Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]1[S:10][C:9]2[CH:11]([C:15]([OH:17])=[O:16])[CH2:12][C:13](=O)[C:8]=2[CH:7]=1.Cl>O.C1(C)C=CC=CC=1.[Zn]>[CH3:5][C:6]1[S:10][C:9]2[CH:11]([C:15]([OH:17])=[O:16])[CH2:12][CH2:13][C:8]=2[CH:7]=1
Reactant: Cc1cc2c(s1)C(C(=O)O)CC2=O
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc2c(s1)C(C(=O)O)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
6.5 cc of acetic acid was added to a suspension of 64.1 g (0.98 g at) of zinc powder and 6.4 g (0.024 mole) of mercuric chloride in 65 cc of water and the mixture was stirred for 30 min. Then a solution of 14 g (0.076 mole) of 2-methyl-4-oxo-5,6-dihydro-4H-cyclopenta[b]thiophene-6-carboxylic acid in 140 cc of toluene, then 60 cc of 10N hydrochloric acid were successively added. The mixture was refluxed for 5 hours then decanted after cooling to ambient temperature. The organic phase was separated. The aqueous phase was extracted with toluene. The organic solutions were collected, washed with water and dried on sodium sulfate. Evaporation of the solvent under reduced pressure provided 9.8 g (yield=71%) of 2-methyl-5,6-dihydro-4H-cyclo-penta[b]thiophene-6-carboxylic acid (mp=105°-107° C.) which was used afterwards without further purification. An analytical sample was obtained by recrystallization in a hexane-ethyl acetate mixture. Mp=107°-109° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:11][CH:12]1[C:24]2[N:23]3[CH:25]=[CH:26][N:27]=[C:22]3[C:21](=[O:28])[NH:20][C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2.C>[OH-].[Na+].CS(C)=O>[C:1]([NH:11][CH:12]1[C:24]2[N:23]3[CH:25]=[CH:26][N:27]=[C:22]3[C:21](=[O:28])[NH:20][C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21)c1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
1.7 g of benzoyl chloride are added over 1 minute to a solution of 3.1 g of 10-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride in 200 ml of 0.1N sodium hydroxide. The mixture is stirred for 2 hours at a temperature in the region of 20° C. and the insoluble material is separated out by filtration, washed twice with 200 ml in total of distilled water and air-dried. The product obtained (3 g) is dissolved in 100 ml of dimethyl sulphoxide and, after addition of decolorizing charcoal, the solution is filtered. The filter is washed with 20 ml of dimethyl sulphoxide and the filtrate and the washings are then combined and 80 ml of distilled water are added at 20° C. The insoluble material is separated out by filtration, washed twice with 50 ml in total of distilled water and with 25 ml of acetone and then dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 1.75 g of 10-benzamido-5H,10H-imidazo[1,2-a]-indeno[1,2-e]pyrazin-4-one are thus obtained, decomposing without melting at 300° C. [N.M.R. spectrum: (200 MHz; DMSO d6 ; δ in ppm): 6.40 (d, J=8.5 Hz, 1H: CH--N); from 7.30 to 7.70 (mt, 8H: --H6, --H7, --H8, --H9, aromatic --H para and meta to the --CO--NH-- and --H of the imidazole); from 7.80 to 8.00 (mt, 3H: aromatic --H ortho to the --CO--NH-- and --H of the imidazole); 9.14 (d, J=8.5 Hz, 1H: --NH--); 12.55 (cplx, 1H: --CO--NH-- of the ring)].
