Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[CH:7]=[C:8]([C:10]([O:12]CC)=[O:11])[O:9][C:5]=2[CH:4]=1.CO.[Li+].[OH-]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[O:9][C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1cc2ccc(OC)cc2o1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2cc(C(=O)O)oc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
To a stirred solution of Product of Step B (0.25 g, 1.21 mmol) in a mixture of THF, MeOH and H2O (5 ml:2 ml:1 ml), LiOH (0.145 g, 6 mmol) in H2O (0.5 ml) was added and the mixture was stirred for 3 h at room temp. The solvents were distilled off and the residue was portioned between EtOAc (20 ml) and 1M HCl (2 ml). The organic layer was washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the title compound (0.21 g, 91%), as a colourless solid. 1H-NMR (DMSO-d6) 7.61 (d, 1H, J=8.67 Hz); 7.54 (s, 1H); 7.24 (d, 1H, J=1.59 Hz); 6.93 (dd, 1H, J=8.67, 2.4 Hz); 3.8 (s, 3H).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([CH2:25][O:26][C:27](=[O:43])[C@H:28]([CH:40]([CH3:42])[CH3:41])[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:21][C:22]([OH:24])=[O:23])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:62][CH2:63]I>O1CCOCC1>[Cl:62][CH2:63][O:23][C:22](=[O:24])[CH2:21][CH:20]([CH2:25][O:26][C:27](=[O:43])[C@H:28]([CH:40]([CH3:42])[CH3:41])[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:19][O:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: ClCI
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)OCCl

Procedure:
3,3-bis (N-CBz-L-valyloxymethyl)-propionic acid (3 g, 5 mmole) was dissolved in dioxane (20 ml). To the solution was added tetrabutylammonium hydroxide aqueous solution (40%, 3.11 ml, 4.8 mmole). The solution was dried in vacuo, and it was coevaporated with toluene several times. The residue was dissolved in methylene chloride (15 ml) and then chloroiodomethane (7.3 ml, 100 mmole) was added to the solution. The reaction solution was refluxed for 18 hr and then evaporated and the product was isolated with silica gel column chromatography. 900 mg.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11]COCCOC)=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([C:22]#[N:23])[N:6]=1)([CH3:4])[CH3:3].FC(F)(F)C(O)=O>>[CH3:4][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([C:22]#[N:23])[N:6]=1)([CH3:1])[CH3:3]
Reactant: COCCOCOc1c(C(C)(C)C)nc(C#N)nc1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1nc(C#N)nc(C(C)(C)C)c1O
Yield: 68.2 %

Procedure:
According to the procedure of Example 18, 4,6-bis(1,1-dimethylethyl) -5-[(2-methoxyethoxy)methoxy]-2-pyrimidine carbonitrile (9.1 g, 28.3 mmol) is treated with trifluoroacetic acid to give 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carbonitrile (4.5 g, 68%); mp 203°-205° C.
Reaction SMILES: COC1C=C(C=CC=1OC)C(C1C=CC(OC)=C(OC)C=1)=O.[C:23]1([O:31][CH3:32])[C:24](=[CH:27][CH:28]=[CH:29][CH:30]=1)[O:25][CH3:26].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:37][O:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH3:49])[C:40]=1[C:41](Cl)=[O:42]>>[CH3:49][O:48][C:44]1[CH:45]=[CH:46][CH:47]=[C:39]([O:38][CH3:37])[C:40]=1[C:41](=[O:42])[C:29]1[CH:28]=[CH:27][C:24]([O:25][CH3:26])=[C:23]([O:31][CH3:32])[CH:30]=1
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: COc1ccccc1OC
Agent: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2c(OC)cccc2OC)cc1OC

