Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15]Cl)([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]([NH2:28])[CH3:27])[CH:22]=[CH:23][C:24]=1[Cl:25].CCN(C(C)C)C(C)C>C(O)C>[CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15][NH:28][CH:26]([C:21]1[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=1)[CH3:27])([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5])[CH3:2]
Reactant: CC(N)c1ccc(Cl)c(Cl)c1
Reactant: CCOP(=O)(CC1CCCCC1)C[C@@H](O)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOP(=O)(CC1CCCCC1)C[C@@H](O)CNC(C)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of 4.24 g of 3-chloro-2(R)-hydroxy-propyl-(cyclohexylmethyl)-phosphinic acid ethyl ester, 2.85 g of 1-(3,4-dichlorophenyl)ethylamine, 1.95 g of Hunig base and 15 ml of ethanol is heated at reflux for 4 days. After cooling to room temperature and removal of the solvent under reduced pressure, the reaction mixture is partitioned between dichloro-methane and water, dried over sodium sulfate and again concentrated to dryness by evaporation. Chromatography on silica gel yields 3-{N-[1-(3,4-dichlorophenyl)ethyl]amino}-2(S)-hydroxy-propyl(cyclohexylmethyl)phosphinic acid ethyl ester, [α]20D =-1.8°±0.9° (c=1.079 in chloroform).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]\[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=1)=O)(C)(C)C>C(Cl)Cl>[CH:25]1(/[CH:24]=[CH:23]\[C:20]2[CH:19]=[CH:18][C:17]([CH2:16][NH2:15])=[CH:22][CH:21]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(/C=C\C2CCCCC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(/C=C\C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
Add trifluoroacetic acid (1 mL) to a solution of (Z)—N-(tert-butoxycarbonyl)-4-(2-cyclohexylvinyl)-benzylamine (0.49 g, 1.5 mmol) in DCM (10 mL). Stir the mixture at room temperature for 2 h, concentrate in vacuo and purify the residue by SCX chromatography to obtain the title compound (0.3 g, 87%, estimate 10% of alkane present). Use this material in the next step without additional purification. MS (ES+) m/z: 199.3 (M-NH3+H)+.
Reaction SMILES: [CH2:1]([C:9]1[O:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>C(O)C.[C].[Pd]>[CH2:1]([CH:9]1[CH2:13][C:12]2[C:11](=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1cc2ccccc2o1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCC1Cc2ccccc2O1
Yield: 94.6 %

Procedure:
Then, 44 g of 2-octylbenzofuran was dissolved in 440 ml of ethanol. To the solution 35 g of 10%-palladium-carbon was added to effect catalytic reduction for 3 hours sunder normal pressure. After the reaction, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (eluent:hexane) to obtain 42 g of liquid 2-octylcoumaran (Yield: 94.6%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[O:11]1CCOCC1>O>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([CH:1]=[O:11])=[O:3])=[CH:5][CH:6]=1
Reactant: C1COCCO1
Reactant: CC(=O)c1ccc(O)cc1
Solvent: O
Product: O=CC(=O)c1ccc(O)cc1

Procedure:
4-Hydroxyacetophenone (15 g., 0.11 mol) was dissolved in 70 ml. dioxane and 8.3 ml. H2O. SeO2 (12.2 g., 0.11 mol) was added and the mixture heated at 80° for 18 hours, then filtered over diatomaceous earth. The filtrate was stripped, taken up in 150 ml. H2O, heated on a steam bath, decolorized with activated carbon, cooled to refrigerator temperature, and hydrate of title product recovered by filtration, 5.72 g. Anhydrous title product was obtained by Kugelrohr distillation; 1H-nmr 5.97 (s, 1H), 6.97 (d, 2H, J=6 Hz), 8.22 (d, 2H, J=6 Hz), 9.68 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[N:5]([C:14]1[CH:19]=[C:18]([CH:20]=C)[N:17]=[C:16]([NH2:22])[C:15]=1[N+:23]([O-:25])=[O:24])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2].I([O-])(=O)(=O)=[O:28].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[CH2:1]([O:3][C:4](=[O:26])[N:5]([C:14]1[CH:19]=[C:18]([CH:20]=[O:28])[N:17]=[C:16]([NH2:22])[C:15]=1[N+:23]([O-:25])=[O:24])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(N(Cc2ccc(C)nc2)C(=O)OCC)c([N+](=O)[O-])c(N)n1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(C=O)nc(N)c1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 81.1 %

