Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][CH:21]([C:24]5[N:28]=[C:27]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=6)[NH:26][N:25]=5)[CH2:20][CH2:19]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[O:41]([CH3:43])[Na]>CO>[CH3:43][O:41][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][CH:21]([C:24]5[N:28]=[C:27]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=6)[NH:26][N:25]=5)[CH2:20][CH2:19]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1
Reactant: Clc1ccc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)n2n1
Reactant: CO[Na]
Solvent: CO
Product: COc1ccc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)n2n1

Procedure:
To a suspension of example 31 (0.2 g, 0.366 mM) in 15 mL of methanol is added NaOCH3 (10 eq.) and the reaction mixture is refluxed for 6 h. The reaction mixture is concentrated and quenched with water. The resulting solid is filtered and dried to obtain the desired compound.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N+:11]([O-])([O-:13])=[O:12].[K+]>S(=O)(=O)(O)O>[N+:11]([C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH2:2][C:1]2=[O:10])=[CH:5][CH:6]=1)([O-:13])=[O:12]
Reactant: O=C1CCc2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1CCc2ccc([N+](=O)[O-])cc21
Reaction time: 1 h
Yield: 59.9 %

Procedure:
1-Indanone (5.00 g, 37.8 mmol) was dissolved in sulfuric acid (40 mL), and thereto was added dropwise a solution of potassium nitrate (3.83 g, 37.8 mmol) in sulfuric acid (10 mL) under ice-cooling. The mixture was stirred for 1 hr under ice-cooling, ice was added to the reaction solution, and the mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration, and purified by silica gel column chromatography (ethyl acetate/hexane=15/85→45/55) to give the title compound (4.01 g, yield 60%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[NH:20]1[CH:24]=[CH:23][C:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)=[N:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:23]=[CH:24][NH:20][N:21]=2)=[CH:33][CH:32]=1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc(-c2cc[nH]n2)cc1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(-c2cc[nH]n2)cc1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-(1H-pyrazol-3-yl)-benzoic acid. MS: 430.3 (M+H).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH2:16][CH2:15][C@@H:2]([OH:1])[C@@H:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([C:24]3[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[CH:36][CH:37]=3)=[CH:7][CH:6]=2)[CH3:14])[CH:18]=1
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2ccc(OCCN3CCCC3)cc2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 68.9 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.190 g, Example 33), 1-[2-(4-bromophenoxy)ethyl]pyrrolidine (0.27 g), 2M aqueous sodium carbonate (0.75 ml) and tetrakis(triphenylphosphine)palladium (0) (0.025 g) in ethanol (2 ml). The reaction mixture was heated at 90° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure, taken up in ethanol and concentrated again (twice). The residue was triturated with acetone and then filtered through silica gel. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give an oil which crystallised under high vacuum over 24 hours. Trituration with diethyl ether resulted in isolation of the title compound as a foam (0.194 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([C:16]4[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=4)[CH:14]=3)[N:9](C3CCCCO3)[N:8]=2)[CH:4]=[N:3]1.Cl>CO.O1CCOCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([C:16]4[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=4)[CH:14]=3)[NH:9][N:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc3c(-c4cnn(C)c4)nn(C4CCCCO4)c3cn2)cn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cn1cc(-c2cc3c(-c4cnn(C)c4)n[nH]c3cn2)cn1
Yield: 34.2 %

Procedure:
3,5-bis(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine in methanol was treated with 4M HCl in 1,4-dioxane at 50° C. for 3 h. Volatile solvent was evaporated in vacuo. The resultant residue was purified by reverse phase HPLC to give 163 as a white solid (34.2%). 1H NMR (500 MHz, DMSO) δ 13.35 (s, 1H), 8.96 (s, 1H), 8.47 (s, 1H), 8.29 (s, 1H), 8.15 (s, 1H), 8.10 (d, J=5.6 Hz, 2H), 3.96 (s, 3H), 3.90 (s, 3H). LC/MS: m/z 280.0 [M+1]
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH:10]=[C:11]([C:17]([O:19]CC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6][C:7]=1[CH3:8].C(O)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:19][C:17]1[C:4]2[C:5](=[N:6][C:7]([CH3:8])=[C:2]([I:1])[CH:3]=2)[N:9]=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=CNc1ccc(I)c(C)n1)C(=O)OCC
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2nc(C)c(I)cc2c1O
Temperature: 25 °C
Yield: 52 %

