Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[C:31]1([CH2:37][C:38]([N:40]=[C:41]=[O:42])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.CCCCCC>[CH3:28][N:25]1[CH2:24][CH2:23][N:22]([CH:19]2[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]3[CH:8]=[C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:41]([NH:40][C:38](=[O:39])[CH2:37][C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[O:42])=[CH:30][CH:29]=4)[CH:12]=[CH:11][N:10]=3)=[O:15])[CH2:21][CH2:20]2)[CH2:27][CH2:26]1
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)CC1
Reactant: O=C=NC(=O)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccccc5)cc4)ccn3)CC2)CC1
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}pyridine (75.2 mg) in tetrahydrofuran (4.0 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 1.83 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2) to provide the titled compound (48.5 mg, 46%) as white powder.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:11]2[NH:10][C:9]3[CH:14]4[CH2:20][CH2:19][N:17]([CH2:18][C:8]=3[C:7]=2[CH:6]=1)[CH2:16][CH2:15]4)(=[O:4])=[O:3].[C:21]([C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[N:27][CH:28]=1)#[CH:22]>>[CH3:29][C:26]1[N:27]=[CH:28][C:23](/[CH:21]=[CH:22]\[N:10]2[C:11]3[CH:12]=[CH:13][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][C:7]=3[C:8]3[CH2:18][N:17]4[CH2:16][CH2:15][CH:14]([C:9]2=3)[CH2:20][CH2:19]4)=[CH:24][CH:25]=1
Reactant: CS(=O)(=O)c1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: C#Cc1ccc(C)nc1
Product: Cc1ccc(/C=C\n2c3c(c4cc(S(C)(=O)=O)ccc42)CN2CCC3CC2)cn1

Procedure:
The coupling of 9-(methylsulfonyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (150 mg, 0.517 mmol; Example 180) and 5-ethynyl-2-methylpyridine (182 mg, 1.55 mmol; prepared as described in International Publication No. WO2005090333) was performed according to the procedure described in Example 20 to afford the title compound as the major product: 1H NMR (300 MHz, methanol-d4) δ ppm 1.70-1.82 (m, 2H), 1.88-2.01 (m, 2H), 2.40 (s, 3H), 2.96-3.24 (m, 5H), 3.10 (s, 3H), 4.32 (s, 2H), 6.91 (d, J=8 Hz, 1H), 7.00 (d, J=8 Hz, 1H), 7.09 (s, 2H), 7.32 (d, J=9 Hz, 1H), 7.61 (dd, J=9, 2 Hz, 1H), 7.87 (s, 1H), 8.04 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 408 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=[O:18])[NH:6][N:5]=1)([CH3:3])[CH3:2].Br[CH2:20][CH2:21][CH2:22][Cl:23].C(Cl)(Cl)Cl.CO>CN(C)C=O>[CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=[O:18])[N:6]([CH2:20][CH2:21][CH2:22][Cl:23])[N:5]=1)([CH3:3])[CH3:2]
Reactant: ClCCCBr
Reactant: COc1cc2c(C(C)C)n[nH]c(=O)c2cc1OC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2c(C(C)C)nn(CCCCl)c(=O)c2cc1OC

Procedure:
1-[4-Isopropyl-6,7-dimethoxy-1(2H)-phthalazinone-2-yl]-3-chloro-propane was prepared analogous to Example 1 (a) by reaction of 4-isopropyl-6,7-dimethoxy-1(2H)-phthalazinone with 1-bromo-3-chloro-propane in dimethylformamide. Rf -value (chloroform/methanol = 50/1) : 0.5.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:29])[C@H:24]([CH:26]([CH3:28])[CH3:27])[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:29])=[O:22])[CH:26]([CH3:28])[CH3:27])=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@H](C(=O)O)C(C)C)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to L-valine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: C#C.[CH2:3]([Mg]Cl)[CH2:4]CC.[F:9][C:10]1[CH:19]=[CH:18][C:13]([O:14][CH2:15][CH:16]=[O:17])=[CH:12][CH:11]=1.[Cl-].[NH4+]>O1CCCC1>[OH:17][CH:16]([CH2:15][O:14][C:13]1[CH:18]=[CH:19][C:10]([F:9])=[CH:11][CH:12]=1)[C:3]#[CH:4]
Reactant: CCCC[Mg]Cl
Reactant: O=CCOc1ccc(F)cc1
Agent: C#C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)COc1ccc(F)cc1
Reaction time: 0.25 h
Yield: 48 %

