Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.[C:9]1([CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]#[N:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(Br)C.P([O-])([O-])([O-])=O>C1COCC1>[C:18]1([C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([CH2:2][CH3:3])[C:16]#[N:17])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: CC(C)[N-]C(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCC(C#N)(c1ccccc1)c1ccccc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
173 ml (0.259 mol) of a 1.5 M solution of LDA in THF were added dropwise to a solution of 50.0 g (0.259 mol) of diphenylacetonitrile in 500 ml of THF (abs.) at −78° C. under argon, and the mixture was then stirred at −30° C. for one hour. Then, at −78° C., 28.23 g (0.259 mol) of ethyl bromide were added. The mixture was allowed to reach room temperature and was stirred for 16 hours. Subsequently, 80 ml of phosphate buffer (pH 7) were added and the mixture was evaporated. The residue was taken up in water and extracted three times with ethyl acetate. The combined organic phases were dried over MgSO4, and the solvent was stripped off under reduced pressure. The crude product was chromatographed on silica gel with n-heptane/acetic acid (20:1). 38.2 g (67%) of 2,2-diphenylbutyronitrile were obtained.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:5]=[CH:4][N:3]=1.C(C1C(Cl)=NC=NC=1CBr)CC.FC1C(C2NC=CN=2)=NC=CC=1.O.[NH2:49][NH2:50]>CCO>[F:23][C:22]1[C:17]([C:13]2[N:12]([CH2:11][C:6]3[N:5]=[CH:4][N:3]=[C:2]([NH:49][NH2:50])[C:7]=3[CH2:8][CH2:9][CH3:10])[CH:16]=[CH:15][N:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: NN
Reactant: CCCc1c(Cl)ncnc1Cn1ccnc1-c1ncccc1F
Agent: CCCc1c(Cl)ncnc1CBr
Agent: Fc1cccnc1-c1ncc[nH]1
Solvent: O
Solvent: CCO
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncnc1NN
Temperature: 70 °C

Procedure:
A mixture of 4-chloro-6-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-pyrimidine (prepared from 5-propyl-6-bromomethyl-4-chloro-pyrimidine and 3-fluoro-2-(1H-imidazol-2-yl)-pyridine essentially as described in Example 1) (2.5 g, 7.5 mmol) and hydrazine monohydrate (1.37 g, 27.4 mmol) in EtOH (15 mL) is heated in a sealed tube at 70° C. overnight. The solvent is removed in vacuo and the residue is triturated with ethyl acetate and ethyl ether. Filtration gives a white solid (131) which is used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[C@H:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C@H:10]2[C:31]([OH:33])=[O:32])=[C:5]([O:34][CH2:35][O:36][CH3:37])[CH:4]=1.[CH2:38]1[CH2:48]CN2C(=NCCC2)C[CH2:39]1.C(Br)C=C>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[C@H:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C@H:10]2[C:31]([O:33][CH2:48][CH:38]=[CH2:39])=[O:32])=[C:5]([O:34][CH2:35][O:36][CH3:37])[CH:4]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCOC)[C@H](C(=O)O)[C@H]2c1ccc2c(c1)OCO2
Solvent: CC#N
Solvent: C=CCBr
Product: C=CCOC(=O)[C@H]1[C@H](c2ccc(OC)cc2OCOC)c2cc(OCCC)ccc2[C@@H]1c1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 109.8 %

Procedure:
(1S,2R,3S)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid (4.8 g, 9.5 mmol) was dissolved in dry acetonitrile (30 ml) and DBU (1.7 ml, 11.4 mmol) was added followed by allyl bromide (3.4 g, 28. mmol). After stirring for 0.5 h. the product was partitioned between 3M aqueous HCl and ethyl acetate. The organic layer was washed with water and brine, then dried (MgSO4 anhyd.) filtered and evaporated to give an oil. The product was purified by column chromatography to provide the title compound as a pale yellow oil (5.7 g, quantitative).
