Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25](I)[CH3:26]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:25][CH3:26])[C:12]2([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: COC(=O)C1(NS(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(C1(C(=O)OC)CC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
Compound 13B (800 mg, 2.76 mmol) dissolved in DMF (10 ml) was added with K2CO3 (1.1 equiv., 420 mg) and ethyl iodide (1.1 equiv., 0.3 ml) and the reaction was stirred at rt overnight. The reaction was diluted with ethyl acetate and washed several times with water and finally with Brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from ethyl ether and petroleum ether afforded 750 mg of 14B as a semisolid. Yield=85.5%. 1HNMR (DMSO, 200 MHz) δ 1.096 (3H, t, J=7.2 Hz), 1.17 (2H, m), 1.43 (2H, bs), 3.34 (2H, m), 3.43 (3H, s), 7.68 (2H, m), 7.79 (2H, m)
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2]1.[NH:24]1[CH:31]=[CH:30][C:28]([NH2:29])=[N:27][C:25]1=[O:26].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>CN(C)C=O>[OH:1][CH:3]([CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2][N:24]1[CH:31]=[CH:30][C:28]([NH2:29])=[N:27][C:25]1=[O:26]
Reactant: CCCCCCCCCCCCCCCCCCOCC1CO1
Reactant: Nc1cc[nH]c(=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOCC(O)Cn1ccc(N)nc1=O
Temperature: 25 °C
Yield: 37.3 %

Procedure:
rac-1,2-Epoxy-3-octadecyloxypropane (2.0 g, 6.13 mmol) is added to a mixture of cytosine (1.0 g, 9.0 mmol) and anhydrous potassium carbonate (40 mg) in dimethyl formamide (25 mL) over a 30 minute period under a nitrogen atmosphere. The resultant mixture is stirred at 80°-90° C. (oil bath temperature) for 48 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo to leave a residue. The residue is stirred with chloroform (50 mL). The undissolved material is filtered in vacuo, and the filtrate is concentrated in vacuo, purified by chromatography and dried in vacuo to afford 1.0 g (37%) of 1-[2'-hydroxy-3'-octadecyloxypropyl]-cytosine (CPR 1149): Thin-layer Chromatography (TLC; 4×8 cm silica gel 60, 0.25 mm thickness): 10:2:0.2 (v/v/v) CHCl3 -CH3OH-30% aqueous ammonia (Rf value=0.66); mp 153°-154° C.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[C:14]([CH3:25])=[C:13]([CH3:26])[N:12]=1>O1CCCC1>[CH3:26][C:13]1[C:14]([CH3:25])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: Oc1ccccc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCO)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCO)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Sodium hydride (7.80 g of a 60% dispersion in mineral oil, 195 mmol) was added in portions to a chilled (0° C.) solution of phenol (18.36 g, 195 mmol) in tetrahydrofuran (200 mL). After the addition was completed the reaction mixture was allowed to stir at ambient temperature for 30 minutes. Solid 3-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]propan-1-ol (16.89 g, 65.0 mmol) was added and the reaction mixture was heated at reflux for 5 days. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (400 mL) and water (100 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by flash chromatography (500 mL silica gel eluting with a gradient of 30-75% ethyl acetate in hexanes) and then heated under high vacuum until it melted. The melt solidified to provide 11.54 g of 3-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]propan-1-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:10]([NH:11][CH3:12])=[CH:9][N:8]=[C:7]([S:13][CH3:14])[N:6]=1.[F:19][C:20]([F:38])([F:37])[C:21]1[CH:22]=[C:23]([C:31]([CH3:36])([CH3:35])[C:32](Cl)=[O:33])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>>[F:29][C:27]([F:28])([F:30])[C:25]1[CH:24]=[C:23]([C:31]([CH3:35])([CH3:36])[C:32]([N:11]([C:10]2[C:5]([O:4][C:3]3[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=3[Cl:1])=[N:6][C:7]([S:13][CH3:14])=[N:8][CH:9]=2)[CH3:12])=[O:33])[CH:22]=[C:21]([C:20]([F:19])([F:37])[F:38])[CH:26]=1
Reactant: CNc1cnc(SC)nc1Oc1ccccc1Cl
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CSc1ncc(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(Oc2ccccc2Cl)n1

Procedure:
The resulting [4-(2-chloro-phenoxy)-2-methylsulfanyl-pyrimidin-5-yl]-methyl-amine was treated with 2-(3,5-bis-trifluormethyl-phenyl)-2-methyl-propionyl chloride as described in Example 43e) to give 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenoxy)-2-methylsulfanyl-pyrimidin-5-yl]-N-methyl-isobutyramide as a white foam, MS (ISP): 564.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:26][O:25][C:23](=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:11][C:6]1[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: COC(=O)CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCCCC(=O)OC)ccc(C(C)=O)c1O
Yield: 59.7 %

