Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[NH:14]1[C:22]2[CH2:21][CH2:20][NH:19][CH2:18][C:17]=2[CH:16]=[CH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[NH:14][CH:15]=[CH:16][C:17]=4[CH2:18]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: c1cc2c([nH]1)CCNC2
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2[nH]ccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[C:25]([O:29][C:30](=[O:40])[NH:31][C:32]1[CH:37]=[CH:36][C:35](CO)=[CH:34][N:33]=1)([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:25]([O:29][C:30](=[O:40])[NH:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:20][Br:24])=[CH:34][N:33]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CO)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Temperature: -20 °C
Reaction time: 5 h
Yield: 66.5 %

Procedure:
Triphenylphosphine (8.70 g, 33.1 mmol) and carbontetrabromide (17.0 g, 51.2 mmol) were added to a suspension of (5-hydroxymethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (7.00 g 31.2 mmol) in CH2Cl2 (200 mL) at room temperature. Stirring was continued for 5 h followed by evaporation of the solvent. Acetonitrile (200 mL) was added and the mixture was cooled to −20° C. for 2 h. The mixture was then filtered and the crystalline residue washed with cold acetonitrile (2×10 mL), to give (5-bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (5.96 g, 67%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:22]=1)[C:19]([OH:21])=O.[C:23]1([C:29]2[CH2:33][CH2:32][NH:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:22]=1)[C:19]([N:31]1[CH2:32][CH2:33][C:29]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:30]1)=[O:21]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: c1ccc(C2=NNCC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(c1cncc(Br)c1)N1CCC(c2ccccc2)=N1
Reaction time: 1 h
Yield: 42.8 %

Procedure:
1,1′-Carbonyldiimidazole (1.7 g) was added to a solution of 5-bromonicotinic acid (2 g) dissolved in DMF (20 ml), at room temperature. The mixture was stirred for 1 hour in a nitrogen atmosphere. To the reaction mixture was dropwise added a solution of 3-phenyl-2-pyrazoline (5.7 g) dissolved in DMF (15 ml), with ice-cooling. The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated. The residue was dissolved in chloroform. The solution was washed with ice water, dried over anhydrous sodium sulfate, and concentrated. The organic layer was purified by silica gel column chromatography (methanol chloroform=1/100) to obtain 1.4 g of a title compound (yield: 41%).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.CN1CCOCC1.[Br:17][C:18]1[CH:19]=[C:20]([C:31](Cl)=[O:32])[C:21]2[O:26][CH:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[C:22]=2[CH:30]=1>C(Cl)(Cl)Cl>[Br:17][C:18]1[CH:19]=[C:20]([C:31]([NH:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[O:32])[C:21]2[O:26][CH:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[C:22]=2[CH:30]=1
Reactant: CC1Oc2c(C(=O)Cl)cc(Br)cc2N(C)C1=O
Reactant: NC1CN2CCC1CC2
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: CC1Oc2c(C(=O)NC3CN4CCC3CC4)cc(Br)cc2N(C)C1=O

Procedure:
To a solution of 1.6 g of 3-aminoquinuclidine and 1.35 g of N-methylmorpholine in 25 ml of chloroform is added a solution of 4.0 g of 6-bromo-3,4-dihydro-2,4-dimethyl-3-oxo -2H-1,4-benzoxazine-8-carboxylic acid chloride in 20 ml of chloroform under cooling and stirring followed by stirring at room temperature for 3 hours. The resultant solution is washed with water, aqueous sodium hydrogen carbonate and then water, and dried over magnesium sulfate. After the solvent is distilled off under reduced pressure, the residue is recrystallized from ethanol-isopropyl ether to give 6-bromo-3,4-dihydro-2,4-dimethyl-3-oxo-N-(3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide, melting at 287°-288° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:22]CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(O)=O)[C:7]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)([CH2:12][CH2:13][CH3:14])[CH2:8][S:9]2)=[CH:4][CH:3]=1.[F:44][C:45]([F:67])([C:63]([F:66])([F:65])[F:64])[CH2:46][CH2:47][CH2:48][CH:49]([CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH:61]=[CH2:62])[C:50]([O:52]CC)=[O:51]>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:22][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][CH:49]([CH2:48][CH2:47][CH2:46][C:45]([F:44])([F:67])[C:63]([F:64])([F:65])[F:66])[C:50]([OH:52])=[O:51])[C:7]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)([CH2:12][CH2:13][CH3:14])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: CCCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O
Reactant: C=CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Product: CCCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 29 and ethyl 2-(4,4,5,5,5,-pentafluoropentyl)-9-decenoate prepared separately, the same procedure as shown in Example 13 was repeated to give 11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(4,4,5,5,5,-pentafluoropentyl)undecanoic acid.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.O.[NH2:30][NH2:31]>C(O)C>[C:12]1([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:30][N:31]=[C:19]([CH2:20][CH2:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[C:3]=3[C:4]2=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN
Reactant: O=C(CCc1cccnc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: O
Solvent: CCO
Product: O=c1c2c(CCc3cccnc3)n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 78 %

