Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18][S:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[N:17]=1>ClCCl.CN(C)C=O>[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18][S:19]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)=[O:9])[N:17]=1
Reactant: Nc1ccc(SCc2csc(N)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1ccc(S(=O)Cc2csc(N)n2)cc1
Yield: 86.3 %

Procedure:
A solution of 3-chloroperbenzoic acid (4.9 g) in dichloromethane (100 ml) was dropwise added to a solution of 2-amino-4-(4-aminophenylthiomethyl)thiazole (5.1 g) in a mixture of dichloromethane (200 ml) and N,N-dimethylformamide (10 ml) at 5° C. with stirring. The mixture was stirred at 5° C. for 1.5 hours with stirring. The precipitates were collected by filtration, washed with ethyl acetate and dried in vacuo to give solid. The solid was recrystallized from ethanol to give 2-amino-4- (4-aminophenylsulfinylmethyl)thiazole (4.70 g, yield: 86.3%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH:13]1[CH2:21][OH:22]>N1C=CC=CC=1.C1CCCCC1>[O:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH:13]1[CH2:21][O:22][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: OCC1Cc2ccccc2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCCCC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 79 %

Procedure:
p-Toluenesulphonyl chloride (26.7 g, 140 mmol) was added to a solution of (2,3-dihydro-benzofuran-2-yl)-methanol (preparation 96) (21 g, 140 mmol) in pyridine (400 mL) and the mixture was stirred at room temperature for 4 days. The reaction mixture was then concentrated in vacuo and the residue was azeotroped with toluene, diluted with ethyl acetate (500 mL) and washed with 2M hydrochloric acid (2×300 mL). The organic solution was dried over magnesium sulfate and concentrated in vacuo to give a brown oil. Trituration of the oil in cyclohexane then afforded the title compound as a white solid in 79% yield, 33.5 g. LRMS APCI m/z 305 [M+H]+
Reaction SMILES: Cl.[Br:2][C:3]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6]2[N:7]([CH:13]([CH3:15])[CH3:14])[C:8]([CH2:10][CH2:11]Cl)=[N:9][C:5]=2[CH:4]=1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O>C(OCC)(=O)C>[Br:2][C:3]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6]2[N:7]([CH:13]([CH3:15])[CH3:14])[C:8]([CH2:10][CH2:11][N:31]3[CH2:32][CH2:33][N:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:29][CH2:30]3)=[N:9][C:5]=2[CH:4]=1
Reactant: CC(C)n1c(CCCl)nc2cc(Br)c3ccccc3c21
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Solvent: CCOC(C)=O
Product: CC(C)n1c(CCN2CCN(c3ccccc3)CC2)nc2cc(Br)c3ccccc3c21

Procedure:
By following the procedure described in Example 16 but condensing 5-bromo-2-(2-chloroethyl)-1-(1-methylethyl)-1H-naphth[1,2-d]imidazole hydrochloride with 1-phenylpiperazine, the compound of the title is obtained. M.p. 211°-213° C. (from ethyl acetate). The corresponding citrate melts at 169°-171° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CO.[H][H]>[Pd].O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COc1ccc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(c3ccc(N)cc3)CC2)cc1
Yield: 74 %

Procedure:
A mixture of 12 parts of 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine, 200 parts of methanol and 225 parts of tetrahydrofuran is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and washed with N,N-dimethylacetamide. The filtrate is poured onto water. The precipitated product is filtered off and crystallized from 1-butanol, yielding 8 parts (74%) of 4-[4-(4-methoxyphenyl)-1-piperazinyl]benzenamine; mp. 191.8° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C:26]1([CH2:32][C:33]([OH:35])=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C[O-].[Na+].Cl>CN(C=O)C.O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C:26]2([CH2:32][C:33]([OH:35])=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:4])[N:6]=1)#[N:24]
Reactant: NC1(CC(=O)O)CCCCC1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1nc(C(=O)NC2(CC(=O)O)CCCCC2)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 20000 %

