 3-bromo-2,6-difluorobenzoic acid and tert-butyl piperazine-1-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[C:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:8][C:9]=1[NH2:10])([O-])=O>C(O)C.Cl.[Fe]>[N:14]1[CH:15]=[CH:16][C:11]([C:7]2[C:6]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[CH:5][C:4]([NH2:1])=[C:9]([NH2:10])[N:8]=2)=[CH:12][CH:13]=1
Reactant: Nc1nc(-c2ccncc2)c(-c2ccncc2)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Nc1cc(-c2ccncc2)c(-c2ccncc2)nc1N
Temperature: 90 °C
Yield: 93 %

Procedure:
To a solution of 5′-nitro-4,2′:3′,4″-terpyridin-6′-amine (0.144 g, 0.490 mmol) in ethanol (5 mL), 0.300 mL of hydrogen chloride and 0.140 g (2.45 mmol) of iron were added. The mixture was heated at 90° C. for 2 h and the solvent was evaporated. The crude mixture was extracted between ethyl acetate and water. The organic layer was dried (MgSO4) and the solvent evaporated to give the title compound (0.120 g, 93% of yield).
Reaction SMILES: I[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][CH:8]1[C:12](=[O:13])[CH:11]=[C:10]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:9]1.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C)C=O.O>[N:22]([CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][CH:8]1[C:12](=[O:13])[CH:11]=[C:10]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:9]1)=[N+:23]=[N-:24]
Reactant: CC(C)COC1=CC(=O)C(Cc2cccc(CCI)c2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COC1=CC(=O)C(Cc2cccc(CCN=[N+]=[N-])c2)C1
Temperature: 50 °C
Yield: 76 %

Procedure:
A mixture of 30 (0.044 g, 0.11 mmol) and sodium azide (0.007 g, 0.11 mmol) in dry N,N-dimethylformamide (0.5 mL) was heated to 50° C. for 45 minutes. The reaction mixture was diluted with water and the resulting mixture extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue so obtained was dried under high vacuum to furnish the desired compound. Yield: 76%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][C@H:12]([C:15]3[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=3[F:23])[C@@H:11]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:10]2)=[N:6][C:7]=1[NH2:8].O=[C:33]([CH3:36])[CH:34]=O.C(=O)(O)[O-]>CO.C(Cl)Cl>[CH3:36][C:33]1[N:8]=[C:7]2[N:6]=[C:5]([N:9]3[CH2:14][CH2:13][C@H:12]([C:15]4[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=4[F:23])[C@@H:11]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[CH2:10]3)[CH:4]=[CH:3][C:2]2=[N:1][CH:34]=1
Reactant: CC(=O)C=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(c2ccc(N)c(N)n2)CC[C@@H]1c1cc(F)c(F)cc1F
Agent: O=C([O-])O
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc2ccc(N3CC[C@H](c4cc(F)c(F)cc4F)[C@@H](NC(=O)OC(C)(C)C)C3)nc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 40 mg (0.09 mmol) of the product of Step B in 2 mL of methanol was added 0.07 mL (0.46 mmol) of 2-oxopropanal solution (40 wt. % in water) and stirred at ambient temperature for 1 h. The reaction mixture was then, diluted with 10 mL of methylene chloride and poured into 10 mL of a saturated aqueous bicarbonate solution. The layers were separated and the aqueous layer extracted with three 10 mL portions of methylene chloride and the combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to yield a tan solid which was purified by preparative thin layer chromatography using an Analtech® 1500 micron plate (1:3 hexane/ethyl acetate solvent) to give the title compound as a tan crystalline solid. LC/MS 474.1 (M+1).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C([O-])([O-])=O.[K+].[K+].[CH2:20]([C:22]([CH3:24])=[O:23])C>>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:20][CH:22]2[CH2:24][O:23]2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCC(C)=O
Reactant: CCCCCOc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCOc1ccc(OCC2CO2)cc1

Procedure:
A mixture of 24.41 g of 4-pentoxyphenol, 56 g of K2CO3, 34.7 ml of epicholorohydrin and 500 ml of methyl ethyl ketone was refluxed overnight. Solvent and solid were removed to yield a residue which was distilled by a Kugelrohr adaptor to give the title compound, bp 175°/0.01 mmHg.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.CCCCCC.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26]>O1CCCC1>[CH3:21][O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]([C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[OH:26]
Reactant: COc1ccccc1C=O
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(O)c2ccccc2OC)cn1
Temperature: 25 °C
Yield: 63 %