Procedure:
The procedure of Example 1 was repeated using a suspension of 4-hydroxy-3-[1-oxo-3-(pyridin-3-yl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (50 mg, 0.14 mmol, prepared in Synthetic Example 2) in ethanol (10 ml), and hydrazine monohydrate (80%, 20 μl, 0.50 mmol, 3.7 eq.), to obtain 5-phenyl-3-[2-(pyridin-3-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4 (5H)-one (yield: 78%).
Reaction SMILES: Cl[C:2]1[N:11]2[CH:12]=[N:13][N:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH:15]1([C:18]2[O:22][N:21]=[C:20]([CH2:23][N+:24]#[C-:25])[N:19]=2)[CH2:17][CH2:16]1.CC(C)([O-])C.[K+]>CN(C=O)C>[CH:15]1([C:18]2[O:22][N:21]=[C:20]([C:23]3[N:24]=[CH:25][N:3]4[C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=5[C:10]5=[N:14][N:13]=[CH:12][N:11]5[C:2]=34)[N:19]=2)[CH2:17][CH2:16]1
Reactant: Clc1nc2ccccc2c2nncn12
Reactant: [C-]#[N+]Cc1noc(C2CC2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)c1nncn1c1c(-c3noc(C4CC4)n3)ncn21

Procedure:
To a stirred slurry of 5-chloro-1,2,4-triazolo[4,3-c]quinazoline (3.5 g, 17 mmol) in 40 ml of dry DMF at 10° C. was first added 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole (purity 80%, 3.4 g, 18 mmol) and then a solution of potassium tert-butoxide (2.55 g, 23 mmol) in 40 ml of DMF, allowing the temperature to rise to room temperature. After 1/2 h the mixture was filtered and the filter cake washed with water and finally with ether and dried, giving the title compound as colorless crystals, m.p. 308°-314° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[CH3:27][O:28][C:29]1[N:34]=[C:33]([C:35](O)=[O:36])[CH:32]=[CH:31][CH:30]=1>>[CH3:26][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:35]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([O:28][CH3:27])[N:34]=2)=[O:36])[CH2:7]1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Reactant: COc1cccc(C(=O)O)n1
Product: COc1cccc(C(=O)NC[C@@H]2[C@H]3CC(C)C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)n1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 6-methoxy-pyridine-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4CCNCC4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:32][O:33][CH2:34][C:35]([OH:37])=O>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH:25]4[CH2:6][CH2:7][N:8]([C:35](=[O:37])[CH2:34][O:33][CH3:32])[CH2:9][CH2:26]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCNCC3)c2)c2ccc(F)cc21
Reactant: COCC(=O)O
Product: COCC(=O)N1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Yield: 243.5 %

Procedure:
Following the general method as outlined in Example 83, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole (Intermediate 21; 188 mg; 0.43 mmol) and 2-methoxyacetic acid (41 mg; 0.46 mmol), 260 mg of the title compound was obtained as a yellow oil after purification by a silica gel chromatography (EtOAc).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:10](=[O:13])[CH2:11][CH2:12][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([CH3:1])[CH:3]=1)[CH3:16]
Reactant: C=CC(=O)OCC
Reactant: Cc1cccc(CCl)c1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCc1cccc(C)c1
Temperature: 110 °C

