Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C-:15]#[N:16].[Na+].C([O-])(O)=O.[Na+]>C(OCC)C.O>[C:15]([C:2]1([OH:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)#[N:16]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)(C#N)CC1
Temperature: 25 °C
Yield: 92.8 %

Procedure:
To a suspension of tert-butyl 4-oxopiperidine-1-carboxylate (2.0 g, 10 mmol) in diethyl ether (40 mL), a solution of NaCN (0.54 g, 11 mmol) and NaHCO3 (1.7 g, 20 mmol) in water (25 mL) was added slowly with vigorous stirring at room temperature. The mixture was stirred overnight, and extracted with Et2O (30 mL×2). The organic phase was washed with water (50 mL), brine (50 mL) and dried over MgSO4, filtered and evaporated gave 2.1 g of the title compound as clear colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=[O:34])[NH:11][CH:12]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][C:24]1[C:28]2[CH:29]=[C:30]([OH:33])[CH:31]=[CH:32][C:27]=2[O:26][CH:25]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH3:9])[C:10]([NH:11][CH:12]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][C:24]1[C:28]2[CH:29]=[C:30]([OH:33])[CH:31]=[CH:32][C:27]=2[O:26][CH:25]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:34]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)NC(C(=O)N1CCCC1Cc1coc2ccc(O)cc12)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)C(=O)NC(C(=O)N1CCCC1Cc1coc2ccc(O)cc12)C(C)C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
To a solution of 31 (0.04 g, 0.082 mmol) in DCM (5 mL) was added TFA (1 mL) at ambient temperature. After 1 h, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash silica gel chromatography (10% MeOH/DCM) to afford 0.011 g (37%) of 32 as a white solid. 1H NMR (CDCl3, 300 MHz) 88.54 (d, 1H); 7.37 (s, 1H); 7.31 (d, 1H); 7.09 (d, 1H); 6.83 (dd, 1H); 4.64 (t, 1H); 4.56-4.51 (m, 1H); 4.09-3.93 (m, 2H); 3.73-3.65 (m, 1H); 3.36 (dd, 1H); 2.35 (t, 1H); 2.19-1.94 (m, 3H); 1.77-1.69 (m, 2H); 1.33 (d, 2H); 1.25-1.19 (m, 1H); 1.04-1.00 (m, 5H); 0.94 (t, 1H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]2[O:7][C:8]([CH3:28])([CH3:27])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][O:18][Si](C(C)(C)C)(C)C)=[CH:13][C:12]3=[O:26])[C:5]=2[CH:4]=1)#[N:2].Cl>CO.O1CCOCC1>[C:1]([C:3]1[CH:30]=[CH:29][C:6]2[O:7][C:8]([CH3:27])([CH3:28])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:12]3=[O:26])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC1(C)C=C(n2ccc(CO[Si](C)(C)C(C)(C)C)cc2=O)c2cc(C#N)ccc2O1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC1(C)C=C(n2ccc(CO)cc2=O)c2cc(C#N)ccc2O1
Yield: 100.2 %