Procedure:
To a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.3 μmol) and (1-amino-cyclohexyl)-acetic acid (245 mg, 1.56 mmol) (Matrix Scientific, Columbia S.C.) in 3 mL of DMF was added NaOMe solid (67 mg, 1.25 mmol). The resultant mixture was heated in a 150° C. oil bath for 7 h. Reaction mixture was diluted with water (100 mL) and acidified by 1 N HCl to pH=3-4. Precipitate was collected, dried and the purified by silica gel chromatography, eluting with 10-70% EtOAc/hexanes to provide the title compound 27 mg (0.06 mmol) in 19% yield. LC-MS ESI−: 443.95 (M−1)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[O:20](C(C(F)(F)F)=O)[C:21]([C:23]([F:26])([F:25])[F:24])=O.Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:21](=[O:20])[C:23]([F:26])([F:25])[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (10 g, 53.69 mmol) and pyridine (8.7 mL, 107.57 mmol) in CH2Cl2 (100 mL) was added dropwise (CF3CO)2O (10.5 mL, 75.54 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 2 h. 2N HCl (60 mL) was then added. The organic layer was dried over MgSO4, filtered, and then concentrated. The resulting residue, the title compound, was used in the next reaction without further purification. MS m/z (MH+-Boc) 183.1, (MH+—C4H9) 227.1; 1H NMR (300 MHz, CDCl3): δ 3.45-3.7 (m, 8H), 1.5 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([F:32])[C:3]=1[CH2:4][NH:5][C:6]1[C:11]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34].C(N(CC)CC)C.ClC1C=CC=C(F)C=1CN1C2C=CC=CC=2S(=O)(=O)N(C2C=CC(=O)N(C)C=2)C1=O>>[F:1][C:2]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([F:32])[C:3]=1[CH2:4][N:5]1[C:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:11]=2[S:12](=[O:13])(=[O:14])[N:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:33]1=[O:34]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(F)c(CNc2ncccc2S(=O)(=O)Nc2ccc(OC)c(OC)c2)c(F)c1
Agent: Cn1cc(N2C(=O)N(Cc3c(F)cccc3Cl)c3ccccc3S2(=O)=O)ccc1=O
Solvent: CCN(CC)CC
Product: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3cccnc32)c(F)c1
Yield: 41.9 %

Procedure:
The title compound (89 mg, 0.18 mmol) was prepared from 2-[(2,6-difluoro-4-methoxybenzyl)amino]-N-(3,4-dimethoxyphenyl)pyridine-3-sulfonamide (198 mg, 0.43 mmol), 1,1′-carbonyldiimidazole (279 mg, 1.72 mmol) and triethylamine (0.12 mL, 0.86 mmol) using the methods of (132).
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]1([CH:18]=CC=[C:14](O)[CH:13]=1)[OH:12]>S(=O)(=O)(O)O>[Cl:1][CH2:2][C:3]1[C:9]2[C:8](=[CH:18][C:11]([OH:12])=[CH:13][CH:14]=2)[O:7][C:5](=[O:6])[CH:4]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Oc1cccc(O)c1
Agent: O=S(=O)(O)O
Product: O=c1cc(CCl)c2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
Under ice-cooling, ethyl 4-chloroacetoacetate (14.0 g, 85.0 mmol) was dissolved in concentrated sulfuric acid (30 mL), resorcinol (8.81 g, 80.0 mmol) was added by small portions, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into ice water, and the precipitated solid was collected by filtration, washed with water, and air-dried to give the title compound (14.1 g, yield 84%) as a beige powder.
Reaction SMILES: [NH:1]1[CH:5]2[C:6]3[N:11]([CH2:12][CH2:13][CH:4]2[S:3][CH:2]1NC)[CH2:10][CH:9]=[CH:8][CH:7]=3.Cl.N1C2C3N(CCC2SC1N(C)S(N(C)C)(=O)=[O:32])CC=CC=3>>[NH:1]1[CH:5]2[C:6]3[N:11]([CH2:12][CH2:13][CH:4]2[S:3][C:2]1=[O:32])[CH2:10][CH:9]=[CH:8][CH:7]=3
Reactant: CN(C)S(=O)(=O)N(C)C1NC2C3=CC=CCN3CCC2S1
Reactant: CNC1NC2C3=CC=CCN3CCC2S1
Agent: Cl
Product: O=C1NC2C3=CC=CCN3CCC2S1

