Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH:19]1([CH2:24][CH2:25][NH2:26])[CH2:23][CH2:22][CH2:21][CH2:20]1.[BH4-].[Na+]>CO>[CH:19]1([CH2:24][CH2:25][NH:26][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:5][CH:4]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: NCCC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCC3CCCC3)cc2)nc1
Reaction time: 18 h
Yield: 52.2 %

Procedure:
Combine 6-(4-formyl-phenoxy)-nicotinamide (0.61 g, 2.54 mmol) with 2-Cyclopentyl-ethylamine (0.38 g, 3.3 mmol), 2 g of 3 {acute over (Å)} molecular sieves, and 10 mL of methanol. Stir for 18 h under nitrogen. Add sodium borohydride (0.5 g, 13.2 mmol), and stir for 24 h. Filter through Celite, remove the solvent in vacuo. Partition the residue between water (50 mL) and ethyl acetate (100 mL). Dry the organic phase (sodium sulfate), filter, and concentrate in vacuo. Adsorb on silica, and purify on an ISCO® 100 g system (eluting with 95:5:0.5 to 90:10:1 chloroform/ethanol/ammonium hydroxide) to afford 0.45 g of product. HPLC retention time: 5.93 min (98.7% purity), ESMS (M+): 340.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH2:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35])[CH3:30]>>[CH3:30][N:29]([CH2:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH:35]/[C:17](=[C:6]1\[C:5](=[O:27])[NH:4][C:12]2[C:7]\1=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)/[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:28]
Reactant: CN(C)Cc1cccc(N)c1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1cccc(CN(C)C)c1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and 3-(dimethylaminomethyl)-aniline
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[C:21]#[CH:22].C(NCC)C>C(#N)C.C(#N)C.C(#N)C.[Pd](Cl)Cl.[Cu]I>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:22]#[C:21][C:15]1[C:14]([Cl:13])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:20])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(I)c(N)c1
Reactant: C#Cc1c(Cl)cccc1Cl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: CCNCC
Solvent: CC#N
Product: COC(=O)c1ccc(C#Cc2c(Cl)cccc2Cl)c(N)c1
Temperature: 120 °C

Procedure:
A mixture of methyl 3-amino-4-iodobenzoate (604 mg, 2.18 mmol) (from Example 3-4), 2,6-dichlorophenylacetylene (447 mg, 2.61 mmol), palladium (II) chloride bis(acetonitrile) (23 mg, 89 μmol), diethylamine (449 μL, 318 mg, 4.35 mmol), and copper (I) iodide (21 mg, 110 μmol) in acetonitrile (10 mL) was heated for 35 min at 120° C. in a microwave apparatus. The mixture was filtered, and the filtrate concentrated, then chromatographed using a gradient of 0-30% heptane/ethyl acetate to give methyl 3-amino-4-(2,6-dichlorophenylethynyl)-benzoate.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1.CC(C)=O>CC(=O)CC>[CH2:1]([NH:6][CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCN
Reactant: O=S1(=O)CCCO1
Solvent: CCC(C)=O
Solvent: CC(C)=O
Product: CC(C)CCNCCCS(=O)(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
Isoamylamine (4 mL, 34.5 mmol) was added to a solution of 1,3-propane sultone (4.7 g, 38 mmol) in 2-butanone (70 mL). The mixture was warmed to reflux. After 30 minutes, the mixture was too thick to stir. Acetone (15 mL) was added. The reflux was maintained for a total of 4 hours. The suspension was cooled at room temperature. The white solid was collected by filtration, rinsed with acetone (10 mL), then with ether (10 mL). Compound CH was obtained as a very light, fluffy white solid (4.48 g, 62% yield). m.p. 220° C.: decomposed. 1H NMR (500 MHz, D2O) δ 0.65 (d, J=6.3 Hz, 6H), 1.29 (q, J=7.7 Hz, 2H), 1.35-1.42 (m, J=6.6 Hz, 1H), 1.86 (qt, J=7.6 Hz, 2H), 2.74 (t, J=7.3 Hz, 2H), 2.81 (t, J=8.1 Hz, 2H), 2.93 (t, J=7.8 Hz, 2H). 13C NMR (125 MHz, D2O) δ 21.3, 21.4, 25.2, 34.2, 46.1, 46.2, 47.9
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]2[C:15]([S:25][CH3:26])=[N:16][N:17]3[C:22](Cl)=[CH:21][C:20]([CH3:24])=[N:19][C:18]=23)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:27]>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]2[C:15]([S:25][CH3:26])=[N:16][N:17]3[C:22]([NH2:27])=[CH:21][C:20]([CH3:24])=[N:19][C:18]=23)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc(C(C)(C)C)cc1
Solvent: CO
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
In an analogous manner to that described in Example 4, from 3-(4-tert-butyl-benzenesulphonyl)-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 3-(4-tert-butyl-benzenesulphonyl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p. >230°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29](Cl)=[O:30]>>[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1cccs1
Product: O=C(Nc1ccc2[nH]cc(C3CCNCC3)c2n1)c1cccs1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.062 mMol) 2-thiophenecarbonyl chloride, the title compound was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=1.Cl.C(O)C>[Fe].O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc([N+](=O)[O-])c2)C1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(N)c2)C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6,8-dichloro-2-methyl-4-(3-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (200 mg, 0.59 mmol, 1.00 equiv), Fe (360 mg, 6.43 mmol, 8.60 equiv), hydrogen chloride (0.02 mL), ethanol (0.6 mL), water (0.2 mL). The resulting solution was stirred for 0.5 h at 80° C. in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 0.2 g (crude) of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenamine as yellow oil.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9]O)=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[O:7]([CH2:8][CH2:9][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1)[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Cc1cccc(N)c1
Reactant: OCCOc1ccccc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: Cc1cccc(NCCOc2ccccc2)c1
Temperature: 210 °C
Yield: 87 %

