Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:14][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)cccc1-c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(-c2ccccc2)c1CBr

Procedure:
A mixture of 3-chloro-2-methyl[1,1'-biphenyl] (10.4 grams, 0.051 mole) and N-bromosuccinimide (9.2 grams, 0.052 mole) in carbon tetrachloride (150 ml) was heated and irradiated with an infrared lamp for two hours. The mixture was cooled and filtered. The filtrate was evaporated under reduced pressure to give a quantitative yield of 2-bromomethyl-3-chloro[1,1'-biphenyl] as a yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4].[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13](F)[C:10]=1[C:11]#[N:12]>>[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([O:4][CH2:3][C@@H:2]([NH2:1])[CH:5]([CH3:7])[CH3:6])[C:10]=1[C:11]#[N:12]
Reactant: N#Cc1c(N)cccc1F
Reactant: CC(C)[C@H](N)CO
Product: CC(C)[C@H](N)COc1cccc(N)c1C#N

Procedure:
Prepared as in Example 24d from (S)-2-amino-3-methylbutan-1-ol and 2-amino-6-fluorobenzonitrile as brown solid (71%). MS 220 (MH+).
Reaction SMILES: [Cl:1][C:2]1[S:19][C:5]2[NH:6][C:7](=S)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[C:20]([NH2:26])(=[O:25])[C:21]([NH:23][NH2:24])=O>CO>[Cl:1][C:2]1[S:19][C:5]2[N:6]3[C:21]([C:20]([NH2:26])=[O:25])=[N:23][N:24]=[C:7]3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: NNC(=O)C(N)=O
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)sc2N1
Solvent: CO
Product: NC(=O)c1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
0.8 g of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione are refluxed in 40 ml of absolute methanol with 1.5 g of oxalic acid amide hydrazide for 1.5 hours. The solution is concentrated to 10 ml and left to crystallize in a refrigerator. The filtered and dried 7-chloro-5-(o-chlorophenyl)-2-(2-oxalylamidohydrazino)-3H-thieno[2,3-e]-1,4-diazepine is refluxed in 100 ml of absolute xylene for 3 hours. The organic phase is evaporated and the residue recrystallized from ethanol to yield 2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine-9-carboxylic acid amide, melting point 248°-251° C.
Reaction SMILES: Br[C:2]1[N:3]([CH2:24][C:25]#[C:26][CH3:27])[C:4]2[C:9](=[O:10])[N:8]([CH2:11][C:12]3[N:21]=[C:20]([CH3:22])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[N:7]=[CH:6][C:5]=2[N:23]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+].N1CCCC(NC(=O)OC(C)(C)C)C1>CS(C)=O.O>[CH2:24]([N:3]1[C:4]2[C:9](=[O:10])[N:8]([CH2:11][C:12]3[N:21]=[C:20]([CH3:22])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[N:7]=[CH:6][C:5]=2[N:23]=[C:2]1[N:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:29]1)[C:25]#[C:26][CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CC#CCn1c(Br)nc2cnn(Cc3nc(C)c4ccccc4n3)c(=O)c21
Agent: CC(C)(C)OC(=O)NC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2cnn(Cc3nc(C)c4ccccc4n3)c(=O)c21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A solution of 240 mg (0.57 mmol) 2-bromo-3-(but-2-ynyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one and 140 mg (0.70 mmol) tert-butyl (R)-piperidin-3-yl-carbamate in 4 ml dimethylsulphoxide was combined with 95 mg (0.90 mmol) sodium carbonate and stirred for 3 h at 80° C. Then another 50 mg tert-butyl piperidin-3-yl-carbamate was added and the mixture was stirred for a further 2 h at 80° C. After cooling to ambient temperature the mixture was combined with 10 ml of water and stirred for 30 minutes. The product thus precipitated was suction filtered, washed with 5 ml of water and dried.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([CH:11]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([N:19]=[C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:18]=3)[OH:12])=[CH:9][N:8]([CH3:33])[C:4]=2[N:5]=[CH:6][N:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([N:19]=[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:18]=3)=[O:12])=[CH:9][N:8]([CH3:33])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cn1cc(C(O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2c(Cl)ncnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cn1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 99 %