Procedure:
(2-Amino-3-nitro-6-vinyl-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (270 mgs/0.755 mmols) was dissolved in acetone (5 mls)/water (5 mls) and osmium tetroxide (2.5% wt in tBuOH) (0.10 mls/0.008 mmols) was added. Stirred for 5 mins to give brown solution then added sodium metaperiodate (500 mgs/3.47 mmols). Orange suspension stirred for 1 hour. Partitioned between EtOAc (100 mls) and sodium thiosulfate pentahydrate (20% wt in H2O) (50 mls). Organic collected, washed with brine, dried over Na2SO4, filtered and concentrated to a brown resin. Purification by column chromatography eluting with EtOAc gave the title compound (220 mgs) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[CH3:34][O:35][C:36]1[C:41]([NH2:42])=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:39]4[CH:40]=[C:41]([NH2:42])[C:36]([O:35][CH3:34])=[N:37][CH:38]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ncc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1N
Yield: 49.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (150 mg, 0.280 mmol) was coupled with 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (Intermediate 60) (86 mg, 0.34 mmol) using sodium carbonate (89 mg, 0.84 mmol) and Pd(PPh3)2Cl2 (10 mg, 0.014 mmol) in DME/water (10/1 mL) to afford 80 mg (49.2% yield) after purification by column (Silica gel 6/120) using 4/1/5 EtOAc/methanol/hexane as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][C:14](=O)[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:42]CCl>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]=[C:14]([Cl:42])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17]
Reactant: ClCCl
Reactant: O=C(Nc1c(Cl)cc(C(F)(F)F)cc1Cl)C(F)(F)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(Cl)c(N=C(Cl)C(F)(F)C(F)(F)F)c(Cl)c1
Reaction time: 18 h

Procedure:
First, 4.3 g (11 mmol) of N-(2,6-dichloro-4-trifluoromethylphenyl)-2,2,3,3,3-pentafluoropropionamide was dissolved in 22 ml of dichloromethane, to which 1.8 ml of carbon tetrachloride and 4.5 g (17 mmol) of triphenylphosphine were added at room temperature, and the mixture was stirred for 18 hours. The reaction mixture was concentrated under reduced pressure, followed by addition of hexane, and undissolved matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 3.8 g of N-(2,6-dichloro-4-trifluoromethylphenyl)-2,2,3,3,3-pentafluoropropionimidoyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=1)([CH3:17])[CH3:16].O>C1COCC1>[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])([OH:28])[CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=1)([CH3:17])[CH3:16]
Reactant: CC(C)C(=O)c1ccc(C(C)C)cc1
Reactant: COc1ccccc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1C(O)(c1ccc(C(C)C)cc1)C(C)C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
To a solution of 2-bromoanisole (5.0 g, 26.7 mmol) in THF (50 mL) was added n-butyllithium (1.6 M, 18 mL, 29 mmol) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction solution was added 1-(4-isopropylphenyl)-2-methylpropan-1-one (5.70 g, 30.0 mmol), and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture which was extracted with ethyl acetate, and the combined organic layer was washed with water, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 3.4 g (yield 43%) of the title compound. Melting point: 85-86° C. (methanol).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.Br[CH2:10][CH2:11][CH2:12][OH:13]>C1(C)C(C)=CC=CC=1>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[CH2:10][CH2:11][CH2:12][OH:13]
Reactant: OCCCBr
Reactant: C[C@@H]1CCC[C@H](C)N1
Solvent: Cc1ccccc1C
Product: C[C@@H]1CCC[C@H](C)N1CCCO

Procedure:
A stirred solution of 460 g. of cis-2,6-dimethylpiperidine in 300 ml. of xylene is treated with 278 g. of 3-bromopropanol over a period of 15 minutes. The mixture is stirred and heated at reflux for 2 hours, then allowed to cool while stirring for 16 hours. The mixture is filtered and the filtrate evaporated at reduced pressure. The residue is distilled at reduced pressure to give cis2,6-dimethyl-1-piperidinepropanol; b.p. 147°-149° C./25 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH:10]=O)=O.[NH2:12][C:13]1[N:17]([NH2:18])[CH:16]=[N:15][N:14]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:10]=[N:18][N:17]2[CH:16]=[N:15][N:14]=[C:13]2[N:12]=1
Reactant: Nc1nncn1N
Reactant: O=CC(=O)c1ccccc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Clc1ccccc1-c1cnn2cnnc2n1

