Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:9])[C:2]([C:7]#[N:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH3:10].O=O>>[CH:4]1[CH:3]=[C:2]([C:7]#[N:8])[C:1]([C:9]#[N:10])=[CH:6][CH:5]=1
Reactant: Cc1ccccc1C#N
Reactant: N
Agent: O=O
Product: N#Cc1ccccc1C#N

Procedure:
750 ml of a catalyst having a particle size of from 0.05 to 0.3 mm are introduced into a quartz reactor which has a diameter of 60 mm and a length of 1000 mm and is provided with an external heater and a quartz frit for uniformly distributing the reaction gas. The catalyst is composed of 5.0% by weight of V2O5, 5.9% by weight of Sb2O3 0.24% by weight of K2O, 0.56% by weight of BaO and 88.3% by weight of γ-Al2O3. The reactor is heated to 470° C. and a gas mixture consisting of 3.25% by volume of o-xylene, 13% by volume of oxygen and 83.75% by volume of ammonia is passed through. The hot reaction gases are cooled to 70° C. with ammonia water in two wash towers arranged in series. An aqueous suspension of crystals is formed, from which the o-phthalodinitrile is isolated by filtration. 2,687 parts of o-xylene give 2,581 parts of o-phthalodinitrile and 195 parts of o-tolunitrile. By reacting the 195 parts of o-tolunitrile again with ammonia and oxygen, a further 170 parts of o-phthalodinitrile are obtained. The total yield of o-phthalodinitrile is 84.8 mol %, based on converted o-xylene.
Reaction SMILES: [NH2:1][C:2]1([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][C:16]3[C:21]4[C:22]([CH3:26])([CH3:25])[CH2:23][O:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)=[O:7])[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:35](Cl)([O:37]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:25][C:22]1([CH3:26])[C:21]2[C:16]([O:15][C:12]3[N:11]=[CH:10][C:9]([N:8]4[C:6](=[O:7])[C:2]5([CH2:5][CH2:4][CH2:3]5)[NH:1][C:35]4=[O:37])=[CH:14][CH:13]=3)=[CH:17][CH:18]=[CH:19][C:20]=2[O:24][CH2:23]1
Reactant: CC1(C)COc2cccc(Oc3ccc(NC(=O)C4(N)CCC4)cn3)c21
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)COc2cccc(Oc3ccc(N4C(=O)NC5(CCC5)C4=O)cn3)c21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1-amino-N-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}cyclobutanecarboxamide (Intermediate 70, 17 mg) was dissolved in dry dichloromethane (1.8 ml). The reaction mixture was cooled down in an ice bath. Triethylamine (39.48 μl, 0.283 mmol) was added at 0° C. Then 0.89 ml of a solution of triphosgene in dry dichloromethane was added dropwise (0.0135 mg, 4.00 mg). The reaction mixture was stirred under argon during 10 min at 0° C., then during 30 min at room temperature. Then an additional 0.25 equivalent of triphosgene in dichloromethane (0.26 M solution) was added at 0° C. and the reaction mixture was stirred under argon an additional 30 min at room temperature. The solvents were removed under vacuum. The residue obtained was purified by flash chromatography on silica gel (Companion system, 4 g silica cartridge) with cyclohexane/ethylacetate as eluents from 100/0 to 55/45. This afforded the title compound (12 mg).
Reaction SMILES: [CH2:1]=O.[C:3]([C:6]1([NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]1)(=[O:5])[NH2:4]>CN(C)C=O>[F:24][C:21]1[CH:20]=[CH:19][C:18]([N:17]2[C:6]3([CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]3)[C:3](=[O:5])[NH:4][CH2:1]2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)N1CCC(Nc2ccc(F)cc2)(C(N)=O)CC1
Reactant: C=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1
Reaction time: 48 h

Procedure:
To a solution of 6.9 parts of paraformaldehyde in 100 parts of N,N-dimethylformamide are added portionwise 46.3 parts of ethyl 4-carbamoyl-4-(4-fluorophenylamino)-1-piperidinecarboxylate. The whole is stirred and refluxed for 20 hours. Then 50 parts of the solvent are distilled off (t°: 142°-152° C.). A second portion of 1 part of paraformaldehyde in 50 parts of N,N-dimethylformamide is added and stirring and refluxing is continued for 48 hours. The N,N-dimethylformamide is distilled off to a volume of about 50 parts and the distillate is poured onto water. The water is decanted and the residue is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is triturated in 2,2'-oxybispropane. The product is filtered off and crystallized from a mixture of benzene and 2,2'-oxybispropane, yielding 17.5 parts of ethyl 1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4,5]decane-8-carboxylate; mp. 153° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[CH3:7][N:8]([CH3:12])[C:9](Cl)=[O:10].C(N(CC)CC)C>C(#N)C.C(OCC)C>[CH3:7][N:8]([CH3:12])[C:9]([N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1)=[O:10]
Reactant: Cc1c[nH]cn1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CC#N
Product: Cc1cn(C(=O)N(C)C)cn1