Procedure:
Following the procedures substantially as described in Example 1, Steps F and G but substituting for the quinolizin-2-one used therein, an equimolar amount of the quinolizin-2-one from Step G of this Example 13, there are produced in sequence: (2RS,10bSR)-N-(1,3,4,6,7,10b-hexahydro-2H-thiazolo[4,5-a]quinolizin-2-yl)-N-methylamine; and (2RS,10bSR)-N-(1,3,4,6,7,10b-hexahydro-2H-thiazolo[4,5-a]quinolizin-2-yl)-N,N',N'-trimethylsulfamide, hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH2:15][CH3:16])[CH:8]=1)[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH:36]2[CH2:38][CH2:37]2)=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:19][C:20]2[C:21]([CH:36]3[CH2:38][CH2:37]3)=[N:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:30][CH:31]=3)=[N:24][CH:25]=2)=[C:9]([O:14][CH2:15][CH3:16])[CH:8]=1)[CH3:2]
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(OCC)c1
Product: CCOC(=O)CCc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c(OCC)c1

Procedure:
In analogy to the procedures described in examples 8A] and 31B], 3-(3-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl ester [Eur. Pat. Appl. (1996), EP 710659/A1] was reacted with 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) to give 3-{4-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-3-ethoxy-phenyl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][CH:6]1Br)(=[O:3])[CH3:2].[OH:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(#N)C.[O-2].[Zn+2]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Reactant: N#Cc1ccc(O)cc1
Agent: [O-2]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(C#N)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 35 %

Procedure:
A suspension of 0.5 g (1.4.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide, 0.25 g (2.1.10-3 mol) of 4-hydroxybenzonitrile and 170 mg (2.1.10-3 mol) of zinc oxide (ZnO) in 4 ml of anhydrous toluene and 4 ml of acetonitrile is stirred at 50° C., under an inert atmosphere, in the presence of a molecular sieve (1 nm), for 48 h. The reaction medium is subsequently filtered on Celite® in ethyl acetate and then washed with a 1N aqueous solution of hydrochloric acid, water, a 1N solution of sodium hydroxide and then a saturated solution of NaCl. The solution obtained is dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The residue obtained is purified by chromatography on silica gel using a hexane/ethyl acetate mixture (2/1 v/v) as the eluent to give 194 mg (yield: 35%) of the expected product.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:10].[C:25](Cl)(=[O:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].C(Cl)Cl>O1CCCC1>[C:25]([NH:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:10])(=[O:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: NCC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)NCC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium acetate (50% in water, 29 ml) was added in three portions to a stirred solution of 2-amino-4′-benzyloxyacetophenone HCl (4.6 g, 17 mmol) and tetrahydrofuran (200 ml). Palmitoyl chloride (19 mmol) in tetrahydrofuran (25 ml) was added dropwise over 20 min yielding a dark brown solution. The mixture was stirred overnight at room temperature. The aqueous fraction was removed by use of a separatory funnel and chloroform/methanol (2/1, 150 ml) was added to the organic layer which was then washed with water (50 ml). The yellow aqueous layer was extracted once with chloroform (50 ml). The organic solutions were then pooled and rotoevaporated until near dryness. The residue was redissolved in chloroform (100 ml) and crystallized by the addition of hexane (400 ml). The flask was cooled to 4° C. for 2 h. The crystals were filtered and washed with cold hexane and dried in a fume hood overnight. The product yield was 3.79 g (8 mmol). An Rf of 0.21 was observed when resolved by thin layer chromatography using methylene chloride. [M+H]+: 479 for C31H45NO3. 1H nmr (δ, ppm, CDCl3), 7.96 (2H, δ, 8.8 Hz, O—Ar—C(O)), 7.40 (5H, m, Ar′CH2O—), 7.03 (2H, δ, 8.8 Hz, O—Ar—C(O)), 6.57 (1H, bs, NH2), 5.14 (2H, s, Ar′CH2O—), 4.71 (2H, s, C(O)CH2NHC(O)), 2.29 (2H, t, 7.4 Hz, C(O)CH2(CH2)13CH3), 1.67 (2H, m, C(O)CH2(CH2)13CH3), 0.87 (3H, t, 6.7 Hz, C(O)CH2(CH2)13CH3).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:8]=[N:9][N:10]=2)[CH:5]=[CH:6][N:7]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.O=[Si]=O.[OH-].[Na+]>C(Cl)Cl.O>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[C:3]3[N:4]([N:8]=[N:9][N:10]=3)[CH:5]=[CH:6][N:7]=2)[CH2:14][CH2:13]1
Reactant: Clc1nccn2nnnc12
Reactant: CN1CCNCC1
Agent: O=[Si]=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CN1CCN(c2nccn3nnnc23)CC1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
8-Chlorotetrazolo[1,5-a]pyrazine (100 g, 0.643 mol, 1 eq.) was suspended in methylene chloride (650 ml) and cooled to 3-7° C. under nitrogen. 1-Methylpiperazine (156 g, 1.56 mol, 2.42 eq) was added at such a rate that the temperature of the reaction mixture was maintained at 3-7° C. The mixture is stirred at approximately 10° C. for 15 minutes after which time conversion to product was ≧99%. Celite 545 (40 g) and water (260 g) were added and the pH of the suspension adjusted to 9.5-9.8 by the addition of 27% sodium hydroxide, with the temperature maintained range at 3-7° C. The suspension was filtered on a pad of Celite 545, and the filter cake washed with methylene chloride. The filtrate was separated into an organic and aqueous phase. The aqueous phase was washed with methylene chloride. The organic phases are washed twice with aqueous sodium hydroxide. The organic phases were combined, and dried over magnesium sulfate prior to addition of activated carbon (pH 8-10). The mixture was filtered on a pad of Celite 545 and the filtered cake washed with methylene chloride. The filtrate was concentrated at reduced pressure and crystallization induced by slow addition of heptane, with further concentration and seeding as necessary. The resulting crystal suspension is cooled to 10-15° C., filtered, washed with n-heptane and dried under vacuum at 27-33° C. to afford the product as a buff coloured solid (114.6 g, 81% yield).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]1[CH:26]([CH:27]=[CH:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:25][CH2:24][CH:23]1[OH:36]>CC(C)=O.O.[Cr]>[O:36]=[C:23]1[CH2:24][CH2:25][CH:26]([CH:27]=[CH:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:22]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]([OH:3])=[O:14]
Reactant: CCCCCC(=O)C=CC1CCC(O)C1CCCCCCCO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: [Cr]
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCC(=O)C=CC1CCC(=O)C1CCCCCCC(=O)O
Reaction time: 1 h
Yield: 26 %