Procedure:
5-Bromo-2-methoxypyridine (41.36 g) (prepared by the method of I. Kompis et al, European Journal of Medicinal Chemistry 1977, 12, 531) in dry tetrahydrofuran (50 ml) was cooled to -85° with stirring under a nitrogen atmosphere. n-Butyl lithium (137 ml of a 1.6M hexane solution) in dry tetrahydrofuran (50 ml) was added dropwise, keeping the temperature below -80°. After stirring for 5 minutes, 2-methoxybenzaldehyde (25.0 g) in dry tetrahydrofuran (150 ml) was added dropwise with stirring, keeping the temperature below -70°. The mixture was stirred whilst allowing to warm to room temperature, then quenched with saturated ammonium chloride solution (150 ml). The organic layer was separated and the aqueous was further extracted with ethyl acetate. The organic layers were combined, dried with anhydrous magnesium sulphate and evaporated to dryness to give an orange gum which was crystallised from dichloromethane/petroleum spirit (60°-80°) to give 1-(2-methoxyphenyl)-1-(6-methoxy-3-pyridyl)-methanol as a pale yellow solid (28.39 g, 63%) m.p 83°-84°.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH2:12][P:13]([O:17]Cl)([O:15]Cl)=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].[CH2:21]([NH2:24])[CH2:22][CH3:23]>CCOCC>[F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH2:12][P:13]([O:17][NH:24][CH2:21][CH2:22][CH3:23])([O:15][NH:24][CH2:21][CH2:22][CH3:23])=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4]
Reactant: CCCN
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Solvent: CCOCC
Product: CCCNOP(=O)(CN(CC(=O)OCC)C(=O)C(F)(F)F)ONCCC
Temperature: 25 °C
Yield: 62.6 %

Procedure:
To a solution of ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (6.6 g, 0.02 mole) in 200 ml. of ether was added propylamine (4.7 g, 0.08 mole) in 50 ml. of ether. The reaction was stirred at room temperature for several hours, then the reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in 100 ml. ether, washed with water, dried over MgSO4, and concentrated in vacuo to yield ethyl N-trifluoroacetyl-N-(bis(propylamino)phosphonomethyl)glycinate (5.1 g), ND =1.4546.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:35])=[C:4]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]2=[O:34])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.F[C:37]1C=C(O)C(C2C3C(=CC=CC=3)N(CC3C=CC(OC)=CC=3)C2=O)=CC=1C#N>>[Cl:1][C:2]1[C:3]2[O:35][CH2:37][C:12]3([C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:13]3=[O:34])[C:4]=2[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: O=C1C(c2c(O)c(Cl)cc3c2OCCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CN2C(=O)C(c3cc(C#N)c(F)cc3O)c3ccccc32)cc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1c(Cl)cc3c(c12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2.40 and making non-critical variations using 3-(7-chloro-6-hydroxy-2,3-dihydro-1,4-benzodioxin-5-yl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one to replace 2-fluoro-4-hydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile, 6-chloro-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one was obtained (65%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.42-7.26 (m, 10H), 7.20-7.15 (m, 1H), 7.11 (s, 1H), 7.03-6.95 (m, 2H), 6.78 (s, 1H), 6.50-6.45 (m, 1H), 5.02 (d, J=8.7 Hz, 1H), 4.76 (d, J=8.7 Hz, 1H), 4.12-3.84 (m, 4H); MS (ES+) m/z 496.2 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH3:10])[CH:4]=1.O>Br.C(O)(=O)C>[CH3:10][S:9][C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc(SC)c1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CSc1cccc(O)c1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 64.6 %

