Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:4]=1[CH:5](Cl)Cl.[OH-].[Na+].[H][H]>[Pd].[C].O>[CH3:5][C:4]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:3]=1[C:2]([F:13])([F:1])[F:14]
Reactant: [H][H]
Reactant: FC(F)(F)c1cc(Cl)ccc1C(Cl)Cl
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(Cl)cc1C(F)(F)F
Temperature: 30 °C
Yield: 122.5 %

Procedure:
A 1000-ml autoclave which is equipped with a mechanical stirrer and made of stainless steel (SUS-316) was charged with 263.6 g (1.0 mol) of the isomeric mixture (the product of the first step) containing 0.72 mol of 2-trifluoromethyl-4-chlorobenzalchloride as a main component, 84 g (2.1 mol) of sodium hydroxide and 420 g of water. Then, 5.3 g (2.0 wt %) of a metal-carried catalyst (5%-Pd/carbon) was added to the autoclave. The atmosphere of the autoclave was replaced by hydrogen, and the autoclave was put into oil bath to increase the temperature to 30° C. At the same time, stir was started while the hydrogen pressure was maintained at 5 kg/cm2. This started absorption of hydrogen. After the lapse of 4 hr, stir was stopped, and the reaction liquid was allowed to cool down. By analysis, conversion of 2-trifluoromethyl-4-chlorobenzalchloride (purity: 72.1%) was 99.9%. Then, the catalyst and the salt were removed by vacuum filtration. The resultant solution was put into a 1000-ml separating funnel, and then the aqueous phase was removed. The organic phase was washed with 500 ml of water and dried with magnesium sulfate. Then, magnesium sulfate was removed by vacuum filtration. As the result, 171.6 g of 2-methyl-5-chlorobenzotrifluoride (purity: 63.8%) was obtained. The yield of this product was 79.0%.
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH2:33])[CH:20]=1.[N:34]1([C:40]2[N:41]=[C:42]([CH2:47][C:48]([O-])=[O:49])[NH:43][C:44](=[O:46])[CH:45]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[Na+]>CN(C)C=O>[N:34]1([C:40]2[N:41]=[C:42]([CH2:47][C:48]([NH:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[O:49])[NH:43][C:44](=[O:46])[CH:45]=2)[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccccc1OCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccccc1OCc1cccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 37.2 %

Procedure:
2 ml of pyridine, 300 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 366 mg of 2-(pyridin-3-ylmethoxy)phenylamine are added to a solution of 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 2 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 20 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 150 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-[2-(pyridin-3-ylmethoxy)phenyl]acetamide are obtained in the form of a brown solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[OH:10].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[O:10][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1
Reactant: OCc1ccc(Cl)c(O)c1
Reactant: Fc1ccc(CBr)cc1
Product: OCc1ccc(Cl)c(OCc2ccc(F)cc2)c1

Procedure:
The title compound was prepared from 2-chloro-5-(hydroxymethyl)phenol and 4-(bromomethyl)-1-fluorobenzene according to the procedure for the preparation of Example 117, part A. 1H NMR (400 MHz, CDCl3): δ 1.71 (1H, t, J=6.0 Hz), 4.65 (2H, d, J=6.4 Hz), 5.12 (2H, s), 6.88-6.90 (1H, m), 7.02 (1H, d, J=2.0 Hz), 7.05-7.10 (2H, m), 7.35 (1H, d, J=8.0 Hz), 7.43-7.46 (2H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH:4]([CH:5]([OH:13])[C:6]([Cl:12])([Cl:11])[C:7]([F:10])([F:9])[F:8])[CH:3]1[C:14]([O:16][CH3:17])=[O:15].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[CH:4]([CH:5]([O:13][C:19](=[O:21])[CH3:20])[C:6]([Cl:11])([Cl:12])[C:7]([F:8])([F:9])[F:10])[CH:3]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C1C(C(O)C(Cl)(Cl)C(F)(F)F)C1(C)C
Solvent: c1ccncc1
Product: COC(=O)C1C(C(OC(C)=O)C(Cl)(Cl)C(F)(F)F)C1(C)C
Reaction time: 8 h
Yield: 93 %