Procedure:
Acetylene gas, dried by passing through a trap containing sulfuric acid, is bubbled at a moderate rate, through 5 ml of vigorously stirred tetrahydrofuran, for 15 minutes. To this acetylenic solution, is then added dropwise, with continued passage of acetylene, 3.5 ml of a 2.4M solution of n-butylmagnesium chloride in tetrahydrofuran (8.4 mmoles) over 45 minutes. The mixture is stirred a further 15 minutes, and a solution of 580 mg (3.9 mmoles) of p-fluorophenoxy acetaldehyde (Example 156) in 3 ml of tetrahydrofuran is added dropwise over 15 minutes. This solution is stirred for 2 more hours, with passage of acetylene, poured into 50 ml of a saturated solution of ammonium chloride, extracted twice with 50 ml of ether, washed with 10 ml of ammonium chloride solution, dried with magnesium sulfate, filtered, and evaporated. The crude subject product is purified by sublimation at 75° C. (0.1 mm) for 5 hours to give 330 mg (48%) of white crystals, mp 46°-47° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:24][C:23](=[O:25])[C:9]3[C:10](=[O:22])[NH:11][C:12]4[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:17]=4[C:8]=3[C:6]=2[CH:7]=1.CC(C[Al]CC(C)C)C.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][C:10](=[O:22])[C:9]=2[CH2:23][OH:25])[CH:7]=1
Reactant: O=c1[nH]c2ccc(C(F)(F)F)cc2c2c1c(=O)oc1ccc(Cl)cc12
Agent: CC(C)C[Al]CC(C)C
Agent: Cl
Solvent: ClCCl
Product: O=c1[nH]c2ccc(C(F)(F)F)cc2c(-c2cc(Cl)ccc2O)c1CO
Temperature: 0 °C
Yield: 69.4 %

Procedure:
To a cold suspension (−78° C.) of 2-chloro-6,8-dihydro-11-(trifluoromethyl)-7H-[1]benzopyrano[3,4-c]quinolin-6,7-dione prepared in Step C (1.0 g, 2.73 mmol) in methylene chloride (20 mL), a solution of Dibal-H (1M in methylene chloride, 13.7 mL, 13.7 mmol) was added dropwise. The reaction mixture was warmed to 0° C. and maintained for 3 hours. The reaction mixture was acidified with 1N HCl and extracted with ethyl acetate twice. The organic layer was separated and washed with water, brine and then dried (MgSO4). Evaporation of the solvent followed by recrystallization of the crude product from ethyl acetate/hexanes afforded the title compound as a white solid (0.7 g, 69%): mp>250° C.; MS m/e 368 (M−H)−.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][C:15](=[O:19])[NH:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35].C([O-])(O)=O.[Na+]>CC(O)C.C(Cl)(Cl)Cl>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][C:15](=[O:19])[NH:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1)=[O:35]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: NC1CCN(Cc2ccc3c(c2)NC(=O)CC3)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: COc1cccc(C(=O)NC2CCN(Cc3ccc4c(c3)NC(=O)CC4)CC2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a CHCl3 (5.00 mL) solution of the compound (250 mg) obtained in Step 1-6, iPr2NEt (370 μL) and 3-methoxybenzoyl chloride (180 mg) were added and the mixture was stirred at room temperature for three days. To the reaction mixture, a saturated aqueous NaHCO3 solution was added and the solution was extracted with CHCl3 four times. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography [(silica gel 60 N, mobile phase: MeOH/CHCl3=0/100 to 10/90; v/v) and (Chromatorex NH, mobile phase: CHCl3) in this order] to obtain a solid. To the solid obtained, IPA was added at room temperature and the mixture was stirred for one hour, filtrated and washed with IPA and hexane to obtain the titled compound (159 mg, a colorless solid).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[C:3]([O:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)=[CH:4][C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(OC)cc3)cc2OC1C(F)(F)F
Temperature: 105 °C
Reaction time: 18 h
Yield: 41.1 %