Procedure:
138 parts of phenylglycol, 214 parts of m-toluidine and 15 parts of triphenyl phosphite are mixed whilst stirring and next heated to 210° C internal temperature. At this temperature, the elimination of water commences. The mixture is then heated to an internal temperature of 223° C in the course of 9 hours. During this time, 18 parts of water have distilled off and the condensation has ended. The excess starting material is then distilled off. 198 parts of N-(2-phenoxyethyl)-m-toluidine, corresponding to a yield of 87% of theory, distil at a boiling point of 186° - 192° C/5 mm Hg.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.[NH3:15]>>[NH2:15][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1NCCO
Reactant: N
Product: Nc1ncc([N+](=O)[O-])c(NCCO)n1
Temperature: 55 °C
Yield: 93 %

Procedure:
21.86 g (0.1 mole) of 2-chloro-4-(2-hydroxyethylamino)-5-nitropyrimidine was dissolved in 500 ml of ammonia saturated ethanol solution, and maintained between 50-60° C. A stream of ammonia was bubbled through the mixture for 13 hours. After completion of the reaction, the reaction product was maintained below 5° C., and the resulting crystal was filtered, washed and dried, thereby giving 18.81 g (93% yield) of light yellow-colored 2-amino-4-(2-hydroxyethylamino)-5-nitropyrimidine.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=2)[N:4]=1.[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C=O)C.C(OCC)(=O)C.O>[N:14]([CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=2)[N:4]=1)=[N+:15]=[N-:16]
Reactant: Clc1ccc2ccc(CBr)nc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc2ccc(Cl)cc2n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(bromomethyl)-7-chloroquinoline (50 mg, 0.195 mmol) in DMF (0.5 ml) was added sodium azide (19.01 mg, 0.292 mmol). Reaction mixture was stirred for 2 h at 90° C. Reaction mixture was diluted with ethyl acetate/water. Layers were separated and organic layer was washed twice with water and with brine, dried over sodium sulfate, filtered and evaporated to afford the title compound. HPLC (Method G) Rt=1.990 min, MS (Method V) [M+H]+=219.1.
Reaction SMILES: [CH:1]1([CH2:5][C@H:6]([NH:26]C(=O)OC(C)(C)C)[CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[C:21]4[C:16](=[C:17]([CH3:22])[N:18]=[CH:19][CH:20]=4)[C:15](=[O:23])[N:14]([CH3:24])[C:13]=3[CH:25]=2)[CH2:4][CH2:3][CH2:2]1.Cl>C(OCC)C>[NH2:26][C@@H:6]([CH2:5][CH:1]1[CH2:2][CH2:3][CH2:4]1)[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:21]3[C:16](=[C:17]([CH3:22])[N:18]=[CH:19][CH:20]=3)[C:15](=[O:23])[N:14]([CH3:24])[C:13]=2[CH:25]=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC3CCC3)NC(=O)OC(C)(C)C)ccc21
Agent: Cl
Solvent: CCOCC
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@@H](N)CC3CCC3)ccc21
Reaction time: 1 h
Yield: 29.7 %

