Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([OH:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:23]2[CH2:22][CH2:21][C:20]([C:17]3[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=3)([OH:26])[CH2:25][CH2:24]2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(OCCCCl)cc1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OC1(c2ccc(Cl)cc2)CCN(CCCOc2ccc(F)cc2)CC1

Procedure:
A mixture of 2.83 g of 1-chloro-3-(p-fluorophenoxy)-propane, 3.18 g of 4-(p-chlorophenyl)-4-hydroxypiperidine, 0.8 g of sodium carbonate and 60 ml of dimethylformamide is heated at a temperature of 80° - 90°C for 10 hours. After cooling, the reaction mixture is poured into water. The precipitate is collected by filtration and dried to give 1-[3-(p-fluorophenoxy)-propyl]-4-(p-chlorophenyl)-4-hydroxypiperidine, M.P. 134 - 135°C. Recrystallization from benzene gives the purified product, M.P. 136° - 137°C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][CH:8](OCC)[O:9]CC.O>C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][CH:8]=[O:9]
Reactant: CCOC(C#CCCCCCl)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=CC#CCCCCCl
Temperature: 62.5 °C
Yield: 95 %

Procedure:
In a reactor equipped with a stirrer, a cooling condenser, a dropping funnel and a thermometer were placed 7-chloro-1,1-diethoxy-2-heptyne (218.7 g:1.0 mol), para-toluenesulfonic acid (8.0 g:0.05 mol), water (170.0 g) and tetrahydrofuran (42.0 g), and stirred at a reaction mixture temperature of from 60 to 65° C. During stirring, the pressure in the reactor was reduced gradually to 26.7 KPa to distill off refluxing ethanol. After stirring for 5 hours, completion of the reaction was confirmed by gas chromatography. The organic phase separated from the aqueous phase of the reaction mixture was washed with a solution of sodium chloride (5.0 g) in water (150.0 g). The organic phase was subjected to removal of the solvent under reduced pressure, and then the residue was distilled under reduced pressure to obtain 7-chloro-2-heptynal [bp: 66-72° C./0.13 KPa, 137.8 g, 0.95 mol]. [Yield: 95.3%]
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH:4]=[CH:3][CH2:2]1.[H][H]>CO.[Pd]>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: COC(=O)c1ccc2c(c1)OCC=C2
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)OCCC2
Yield: 37.2 %

Procedure:
A mixture of methyl 2H-chromene-7-carboxylate (372 mg, 1.96 mmol) and 10% Pd/C (25 mg) in methanol (15 mL) is stirred under 1 atm of hydrogen at rt for 3 h. The mixture is filtered through Celite and the filtrate is concentrated to a yellow residue. The crude product is purified by flash chromatography on SiO2. Elution with hexanes-EtOAc (95:5) gives 140 mg (37%) of methyl chromane-7-carboxylate as a clear oil: 1H NMR (400 MHz, CDCl3) δ 7.51, 7.47, 7.10, 4.23, 3.91, 2.85, 2.04.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([O:9][CH2:10][C:11]1[N:12]([CH2:24][C:25]2([C:28]([OH:30])=O)[CH2:27][CH2:26]2)[C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:23]=1)[CH3:8]>ClCCl.CN(C=O)C>[CH2:7]([O:9][CH2:10][C:11]1[N:12]([CH2:24][C:25]2([C:28]([Cl:4])=[O:30])[CH2:27][CH2:26]2)[C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:23]=1)[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(C(=O)O)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(C(=O)Cl)CC1
Reaction time: 2 h

Procedure:
Oxalyl chloride (1.6 mL, 18 mmol) was added dropwise over a period of 5 minutes to a suspension of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-C]quinolin-1-yl]methyl}cyclopropanecarboxylic acid (2.0 g, 6.2 mmol) in dichloromethane (50 mL) containing one drop of DMF. The reaction mixture was stirred for two hours and then concentrated under reduced pressure to provide 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopropanecarbonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:15]3[N:14]=2)[CH:7]=1.[Cl-].[NH4+:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH2:31])=[O:23])=[C:15]3[N:14]=2)[CH:7]=1
Reactant: [NH4+]
Reactant: COCCOc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Agent: [Cl-]
Product: COCCOc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(N)=O)c2n1
Yield: 55 %

