Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([C:26](Cl)=[O:27])[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2>>[S:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[CH2:2][NH:1][C:26]([C:13]1([CH2:12][CH2:11][CH2:10][CH2:9][Br:8])[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:27]
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: NCc1cccs1
Product: O=C(NCc1cccs1)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 2-(aminomethyl)-thiophene and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [OH-].[Na+].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:12]=O)[C:6]=2[CH:5]=[CH:4]1.[CH3:14][C:15]([NH:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](=[O:31])[CH3:30])([CH3:17])[CH3:16]>C(O)C.O>[CH3:17][C:15]([NH:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](=[O:31])[CH:30]=[CH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][NH:3]2)([CH3:14])[CH3:16]
Reactant: CC(=O)c1ccccc1OCCCNC(C)(C)C
Reactant: O=Cc1cccc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)NCCCOc1ccccc1C(=O)C=Cc1cccc2[nH]ccc12
Reaction time: 0.33 h
Yield: 72.9 %

Procedure:
3 ml of 50% sodium hydroxide solution and then 1.484 g of indole-4-carboxaldehyde were added to a solution of 2.55 g of 1-[2-{3-(1,1-dimethylethylamino)-propoxy}-phenyl]-ethanone in 35 ml of ethanol and the mixture was stirred under an inert atmosphere for 20 minutes. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over a deshydrant, filtered and evaporated to dryness under reduced pressure. The residue was chromatographed over silica and eluted with a 9-1 ethyl acetate-triethylamine mixture to obtain 2.804 g of 1-[2-{3-(1,1-dimethylethylamino)-propoxy}-phenyl]-3-[1H-indol-4-yl]-2-propen-1-one.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][S:5][C:6]=1[CH3:7].[Br:12]N1C(=O)CCC1=O>CN(C=O)C>[Br:12][C:4]1[S:5][C:6]([CH3:7])=[C:2]([CH3:1])[C:3]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1csc(C)c1C
Solvent: CN(C)C=O
Product: COC(=O)c1c(Br)sc(C)c1C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a solution of methyl 4,5-dimethylthiophene-3-carboxylate (1.89 g, 11.10 mmol) in DMF (10 mL) was added N-bromosuccinimide (2.37 g, 13.32 mmol) at room temperature. The reaction mixture turned orange over time and was allowed to stir for 2 h, at which time LC-MS analysis indicated complete consumption of the methyl 4,5-dimethylthiophene-3-carboxylate. To the solution was added MTBE and water. The aqueous layer was extracted with MTBE (2×), the combined orange organic layer was washed with 1% sodium thiosulfate, followed by water (2×). The organic phase was dried over Na2SO4 and concentrated to give yellow oil. The crude reaction mixture was purified on Biotage system (isocratic elution 2% EtOAc:98% Hexanes) to give the titled compound as a light yellow solid (2.61 g, 10.5 mmol, 94% yield). LC/MS m/z 249 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]([O:22][CH3:23])[CH:16]=[C:17]2[C:21]=1[NH:20][CH:19]=[CH:18]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].N1C2C(=CC=CC=2C(C2C=CC=CC=2)CC(NC)=O)C=C1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]([C:13]1[CH:14]=[C:15]([O:22][CH3:23])[CH:16]=[C:17]2[C:21]=1[NH:20][CH:19]=[CH:18]2)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=C(c1ccccc1)c1cc(OC)cc2cc[nH]c12
Agent: CNC(=O)CC(c1ccccc1)c1cccc2cc[nH]c12
Product: CCOC(=O)CC(c1ccccc1)c1cc(OC)cc2cc[nH]c12

Procedure:
3-(5-Methoxy-1H-indol-7-yl)-3-phenyl-propionic acid ethyl ester CLXXX was prepared from 3-(5-methoxy-1H-indol-7-yl)-3-phenyl-acrylic acid ethyl ester using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-propionamide XIX (Example 4).
Reaction SMILES: [F:1][C:2]1[C:3]([N:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][C:40]2=[O:46])=[CH:4][C:5]([O:37][CH3:38])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21]([C:31]4[CH:35]=[CH:34][O:33][N:32]=4)CC4C=CC(OC)=CC=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:36])[CH:7]=1>C(O)(C(F)(F)F)=O>[F:1][C:2]1[C:3]([N:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][C:40]2=[O:46])=[CH:4][C:5]([O:37][CH3:38])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:31]4[CH:35]=[CH:34][O:33][N:32]=4)(=[O:19])=[O:20])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:36])[CH:7]=1
Reactant: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(F)c(-n4ccc(C)cc4=O)cc3OC)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-n2ccc(C)cc2=O)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Yield: 1.6 %