Procedure:
To 50 mg (0.16 mmol) of methyl 2,2-dimethyl-3-(1-hydroxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate obtained in Example 1, 0.2 ml of acetic anhydride and 0.2 ml of pyridine were added, and the mixture was left overnight at room temperature. In the same manner as in Example 9, 53 mg of methyl 2,2-dimethyl-3-(1-acetoxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate was obtained as a colorless oily substance. Yield: 93%. The physical property values were the same as those in Example 7.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:26]#[C:27][C:28]4([NH:36]C(=O)OC(C)(C)C)[CH2:33][O:32]C(C)(C)[O:30][CH2:29]4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>CCO.C(C(O)=O)(F)(F)F.[Pd]>[NH2:36][C:28]([CH2:27][CH2:26][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:11]([C:1]23[CH2:2][CH:3]4[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]4)[CH2:10]2)[CH2:8]3)[CH:12]=1)([CH2:33][OH:32])[CH2:29][OH:30]
Reactant: CCCCCCCCOc1ccc(C#CC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C12CC3CC(CC(C3)C1)C2
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCCCCCCCOc1ccc(CCC(N)(CO)CO)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 1 h
Yield: 80.3 %

Procedure:
A slurry of the product of Step B (0.04 g, 0.068 mmol) and 10% Pd/C (0.04 g) in a mixture of EtOH: CF3CO2H (10 ml: 2 drops) was stirred for 36 h under H2. The mixture was filtered through Celite bead and washed with EtOH (10 ml). The filtrates were evaporated to dryness and the residue was dissolved in MeOH:CH2Cl2 1:1 (5 ml) and 5 drops of concentrated HCl was added. The mixture was stirred for 1 h and solvents were evaporated to dryness. The residue was crystallized from CH3CN to give the titled compound (0.025 g, 81%) as colourless powder. 1H-NMR (CDCl3) 0.79 (t, 3H, J=6.57 Hz); 1.12-1.21 (m, 7H); 1.37-1.41 (m, 2H); 1.69 (s, 6H); 1.73-1.88 (m, 3H); 2.00 (b, 9H); 2.48-2.52 (m, 2H); 3.61 (d, 2H, J=11.84 Hz); 3.67 (d, 2H, J=12.2 Hz); 3.85 (tr, 2H, J=6.22 Hz); 6.69 (d, 1H, J=8.13 Hz); 6.88-7.93 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:6][N:7]([CH2:11][CH2:12][O:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:8][CH2:9][CH:10]=1)=[O:4].[OH-].[Na+].O.[ClH:33]>C(O)C>[ClH:33].[CH3:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:14][O:13][CH2:12][CH2:11][N:7]1[CH2:8][CH2:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH2:6]1
Reactant: COC(=O)C1=CCCN(CCOC=C(c2ccccc2C)c2ccccc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C(=COCCN1CCC=C(C(=O)O)C1)c1ccccc1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76 %

Procedure:
1-(2-((2,2-bis(2-Methylphenyl)ethenyl)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester (0.70 g, 0.0018 mol, prepared similarly to the method described in Example 65) was dissolved in ethanol (30 ml) and 10 N sodium hydroxide solution (1.79 ml) was introduced. The reaction mixture was stirred at room temperature for 2.5 h and water (100 ml) was added, followed by 2 N hydrochloric acid solution to pH 10. Ethanol was removed by evaporation under reduced pressure, and the aqueous solution was washed with ethyl acetate (20 ml). The aqueous phase was separated, acidified to pH 2 with 2 N hydrochloric acid solution, and extracted with dichloromethane (4×50 ml). The combined extracts was dried (MgSO4) and the residue was crystallized from propanol/toluene to give the title compound (0.53 g, 76%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[CH2:16]([O:18][CH2:19][CH2:20]Br)[CH3:17]>>[CH2:16]([O:18][CH2:19][CH2:20][O:8][C:4]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[C:2]([NH2:1])[N:6]([CH3:7])[N:5]=1)[CH3:17]
Reactant: Cc1ccc(-c2c(O)nn(C)c2N)cc1
Reactant: CCOCCBr
Product: CCOCCOc1nn(C)c(N)c1-c1ccc(C)cc1