Procedure:
A solution containing 4-methylimidazole (16.4 g), N,N-dimethylcarbamoyl chloride (30 g) and triethylamine (30 g) in acetonitrile (125 mL) is stirred at reflux for 20 hours. Upon cooling, the reaction is diluted with diethyl ether (1000 mL) and then filtered. The filtrate is concentrated and the residue is distilled under reduced pressure. 1-(Dimethylcarbamoyl)-4-methylimidazole is obtained as a colorless liquid, b.p. 104°-106° at 0.35 mm Hg.
Reaction SMILES: [N:1]1[N:5]2[C:6](O)=[CH:7][CH:8]=[N:9][C:4]2=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:13].CN(C)C1C=CC=CC=1>>[Cl:13][C:6]1[N:5]2[N:1]=[CH:2][CH:3]=[C:4]2[N:9]=[CH:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2ccnn12
Solvent: CN(C)c1ccccc1
Product: Clc1ccnc2ccnn12
Temperature: 25 °C

Procedure:
To a solution of pyrazolo[1,5-a]pyrimidin-7-ol (C-1) (19.0 g, 14.1 mmol, 1.0 eq) in phosphoroxychloride (100 mL, 1.06 mol, 76 eq) at RT, N,N-dimethylaniline (7.0 g, 58.0 mmol, 4.1 eq) is added dropwise and the resulting mixture is stirred at reflux overnight. The mixture is allowed to cool to RT and concentrated in vacuo to remove the phosphoroxychloride. The residue is poured into ice water (200 mL), neutralized with saturated aqueous NaHCO3 solution to adjust the pH to 8-9 while keeping the temperature below 5° C. The mixture is stirred at RT for 30 min and then extracted with ethyl acetate (4×200 mL). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo and the residue is purified by flash column chromatography on silica gel (1-3% ethyl acetate-petroleum ether) to afford the product, 7-chloropyrazolo[1,5-a]pyrimidine (C-2).
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]=O.O>C1CCCCC1>[CH:1]1([N:7]2[CH2:8][CH2:9][CH2:10][NH:11][CH2:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=O
Reactant: NCCCNC1CCCCC1
Solvent: O
Solvent: C1CCCCC1
Product: C1CCC(N2CCCNC2)CC1
Yield: 73.8 %