Procedure:
1-(5-Fluoro-2-methoxy-4-(4-methyl-2-oxopyridin-1(2H)-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (18 mg, 0.028 mmol) was taken up in TFA (2 mL) in a microwave vial and irradiated to 70° C. for 1 h. Concentration under a stream of N2 followed by column chromatography (5 g Redisep gold column, 0-80% [3:1 EtOAc/EtOH]/hept gradient with 10% DCM) afforded 1-(5-fluoro-2-methoxy-4-(4-methyl-2-oxo-1(2H)-pyridinyl)phenyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide (0.24 mg, 0.459 μmol, 1.640% yield) as a colorless residue. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.55 (s, 3 H) 3.72 (s, 3 H) 6.64 (d, J=1.76 Hz, 1 H) 6.88 (d, J=9.74 Hz, 1 H) 6.98-7.02 (m, 2 H) 7.11 (d, J=6.84 Hz, 1 H) 7.32 (d, J=1.35 Hz, 2H) 7.80-7.90 (m, 2 H) 8.15 (d, J=2.07 Hz, 1 H) 8.23 (d, J=5.39 Hz, 1 H) 8.29 (d, J=1.66 Hz, 1 H). m/z (ESI) 523.0 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([O:13][C:14]([C:16]1[C:17]2[CH2:24][CH2:23][C:22](=O)[C:18]=2[NH:19][C:20]=1[CH3:21])=[O:15])[CH3:12].N1CCCCC1>CN(C=O)C>[CH2:11]([O:13][C:14]([C:16]1[C:17]2[CH2:24][CH2:23]/[C:22](=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)/[C:18]=2[NH:19][C:20]=1[CH3:21])=[O:15])[CH3:12]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCOC(=O)c1c(C)[nH]c2c1CCC2=O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)[nH]c2c1CC/C2=C1/C(=O)Nc2ccccc21
Temperature: 110 °C
Reaction time: 72 h
Yield: 57.9 %

Procedure:
A mixture of oxindole (44 mg, 0.33 mmol) and 2-methyl-6-oxo-1,4,5,6-tetrahydro-cyclopenta[b]pyrrole-3-carboxylic acid ethyl ester (Example A, 62 mg, 0.3 mmol) in DMF (5 mL)-piperidine (0.5 mL) was heated at 110° C. with stirring for 72 hours. Most of the solvent was removed under reduced pressure and the residue was diluted with ethanol. The resulted precipitate was collected by filtration, washed with ethanol and dried to give 56 mg (58%) of the titled compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[C:23]([CH2:24][O:25]COCCOC)=[C:22]([Cl:32])[N:21]=[C:20]2[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:14][CH:13]=1)=[O:5].C(=O)(O)[O-].[Na+]>F[B-](F)(F)F.[H+].C(#N)C>[CH3:1][O:2][NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[C:23]([CH2:24][OH:25])=[C:22]([Cl:32])[N:21]=[C:20]2[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:14][CH:13]=1)=[O:5]
Reactant: CCCCc1nc(Cl)c(COCOCCOC)n1Cc1ccc(-c2ccccc2C(=O)NOC)cc1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [H+]
Solvent: CC#N
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)NOC)cc1
Yield: 66.3 %