Procedure:
An ambient temperature suspension of (S)-tert-butyl (1-cyclobutyl-3-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)propan-2-yl)carbamate (70 mg, 0.155 mmol) in diethyl ether (1 mL) was treated with HCl (4M in 1,4-dioxane) (0.775 mL, 3.10 mmol) and stirred for 1 h. The resulting mixture was concentrated under reduced pressure to a yellow solid. The crude material was purified by reverse phase high performance liquid chromatography (Phenomenex Luna C18 30×100 mm 10 micron; water/methanol/TFA gradient elution). Fractions containing product were concentrated under reduced pressure. The resulting residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The layers were separated and the aqueous was extracted twice more with ethyl acetate. The pooled organics were washed once with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford (S)-8-(2-amino-3-cyclobutylpropoxy)-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (17 mg, 0.046 mmol, 30% yield) as a white solid. LC/MS, (ESI) m/z 352.3 [(M+H)+, calcd for C21H26N3O2 352.2]; HPLC retention time (method C): tR=14.15 min; HPLC retention time (method D): tR=14.78 min; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.64 (d, J=5.8 Hz, 1H), 8.15 (d, J=9.0 Hz, 1H), 7.82 (d, J=5.8 Hz, 1H), 6.89 (dd, J=8.9, 2.4 Hz, 1H), 6.84 (d, J=2.3 Hz, 1H), 4.04 (dd, J=8.9, 3.9 Hz, 1H), 3.86 (dd, J=8.8, 7.5 Hz, 1H), 3.73 (s, 3H), 3.23 (tdd, J=7.5, 5.5, 3.8 Hz, 1H), 3.16 (s, 3H), 2.60-2.43 (m, 1H), 2.21-2.08 (m, 2H), 2.01-1.81 (m, 2H), 1.80-1.55 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[C:12](/[CH3:24])=[CH:13]/[C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH:10]=2)[NH:5][CH2:4][CH2:3]1.[CH2:26]=O.Cl>C(O)=O>[CH3:26][N:5]1[C:6]2[C:11](=[CH:10][C:9](/[C:12](/[CH3:24])=[CH:13]/[C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=3)=[CH:8][CH:7]=2)[C:2]([CH3:25])([CH3:1])[CH2:3][CH2:4]1
Reactant: COC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCN3)cc1
Reactant: C=O
Agent: Cl
Solvent: O=CO
Product: COC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCN3C)cc1
Temperature: 95 °C

Procedure:
A mixture of 3.64 g of methyl 4-[(E)-2-(4,4-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl)-2-methylvinyl]benzoate, 5 ml of 90% formic acid and 5 ml of 40% aqueous formaldehyde is heated at 95° C. for 12 hours. The reaction medium is then cooled and 1.5 ml of concentrated hydrochloric acid is added. The formic acid and excess formaldehyde are removed by evaporation in vacuo. The resulting mixture is then made strongly basic and extracted with dichloromethane. The dichloromethane extracts are combined, dried (MgSO4) and evaporated in vacuo to give the title compound.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:41])[NH:10][C@@H:11]([CH2:35][C:36]2[N:37]=[CH:38][S:39][CH:40]=2)[C:12]([NH:14][CH2:15][C:16]2[N:17]=[N:18][N:19]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=3)[CH:20]=2)=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:26]=[C:21]([N:19]2[CH:20]=[C:16]([CH2:15][NH:14][C:12](=[O:13])[C@@H:11]([NH:10][C:9]([C@H:8]3[O:7][C@@H:6]3[C:4]([OH:5])=[O:3])=[O:41])[CH2:35][C:36]3[N:37]=[CH:38][S:39][CH:40]=3)[N:17]=[N:18]2)[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:24]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)NCc1cn(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nn1
Agent: [Li+]
Agent: [OH-]
Product: O=C(NCc1cn(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nn1)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)O
Yield: 83 %

