Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:20][CH2:21][OH:22])(=[N:10][S:11]([CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])(=[O:13])=[O:12])=[O:9])=[CH:4][CH:3]=1.Cl.[Br:24][C:25]1[C:26]([O:32][C@H:33]([CH3:37])[C@H:34]([OH:36])[CH3:35])=[N:27][C:28](Cl)=[N:29][CH:30]=1>C(#N)C.O1CCOCC1>[Br:24][C:25]1[C:26]([O:32][C@H:33]([CH3:37])[C@H:34]([OH:36])[CH3:35])=[N:27][C:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH2:20][CH2:21][OH:22])(=[N:10][S:11]([CH2:14][CH2:15][Si:16]([CH3:18])([CH3:17])[CH3:19])(=[O:12])=[O:13])=[O:9])=[CH:4][CH:3]=2)=[N:29][CH:30]=1
Reactant: C[C@@H](O)[C@@H](C)Oc1nc(Cl)ncc1Br
Reactant: C[Si](C)(C)CCS(=O)(=O)N=S(=O)(CCO)c1ccc(N)cc1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: C[C@@H](O)[C@@H](C)Oc1nc(Nc2ccc(S(=O)(CCO)=NS(=O)(=O)CC[Si](C)(C)C)cc2)ncc1Br
Temperature: 70 °C
Reaction time: 24 h

Procedure:
A solution of 205 mg (0.56 mmol) of (RS)—S-(4-aminophenyl)-S-(2-hydroxyethyl)-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximide in 2 ml of acetonitrile is mixed with 0.15 ml of a 4N solution of HCl in dioxane. 175 mg (0.62 mmol) of (2R,3R)-3-[(5-bromo-2-chloropyrimidin-4-yl)oxy]-butan-2-ol in 2 ml of acetonitrile is added, and the batch is stirred for 24 hours at 70° C. Then, it is stirred for another 24 hours at 85° C. The solvent is removed, and the remaining residue is purified by chromatography (DCM/EtOH 9:1). 110 mg (0.18 mmol, corresponding to 32% of theory) of the product is obtained.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[N+:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41](Cl)(=[O:43])=[O:42])([O-:34])=[O:33]>C(Cl)Cl>[F:24][C:4]([F:3])([F:23])[C:5]([C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([S:41]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[N+:32]([O-:34])=[O:33])(=[O:42])=[O:43])[CH2:19][CH2:18]2)=[CH:15][CH:16]=1)([OH:10])[C:6]([F:9])([F:8])[F:7]
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 0.33 h
Yield: 40.8 %

Procedure:
To a 15 mL round-bottomed flask was added 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (0.25 g, 0.62 mmol, Example 91), triethylamine (0.26 mL, 1.9 mmol) and CH2Cl2 (6 mL). To this solution at room temperature was added 2-nitrobenzenesulfonyl chloride (0.14 g, 0.62 mmol, Sigma-Aldrich, St. Louis, Mo.). The mixture was stirred for 20 min and then was concentrated onto silica gel. Purification by silica gel chromatography (0 to 6% MeOH in CH2Cl2) afforded 1,1,1,3,3,3-hexafluoro-2-(4-(4-(2-nitrophenylsulfonyl)piperazin-1-yl)phenyl)-2-propanol (0.13 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=O)=[CH:4][CH:3]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[OH:18])(=[O:10])=[O:11])=[CH:6][CH:7]=1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(O)c1ccc(Cl)cc1
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)c1ccccc1O
Yield: 92 %

Procedure:
A 193 g (1.0 mole) quantity of p-chlorobenzenesulfonic acid, 188 g (2.0 moles) of phenol and 10 g of 12-molybdophosphoric acid (H3PMol12O40. hydrate) were refluxed with heating and stirring. An azeotropic mixture of the water formed and phenol were cooled and subjected to phase separation to reflux the phenol thus separated to the reaction system. After 6 hours of reaction, the reaction mixture was cooled and the catalyst was separated by filtration. After the mother liquor was washed with water, the phenol was distilled off under reduced pressure, giving 247 g of (4-chlorophenylsulfonyl)phenol in a yield of 92% (melting point 142° to 145° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: Nc1ccccc1S
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1CSc1ccccc1N
Yield: 73.4 %