Procedure:
In 10.5 ml of methanol, is dissolved 1.04 g of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-t-butyldimethylsilyloxymethyl-1-pyridinyl)-2H-benzo[b]pyran obtained in Example 8. Then, 2.59 ml of a 4N hydrochloric acid in dioxane is added to the solution at 0° C., and the resulting mixture is reacted at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure, the residue is mixed with ethyl acetate and water and the product is extracted into the ethyl acetate. The organic layer is washed with saturated aqueou solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using 1/20 mixture of methanol/methylene chloride as a developing solvent to obtain 0.76 g of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-hydroxymethyl-1-pyridinyl)-2H-benzo[b]pyran.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:12])([F:13])[F:11])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1cc(C(F)(F)F)ccc1Br
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a mixture of 2-bromo-5-(trifluoromethyl)benzaldehyde (5 g, 20 mmol) in THF (20 mL) at 0° C. was added sodium borohydride (0.8 g, 20 mmol). The resulting mixture was stirred at 0° C. to ambient temperature for 1 h. The reaction was quenched by addition of an aqueous solution of NaHCO3. The resulting solution was extracted with EtOAc twice. The combined extracts were washed with brine, dried (MgSO4), filtered and concentrated to give the desired alcohol as a white solid (4.4 g). 1H NMR (CDCl3) δ 7.81 (s, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.42 (dd, J=8.3 Hz, 2.0 Hz, 1H), 4.81 (d, J=6.3 Hz, 2H), 2.03 (m, 1H).
Reaction SMILES: O=[C:2]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[N:11]1([CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([NH2:8])=[CH:9][CH:10]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Nc1ccc(CC(=O)N2CCCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(CCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
To a solution of 1.22 g of 4-(2-oxo-2-pyrrolidin-1-ylethyl)aniline obtained in stage b) below in 100 mL of tetrahydrofuran are added, under argon, 1.1 g of lithium aluminium hydride. The reaction mixture is stirred for one hour at room temperature and then cooled to 0° C. and treated successively with 1.1 mL of water, 1.1 mL of 15% (by weight) sodium hydroxide solution and 3.4 mL of water. The solid formed is filtered off and washed with ethyl acetate, and the filtrate is concentrated under reduced pressure to give 1.15 g of 4-(2-pyrrolidin-1-ylethyl)aniline, the characteristics of which are as follows:
Reaction SMILES: [OH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3](O)=[O:4].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OC(=O)[NH:48][CH2:49][CH2:50][CH2:51][C:52]1([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[NH:56][N:55]=[C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[CH:58]=2)[S:53]1)(C)(C)C.CCN(C(C)C)C(C)C.Cl>C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>[NH2:48][CH2:49][CH2:50][CH2:51][C:52]1([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[N:56]([C:3](=[O:4])[C@@H:2]([OH:1])[CH:6]([CH3:8])[CH3:7])[N:55]=[C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[CH:58]=2)[S:53]1
Reactant: CC(C)(C)OC(=O)NCCCC1(c2ccccc2)NN=C(c2cccc(F)c2)S1
Reactant: CC(C)[C@H](O)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)[C@H](O)C(=O)N1N=C(c2cccc(F)c2)SC1(CCCN)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(S)-2-hydroxy-3-methylbutyric acid (13.5 mg, 0.11 mmol) and PyBOP (60 mg, 0.12 mmol) were combined in THF (0.4 mL) and stirred for 10 minutes. To this mixture was added {3-[5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-propyl}-carbamic acid tert-butyl ester (20 mg, 0.05 mmol) and DIEA (31 mg, 0.24 mmol). After stirring at room temperature for 24 hours, the reaction mixture was diluted with 10% Na2CO3 (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed (1:4 ethyl acetate/hexanes) to provide Boc-protected diastereomer A (less polar, 2.0 mg) and Boc-protected diastereomer B (more polar, 4.2 mg). To the Boc-protected diastereomer A was added HCl (1 mL, 4M in dioxane) at 0° C. After warming to, room temperature and stirring for 1 hour, the mixture was concentrated under a stream of N2. The residue was dissolved in an ether/dioxane mixture and precipitated with hexanes. The solid was filtered and washed with hexanes to provide the final product as yellow solid. MS ESI (+) m/z 416 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 8.4 (br s, 3H), 7.5 (m, 2H), 7.43-7.28 (m, 4H), 7.24-7.11 (m, 3H), 4.66 (br s, 1H), 3.30 (br s, 1H), 3.15-2.92 (m, 2H), 2.73 (m, 1H), 2.30 (m, 1H), 2.18 (m, 1H), 1.81-1.49 (m, 2H), 1.10 (br m, 3H), 0.9 (br m, 3H).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:18][C:12]=3[S:11](=[O:28])(=[O:27])[N:10]=2)=[C:5]([OH:29])[C:4]2[S:30][CH:31]=[CH:32][C:3]1=2.[C:33]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>CN(C)C(=O)C>[CH2:20]([O:19][C:17]1[CH:16]=[CH:15][C:13]2[NH:14][C:9]([C:6]3[C:7](=[O:8])[N:2]([N:1]=[C:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[C:3]4[CH:32]=[CH:31][S:30][C:4]=4[C:5]=3[OH:29])=[N:10][S:11](=[O:28])(=[O:27])[C:12]=2[CH:18]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2sccc21
Reactant: O=C1CCCCC1
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2sccc2n1N=C1CCCCC1
Yield: 72.5 %