Procedure:
A 50 mL flask was charged with the substituted ethyl 2H-1-benzopyran-3-carboxylate from Step 2 (1.44 g, 4.43 mmol), 4-methoxyphenol (0.62 g, 4.99 mmol), K2CO3 (0.84 g, 6.07 mmol), and DMSO (10 mL). The reaction was stirred at 105° C. for 18 hours, poured into water extracted with ethyl acetate, washed with water, brine, dried over MgSO4 and concentrated in vacuo, to give a brown oil which was passed through a column of silica gel with 5% ethyl acetate/hexanes to give a yellow solid (0.78 g, 41%): mp 115.8–117.0° C. 1H NMR (CDCl3/300 MHz) 7.66 (s, 1H), 7.32 (s, 1H), 7.04 (d, 2H, J=9.3 Hz), 6.98 (d, 2H, J=9.1 Hz), 6.38 (s, 1H), 5.65 (q, 1H, J=6.8 Hz), 4.33 (m, 2H), 3.86 (s, 3H), 1.37 (t, 3H, J=7.2 Hz). 19F NMR (CDCl3/282 MHz) −78.9 (d, J=6.5 Hz).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][Br:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Br-:11].[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P+:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: [Br-]
Product: c1ccc(CCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-phenylbutyl bromide from the Step A (24.7 g) and triphenylphosphine (19.00 g) in toluene (100 mL) was heated at 120-130° C. for 3 days. The reaction was cooled to rt and the solid precipitate was collected by filtration, washed with toluene and air dried. The solid was dissolved in a 2:1 mixture of water and acetonitrile and gave the title compound (30.6 g) as a white solid after lyopholization.
Reaction SMILES: I[CH2:2][CH:3]([CH3:17])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12](C)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16].CC[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22].[CH3:25][OH:26]>>[CH3:25][O:26][C:12]1[CH:13]=[CH:14][C:9]2[O:8][CH2:7][C:6](=[O:16])[N:5]([CH2:4][C@H:3]([CH3:17])[CH2:2][N:20]3[CH2:21][CH2:22][CH:7]([O:8][CH2:9][CH2:10][CH3:11])[CH2:24][CH2:23]3)[C:10]=2[CH:11]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccc2c(c1)N(CC(C)CI)C(=O)CO2
Reactant: CO
Product: CCCOC1CCN(C[C@@H](C)CN2C(=O)COc3ccc(OC)cc32)CC1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
A 7 mL vial was charged with the crude 4-(3-iodo-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one (1 equiv), Et3N (0.5 mL) and the secondary amine (1.2-1.5 equiv). This mixture was shaken at 60° C. for 72 h and thereafter diluted with MeOH (10 mL) and concentrated with basic Al2O3 (2 g) and purified by flash chromatography.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][CH:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH2:47][CH3:48])[N:25]3[N:49]=[CH:50][N:51]=[C:24]23)=[CH:19][CH:18]=1)[CH3:15]>C(OCC)(=O)C>[CH2:45]([C:26]1[N:25]2[N:49]=[CH:50][N:51]=[C:24]2[N:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH:14]([CH3:15])[CH3:13])=[CH:18][CH:19]=2)[C:28](=[O:29])[C:27]=1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]2[NH:3][C:4](=[O:7])[O:5][N:44]=2)=[CH:33][CH:32]=1)[CH2:46][CH2:47][CH3:48]
Reactant: O=C([O-])O
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)C)cc2)c2ncnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc(OC(C)C)cc2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogen carbonate (2.2 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({4-[4-(1-methylethoxy)phenyl]-5-oxo-7-butyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.69 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.26 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.31 g, 40%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:50])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([C:30]3[CH:34]=[C:33]([C:35]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[NH:36])[S:32][C:31]=3[S:45][CH3:46])(=[O:29])=[O:28])[CH:22]=2)=[C:16]([N+:47]([O-])=O)[CH:15]=1)=[O:12])[CH3:2].[NH4+].[Cl-]>CCO.[Fe]>[CH2:1]([O:3][C:4](=[O:50])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([C:30]3[CH:34]=[C:33]([C:35]([NH:37][C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])=[NH:36])[S:32][C:31]=3[S:45][CH3:46])(=[O:29])=[O:28])[CH:22]=2)=[C:16]([NH2:47])[CH:15]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)CCCCCNC(=O)Nc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CCCCCNC(=O)Nc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(N)c1