Procedure:
Prepared by the method described in Example 76, Step F using (R)-5-(2-(5-fluoro-2-(2-methoxyethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and ammonium chloride to yield the title compound as a white solid (32.6 mg, 55% yield). MS (apci) m/z=400.1 (M+H).
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][CH2:7][C:8]1[S:9][CH:10]=[C:11]([CH3:13])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.CN(C)[CH:29]=[O:30]>>[Si:5]([O:6][CH2:7][C:8]1[S:9][C:10]([CH:29]=[O:30])=[C:11]([CH3:13])[CH:12]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:15])[CH3:14]
Reactant: Cc1csc(CO[Si](C)(C)C(C)(C)C)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)sc1C=O

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 10 (10b) using t-butyl(dimethyl) [(4-methyl-2-thienyl)methoxy]silane (2.5 g, 10 mmol) that was obtained in Example 11 (11a), 1.6 M solution of n-butyllithium in hexane (7.8 mL, 12 mmol), and N,N-dimethylformamide (1.6 mL, 21 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 5:95) as the eluent to afford the title compound (2.5 g) in a yield of 89% as a pale yellowish oily product.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][C:10]1[N:11]=[CH:12][NH:13][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]I.CN(C=O)C>[CH3:9][C:10]1[N:11]=[CH:12][N:13]([C:2]2[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)[CH:14]=1
Reactant: Nc1ccc(I)cn1
Reactant: Cc1c[nH]cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(N)nc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a seal tube charged with 5-iodopyridin-2-amine 143-1 (1.1 g, 5 mmol), 4-methyl-1H-imidazole 143-2 (0.61 g, 7.4 mmol), CuI (0.31 g, 1.63 mmol) and Cs2CO3 (3.25 g, 10 mmol) was added DMF (10 mL). The reaction vessel was flushed with nitrogen and sealed. The reaction was stirred at room temperature for 30 minutes before being heated up to 110° C. for 24 hours. The reaction was diluted into ethyl acetate and the salt was removed by filtration. The filtrate was dried and the residue was purified by silica gel flash chromatography, eluted with 10% methanol in ethyl acetate to give 5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine 143-3 as off-white solid. MS m/z 175.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[C:19]([O:24][CH3:25])[CH:18]=4)[N:11]([C@H:26]([C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34]CC)=[O:33])=[CH:30][CH:29]=3)[CH3:27])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[C:19]([O:24][CH3:25])[CH:18]=4)[N:11]([C@H:26]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:37][CH:38]=3)[CH3:27])[N:10]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2cnc3cc(OC)ccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2cc(-c3cc(-c4cc(Cl)cc(Cl)c4)nn3[C@@H](C)c3ccc(C(=O)O)cc3)cnc2c1

Procedure:
To a solution of the intermediate from step G (67 mg, 0.12 mmol) in 4 mL of 1:1 THF/MeOH was added sodium hydroxide (5N, 1 mL). After stirring the reaction at room temperature for 1 hour it was concentrated in vacuo to remove THF/MeOH. The resulting aqueous mixture was acidified with 1N HCl until the pH was slightly acidic (pH=5). The resulting solution was extracted with EtOAc (3×), and the combined organic layers were then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting white solid was used without further purification.
Reaction SMILES: S(=O)(=O)(O)N.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([N+:16]([O-:18])=[O:17])=[C:12]([CH:15]=1)[CH:13]=[O:14].CC(C)=[O:21].O.Cl([O-])=O.[Na+]>O>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([N+:16]([O-:18])=[O:17])=[C:12]([CH:15]=1)[C:13]([OH:21])=[O:14]
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1
Reactant: CC(C)=O
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sulfamic acid (15.73 g, 0.162 mol) is added to a solution of 5-methoxy-2-nitrobezaldehyde (19.6 g, 0.108 mol) in an acetone/water (1:1) mixture. Sodium chlorite (18.31 g, 80% real, 0.162 mol) is then added to the reaction mixture at a rate which maintains the reaction mixture temperature below 40° C. The resultant reaction mixture is stirred at room temperature for 24 hours and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with 2N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1.[C:21]1([CH3:29])[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH2:29][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)[CH2:10]1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCNC2)c(Cl)c1
Reactant: Cc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3cccc(C)c3)C2)c(Cl)c1
Temperature: 27.5 °C
Reaction time: 15 h
Yield: 83.1 %