Procedure:
Following General Procedure A, the title compound (1.7 g, 74%) was prepared from 2-aminobenzenethiol (1.1 g, 8.47 mmol), methyl 2-(bromomethyl)benzoate (1.9 g, 8.47 mmol), and K2CO3 (3.5 g, 25.4 mmol) in DMF (50 ml).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([C:10]([F:13])([F:12])[F:11])[CH:4]=1.F[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[C:5]([C:10]([F:11])([F:12])[F:13])[CH:4]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: COc1ccc(O)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Oc2ccc(C#N)cc2)c(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A solution of 4 g (20.82 mmol) of 4-methoxy-2-trifluoromethyl-phenol and 2.52 g (20.82 mmol) of 4-fluorobenzonitrile in 60 mL DMSO was combined with 5.75 g (41.64 mmol) of potassium carbonate and stirred for 3 h at 120° C. The reaction mixture was diluted with water, and extracted three times with dichloromethane. The organic phase was washed twice with water, dried on sodium sulphate and evaporated down. The residue was purified by chromatography (reversed phase).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([CH3:16])[CH:10]=1.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:16][C:11]1[CH:10]=[C:9]([Br:8])[CH:15]=[CH:14][C:12]=1[NH:13][C:5]([CH3:6])=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(Br)ccc1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(Br)cc1C
Temperature: 85 °C
Reaction time: 0.67 h
Yield: 99.9 %

Procedure:
Acetic anhydride (15.2 ml, 0.16 mol) was added dropwise to a stirred mixture of 4-bromo-2-methylaniline (10.0 g, 0.054 mol) and sodium acetate (2.52 g, 0.056 mol) in toluene (150 ml). Once the addition was complete the mixture was warmed to 85° C. and stirred for 40 minutes. The mixture was cooled to room temperature, diluted with ethyl acetate and washed with water. The organic solution was evaporated in vacuo, a further quantity of toluene was added and then the solvent was evaporated to give 4-bromo-2-methylacetanilide (12.3 g), as a colourless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.CN(C=O)C.C(Cl)(=O)C([Cl:21])=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([Cl:21])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3,5-Difluorophenylacetic acid (30 g, 0.174 mol) (Aldrich) was dissolved in dichloromethane and this solution was cooled to 0° C. DMF (0.5 mL, catalytic) was added followed by the dropwise addition of oxalyl chloride (18 mL, 0.20 mol) over a 5 minute period. The reaction was stirred for 3 h and then rotoevaporated at reduced pressure to give an oil which was placed on a high vacuum pump for 1 h to afford 3,5-difluorophenylacetyl chloride as a thin yellow oil. Other acid chlorides can be prepared in a similar manner.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[Cl:5][C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[C:12]1([C:17]([NH:19][NH2:20])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[Cl:5][C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[C:12]1([C:17]([NH:19][NH:20][C:3](=[S:4])[NH:2][CH3:1])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1csc(C2(C(=O)NN)CCCC2)c1Cl
Reactant: CN=C=S
Solvent: CCO
Product: CNC(=S)NNC(=O)C1(c2scc(C)c2Cl)CCCC1
Temperature: 75 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
Methyl isothiocyanate (62 mg) was added to an ethanol (10 ml) solution of 1-(3-chloro-4-methyl-2-thienyl)cyclopentanecarbohydrazide (200 mg), followed by stirring at 75° C. for 3 hours. The reaction solution was subjected to evaporation under reduced pressure and the resulting crude product washed with ether to obtain 167 mg of 2-{[1-(3-chloro-4-methyl-2-thienyl)cyclopentyl]carbonyl}-N-methylhydrazinecarbothioamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20])[CH:6]=[CH:7][CH:8]=O.[O:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][CH2:8][CH:31]2[O:27][C:28](=[O:33])[NH:29][C:30]2=[O:32])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20]
Reactant: O=C1COC(=O)N1
Reactant: COc1cc(C=CC=O)ccc1OCc1nc(-c2ccccc2)oc1C
Product: COc1cc(CCCC2OC(=O)NC2=O)ccc1OCc1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Working Example 11, 3-methoxy-4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)cinnamaldehyde was condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation to yield 5-[3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.161-162° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7]2.C([Sn](CCCC)(CCCC)[C:23]([O:25][CH2:26][CH3:27])=[CH2:24])CCC>C1(C)C=CC=CC=1.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>[CH2:26]([O:25][C:23]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7]2)=[CH2:24])[CH3:27]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cccc2ccc(-c3ccccc3)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1cccc2ccc(-c3ccccc3)nc12
Temperature: 80 °C