Procedure:
A mixture of 14.0 g of 3-methylbenzyl chloride and 50.0 g of ethyl acrylate dissolved in 300 ml of dry toluene was heated to 110° C. Separatively, 3.0 g of 2,2'-azobisisobutyronitrile(AIBN) and 32.0 g of tri-n-butyltin hydride were dissolved in 200 ml of dry toluene, which was added to the above mixture over a period of 2 hours. This reaction mixture was further heated at the boiling temperature for 2 hours and then cooled to the ambient temperature. The residues obtained after removing the solvent from the mixture were purified by silica gel column chromatography to provide ethyl-4-(3-methylphenyl)butanoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:15][CH2:16][N:17]([CH3:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
To a solution of 4-bromo-1H-pyrazole (5 g, 34 mmol) in DMF were added K2CO3 (11.75 g, 85.03 mmol, 2.5 eq.) and 2-chloro-N,N-dimethylethanamine HCl (7.35 g, 51 mmol, 1.5 eq) and the mixture was stirred at RT for 12 h. The mixture was quenched with water and extracted with DCM (3×150 ml). The combined organic layer was washed with water, brine and dried over sodium sulphate. The solvent was distilled off to afford the crude residue which was purified by column chromatography (60-120 silica gel, 1% methanol in DCM) to give the product in 86% yield (6.4 g). 1H NMR (300 MHz, DMSO-d6): δ 7.95 (s, 1H), 7.25 (s, 1H), 4.18 (t, 2H), 2.61 (t, 2H), 2.15 (s, 6H); LC-MS (ESI): Calculated mass: 218.09; Observed mass: 219.8[M+H]+ (RT: 0.439 min).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@H:12]3[C@H:17]4[CH2:18][C@H:14]([CH2:15][C@@H:16]4[F:19])[N:13]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:5][C:4]=2[CH:3]=1.[CH3:27][C:28]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30](C(OC(C)(C)C)=O)[N:29]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[F:19][C@H:16]1[CH2:15][C@H:14]2[CH2:18][C@@H:17]1[C@@H:12]([C:6]1[NH:7][C:8](=[O:11])[C:9]3[S:10][C:2]([C:32]4[CH:31]=[N:30][NH:29][C:28]=4[CH3:27])=[CH:3][C:4]=3[N:5]=1)[N:13]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@H]([C@H]1c1nc3cc(Br)sc3c(=O)[nH]1)[C@@H](F)C2
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1[nH]ncc1-c1cc2nc([C@@H]3[C@H]4C[C@H](C[C@@H]4F)N3C(=O)OC(C)(C)C)[nH]c(=O)c2s1
Temperature: 100 °C
Reaction time: 3 h
Yield: 35.2 %

Procedure:
tert-Butyl (1R*,3S,4R*,5S)-3-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-5-fluoro-2-azabicyclo[2.2.1]heptane-2-carboxylate (300 mg) and tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (416 mg), sodium carbonate (215 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (55 mg) was added, and the atmosphere in the flask was purged again with argon. The reaction system was stirred at 100° C. for 3 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained pale-yellow solid was purified by high performance liquid chromatography {column: L-column 2 ODS (20 mm i.d.×50 mm L), mobile phase: 0.1% aqueous trifluoroacetic acid solution/0.1% trifluoroacetic acid-acetonitrile solution}. The object fraction was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was concentrated under reduced pressure. The residue was collected by filtration and washed with water (3 mL) to give the title compound (106 mg) as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH2:21]([Mg]Br)[CH:22]([CH3:24])[CH3:23]>>[CH2:21]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)C[Mg]Br
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(CC(C)C)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 416 was used, staring from (1-Chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and isobutyl-magnesium bromide to give (1-Isobutyl-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 311 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>CC(C)=O.[I-].[K+]>[CH3:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[O:8][CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1cc(Cl)ccc1O
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(Cl)ccc1OCC(=O)C(C)(C)C
Yield: 79.1 %