Procedure:
2',6',3,4-Tetramethoxybenzophenone was prepared analogously to 3,4,3',4'-tetramethoxybenzophenone except using veratrole (1.3 mL, 10 mmol), aluminum chloride (1.47 g, 11 mmol) and 2,6-dimethoxybenzoyl chloride (2.0 mL, 10 mmol) with a reaction time of 24 hours at room temperature. The crude mixture was purified by flash column chromatography (silica gel, 4% ethyl acetate/methylene chloride) to afford 2.11 g (70%) of the product as a white solid: mp 128-129° C.; 1H NMR (CDCl3) δ 7.66-7.60 (m, 1H), 7.40-7.20 (m, 2H), 6.88-6.79 (m, 1H), 6.67-6.65 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.71 (s, 6H); 13C NMR (CDCl3) δ 193.8, 157.4, 153.4, 148.9, 130.9, 130.5, 125.3, 118.0, 110.2, 109.9, 104.0, 55.9, 55.8; Anal. Calcd for C17H18O5. Theoretical: C, 67.54; H, 6.00. Found: C, 66.51; H, 5.91.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])=[C:12]([CH3:20])[NH:11][C:10]([CH3:21])=[C:9]2[C:22]([O:24][CH2:25][CH2:26][C:27]#[N:28])=[O:23])[CH:5]=[CH:6][CH:7]=1.I[C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][CH2:37][CH2:38][C:39]#[N:40])=[O:35])=[CH:32][CH:31]=1.C(N(CC)CC)C.O>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH2:17][CH:18]=[CH:19][C:30]3[CH:31]=[CH:32][C:33]([C:34]([O:36][CH2:37][CH2:38][C:39]#[N:40])=[O:35])=[CH:41][CH:42]=3)=[O:15])=[C:12]([CH3:20])[NH:11][C:10]([CH3:21])=[C:9]2[C:22]([O:24][CH2:25][CH2:26][C:27]#[N:28])=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCC#N)C1c1cccc(Cl)c1
Reactant: N#CCCOC(=O)c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1=C(C(=O)OCC=Cc2ccc(C(=O)OCCC#N)cc2)C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1

Procedure:
307 mg (0.77 mmol) of 5-(2-propene-1-yl) 3-(2-cyanoethyl) 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, 278 mg (0.92 mmol) of 2-cyanoethyl 4-iodobenzoate, 19 mg(0.08 mmol) of palladium acetate and 0.14 ml (1.0 mmol) of triethylamine were heated at 100° C. under stirring in 5 ml of DMF overnight. Water was added to the reaction mixture. After the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=2/1) to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.[CH2:24]([S:31][CH:32]([CH:35]([O:38][CH3:39])[O:36][CH3:37])[CH2:33][NH2:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH2:24]([S:31][CH:32]([CH:35]([O:36][CH3:37])[O:38][CH3:39])[CH2:33][NH:34][C:12]([C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[N:2]([CH3:1])[S:15]([C:18]1[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=1)(=[O:17])=[O:16])=[O:13])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1nccn1C
Reactant: COC(OC)C(CN)SCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(OC)C(CNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3nccn3C)c2[nH]1)SCc1ccccc1
Yield: 102.2 %

Procedure:
A solution of 7-{methyl[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}-1H-indole-2-carboxylic acid (2.64 g), 2-(benzylthio)-3,3-dimethoxypropan-1-amine (2.10 g), N-ethyldiisopropylamine (3.2 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.6 g) in N,N-dimethylformamide (40 mL) was stirred at room temperature for 16 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=35:65-50:50) to give the title compound (4.5 g, yield: 100%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([CH:16]3[CH2:32][N:20]4[C:21]5[C:26]([C:27]([CH2:28][C:29]([OH:31])=[O:30])=[C:19]4[CH2:18][CH2:17]3)=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:14]=[N:13][CH:12]=2)(O)[CH3:9])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([CH:16]3[CH2:32][N:20]4[C:21]5[C:26]([C:27]([CH2:28][C:29]([OH:31])=[O:30])=[C:19]4[CH2:18][CH2:17]3)=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:14]=[N:13][CH:12]=2)=[CH2:9])=[CH:4][CH:3]=1
Reactant: CC(O)(c1ccc(F)cc1)c1cnnn1C1CCc2c(CC(=O)O)c3ccccc3n2C1
Agent: Cl
Solvent: C1COCCO1
Product: C=C(c1ccc(F)cc1)c1cnnn1C1CCc2c(CC(=O)O)c3ccccc3n2C1
Temperature: 25 °C