Procedure:
A solution of diethyl 2-{[(5-iodo-6-methyl-2-pyridinyl)amino]methylene}malonate Prep 3(1.09 g) in 20 mL diphenyl ether is heated at 250° C. for 2 h with removal of ethanol via a Dean-Stark trap. The reaction is cooled to room temperature. Hexanes (15 mL) are added and the solid is filtered, washed thoroughly with hexanes, and dried. The crude solid is dissolved in CH2Cl2/MeOH and adsorbed onto silica. Purification by chromatography (eluent CH2Cl2 (1L), 1% MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (2L)) affords the product as a yellow-green solid (0.50 g, 52%). Physical characteristics are as follows: m.p. 275-277° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 12.80, 8.72, 8.47, 4.21, 2.74, 1.27; IR (drift) 2981, 1718, 1606, 1524, 1407, 1376, 1356, 1319, 1291, 1244, 1192, 1185, 1109, 809, 623 cm−1; MS (ESI) m/z 358.9 (M+H)+, 356.9 (M−H)−; Anal. Calcd for C12H11IN2O3: C, 40.24; H, 3.10; N, 7.82; Found: C, 40.15; H, 3.05; N, 7.81.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:12])([F:11])[C:5]([NH:7][CH:8]([CH3:10])[CH3:9])=[O:6].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.O>CN(C=O)C>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][N:7]([CH:8]([CH3:10])[CH3:9])[C:5](=[O:6])[C:4]([F:12])([F:11])[F:3]
Reactant: CC(C)NC(=O)C(F)(F)F
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(CCCCBr)C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 24 %

Procedure:
21 g (520 mmol) of 60% sodium hydride are suspended in 700 ml of anhydrous DMF under an inert atmosphere, and the mixture is cooled to 0° C. 40.5 g (260 mmol) of 2,2,2-trifluoro-N-isopropylacetamide are slowly added portionwise. After 15 minutes, 62 ml (520 mmol) of 1,4-dibromobutane are added. The reaction medium is then heated at 60° C. for 3 hours, and then cooled to room temperature, poured into 1 L of water and extracted with ethyl acetate. The organic phase is washed with water and dried, and the residue obtained is purified by distillation. A colorless oil is obtained (m=0.18 g, yield=24%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[C:20]([CH3:28])[CH:19]=3)[C:9]=2[CH3:29])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[C:20]([CH3:28])[CH:19]=3)[C:9]=2[CH3:29])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(N)(=O)=O)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2c(C(=O)O)sc(-c3ccc(Cl)cc3)c2C)ccc1S(N)(=O)=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
Ethyl 5-(4-chlorophenyl)-4-methyl-3-(3-methyl-4-sulfamoylphenyl)thiophene-2-carboxylate (41c, 0.6 g, 1.33 mmol) was suspended in ethanol (20 ml) and a solution of sodiumhydroxide (0.1 g, 2.66 mmol) in water (2 ml] was added to it at 25° C. The reaction mixture was then heated at 75° C. under stirring for 2 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue so obtained was then diluted with water (5 ml) and the mixture was cooled using ice bath. To the cooled mixture was added 10% aqueous HCl to bring the pH of the mixture between about 5 and 6. The mixture was then extracted with ethyl acetate (2×35 ml). The combined organic layer was then dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain the title compound (0.53 g, 94%).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:12]([O:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH2:12]([O:14][C:15](=[O:19])[CH:16]=[C:17]([O:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH3:18])[CH3:13]
Reactant: Oc1cccc2c1CCCC2
Reactant: CC#CC(=O)OCC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)Oc1cccc2c1CCCC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
A mixture of 5,6,7,8-tetrahydro-naphthalen-1-ol (3.00 g, 20.24 mmol) and ethyl-2-butynoate (13.62 g, 121.46 mmol) in tetrahydrofuran (100 mL) was treated with potassium carbonate (3.10 g, 22.43 mmol) and 4-dimethylaminopyridine (0.26 g, 2.12 mmol). The reaction was then heated at 85° C. overnight. At this time, the reaction was cooled to 25° C. and was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL) and was washed with water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were then dried over magnesium sulfate, filtered, rinsed with ethyl acetate and concentrated in vacuo. The material was taken up in ethyl acetate and absorbed onto silica gel. Purification by Analogix flash chromatography (115 g, 1-10% ethyl acetate/hexanes) afforded 3-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-but-2-enoic acid ethyl ester (3.82 g, 72%) as a light yellow oil: HR-ES-MS m/z calculated for C26H34N4O5 [M+H]+ 483.2602, observed 483.2603; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (t, J=7.1 Hz, 3H), 1.61-1.77 (m, 4H), 2.44 (s, 3H), 2.46 (br. s., 2H), 2.76 (br. s., 2H), 3.98 (q, J=7.1 Hz, 2H), 4.57 (s, 1H), 6.84 (d, J=7.7 Hz, 1H), 7.03 (d, J=7.7 Hz, 1H), 7.18 (t, J=7.7 Hz, 1H).
Reaction SMILES: CC[O:3][C:4]([C:6]1([CH3:17])[CH2:9][CH2:8][N:7]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:5].[OH-].[Na+]>CCO>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][C:6]1([CH3:17])[C:4]([OH:5])=[O:3])=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC(=O)C1(C)CCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC1(C)C(=O)O
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of 2-methyl-azetidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester, Intermediate 11 (1 eq.) in EtOH was added an aqueous solution of 2N NaOH (2 eq.). The reaction was stirred at 20° C. for 15 h. The solvent was removed under reduced pressure and the crude was partitioned between water and EtOAc. The organic layer was discarded and the aqueous layer was acidified by addition of a solution of citric acid 10% in water until pH=3 and thoroughly extracted by EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to afford 2-methyl-azetidine-1,2-dicarboxylic acid 1-tert-butyl ester.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:10])[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]([CH3:22])[C:20]#[N:21]>CN(C)C=O>[CH3:10][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]([CH3:22])[C:20]#[N:21]
Reactant: CN(C#N)c1ccccc1CBr
Reactant: Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1OCc1ccccc1N(C)C#N
Temperature: 20 °C
Reaction time: 0.67 h
Yield: 124.8 %