Procedure:
283 g (2 moles) of 4-chloro-2-methylphenol, 300 g of potassium carbonate and 2 g of potassium iodide were suspended in 2 l of anhydrous acetone and the suspension was heated to the boil. 359 g (2 moles) of bromopinacolone were then gradually added dropwise, while stirring, and the reaction mixture was heated for 5 hours under reflux. Thereafter, first the solvent, and then the ketone were distilled off under reduced pressure. 381 g (79% of theory) of 1-(2-methyl-4-chlorophenoxy)-3,3-dimethyl-butan-2-one of boiling point 109°-112°C/0.1 mm were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[NH:4][N:5]=[C:6]([Cl:9])[C:7]=1Cl.[CH3:11][O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][NH2:24])=[CH:15][CH:14]=1>C(O)C>[Cl:1][C:2]1[C:3](=[O:10])[NH:4][N:5]=[C:6]([Cl:9])[C:7]=1[NH:24][CH2:23][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([O:12][CH3:11])=[CH:14][CH:15]=1
Reactant: O=c1[nH]nc(Cl)c(Cl)c1Cl
Reactant: COc1ccc(CN)c2ccccc12
Solvent: CCO
Product: COc1ccc(CNc2c(Cl)n[nH]c(=O)c2Cl)c2ccccc12
Reaction time: 4 h

Procedure:
A mixture comprising 800 mg of 4,5,6-trichloro-3(2H)pyridazinone, 2.68 g of 4-methoxy-1-naphthylmethylamine and 10 ml of ethanol, was refluxed under stirring for 4 hours. After cooling, precipitated crystals were collected by filtration. Then, the product was dissolved in hot ethyl acetate and treated by silica gel. The filtrate was concentrated, and precipitated crystals were collected by filtration to obtain 330 mg of the above identified compound as colorless crystals having a melting point of from 228° to 231° C.
Reaction SMILES: [CH3:1][C:2]1[N:13]([C@@H:14]2[CH2:19][O:18][C@@H:17]([CH2:20][OH:21])[CH2:16][CH2:15]2)[C:5]2=[C:6]3[S:12][CH:11]=[CH:10][C:7]3=[N:8][CH:9]=[C:4]2[N:3]=1.N1C=CC=CC=1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:38][C:28]1[CH:33]=[CH:32][C:31]([S:34]([O:21][CH2:20][C@H:17]2[CH2:16][CH2:15][C@H:14]([N:13]3[C:5]4=[C:6]5[S:12][CH:11]=[CH:10][C:7]5=[N:8][CH:9]=[C:4]4[N:3]=[C:2]3[CH3:1])[CH2:19][O:18]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CO)OC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](n3c(C)nc4cnc5ccsc5c43)CO2)cc1
Temperature: 25 °C
Yield: 55.2 %

Procedure:
To a solution of [(2R,5S)-5-(2-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)tetrahydro-2H-pyran-2-yl]methanol (60.1 mg, 0.198 mmol) in methylene chloride (2.3 mL) and pyridine (51 μL, 0.62 mmol) was added p-toluenesulfonyl chloride (38.7 mg, 0.203 mmol) and 4-dimethylaminopyridine (1.2 mg, 0.010 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was concentrated, diluted with methanol, and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (50 mg, 55%). LCMS calculated for C22H24N3O4S2 (M+H)+: m/z=458.1. Found: 458.1.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35](O)=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[C:30]([C:35]([N:3]3[CH2:4][C@H:5]4[C@H:1]([CH2:8][CH2:7][CH2:6]4)[C@H:2]3[CH2:9][NH:10][C:11]([C:13]3[N:20]4[C:16]([S:17][CH:18]=[CH:19]4)=[N:15][C:14]=3[CH3:21])=[O:12])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:27][CH:28]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Reactant: O=C(O)c1ccccc1-c1ccc(F)cc1
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2CCC[C@H]2CN1C(=O)c1ccccc1-c1ccc(F)cc1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with commercially available 4′-fluoro-biphenyl-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[CH3:18][CH:19]([CH3:42])[CH:20]([NH:25][C:26]([C:28]1[S:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=2)=[CH:31][N:32]=1)=[O:27])[C:21]([O:23][CH3:24])=[O:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:39][C:36]2[CH:37]=[CH:38][C:33]([C:30]3[S:29][C:28]([C:26]([NH:25][CH:20]([CH:19]([CH3:42])[CH3:18])[C:21]([O:23][CH3:24])=[O:22])=[O:27])=[N:32][CH:31]=3)=[CH:34][CH:35]=2)=[C:4]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1Oc1ccccc1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccc(Cl)cc3Oc3ccccc3)cc2)s1)C(C)C
Yield: 60 %