Procedure:
1-Methoxy-3-methylsulfanyl-benzene (32.87 g, 0.213 mol) was dissolved in a mixture of 30% hydrogen bromide in acetic acid (96 ml) and 48% aqueous hydrobromic acid (24 ml). The reaction was heated to reflux, and stirred at this temperature under nitrogen for 5.5 h. After cooling to room temperature the reaction mixture was poured into water (600 ml) and extracted with diethylether (3×300 ml). The combined organic extracts were washed with water (2×150 ml), brine (100 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate:pentane (1:19 changing to 3:37 then 1:9, by volume) and the product was azeotroped with toluene (2×100 ml) to give 3-Methylsulfanyl-phenol (19.3 g) as a crimson oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[OH:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].Cl>N1C=CC=CC=1.[Cu]I>[CH3:18][O:17][C:15](=[O:16])[C:14]1[CH:19]=[CH:20][C:11]([O:10][C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(Br)cn1
Reactant: COC(=O)c1ccc(O)cc1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(OC)nc2)cc1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
A suspension of 5-bromo-2-methoxy-pyridine (5.9 g, 30 mmol), methyl 4-hydroxy-benzoate (4.0 g, 26 mmol), K2CO3 (4.7 g, 34 mmol), Cu powder (0.25 g, 4 mmol) and CuI (0.25 g, 1.3 mmol) in pyridine (25 ml) was refluxed for 10 h and allowed to cool to room temperature. The resulting mixture was poured in 100 g of crushed ice, neutralized with HCl to pH 7.5 and extracted with diethyl ether. The extract was evaporated in vacuo, the residue was separated by column chromatography on silica (eluent hexanes-ethyl acetate 8:1) to give 2.8 g (35%) of 4-(6-methoxy-pyridin-3-yloxy)-benzoic acid methyl ester as colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:58])[C@H:10]([CH:55]([CH3:57])[CH3:56])[N:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[N:35](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:34]=[N:33][N:32]=2)=[CH:21][CH:20]=1)[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[CH2:1]([O:8][C:9](=[O:58])[C@H:10]([CH:55]([CH3:57])[CH3:56])[N:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:32][N:33]=[N:34][N:35]=2)=[CH:21][CH:20]=1)[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C
Reaction time: 2 h

Procedure:
A solution of 91 g (about 100 mmol) of crude N-[(2'-(1-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl)methyl]-N-valeryl-(L)-valine benzyl ester in 300 ml of dioxane is treated at 60° with 300 ml of 1N hydrochloric acid and kept at 60° for 2 hours. The dioxane is then evaporated in vacuo and the aqueous phase is rendered alkaline with 2N potassium hydroxide solution. Neutral portions are extracted with ether. The aqueous phase gives the crude title compound as an oil (Rf 0.40 in system A2) by acidifying and extracting with ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].[C:25]([NH:32][C@@H:33]([C:38](O)=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:38](=[O:39])[C@H:33]([NH:32][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:34][CH:35]([CH3:37])[CH3:36])=[CH:21][CH:22]=1)[NH:5][C:6](=[O:7])[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)c1c(C)cccc1Cl
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(NC(=O)[C@@H](CC(C)C)NC(=O)OC(C)(C)C)cc1)NC(=O)c1c(C)cccc1Cl
Yield: 102 %

Procedure:
A solution of 4-amino-N-[(2-chloro-6-methylphenyl)carbonyl]-L-phenylalanine methyl ester (561 mg, 1.61 mmol), prepared using procedure described in Example 68. in DMF (4.5 mL) was treated with N-Boc-D-leucine (393.2 mg, 1.7 mmol), HBTU (644.3 mg, 1.7 mmol) and DIPEA (0.62 mL, 3.50 mmol) at room temperature for 6 hr. The reaction mixture was diluted to 30 mL with water and the white precipitate was collected by filtration and was washed with water (2×2 mL). After drying under vacuum, the light yellow powder was recrystallized from ethyl acetate-hexane to give N-(2-chloro-6-methylbenzoyl)-4-[[(2R)-2-[(1,1dimethylethoxy)carbonyl]amino-4-methyl-1-oxopentyl]amino]-L-phenylalanine methyl ester (920 mg) as a white solid. MS 560 (M+H, 1 Cl). This solid was dissolved in 4 N HCl in dioxane (5 mL). The solution was stirred at room temperature overnight. After dilution with ether, the white suspension was allowed to stand at −5° C. for 1 hr. The white solid was collected by filtration and was dried under vacuum for 5 hr. The above solid was then dissolved in 20 mL of water and the solution was treated with sodium bicarbonate followed by K2CO3 to PH >9. The mixture was then extracted with dichloromethane (2×25 mL) and was dried over sodium sulfate. After removal of solvent, the residue was then dried under vacuum at 50° C. overnight to give white solid (520 mg, 1.1 mmol) in 70% overall yield. HRMS: Obs. 460.1997, Calc. 460.2003 (M+H).