Procedure:
6-(3-{3′-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-2-nitro-biphenyl-4-yl}-ureido)-hexanoic acid ethyl ester (74 mg, 98.9 μmol, Example 278: step b) in EtOH (5 mL) was reduced as in Example 20: step c using Fe (28 mg, 0.50 mmol) and aqueous NH4Cl solution (50 mg, 0.93 mmol, 10 mL). The solvents were removed from the filtrate in vacuo. The crude was diluted in EtOAc and washed with water and brine. The organic layer was dried over magnesium sulfate. The solvents were removed in vacuo to yield the title compound as a brown oil (70.8, quantitative). ESI-MS (m/z): Calcd. for C33H43N5O7S3: 718.2 (M+1); found: 718.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[CH:8]1([O:16][CH2:17]CO)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:8]1([O:16][CH2:17][CH2:1][O:2][C:3]2[S:4][CH:5]=[CH:6][CH:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COc1cccs1
Reactant: OCCOC1CCCCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: c1csc(OCCOC2CCCCCCC2)c1
Yield: 61.9 %

Procedure:
As in Example 1, a solution of 2-methoxythiophene (11.4 g) and 2-(cyclooctyloxy) ethanol (13.78 g) in benzene (200 mL) containing para-toluenesulfonic acid (0.1 g) was stirred at reflux for 3 days in a flask equipped with a Soxhlet extractor charged with 4 Å molecular sieves. After the reaction was worked up in the usual manner, the crude product was purified by HPLC (hexane-diethyl ether; 2.4: 1) to give 12.6 g of 2-[[2-(cyclooctyloxy) ethyl]oxy]thiophene as a colorless oil. A small portion was distilled in a Kugelrohr apparatus (~130 ° C./0.02 mm) to furnish the analytical specimen.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][NH:7][C:8](N)=O.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O.[OH-].[Na+].Cl.CN(C)[CH:24]=[O:25]>>[CH2:17]([O:16][C:11]([C:12]1[C:14]([CH:24]=[O:25])=[CH:8][NH:7][N:6]=1)=[O:15])[CH3:18]
Reactant: NNC(N)=O
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1n[nH]cc1C=O
Temperature: 60 °C

Procedure:
Phosphorus oxychloride (5.07 ml) was added dropwise to dimethylformamide (8.4 ml) at 0° C. under nitrogen. Ethyl pyruvate semicarbazide (4.3 g, Reference Example 58) was added portionwise to the stirring solution at 0° C. under a nitrogen positive pressure. The reaction mixture was heated at 60° C. for 2.5 hours and cooled to ambient temperature before pouring slowly onto ice (30 g). The pH of the reaction mixture was adjusted to pH12 with 6.25M sodium hydroxide solution whilst maintaining the temperature at 0° C. The aqueous reaction mixture was heated at 60° C. for 5 minutes and cooled to 0° C. The pH was re-adjusted to pH6 with 1M hydrochloric acid. The resulting precipitate which formed after 1 hour was collected by filtration to yield 4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.02 g) as a pale yellow solid. LC-MS (Method J): RT=2.55 minutes, 169.27 (M+H)+, 167.30 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1B1OC(C)(C)C(C)(C)O1)[C:5]([O:7][CH3:8])=[O:6].Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]([F:30])[F:29].[F-].[Cs+].O>O1CCOCC1.CC(OC)(C)C.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:29][CH:28]([F:30])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[CH3:1]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: FC(F)c1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccccc2C(F)F)c(C)c1
Temperature: 90 °C

Procedure:
A mixture of methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Combiblocks PN-8756, 1.9 g, 6.7 mmol), 1-bromo-2-difluoromethyl-benzene (Fluorochem 023878, 1.7 g, 8.1 mmol), cesium fluoride (3.1 g, 20 mmol) and PdCl2(PPh3)2 (142 mg, 0.20 mmol) was prepared in dioxane (20 mL) and water (10 mL) under N2 atmosphere. The resulting mixture was heated at 90° C. for 2 hours. The reaction mixture was diluted with MTBE (60 mL), and then washed with water (2×50 mL) and brine (50 mL). The aqueous layers were extracted with MTBE (50 mL). The organic layers were combined, dried (MgSO4) and concentrated under reduced pressure. After purification by flash chromatography (silica, DCM/heptane), the title compound was obtained as a colorless oil (1.4 g, 76%). HPLC (Method A) Rt 5.0 min (purity: 99.1%). 1H NMR (DMSO-d6, 300 MHz) δ 7.93 (s, 1H), 7.84 (dd, J=7.9, 1.4 Hz, 1H), 7.75 (m, 1H), 7.67-7.56 (m, 2H), 7.28 (m, 2H), 6.55 (t, J=55 Hz, 1H), 3.88 (s, 3H), 2.06 (s, 3H).
Reaction SMILES: O1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([Li])[CH2:7][CH2:8][CH3:9]>CCCCCC>[CH2:2]=[CH:3][CH:4]=[CH2:5].[CH2:2]=[CH:3][C:4]1[CH:5]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:2]=[CH:3][CH:4]=[CH2:5].[CH2:2]=[CH:3][C:4]1[CH:5]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [Li]CCCC
Reactant: C1CCOC1
Solvent: CCCCCC
Product: C=CC=C
Product: C=Cc1ccccc1
Reaction time: 3.5 h