Procedure:
The title compound was synthesized analogous to Example 9, using 4-chloro-1-isocyanato-2-phenoxybenzene and intermediate 2. Yield: 60%; 1HNMR (DMSO-d6, 300 MHz): δ 9.61 (s, 1H), 8.73 (s, 1H), 8.71 (d, 1H), 8.4 (d, 1H), 8.36 (s, 1H), 7.74 (d, 2H), 7.54 (d, 2H), 7.44 (d, 2H), 7.2 (dd, 1H), 7.11 (d, 2H), 7.03 (dd, 1H), 6.86 (d, 1H), 4.33, (m, 1H), 3.68 (s, 3H), 2.26 (m, 1H), 0.95 (d, 6H); MS (ES+) m/z 579 (M+1).
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:64][O:65][C:66](=[O:78])[CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH3:77])[CH2:16][S:17][CH2:18][C@H:19]([NH:46]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:20](=[O:45])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1CCCCC1>C(#N)C>[C:66]([O:65][CH2:64][C@@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:16][S:17][CH2:18][C@H:19]([NH2:46])[C:20]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[O:45])(=[O:78])[CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH3:77]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCCCNC(=O)OCC1c2ccccc2-c2ccccc21)OC(=O)CCCCCCCCCCC
Solvent: C1CCNCC1
Solvent: CC#N
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCCCCN)OC(=O)CCCCCCCCCCC
Reaction time: 0.5 h

Procedure:
A solution of (12R,16R)-12-(((9H-fluoren-9-yl)methoxy)carbonylamino)-1-(9H-fluoren-9-yl)-3,11-dioxo-2-oxa-14-thia-4,10-diazaheptadecane-16,17-diyl didodecanoate in acetonitrile (0.1M) was stirred at room temperature. Piperidine (final conc. 20%) was then added and the reaction stirred for 30 minutes. After concentration, the product was purified by flash chromatography on an ISCO COMBIFLASH® system using a 0-20% MeOH (1% NH3)/DCM gradient to give (R)-3-((R)-2-amino-3-(5-aminopentylamino)-3-oxopropylthio)propane-1,2-diyl didodecanoate. 1H NMR (DMSO d-6): δ 7.91 (t, 1H), 5.09 (m, 1H), 4.26-4.32 (dd, 1H), 4.08-4.12 (m, 1H), 3.24-3.36 (m, 8H), 3.05-3.08 (m, 2H), 3.06 (m, 1H), 2.80 (m, 1H), 2.74 (t, 1H), 2.67 (dd, 1H), 2.60 (dd, 1H), 2.29-2.34 (q, 4H), 1.48-1.54 (m, 4H), 1.32-1.40 (m, 4H), 1.21-1.34 (m, 32H), 0.88 (t, 6H). LRMS [M+H]=645.1.
Reaction SMILES: Br[CH2:2][C:3](=[O:25])[C@:4]1([OH:24])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[C:26]([O-:29])(=[O:28])[CH3:27].[K+]>CC(C)=O.C(OCC)(=O)C>[C:26]([O:29][CH2:2][C:3](=[O:25])[C@:4]1([OH:24])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1)(=[O:28])[CH3:27]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CBr
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 0 °C
Yield: 91.3 %

Procedure:
3.0 g of 21-bromo-17-hydroxy-1,4-pregnadiene-3,20-dione is stirred in 60 ml of acetone with 3.0 g of potassium acetate at 50° C. The reaction mixture is introduced into ice water after 2 hours, the thus-precipitated product is suctioned off, dissolved in ethyl acetate, washed with water, and dried over sodium sulfate, thus producing 2.6 g of 21-acetoxy-17-hydroxy-1,4-pregnadiene-3,20-dione, mp 214° C.