Procedure:
A solution of 14 g. of o-chlorophenylglyoxal, 10.6 g. of 3,4-diamino-4H-1,2,4-triazole and 6.3 g. of sodium acetate in 180 ml. of 67% acetic acid is heated on a steam bath and then filtered through celite. The filtrate is heated for an additional hour and then allowed to stand at room temperature for several days, producing the desired product as a cream colored solid, m.p. 162°-165° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[F:13].[C:14]([O:18][C:19]([N:21]1[CH2:28][CH:27]2[O:29][CH:23]([CH2:24][NH:25][CH2:26]2)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH:23]2[O:29][CH:27]([CH2:26][NH:25][CH2:24]2)[CH:28]1[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[F:13])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: N#Cc1ccc(OCCBr)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CNCC(O2)C1CCOc1ccc(C#N)cc1F
Temperature: 60 °C
Reaction time: 120 h
Yield: 65.8 %

Procedure:
A suspension of 4-(2-bromoethoxy)-3-fluorobenzonitrile (21.6 g, 0.0885 mol; see step (v) above), 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (21.1 g, 0.07965 mol; see WO 01/28992) and dry K2CO3 (48.9 g, 0.354 mol) in 200 mL of dry acetonitrile was stirred at 60° C. for five days under a nitrogen atmosphere. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel, using 27% ethyl acetate in petroleum ether as eluent, to yield 20.5 g of the sub-title compound as a solid.
Reaction SMILES: [C:1]([C@@H:3]([NH:5][C:6](=[O:12])OC(C)(C)C)[CH3:4])#[N:2].[C:13](Cl)(=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]C>>[C:1]([C@@H:3]([NH:5][C:6](=[O:12])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:4])#[N:2]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: C[C@@H](C#N)NC(=O)OC(C)(C)C
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@@H](C)C#N
Yield: 53 %

Procedure:
General procedures D was used to deprotect 1.17 mmols of (S)-tert-butyl 1-cyanoethylcarbamate to the corresponding amine. General procedure F was then use to couple to amine to 1.521 mmols of oleoyl chloride. After standard purification techniques, 0.62 mmols (53%) of the title product was recovered. 1H NMR (500 MHz, CDCl3) δ 6.08 (s, 1H), 5.40-5.28 (m, 2H), 5.00-4.90 (m, 1H), 4.12 (q, J=7.2, 0H), 2.20 (dd, J=6.6, 8.5, 2H), 2.00 (dd, J=6.3, 12.0, 4H), 1.68-1.58 (m, 2H), 1.54 (d, J=7.2, 3H), 1.38-1.20 (m, 24H), 0.87 (t, J=6.9, 3H). 13C NMR (126 MHz, CDCl3) δ 172.49, 130.02, 129.66, 119.35, 36.11, 35.63, 31.88, 29.74, 29.68, 29.50, 29.31, 29.20, 29.14, 29.08, 27.20, 27.14, 25.30, 22.67, 19.43, 14.11.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[C:17]([Br:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21].CN(C)[CH:24]=[O:25]>C(OCC)C>[Br:19][C:17]1[C:16]([F:20])=[CH:15][C:14]([F:21])=[C:13]([CH:18]=1)[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: Fc1cc(F)c(Br)cc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1cc(Br)c(F)cc1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 61.1 %

Procedure:
A 1.6 M solution of butyl lithium in hexane (114 mL, 182 mmol) is added to a −78° C. solution of 1,5-dibromo-2,4-difluorobenzene (41.3 g, 152 mmol) in diethyl ether (290 mL). Dimethylformamide (14.4 g, 198 mmol) is added and the reaction is stirred at −78° C. for 15 minutes. The reaction is quenched with 1 N HCl (300 mL), is diluted with water, and extracted three times with ethyl acetate. The organic layer is dried over sodium sulfate and the solvent is removed under reduced pressure to give crude material that is purified by silica gel chromatography with a linear gradient of 0% to 50% CH2Cl2 in hexanes over 30 minutes to give the title compound (20.51 g, 61%). GC-MS m/e (79Br/81Br) 220, 222.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:20])=[C:4]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:5]([I:14])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[C:7]=1[I:8].[C:21]([O:24][CH:25]([CH:29]([O:35][C:36](=[O:38])[CH3:37])[CH2:30][O:31][C:32](=[O:34])[CH3:33])[C:26](Cl)=[O:27])(=[O:23])[CH3:22]>CC(N(C)C)=O>[C:21]([O:24][CH:25]([CH:29]([O:35][C:36](=[O:38])[CH3:37])[CH2:30][O:31][C:32](=[O:34])[CH3:33])[C:26]([NH:1][C:2]1[C:7]([I:8])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[C:5]([I:14])=[C:4]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:3]=1[I:20])=[O:27])(=[O:23])[CH3:22]
Reactant: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(=O)Cl
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(COC(C)=O)c1I
Solvent: CC(=O)N(C)C
Product: CC(=O)OCc1c(I)c(COC(C)=O)c(I)c(NC(=O)C(OC(C)=O)C(COC(C)=O)OC(C)=O)c1I
Reaction time: 20 h
Yield: 78.8 %