Procedure:
To a solution of (4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(5-((diphenylmethylene)amino)pyridin-3-yl)methanol (Preparation 228, 11.4 g, 25 mmol) in CH2Cl2 (150 mL), Dess-Martin periodinane (15.9 g, 37 mmol) was added in portions. The reaction mixture was stirred at room temperature for 10 hours and then aqueous NaOH (30 mL) was added. The mixture was stirred for a further 0.5 hours. The mixture was then separated and the aqueous layer was exacted by CH2Cl2 (100 mL×2). The combined organic layers were concentrated and washed with ether to provide the title compound as a brown solid in 99% yield, 11 g.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH:20]([S:23]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)(=[O:25])=[O:24])([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:7]([CH2:9][N:28]3[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:26]([S:23]([CH:20]([CH3:22])[CH3:21])(=[O:24])=[O:25])=[CH:27]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)CCCn1c(CCl)nc2cc(Cl)ccc21
Reactant: CC(C)S(=O)(=O)c1c[nH]c2ccccc12
Product: CC(C)S(=O)(=O)c1cn(Cc2nc3cc(Cl)ccc3n2CCCS(C)(=O)=O)c2ccccc12

Procedure:
The title compound was prepared in analogy to Example 1-2 by using 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole and 3-(isopropylsulfonyl)-1H-indole instead of 3-(methylsulfonyl)-1H-indole and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.Br[CH2:9][CH2:10][C:11]#[N:12]>C(O)C.[OH-].[Na+]>[C:11]([CH2:10][CH2:9][S:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1)#[N:12]
Reactant: N#CCCBr
Reactant: Sc1nnc(S)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#CCCSc1nnc(S)s1

Procedure:
2,5-Dimercapto-1,3,4-thiadiazole (7.50 g) was dissolved in a mixture of 50 ml of ethanol and 50 ml of 1N-sodium hydroxide solution to which 4.15 ml of 3-bromopropionitrile was added under stirring. After stirring for 48 hours at room temperature, the mixture was concentrated under reduced pressure. The concentrate was extracted with ethyl acetate. The extract was dried over sodium sulfate and distilled off to remove the solvent. The residue was washed with ethyl ether to give 7.74 g of 2-(2-cyanoethylthio)-5-mercapto-1,3,4-thiadiazole as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[C@@H:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:20][CH:19]=2)[C:16]2[C:11](=[CH:12][C:13]([O:32]C)=[CH:14][CH:15]=2)[O:10][CH2:9]1.Cl.N1C=CC=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[C@@H:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)=[CH:20][CH:19]=2)[C:16]2[C:11](=[CH:12][C:13]([OH:32])=[CH:14][CH:15]=2)[O:10][CH2:9]1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccccc1F)[C@H]2c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2c(c1)OC[C@@H](c1ccccc1F)[C@H]2c1ccc(OCCN2CCCC2)cc1

Procedure:
In an manner analogous to that described in step 5 for Example 10, (±)-cis-3-(2-fluorophenyl)-7-methoxy-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane (0.20 g, 0.41 mmol) was de-methylated by heating with pyridine hydrochloride to give the title compound as an off-white foam.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH:6]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[C:13](=[O:21])[C:12]3[CH:22]=[CH:23][CH:24]=[CH:25][C:11]=3[C:10]=2[CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+]>O1CCCC1>[CH:1]1([C:13]2([OH:21])[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[C:16]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[C:11]3[CH:25]=[CH:24][CH:23]=[CH:22][C:12]2=3)[CH2:3][CH2:2]1
Reactant: O=c1c2ccccc2c2ccccc2c2ccccc12
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(C2CC2)c2ccccc2-c2ccccc2-c2ccccc21