Procedure:
A mixture of ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate (0.73 g), m-tolualdehyde (356 mg) and sodium triacetoxyborohydride (1.57 g) in CH2Cl2 (30 ml) was stirred at 25-30° C. for 15 hours. The 10% K2CO3 solution (20 ml) was added to a reaction mixture and resultant mixture was stirred at ambient temperature for 30 minutes and extracted with CH2Cl2 and washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (97:3). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2E)-3-(5-chloro-6-{[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (820 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([N:22]([CH3:24])[CH3:23])=[CH:19][CH:20]=3)[O:15][CH:14](N3CCOCC3)[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:42](Cl)(=[O:44])C.C(=O)(O)[O-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([N:22]([CH3:23])[CH3:24])=[CH:19][CH:20]=3)[O:15][CH:14]([O:44][CH3:42])[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: COc1cc(C2CC(N3CCOCC3)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Reactant: CC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1cc(C2CC(OC)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A mixture of [4-(3-bromo-4,5-dimethoxyphenyl)-2-morpholin-4-yl-chroman-7-yl]-dimethyl-amine (10 mg; 0.021 mmol) and p-toluene sulphonic acid (8 mg) in methanol (1 ml) was stirred overnight at room temperature. The mixture was cooled to 0° C. Acetyl chloride (10 μl) was added and the reaction was stirred at room temperature for 0.5 h. TLC showed formation of product. Another 10 μl of acetyl chloride was added at 0° C., and the mixture was stirred for 0.5 h at room temperature. It was neutralized with saturated sodium bicarbonate and extracted with dichloromethane. The extract was washed with saturated sodium chloride solution, dried and evaporated. The title compound was obtained by passing the crude product through a bond-elute (hexane:ethyl acetate=9:1 as eluent) (yield: 51%). 1H NMR (acetone-d6): 7.00, 6.99, 6.97 and 6.93 (d each, J=1.8 Hz; 2H), 6.54 (t, J=9.6 Hz; 1H), 6.28-6.31 (two doublets overlapped, J=8.5 Hz; fine splitting J=2.2 Hz; 1H), 6.22-6.23 (two doublets, J=3.3 Hz; 1H), 5.18 (t, J=2.5 Hz) and 5.12 (dd, J=2.4, 7.8 Hz) (1H), 4.08-4.15 (m, 1H), 3.87, 3.84, 3.80 and 3.79, (s each, 6H), 3.53 and 3.47 (s each, 3H), 2.91 and 2.90 (s each, 6H), 2.29-2.35 (m) and 1.98-2.19 (m, overlapping with acetone signal) (2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[CH2:23]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](=[O:35])[C:27]1=[O:36])[C:24]#[CH:25]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:25]#[C:24][CH2:23][N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28](=[O:35])[C:27]3=[O:36])[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: C#CCN1C(=O)C(=O)c2ccccc21
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Solvent: CCOC(C)=O
Product: Cc1nnc2n1-c1sc(C#CCN3C(=O)C(=O)c4ccccc43)cc1C(c1ccccc1Cl)=NC2

Procedure:
This compound was prepared as described in Example 37 by coupling of 4-(2-chlorophenyl)-2-iodo-9-methyl 6H-thieno[ 3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepine with 1-(2-propynyl)-1H-indole-2,3-dione [ref. A. Lindquist et al., Acta Pharm. Suecica 9, 99 (1972)]. Chromatographic isolation and crystallization from methanol/ethyl acetate gave orange crystals with m.p. 185°-190° C. with foaming at 130°-140° C. These crystals contained according to analytical and spectral data molar amounts of ethyl acetate.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=4)=[CH:13][C:12]3=[O:24])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][CH2:28][C:3]1=2.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:48].Cl>>[ClH:48].[ClH:48].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=4)=[CH:13][C:12]3=[O:24])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:25][NH:26][CH2:27][CH2:28][C:3]1=2
Reactant: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCN(C(=O)OC(C)(C)C)C5)c(=O)c2)nc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCNC5)c(=O)c2)nc1
Yield: 30 %