Procedure:
In a sealed tube, to the suspension of 8-bromo-2-phenylquinoline (0.1 g, 0.352 mmol) in toluene (5 mL) was added PdCl2(PPh3)2 (0.012 g, 0.017 mmol) and tributyl (1-ethoxyvinyl)stannane (0.15 g, 0.422 mmol) under N2. The reaction was heated at 80° C. for 12 h, then cooled to RT. The solvent was removed and the crude material was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]([CH:21]([CH2:26][CH2:27][CH3:28])[CH2:22][C:23]([OH:25])=O)[C:13]3=[O:29])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>C1COCC1.O>[CH2:30]([NH:37][C:23](=[O:25])[CH2:22][CH:21]([N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]([CH2:11][C:9]2[C:10]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=3[S:7][CH:8]=2)[C:13]1=[O:29])[CH2:26][CH2:27][CH3:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCC(CC(=O)O)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CCCC(CC(=O)NCc1ccccc1)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Reaction time: 16 h
Yield: 94.3 %

Procedure:
To the suspension of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid (20 mg, 0.049 mmol) in THF (1.0 mL) at room temperature are added benzyl amine (0.027 mL, 0.245 mmol) and 1-hydroxybenzotriazole (32 mg, 0.24 mmol). Then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (40 mg, 0.21 mmol) is added and the reaction mixture is stirred for 16 hr. Water (5 mL) is added and the mixture is extracted with EtOAc (3×10 mL). The organic layers are combined, dried over MgSO4 and concentrated to give crude product. The crude is filtered through a short path of silica gel eluting first with CH2Cl2 then with 50% EtOAc in hexanes to give 23 mg (95%) of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid benzylamide. LCMS (ESMS): m/z 498.22 (M+H+).
Reaction SMILES: Br[C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].C(#N)C.C(=O)([O-])O.[Na+:18].[S:19](S([O-])=O)([O-:21])=[O:20].[Na+].[Na+]>O>[F:9][C:2]([F:10])([S:19]([O-:21])=[O:20])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].[Na+:18]
Reactant: O=S([O-])S(=O)[O-]
Reactant: OCCC(F)(F)C(F)(F)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=S([O-])C(F)(F)C(F)(F)CCO
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
A 2 litter reactor was charged with 151 g (0.67 mol) of 4-bromo-3,3,4,4-tetrafluorobutan-1-ol, 600 ml of acetonitrile, 600 ml of water, 112 g (1.33 mol/2.0 equivalent)) of sodium hydrogencarbonate, and 235 g (1.35 mol/2.0 equivalent) of sodium dithionite in a nitrogen stream. The mixture was stirred at room temperature for 12 hours. The reaction solution was extracted four times with 500 ml of acetonitrile. The solvent was evaporated from the resulting organic layer to obtain 120 g of the target sodium 1,1,2,2-tetrafluoro-4-hydroxybutane-1-sulfinate. The purity of the product was 80% and the yield was 77%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=[O:9])[N:6]=1.[Cl:14]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[S:3][C:4]([Cl:14])=[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CON=C(C(=O)O)c1csc(N)n1
Solvent: CN(C)C=O
Product: CON=C(C(=O)O)c1nc(N)sc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 500 mL of DMF were added 50.0 g (250 mmol) of 2-amino-α-(methoxyimino)-4-thiazoleacetic acid and 35 g (260 mmol) of N-chlorosuccinimide. The mixture was stirred at room temperature overnight, after which time mass spectral analysis showed no more starting material to be present. The light brown solution was used without further purification.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:9](CC(C)(C)C)(C)[CH3:10]>ClC(Cl)C>[CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH2:10])=[CH2:1]
Reactant: C=Cc1ccccc1
Reactant: CC(C)CC(C)(C)C
Solvent: CC(Cl)Cl
Product: C=Cc1ccccc1C=C