Procedure:
A mixture of 4.30 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 5.10 g of methyl 8-bromooctanoate and 4.55 g of anhydrous potassium carbonate in 100 ml of anhydrous acetone and 30 ml of anhydrous dimethyl formamide was stirred at reflux for 20 hours. The usual workup followed by purification by high pressure liquid chromatography using a solvent of 15% ethyl acetate-hexane gave 4.5 g (58% yield) of 8-(4-acetyl-3-hydroxy-2-propylphenoxy)octanoic acid methyl ester, the titled compound, mp 39°-41°, after crystallization from hexane.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][NH2:22].[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:22][CH2:21][CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[F:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCCc1ccccc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
0.38 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 0.200 ml 2-(2-fluoro-phenyl)-ethyl-amine (1.5 mmol) were dissolved in 4.5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2.5 h. After cooling down to rt, 85 mg (2.25 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 3 h. After cooling down to rt, the reaction mixture was treated with 4 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 280 mg light yellow oil (65%). MS (ISP) 286.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:5][S:11]([CH3:10])(=[O:13])=[O:12]
Reactant: OCc1ccccc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a solution of 2-fluorobenzyl alcohol (4.40 g, 34.9 mmol) in dichloromethane (40 mL) was added methanesulfonyl chloride (3.24 mL, 41.9 mmol) and triethylamine (5.84 mL, 41.9 mmol) on an ice bath, the solution was warmed to room temperature and stirred overnight. The reaction solution was diluted with dichloromethane, washed with an aqueous solution of 5% sodium bicarbonate, then, dried over anhydrous magnesium sulfate, the solvent was evaporated, and the title compound (4.62 g, 65%) was obtained as a brown oil. This was used in the next reaction without purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15]([C:17]1[CH:38]=[CH:37][C:20]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[CH:25]=2)=[O:22])=[CH:19][CH:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15]([C:17]1[CH:38]=[CH:37][C:20]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([C:33]([F:34])([F:35])[F:36])(=[O:31])=[O:32])[CH:25]=2)=[O:22])=[CH:19][CH:18]=1)=[O:16]
Reactant: NNC(=O)c1ccc(C(=O)Nc2cccc(S(=O)(=O)C(F)(F)F)c2)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(C(=O)Nc2cccc(S(=O)(=O)C(F)(F)F)c2)cc1
Temperature: 100 °C
Yield: 76 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-(hydrazinocarbonyl)-N-{3-[(trifluoromethyl)sulfonyl]phenyl}benzamide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 80 mg of the title compound (76%) as a yellow solid in 76% purity by HPLC (Rt: 4.96, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>C(#N)C.CN(C)C1C=CN=CC=1>[S:29]([O:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:8][CH:7]=1)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC#Cc1ccc(OCCCN2CCCCC2)cc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCC#Cc2ccc(OCCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81975.1 %