Reaction SMILES: C(O)(=O)C.COC1CCC(OC)O1.FC(F)(F)C(O)=O.[F:21][C:22]([F:54])([F:53])[O:23][C:24]1[CH:25]=[C:26]([CH:30]2[N:34]([C:35]3[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=3)[C:33](=[O:43])[C:32](NC3C=CC(C#N)=CC=3)=[CH:31]2)[CH:27]=[CH:28][CH:29]=1.O=C1C(=O)[CH2:59][CH:58]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64](OC(F)(F)F)[CH:63]=2)[N:57]1C1C=CC(C#N)=CC=1.C[C@@H](N)C1C=CC=CC=1>C1(C)C=CC=CC=1.C1COCC1.O>[O:43]=[C:33]1[C:32]([NH:57][C@@H:58]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH3:59])=[CH:31][C@@H:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:22]([F:21])([F:54])[F:53])[CH:25]=2)[N:34]1[C:35]1[CH:36]=[CH:37][C:38]([C:39]#[N:40])=[CH:41][CH:42]=1
Reactant: N#Cc1ccc(N2C(=O)C(=O)CC2c2cccc(OC(F)(F)F)c2)cc1
Reactant: N#Cc1ccc(NC2=CC(c3cccc(OC(F)(F)F)c3)N(c3ccc(C#N)cc3)C2=O)cc1
Agent: COC1CCC(OC)O1
Agent: C[C@@H](N)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H](NC1=C[C@@H](c2cccc(OC(F)(F)F)c2)N(c2ccc(C#N)cc2)C1=O)c1ccccc1
Temperature: 40 °C
Reaction time: 1.75 h
Yield: 26 %

Procedure:
Add acetic acid (6.32 mL, 110 mmol), 2,5-dimethoxytetrahydrofuran (10.7 mL, 82.8 mmol), water (25 mL), and trifluoroacetic acid (4.2 mL, 55.2 mmol) sequentially to a mixture of (±)-4-[5-(3-trifluoromethoxy-phenyl)-2-oxo-3-(4-cyano-phenylamino)-2,5-dihydro-pyrrol-1-yl]-benzonitrile (12.7 g, 27.6 mmol) and THF (83 mL). Heat the reaction mixture to 40° C. for 18 hours. Observe significant formation of (±)-4-[2,3-dioxo-5-(3-trifluoromethoxy-phenyl)-pyrrolidin-1-yl]-benzonitrile (LC-MS ESI m/z: 361 (M+H)+, Tr=2.34 min., method 2). Cool the reaction mixture to room temperature and add toluene (150 mL) in a single portion. Wash the mixture with water and then with brine. Dry over sodium sulfate, filter and add (R)-(+)-α-methyl benzylamine (7.1 mL, 55.2 mmol). Stir the solution at 45° C. for 1.75 hours. Concentrate the reaction mixture and purify by silica gel chromatography (15% EtOAc-hexane) to yield 4-[(S)-2-oxo-3-((R)-1-phenyl-ethylamino)-5-(3-trifluoromethoxy-phenyl)-2,5-dihydro-pyrrol-1-yl]-benzonitrile (3.34 g, 26%) as a red oil, LC-MS ESI m/z: 464 (M+H)+, Tr=3.09 min., method 2 and 4-[(R)-2-oxo-3-((R)-1-phenyl-ethylamino)-5-(3-trifluoromethoxy-phenyl)-2,5-dihydro-pyrrol-1-yl]-benzonitrile (4.05 g, 32%) as a foam, LC-MS ESI m/z: 464 (M+H)+, Tr=3.04 min., method 2.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([CH2:24][CH:25]=[CH:26][CH2:27][P:28]([O:33]CC)([O:30][CH2:31][CH3:32])=[O:29])[CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].[OH-].[Li+]>CO.O>[CH2:31]([O:30][P:28]([CH2:27][CH:26]=[CH:25][CH2:24][CH:4]([CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21])[C:3]([OH:36])=[O:2])([OH:33])=[O:29])[CH3:32]
Reactant: CCOP(=O)(CC=CCC(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)C(=O)OC)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOP(=O)(O)CC=CCC(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)C(=O)O
Temperature: 70 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
A mixture of 2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester 4C (25 mg, 0.048 mmol) and lithium hydroxide (200 mg) in a mixture of methanol (3 mL) and water (1 mL) was stirred at 70° C. for 2 hours. The organic solvent was evaporated and the residue acidified with 2N HCl and extracted with ethyl acetate/acetonitrile. The organic extract was concentrated, and the residue was purified by preparative reverse-phase HPLC (acetonitrile and 0.1% aqueous CF3COOH), affording 2-[4-(ethoxy-hydroxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid 4E as an oil (15 mg, 89%); 1H NMR (300 MHz, CD3OD) δ 1.25 (t, J=6.9 Hz, 3H), 1.81 (s, 3H), 2.1-2.6 (m, 8H), 3.40 (d, J=6.6 Hz, 2H), 3.77 (s, 3H), 3.97 (m, 2H), 5.1-5.3 (m, 3H), 5.67 (brs, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:30])[N:10]2[CH:13]([CH3:29])[CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:21][CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH:13]([N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[N:7]=[CH:8][C:9]2=[O:30])[CH3:29])[CH2:16][CH2:17]1
