Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[C:9]2[C:10]([CH3:15])=[CH:11][C:12](=[O:14])[O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[S:19]>O.CC(C)=O>[CH3:16][N:17]([CH3:21])[C:18](=[S:19])[O:3][C:4]1[C:9]2[C:10]([CH3:15])=[CH:11][C:12](=[O:14])[O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)C(=S)Cl
Reactant: Cc1cc(=O)oc2cccc(O)c12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(=O)oc2cccc(OC(=S)N(C)C)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
410 mg (7.3.10-3 mol) of potassium hydroxide are added under an inert atmosphere to a suspension of 1 g (5.7.10-3 mol) of 5-hydroxy-4-methyl-2H-1-benzopyran-2-one in 10 ml of water and 10 ml of acetone. After 10 minutes at room temperature, 770 mg (6.2.10-3 mol) of dimethylthiocarbamoyl chloride in 10 ml of acetone are added at 0° C. The reaction mixture is stirred for 2 hours at room temperature and then, after evaporation of the acetone, the expected derivative is precipitated in water to give 1.35 g (yield: 90%) of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1.[NH2:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:18]=2[N:19]=1.[C:25](N1C=CN=C1)(N1C=CN=C1)=S>C(Cl)CCl>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH3:25])[C:11]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:18]=4[N:19]=3)=[N:12][C:6]=2[CH:5]=1)=[O:13]
Reactant: Nc1nc2cc(F)ccc2s1
Reactant: CNc1ccc(C(=O)OC)cc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(c1)nc(Nc1nc3cc(F)ccc3s1)n2C
Yield: 65.2 %

Procedure:
1-Methyl-2-(5-fluoro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (1.16 g) was prepared by following General Procedure D starting from 3-amino-4-methylamino-benzoic acid methyl ester (0.9 g), 2-amino-5-fluoro-benzothiazole (0.84 g), 1,1′-thiocarbonyldiimidazole (1.07 g), and EDC (1.15 g). LC/MS: m/z 358.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[OH:25][C@@H:26]([C@H:28]1[C:48](=[O:49])[N:30]2[CH:31]([C:35]([O:37]CC3C=CC([N+]([O-])=O)=CC=3)=[O:36])[C:32](=O)[CH2:33][C@H:29]12)[CH3:27].[C:50]([C@@H:53]1[CH2:57][C@H:56]([SH:58])[CH2:55][N+:54]1([CH3:60])[CH3:59])(=[O:52])[NH2:51]>C(#N)C.C(OCC)C>[C:50]([C@@H:53]1[CH2:57][C@H:56]([S:58][C:32]2[CH2:33][C@@H:29]3[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:48](=[O:49])[N:30]3[C:31]=2[C:35]([O-:37])=[O:36])[CH2:55][N+:54]1([CH3:60])[CH3:59])(=[O:52])[NH2:51]
Reactant: C[N+]1(C)C[C@@H](S)C[C@H]1C(N)=O
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@H]3C[C@@H](C(N)=O)[N+](C)(C)C3)C[C@H]12
Reaction time: 1 h

Procedure:
210 μl of diisopropylethylamine and 250 μl of diphenylphosphoryl chloride were simultaneously added, whilst ice-cooling, to a solution of 400 mg of 4-nitrobenzyl (5R, 6S)-6-[(1R)-1-hydroxyethyl]-2oxo-1-carbapenam-3-carboxylate dissolved in 5 ml of dry acetonitrile, and the mixture was stirred for 1 hour, whilst ice-cooling. At the end of this time, a solution of 447 mg of the crude (2S, 4S)-2-carbamoyl-1,1-dimethyl-4-mercaptopyrrolidinium salt prepared as described in Example 1-(1) in 5 ml of dry acetonitrile was added to the mixture, whilst ice-cooling, and then the mixture was allowed to stand for 4 hours at the same temperature and then for 2 days in a refrigerator. The reaction mixture was then poured into diethyl ether and the resulting deposit was washed repeatedly by decantation. The crude product was dissolved in a mixture of 30 ml of tetrahydrofuran and 30 ml of a 0.1M phosphate buffer (pH 7.0) and hydrogenated at room temperature for 2.5 hours in the presence of 450 mg of 10% w/w palladium-on-charcoal. At the end of this time, insoluble materials were removed by filtration using a Celite filter aid. The aqueous layer was concentrated by evaporation under reduced pressure, and the residue was transferred to a column packed with Diaion HP-20AG (Mitsubishi Chemicals Industries, Ltd.). Fractions eluted with water were collected and lyophilized to afford the title compound as a powder. This was further purified using a Lobar column (Merck, LiChroprep RP-8 size B) and fractions eluted with a 5% by volume aqueous methanolic solution were collected and concentrated by evaporation under reduced pressure followed by lyophilization, to afford 208 mg of the title compound.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C:12]2[N:17]3[C:18](=[O:27])[CH:19]([NH:20][C:21](=[S:26])[CH2:22][CH2:23][C:24]#[N:25])[C@H:16]3[S:15][CH2:14][C:13]=2[O:28][CH3:29])=[O:11])=CC=1)([O-])=O.O1CCCC1.Cl>CO.[Pd].C(O)C>[C:24]([CH2:23][CH2:22][C:21]([NH:20][CH:19]1[C:18](=[O:27])[N:17]2[C:12]([C:10]([OH:11])=[O:9])=[C:13]([O:28][CH3:29])[CH2:14][S:15][C@H:16]12)=[S:26])#[N:25]
Reactant: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=S)CCC#N)[C@H]2SC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: CO
Product: COC1=C(C(=O)O)N2C(=O)C(NC(=S)CCC#N)[C@H]2SC1
Reaction time: 3 h

Procedure:
To a solution of 1 g. of 7-cyanomethylthioacetamido-3-methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester in 60 ml. of tetrahydrofuran and 100 ml. of methanol containing 5 drops of 1N hydrochloric acid is added 1 g. of prereduced 5% palladium on charcoal in 40 ml. of ethanol. The mixture is hydrogenated for 3 hours at room temperature at 50 psi. The catalyst is filtered and washed with tetrahydrofuran and water. The filtrate and washings are combined, solvent is removed in vacuo and the residue is taken up in an ethyl acetate water mixture. The pH of the aqueous layer is adjusted to 7.5 and the ethyl acetate is removed. Fresh ethyl acetate is added and the pH is adjusted to 2.5. The ethyl acetate layer is removed, washed with water and dried over sodium sulfate. Removal of the solvent in vacuo yields the product 7-cyanomethylthioacetamido-3-methoxy-3-cephem-4-carboxylic acid as a foam.