Procedure:
312 g of N-cyclohexyl-1,3-propanediamine are slowly added dropwise at 60° C. to a suspension of 66 g of paraformaldehyde in 200 ml of cyclohexane. The water of reaction is then removed by boiling under reflux on a water separator. Insoluble constituents are removed by filtration and the filtrate is subjected to fractional distillation. 248 g of N-cyclohexyl-hexahydropyrimidine boiling at from 87° to 91° C. at 0.3 mbar are obtained.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]([CH3:30])([NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)=[O:8])[CH3:5].[Li+].[OH-].Cl>O1CCOCC1.C(OCC)(=O)C>[CH3:30][C:4]([NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]=1[O:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=1)=[O:8])([CH3:5])[C:3]([OH:31])=[O:2]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccsc2c1OCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(NC(=O)c1ccc2ccsc2c1OCc1ccc(C(F)(F)F)cc1)C(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
308 mg 2-methyl-2-{[7-(4-trifluoromethyl-benzyloxy)-benzo[b]thiophene-6-carbonyl]-amino}-propionic acid methyl ester was dissolved in 5 ml of 1,4-dioxane. To this was added 3.4 ml of 1 M LiOH (aq), and the reaction was stirred for 1 h at 60° C. and overnight at room temperature. The reaction mixture was diluted with 10 ml of ethyl acetate, acidified to pH 3 with 2N HCl (aq) and extracted with 10 ml ethyl acetate four times. The combined organic layers were washed with brine, dried over sodium sulphate and concentrated in vacuo to give 299 mg of 2-methyl-2-{[7-(4-trifluoromethyl-benzyloxy)-benzo[b]thiophene-6-carbonyl]-amino}-propionic acid.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=2)[C:10]2([CH2:26][N:25]([C:27](=[O:29])[CH3:28])[CH2:24]2)[CH2:9]1)=O)(C)(C)C.[ClH:30]>CCOC(C)=O>[ClH:30].[C:27]([N:25]1[CH2:24][C:10]2([C:11]3[C:16](=[CH:15][C:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[NH:8][CH2:9]2)[CH2:26]1)(=[O:29])[CH3:28]
Reactant: CC(=O)N1CC2(C1)CN(C(=O)OC(C)(C)C)c1cc(Cc3ccccc3)ccc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)N1CC2(CNc3cc(Cc4ccccc4)ccc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Acetyl-6′-benzyl-1′,2′-dihydrospiro[azetidine-3,3′-indole]-1′-yl-carboxylic acid tert-butyl ester was taken up in saturated HCl in EtOAc (5 mL). The reaction was stirred for 1 h at ambient temperature and then concentrated in vacuo. The residue was taken up in MeOH and concentrated in vacuo again to yield the title compound. MS: [M+H]+=293.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9]C(C)(C)C)=O)[C@H:4]([C:14]2[NH:18][C:17]3[C:19]4[C:24]([CH:25]=[CH:26][C:16]=3[N:15]=2)=[CH:23][C:22]2[C:27]3[C:32]([CH2:33][O:34][C:21]=2[CH:20]=4)=[CH:31][C:30]([B:35]2[O:39][C:38]([CH3:41])([CH3:40])[C:37]([CH3:43])([CH3:42])[O:36]2)=[CH:29][CH:28]=3)[CH2:3]1.Cl.[CH3:45][O:46][C:47]([NH:49][C@@H:50]([CH:54]([CH3:56])[CH3:55])C(O)=O)=[O:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.CN(C=O)C.CO>[CH3:55][CH:54]([CH3:56])[C@H:50]([NH:49][C:47](=[O:48])[O:46][CH3:45])[C:7]([N:5]1[CH2:6][C@@H:2]([CH3:1])[CH2:3][C@H:4]1[C:14]1[NH:18][C:17]2[C:19]3[C:24]([CH:25]=[CH:26][C:16]=2[N:15]=1)=[CH:23][C:22]1[C:27]2[C:32]([CH2:33][O:34][C:21]=1[CH:20]=3)=[CH:31][C:30]([B:35]1[O:39][C:38]([CH3:41])([CH3:40])[C:37]([CH3:42])([CH3:43])[O:36]1)=[CH:29][CH:28]=2)=[O:9]
Reactant: C[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2-5)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(B2OC(C)(C)C(C)(C)O2)ccc1-4)C(C)C
Reaction time: 4 h
Yield: 57.3 %

Procedure:
(2S,4S)-tert-butyl 4-methyl-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (950 mg, 1.63 mmol) was dissolved in DCM (12 mL), MeOH (3 mL) and HCl (4 M in dioxane, 3 mL) was added. The reaction mixture was stirred for 4 h and then concentrated under reduced pressure. The crude residue was treated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (285 mg, 1.63 mmol), HATU (620 mg, 1.63 mmol) and DMF (15 mL), then DIPEA (1.42 mL, 8.15 mmol) was added dropwise. After 1 h, the mixture was diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc) to afford methyl [(2S)-3-methyl-1-{(2S,4S)-4-methyl-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-1-oxobutan-2-yl]carbamate (596 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:12]([CH3:18])=[C:13]([CH2:16][OH:17])[S:14][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[C:12]([CH3:18])=[C:13]([CH:16]=[O:17])[S:14][CH:15]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1c(S(=O)(=O)c2ccc(Cl)cc2)csc1CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: Cc1c(S(=O)(=O)c2ccc(Cl)cc2)csc1C=O
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a suspension of [4-(4-chloro-benzenesulfonyl)-3-methyl-thiophen-2-yl]-methanol (786 mg, 2.60 mmol), 4-methylmorpholine N-oxide (0.46 g, 3.9 mmol), and powdered 4 Å molecular sieves (1.3 g, activated by brief heating in vacuo) in CH2Cl2 (7 mL) was added tetrapropylammonium perruthenate (46 mg, 0.13 mmol). The resulting mixture was stirred for 1 hour, after which it was filtered through a plug of silica (ca. 25 g) eluting with EtOAc. The eluate was evaporated in vacuo and the product was purified by chromatography on silica gel on a FlashMaster system using as eluent heptane/ethyl acetate (linear gradient elution from 1:0 to 1:1). Fractions containing the product were pooled and evaporated in vacuo to yield the title compound (644 mg, 82%). 1H NMR (CDCl3): 2.60 (s, 3 H), 7.53 (d, J=9.0 Hz, 2 H), 7.87 (d, J=8.5 Hz, 2 H), 8.53 (s, 1 H), 10.01 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[I:12]N1C(=O)CCC1=O.O>ClCCl>[I:12][C:11]1[C:4]2[C:3]([O:2][CH3:1])=[N:8][CH:7]=[N:6][C:5]=2[NH:9][CH:10]=1
Reactant: COc1ncnc2[nH]ccc12
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: ClCCl
Product: COc1ncnc2[nH]cc(I)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (3, 3.20 g, 21.4 mmol) in 280 mL of dichloromethane, N-iodosuccinimide (5.3 g, 24.0 mmol) suspended in dichloromethane was added. The reaction was stirred at room temperature for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was washed with ethyl acetate and hexane to provide the desired compound (35, 4.80 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20](O)=[O:21])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:26]=1.Cl.[CH3:28][O:29][C:30](=[O:35])[C@H:31]([CH2:33]O)[NH2:32].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:20]4[O:21][CH2:33][C@@H:31]([C:30]([O:29][CH3:28])=[O:35])[N:32]=4)[CH:23]=[CH:24][CH:25]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:26]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)O)c1)C2=O
Reactant: COC(=O)[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)[C@@H]1COC(c2cccc(N3C[C@@H]4CCCN4c4nc(SC)ncc4C3=O)c2)=N1
Reaction time: 4 h
Yield: 75.1 %