Procedure:
Swell 2.8 kg of styrene copolymer with 40 mol. percent of divinylbenzene, obtained in the presence of 100 percent by weight of isooctane, in 9 liters of dichloroethane, add a mixture of 2.0 kg of KNO3 and 5 liters of concentrated sulphuric acid, and keep for six hours at a temperature of -5° to 0° C. Proceed as in Example 1. The obtained textured nitro polymer contains 5.4 percent by weight of nitrogen.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(OCC)(=O)C>[CH3:17][S:18]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Oc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.8 %

Procedure:
To a mixture of 3-hydroxybenzaldehyde (25.31 g), triethylamine (23.07 g) and ethyl acetate (500 mL) was added methanesulfonyl chloride (26.12 g) at 0° C. The mixture was stirred at room temperature for 15 hrs. The reaction mixture was washed successively with water, 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-formylphenyl methanesulfonate as a pale-yellow oil (41.40 g, yield 100%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:32])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20](Cl)[C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[S:24][C:22]=3[N:23]=2)=[CH:14][CH:13]=1>>[CH3:9][O:10][C:11](=[O:32])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[S:24][C:22]=3[N:23]=2)=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C(F)(F)F)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccccc3)c3cc(C(F)(F)F)sc3n2)cc1

Procedure:
The reaction procedure as above wherein benzylamine is reacted with 4-(4-chloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-(4-benzylamino-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:8]([CH3:19])([CH3:18])[CH2:7][CH2:6][C:5]2([CH3:21])[CH3:20].C([Li])(C)(C)C.[C:27](=[O:29])=[O:28].Cl>O1CCCC1.CCCCC>[CH2:12]([C:11]1[C:2]([C:27]([OH:29])=[O:28])=[CH:3][C:4]2[C:5]([CH3:20])([CH3:21])[CH2:6][CH2:7][C:8]([CH3:19])([CH3:18])[C:9]=2[CH:10]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C=O
Reactant: CCCCCCc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCCc1cc2c(cc1C(=O)O)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
15 g of 6-bromo-7-hexyl-1,1,4,4-tetramethyl-1, 2,3,4-tetrahydro-naphthalene were dissolved in 180 ml of tetrahydrofuran and treated dropwise at -78° C. with 64.5 ml of a 1.5 molar solution of tert.butyl-lithium in pentane. After stirring at -78° C. for 1 hour, a carbon dioxide stream was conducted vigorously into the reaction vessel for 2 hours. Subsequently, the reaction mixture was acidified by the addition of 190 ml of 2N hydrochloric acid, extracted several times with ethyl acetate, washed with water, dried over sodium sulfate and evaporated. The oily crude product was filtered over silica gel (eluent hexane, then hexane/ethyl acetate=4:1) and recrystallized from hexane. There were obtained 7.6 g of 3-hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-carboxylic acid in colorless crystals, m.p. 98°-99° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[O:9])=[C:4]([F:18])[CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[C:4]([F:18])[CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(Br)cc2F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O
Product: O=C(c1ccc(O)cc1)c1ccc(Br)cc1F
Temperature: 25 °C
Yield: 92.7 %