Reaction SMILES: CS(NCCCCCCC(OCC)=O)(=O)=O.C(S(NCCCCCCC(OCC)=O)(=O)=O)CC.C([O:38][CH:39]([CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH2:40][CH2:41][CH2:42][N:43]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][C:56]([O:58]CC)=[O:57])[S:44]([CH2:47]CC)(=[O:46])=[O:45])(=O)C>>[OH:38][C@H:39]([CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[C:40]#[C:41][CH2:42][N:43]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][C:56]([OH:58])=[O:57])[S:44]([CH3:47])(=[O:45])=[O:46]
Reactant: CCCCCC(CCCN(CCCCCCC(=O)OCC)S(=O)(=O)CCC)OC(C)=O
Agent: CCCS(=O)(=O)NCCCCCCC(=O)OCC
Agent: CCOC(=O)CCCCCCNS(C)(=O)=O
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the ethyl 7-(methanesulfonamido)heptanoate is replaced by an equimolar amount of ethyl 7-(propanesulfonamido)heptanoate (Example Q). The product of Step A is thus ethyl 7-[N-(4-acetoxynonyl)propanesulfonamido]heptanoate. The subsequent hydrolysis step yields 7-[N-(4-hydroxynonyl)-propanesulfonamido]heptanoic acid (B).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16]([SH:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].O>CN(C)C(=O)C>[CH2:16]([S:28][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: CCCCCCCCCCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCSc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
A suspension consisting of 75.66 g (0.55 mol) of 4-chlorobenzonitrile, 106.42 g (0.77 mol) of potassium carbonate and 111.32 g (0.55 mol) of 1-dodecanethiol is heated, with stirring, under an inert gas atmosphere in 280 ml of N,N-dimethylacetamide to 130° C. and is then stirred at this temperature for 24 hours. After cooling the reaction mixture to room temperature, it is poured on a mixture of 700 g of ice and 750 ml of water. The mixture is filtered and the filter cake is washed with water. The product is recrystallised from methanol and dried at 50° C. under vacuum, affording 160.2 g (96% of theory) of 4-(dodecyl-thio)benzonitrile.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[C:4](=[O:12])[N:3]1[C:13]1[CH2:14][O:15][C:16](=[O:18])[CH:17]=1.C(N(C(C)C)CC)(C)C.[CH3:28][C:29]1[C:37]([C@@H:38]2[CH2:40][O:39]2)=[CH:36][CH:35]=[C:34]2[C:30]=1[CH2:31][O:32][C:33]2=[O:41]>C(O)C>[OH:39][C@H:38]([C:37]1[C:29]([CH3:28])=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:41])[O:32][CH2:31]2)[CH2:40][N:9]1[CH2:8][CH2:7][C:5]2([C:4](=[O:12])[N:3]([C:13]3[CH2:14][O:15][C:16](=[O:18])[CH:17]=3)[CH:2]([CH3:1])[CH2:6]2)[CH2:11][CH2:10]1
Reactant: CC1CC2(CCNCC2)C(=O)N1C1=CC(=O)OC1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c([C@@H](O)CN2CCC3(CC2)CC(C)N(C2=CC(=O)OC2)C3=O)ccc2c1COC2=O
Temperature: 80 °C

Procedure:
3-Methyl-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-22, 0.257 mmol) was dissolved in ethanol (3 mL), and treated with diisopropylethylamine (135 μl, 0.771 mmol) followed by (R)-4-methyl-5-(oxiran-2-yl)isobenzofuran-1(3H)-one (I-4B, 73.3 mg, 0.385 mmol). The mixture was heated at 80° C. in a sealed tube for 12 hours. The reaction mixture was then cooled to room temperature and concentrated. The resulting crude product was purified by column chromatography