Procedure:
The method of Preparation 37 was used to prepare the title compound from 5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-ol (Preparation 3a) and 2-bromoethyl ethyl ether.
Reaction SMILES: [N+](=[CH2:3])=[N-].[Br:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[C:8]([OH:15])=[CH:7][CH:6]=1>C(OCC)C.CO>[Br:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[C:8]([O:15][CH3:3])=[CH:7][CH:6]=1
Reactant: C=[N+]=[N-]
Reactant: COC(=O)c1nc(Br)ccc1O
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1nc(Br)ccc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of diazomethane in diethyl ether (about 0.4 M) is added in excess to a solution of 2.3 mmol of methyl 6-bromo-3-hydroxypyridine-2-carboxylate [321601-48-3] in 30 ml of methanol at 0° C. The mixture is stirred at 0° C. for 2 hours, then quenched with magnesium sulphate, filtered and evaporated. The crude title compound is identified by means of the Rf.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[OH:14][CH2:15][C@@H:16]1[O:20][C:19]([C:21]2[NH:25][C:24]([C:26]3[CH:27]=[C:28]([OH:38])[CH:29]=[C:30]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:31]=3)=[CH:23][CH:22]=2)=[N:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:11]1([S:8]([C:5]2[N:6]=[CH:7][C:2]([O:38][C:28]3[CH:27]=[C:26]([C:24]4[NH:25][C:21]([C:19]5[O:20][C@@H:16]([CH2:15][OH:14])[CH2:17][N:18]=5)=[CH:22][CH:23]=4)[CH:31]=[C:30]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:29]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:13][CH2:12]1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Reactant: O=S(=O)(c1ccc(Cl)cn1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)C3CC3)nc2)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
5-Chloro-2-(cyclopropylsulfonyl)pyridine (168 mg, 0.77 mmol) synthesized in Example (125c) and 3-{5-[(5R)-5-(Hydroxylmethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenol (401 mg, 1.16 mmol) synthesized in Example (125g) were dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (213 mg, 154 mmol) was added, followed by stirring at 100° C. for 3 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (30 mL) was added, and extraction was carried out twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0.5%-5%) to afford the desired compound (139 mg, yield 34%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:28])[C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21]O)=[C:19]([CH3:23])[N:18]=[C:17]1[CH2:24][N:25]([CH3:27])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:48]1(=[O:58])[NH:52][C:51](=[O:53])[C:50]2=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]12.N(C(OCC)=O)=NC(OCC)=O>>[Br:15][C:13]1[CH:12]=[CH:11][C:10]([N:16]2[C:20]([CH2:21][N:52]3[C:48](=[O:58])[C:49]4=[CH:57][CH:56]=[CH:55][CH:54]=[C:50]4[C:51]3=[O:53])=[C:19]([CH3:23])[N:18]=[C:17]2[CH2:24][N:25]([CH3:26])[CH3:27])=[C:9]([C:8](=[O:28])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:14]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1nc(CN(C)C)n(-c2ccc(Br)cc2C(=O)c2ccccc2Cl)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(CN(C)C)n(-c2ccc(Br)cc2C(=O)c2ccccc2Cl)c1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 3, 2'-chloro-5-bromo-2-[2-[(dimethylamino)methyl]-4-methyl-5-hydroxymethylimidazol-1-yl]benzophenone, triphenylphosphine, phthalimide and thereafter diethyl azodicarboxylate are reacted together to give N-[[1-[4-bromo-2-(o-chlorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol- 5-yl]methyl]-phthalimide.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10]Br)[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:21][CH2:10][C:8]1[C:7]([F:12])=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: N#Cc1cc(F)c(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1cc(F)c(COc2ccc(Cl)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 36 h
Yield: 21.2 %