Procedure:
A mixture of 75 (1.50 g, 5.08 mmol) and AlCl3 (3.50 g, 26.2 mmol) were refluxed in benzene (50 mL) for 3 h and then cooled to RT. Water (100 mL) was cautiously added dropwise, and the mixture was extracted with Et2O (3×100 mL). The combined ethereal extracts were washed with water (200 mL), brine (200 mL), and dried over MgSO4. Concentration afforded 1.39 g (97%) of 76 that was used without further purification. 1H NMR (400 MHz, CDCl3): δ 5.73 (br s, 1H), 6.90 (d, J=8.8 Hz, 2H), 7.35-7.41 (m, 3H), 7.77 (d, J=8.4 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]2[CH2:13][CH2:12][CH:11](Cl)[CH2:10]2)=[CH:4][C:3]=1[F:15].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C)C=O>[Br:1][C:2]1[C:3]([F:15])=[CH:4][C:5]([CH:9]2[CH2:13][CH2:12][CH:11]([N:20]3[C:16](=[O:26])[C:17]4[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:19]3=[O:21])[CH2:10]2)=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(C2CCC(Cl)C2)c(F)cc1Br
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C1CCC(c2cc(F)c(Br)cc2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A solution of 29.6 g (0.1 mol) of 1-bromo-4-(3-chlorocyclopentyl)-2,5-difluorobenzene in 150 ml of dry dimethylformamide was treated with 19.4 g (0.105 mol) of potassium phthalimide and the resulting suspension stirred at 100° for 8 hours and room temperature overnight. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and water. The aqueous layer was reextracted with methylene chloride and the combined organic layers were washed with water, dried (MgSO4), filtered, and evaporated in vacuo to give 36.8 g of the title compound as a viscous oil which crystallized on standing and had mp 44°-47°.
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]([CH3:24])([CH3:23])[CH2:10][N:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Br:21])[CH:17]=2)[C:12]1=[O:22])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O=P(Cl)(Cl)Cl.CN([CH:33]=[O:34])C>>[C:1]([O:7][CH2:8][C:9]([CH3:24])([CH3:23])[CH2:10][N:11]1[CH:20]=[C:19]([CH:33]=[O:34])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Br:21])[CH:17]=2)[C:12]1=[O:22])(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: CC(C)(COC(=O)C(C)(C)C)Cn1ccc2cc(Br)ccc2c1=O
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(COC(=O)C(C)(C)C)Cn1cc(C=O)c2cc(Br)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 3-(6-bromo-1-oxoisoquinolin-2(1H)-yl)-2,2-dimethylpropyl pivalate (51.3 g) in DMF (150 mL) at 75° C. (flask fitted with a CaCl2 drying tube) was treated dropwise over ˜20 min with a freshly prepared solution of Vilsmeyer Haak reagent [freshly prepared by dropwise addition of POCl3 (182 mL) over ˜40 min to DMF (302 mL) at 0° C. and then stirred for 1 h at room temperature]. Heating was continued for 8 h, and then the reaction mixture was cooled to room temperature and stirred overnight. The mixture was poured onto ice water (6 L) [CAUTION: exotherm] and extracted with tert-butyl methyl ether (2×2.5 L). The combined organics were washed with 20% w/v aqueous brine (2.5 L), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified (SiO2 chromatography, eluting with 10% to 20% ethyl acetate/isohexane) to give the subtitle product (41.5 g).
Reaction SMILES: C[O-].[Na+].CO.[N+](C1C=CC=CC=1S([NH:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)=O)([O-])=O>O1CCOCC1>[CH:19]([NH2:18])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 102.7 %

Procedure:
A 28% sodium methoxide/methanol solution (0.34 ml; 1.52 molar equivalents) was added to a solution of N-(2-nitrobenzenesulfonyl)benzhydrylamine (401.6 mg) in dry dioxane (3 ml) at room temperature in an argon atmosphere, followed by stirring for 23 hours at room temperature. The reaction solvents were removed by evaporation under reduced pressure, and water (10 ml), 2 N sulfuric acid (1.5 ml) and ether (15 ml) were added to the resulting concentrate, followed by extraction and solution separation. The organic layer was extracted again with water (5 ml). To the resulting aqueous layer, 5 N sodium hydroxide (1 ml) was added, and extraction was conducted twice with ether (13 ml), followed by drying over sodium sulfate, filtration, concentration and drying under vacuum to obtain benzhydrylamine (205.2 mg; yield: quantitative).