Reactant: COc1ccc2ncc(=O)n(C(C)CN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(C(C)CN3CCC(N)CC3)c2c1
Reaction time: 2 h
Yield: 105.4 %

Procedure:
A solution of tert-butyl {1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)propyl]piperidin-4-yl}carbamate (Intermediate 222, 200 mg, 0.48 mmol) in dichloromethane (30 mL) was treated with trifluoroacetic acid (3 mL). After 2 hours, the reaction was concentrated to dryness. The residue was partitioned between 15% methanol/chloroform. The aqueous phase was re-extracted 3× with 15% methanol/chloroform. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness giving 160 mg (100%) of the crude product as an oil.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:34])[N:14]([C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)[CH3:15])=[CH:6][CH:5]=1.O1CCCC1.CO.O>C(O)(=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:34])[N:14]([C:16]2[CH:17]=[C:18]([C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=3)[CH:19]=[CH:20][CH:21]=2)[CH3:15])=[CH:8][CH:9]=1
Reactant: COC(=O)CCc1ccc(-c2cccc(N(C)C(=O)NCCc3ccc(F)cc3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CN(C(=O)NCCc1ccc(F)cc1)c1cccc(-c2ccc(CCC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
200 mg (5 mmol, 10 eq) of sodium hydroxide are added to a solution of 221 mg (0.51 mmol, 1 eq) of methyl 3-(3′-{3-[2-(4-fluorophenyl)ethyl]-1-methylureido}biphenyl-4-yl)propanoate in 6 ml of an 8/2 tetrahydrofuran/methanol mixture. The reaction mixture is stirred for 3 hours at room temperature. The reaction is stopped by addition of 10 mL of water and 2 mL of acetic acid and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 180 mg of 3-(3′-{3-[2-(4-fluorophenyl)ethyl]-1-methylureido}biphenyl-4-yl)propanoic acid are obtained (m.p.=146° C.). Yield=84%
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][C:4]=1[O:12][CH3:13])#[N:2].[OH:14][CH2:15][C:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:18](O)=[O:19])[NH2:17].[Na].Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[O:11]=[C:10]1[NH:17][C:16]([CH2:18][OH:19])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15](=[O:14])[N:9]1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([O:12][CH3:13])[CH:5]=1
Reactant: NC(CO)(C(=O)O)c1ccccc1
Reactant: COc1cc(N=C=O)ccc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(N2C(=O)NC(CO)(c3ccccc3)C2=O)ccc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 384 mg of 4-cyano-3-methoxyphenyl isocyanate (prepared according to WO 2007/137874) in 8 mL dioxane is added to a solution of 200 mg of 2-hydroxymethyl-2-phenylglycine (prepared according to literature procedure) in an aqueous solution of 1.8 mL 1N sodium hydroxyde in 2 mL of water. The mixture is stirred at room temperature overnight, acidified by adding 3 mL 12N HCl and heated at 110° C. for 2 hours. The solution is then treated with a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate, dried over sulfate magnesium, filtered, evaporated and purified over silica gel while eluting with 60/40 heptane/ethyl acetate mixture to give the expected product.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:17]1[CH:29]=[CH:28][C:27]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C:19]=2[CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][N:12]([C:17]3[CH:29]=[CH:28][C:27]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH2:20][C:19]=4[CH:18]=3)[CH2:11]2)[CH2:15]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2CN(c3ccc4c(c3)Cc3ccccc3-4)CC2C1