Procedure:
The product of Example 324B (0.20 g, 0.42 mmol) and cyclohexanone (2.0 g, 20 mmol) in N,N-dimethylacetamide (4 mL) were reacted at 130° C. for 60 minutes in a microwave reactor in a sealed tube. The solvent was removed under reduced pressure and the resulting residue was triturated with diethyl ether (8 mL), filtered and dried to give the title compound (0.167 g 73%).
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:25]=[CH:24][S:23][CH:22]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:8]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:25]=[CH:24][S:23][CH:22]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccsc3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccsc3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
A mixture of ethyl 3-[4-phenyl-1-[4-(3-thienylmethoxy)benzyl]-3-pyrrolyl]propionate (624 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature for 5 hours, and 1N hydrochloric acid (3 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-(3-thienylmethoxy)benzyl]-3-pyrrolyl]propionic acid (421 mg, yield: 72%). This was recrystallized from ethyl acetate-hexane. Melting point: 118–119° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:16][CH2:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[C:23](=O)[CH2:22][CH2:21]3)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([O:16][CH2:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[C:23](=[S:39])[CH2:22][CH2:21]3)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: COC1(c2cc(F)cc(OCc3ccc4c(c3)CCC(=O)N4C)c2)CCOCC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COC1(c2cc(F)cc(OCc3ccc4c(c3)CCC(=S)N4C)c2)CCOCC1
Temperature: 90 °C
Yield: 28 %

Procedure:
Using the procedure described in Example 1, except that the reaction mixture was heated to 90° C. for 2 hours, 4-[5-fluoro-3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylmethoxy)phenyl]-4-methoxytetrahydropyran was reacted with Lawesson's Reagent to give 4-[5-fluoro-3-(1-methyl-2-thioxo-1,2,3,4-tetrahydroquinolin-6-ylmethoxy)phenyl]-4-methoxytetrahydropyran in 28% yield, m.p. 136°-138° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19]1[C:20]([F:31])=[CH:21][N:22]=[C:23]2[C:28]=1[N:27]=[C:26]([O:29][CH3:30])[CH:25]=[CH:24]2>>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[N:27]=3)[N:22]=[CH:21][C:20]=2[F:31])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2ncc(F)c(Br)c2n1
Reactant: O=C(OCc1ccccc1)N1CCCNCC1
Product: COc1ccc2ncc(F)c(N3CCCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
According to procedure F and starting from [1,4]diazepane-1-carboxylic acid benzyl ester (commercial) and 8-bromo-7-fluoro-2-methoxy-[1,5]naphthyridine, the title compound was isolated as a brown oil (1.62 g, 51%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[N:15]=[CH:14]3)=[C:6]([CH:9]=1)[C:7]#[N:8].[ClH:21].C1(C)C=CC=CC=1.CCO>CO.[OH-].[OH-].[Pd+2]>[ClH:21].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[N:15]=[CH:14]3)=[C:6]([CH:9]=1)[CH2:7][NH2:8]
Reactant: Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CO
Product: Cn1ncc2cc(Oc3ccc(F)cc3CN)ccc21
Reaction time: 18 h
Yield: 99.1 %