Reaction SMILES: [I-].C[N+]1C=CN([C:8](=[O:30])/[N:9]=[C:10]2\[S:11][C:12]([CH3:29])=[CH:13][N:14]\2[C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[O:22][C:17]=3[CH:16]=2)C=1.C(N(CC)C(C)C)(C)C.[CH2:40]([NH:47][CH2:48][C:49]#[C:50][CH3:51])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH2:40]([N:47]([CH2:48][C:49]#[C:50][CH3:51])[C:8](/[N:9]=[C:10]1\[S:11][C:12]([CH3:29])=[CH:13][N:14]\1[C:15]1[CH:28]=[CH:27][C:18]2[O:19][C:20]([F:26])([F:25])[C:21]([F:23])([F:24])[O:22][C:17]=2[CH:16]=1)=[O:30])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC#CCNCc1ccccc1
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)n2cc[n+](C)c2)s1
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCN(Cc1ccccc1)C(=O)/N=c1\sc(C)cn1-c1ccc2c(c1)OC(F)(F)C(F)(F)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (Z)-3-methyl-1-(5-methyl-3-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2(3H)-ylidenecarbamoyl)-1H-imidazol-3-ium iodide (Example 81A, 0.75 mL of 0.14 M in acetonitrile, 58 mg, 0.1 mmol) was added to a 20 mL vial followed by N,N-diisopropylethylamine (0.75 mL of 0.14 M in acetonitrile, 18 mg, 0.13 mmol). Subsequently, N-benzylbut-2-yn-1-amine (0.57 mL of 0.2 M in acetonitrile, 0.11 mmol) was added. The resulting mixture was shaken at room temperature overnight. It was then concentrated in vacuo and the residue was taken up in 1:1 MeOH/DMSO and purified by reverse phase HPLC (acetonitrile/water 0.1% TFA gradient elution method). 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 1.75 (3H) 2.24 (3H) 4.05 (2H) 4.55 (2H) 7.01-7.10 (1H) 7.17-7.29 (4H) 7.29-7.35 (1H) 7.40-7.54 (1H) 7.58-7.63 (1H) 7.66-7.94 (1H); MS (ESI+) m/z 506 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[N:13]=[C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]2[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31]
Reactant: COc1ccc(OC)c(Sc2nc3c(N)ncnc3[nH]2)c1
Reactant: Fc1ccccc1CCBr
Product: COc1ccc(OC)c(Sc2nc3c(N)ncn(CCc4ccccc4F)c-3n2)c1

Procedure:
The title compounds were prepared from 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and 1-(2-bromo-ethyl)-2-fluoro-benzene by a procedure similar to examples 1 and 2. The isomers were separated by preparative HPLC. 8-(2,5-Dimethoxy-phenylsulfanyl)-9-[2-(2-fluoro-phenyl)-ethyl]-9H-purin-6-ylamine: Yield 37%, 1H NMR (DMSO-d6) δ 8.27 (s, 1H), 7.28-7.22 (m, 1H), 7.12-7.00 (m, 4H), 6.87 (dd, J=8.8, 3.2 Hz, 1H), 6.55 (d, J=3.2 Hz, 1H), 4.45 (t, J=6.8, Hz, 2H), 3.72 (s, 3H), 3.62 (s, 3H), 3.08 (t, J=6.8, 2H); LC-MS [M+H]+ 426.1. 8-(2,5-Dimethoxy-phenylsulfanyl)-3-[2-(2-fluoro-phenyl)-ethyl]-3H-purin-6-ylamine: Yield, 18%, 1H NMR (DMSO-d6) δ 8.37 (s, 1H), 8.19 (bs, 2H), 7.33-7.08 (m, 7H), 4.55 (t, J=7.2 Hz, 2H), 3.76 (s, 3H), 3.73 (s, 3H), 3.23 (t, J=7.2 Hz, 2H); LC-MS [M+H]+ 426.1.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]3[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=[CH:41]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]3[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=[CH:41]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccc(OCCCCn3cnc4ccccc43)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(C)ccc(OCCCCn3cnc4ccccc43)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-7-[4-(benzimidazol-1-yl)-butyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[C@H:22]([CH3:23])[CH2:21][O:20][C@H:19]([C:24]([OH:26])=O)[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1[F:27])#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:61]([NH2:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[C@H:22]([CH3:23])[CH2:21][O:20][C@H:19]([C:24]([NH:68][CH2:61][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)=[O:26])[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1[F:27])#[N:2]
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)O)OC[C@H]2C)n1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)OC[C@H]2C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