Procedure:
A solution of cyclopropylmagnesium bromide in dry tetrahydrofuran (prepared from cyclopropylbromide (4.54 g, 37.5 mmol), magnesium turnings (0.91 g, 37.5 mmol) and dry tetrahydrofuran (30 ml)) was placed under an atmosphere of nitrogen. A solution of 9H-tribenzo[a,c,e]cyclohepten-9-one (1.92 g, 7.5 mmol) (prepared according to W. Tochtermann, Chem. Ber., 97, 1329 (1964)) in tetrahydrofuran (20 ml) was added dropwise and when addition was complete the mixture was heated at reflux temperature for 30 minutes. The reaction mixture was cooled on an ice-bath and saturated ammonium chloride (50 ml) was added carefully. The organic layer was separated and the aqueous phase extracted with diethyl ether (2×100 ml). The combined organic extracts were dried (MgSO4) and the solvent was evaporated in vacuo affording 2.69 g of 9-cyclopropyl-9H-tribenzo[a,c,e]cyclohepten-9-ol.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:34]=[CH:33][C:12]([NH:13][C:14]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:23][C:15]=2[C:16]([O:18]C(C)(C)C)=[O:17])=[CH:11][CH:10]=1>>[F:8][C:9]1[CH:34]=[CH:33][C:12]([NH:13][C:14]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:23][C:15]=2[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2ccccc2)cc1Nc1ccc(F)cc1
Yield: 29.6 %

Procedure:
Trifluoroacetic acid 9.0 mL solution of tert-butyl 2-(4-fluoroanilino)-4-phenylbenzoate 0.44 g was stirred at room temperature for 1 hour. The solvent of reaction mixture was removed under reduced pressure, ethyl acetate and water were added to it, and it was adjusted to pH5.0 with saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and collected, and the solvent was removed under reduced pressure. Diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 2-(4-fluoroanilino)-4-phenylbenzoic acid 0.11 g of pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[K+].Cl>CO.O>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([F:19])([F:20])[C:15]([F:16])([F:17])[F:18])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(OCC(F)(F)C(F)(F)F)cc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OCC(F)(F)C(F)(F)F)cc1O
Yield: 55 %

Procedure:
To a solution of methyl 2-hydroxy-4-(2,2,3,3,3-pentafluoropropoxy)benzoate (obtained in example 1) (0.72 g, 2.40 mmol) in MeOH (9.7 mL), KOH (0.51 g, 86%; 7.80 mmol) dissolved in H2O (3 mL) was added and the resulting mixture was refluxed for 4 hours. The mixture was allowed to cool and MeOH was evaporated. The residue thus obtained was treated with H2O (5 mL) and the resulting solution was acidified with 6 N HCl. The white solid formed was collected by filtration, washed with cold H2O and dried in vacuo, yielding the title compound (55% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=[CH2:19])[CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH3:2].ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1([CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:19][O:29]1)=[O:20])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(CCCCOCCC1CCCCC1)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)C1(CCCCOCCC2CCCCC2)CO1

Procedure:
5.3 g of the title compound, in the form of an oil, which is purified by chromatography on silica gel (migrating agent: 9:1 petroleum ether/ethyl acetate), are obtained by the procedure described in Example (1a) from 11.2 g of 6-(2-cyclohexylethoxy)-2-methylenehexanoic acid ethyl ester and 13.7 g of m-chloroperbenzoic acid in 100 ml of methylene chloride.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:18].[N+](=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N-]>ClCCCl.ClC(Cl)C>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][O:17][C:12]1[C:11]2[CH:10]=[C:9]([CH3:18])[N:8]([CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]=2[CH:15]=[CH:14][N:13]=1)[CH3:32]
Reactant: Cc1cc2c(O)nccc2n1Cc1ccccc1-c1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)COc1nccc2c1cc(C)n2Cc1ccccc1-c1ccccc1

Procedure:
To a solution of intermediate (5) (0.557 g, 1.77 mmole) in 1,2-dichloroethane (250 mL) rhodium(II) trifluoroacetate dimmer (0.058 g, 0.0885 mmole) was added, the reaction was heated to reflux. Then the solution of ethyl diazoacetate (90%, 0.2 mL, 1.77 mmole) in dichloroethane (35 mL) was added via a syringe pump to the mixture over 16 h. The reaction mixture was refluxed for an additional 2 h. The solvent was evaporated and the residue was purified by column chromatography (3:1 Hex:EtOAc) to afford intermediate (6) as a yellow solid. Yield: 0.272 g, 38%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH2:12][NH2:13])=[CH:10][CH:11]=2)[N:6]=1.[C:14](OCC)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1>C(O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH2:12][NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=3)=[CH:10][CH:11]=2)[N:6]=1
Reactant: CCOC(=O)c1cccnc1
Reactant: NCc1ccc(-c2csc(N)n2)s1
Solvent: CCO
Product: Nc1nc(-c2ccc(CNC(=O)c3cccnc3)s2)cs1