Procedure:
tert-Butyl 5-methyl-7-(4-(5-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (245 mg, 0.520 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (57 mg, 30%) as a yellow solid: mp 295-305° C.; 1H NMR (500 MHz, CD3OD) δ 8.76 (d, J=1.8 Hz, 1H), 8.34 (d, J=6.9 Hz, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.94 (d, J=7.2 Hz, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.61 (d, J=1.7 Hz, 1H), 7.23 (d, J=1.8 Hz, 1H), 7.17 (dd, J=8.3, 1.8 Hz, 1H), 7.04 (dd, J=7.1, 2.1 Hz, 1H), 4.53 (s, 2H), 3.79 (s, 3H), 3.71 (t, J=6.2 Hz, 2H), 3.25 (t, J=6.2 Hz, 2H), 2.61 (s, 3H); ESI MS m/z 371 [M+H]+; HPLC (Method B) 97.3% (AUC), tR=10.9 min.
Reaction SMILES: C([S:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:12]([CH2:28][S:29][CH:30]([F:32])[F:31])[CH2:11]1)(=O)C1C=CC=CC=1.C[O-].[Na+].CO.C(O)(=O)C>CO.O1CCCC1>[F:32][CH:30]([F:31])[S:29][CH2:28][C@@H:12]1[CH2:11][C@H:10]([SH:9])[CH2:14][N:13]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16]
Reactant: O=C(S[C@H]1C[C@@H](CSC(F)F)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](S)C[C@H]1CSC(F)F
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of (2S,4S)-4-benzoylthio-2-(difluoromethyl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.0 g) in a mixture of methanol (10 ml) and tetrahydrofuran (10 ml) was added 28% sodium methoxide-methanol solution (0.52 ml) under an atmosphere of nitrogen at 2°-5° C. The mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added glacial acetic acid (1 ml) and the mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (50 ml). The solution was washed twice with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (80 g) eluting with a mixture of n-hexane and ethyl acetate (2:1, V/V). The fractions containing the desired compound were collected and concentrated under reduced pressure to give (2S, 4S)-2-(difluoromethyl)thiomethyl-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.58 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[C:26](=O)[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(O)(C(F)(F)F)=O.C([BH3-])#N.[Na+]>C(O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCC(=O)c1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 20 °C
Reaction time: 96 h
Yield: 51.5 %

Procedure:
To a solution of ethyl 4-{7-[5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl]-1H-indol-3-yl}-4-oxobutanoate (D52) (300 mg) and TFA (5 mL) in ethanol (15 mL) and DCM (15 mL) was added sodium cyanoborohydride (235 mg) in portions. The reaction mixture was stirred at 20° C. for 4 days. The mixture was diluted with DCM (30 mL) and washed with water. The organic phase was separated and dried over anhydrous sulphate. After filtration, the solvent was evaporated to give the crude product, which was purified by preparative TLC separation to afford ethyl 4-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]butanoate (D53) as a white solid (150 mg). MS (ES): C25H26ClN3O4 requires 467; found 468.2 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][C:10](=[O:13])[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].[CH3:16]I>CS(C)=O.O>[CH3:16][N:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=2[O:11][C:10]1=[O:13]
Reactant: O=c1[nH]c2cccc([N+](=O)[O-])c2o1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cn1c(=O)oc2c([N+](=O)[O-])cccc21
Reaction time: 16 h
Yield: 84.7 %