A mixture of (2S,5R)-4-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-5-methyl-2-morpholinecarboxylic acid (302 mg, 0.81 mmol), HATU (340 mg, 0.89 mmol), and Hünig's base (0.21 mL, 1.20 mmol) in DMF (5 mL) was stirred at room temperature for 10 minutes. Benzylamine (0.100 mL, 0.92 mmol) was then added and stirring continued at room temperature for 17 hours. LC-MS indicated about 50% conversion so another portion each of Hünig's base (0.21 mL, 1.20 mmol) and HATU (340 mg, 0.89 mmol) were added. After about 10 minutes more benzylamine (0.100 mL, 0.92 mmol) was added, and the mixture was stirred for an additional 1.5 hours, then diluted with EtOAc (25 mL) and washed successively with water, saturated aqueous NaHCO3, and brine (25 mL each). The organic phase was then dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (40 g SiO2, 15-50% EtOAc in hexanes gradient) to give the title compound (302 mg) as a yellow oil. LC-MS (ES) m/z=461 [M+H]+.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].C(N(CC)CC)C.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19].[CH3:22][N:23]([CH3:28])[S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:22][N:23]([CH3:28])[S:24]([N:7]1[C:8]([CH3:9])=[C:4]([CH2:3][O:2][Si:18]([CH3:20])([CH3:19])[CH3:17])[N:5]=[CH:6]1)(=[O:26])=[O:25]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: C[Si](C)(C)Cl
Reactant: Cc1[nH]cnc1CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(CO[Si](C)(C)C)ncn1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
A suspension of 4-(hydroxymethyl)-5-methylimidazole hydrochloride (14.9 g) in dry dichloromethane (500 ml) containing triethylamine (50 g) was treated with trimethylsilyl chloride (21.7 g) and the reaction mixture was stirred at room temperature overnight. Dimethylsulphamoyl chloride (14.3 g) was added and the reaction mixture was again stirred at room temperature overnight. The resulting suspension was filtered and the collected solid was washed with dichloromethane (100 ml). The filtrate was concentrated onto silica and purification by FCC eluting with hexane:ether (4:1) gave the title compound as an oil (7.2 g), t.l.c. (ether) Rf 0.5.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:10]1CCCC1.[Br:15][C:16]([F:26])([F:25])[C:17]([F:24])([F:23])[CH2:18][CH2:19][CH2:20][CH2:21]O.C(N(CC)CC)C>O>[C:1]([OH:8])(=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15][C:16]([F:25])([F:26])[C:17]([F:23])([F:24])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: OCCCCC(F)(F)C(F)(F)Br
Reactant: O=C(Cl)c1ccccc1
Reactant: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCC(F)(F)C(F)(F)Br
Product: O=C(O)c1ccccc1
Reaction time: 10 h
Yield: 82 %

Procedure:
A 300 mL reactor was charged under nitrogen with 14.0 g (99.6 mmol/1.3 equivalents) of benzoyl chloride and 150 mL of tetrahydrofuran (a dehydrated product), following by putting it in an ice bath. 20.0 g (79.0 mmol/1.0 equivalent) of 6-bromo-5,5,6,6-tetrafluorohexan-1-ol was added thereto, followed by adding dropwise of 12.0 g (119 mmol/1.5 equivalents) of triethylamine. After the dropping, stirring was conducted at 60 degrees for 10 hours. Then, 100 mL of water was added, and extraction was conducted two times with 200 mL of diisopropyl ether. The obtained organic layer was washed further with diluted hydrochloric acid, sodium bicarbonate water and brine, followed by removing water by sodium sulfate and conducting filtration. Then, isopropyl ether was distilled out, thereby obtaining 24.4 g of the target 6-bromo-5,5,6,6-tetrafluorohexane benzoate. Upon this, purity was 95%, and yield was 82%.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.CO[CH:11]=[CH:12][C:13](=O)[CH3:14]>>[CH3:14][C:13]1[CH:12]=[CH:11][C:3]2[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]=2[N:1]=1
Reactant: COC=CC(C)=O
Reactant: NC1=CC(=O)CCC1
Product: Cc1ccc2c(n1)CCCC2=O
Temperature: 120 °C
Yield: 69.8 %

Procedure:
A mixture of 3-aminocyclohex-2-enone (22 g., 0.2 mol.) and 4-methoxybut-3-en-2-one (20.0 g., 0.2 mol), in an apparatus equipped for downward distillation, was heated in an oil bath at 120° C until the theoretical amount of distillate had been collected (13 ml.). The cooled residue was dissolved in 2N HCl (50 ml.) and extracted with ethyl acetate (3 × 50 ml.) and the combined extracts discarded. The aqueous solution was adjusted to pH 9.0 with sodium carbonate and extracted with chloroform (3 × 50 ml.). The combined extracts were dried (MgSO4) and the solvent removed in vacuo and the residual oil distilled to give the title compound (22.5 g., 72%) b.p. 72°-6°/0.1 mm Hg. The free base was dissolved in ether and treated with an excess of ethereal hydrogen chloride. The resultant solid was isolated and recrystallised from isopropanol to give the hydrochloride of the title compound as colourless needles m.p. 225° C. (Found: C, 60.9; H, 6.3; N, 6.99. C10H11NO.HCl requires: C, 60.7; H, 6.1; N, 7.1%).