Procedure:
To a solution of 4.0 g of 2-amino-4-(5-aminomethyl-2-thienyl)thiazole in 100 ml of ethanol is added 2.85 g of ethyl nicotinate, and refluxed for 8 hours. After the reaction mixture is cooled with ice, the precipitated crystals are collected by filtration and recrystallized from dimethylformamide to give 2-amino-4-(5-nicotinoylaminomethyl-2-thienyl)thiazole, melting at 240°-241° C. with decomposition.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[C:10]1([C:16]#[CH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:9][S:8][C:5]1[N:4]=[CH:3][C:2]([C:17]#[C:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][N:6]=1
Reactant: C#Cc1ccccc1
Reactant: CSc1ncc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1ncc(C#Cc2ccccc2)cn1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (120 mg, 0.16 mmol) were dissolved in 50 ml THF and 5-bromo-2-methylsulfanyl-pyrimidine (840 mg, 4.1 mmol) and phenylacetylene (410 μl, 4.1 mmol) were added at room temperature. Triethylamine (1.36 ml, 12.3 mmol), triphenylphosphine (28 mg, 0.12 mmol) and copper(I)iodide (19 mg, 0.08 mmol) were added and the mixture was stirred for 3 hours at 65° C. The reaction mixture was cooled and extracted once with saturated NaHCO3 solution and three times with ethyl acetate. The organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness. The crude product was purified by flash chromatography on silicagel (heptane:ethyl acetate 100:0→50:50). The desired compound was obtained as a light yellow solid (400 mg, 44%), MS: m/e=227.3 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]3[C:11]=2[CH2:12][N:13]([CH3:23])[C:14]3=[O:22])[CH:7]=[N:6]1>CCO.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:10]([C:8]2[CH:7]=[N:6][N:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH:9]=2)=[C:11]2[C:15]=1[C:14](=[O:22])[N:13]([CH3:23])[CH2:12]2
Reactant: CN1Cc2c(-c3cnn(CCCO)c3)ccc([N+](=O)[O-])c2C1=O
Agent: [Pd]
Solvent: CCO
Product: CN1Cc2c(-c3cnn(CCCO)c3)ccc(N)c2C1=O
Reaction time: 2 h

Procedure:
A suspension of 4-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (Compound 1D, 920 mg, 2.91 mmol) and 10% Pd/C (50% H2O) (1.41 g, 0.66 mmol) in EtOH (85 mL) was hydrogenated at rt for 2 h. The crude mixture was filtered through a pad of Celite, rinsed thoroughly with MeOH and EtOAc, concentrated in vacuo, and purified using a Teledyne ISCO CombiFlash® Rf system (eluting with 0-5% MeOH:CH2Cl2) to isolate the desired compound as 634 mg as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J=0.5 Hz, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 6.61 (d, J=8.3 Hz, 1H), 6.05 (s, 2H), 4.59 (t, J=5.1 Hz, 1H), 4.45 (s, 2H), 4.17 (t, J=7 Hz, 2H), 3.41 (q, J=6.1 Hz, 2H), 3.03 (s, 3H), 1.94 (quin, J=6.1 Hz, 2H). MS (ESI): m/z 287.13 [M+H]+. UPLC: tR=0.89 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Cl[C:10]1[CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:14][CH:15]=1>[Cu]>[F:17][C:16]([F:19])([F:18])[C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)[CH:11]=1
Reactant: Oc1ccc(O)cc1
Reactant: FC(F)(F)c1cccc(Cl)c1
Agent: [Cu]
Product: Oc1ccc(Oc2cccc(C(F)(F)F)c2)cc1

Procedure:
from hydroquinone and 3-chlorobenzotrifluoride with the addition of a catalytic amount of copper powder there is obtained p-(α,α,α-trifluoro-m-tolyloxy)-phenol which distils in a bulb-tube at 140° C./0.05 Torr; nD20 =1.5370.
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[K].C(O[C:18]([S-])=[S:19])C.Cl>N1C=CC=CC=1>[Cl:13][C:9]1[CH:10]=[C:11]2[O:12][C:18](=[S:19])[NH:1][C:2]2=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=1
Reactant: COC(=O)c1cc(Cl)cc(O)c1N
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K]
Solvent: c1ccncc1
Product: COC(=O)c1cc(Cl)cc2oc(=S)[nH]c12
Temperature: 125 °C
Yield: 99.3 %