eluting with a 0-20% MeOH/EtOAc gradient to give the title product as a mixture of diastereomers. LC-MS (IE, m/z): 441.3 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:20])[CH:3]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(CC)CC.C[C:38](C)([OH:41])C#N>C(OCC)C.ClCCl>[C:21]([C:38]([C:3]1[C:4](=[O:20])[O:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][C:2]=1[OH:1])=[O:41])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1C=C(O)CC(c2ccccc2)(c2ccccc2)O1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(O)C#N
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1C(=O)C(=O)c1ccccc1
Reaction time: 0.25 h

Procedure:
The desired compounds were prepared by adding 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (0.500 g, 1.88 mmol) and dry dichloromethane (10.0 mL) to a reaction vessel followed by the addition of the benzoyl chloride (0.22 mL, 1.88 mmol) and Et3N (0.28 mL, 2.0 mmol). The mixture was allowed to stir for 15 min. and then diluted with diethyl ether. The mixture was then washed with sat'd NaHCO3 (2×) and the organic layer dried with MgSO4. The solvent was then removed in vacuo, the residue redissolved in CH3CN and then treated with Et3N (0.56 mL, 4.0 mmol) and acetone cyanohydrin. The mixture was allowed to stir for 18 h and then diluted with diethyl ether. The mixture was then washed with 1.0N HCl, dried with NaSO4, and the solvent removed in vacuo. Purification was achieved by submitting the final residue to column chromatograpy (SiO2, 3/2 hexane/ethyl acetate) to provide a solid (0.357 g, 66°-68° C.). 1H NMR (400 MHz, CDCl3) δ7.495-7.208 (m, 15H), 3.558 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](OC2C=CC(Cl)=CC=2)[C:5]([C:16]#[N:17])=[CH:4][N:3]=1.[CH3:18][O:19][CH2:20][CH2:21][CH2:22][NH:23][S:24]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25].[NH2:34][CH2:35][CH:36]([OH:39])[CH2:37][OH:38]>CC(O)CC>[C:16]([C:5]1[C:6]([NH:34][CH2:35][CH:36]([OH:39])[CH2:37][OH:38])=[N:7][C:2]([NH:31][C:30]2[CH:29]=[CH:28][C:27]([S:24](=[O:26])(=[O:25])[NH:23][CH2:22][CH2:21][CH2:20][O:19][CH3:18])=[CH:33][CH:32]=2)=[N:3][CH:4]=1)#[N:17]
Reactant: NCC(O)CO
Reactant: N#Cc1cnc(Cl)nc1Oc1ccc(Cl)cc1
Reactant: COCCCNS(=O)(=O)c1ccc(N)cc1
Solvent: CCC(C)O
Product: COCCCNS(=O)(=O)c1ccc(Nc2ncc(C#N)c(NCC(O)CO)n2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 39.1 %

Procedure:
A suspension of 2-chloro-4-(4-chlorophenoxy)-5-cyanopyrimidine (Method 115; 179 mg, 0.68 mmol) and 4-[N-(3-methoxypropyl)sulphamoyl]aniline (Method 4; 149 mg, 0.61 mmol) in 2-butanol (6 ml) was heated and stirred at 50° C. for 5 hours. 3-Amino-1,2-propanediol (309 mg, 3.4 mmol) was then added and the temperature was raised to 90° C. and the reaction was stirred at this temperature for a further 18 hours. The solvent was removed by evaporation and the resulting solid was recrystallized from ethanol to give the title compound (104 mg, 39%). NMR: 1.55 (m, 2H), 2.75 (m, 2H), 3.15 (s, 3H), 3.25 (m, 2H), 3.40 (m, 3H), 3.60 (m, 1H), 3.75 (m, 1H), 4.70 (t, 1H), 5.85 (m, 1H), 7.35 (t, 1H), 7.55 (brs, 1H), 7.70 (d, 2H), 7.95 (d, 2H), 8.40 (s, 1H), 10.20 (s, 1H); m/z: 436.