Procedure:
1 g (0.024 mol) of a 60% sodium hydride suspension is suspended in 10 ml of dimethylformamide and admixed with a solution of 2.2 g (0.02 mol) of ortho-cresol in 10 ml of dimethylformamide, and the mixture is stirred at 20° C. for 40 minutes. A solution of 11.3 g (0.02 mol) of 40% pure N-(2-bromomethylphenyl)-N-methyl-cyanamide in 10 ml of dimethylformamide is added, and the mixture is stirred at 20° C. for 18 hours. The mixture is stirred into 200 ml of ice/sodium chloride solution and extracted with ether. The combined organic phases are dried over Na2SO4 and concentrated under reduced pressure. The residue is chromatographed over silica gel using cyclohexane/ethyl acetate (3:1). 6.3 g of N-[2-(2-methylphenoxymethyl)-phenyl]-N-methyl-cyanamide of a content of 40% (HPLC) are obtained.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:8][NH:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]1[C:15]1([C:18]([OH:20])=O)[CH2:17][CH2:16]1.[NH2:21][C:22]1[CH:23]=[C:24]2[CH2:40][C:29]3([O:34][C:33]4[CH:35]=[CH:36][CH:37]=[N:38][C:32]=4[NH:31][C:30]3=[S:39])[CH2:28][C:25]2=[N:26][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[O:2]=[C:3]1[CH2:8][NH:7][CH:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][N:4]1[C:15]1([C:18]([NH:21][C:22]2[CH:23]=[C:24]3[CH2:40][C:29]4([O:34][C:33]5[CH:35]=[CH:36][CH:37]=[N:38][C:32]=5[NH:31][C:30]4=[S:39])[CH2:28][C:25]3=[N:26][CH:27]=2)=[O:20])[CH2:16][CH2:17]1
Reactant: Nc1cnc2c(c1)CC1(C2)Oc2cccnc2NC1=S
Reactant: O=C1CNC(c2ccccc2)CN1C1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C1CNC(c2ccccc2)CN1C1(C(=O)Nc2cnc3c(c2)CC2(C3)Oc3cccnc3NC2=S)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-(2-oxo-5-phenylpiperazin-1-yl)cyclopropanecarboxylic acid hydrochloride (57 mg, 0.22 mmol) [Wood et al. US 2007/0265225], 3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,2′-pyrido[3,2-b][1,4]oxazine]-3′(4′H)-thione (Intermediate 1, 57 mg, 0.20 mmol) and HATU (84 mg, 0.22 mmol) in DMF (2 mL) is treated with N-methylmorpholine (0.096 mL, 0.88 mmol). The mixture is stirred at rt for 18 h and is then purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and lyophilized to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[F:37][C:38]([F:50])([F:49])[O:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:43]3[CH:42]=[CH:41][C:40]([O:39][C:38]([F:37])([F:49])[F:50])=[CH:45][CH:44]=3)=[CH:24][CH:23]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCCCCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCC(Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Yield: 34.2 %