Procedure:
500 ml of butadiene and 270 ml of styrene are polymerized in 2,700 ml of mineral oil (viscosity 2.3° E/50° C) in the presence of 6.0 ml of tetrahydrofuran at 50° C, by means of 10 ml of a 5% strength solution of n-butyl-lithium in hexane. The polymerization time is 3.5 hours. A random butadiene-styrene copolymer is formed, which according to the IR spectrum contains 40% of styrene and has a 1,2-vinyl content of the butadiene units of 27%, based on copolymerized butadiene. The number-average molecular weight, determined in toluene at 37° C by means of a membrane osmometer, is about 75,000. 20 ml of a homogeneous catalyst solution, comprising 0.3 g of nickel-II acetylacetonate, 10 ml of a 20% strength aluminum-triisobutyl solution in hexane and 10 ml of toluene, are then added to the polymer solution. Hydrogenation is carried out under a pressure of 10 bars of hydrogen at 75° C. After the hydrogenation, the proportion of olefinic double bonds in the random butadiene-styrene copolymer was found to have been reduced to a residual proportion of about 0.5% (determined from the IR spectrum). The ratio of the extinction of the styrene bands in the IR spectrum (recorded by means of an IR-spectrophotometer from Perkin-Elmer, Model 521), i.e., E(1,180)/E(1,150) and E(1,190)/E(1,180), of the selectively hydrogenated random butadiene-styrene copolymer is respectively 0.72 and 0.18. In the 13C-NMR spectrum, the ratio ΣCH2 (β and ethyl)/ΣCH2 (γ, δ and more remote) is 1:1.15.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].Cl[CH2:13][CH:14]=[C:15]([CH3:35])[CH2:16][CH2:17][CH2:18][C:19]([Cl:34])([CH3:33])[CH2:20][CH2:21][CH2:22][C:23]([Cl:32])([CH3:31])[CH2:24][CH2:25][CH2:26][C:27]([Cl:30])([CH3:29])[CH3:28].CCCCCC.O>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:35][C:15]1([CH2:16][CH2:17][CH2:18][C:19]([Cl:34])([CH3:33])[CH2:20][CH2:21][CH2:22][C:23]([Cl:32])([CH3:31])[CH2:24][CH2:25][CH2:26][C:27]([Cl:30])([CH3:29])[CH3:28])[CH2:14][CH2:13][C:8]2[C:6](=[C:5]([CH3:9])[C:4]([CH3:10])=[C:3]([OH:11])[C:2]=2[CH3:1])[O:7]1
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: CC(=CCCl)CCCC(C)(Cl)CCCC(C)(Cl)CCCC(C)(C)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)(Cl)CCCC(C)(Cl)CCCC(C)(C)Cl)O2
Temperature: 30 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
Trimethylhydroquinone (8.4 g), 1,7,11,15-tetrachloro-3,7,11,15-tetramethyl-hexadec-2-ene (22 g) and acetic acid (30 cc) are introduced into a 250 cc reactor. A solution of zinc chloride (1.5 g) in anhydrous acetic acid (15 cc) is then added in the course of 10 minutes. The temperature rises from 25° to 30° C. The reaction mixture is stirred for 2 hours at 30° C. and is then poured into a mixture of hexane (100 cc) and water (100 cc). The organic phase is separated by decanting and washed with a mixture (100 cc) of methanol and water (50:50 by volume). A white precipitate forms in the hexane phase, and this is filtered off and washed with a mixture (50 cc) of methanol and water (50:50 by volume). After the precipitate has been dried under reduced pressure, 2,5,7,8-tetramethyl-2-(4',8',12'-trichloro-4',8',12'-trimethyl-tridecyl)-chroman-6-ol (14.3 g) is obtained in the form of white crystals melting at 102°-104° C. The yield is 62%.