Procedure:
Followed general procedure using: the corresponding peptidomimetic epoxide ethyl ester 43 (94 mg, 0.15 mmol); LiOH (3.7 mg, 0.15 mmol); after extraction afforded the desired product as a white solid (72 mg, 80.3%). 1H NMR (DMSO-d6, 400 MHz): δ 8.99-8.98 (d, 1H, J=1.92 Hz); 8.92 (s, 1H); 8.79-8.77 (t, 1H); 8.63 (s, 2H); 8.57-8.55 (d, 1H, J=8.27 Hz); 8.27 (s, 1H); 7.34-7.33 (d, 1H, J=1.85 Hz); 4.71-4.66 (m, 1H); 4.43-4.42 (d, 2H, J 5.67 Hz); 3.58-3.57 (d, 1H, J=1.73 Hz); 3.36-3.35 (d, 1H, J=1.70 Hz); 3.28-3.10 (m, 2H). 13C NMR (DMSO-d6, 100 MHz): 170.67, 169.07, 165.80, 154.06, 153.29, 146.93, 138.32, 132.48, 132.14, 122.38, 121.11, 116.18, 53.22, 52.90, 51.96, 34.64, 33.51. HRMS-ESI: m/z [M+H+] calculated for C21H16F6N6O5S: 579.4443, observed: m/z 579.0890 (M+H+); m/z 577.0775 (M+H+). HPLC method 2: Rt=24.5 min; purity=95.3%.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[NH:27]1[C:35]2[C:30](=[C:31]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1>CS(C)=O.C(OCC)(=O)C.CCCCCC>[NH:27]1[C:35]2[C:30](=[C:31]([N:36]3[CH2:41][CH2:40][N:39]([CH2:11][CH:12]4[O:25][C:16]5=[C:17]6[C:21](=[CH:22][CH:23]=[C:15]5[O:14][CH2:13]4)[NH:20][C:19](=[O:24])[CH2:18]6)[CH2:38][CH2:37]3)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C1Cc2c(ccc3c2OC(CN2CCN(c4cccc5[nH]ccc45)CC2)CO3)N1
Temperature: 80 °C
Yield: 73.3 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.0 g, 2.7 mmole) and 4-(1H-indol-4-yl)-piperazine (2.0 g, 10 mmole) were combined in 30 ml of dry DMSO and heated to 80° C. for 4 hours under an argon atmosphere. After cooling to room temperature, the mixture was diluted with 400 ml of 1:1 ethyl acetate/hexane and washed with 400 ml of saturated sodium bicarbonate solution, with two 250 ml portions of water and with saturated brine. The mixture was dried over sodium sulfate, filtered and concentrated in vacuum to yield an oil, which was column chromatographed on silica gel using 0.5% methanol/CHCl3 as eluant. The free base of the title compound (0.80 g) thus obtained was crystallized from methanol with the addition of one equivalent of fumaric acid to give 077 g of the (S) enantiomer of the title compound as a white solid fumarate, m.p. 237°-238° C.
Reaction SMILES: [OH:1][C@@H:2]([CH2:25][OH:26])[CH2:3][C:4]1[CH:5]=[C:6]([F:24])[C:7]([C:10]2([F:23])[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[N:8][CH:9]=1.Cl.C(OCC)C>ClCCl.O1CCOCC1>[F:24][C:6]1[CH:5]=[C:4]([CH2:3][C@@H:2]([OH:1])[CH2:25][OH:26])[CH:9]=[N:8][C:7]=1[C:10]1([F:23])[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2ncc(C[C@@H](O)CO)cc2F)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: OC[C@H](O)Cc1cnc(C2(F)CCNCC2)c(F)c1
Yield: 113.4 %

Procedure:
A solution of 25 (1.70 g, 4.6 mmol) in dichloromethane (10 mL) was stirred with 4 mol/L HCl in dioxane (15 mL) in a closed vessel overnight at room temperature. The resulting suspension was stirred for 1 h with ethyl ether. The solid precipitated was collected by filtration and washed several times with ethyl ether to afford 1.42 g (100%) of 26 as a pale yellow foam (HCl salt). The identity of compound 26 was confirmed by LC/MS and was used directly for the next step. LC/MS (M+1) 310.
Reaction SMILES: [K].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[C:13]([O:19][CH2:20]Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:20][O:19][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11])=[CH:7][CH:8]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOC(=O)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.2 %