Procedure:
The title compound was prepared from refluxing a solution of (7-{5-[1-(4-Fluoro-phenyl)-1-hydroxy-ethyl]-[1,2,3]triazol-1-yl}-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)-acetic acid (EXAMPLE 5) in a 1:1 mixture of Dioxane: 2M HCl for 24 h. The reaction mixture was cooled to room temperature then extracted with EA, washed with brine, dried over Na2SO4 and evaporated. Purification by Combi-flash EA/Hex 50-100% afforded the desired compound. MS (+ESI) m/z: 417.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][CH:13]([OH:15])[CH3:14])=[C:6]([CH3:16])[CH:5]=1)([O-])=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:29].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:29].[ClH:29].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][CH:13]([OH:15])[CH3:14])=[C:6]([CH3:16])[CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1NCCC(C)O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1cc(N)ccc1NCCC(C)O

Procedure:
The 4-(4-nitro-2-methylphenylamino)butan-2-ol (27) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH:3]=1.[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[C:17](=O)[CH2:16]2.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:17]2[CH:18]3[CH2:21][CH2:22][N:15]([CH2:20][CH2:19]3)[CH2:16]2)=[C:4]([CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH:3]=1
Reactant: COC(Cc1cc(Br)ccc1N)OC
Reactant: O=C1CN2CCC1CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(Cc1cc(Br)ccc1NC1CN2CCC1CC2)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.3 %

Procedure:
Compound 67 (160 mg, 0.615 mmol) and quinuclidin-3-one (115.5 mg, 0923 mmol) were stirred in acetic acid (5 mL) under argon in the presence of anhydrous sodium sulfate (874 mg, 6.150 mmol) at room temperature for 30 minutes. Sodium triacetoxyborohydride (391 mg, 1.845 mmol) was then added and the mixture stirred for 24 hours at room temperature. Thin layer chromatography in a solvent system of 2M NH3 in methanol:CH2Cl2, 5:95 shows incomplete consumption of 67, thus a second portion of quinuclidin-3-one (38.4 mg, 0.307 mmol) is added and the mixture stirred for a further 20 hours. After dilution with a mixture of 8:1 ethyl acetate:hexanes, the reaction is quenched with saturated sodium bicarbonate. The mixture was transferred to a separatory funnel and the organic layer separated. The organic layer was dried over sodium sulfate and concentrated under reduced pressure and the residue purified via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 2.5:97.5 to 5:95) to yield a colorless residue, 68 (137 mg, 60.3%). 1H NMR (DMSO-d6) δ 1.25-1.39 (m, 1H), 1.53-1.80 (2×m, 3H), 1.86-1.94 (m, 1H), 2.64-2.77 (m, 4H), 2.80 (d, 2H, J=5.2 Hz), 3.14-3.24 (m, 1H), 3.27 and 3.29 (2×s, 6H), 3.34-3.40 (m, 1H), 4.54 (t, 1H, J=5.2 Hz), 5.04 (d, 1H, J=5.8 Hz), 6.43 (d, 1H, J=8.3 Hz), 7.13-7.15 (m, 1H), 7.17 (s, 1H); ESI-MS (m/z, %): 369/371 (MH+, 100%).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][CH:16]([F:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([NH2:27])[CH3:26])=[CH:21][C:20]=1[CH3:28]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:27]([CH:25]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH:16]([F:15])[F:29])=[C:20]([CH3:28])[CH:21]=3)[CH3:26])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)ccc1OCC(F)F
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ccc1OCC(F)F
Yield: 65 %