Procedure:
To a mixture of methyl 2-amino-5-chloro-3-hydroxybenzoate (4.00 g, 19.84 mmol) in anhydrous pyridine (30 mL) was added potassium-O-ethylxanthate (3.50 g, 21.82 mmol), and the reaction mixture heated to 125° C. for 3 h under nitrogen atmosphere. The warm solution was poured into a mixture of concentrated HCl (12 mL) and ice (120 mL), the resulting precipitate filtered, and dried under vacuum to provide methyl 6-chloro-2-thioxo-2,3-dihydrobenzoxazole-4-carboxylate (4.80 g, 99%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.81 (d, J=1.9 Hz, 1H), 7.48 (d, J=1.9 Hz, 1H), 4.01 (s, 3H); MS (ESI+) m/z 244 (M+H).
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[C:18]1[N:19]=[CH:20][N:21]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[CH:22]=1>>[CH:1]1([NH:5][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([N:21]3[CH:22]=[C:18]([C:8]4[C:9]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[N:10][O:11][C:7]=4[CH3:6])[N:19]=[CH:20]3)[CH:24]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C(=O)O)c2)cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C(=O)NC3CCC3)c2)cn1
Yield: 45 %

Procedure:
As described for Example 71, cyclobutylamine was converted, using 3-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (52 mg, 45%) which was obtained as an off-white solid. MS: m/e=399.1 [M+H]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[Cl:29])[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4cccc(Cl)c4Cl)c3O2)cc1
Product: CNCC1Cc2cc(Cl)cc(-c3cccc(Cl)c3Cl)c2O1

Procedure:
The title compound was prepared (0.051 g, 40%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,3-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.165 g, 0.341 mmol) and methylamine (0.106 g, 3.41 mmol). mp 219-221° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[C:4]([O:10][CH:11]2[CH2:13][CH2:12]2)[CH:3]=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:10][CH:11]2[CH2:13][CH2:12]2)[CH:3]=1
Reactant: COc1ccc(Br)cc1OC1CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Br)cc1OC1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.6 %

Procedure:
To 300 ml of dehydrated dichloromethane solution containing 60.0 g (247 mmol) of 4-bromo-2-cyclopropoxy-1-methoxybenzene obtained in Reference Example 7-(c) was added 300 ml of dichloromethane solution containing 1M boron tribromide under argon atmosphere at −70° C. After completion of the addition, the mixture was gradually raised to 0° C., and stirred at the same temperature for 30 minutes. After completion of the reaction, the reaction mixture was poured into ice-water, and extracted with toluene. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 58.6 g of the title compound as a blue-greenish solid substantially quantitatively.
Reaction SMILES: [BrH:1].S(=O)(=O)(O)O.[F:7][C:8]([F:22])([F:21])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]=1[CH2:19]O>O>[Br:1][CH2:19][C:10]1[C:9]([C:8]([F:22])([F:21])[F:7])=[CH:14][CH:13]=[CH:12][C:11]=1[C:15]([F:18])([F:17])[F:16]
Reactant: Br
Reactant: OCc1c(C(F)(F)F)cccc1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: FC(F)(F)c1cccc(C(F)(F)F)c1CBr
Temperature: 25 °C

Procedure:
To 1 ml of a mixture of 48% aqueous HBr solution and conc. sulfuric acid (2:1 v/v) were added 0.81 g (3.3 mmol) (2,6-bis-trifluoromethyl-phenyl)-methanol and the solution heated to reflux for 6 h. Then the reaction mixture was cooled to rt, diluted with water and extracted with tert-butyl methyl ether. The combined extracts were washed with brine, dried over Na2SO4, filtered and evaporated. Kugelrohr distillation provided 2-bromomethyl-1,3-bis-trifluoromethyl-benzene as colourless oil of b.p. 135-140° C./22 mbar: MS (EI): 307.9 and 305.9 (M+.), 227.1 (((M-Br)+.), 100%).