Procedure:
The potassium salt of 4-hydroxyphenylacetic acid (9.5 g, 0.05 mL) was suspended in dimethylformamide (25 mL). Chloromethyl pivalate (7.53 g, 0.05 mol) was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed, first with aqueous 5% NaHCO3 (100 mL) and then twice with water, then was dried over anhydrous MgSO4, filtered and evaporated to yield pivalyloxymethyl 4-hydroxyphenylacetate, melting at 159°-161° C. (yield 70.2%).
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[Na+].CN(C)C=O.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[NH:29][C:28](=[O:30])[CH2:27][C:26](=[O:31])[N:25]([CH3:32])[C:24]=2[CH:33]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S(OCC)(OCC)(=O)=O>C(OCC)(=O)C.O>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[N:29]([CH2:1][CH3:2])[C:28](=[O:30])[CH2:27][C:26](=[O:31])[N:25]([CH3:32])[C:24]=2[CH:33]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)[O-]
Reactant: CN1C(=O)CC(=O)Nc2ccc(OCc3ccccc3)cc21
Agent: CCOS(=O)(=O)OCC
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN1C(=O)CC(=O)N(C)c2cc(OCc3ccccc3)ccc21
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Sodium t-butoxide (330 mg, 3.43 mmol) was added to a N,N-dimethylformamide (5 mL) solution of 8-benzyloxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.01 g, 3.4 mmol) under ice cooling, and the mixture was stirred under ice cooling for 30 minutes. Thereafter, diethyl sulfate (0.51 mL, 3.69 mmol) was added, and the mixture was stirred for 6 hours under ice cooling. Water was added to the reaction solution, and ethyl acetate (20 mL) extraction was performed. The resulting organic layer was washed with water, and the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from 50% ethanol (9 mL). Precipitated crystals were collected by filtration, washed with 50% ethanol, and dried at 60° C., thereby obtaining 760 mg of light-yellow, powdery 7-benzyloxy-1-ethyl-5-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (yield: 69%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:31][CH3:32])=[C:12]([CH:30]=2)[CH2:13][NH:14][CH:15]2[CH2:20][CH2:19][CH:18]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]2)[CH:5]=[C:4]([CH3:33])[N:3]=1.[Cl:34][C:35]1[C:36]2[C:46]([F:47])=[CH:45][CH:44]=[C:43]([F:48])[C:37]=2[S:38][C:39]=1[C:40](Cl)=[O:41]>>[Cl:34][C:35]1[C:36]2[C:46]([F:47])=[CH:45][CH:44]=[C:43]([F:48])[C:37]=2[S:38][C:39]=1[C:40]([N:14]([CH2:13][C:12]1[CH:30]=[C:8]([C:6]2[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH3:33])[CH:5]=2)[CH:9]=[CH:10][C:11]=1[O:31][CH3:32])[CH:15]1[CH2:16][CH2:17][CH:18]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][CH2:20]1)=[O:41]
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2cc(C)nc(C)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2cc(C)nc(C)c2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 92 (268 mg, 0.59 mmol) is treated with acid chloride 8 (205 mg, 0.77 mmol) using Method D to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.O.[C:19](#[N:22])[CH:20]=[CH2:21]>>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][CH2:21][CH2:20][C:19]#[N:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC#N
Reactant: CC(C)(C)OC(=O)NCCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCOCCC#N
Temperature: 50 °C

Procedure:
[2-(2-Cyano-ethoxy)-ethyl]-carbamic acid tert-butyl ester (430 mg) was prepared starting from (2-hydroxy-ethyl)-carbamic acid tert-butyl ester (320 mg) in acrylonitrile (1.5 mL). The reaction was heated to 50° C. for 1 h. The reaction was added to ethyl acetate (20 mL) and water (20 mL). The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organics were dried over sodium sulfate and then filtered. The solvent was evaporated and crude compound was purified by flash chromatography using hexane:ethyl actetate gradient.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@H:24]([OH:39])[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([OH:38])=[C:31]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:32]=1>>[OH:39][C@H:24]([CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([OH:38])=[C:31]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:32]=1)[CH2:23][NH:22][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN)ccc1O
Product: CCCCS(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from butane-1-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example 228) and N-[5-((2S)-3-amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 14) according to the procedure of Example 278 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.83 (t, J=7.3 Hz, 3 H), 1.25–1.40 (m, 2 H), 1.55–1.70 (m, 2 H), 1.80–1.95 (m, 2 H), 2.50–2.80 (m, 5 H), 2.92 (s, 3 H), 2.85–3.30 (m, 2 H), 3.50–3.65 (m, 2 H), 3.70–3.90 (m, 3 H), 6.61 (dd, J=8.8, 2.9 Hz, 1 H), 6.70–6.80 (m, 2 H), 6.88 (d, J=8.9 Hz, 2 H), 7.05 (d, J=8.9 Hz, 2 H); MS (ES) m/z: 571.0 (MH+); HRMS Calcd. for C25H39N4O7S2 (MH+): 571.2261. Found: 571.2279.