Procedure:
8N Jones' reagent (3.24 ml.; J. Chem. Soc., 1953, 461) was added to a stirred solution of 2-(7-hydroxyheptyl)-3-(3-oxo-1-octenyl)cyclopentanol (1.4 g., 0.0043 mole) in acetone (10 ml.) at 15°-25°C., at a rate such that the deep red coloration caused by the addition of one drop of reagent had changed to green before addition of the next drop. The reaction mixture was diluted with sufficient water to dissolve the precipitated chromium salts, and was then extracted three times with diethyl ether. The combined ether extracts were washed with 2N aqueous sulphuric acid and then added to 10% aqueous sodium carbonate (100 ml.) and stirred for 1 hour. The aqueous layer (containing the desired acid as the sodium salt) was separated and washed with diethyl ether. The solution was then covered with a layer of diethyl ether, cooled to below 20°C. and acidified to pH 1 by the dropwise addition of concentrated hydrochloric acid. The ether layer was separated and the aqueous layer was again extracted with diethyl ether. The combined extracts were dried over magnesium sulphate, and the other was removed in vacuo to give the crude acid (0.79 g.). This was purified by preparative thin layer chromatography on silica gel using a 65:15:1 mixture of benzene, dioxane and acetic acid as solvent. Evaporation gave pure 7-[2-oxo-5-(3-oxo-1-octeny)cyclopentyl]heptanoic acid (0.38 g., 26%), λmax 228 mμ, ε 11,600 (ethanol), νmax 1730 cm-1, 1700 cm-1, 1670 cm-1, 1625 cm-1 and 980 cm-1 (liquid film). N.M.R. (approximately 10% solution in deuterochloroform) 0.9 δ(triplet J=5c/s, terminal CH3), 1.2-2.0 δ(overlapping multiplets, cyclic and chain CH2), 2.0-2.8 δ (multiplet CH2C=O), 6.17 δ (doublet J=16c/s, CH=CHC=O) and 6.8 δ (doublet of doublets J=16c/s and ##EQU4##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: O=S(=O)(c1cccc(Cl)c1)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(N2CCC(S(=O)(=O)c3cccc(Cl)c3)CC2)nc1
Yield: 27.6 %