Temperature: 85 °C
Reaction time: 18 h
Yield: 58.1 %

Procedure:
A mixture of 3-Boc-3,7-diazabicyclo[3.3.0]octane (340 mg, 1.6 mmol; see WO 0181347), 2-bromofluorene (0.47 g, 1.9 mmol), tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3; 44 mg, 0.048 mmol; Strem), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP; 50 mg, 0.080 mmol; Strem) and Cs2CO3 (1.0 g, 3.2 mmol; Aldrich) in toluene (25 mL) in a sealed tube was warmed to 85° C. and stirred for 18 h. The material was cooled to ambient temperature, filtered, concentrated under reduced pressure and purified by flash chromatography (silica gel, 50% gradient of EtOAc in hexanes) to afford the title compound (350 mg, 0.93 mmol; 58% yield): MS (DCI/NH3) m/z 377 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].Cl>CO.[Pd]>[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC=C(c2cccc(S(C)(=O)=O)c2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)N1CCC(c2cccc(S(C)(=O)=O)c2)CC1

Procedure:
4-(3-Methanesulfonyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid methyl ester (2.0 g) was dissolved in methanol (40 ml). Concentrated hydrochloric acid (2 ml) and Pd/C (500 mg) were added. The resulting mixture was hydrogenated under a hydrogen gas pressure (50 psi) for 8 h and then filtered through a pad of celite. The solvent was evaporated in vacuum and the residue was purified by flash chromatography (CH2Cl2:MeOH, 3:1 (v/v)). Yield 0.92 g MS m/z (relative intensity, 70 eV) 297 (M+, 54), 282 (62), 238 (bp), 115 (92), 56 (93).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:29])[C:27]=4[Cl:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)[CH2:39][CH2:38]1>CCOC(C)=O>[CH3:36][N:37]1[CH2:38][CH2:39][N:40]([C:43]2[CH:48]=[CH:47][C:46]([NH:49][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[CH:24]=[N:25][N:26]([CH3:29])[C:27]=6[Cl:28])=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:45][CH:44]=2)[CH2:41][CH2:42]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Cn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)c1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(NC=C3C(=O)Nc4cc(C(=O)c5cccc(NC(=O)c6cnn(C)c6Cl)c5)ccc43)cc2)CC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
A small screw cap test tube was charged with 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.237 mmol) and THF (2.5 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (59.2 mg, 0.309 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (5 mL) and Hexanes (40 mL). The precipitate that formed was then filtered and washed with acetone (5 mL) to afford the title compound in 71% yield (0.100 g, 0.168 mmol).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9](O)=[O:10])=[C:7]([F:12])[C:6]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:5]([F:21])[CH:4]=1.Cl.[CH3:23][NH:24][CH3:25].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[NH2:2][C:3]1[C:8]([C:9]([N:24]([CH3:25])[CH3:23])=[O:10])=[C:7]([F:12])[C:6]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:5]([F:21])[CH:4]=1
Reactant: CNC