Procedure:
Intermediate (4t) (1.13 g, 4.23 mmol; prepared as in Example 94, Steps A-C) was dissolved in methanol (50 mL) and 20% palladium hydroxide on activated carbon (0.50 g, 0.71 mmol) was added to the solution under nitrogen atmosphere. After the addition of concentrated HCl (12 N, 5.0 mL, 60 mmol), the mixture was stirred under hydrogen atmosphere overnight (18 hours). The mixture was filtered and palladium hydroxide was washed with MeOH. After evaporation, the crude residue was azeotroped with a mixture of toluene and EtOH to dryness to compound (5t) as a white powder (1.29 g, 99% yield) 1HNMR (400 MHz, CDCl3) δ 8.72 (br, 3H), 8.01 (s, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.57 (dd, J=9.4, 2.3 Hz, 1H), 7.38 (s, 1H), 7.19 (d, J=3.1 Hz, 1H), 7.04 (td, J=74.8, 3.1 Hz, 1H), 7.02 (dd, J=195.1, 4.7 Hz, 1H), 4.07 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][N+:10]([O-:12])=[O:11])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1cc(Cl)nc(Cl)c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])Nc1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,6-Dichloropyridin-4-amine (3.0 g, 18 mmol) was carefully added to concentrated sulfuric acid (20 mL). The mixture was cooled in an ice bath, and fuming nitric acid (2.6 mL) was added dropwise via pipette. The mixture was warmed to room temperature and stirred for 1 h, then poured onto crushed ice, resulting in a white precipitate. The white precipitate was collected by filtration, washed with cold water, and dried to afford the title compound (3.7 g), which was used for next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:8]=[CH:7][N:6]=1.[C:27]([O:31][CH2:32][CH2:33][C:34](O)=[O:35])([CH3:30])([CH3:29])[CH3:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:27]([O:31][CH2:32][CH2:33][C:34]([N:16]1[CH2:17][CH2:18][CH:13]([O:12][C:9]2[C:10]([CH3:11])=[C:5]([O:4][C:3]3[CH:19]=[CH:20][C:21]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:22][C:2]=3[F:1])[N:6]=[CH:7][N:8]=2)[CH2:14][CH2:15]1)=[O:35])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OCCC(=O)O
Reactant: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCN(C(=O)CCOC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
Mixture of 4-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine (76 mg, 0.2 mmole), 3-tert-butoxy-propionic acid (0.26 mmole, 1.3 eq), HATU (0.26 mmole, 1.3 eq), and triethylamine (0.4 mmole, 2 eq) in 2 mL DMF was stirred at room temp for 2 hours. Mixture was purified by HPLC to give compound C161 as a white solid (88 mg, 86%). 1H NMR (CDCl3, 400 MHz) δ 1.20 (s, 9H), 1.91-1.96 (m, 2H), 2.02-2.10 (m, 2H), 2.22 (s, 3H), 2.72 (t, 2H), 3.11 (s, 3H), 3.62-3.64 (m, 2H), 3.72 (t, 2H), 3.86-3.91 (m, 2H), 5.41-5.46 (m, 1H), 7.44 (t, 1H), 7.78-7.82 (m, 2H), 8.23 (s, 1H). Exact mass calculated for C24H32FN3O6S 509.2, found 510.6 (MH+).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@@H:7]([OH:14])[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2].[F:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)N>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([O:14][C:22]2[CH:21]=[CH:19][CH:18]=[C:17]([F:16])[CH:23]=2)[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2[C@@H](O)C[C@@H]1C
Reactant: Nc1cccc(F)c1
Product: CC(=O)N1c2ccccc2[C@H](Oc2cccc(F)c2)C[C@@H]1C
Yield: 48 %

Procedure:
A compound was produced in the same manner as in Example 12, using 100 mg of trans-1-acetyl-4-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline and 112 mg of 3-fluoroaniline, and thus 70 mg (47%) of the title compound was obtained as a colorless oily substance.
Reaction SMILES: O.[N+:2]([C:5]1[CH:6]=[C:7]([SH:11])[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH2:14]>O1CCCC1>[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([S:11][C:7]1[CH:6]=[C:5]([N+:2]([O-:4])=[O:3])[CH:10]=[CH:9][CH:8]=1)[CH3:14]
Reactant: C=C(C)c1ccccc1
Reactant: O=[N+]([O-])c1cccc(S)c1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Sc1cccc([N+](=O)[O-])c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a mixed solution of water (1.6 mL)-concentrated sulfuric acid (1.6 mL) was added 3-nitrothiophenol (0.5 g), and the mixture was stirred at room temperature for 1 hour. To the mixture was added a solution of α-methylstyrene (0.38 g) in tetrahydrofuran (1.6 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/2) to give 3-(1-methyl-1-phenylethylthio)nitrobenzene (0.88 g). This material was dissolved in tetrahydrofuran (10 mL). To the solution were added methanol (10 mL), nickel (II) bromide (35 mg) and sodium borohydride (0.37 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Then the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/2) to give the title compound (0.69 g).
Reaction SMILES: [OH-].[Li+].[CH3:3][CH:4]([CH3:46])[CH2:5][CH2:6][N:7]([CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([NH:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[N:15]([CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:14]=2[CH:40]=1)=[O:9]>O1CCCC1.O.C(OCC)C>[CH3:44][CH:43]([CH3:45])[CH2:42][CH2:41][N:7]([CH2:6][CH2:5][CH:4]([CH3:46])[CH3:3])[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([NH:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[N:15]([CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[C:14]=2[CH:40]=1)=[O:9]
Reactant: COC(=O)c1ccc(Nc2nc3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3n2CCCNC(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc2nc(Nc3ccc(C(=O)O)cc3)n(CCCNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Yield: 79 %