Procedure:
To a solution of 1-{3-[4-(4-hydroxybut-1-yn-1-yl)phenoxy]propyl}piperidine (393 mg) in acetonitrile (10 mL) are added successively triethylamine (0.446 mL), 4-dimethylaminopyridine (18 mg) and tosyl chloride (617 mg). The mixture is stirred overnight at room temperature, concentrated under reduced pressure and purified by chromatography over silica gel to give 495 g of 1-{3-[4-(4-tosyloxybut-1-yn-1-yl)phenoxy]propyl}piperidine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.[Mg].[C:11]([N:18]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>O1CCCC1>[Cl:9][C:4]1[CH:3]=[C:2]([C:20]2([OH:23])[CH2:21][CH2:22][N:18]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:19]2)[CH:7]=[CH:6][C:5]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Clc1ccc(Br)cc1Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
Preparation according to Preparation 1: 4-bromo-1,2-dichlorobenzene (2.0 g, 8.85 mmol), dry tetrahydrofuran (35 mL), magnesium turnings (0.21 g, 8.85 mmol) and 1-N-boc-3-pyrrolidinone (1.63 g, 8.85 mmol). Refluxed for 1 h before addition of 1-N-boc-3-pyrrolidinone and 2 h after addition. Yield: 1.0 g. MS m/z (rel. intensity, 70 eV) 332 (M+, 1), 275 (41), 232 (37), 231 (28), 230 (52), 57 (bp).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)=[NH:21])[CH:17]=3)[CH:12]=[CH:11]2)[CH2:6][CH2:5]O[CH2:3][CH2:2]1.I.[ClH:28]>CCOCC.CO>[ClH:28].[ClH:28].[N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)=[NH:21])[CH:17]=3)[CH:12]=[CH:11]2)[CH2:6][CH2:5][CH2:3][CH2:2]1
Reactant: N=C(Nc1ccc2ccn(CCCN3CCOCC3)c2c1)c1cccs1
Agent: Cl
Agent: I
Solvent: CCOCC
Solvent: CO
Product: N=C(Nc1ccc2ccn(CCCN3CCCC3)c2c1)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Reaction performed as described in Example 40, compound 150. Following isolation of the HI salt by precipitation (193.5 mg), the salt was dissolved in ethanol. Treated amberlite resin (3.00 g) was added to the solution, and the mixture stirred at room temperature for 30 minutes. The reaction was diluted with ethyl acetate (30 mL) and filtered. The filtrate was concentrated to afford a yellow oil. The material was absorbed onto silica gel and purified by silica gel column chromatography (5-10% 2M ammonia in methanol, 95-90% dichloromethane). The resulting yellow oil was found to be the desired product, compound 154, by 1H-NMR. The oil was dissolved in anhydrous dichloromethane (5 mL) and transferred to an argon purged reaction vial. The solution was treated with 1M hydrochloric acid in ether (3 mL) and the salt oiled out immediately. The reaction was stirred for 10 minutes and filtered. The vial and the filter were washed with ethyl acetate and the filtrate discarded. The yellow-brown oil which remained in the reaction vial was dissolved in methanol and the solution poured through the filter. The filter was washed with methanol and all organics combined and concentrated to afford a yellow oil. Additional drying under high vacuum afforded a yellow solid, compound 155. Yield: 116 mg of yellow solid. 1H-NMR (DMSO-d6) δ 7.73-7.72 (d, J=3.6 Hz, 1H), 7.60-7.59 (d, J=4.5, 1H), 7.46-7.43 (d, J=8.1 Hz, 1H), 7.21-7.20 (d, J=3 Hz, 1H), 7.11-7.08 (t, J=4.8 Hz, 1H), 6.92 (s, 1H), 6.60-6.57 (dd, J=1.2, 8.4 Hz, 1H), 6.34-6.33 (d, J=3 Hz, 2H), 4.16-4.12 (t, J=6.9 Hz, 2H), 2.46 (s, 4H), 2.36-2.31 (t, J=6.6 Hz, 2H), 1.93-1.83 (quintet, J=6.7 Hz, 2H), 1.67 (s, 4H). MW 353.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1F.C(OCC)(=O)[CH2:14][C:15]([O:17]CC)=[O:16]>>[F:9][C:6]1[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=[C:2]([F:1])[C:7]=1[CH2:14][C:15]([OH:17])=[O:16]
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: CCOC(=O)CC(=O)OCC
Product: O=C(O)Cc1c(F)cc([N+](=O)[O-])cc1F

Procedure:
The title compound 2,6-difluoro-4-nitrophenylacetic acid (16.0 g) was prepared from 3,4,5-trifluoronitrobenzene (14.8 g) and diethyl malonate (35 mL) in the same manner as described for REFERENCE EXAMPLE 1. MS (EI+) m/z: 217 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[C:24]3[O:23][CH2:22][C:21](=[O:25])[N:20]([CH3:26])[C:19]=3[CH:18]=[CH:17][CH:16]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37]>>[CH3:39][O:38][C:36]([C:35]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([OH:14])([C:15]3[C:24]4[O:23][CH2:22][C:21](=[O:25])[N:20]([CH3:26])[C:19]=4[CH:18]=[CH:17][CH:16]=3)[C:10]([F:11])([F:12])[F:13])=[C:4]([Cl:28])[CH:3]=2)=[CH:31][C:30]=1[F:29])=[O:37]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1cccc2c1OCC(=O)N2C)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3cccc4c3OCC(=O)N4C)C(F)(F)F)c(Cl)c2)cc1F

Procedure:
In analogy to Example 17, step 2, 8-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid to give the title compound as a light yellow oil. MS (m/e)=552.3 [M+H+].
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:21])/[CH2:10][CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:3][CH2:4][OH:5].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:21])/[CH2:10][CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])(=[O:24])[CH3:23]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC(C)CCO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCC(C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C

Procedure:
In 10 ml. of pyridine was dissolved 2.9 g. of the product obtained in Example 17, and to the solution was added 1.1 g. of acetic anhydride under stirring. The resulting mixture was then refluxed for 1 hour. The reaction mixture was then poured into 50 ml. of water, and was then extracted with n-hexane. The extract was washed with water and dried. The solvent was removed by evaporation. The residual oily product was purified by silica gel column chromatography to obtain 3.1 g. of the desired oily product.
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[Mg].F[SiH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=3)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>C1COCC1>[CH2:3]([Si@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:20]=[C:21]([F:27])[C:22]([F:26])=[C:23]([F:25])[CH:24]=3)=[CH:17][CH:18]=2)[CH2:9][CH2:8]1)[CH2:2][CH3:1]
Reactant: Fc1cc(-c2ccc(C3CC[SiH](F)CC3)cc2)cc(F)c1F
Reactant: CCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](c2ccc(-c3cc(F)c(F)c(F)c3)cc2)CC1