Procedure:
3-{4-[1-(4-Bromo-phenoxyl)-heptyl]-benzoylamino}-propionic acid methyl ester (isomer 1, 100 mg, 0.21 mmol), potassium carbonate (85 mg, 0.63 mmol), 4-trifluoromethoxylphenyl boronic acid (86 mg, 0.42 mmol) and tetrakis-(triphenylphosphine)palladium (24 mg, 0.021 mmol) are place in a flask. After the reaction is purged with N2 for several times, THF/H2O (20 ml/5 ml) is added. The resulting solution is refluxed overnight, concentrated and acidified by 1 N HCl (0.6 mL), extracted with ethyl acetate. Combined organic layers are washed with water and brine, dried over sodium sulfate, purified by reverse phase HPLC to give the title compound (40 mg). MS (ES): 526.2 [M−H]−.
Reaction SMILES: [CH3:1][C@H:2]1[C@:19]([OH:25])([C:20]([S:22][CH2:23][F:24])=[O:21])[C@:18]2([CH3:26])[C@H:4]([C@H:5]3[C@:15]([F:28])([C@@H:16]([OH:27])[CH2:17]2)[C@:14]2([CH3:29])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[C@@H:7]([F:30])[CH2:6]3)[CH2:3]1>C(O)CCC>[CH3:8][CH2:9][C:10]([O:25][C@@:19]1([C:20]([S:22][CH2:23][F:24])=[O:21])[C@@:18]2([CH3:26])[CH2:17][C@H:16]([OH:27])[C@:15]3([F:28])[C@:14]4([CH3:29])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]4)=[O:11])[C@@H:7]([F:30])[CH2:6][C@H:5]3[C@@H:4]2[CH2:3][C@H:2]1[CH3:1])=[O:11]
Reactant: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)SCF
Solvent: CCCCO
Product: CCC(=O)O[C@]1(C(=O)SCF)[C@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 1 h
Yield: 151 %

Procedure:
The crude fluticasone (10 g) is dissolved in 1-butanol (200 ml) at 115–120° C. Gradually cool to ambient temperature and stirred for 1 hr. The crystallized product is filtered and washed with 1-butanol (10 ml). Dried at 60–62° C. to obtain pure fluticasone propionate (recovery 8.5 g, purity 99.40%).
Reaction SMILES: Br.Br[CH2:3][CH2:4][NH2:5].C(COC)OC.Cl.[CH2:13]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:13]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]2[O:35][CH2:3][CH2:4][N:5]=2)=[CH:32][CH:31]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Reactant: NCCBr
Agent: Br
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCNc1ccc(C2=NCCO2)cc1