Procedure:
Lithium hydroxide (141 mg, 5 eq) is added to methyl 4-[(6-{[bis(3-methylbutyl)amino]carbonyl}-1-{3-[(tert-butoxycarbonyl)amino]propyl}-1H-benzimidazol-2-yl)amino]benzoate prepared according to reaction diagram A, Example A1, (405 mg, 1 eq) in a mixture of tetrahydrofuran (4 ml) and water (3 ml). The mixture is heated under reflux for 18 hours then cooled down to ambient temperature and concentrated under reduced pressure at 40° C. Dichloromethane (50 ml) and water (20 ml) are added to the residue. The mixture is acidified by the addition of acetic acid to pH 5. After decantation and extractions, the combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The solid obtained is taken up in ethyl ether in order to produce the expected compound (309 mg; 79%).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[N:14]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)=[N+:15]=[N-:16].N(C1C=C(O)C=CC=1)=[N+]=[N-]>>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH:3]=[C:4]([C:5]3[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=3)[N:16]=[N:15]2)=[CH:18][CH:19]=1
Reactant: C[Si](C)(C)C#Cc1ccc(O)cc1
Reactant: [N-]=[N+]=Nc1ccc(O)cc1
Agent: [N-]=[N+]=Nc1cccc(O)c1
Product: Oc1ccc(-c2cn(-c3ccc(O)cc3)nn2)cc1
Yield: 59.9 %

Procedure:
4-BPT was prepared in a similar manner as 3-BPT, using 4-TMSE-phenol (3.50 g, 18.4 mmol) and 4-azidophenol (3.73 g, 27.9 mmol) instead of 3-TMSE-phenol and 3-azidophenol. This gave 2.79 g (60% yield) of a purple crystal. 1H NMR (MeOD-d4, 300 MHz, ppm): 8.62 (s, 1H, triazol-H), 7.75-7.68 (m, 4H, Ar—H), 6.99 (d, 2H, J=9.0 Hz, Ar—H), 6.90 (d, 2H, J=8.7 Hz, Ar—H). 13C NMR (MeOD-d4, 75 MHz, ppm): 159.7, 159.3, 149.8, 131.0, 128.4, 123.4, 123.0, 119.4, 117.3, 116.9.
Reaction SMILES: O=O.[CH2:3]([S:10][C@H:11]1[N:14](C(=C(C)C)C(OCC2C=CC(OC)=CC=2)=O)[C:13](=[O:31])[C@@H:12]1[Br:32])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[O-].[Na+].CSC>ClCCl.CO>[CH2:3]([S:10][C@H:11]1[NH:14][C:13](=[O:31])[C@@H:12]1[Br:32])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc(COC(=O)C(=C(C)C)N2C(=O)[C@H](Br)[C@H]2SCc2ccccc2)cc1
Agent: C[O-]
Agent: O=O
Agent: [Na+]
Solvent: CO
Solvent: CSC
Solvent: ClCCl
Product: O=C1N[C@H](SCc2ccccc2)[C@H]1Br
Reaction time: 16 h
Yield: 64.3 %

Procedure:
Ozonised oxygen was bubbled through a solution of p-methoxybenzyl 2-[(3S, 4R)-4-benzylthio-3-bromo-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (2 g, 4 mmol) in dichloromethane (40 ml) at -78° C. and the reaction monitored by infra-red spectroscopy. When the band at 1780 cm-1 had disappeared, methanol (4 ml) together with a trace of sodium methoxide and dimethyl sulfide (1 ml) was added and stirring continued at room temperature for 16 h. The reaction was evaporated and the residue purified by flash chromatography using 1:1 ether:pentane as the eluting solvent. Evaporation of the appropriate fractions gave the product as a colourless oil (0.7 g, 64%). 1H NMR δ (CDCl3) 3.87 (2H, s, SCH2), 4.52 (1H, m, H4), 4.69 (1H, d, H3) 5.85 (1H, bs, NH), 7.18-7.39 (5H, m, Ph--H).