Reaction SMILES: C([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Br:25])[CH:24]=1)[C@@H:9]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[F:18])O)(C)(C)C.C(OC(=O)N[C@H](C1C=C(F)C=CC=1F)[C@@H](C1C=NC=C(Br)C=1)O)(C)(C)C.CC(C)([O-])C.[K+].C(OCC)(=O)C>O1CCCC1.O>[Br:25][C:23]1[CH:24]=[C:19]([C@@H:8]2[C@@H:9]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=3[F:18])[O:26][C:6](=[O:5])[NH:7]2)[CH:20]=[N:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cncc(Br)c1)[C@H](O)c1cc(F)ccc1F
Agent: CC(C)(C)OC(=O)N[C@H](c1cc(F)ccc1F)[C@H](O)c1cncc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1N[C@H](c2cncc(Br)c2)[C@@H](c2cc(F)ccc2F)O1
Temperature: -7 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A mixture of tert-butyl((1R,2R)-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)-2-hydroxyethyl)carbamate and tert-butyl((1R,2R)-2-(5-bromopyridin-3-yl)-1-(2,5-difluorophenyl)-2-hydroxyethyl)carbamate (about 6:1 ratio) (101 g, 236 mmol) in tetrahydrofuran (590 mL) was cooled to −7° C. with a methanol/ice bath. To this mixture was added a solution of 1 M potassium tert-butoxide in tetrahydrofuran (590 mL, 590 mmol) via an addition funnel while maintaining the internal temperature <3° C. The reaction mixture was stirred with a cooling bath for 30 min and then allowed to warm up to room temperature. After 20 h, the reaction was deemed complete by LC/MS. The reaction mixture was concentrated to dryness to give crude product. Another identical scale reaction was performed. The crude products of the two batches were combined to work up together. They were treated with ethyl acetate (1.75 L) and water (1.75 L). The layers were separated. The organic layer was washed with brine (1.75 L), dried (sodium sulfate), and evaporated to give 161.5 g of crude product as a brown solid. This was purified by ISCO to give 67.1 g (42% yield). LC/MS (ES+) 355/357 (M+H, 100; Br isotope pattern); 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J=2.2 Hz, 1H), 8.53 (d, J=1.8 Hz, 1H), 7.97 (t, J=2.0 Hz, 1H), 7.29-7.23 (m, 1H), 7.18-7.09 (m, 2H), 6.40 (s, 1H), 5.56 (d, J=5.7 Hz, 1H), 4.84 (d, J=5.5 Hz, 1H); Calcd for C14H9N2BrF2O2: C, 47.34; H, 2.55; N, 7.86; Br, 22.50; F, 10.69. Found: C, 47.29; H, 2.61; N, 7.87; Br, 22.40; F, 10.37. Note: Chiral HPLC of the above sample showed 4.7% of the enantiomer. The (4S,5S) enantiomer can be purged by recrystallization from methanol to give >99.9 ee with 67% recovery.
Reaction SMILES: Cl.[C:2]([O:18][CH3:19])(=[O:17])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][C:9](=[O:16])[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:6].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:2]([O:18][CH3:19])(=[O:17])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][C:9]([N:10]1[CH2:15][CH2:14][N:13]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][CH2:11]1)=[O:16])=[O:6]
Reactant: BrCc1ccccc1
Reactant: COC(=O)/C=C/C(=O)OCC(=O)N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)/C=C/C(=O)OCC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
Methyl 2-oxo-2-piperazinylethyl (2E)but-2-ene-1,4-dioate hydrochloride (14) (0.50 g, 1.71 mmol) was reacted at ca. 0° C. with benzyl bromide (BnBr) (0.243 mL, 0.35 g, 2.05 mmol) and diisopropylethylamine (DIEA) (1.00 mL, 0.74 g, 5.76 mmol) in dichloromethane (DCM) followed by warming to room temperature. After aqueous work-up, the crude product was purified by mass-guided preparative HPLC to afford 0.18 g (27% yield) of the title compound (15) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.08-7.01 (m, 5H), 6.72-6.71 (m, 2H), 4.60 (s, 2H), 3.58-3.57 (s, 3H), 3.23-3.19 (br S, 2H), 3.30 (s, 2H), 3.1.19-3.11 (br S, 2H), 2.23 (br S, 4H); MS (ESI) m/z 347.13 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][CH2:10][C:11](=[S:13])C.[CH2:14](N(CC)CC)C>C(Cl)Cl>[I:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[NH:6][C:10]([CH3:9])=[C:11]2[S:13][CH3:14]
Reactant: CCN(CC)CC
Reactant: Nc1ccc(I)cc1
Reactant: CCC(C)=S
Solvent: ClCCl