Procedure:
A solution of 0.20 g of 1-[(2'-methoxyaminocarbonylbiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-(2-methoxyethoxymethoxymethyl)imidazole in 60 ml of 1.5M aqueous tetrafluoroboric acid/acetonitrile was stirred for 20 hours at 25°. The reaction mixture was poured into dilute sodium bicarbonate solution, and the resulting mixture was extracted with diethyl ether. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (elution: methanol/chloroform) provided 0.11 g of 1-[(2'-methoxyaminocarbonylbiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole. NMR (200 MHz, CDCl3) δ11.31 (br s, 1H); 7.48 (m, 1H); 7.41-7.33 (m, 5H); 7.09 (d, 2H); 5.27 (br s, 3H); 4.32 (d, 2H); 3.44 (s, 3H); 2.49 (t, 2H); 1.48 (quint., 2H); 1.25 (sext., 2H); 0.80 (t, 3 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:21]2[CH2:24][NH:23][CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:21]2[CH2:22][N:23]([CH3:25])[CH2:24]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2OC2CNC2)CC1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CC(Oc2ccccc2N2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
4-[2-(Azetidin-3-yloxy)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (Preparation 47A, Step 4) (140 mg, 0.42 mmol) was dissolved in CH2Cl2 (2 mL). Acetic acid (0.15 mL) and formalin (85 μL, 1.05 mmol) were added, and the mixture was cooled to 0° C. Sodium triacetoxyborohydride (249 mg, 1.17 mmol) was added, and the solution was stirred for about 16 hours. Methylene chloride (15 mL) was added, and the solution was washed with saturated NaHCO3 (5 mL) and brine (5 mL) and then dried over magnesium sulfate and concentrated to a colorless oil (300 mg, 21%).
Reaction SMILES: C(=O)([O-])O.[CH3:5][N:6]([CH3:34])[C:7]1[CH:33]=[CH:32][C:10]([CH:11]=[N:12][N+:13]2[CH:17]=[CH:16][N:15]([N:18]=[CH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[C:14]=2[CH:29]([CH3:31])[CH3:30])=[CH:9][CH:8]=1.[CH3:35][S:36]([OH:39])(=[O:38])=[O:37]>CO>[CH3:35][S:36]([O-:39])(=[O:38])=[O:37].[CH3:28][N:26]([CH3:27])[C:23]1[CH:22]=[CH:21][C:20]([CH:19]=[N:18][N+:15]2[CH:16]=[CH:17][N:13]([N:12]=[CH:11][C:10]3[CH:32]=[CH:33][C:7]([N:6]([CH3:5])[CH3:34])=[CH:8][CH:9]=3)[C:14]=2[CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)O
Agent: CC(C)c1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Agent: O=C([O-])O
Solvent: CO
Product: CS(=O)(=O)[O-]
Reaction time: 0.17 h

Procedure:
48 mg of 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-isopropylimidazolium hydrogen carbonate are dissolved in 4 ml of methanol and 9.6 mg of methanesulfonic acid are added thereto. After 10 minutes, the solution is concentrated at room temperature in a vacuum and the product is crystallized by the addition of ether. There is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-isopropylimidazolium methanesulfonate of melting point 238°-239°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:11][CH2:12][CH2:13][CH2:14][N:15]([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[Sn](Cl)Cl>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([S:11][CH2:12][CH2:13][CH2:14][N:15]([CH:16]([CH3:18])[CH3:17])[CH:19]([CH3:20])[CH3:21])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1cc(SCCCN(C(C)C)C(C)C)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Cc1cc(SCCCN(C(C)C)C(C)C)ccc1N

Procedure:
In a manner similar to Preparation 39 react 3-[(3-methyl-4-nitrophenyl)thio]-N,N-bis(1-methylethyl)propanamine with tin(11) chloride in ethanol to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:16](Cl)(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].N#N>O.C(Cl)Cl>[C:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCC(=O)Cl
Reactant: O=Cc1ccc(O)cc1
Agent: N#N
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCC(=O)Oc1ccc(C=O)cc1
Reaction time: 20 h
Yield: 86.2 %

Procedure:
To a 250 mL dry round bottom flask were added 4-hydroxybenzaldehyde (6.11 g, 50.0 mmol) and anhydrous CH2Cl2 (50 mL). The solution was cooled in an ice-water bath, then pyridine (8.09 mL, 100 mmol) was added. To the resulting solution, octanoyl chloride (10.3 mL, 60 mmol) was added slowly under stirring and N2. The mixture was first stirred at 0° C. for 2 hours, then at room temperature for 20 hours. To the reaction mixture, water (100 mL) was added and the CH2Cl2 layer was separated. The aqueous layer was extracted continually with CH2Cl2 (100 mL×2). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give 4-formylphenyl octanoate (10.7 g) as colorless oil. Yield: 86%. 1H NMR (CDCl3, 300 MHz): δ=9.98 (s, 1H), 7.91 (d, J=8.7 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 2.58 (t, J=6.9 Hz, 2H), 1.38-0.86 (m, 13H). 13C NMR (CDCl3, 75.5 MHz): δ=191.0, 171.7, 155.6, 134.0, 131.3, 122.5, 34.5, 31.7, 29.1, 29.0, 24.9, 22.7, 14.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[C:14]([F:22])[CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:7][C:6]2[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][CH3:10])(=[O:19])=[O:20])=[C:14]([F:22])[CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Reactant: CSc1ccc(Cl)cc1N
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Yield: 66.1 %