Procedure:
Using the procedure from Example 7A, 4-[(3-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2-chloro-5-nitropyridine (122 mg, 0.76 mmol), DIEA (0.2 ml, 1.14) and 1,4-dioxane (0.3 ml) to afford the title compound (40 mg), a yellow solid, in 28% yield.
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.[CH:8]1([N:12]2[CH:17]=[C:16]([O:18]C)[C:15](=[O:20])[C:14]([C:21]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:24]=[CH:23][CH:22]=3)=[N:13]2)[CH2:11][CH2:10][CH2:9]1.O>C(#N)C>[CH:8]1([N:12]2[CH:17]=[C:16]([OH:18])[C:15](=[O:20])[C:14]([C:21]3[N:25]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:24]=[CH:23][CH:22]=3)=[N:13]2)[CH2:11][CH2:10][CH2:9]1
Reactant: COc1cn(C2CCC2)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=c1c(O)cn(C2CCC2)nc1-c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
To a solution of sodium iodide (2.11 g) in acetonitrile (84.3 mL) was added at room temperature chlorotrimethylsilane (1.78 mL) and the mixture was stirred for 30 min. Then, 1-cyclobutyl-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (0.91 g) was added, and the mixture was stirred at room temperature for 30 min, and further refluxed for 3 hr. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was stirred for 30 min, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with diisopropyl ether, and collected by filtration to give the title compound (800 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([F:9])[C:7]=1F.[NH3:14]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([F:9])[C:7]=1[NH2:14]
Reactant: Fc1cc(C(F)(F)F)cc(F)c1F
Reactant: N
Solvent: C1CCOC1
Product: Nc1c(F)cc(C(F)(F)F)cc1F

Procedure:
In a stainless steel autoclave, 500 g of 3,4,5-trifluoro-benzotrifluoride are introduced, 2,000 ml of tetrahydrofuran are added, and 150 g of liquid ammonia are forced in. The autoclave is heated to 120° to 130° C. for 5 hours with stirring, then cooled, and the pressure is released at 20° C. In addition to the solvent and the starting material, 272 g of 3,5-difluoro-4-amino-benzotrifluoride of a boiling point of 58° to 60° C. at 16 mbar are obtained by distillation.
Reaction SMILES: FC1C=C(CN)C=NC=1.[O:10]1[CH:14]=[CH:13][N:12]=[C:11]1[CH2:15][NH2:16].[CH3:17][C:18]1[N:19]=[C:20]([N:26]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:27]2=[O:38])[S:21][C:22]=1[C:23](O)=[O:24]>>[CH3:17][C:18]1[N:19]=[C:20]([N:26]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34]([F:35])([F:36])[F:37])[C:27]2=[O:38])[S:21][C:22]=1[C:23]([NH:16][CH2:15][C:11]1[O:10][CH:14]=[CH:13][N:12]=1)=[O:24]
Reactant: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)O
Reactant: NCc1ncco1
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)NCc1ncco1
Yield: 58 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with oxazol-2-ylmethanamine to react with 4-methyl-2-(2-oxo-3-(4,4,4-trifluorobutyl)imidazolidin-1-yl)thiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 58% yield: 1H NMR (300 MHz, CDCl3) δ 7.63 (s, 1H), 7.07 (s, 1H), 6.34-6.37 (m, 1H), 4.70 (d, J=5.3 Hz, 2H), 4.16-4.11 (m, 2H), 3.64-3.58 (m, 2H), 3.43-3.39 (m, 2H), 2.63 (s, 3H), 2.21-2.08 (m, 2H), 1.91-1.81 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.4, 160.6, 157.6, 155.6, 153.4, 139.2, 127.2, 117.2, 42.9, 42.3, 42.0, 37.2, 31.7, 31.3, 30.9, 30.6, 20.2, 17.3; MS (ES+) m/z 417.7 (M+1).