Procedure:
(S)-3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic acid (150 mg, 0.405 mmol) obtained in Step 1 of Example 56 was dissolved in dichloromethane (5 mL), and the mixture was stirred for 4 hours after adding L-serine methyl ester hydrochloride (95.0 mg, 0.607 mmol), triethylamine (0.0850 mL, 0.607 mmol), 1-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride (93.0 mg, 0.486 mmol), and 1-hydroxybenzotriazole.monohydrate (62.0 mg, 0.405 mol). The mixture was diluted with chloroform and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in THF (5 mL), and the mixture was stirred at room temperature for 30 minutes after adding triphenylphosphine (212 mg, 0.810 mmol) and a 40% toluene solution of diethyl azodicarboxylate (0.367 mL, 0.810 mmol). The mixture was concentrated, and the resulting residue was purified by silica gel column chromatography to give methyl (S)-2-{3-[(S)-9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl]phenyl}-4,5-dihydro-1,3-oxazole-4-carboxylate (138 mg, 75%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15](=[O:23])[CH2:14][CH2:13]1)[NH:6][C:5]2=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N12CCCN=C1CCCCC2.[NH2:63][C@H:64]1[C@H:68]([F:69])[CH2:67][N:66]([C:70]([O:72][CH2:73][C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)=[O:71])[CH2:65]1>CN(C)C=O.O>[F:69][C@H:68]1[C@H:64]([NH:63][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=3)[N:8]=[C:7]([N:12]3[CH2:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[S:15](=[O:23])[CH2:14][CH2:13]3)[N:6]=2)[CH2:65][N:66]([C:70]([O:72][CH2:73][C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)=[O:71])[CH2:67]1
Reactant: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)[nH]c(=O)c2c1
Reactant: N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)nc(N[C@@H]3CN(C(=O)OCc4ccccc4)C[C@H]3F)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.8 %

Procedure:
A suspension of 6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4 (5H)-yl)quinazolin-4(3H)-one (600 mg, 1.77 mmol, prepared in analogy to the one in Example 91), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.02 g, 2.3 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (400 mg, 2.6 mmol) in anhydrous N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 minutes. Then a solution of benzyl trans-3-amino-4-fluoropyrrolidine-1-carboxylate (500 mg, 2.1 mmol) in N,N-dimethylformamide (5 mL) was added dropwise. After being heated at 60° C. overnight, the mixture was diluted with water (50 mL), extracted with dichloromethane (50 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (gradient eluting with 10% to 25% ethyl acetate in dichloromethane) to afford 415 mg of the desired product as a yellow solid (yield was 41.8%).
Reaction SMILES: [C:1]([N:9]1[CH2:13][C@H:12]([O:14]CC2C=CC=CC=2)[CH2:11][C@H:10]1[C:22]1[N:23]([CH3:41])[C:24](=[O:40])[C:25]([OH:39])=[C:26]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[O:29])[N:27]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O.[Pd]>[C:1]([N:9]1[CH2:13][C@H:12]([OH:14])[CH2:11][C@H:10]1[C:22]1[N:23]([CH3:41])[C:24](=[O:40])[C:25]([OH:39])=[C:26]([C:28]([NH:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)=[O:29])[N:27]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c([C@@H]2C[C@@H](OCc3ccccc3)CN2C(=O)c2ccccc2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: Cn1c([C@@H]2C[C@@H](O)CN2C(=O)c2ccccc2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Reaction time: 8 h