Reactant: Nc1cc(F)c(OCc2ccccc2)c(F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1c(N)cc(F)c(OCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.3 %

Procedure:
To a solution of 6-amino-3-benzyloxy-2,4-difluorobenzenecarboxylic acid hydrochloride (2.07 g) in DMF (30 mL) were added dimethylamine hydrochloride (1.07 g), 1-hydroxybenzotriazole (1.51 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.89 g) and triethylamine (2.0 g), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water, saturated aqueous sodium bicarbonate, water and brine, dried over sodium sulfate and purified by column chromatography (hexane:ethyl acetate=1:2) on silica gel to give 6-amino-3-benzyloxy-2,4-difluoro-N,N-dimethylbenzamide (1.19 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31]([OH:33])=O)[CH2:25]2)=[O:22])=[CH:17][CH:16]=1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1>>[CH:34]1([NH:37][C:31]([CH2:30][N:26]2[CH2:27][CH2:28][CH2:29][CH:24]([NH:23][C:21](=[O:22])[C:18]3[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])=[N:20][CH:19]=3)[CH2:25]2)=[O:33])[CH2:36][CH2:35]1
Reactant: NC1CC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)O)C2)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)NC3CC3)C2)cn1
Yield: 63 %

Procedure:
As described for example 42, (3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl-acetic acid (70 mg, 0.16 mmol) was converted, using cyclopropylamine instead of methylamine, to the title compound (52 mg, 63%) which was obtained as a white solid. MS: m/e=490.5 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C=O)C.C1(C)C=CC=CC=1>[I:1][C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(I)cc(I)c1I
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(I)cc(I)c1I
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 15.0 g (30.0 mmol) of 2,3,5-triiodobenzoic acid and 19.0 g (150 mmol) of oxalyl chloride in 60 ml of dry dichloromethane was placed under nitrogen and cooled to 0° C. Two drops of dry DMF were added, the ice bath was removed and the resulting suspension was stirred at room temperature for 1.5 hrs. The resulting brown solution was concentrated in vacuo to produce a tan solid. The solid was dissolved in 30 ml of dry toluene and was concentrated in vacuo. The toluene concentration was repeated two more times to yield 2,3,5-triiodobenzoyl chloride as a tan solid.
Reaction SMILES: C(N(CC)CC)C.[SH:8][CH2:9][C:10]([OH:12])=[O:11].[CH2:13]([CH:16]1[C:20](O)([CH3:21])[CH:19]=[CH:18][C:17]1=[O:23])[CH:14]=[CH2:15]>C1(C)C=CC=CC=1>[CH2:13]([C:16]1[C:17](=[O:23])[CH2:18][CH:19]([S:8][CH2:9][C:10]([OH:12])=[O:11])[C:20]=1[CH3:21])[CH:14]=[CH2:15]
Reactant: O=C(O)CS
Reactant: C=CCC1C(=O)C=CC1(C)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCC1=C(C)C(SCC(=O)O)CC1=O
Reaction time: 1 h
Yield: 90.7 %

Procedure:
Into the same flask as used in Example 1, triethylamine (10 g), mercaptoacetic acid (30 g) and toluene (50 g) were charged, and 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (15.2 g) was dropwise added thereto at a temperature of 20° to 40° for 1 hour. Thereafter, the reaction mixture was stirred at a temperature of 50° to 70° C. for 4 hours. After completion of the reaction, the mixture was evaporated under reduced pressure. The residue was dissolved in a 5% aqueous solution of sodium bicarbonate (100 g), and undissolved materials were filtered off. The filtrate was treated with an acid and extracted with diethyl ether. Diethyl ether was evaporated off from the organic layer to obtain 2-allyl-3-methyl-4-carboxymethylthio-2-cyclopentenone (20.5 g). Yield, 90.5%. nD20 1.5567.