Procedure:
To a stirred solution of 2,5-difluoro-4-(bromomethyl)benzonitrile (Preparation 22, 530 mg, 2.30 mmol) and 3,4-dichlorophenol (375 mg, 2.30 mmol) in acetone (12 mL) was added potassium carbonate (954 mg, 6.90 mmol). The mixture was stirred at room temperature for 36 hours. The reaction mixture was then poured into water (25 mL) and extracted with EtOAc (3×25 mL). The combined organics were dried over sodium sulphate and evaporated to yield the crude product as a yellow oil, which was purified by silica gel chromatography eluting with 50% heptanes in DCM to afford the title compound as a white solid (153 mg, 22%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])=[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:4]=1)#[N:7]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(N)c(Nc2ccc(F)cc2F)c1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(C#N)cc1Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-amino-3-(2,4-difluorophenylamino)benzonitrile (1.2 g) and methanesulfonyl chloride (0.45 ml) in pyridine (12 ml) was stirred for 4 hours at room temperature. Pyridine was evaporated and the residue was stirred with an aqueous solution of sodium hydroxide (5%; 40 ml) for 10 minutes. The solution was washed with toluene, acidified to pH 3 with hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried and evaporated to dryness. The residue (1.4 g) was recrystallized from ethanol to give colorless prisms of 4'-cyano-2'-(2,4-difluorophenylamino)methanesulfonanilide (1.2 g).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(CC)CC)C.[Si:22]([C:26]#[CH:27])([CH3:25])([CH3:24])[CH3:23]>C1COCC1.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.[Cu]I>[CH3:23][Si:22]([C:26]#[C:27][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])([CH3:25])[CH3:24]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)c1cccc(I)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1cccc(C#C[Si](C)(C)C)c1
Reaction time: 18 h

Procedure:
A mixture of tert-butyl 3-iodobenzoate (I15) (4.02 g, 13.2 mmol), Pd(PPh3)4 (0.38 g, 0.33 mmol) and copper(I) iodide (0.13 g, 0.68 mmol) was dissolved in anhydrous THF (50 mL) under a nitrogen atmosphere and the resulting solution degassed by bubbling nitrogen through it. Triethylamine (9.2 mL, 66 mmol) was added and the mixture was then stirred for 10 minutes before addition of TMS-acetylene (3.8 mL, 27 mmol). The resulting mixture was then stirred for 18 hours. The mixture was concentrated under reduced pressure and purified using silica gel column chromatography (0-10% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I16) (3.57 g, 99%) as a cream crystalline solid; 1H NMR (400 MHz, CDCl3) δ 8.06 (ddd, J=1.7, 1.7, 0.5 Hz, 1H), 7.92 (ddd, J=7.9, 1.3, 1.3 Hz, 1H), 7.60 (ddd, J=7.7, 1.4, 1.4 Hz, 1H), 7.35 (ddd, J=7.8, 7.8, 0.5 Hz, 1H), 1.59 (s, 9H), 0.26 (s, 9H). LCMS Method C: rt 7.46 min.
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:11]3(COOC3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH2:18]>C(O)(=O)C>[F:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:11](=[O:18])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O
Reactant: Fc1cccnc1N1CCC2(CC1)COOC2
Solvent: CC(=O)O
Product: O=C1CCN(c2ncccc2F)CC1

Procedure:
8-(3-fluoro-pyridin-2-yl)-2,3-dioxa-8-azaspiro[4.5]decane 17 (347 g, 1.456 Mol) was dissolved in acetic acid (700 mL) and water (140 mL) and the mixture heated to 85° C. under nitrogen for 18 h. LC/MS shows the reaction at 92% conversion at this stage. The mixture was evaporated to dryness in vacuo, to leave orange oil. This material was used directly in the next step without further purification
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Li]CCCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C>O1CCCC1>[O:9]1[C:5]2[CH:4]=[CH:3][C:2]([B:16]([OH:21])[OH:17])=[CH:10][C:6]=2[CH:7]=[CH:8]1
Reactant: Brc1ccc2occc2c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2occc2c1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
The solution of 5-bromo-1-benzofuran (1.0 g, 5.08 mmol) in dry tetrahydrofuran (50 mL) was kept below −60° C. under nitrogen, while BuLi (6.09 mmol, 2.5M solution in hexane) was added dropwise. It was warmed to −30° C. during 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below −60° C. followed by dropwise addition of triisopropyl borate (1.44 g, 7.66 mmol). After warming to room temperature the mixture was quenched with hydrochloric acid (30 mL, 2N) and stirred for 1 h. The alkaline aqueous layer was brought to pH 5 and extracted with ethyl acetate (3×80 mL). All organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give (1-benzofuran-5-yl)boronic acid (500 mg, crude), which was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+:13].I[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18]>O.C(O)(C)C>[CH3:18][CH:17]([CH3:19])[CH2:16][CH2:15][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:4][CH:3]=1.[Na+:13]
Reactant: O=S(=O)(O)c1ccc(O)cc1
Reactant: CC(C)CCI
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)CCOc1ccc(S(=O)(=O)[O-])cc1