Procedure:
Following General Procedure B, the title compound (380 mg, 66%) was prepared from 5-chloro-2-(methylthio)aniline (273 mg, 1.57 mmol) and 4-chloro-2-fluorobenzene-1-sulfonyl chloride (360 mg, 1.57 mmol).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:11]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:10][CH2:9][N:8]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:7]1)=[O:5])C.[OH-].[Li+]>O1CCCC1>[C:26]([O:25][C:23]([N:8]1[CH2:9][CH2:10][C@@H:11]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](C(=O)O)C1
Reaction time: 68 h
Yield: 112.1 %

Procedure:
In a flask (3R,4R)-4-benzyloxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2.98 g, 7.33 mmol) was dissolved in tetrahydrofuran (120 mL) and lithium hydroxide (15 mL of a 1N aqueous solution, 15 mmol) was added. The mixture was stirred for 68 hours. The reaction was concentrated in vacuo to one-third the original volume. Water (50 mL) and diethyl ether (50 mL) were added and the layers separated. The aqueous layer was extracted with diethyl ether twice (30 mL). The aqueous layer was acidified with aqueous hydrochloric acid (6.5 mL of a 2M solution) and then extracted with ethyl acetate three times (30 mL). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated in vacuo to give a crude white solid (3.11 g) which was used without further purification. 1H NMR (300 MHz, CDCl3), δ: 7.36 (m, 5H), 5.12 (m, 2H), 4.91 (bs, 1H), 4.24 (bs, 1H), 4.09 (bs, 1H), 3.92 (bs, 1H), 3.01 (bs, 1H), 2.87 (m, 1H), 2.44 (m, 1H), 2.05 (bs, 1H), 1.45 (s, 9H), 1.40 (m, 1H).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[N+](=[CH2:12])=[N-]>C(Cl)Cl>[Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:12])=[O:4]
Reactant: CC(C)CC(Br)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)C(Br)CC(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-bromo-4-methylpentanoic acid (9.86 mmol, 1.31 g) in CH2Cl2 (100 mL), was added slowly a solution of diazomethane until no bubbles appears. The mixture was stirred at r.t. for 0.25 h. The volatiles were removed under reduced pressure to leave a yellow liquid. The crude methyl ester was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]([N+:19]([O-])=O)=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:11]>CCO.Cl.[Fe]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:11]
Reactant: C[C@@H](Oc1cccnc1[N+](=O)[O-])c1c(Cl)ccc(F)c1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: C[C@@H](Oc1cccnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 85 °C

Procedure:
Iron (365 mg) was added to a stirred solution of 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-2-nitropyridine (321 mg, 0.97 mmol) in a mixture of EtOH (2 mL) and 2M HCl (0.2 mL) at 0° C. The resulting solution was heated to 85° C. for 2 h. Celite (0.5 g) was added to the cooled reaction mixture. This mixture was filtered over a bed of celite and evaporated to give the title compound as a dark oil. MS (APCI) (M+H)+ 301.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1([CH3:19])[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[NH2:4].[C:20](OC(=O)C)(=O)[CH3:21]>ClCCl>[CH3:10][C:7]1([CH3:11])[N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:5]([CH3:19])([C:3]2[N:4]=[C:20]([CH3:21])[O:1][N:2]=2)[CH2:9][O:8]1
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OCC1(C)C(N)=NO
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: Cc1nc(C2(C)COC(C)(C)N2C(=O)OC(C)(C)C)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 146 mg of tert-butyl 4-(N′-hydroxycarbamimidoyl)-2,2,4-trimethyl-1,3-oxazolidine-3-carboxylate in 4 ml of dichloromethane was added 55 μl of acetic anhydride, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and to the obtained residue were added 4 ml of DMF, followed by stirring at 110° C. for 15 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 113 mg of tert-butyl 2,2,4-trimethyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)-1,3-oxazolidine-3-carboxylate.
Reaction SMILES: C([Li])CCC.C1([SiH3])C=CC=CC=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21]([CH3:25])=[CH:20][CH2:19][CH2:18]2.[H][H]>C1COCC1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]([CH3:25])[CH2:20][CH2:19][CH2:18]2
Reactant: COc1ccc2c(c1)CCC=C2C
Reactant: [H][H]
Agent: [Li]CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCCC2C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70.3 %