Procedure:
5-Amino-2,4,6-triiodo-1,3-di-(acetoxymethyl)benzene (2.0 g, 3.25 mmol) was dissolved in dimethylacetamide (4 ml) at room temperature. 2,3,4-Triacetoxybutyryl chloride (7.4 g, 26.4 mmol) was added and the mixture was stirred for 20 h. The work up was carried out as in Example 24i. A white crystalline product 2.2 g (79%), was isolated.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[O:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:13]([CH3:16])([O-:15])=[O:14].C(N(CC)CC)C>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]([OH:12])([CH2:16][N+:13]([O-:15])=[O:14])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(O)(C[N+](=O)[O-])C1
Yield: 97 %

Procedure:
3-Oxoazetidine-1-carboxylic acid tert-butyl ester (500 mg, 2.9 mmol) was dissolved in ethanol (1.5 mL) and to this was added nitromethane (0.6 mL) and triethylamine (cat.). The reaction was stirred for eighteen hours and the solvent was then removed under reduced pressure to yield the title compound as a white solid (650 mg, 97%). δH (d6-DMSO) 6.42 (1H, s), 4.86 (2H, s), 4.04 (2H, d, J 9.2 Hz), 3.75 (2H, d, J 9.2 Hz), 1.39 (9H, s). LCMS (ES+) RT (pH 10) 1.73 min (M−H)− 231.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].CC([O-])(C)C.[K+].Cl[C:13]1[N:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:14]=1[C:15]([NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([C:24]([F:27])([F:26])[F:25])[CH2:20][CH2:19]1)=[O:16]>C1COCC1.O>[Cl:32][C:30]1[CH:29]=[CH:28][C:14]([C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([F:27])([F:26])[F:25])[CH2:20][CH2:19]2)=[O:16])=[C:13]([O:5][CH2:4][CH2:3][O:2][CH3:1])[N:31]=1
Reactant: COCCO
Reactant: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1ccc(Cl)nc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1nc(Cl)ccc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1
Reaction time: 0.08 h

Procedure:
2-Methoxyethanol (550 μL, 6.94 mmol) is added at rt to KOtBu (750 mg, 6.35 mmol) in THF (30 mL) and it is stirred for 5 min. 2,6-Dichloro-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (2.00 g, 5.86 mmol) is added to the reaction mixture and it is stirred for 10 min at rt. The reaction mixture is diluted with water, filtered and the filtrate is concentrated. The residue is treated with water, filtered off, washed with water and dried.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25]>C(OCC)C>[C:24]([C:23]1[CH:22]=[C:21]([NH:20][C:14](=[O:16])[C:13]([N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:17])[CH:28]=[CH:27][CH:26]=1)#[N:25]
Reactant: N#Cc1cccc(N)c1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: N#Cc1cccc(NC(=O)C(=O)N2CCC(Cc3ccc(F)cc3)CC2)c1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) and 3-aminobenzonitrile (Aldrich) according to the method described in Example 1c. Melting Point: 135-138° C. (diethylether)
Reaction SMILES: BrBr.[CH2:3]([CH:7]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][NH:10][C:9](=[O:19])[CH2:8]1)[CH2:4][CH2:5][CH3:6]>CC(O)=O>[CH2:3]([C:7]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][NH:10][C:9](=[O:19])[CH:8]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC1CC(=O)NN=C1c1ccccc1
Agent: BrBr
Solvent: CC(=O)O
Product: CCCCc1cc(=O)[nH]nc1-c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of bromine (0.94 ml, 18.2 mmol) in HOAc (10 mL) is added dropwise to a solution of 5-butyl-6-phenyl-4,5-dihydro-2H-pyridazin-3-one (3-8g, 16.5 mmol) in HOAc (40 mL) at 80° C. After the addition is complete, the heating is continued for 30 minutes and the solvent is evaporated in vacuo. The residue is partitioned between saturated aqueous NaHCO3 solution (50 mL) and EtOAc (50 mL) and the organic layer washed with water (35 mL), brine (35 mL), and then dried (Na2SO4). Evaporation of the solvent in vacuo provides the desired product as a yellow solid. LC-MS (M+1) 229. 1H NMR (δ, CDCl3) 12.39 (s, 1H), 7.39-7.48 (m, 5H), 6.83 (s, 1H), 2.41 (t, J=7.2 Hz, 2H), 1.20-1.43 (m, 4H), 0.77 (t, J=7.7 Hz, 3H).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:16]([NH:20][OH:21])([CH3:19])([CH3:18])[CH3:17]>C1C=CC=CC=1>[CH2:1]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[N+:20]([C:16]([CH3:19])([CH3:18])[CH3:17])[O-:21])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)(C)NO
Reactant: CCCCCCOc1ccc(C=O)cc1
Solvent: c1ccccc1
Product: CCCCCCOc1ccc(C=[N+]([O-])C(C)(C)C)cc1
Yield: 55.8 %