Reaction SMILES: O[C:2]1([CH2:8][C@H:9]2[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[N:10]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(S(F)(F)[F:29])CC.C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[F:29][C:2]1([CH2:8][C@H:9]2[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[N:10]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2(O)CCCCC2)COC1(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](CC2(F)CCCCC2)COC1(C)C
Temperature: -78 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
(S)-tert-Butyl 4-((1-hydroxycyclohexyl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (2.70 g, 8.63 mmol) was dissolved in CH2Cl2 and the solution was cooled to −78° C. DAST (2.78 g, 17.2 mmol, 2.0 equiv) was added via syringe and the solution was stirred overnight with concomitant warming to rt. LC-MS showed consumption of the starting alcohol. Satd aq NaHCO3 was added and the mixture was stirred for 1 h. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, and filtered. The resulting solution was treated with m-CPBA (1.5 g, 8.6 mmol) and stirred for 3 h. After this time the olefinic by-products from the fluorination were consumed. The excess m-CPBA was quenched by addition of 10% aq Na2S2O3 (50 mL). The layers were separated and the organic layer was washed with satd aq NaHCO3 and brine, dried over Na2SO4, filtered and evaporated. Flash chromatography on silica, eluting with 0-29% EtOAc in hexanes, afforded (S)-tert-butyl 4-((1-fluorocyclohexyl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (725 mg).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8][NH2:9]>[Co]>[CH3:8][N:9]1[CH2:4][CH2:3][CH2:2][CH2:1]1.[CH3:8][N:9]=[C:1]([OH:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C1C=CC(=O)O1
Reactant: CN
Agent: [Co]
Product: CN1CCCC1
Product: CN=C(O)CCC(=O)O
Yield: 5 %
Yield: 6 %

Procedure:
An aqueous solution of maleic anhydride and methylamine (20 wt % of maleic anhydride/methylamine, molar ratio 1:1.5) was hydrogenated over a cobalt catalyst at 250° C. and 250 bar. Following subsequent purification, by distillation, of the hydrogenation product stream there were obtained 71% of N-methylpyrrolidone, 5% of N-methylpyrrolidine, and 6% of succinic acid-N-methylimide. There remained 17% of residue (calculated as succinic acid-N-methylamide).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[NH2:14][C:15]1[N:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].O>N1C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]1[O:6][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[N:23][C:15]=2[N:14]=1
Reactant: Nc1ncccc1C(=O)O
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: O=c1oc(-c2ccccc2C(F)(F)F)nc2ncccc12
Temperature: 25 °C
Yield: 59.4 %

Procedure:
2-(Trifluoromethyl)benzoyl chloride (4.2 ml, 29.2 mmol) is added dropwise to a solution of 2-aminonicotinic acid (2.04 g, 14.76 mmol) in 20 ml of pyridine. The reaction mixture is heated at 158 C. for 30 min then cooled to room temperature. The reaction is poured into 200 ml of water and an oil forms which solidifies upon stirring. The solid is collected by vacuum filtration and washed with water and diethyl ether. The product is dried to give 2-(2-trifluoromethyl-phenyl)-pyrido[2,3-d][1,3]oxazin-4-one (2.56 g, 60% yield) which may be used in the next step without further purification.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH2:25].[Br:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36]>CN(C=O)C>[Br:31][CH2:32][CH2:33][CH2:34][C:35]([NH:25][C:24]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:23]=1[F:22])=[O:36]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)CCCBr