Procedure:
The title compound is prepared in 65% yield (136 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethanamine hydrochloride (143 mg, 0.57 mmol, Amine-27, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: CI.FC(F)(F)C(O)=O.C(O[C:15](=O)[NH:16][C:17]1[C:18]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])=[N:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:21][CH:22]=1)(C)(C)C.C(O)(C)(C)C.[F:43][C:44]([F:62])([F:61])[C:45]1[CH:46]=[C:47]([C:55]([CH3:60])([CH3:59])[C:56](Cl)=[O:57])[CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1>>[F:43][C:44]([F:62])([F:61])[C:45]1[CH:46]=[C:47]([C:55]([CH3:60])([CH3:59])[C:56]([N:16]([CH3:15])[C:17]2[C:18]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH3:36])=[N:19][C:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[N:21][CH:22]=2)=[O:57])[CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccccc1Oc1nc(-c2ccccc2)ncc1NC(=O)OC(C)(C)C
Solvent: CI
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)(C)O
Product: Cc1ccccc1Oc1nc(-c2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
In an analougous manner to that described in Examle 72 a) there was obtained from 2-phenyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid, diphenylphosphorylazide and t-butanol (2-phenyl-4-o-tolyloxy-pyrimidin-5-yl)-carbamic acid tert.-butyl ester, which was methylated with methyliodide and than deprotected with trifluoracetic acid according to Example 72 b) c). The resulting methyl-(2-phenyl-4-o-tolyloxy-pyrimidin-5-yl)-amine was treated with 2-(3,5-bis-trifluormethyl-phenyl)-2-methyl-propionyl chloride as described in Example 72 e) to give 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-phenyl-4-o-tolyloxy-pyrimidin-5-yl)-isobutyramide as a white foam, MS (ISP): 574.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:4]>[Pt]=O.C(O)C>[NH2:13][C:12]1[C:7]([O:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)COc1ncccc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Product: COC(=O)COc1ncccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
A mixture of 0.3 g of 2-(methoxycarbonyl)methoxy-3-nitropyridine, 20 mg of platinum oxide, and 1.4 ml of ethanol was stirred at room temperature under an atmosphere of hydrogen gas for 3 hours. The gas in the atmosphere on the reaction system was replaced with nitrogen gas, and the reaction mixture was filtered through Celite. The filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 0.22 g of 3-amino-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:21])[CH2:10][CH2:11][C@@H:12]([OH:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:22](Cl)[O:23][CH3:24].CCN(C(C)C)C(C)C>C(Cl)Cl>[Si:1]([O:8][C@H:9]([CH3:21])[CH2:10][CH2:11][C@@H:12]([O:20][CH2:22][O:23][CH3:24])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: COCCl
Reactant: CCOC(=O)/C=C/[C@H](O)CC[C@@H](C)O[Si](C)(C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)/C=C/[C@@H](CC[C@@H](C)O[Si](C)(C)C(C)(C)C)OCOC
Reaction time: 8 h

Procedure:
To a stirred solution of the compound (30, ethyl(4R,7R,E)-7-((tert-butyldimethylsilyl)oxy)-4-hydroxyoct-2-enoate) in dry CH2Cl2 solvent, MOMCl (2 equiv), DIPEA (3 equiv) were added and stirred for 8 h. On completion of the reaction (by checking TLC), the organic layer was extracted in DCM, washed with brine, dried over anhydrous Na2SO4. The solvent was removed in vacuum, concentrated and subjected for chromatographic separation. The eluent was allowed to come in a solution of pet ether:EtOAC=90:10 as a pale yellow liquid [α]25=+23.22 (c 1.24, CHCl3); 1H NMR (200 MHz, CDCl3): δ 6.69-6.80 (dd, 1H), 5.96 (d, 1H), 4.57 (m, 2H), 4.14 (m, 3H), 3.81 (m, 1H), 1.40 (t, 3H), 1.23 (d, 2H), 0.84 (s, 9H), −0.4 (s, 6H); 13C NMR (CDCl3, 50 MHz): 166.04, 147.76, 121.95, 94.48, 75.04, 68.07, 60.37, 55.55, 34.94, 30.78, 25.92, 23.85, 18.12, 14.28, −4.29; −4.67.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][C:27]([CH3:32])([CH2:30][NH2:31])[CH2:28][NH2:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:29][CH2:28][C:27]([CH3:32])([CH3:26])[CH2:30][NH2:31])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: CC(C)(CN)CN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(C)(C)CN)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2,2-dimethylpropane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (d, J=1.2 Hz, 1 H), 7.99 (s, 1 H), 7.88 (d, J=7.2 Hz, 1 H), 7.73-7.70 (m, 2 H), 7.61-7.57 (m, 2 H), 6.07 (s, 1 H), 5.31 (s, 2 H), 4.50 (s, 2 H), 3.73 (s, 2 H), 3.49 (s, 2 H), 2.99 (s, 2 H), 2.47 (s, 3 H), 1.10 (s, 6 H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Reactant: C1CCNC1
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)N4CCCC4)cc3C)cc12