Procedure:
2.5 g (20 mmol) of n-propyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 6.5 g (20 mmol) of 4'-(4-fluoro-4-silacyclohexyl)-3,4,5-trifluorobiphenyl to obtain 4'-(trans-4-n-propyl-4-silacyclohexyl)-3,4,5-trifluorobiphenyl. The silacyclohexane rings of this product were a mixture of trans and cis isomers. They were separated by means of chromatography to obtain 5.9 g of the trans isomer (yield 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=4[O:24][CH3:25])[C:13](=[O:14])[C:4]=2[CH:3]=1)=[C:9]([C:26]([NH2:28])=O)[N:8]=[CH:7]3.P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=4[O:24][CH3:25])[C:13](=[O:14])[C:4]=2[CH:3]=1)=[C:9]([C:26]#[N:28])[N:8]=[CH:7]3
Reactant: COc1ccc(CN2Cc3c(C(N)=O)ncn3-c3ccc(Cl)cc3C2=O)c(OC)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(C#N)ncn3-c3ccc(Cl)cc3C2=O)c(OC)c1
Yield: 62 %

Procedure:
8-Chloro-5-(2,4-dimethoxy-benzyl)-6-oxo-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid amide (5.9 g, 13.8 mmol) and phosphorous oxychloride (1.4 mL, 15.2 mmol) were mixed in dioxane (55 mL) and refluxed overnight. The resulting yellow solution was evaporated and the residue purified by chromatography on silica gel in CH2Cl2/acetone 20:1. One obtained a white foam (3.5 g, 61%). m/z 408 (MH+)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]#[N:23])=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([C:13]([NH:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.O=[C:25]([CH3:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH2:30]([O:29][C:27]([C:26]1[C:25]([CH3:32])=[N:1][C:2]2[C:3]([C:22]=1[NH2:23])=[C:4]([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([C:13](=[O:14])[NH:15][CH:16]([CH3:18])[CH3:17])[CH2:9][CH2:8]1)[CH:19]=[CH:20][CH:21]=2)=[O:28])[CH3:31]
Reactant: CC(C)NC(=O)C1CCC(COc2cccc(N)c2C#N)CC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCC(C(=O)NC(C)C)CC3)c2c1N

Procedure:
Prepared as in Example 2a from 4-((3-amino-2-cyanophenoxy)methyl)-N-isopropylcyclohexanecarboxamide (Example 126b) and ethyl 3-oxobutanoate as a pale yellow solid (37%). 1H NMR (400 MHz, DMSO-d6) δ 1.01 (d, J=6.4 Hz, 6H), 1.32 (t, J=7.2 Hz, 3H), 1.38-1.81 (m, 8H), 1.88 (m, 1H), 2.25 (m, 1H), 2.55 (s, 3H), 3.82 (bro, J=7.6 Hz, 1H), 4.10 (d, J=6.4 Hz, 2H), 4.31 (q,J=7.6 Hz, 2H), 6.93 (d,J=7.6 Hz, 1H), 7.22 (d,J=8.8 Hz, 1H), 7.50 (m, 2H), 8.09 (s, 2H). MS 428 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][C:30](O)=[O:31]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:30](=[O:31])[CH2:29][O:28][CH2:27][CH2:26][O:25][CH3:24])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: COCCOCC(=O)O
Product: COCCOCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and (2-methoxy-ethoxy)-acetic acid to yield (3aR,4S,7aR)-4-[2-(2-methoxy-ethoxy)-acetoxy]-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 430; RT=7.850 min; HPLC Method I
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26]>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.O>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:21]2[CH:22]=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:19]([O:18][CH3:17])[CH:20]=2)=[N:9][CH:10]=1)([O-:16])=[O:15]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: O=[N+]([O-])c1ccc(Br)nc1
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: O
Product: COc1cc(-c2ccc([N+](=O)[O-])cn2)cc(OC)c1OC
Temperature: 70 °C
Reaction time: 12 h
Yield: 80.9 %

Procedure:
Under nitrogen, tetrakis(triphenylphosphine)palladium (504.6 mg, 0.437 mmol) and a 2.0 M aqueous sodium carbonate (25 mL, 50 mmol) were added to a solution of 2-bromo-5-nitropyridine (2.87 g, 14.1 mmol) and 3,4,5-trimethoxyphenylboronic acid (3.00 g, 14.2 mmol) in ethanol-toluene (1:5, 90 mL), and the resulting mixture was stirred at 70° C. for 12 hours. Water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel and crude crystals were obtained. The crude crystals were recrystallized from chloroform-hexane to provide 5-nitro-2-(3,4,5-trimethoxyphenyl)pyridine as yellow needles (melting point: 134.0-136.5° C. )(3.31 g, yield: 81%).