Procedure:
A solution of 4-hydroxybenzenesulfonic acid (10.0 grams, 43.1 mmole) and sodium hydroxide (3.3 grams, 83 mmole) in water (40 mL) was mixed with a solution of 1-iodo-3-methylbutane (11.3 mL, 86.4 mmole) in isopropanol (60 mL) and the resulting mixture was heated at reflux for 2 days. The isopropanol was removed by evaporation under vacuum. The title compound, 10.0 grams (87%), was collected by filtration and washed with isopropanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[C:25]([N+:33]([O-:35])=[O:34])[CH:24]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH:13]=2)(=[O:11])=[O:10])(=[O:30])=[O:31])=[C:25]([N+:33]([O-:35])=[O:34])[CH:24]=1
Reactant: COc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccccc2NS(=O)(=O)c2cc3ccccc3s2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-aminophenyl) amide (1 mmol, prepared as in Example 1) in DCM (2 mL) and pyridine (2 mL), 4-methoxy-2-nitrobenzenesulfonyl chloride (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (10 mL). The organic phase was washed with 10% aqueous HCl (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 348 mg of benzo[b]thiophene-2-sulfonic acid [2-(4-methoxy-2-nitro-benzenesulfonylamino)phenyl]-amide. LC: Tr 1.09 min; MS: 520.7 (M+1)+.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7](Cl)[N:6]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:4]=1.Cl>O1CCCC1>[NH2:1][C:7]1[C:8]([N+:9]([O-:11])=[O:10])=[C:3]([Cl:2])[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:6]=1
Reactant: N
Reactant: O=[N+]([O-])c1c(Cl)nc(-c2ccc(F)cc2)nc1Cl
Agent: Cl
Solvent: C1CCOC1
Product: Nc1nc(-c2ccc(F)cc2)nc(Cl)c1[N+](=O)[O-]
Yield: 87 %

Procedure:
28% aqueous ammonia (3.1 mL) was added to a solution of 4,6-dichloro-2-(4-fluorophenyl)-5-nitropyrimidine (5.0 g, 17.4 mmol) in tetrahydrofuran (50 mL) at −50° C. until the starting material disappeared. After addition of 3N hydrochloric acid (5 mL) to the reaction solution at the same temperature, the reaction temperature was raised and then the mixture was concentrated in vacuo. Water was added to the residue, and the resulting suspension was filtered, then dried to give the objective compound as a solid (4.05 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH3:11])[CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)C(=O)Oc1ccc(Cl)cc1
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](COCCCCN2CCCCC2)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the method described in example 12.1, trans-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester was reacted with piperidine in N,N-dimethylacetamide at 50° C. for 2 hours to yield trans-methyl-[4-(4-piperidin-1-yl-butoxymethyl)-cyclohexylmethyl]-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 451 (MH+, 1Cl).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(CO)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 69 h
Yield: 88 %

Procedure:
To a solution of the alcohol from above (200 mg, 0.796 mmol) in CH2Cl2 (8 mL) was added activated MnO2 (814 mg, 7.96 mmol) and the mixture stirred at room temperature for 69 h. The reaction mixture was filtered through Celite and the cake was washed with CH2Cl2. The solvent was removed from the filtrate under reduced pressure to give the desired aldehyde as colourless crystals (175 mg, 88%). 1H NMR (CDCl3) δ1.43 (s, 9H), 2.89 (m, 2H), 3.41 (m, 2H), 4.55 (br s, 1H), 7.37 (d, 2H, J=8.1 Hz), 7.83 (d, 2H, J=7.8 Hz), 9.99 (s, 1H).