Product: CSc1c(C)[nH]c2ccc(I)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 11 %

Procedure:
A solution of 10.9 g (91 mmole) of 5-butylhypochlorite in 40 mL of CH2Cl2 was added dropwise to a solution of 20.0 g (91 mmole) of 4-iodoaniline in 300 mL of CH2Cl2 at -70° C. After 10 min, a solution of 7.43 mL (91 mmole) of methylthioacetone in 40 mL of CH2Cl2 was added dropwise. After stirring for 90 min, 12.7 mL of triethylamine was added. The reaction was allowed to warm to room temperature. The mixture was washed with water, dried (K2CO3) and the solvent evaporated in vacuo. The residue was extracted with hot hexane. The precipitated crystals were collected to give 2.95 g (11% yield) of the title compound. The mp after recrystallization from CH2Cl2 -hexane was 95°-97° C.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][CH2:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14].[K]>CN(C)C=O>[C:2]1([CH2:1][O:15][C:13](=[O:14])[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][OH:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CCO)C(=O)O
Reactant: BrCc1ccccc1
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(CCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
A mixture of benzyl bromide (37.4 g) and 4-hydroxy-2,2-dimethylbutanoic acid, monopotassium salt, (3.4 g) in dimethylformamide (35 mL) was stirred at room temperature for 18 hours. The precipitate was filtered off and the filtrate was evaporated. The residue was chromatographed on silica gel eluting with 2:1 dichloromethane:ethyl acetate to give 3.95 g (89%) of 4-hydroxy-2,2-dimethylbutanoic acid phenylmethyl ester as a colorless oil. A sample was evaporatively distilled to give the analytical sample: bp 160°-165° C./0.25 mm; IR (CHCl3) 3595 (OH), 1707 (C=O) and 687 cm-1 (C6H5); NMR (CDCl3) δ 1.23 (s, 6, CH3), 1.85 (t, 2, CH2), 3.67 (t, 2, CH2), 5.11 (s, 2, CH2) and 7.34 (s, 5, Ph); MS m/e 222,91.
Reaction SMILES: CP(C)C.O1CCCC1.[CH2:10]([O:12][C:13]([C@:15]1([N:28]=[N+]=[N-])[C@@H:20]([OH:21])[CH2:19][C@@H:18]2[C@H:16]1[C@@:17]2([F:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:14])[CH3:11].C(=O)([O-])O.[Na+]>O1CCCC1.O.C(OCC)C>[CH2:10]([O:12][C:13]([C@:15]1([NH2:28])[C@@H:20]([OH:21])[CH2:19][C@@H:18]2[C@H:16]1[C@@:17]2([F:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:14])[CH3:11]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@H](O)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Agent: CP(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@@H]1O)[C@]2(F)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
0.89 mL of a solution of 1M trimethylphosphine/tetrahydrofuran was added to 245 mg of (1R,2R,3S,5R,6R)-2-azido-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 7.0 mL of tetrahydrofuran and 0.7 mL of water, and the mixture was stirred for 12 hours at room temperature. After the mixture was diluted with 14 mL of diethyl ether, a saturated aqueous solution of sodium hydrogen carbonate was added thereto, and the mixture was stirred for 1 hour at room temperature. After separation, the aqueous layer was extracted twice with chloroform. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure The residue was purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: chloroform-ethanol=50:1), thereby yielding 163 mg of (1R,2R,3S,5R,6R)-2-amino-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [N:1]([C@@H:4]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C@H:5]([OH:24])[CH2:6][N:7]([CH2:19][C:20]([F:23])([CH3:22])[CH3:21])[S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O.C(OCC)(=O)C>[NH2:1][C@@H:4]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C@H:5]([OH:24])[CH2:6][N:7]([CH2:19][C:20]([F:23])([CH3:21])[CH3:22])[S:8]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)(=[O:9])=[O:10]
Reactant: COc1ccc(C[C@H](N=[N+]=[N-])[C@H](O)CN(CC(C)(C)F)S(=O)(=O)c2ccc(OC)cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C[C@H](N)[C@H](O)CN(CC(C)(C)F)S(=O)(=O)c2ccc(OC)cc2)cc1
Reaction time: 24 h
Yield: 55 %

Procedure:
Azide 18f and triphenyl phosphine (1.2 eq) was dissolved in a solution of THF/H2O (4:1). The reaction mixture was allowed to run for 24 h. Upon completion the reaction was diluted with ethyl acetate and extracted 3 times. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was removed under vacuum and the residue was purified using flash chromatography 60% ethylacetate/hexanes followed by 3% MeOH/CH2Cl2. 55% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.74 (d, J=8.6 Hz, 2H), 7.09 (d, J=8.3 Hz, 2H), 6.98 (d, J=8.5 Hz, 2H), 6.82 (d, J=8.1 Hz, 2H), 3.93-3.90 (m, 1H), 3.85 (s, 3H), 3.77 (s, 3H), 3.51 (dd, J=27.4, 15.1 Hz, 1H), 3.41-3.20 (m, 3H), 3.04-3.01 (m, 1H), 2.88 (d, J=13.7 Hz, 1H), 2.33 (dd, J=13.4, 10.5 Hz, 1H), 1.46 (d, J=21.6 Hz, 3H), 1.37 (d, J=21.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C@H:9]([NH:11][S@@](C(C)(C)C)=O)[CH3:10])[CH:4]=1.[ClH:20].O1CCOCC1>CO>[ClH:20].[ClH:20].[F:18][C:2]([F:1])([F:19])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C@H:9]([NH2:11])[CH3:10])[CH:4]=1
Reactant: C[C@@H](N[S@](=O)C(C)(C)C)c1cc(C(F)(F)F)ccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H](N)c1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2-methyl-propane-2-sulfinic acid [(R)-1-(4-trifluoromethyl-pyridin-2-yl)-ethyl]-amide (225 mg, 0.76 mmol) in MeOH (4 mL) was added 4.0 M hydrogen chloride in dioxane (0.48 mL, 1.9 mmol). The reaction mixture was stirred at room temperature for 30 min then concentrated and dried under high vacuum to afford 225 mg of (R)-1-(4-trifluoromethyl-pyridin-2-yl)-ethylamine dihydrochloride as a viscous colorless oil which was used without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11])(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:17]1[C:27]2=[C:28]3[C:23](=[CH:24][CH:25]=[CH:26]2)[CH2:22][CH2:21][CH2:20][N:19]3[C:18]1=[O:29].O>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH:21]1[CH2:22][C:23]2[C:28]3=[C:27]([CH2:17][C:18](=[O:29])[N:19]3[CH2:20]1)[CH:26]=[CH:25][CH:24]=2)=[O:11])(=[O:3])[CH3:2]
Reactant: O=C1Cc2cccc3c2N1CCC3
Reactant: CC(=O)OCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCCCCCC(=O)C1Cc2cccc3c2N(C1)C(=O)C3
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
6-Acetyloxyhexanoic acid chloride (16.7 g, 86.6 mmol) in absolute CH2Cl2 (50 ml) is added in drops at 0° C. within 10 minutes to a suspension of anhydrous aluminum chloride (61.5 g, 461.6 mmol) in absolute CH2Cl2 (500 ml), and it is stirred for 15 minutes at this temperature. 5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one (10.0 g (57.7 mmol) in absolute CH2Cl2 (100 ml) is added in drops within 15 minutes at 0° C., then it is heated to boiling temperature and stirred for 30 minutes. It is cooled to 0° C., hydrolyzed with ice and dispersed between water (300 ml) and CH2Cl2 (100 ml). The aqueous phase is extracted with CH2Cl2 (2×100 ml), the combined organic phases are washed with 2N hydrochloric acid (2×250 ml), water (2×250 ml), semi-concentrated aqueous Na2CO3 solution (2×250 ml), concentrated aqueous Na2CO3 solution (2×250 ml) and concentrated common salt solution (1×250 ml), dried (sodium sulfate/activated carbon), and the solvent is removed in a rotary evaporator.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C=C(C#N)C=CC=3OCC2=O)CC1.[F:52][C:53]1[CH:58]=[CH:57][C:56]([F:59])=[CH:55][C:54]=1/[CH:60]=[CH:61]/[CH:62]=O.C([BH3-])#N.[Na+]>ClCCl.CO>[F:52][C:53]1[CH:58]=[CH:57][C:56]([F:59])=[CH:55][C:54]=1/[CH:60]=[CH:61]/[CH2:62][NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1
Reactant: N#Cc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Reactant: O=C/C=C/c1cc(F)ccc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)N(CCN1CCC(NC/C=C/c3cc(F)ccc3F)CC1)C(=O)CO2
Yield: 30.9 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 58) (1.5 mmol), (2E)-3-(2,5-difluorophenyl)acrylaldehyde (202 mg, 1.2 mmol) (FR 2872164) (200 mg, 1.1 mmol) and sodium cyanoborohydride were reacted as described under Example 21. Chromatography on silica gel with dichloromethane/methanol gave 168 mg (25%) product