Procedure:
A solution of 4-hexyloxybenzaldehyde (3.83 g, 18.6 mmol) in 120 mL of benzene was refluxed with N-tert-butylhydroxylamine (3.32 g, 37.2 mmol) for 18 hours. The reaction mixture was then concentrated by rotary evaporation and the resulting residue was purified by silica gel column chromatography using 50:50 ethyl acetate/hexane to afford the title compound (2.88 g, 55.8 % yield) as a solid, m.p. 69.0° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[C:9]([CH:15]([CH3:17])[CH3:16])[CH:8]=1)(=[O:5])=[O:4].[BH4-].[Na+]>CO>[F:18][C:2]([F:1])([F:19])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[C:9]([CH:15]([CH3:17])[CH3:16])[CH:8]=1)(=[O:4])=[O:5]
Reactant: CC(C)c1cc(OS(=O)(=O)C(F)(F)F)ccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1cc(OS(=O)(=O)C(F)(F)F)ccc1CO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-formyl-3-isopropyl-phenyl 1,1,1-trifluoro-methanesulfonate (Intermediate 148, 540.0 mg, 1.82 mmols) in 7 mL MeOH at 0° C. was added NaBH4 (72.0 mg, 1.91 mmols). After stirring 2 hours at 0° C. the reaction was carefully quenched with H2O and extracted with Et2O. The combined organic layers were washed with H2O and saturated aqueous NaCl, dried (MgSO4), and concetrated under reduced pressure. The title compound was isolated by column chromatography (5-10% EtOAc-hexanes) as a colorless oil, 355.0 mg (90%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH3:20][SH:21]>>[CH3:20][S:21][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: CS
Product: CSCCCCOc1ccc2c(c1)C(C)(C)OC(=O)N2

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and methylmercaptan.
Reaction SMILES: N([O-])=O.[Na+].N[CH:6]1[CH:12]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[ClH:22]>O.[Cu]Cl>[Cl:22][CH:6]1[CH:12]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: NC1CCCCCC1CC(=O)c1ccccc1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(CC1CCCCCC1Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 5 g of sodium nitrite in 20 ml of water is slowly added dropwise at 0°C, whilst stirring, to a solution of 11 g of crude 3-amino-4-cycloheptyl-acetophenone in 70ml of concentrated hydrochloric acid. After completion of the addition the mixture is stirred for a further 30 minutes at 0°C. The reaction solution is then added dropwise at 0 to 5°C, whilst stirring, to a solution of 7 g of freshly prepared copper-(I) chloride in 30 ml of concentrated hydrochloric acid. After completion of the addition, the mixture is stirred for a further hour at room temperature and a further hour at 40 to 50°C. The reaction mixture is now extracted three times with 200 ml of ether at a time. The organic phases are successively washed with water, 2 N sodium hydroxide solution and again with water, dried over sodium sulphate and evaporated in vacuo. Distillation of the evaporation residue in a high vacuum yields crude 3-chloro-4-cycloheptyl-acetophenone in the fraction boiling at about 130°C/0.05 mm Hg.