Procedure:
(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl)(pyrrolidin-1-yl)methanone was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and pyrrolidine following the procedures described for Example 117. 1H NMR (methanol-d4): δ 8.60 (s, 1H), 8.42 (s, 1H), 8.09 (d, 1H), 7.34 (s, 1H), 7.23 (s, 1H), 7.05-7.15 (m, 3H), 3.49 (t, 2H), 3.27 (t, 2H), 3.05-3.17 (m, 4H), 2.42 (s, 3H), 2.26 (s, 3H), 1.88-1.91 (m, 2H), 1.73-1.77 (m, 2H). LRMS [M+H]=425.2
Reaction SMILES: C(O)(=O)C.Br.[CH2:6]([C:8]1[CH:13]=[C:12](CC#N)[CH:11]=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=1)[CH3:7].[C:25]([O:28][CH2:29]C)(=[O:27])[CH3:26]>>[CH2:6]([C:8]1[CH:13]=[C:12]([CH2:26][C:25]([O:28][CH3:29])=[O:27])[CH:11]=[CH:10][C:9]=1[C:17]1[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=1)[CH3:7]
Reactant: CCc1cc(CC#N)ccc1-c1ccc(OC)cc1
Reactant: CCOC(C)=O
Agent: Br
Solvent: CC(=O)O
Product: CCc1cc(CC(=O)OC)ccc1-c1ccc(O)cc1
Temperature: 100 °C
Reaction time: 10 h
Yield: 85 %

Procedure:
Acetic acid (55 ml) and hydrobromic acid (55 ml) were added to (2-ethyl-4′-methoxy-1,1′-biphenyl-4-yl)acetonitrile (5.5 g, 22 mmol) obtained in Example (26-3), and the mixture was stirred at 100° C. for 10 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added thereto and the mixture was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. After methanol (150 ml) was added to the residue obtained by removing the solvent under reduced pressure, sulfuric acid (3 ml) was added to the mixture under ice-cooling. After the mixture was stirred at room temperature for 1 hour, the solvent was removed under reduced pressure. After ethyl acetate was added to the obtained residue, the mixture was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=5/1-2/1) to give methyl (2-ethyl-4′-hydroxy-1,1′-biphenyl-4-yl)acetate as a colorless solid (5.0 g, yield: 85%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:65]=[C:66]([CH:71]=[CH:72][CH:73]=1)[C:67]([O:69][CH3:70])=[O:68]>>[CH3:70][O:69][C:67](=[O:68])[C:66]1[CH:71]=[CH:72][CH:73]=[C:64]([NH:63][C:30]([C@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])[CH:65]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(=O)c1cccc(N)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(NC(=O)[C@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)c1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.53 mmol), was reacted with diisopropylethylamine (0.28 g, 2.1 mmol), diphenylphosphinic chloride (0.38 g, 1.6 mmol), then reacted with methyl 3-aminobenzoate (Aldrich) (0.12 g, 0.8 mmol) to give rac-3-{[(2′S,3′R,4′S,5′S)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-benzoic acid methyl ester as a off white solid (Yield, 0.07 g, 22%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:13](=O)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:1][CH2:2][CH2:3][C:4]1[N:5]=[N:6][C:7]2[C:12]([C:13]=1[Cl:17])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=c1c(CCCl)n[nH]c2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Product: ClCCc1nnc2ccccc2c1Cl

Procedure:
3-(2-Chloroethyl)-4-oxo-(1H)-cinnoline (9 g, 0.043 mol) and phosphorus oxychloride (90 ml) were heated under reflux for 1 hour. After allowing to cool, the excess phosphorus oxychloride was evaporated under reduced pressure and the residue was poured onto ice (100 g), basified with concentrated ammonia solution, and extracted with chloroform (3×100 ml). The chloroform extracts were combined, dried over magnesium sulphate and evaporated under reduced pressure to give a solid, 8.00 g. Recrystallization from diethyl ether gave the title compound, m.p. 81-82°.