Procedure:
3.94 g (21.9 mmol) of 7-nitro-2-benzoxazolinone (for preparation of the latter compound, and European patent EPO189612 and references cited therein) were dissolved in 40 ml of DMSO after which 1.72 g of 85% powdered KOH (26.2 mmol) were added. While stirring and cooling (water) 3.72 g (26.2 mmol) of MeI dissolved in 6 ml of DMSO, were added dropwise over a period of 10 minutes. Stirring was continued at room temperature for 16 hrs, during the latter period an extra amount of MeI (0.5 g) was added. After the reaction was completed, the reaction mixture was diluted with water after which extraction took place with CH2Cl2. The combined organic fractions were washed with respectively water and brine after which the organic fraction was dried on MgSO4. After removal of the drying agent and evaporation of the solvent in vacuo, 4.1 g of a solid residue was left. Flash column chromatography (SiO2, eluent: CH2Cl2) of the latter yielded 3.6 g (85%) of pure 3-methyl-7-nitro-2-benzoxazolinone.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][CH:5]=[C:6]([C:8](=[O:11])[CH2:9]Br)[N:7]=1.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH:24][CH2:25][CH2:26]O)[CH3:23])=[CH:17][CH:16]=1>>[OH:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH:22]([N:24]2[CH2:25][CH2:26][O:11][CH:8]([C:6]3[N:7]=[C:3]([C:2]([F:13])([F:12])[F:1])[S:4][CH:5]=3)[CH2:9]2)[CH3:23])=[CH:19][CH:20]=1
Reactant: CC(Cc1ccc(O)cc1)NCCO
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Product: CC(Cc1ccc(O)cc1)N1CCOC(c2csc(C(F)(F)F)n2)C1

Procedure:
Prepared by analogy to Example 22 by reaction of 2-trifluoromethyl-4-bromoacetyl-thiazole with N-[2-(4-hydroxyphenyl)-1-methylethyl]-2-hydroxyethanamine followed by purification of the base on a silica gel column using chloroform/ethyl acetate=3:1 as eluant.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[F-:10].[K+]>COCCOCCOCCOCCOC.C1OCCOCCOCCOCCOCCOC1>[F:10][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1
Reactant: CSc1nccc(Cl)n1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: COCCOCCOCCOCCOC
Agent: [K+]
Product: CSc1nccc(F)n1
Temperature: 150 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
To a solution of 35.7 g (0.22 mol) of 4-chloro-2-methylthiopyrimidine (Aldrich Chemical Co., Milwaukee, Wis., USA) in 135 mL of tetraglyme was added 18-crown-6 (1.33 g) and potassium fluoride (Anhydrous, Aldrich Chemical Co., Milwaukee, Wis., USA, 80 g). The mixture was heated at 150° C.with stirring for 16 hours. The mixture was then cooled and distilled under reduced pressure to give 20 g (62%) of 4-fluoro-2-methylthiopyrimidine as a liquid.
Reaction SMILES: [OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:6]=1)([CH3:4])[CH3:3].[CH:16]([Mg]Br)([CH3:18])[CH3:17].Cl>O1CCOCC1.O1CCCC1.[Cu]I>[OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]([CH:11]([C:12]#[N:13])[C:14]#[N:15])[CH:16]([CH3:18])[CH3:17])[CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)[Mg]Br
Reactant: CC(C)(O)c1cc(C=C(C#N)C#N)no1
Agent: [Cu]I
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)C(c1cc(C(C)(C)O)on1)C(C#N)C#N
Reaction time: 1 h

Procedure:
1.02 g of {[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]methylidene}malononitrile was dissolved in 50 ml of 1,4-dioxane. Thereto, 0.05 g of copper(I) iodide was added and 15 ml of a 1 M solution of i-propylmagnesium bromide in tetrahydrofuran was then added under ice-cooling. The mixture was stirred for 1 hour under ice-cooling. The reaction mixture was added to 0.1 M hydrochloric acid and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.40 g of {1-[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]-2-methylpropyl}malononitrile.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:11]=1[C:12]([CH2:14][CH2:15][C:16](OC)=[O:17])=O)([CH3:4])([CH3:3])[CH3:2].O.[NH2:27][NH2:28]>>[C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:11]=1[C:12]1[CH2:14][CH2:15][C:16](=[O:17])[NH:27][N:28]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: COC(=O)CCC(=O)c1cc(C)ccc1OCC(O)CNC(C)(C)C
Solvent: O
Product: Cc1ccc(OCC(O)CNC(C)(C)C)c(C2=NNC(=O)CC2)c1

Procedure:
Methyl 3-[2-(3-t-butylamino-2-hydroxypropoxy)-5-methylbenzoyl]propionate was cyclised with hydrazine hydrate in a similar manner to the procedure described in Example 2 (ii) to give 6-[2-(3-t-butylamino-2-hydroxypropoxy)-5-methylphenyl]-4,5-dihydro-3(2H)-pyridazinone, m.p. 126°-127.5°. The hydrochloride had m.p. 206.5°-209.5°.