Reaction SMILES: [BrH:1].[F:2][C:3]([F:11])([F:10])[C:4]1[S:8][C:7](N)=[N:6][N:5]=1.BrBr.N([O-])=O.[Na+].[OH-].[Na+]>O>[Br:1][C:7]1[S:8][C:4]([C:3]([F:11])([F:10])[F:2])=[N:5][N:6]=1
Reactant: Nc1nnc(C(F)(F)F)s1
Reactant: Br
Agent: BrBr
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1nnc(Br)s1
Temperature: 25 °C
Yield: 54 %

Procedure:
To 3 mL of 48% aqueous HBr was added 1.0 g (5.9 mmol) of 5-(trifluoromethyl)-1,3,4-thiadiazol-2-amine with stirring. The mixture was cooled in a salt ice-water bath, and 2.27 mL (44 mmol) of bromine was added slowly dropwise. The salt ice-water bath was replaced with an ice-water bath and a solution of 1.05 g (15 mmol) of sodium nitrite in 1.5 mL of water was added slowly dropwise. The reaction mixture was stirred for 1 h and then let warm to room temperature. The mixture was neutralized with 5M aqueous sodium hydroxide, and the resulting precipitate was filtered off. The filtrate was extracted with chloroform, and the extract was dried over magnesium sulfate before being concentrated to afford 750 mg (54%) of 2-bromo-5-(trifluoromethyl)-1,3,4-thiadiazole, 330 mg (1.4 mmol) of which was added to a solution of 240 mg (1.6 mmol) of (3S)-4,4-dimethyl-3-pyrrolidinol hydrochloride and 0.73 mL (4.2 mmol) of N,N-diisopropylethylamine in 5 mL of isopropanol. The reaction mixture was heated at reflux for 2 h, and then concentrated. The residue was purified by silica gel chromatography eluting with 0.3:9.7 methanol dichloromethane to afford 328 mg (88%) of (3S)-4,4-dimethyl-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-pyrrolidinol. 1H NMR (300 MHz, DMSO-d6) δ 5.31 (d, J=5 Hz, 1H), 3.89-3.76 (m, 2H), 3.40-3.22 (m, 3H), 1.02 (s, 3H), 1.00 (s, 3H). Cl-LCMS m/z 268 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(O)C.O.Br[CH2:18][CH2:19][CH2:20][OH:21]>O.ClCCl>[N:7]1([CH2:18][CH2:19][CH2:20][OH:21])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: OCCCBr
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: OCCCN1CCCCC1
Reaction time: 20 h

Procedure:
A solution of potassium carbonate (24.9 g) and piperidine (130 mL) in 1:1 ethanol-water (130 mL) was treated with 3-bromopropan-1-ol (25.0 g). The resulting mixture was stirred vigorously for 20 h. Dichloromethane (200 mL) and water (50 mL) were added and the aqueous phase was extracted with dichloromethane (2×100 mL). The combined organic extracts were dried (magnesium sulfate) and evaporated in vacuo. Kugelrohr distillation of the residue (5-10 mm Hg, 120° C.) gave the title compound as a colorless oil (13.9 g).
Reaction SMILES: [CH:1]([C:3]([F:10])([F:9])[C:4]([F:8])([F:7])[CH:5]=[CH2:6])=[CH2:2].[Cl:11][SiH:12]([Cl:14])[Cl:13]>C(Cl)Cl.O.Cl.Cl.Cl[Pt](Cl)(Cl)Cl>[Cl:11][Si:12]([Cl:14])([Cl:13])[CH2:2][CH2:1][C:3]([F:10])([F:9])[C:4]([F:8])([F:7])[CH2:5][CH2:6][Si:12]([Cl:14])([Cl:13])[Cl:11]
Reactant: C=CC(F)(F)C(F)(F)C=C
Reactant: Cl[SiH](Cl)Cl
Agent: Cl[Pt](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: FC(F)(CC[Si](Cl)(Cl)Cl)C(F)(F)CC[Si](Cl)(Cl)Cl
Temperature: 40 °C
Yield: 96 %

Procedure:
1,2-Diethenyltetrafluoroethane (1 g, 6.5 mmol) and 4 mg of hydrogen hexachloroplatinate (IV) hydrate were dissolved in dried CH2Cl2 (15 mL). Trichlorosilane (10 mL, 9.9 mmol) was added dropwise to the stirred solution. The reaction mixture was heated at 40° C. overnight, followed by removal of excess HSiCl3 and solvent by vacuum evaporation. The crude product was recovered in a yield of greater than about 96% (2.6 g). 1H NMR (400 Mz, CDCl3): δ 2.4 (m, 4H), 1.4 (m, 4H). 29Si NMR (CDCl3): 14.1 (s). 19F NMR (CDCl3): −115.1 (t, J=12 Hz, 4F).