Procedure:
In a dry sealable Schlenk flask under an argon atmosphere 0.0592 g (0.099 mmol) (S,S)-ethylene-1,2-bis(η5 -4,5,6,7-tetrahydro- 1 -indenyl)titanium (S)-1,1'-binaphth-2,2'-diolate was dissolved in THF (10 mL). The vessel was degassed by exposure to vacuum (2×~10 sec), put under an atmosphere of hydrogen and subsequently cooled to 0° C. in an ice water bath. After equilibration, a solution of n-butyllithium (0.122 mL, 1.58 M in hexanes, 0.193 mmol, 1.95 equiv) was added and the mixture was allowed to stir for 10 min. Phenylsilane (0.031 mL, 0.243 mmol, 2.5 equiv) and 0.378g (2.19 mmol, 22 equiv) 6-methoxy-1-methyl-3,4-dihydronaphthalene were then added. The flask was sealed and the solution moved into a dry box and transferred to a Parr® high pressure reaction vessel containing a magnetic stir bar. The pressure vessel was sealed and moved to a fume hood where it was charged to 1800 psig with hydrogen and placed in an oil bath at 68° C. The reaction mixture was allowed to stir for 132 h. The vessel was cooled to room temperature, vented and opened to air. The reaction mixture was worked up by partitioning between diethyl ether hexane (1/4) and water and separating the layers. The organic extract was concentrated and chromatographed on 50 mL silica gel to yield 0.268g (1.54 mmol, 70%) of 6-methoxy-1-methyl-1,2,3,4-tetrahydronaphthalene with an ee of 94.7%.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][CH2:15][C:14]([NH:23][CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:33](B)#N.[Na].C(O)(=O)C>C(#N)C>[CH2:1]([N:8]([CH2:10][C:11]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][CH2:15][C:14]([N:23]([CH3:33])[CH3:24])([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC1(c2ccccc2)CCC(CN(C)Cc2ccccc2)(c2ccccc2)CC1
Reactant: BC#N
Agent: C=O
Agent: [Na]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(Cc1ccccc1)CC1(c2ccccc2)CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of the title compound from step 10 (diastereomer mixture) (0.350 g, 0.878 mmol) and formalin (1.23 mL, 37% aqueous solution) in acetonitrile (15 mL) was mixed in portions with sodium cyanoboron hydride (0.250 g, 3.86 mmol) and stirred for 45 min at room temperature. Conc. acetic acid was then added until a neutral reaction occurred and the mixture was subsequently stirred for 45 min at room temperature. For work up the solvent was removed in a vacuum, the residue taken up in 2N NaOH (40 mL) and then extracted with ether (3×40 mL). The organic solution was dried over Na2SO4, filtered and concentrated to low volume in a vacuum. The remaining residue was purified by Chromatotron and with cyclohexane/ethyl acetate 1:1. Separation of the diastereomers could not be achieved.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@@H:40]2[NH:49][CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:29]=[C:30]2[C:34]=1[C:33]([CH3:36])([CH3:35])[CH2:32][CH2:31]2.CCN(C(C)C)C(C)C.[CH2:61]([O:68][C:69]([C@@H:71]1[CH2:74][C@H:73]([C:75](O)=[O:76])[CH2:72]1)=[O:70])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>CN(C=O)C.O>[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@@H:40]2[N:49]([C:75]([C@@H:73]3[CH2:74][C@H:71]([C:69]([O:68][CH2:61][C:62]4[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=4)=[O:70])[CH2:72]3)=[O:76])[CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:29]=[C:30]2[C:34]=1[C:33]([CH3:35])([CH3:36])[CH2:32][CH2:31]2
Reactant: COc1ccc2c(n1)CCN[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Reactant: O=C(O)[C@H]1C[C@@H](C(=O)OCc2ccccc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@@H](C(=O)OCc3ccccc3)C1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Yield: 43.4 %

Procedure:
HATU (9.88 g, 25.99 mmol) was added to a solution of (R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide (8.0 g, 21.65 mmol), DIEA (7.40 mL, 43.31 mmol) and the crude cis-3-((benzyloxy)carbonyl)cyclobutanecarboxylic acid (6.59 g, 28.15 mmol) in DMF (150 mL) at room temperature, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20→50% ethyl acetate/hexane). The obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (5.50 g, 9.39 mmol, 43.4%) as white crystals.