Procedure:
To a slurry of 15 g. of 2-bromoethylamine hydrobromide in 150 ml. of glyme was added simultaneously solutions of 31 g. of 4-(hexadecylamino)benzoyl chloride hydrochloride in 60 ml. of glyme and 50 cc. of triethylamine (dropwise). Upon addition of 0.5 g. of 4-dimethylaminopyridine the "solution" was stirred at room temperature overnight. The solution was refluxed for one hour and filtered. The solid was oven dried and portitioned between CH2Cl and water. The layers were separated and the organic phase dried over MgSO4. The organic layer was concentrated to about 100 ml. and 4-(hexadecylamino)benzoyl chloride hydrochloride diluted with an equal volume of hexane. The combined product (4.15 g.) was preabsorbed on 40 g. of silica III and placed on a column of silica III (800 g.). Fractions were collected by U.V. (CH2Cl2 -EtOH 97-3) and samples with the same TLC combined giving 3.8 g. after recrystallization from cyclohexane. A 210 mg. sample was recrystallized from acetonitrile and CH2Cl2 /hexane giving 149 mg., m.p. 123°-125° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:11][S:12][CH2:13]Cl.C(N(CC)CC)C>>[C:1]([O:10][CH2:11][S:12][CH3:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CSCCl
Reactant: CCCCCCCC(=O)O
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)OCSC

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting octanoic acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 90° C./2 mm Hg, nD20 1.4577.
Reaction SMILES: O1[C:5]2([CH2:9][CH2:8][N:7]([C@H:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]3[O:16][CH2:17][CH2:18][C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[CH2:6]2)[O:4]CC1.Cl>CC(=O)CC.O>[ClH:25].[O:4]=[C:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[O:16][CH2:17][CH2:18][C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])[CH2:6]1
Reactant: Clc1cccc(Cl)c1CCO[C@H]1CCCC[C@@H]1N1CCC2(C1)OCCO2
Agent: Cl
Solvent: O
Solvent: CCC(C)=O
Product: O=C1CCN([C@H]2CCCC[C@@H]2OCCc2c(Cl)cccc2Cl)C1

Procedure:
A mixture of (1R,2R)/(1S,2S)-2-[1,4-dioxa-7-azaspiro[4.4]non-7-yl]-1-(2,6-dichlorophenethoxy)cyclohexane (15.85 g, 38.9 mmol, step ix) and 6M HCl aqueous solution (100 mL) in 2-butanone (400 mL) was refluxed for 16 hours. The cooled reaction mixture was diluted with water (100 mL) and the organic solvent was evaporated in vacuo. The organic layer was further diluted with water (400 mL), extracted with diethyl ether (500 mL) and with dichloromethane (2×600 mL). The combined dichloromethane extracts were dried over sodium sulfate and the solvent was evaporated in vacuo. Azeotropic distillation with toluene provided the title compound which was further dried under high vacuum for 15 min. The hydrochloride salt was crystallized by triturating in diethyl ether, the crystals were collected and recrystallized from a mixture of ethanol-diethyl ether to yield 11.85 g of pure product (77% yield), having the elemental analysis indicated in Table 1.
Reaction SMILES: [CH2:1]([N:4]([CH2:9][CH:10]=[CH2:11])[CH2:5][C:6]([OH:8])=O)[CH:2]=[CH2:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:24][C:25]1[C:30]2[C:31](=[O:45])[N:32]3[CH2:44][CH2:43][C@H:33]3[C:34]3[N:35]([CH:36]=[N:37][C:38]=3[C:39](=[N:41]O)[NH2:40])[C:29]=2[CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[CH2:9]([N:4]([CH2:5][C:6]1[O:8][N:41]=[C:39]([C:38]2[N:37]=[CH:36][N:35]3[C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:24])[C:30]=4[C:31](=[O:45])[N:32]4[CH2:44][CH2:43][C@H:33]4[C:34]=23)[N:40]=1)[CH2:1][CH:2]=[CH2:3])[CH:10]=[CH2:11]
Reactant: C=CCN(CC=C)CC(=O)O
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: C=CCN(CC=C)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)no1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 49.2 %

Procedure:
36.5 g (235 mmol) of diallylglycine were dissolved in 165 ml of N,N-dimethylformamide and treated portionwise with 40.5 g (250 mmol) of 1,1'-carbonyldiimidazole. After stirring for 10 minutes 40 g (126 mmol) of (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime were added and the mixture was stirred at room temperature for 1 hour and at 110° for 3.5 hours. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel while eluting with methylene chloride/ethyl acetate 1/1. There were obtained 27.1 g (45%) of (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 181°-182.5°.