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CCCBr)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.5 %

Procedure:
WSC (2.1 g, 11 mmols) and HOBt (1.49 g, 11 mmols) were added to a DMF (30 ml) solution of 2,4-difluoroaniline (1.29 g, 10 mmols) and 4-bromobutyric acid (2.5 g, 15 mols), and stirred at room temperature for 12 hours. The reaction mixture was extracted with ether. The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through preparative thin-layer chromatography (developer: hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 1.6 g (yield: 58%) of 4-bromo-N-(2,4-difluorophenyl)butanamide as colorless needle-like crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:8][O:9][CH:10]=1)=[O:5])C.C(OC(C1C(C2C=CC(F)=CC=2)=NOC=1)=O)C>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:10][O:9][N:8]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1conc1-c1ccc(Cl)cc1
Agent: CCOC(=O)c1conc1-c1ccc(F)cc1
Product: O=C(O)c1conc1-c1ccc(Cl)cc1
Yield: 100.1 %

Procedure:
As described for example 323d, 3-(4-chloro-phenyl)-isoxazole-4-carboxylic acid ethyl ester (57.0 g, 226.5 mmol) was converted, instead of 3-(4-fluoro-phenyl)-isoxazole-4-carboxylic acid ethyl ester, to the title compound (50.7 g, 92%) which was obtained as a light yellow solid. MS: m/e=222.3 [M−H]−.
Reaction SMILES: [OH-].[Li+].O.C([O:6][P:7]([CH2:15][C@@H:16]([OH:19])[CH2:17][NH2:18])([CH:9]1[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1)=[O:8])C>C(O)C>[NH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][P:7]([CH:9]1[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1)(=[O:6])[OH:8]
Reactant: CCOP(=O)(C[C@@H](O)CN)C1CC=CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC[C@H](O)CP(=O)(O)C1CC=CCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.2 g of lithium hydroxide and 4 ml of water are added to a solution of 1.1 g of 3-amino-2(S)-hydroxy-propyl-(cyclohex-3-enyl)-phosphinic acid ethyl ester in 4 ml of ethanol. The mixture is heated to 60° and stirred for 20 hours. The mixture is then allowed to cool to room temperature, adjusted to pH 7 with aqueous phsophoric acid, concentrated to dryness by evaporation, taken up with methanol/water and filtered. After removal of the solvent there remains behind a foam which, after crystallisation from ethanol/methanol, yields 3-amino-2(S)-hydroxy-propyl-(cyclohex-3-enyl)-phosphinic acid in the form of white crystals having a melting point of 221°-225°.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23].CN(CCN)C.COC1C=CC(N2CCNCC2)=CC=1>O1CCCC1>[CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:23][CH3:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7]
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)CCN
Agent: COc1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(C(=O)NCCN(C)C)CC2)cc1
Yield: 24 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 4.9 g (0.03 mole) of 1,1'-carbonyldiimidazole, 2.6 g (0.03 mole) of unsym-dimethylethylenediamine, and 5.8 g (0.03 mole) of 1-(4-methoxyphenyl)piperazine in a total of 200 ml of tetrahydrofuran gave an oil which solidified. After trituration with petroleum ether (30°-60° C.), the collected solid was recrystallized from cyclohexanebenzene to yield 2.2 g (24%) of the title compound as a white, crystalline solid, m.p. 79°-82° C.