Procedure:
The title compound of Step 2 was dissolved in AcOH and 10% Pd/C (10% weight) was added. The mixture was stirred under H2 at atmosphere overnight. Pd/C was filtered, AcOH evaporated in vacuo, and the resulting title compound was washed with methanol.
Reaction SMILES: C(OC(N1C2C(=CC(C3C=CC=CC=3OC)=CC=2)C(C(O)C)=CC1(C)C)=O)(C)(C)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[NH:45][C:44]([CH3:50])([CH3:49])[CH:43]=[C:42]2[CH:51]([O:53][CH2:54][CH2:55][C:56]1C=CC=C[CH:57]=1)[CH3:52].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.C(Br)CC1C=CC=CC=1>[CH2:54]([O:53][CH:51]([C:42]1[C:41]2[C:46](=[CH:47][CH:48]=[C:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[O:32][CH3:31])[CH:40]=2)[NH:45][C:44]([CH3:50])([CH3:49])[CH:43]=1)[CH3:52])/[CH:55]=[CH:56]/[CH3:57]
Reactant: COc1ccccc1-c1ccc2c(c1)C(C(C)OCCc1ccccc1)=CC(C)(C)N2
Agent: BrCCc1ccccc1
Agent: COc1ccccc1-c1ccc2c(c1)C(C(C)O)=CC(C)(C)N2C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: C/C=C/COC(C)C1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Yield: 140.4 %

Procedure:
6-(2-Methoxyphenyl)-2,2-dimethyl-4-(1-phenethyloxyethyl)-1,2-dihydroquinoline 4-(1-Hydroxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester (100 mg) was treated with 360 μL of 1 M solution of sodium bis(trimethylsilyl)amide in THF and 45 μL of phenethyl bromide to give the alkylated product, which was deprotected to yield 62 mg of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]([F:18])([F:17])[CH3:16])[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:17][C:15]([F:18])([CH3:16])[CH2:14][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][OH:11]
Reactant: COC(=O)[C@H](CC(C)(F)F)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(F)(F)C[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-4,4-difluoropentanoate (70 mg, 0.262 mmol) in tetrahydrofuran (4 mL) at −10° C., was added Lithium aluminum hydride, 2M in THF (0.262 mL, 0.524 mmol). The reaction mixture was stirred at −10° C. for 2 h, then quenched with aqueous ammonium chloride (5 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (S)-tert-butyl (4,4-difluoro-1-hydroxypentan-2-yl)carbamate (38 mg, 0.159 mmol, 61% crude yield) as colorless oil. The material was carried forward without further purification. 1H NMR (400 MHz, CDCl3): δ ppm 3.89 (d, J=4.00 Hz, 2H), 2.10-2.14 (m, 1H), 1.61-1.66 (m, 2H), 1.51 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [CH2:1]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C@@H:14]4[C:19]([CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:23])=[CH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[CH2:2][CH2:3][CH3:4].[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCOCC>N1C=CC=CC=1.C1C=CC=CC=1>[CH2:1]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C@@H:14]4[C:19]([CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[O:23][C:32](=[O:33])[CH2:31][CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCCC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC(=O)CCc1ccccc1
Reaction time: 16 h
Yield: 60 %

Procedure:
Cool 13β-butyl-17β-hydroxy-gon-4-en-3-one (0.10 g.) in pyridine (0.3 cc.) to -20° and add 3-phenylpropionyl chloride (0.10 g.) in benzene (0.3 cc.). Stir the mixture at -10° for 16 hours, add ice-cold water, ether (15 cc.) and benzene (15 cc.). Separate the organic layers and wash in turn with 2N sodium hydroxide solution, water and brine, and dry. Evaporate the solvent to an uncrystallizable gum, and take up in a little benzene and filter through neutral alumina (5 g.), then wash with more benzene. Evaporate the resulting benzene solution to obtain the title compound as a gum (0.085 g.); infrared absorption peaks at 5.78, 5.99, 13.3, 14.3 μ, with no absorption due to hydroxyl.