Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn](CCCC)(CCCC)CCCC)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:24][CH:25]([NH:33][C:34]([C:36]1[C:44]2[C:39](=[N:40][CH:41]=[C:42](Br)[N:43]=2)[N:38]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH:37]=1)=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.CN(C=O)C>CCOCC.[Cu]I.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>[CH3:24][CH:25]([NH:33][C:34]([C:36]1[C:44]2[C:39](=[N:40][CH:41]=[C:42]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[NH:8][N:7]=3)[N:43]=2)[N:38]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:52])([CH3:51])[CH3:53])[CH:37]=1)=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: CC(Cc1ccccn1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(F)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(Cc1ccccn1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Temperature: 90 °C
Reaction time: 15 h
Yield: 60.8 %

Procedure:
6-Fluoro-3-tributylstannyl-1H-indazole (0.20 g, 0.47 mmol), copper(I) iodide (12 mg, 0.06 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methyl-2-pyridin-2-yl-ethyl)-amide (200 mg, 0.41 mmol) were combined with DMF (6 mL) to give a yellow solution. The mixture was degassed with nitrogen for 10 min then tetrakis(triphenylphosphine)palladium (0) (23 mg, 0.02 mmol) was added. The reaction was stirred at 90° C. under nitrogen for 15 h. The reaction mixture was cooled, diluted with ether (60 mL) and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-3% methanol in dichloromethane with 0.5% ammonium hydroxide) to give 136 mg (61%) of 2-(6-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methyl-2-pyridin-2-yl-ethyl)-amide as a foaming solid. MS: (M+H)+=546.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:13])=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1.[CH3:18][N:19]([CH3:27])[C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1>O1CCCC1>[C:9]([C:7]1[CH:8]=[C:3]([CH2:2][NH:26][C:23]2[CH:24]=[CH:25][C:20]([N:19]([CH3:27])[CH3:18])=[CH:21][CH:22]=2)[CH:4]=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[OH:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: CN(C)c1ccc(N)cc1
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1O
Solvent: C1CCOC1
Product: CN(C)c1ccc(NCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1

Procedure:
4-Bromomethyl-2,6-di-tert-butyl-phenol (2.42 g, 0.008 mole) was dissolved in 50 mL of dry tetrahydrofuran. In a separate conical flask N,N-dimethyl-benzene-1,4-diamine (2.17 g, 0.016 mole) was dissolved in 25 mL of tetrahydrofuran and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottom flask containing solution of 4-Bromomethyl-2,6-di-tert-butyl-phenol was kept in oil-bath at 85° C. Solution in the flask was continuously stirred with the help of magnetic stirrer. N, N-dimethyl-para-phenylene diamine solution was added drop-by-drop, from funnel to the flask in acidic medium for a span of 4-5 hours till all the solution was poured out. The reaction was terminated after that and the final reaction mixture was allowed to attain room temperature.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:11]=1[C:12]([CH2:14][CH2:15][C:16](OC)=[O:17])=O)([CH3:4])([CH3:3])[CH3:2].O.[NH2:28][NH2:29]>>[C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:11]=1[C:12]1[CH2:14][CH2:15][C:16](=[O:17])[NH:28][N:29]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CCC(=O)c1cc(OC)ccc1OCC(O)CNC(C)(C)C
Reactant: NN
Solvent: O
Product: COc1ccc(OCC(O)CNC(C)(C)C)c(C2=NNC(=O)CC2)c1

Procedure:
Methyl 3-[2-(3-t-butylamino-2-hydroxypropoxy)-5-methoxybenzoyl]propionate was cyclised with hydrazine hydrate in a similar manner to that described in Example 2 (ii) to give 6-[2-(3-t-butylamino-2-hydroxypropoxy)-5-methoxyphenyl]-4,5-dihydro-3(2H)-pyridazinone (m.p. 127°-128° C). The hydrochloride, crystallised from methanolether, had m.p. 227°-229° C. (Found: C, 56.24; H, 7.24; Cl, 9.06; N, 10.75; C18H27N3O4.HCl requires: C, 56.03; H, 7.31; Cl, 9.19; N, 10.88%)
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:56])[C@@H:6]([NH:23][C:24]([C@@H:26]1[CH2:35][C:34]2[CH:33]=[C:32]3[O:36][CH2:37][C@H:38]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]5[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=5)=[CH:42][CH:41]=4)[O:39][C:31]3=[CH:30][C:29]=2[CH2:28][NH:27]1)=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])=[CH:10][CH:9]=1.[N:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[C:63](Cl)=[O:64]>>[CH3:3][O:4][C:5](=[O:56])[C@@H:6]([NH:23][C:24]([C@@H:26]1[CH2:35][C:34]2[CH:33]=[C:32]3[O:36][CH2:37][C@H:38]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]5[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=5)=[CH:42][CH:41]=4)[O:39][C:31]3=[CH:30][C:29]=2[CH2:28][N:27]1[C:63]([C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][N:57]=1)=[O:64])=[O:25])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])=[CH:12][CH:13]=1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)c1ccccn1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester dihydrochloride (25 mg) was reacted with pyridine-2-carbonyl chloride according to General Procedure F. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+5% MeOH) to give (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(pyridine-2-carbonyl)-2,3,6,7,8,9 hexahydro-[1,4]dioxino[2,3-g]-isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester. This ester was hydrolyzed according to General Procedure B to give the title compound (8 mg). LCMS (m/z): 860.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=1[NH2:6].I[CH3:15]>O1CCCC1>[Cl:3][C:4]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=1[NH:6][CH3:15]
Reactant: CI
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 33.3 %

Procedure:
To a suspension of sodium hydride (60% in oil, 1.2 g, 30 mmol) in tetrahydrofuran (100 ml), cooled in an ice bath, was added slowly a solution of 2-chloro-5-nitroaniline (5 g, 29 mmol) in tetrahydrofuran (10 ml) followed by a solution of iodomethane (1.8 ml, 29 mmol) in tetrahydrofuran (10 ml). After stirring at room temperature for 20 hours, the mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (100 ml) and water (100 ml). The organic layer was washed with saturated aqueous sodium chloride solution (50 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane-hexane (1:3) and recrystalized (ethyl ether) to provide (2-chloro-5-nitro-phenyl)-methyl-amine (1.8 g, 33% yield) as orange crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:3]=1.[CH3:16][C:17]1([CH3:30])[CH2:22][CH:21]([NH:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][C:19]([CH3:29])([CH3:28])[NH:18]1.C(=O)(O)[O-].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:24]([N:23]([C:2]1[N:7]=[C:6]([N:23]([CH:21]2[CH2:22][C:17]([CH3:30])([CH3:16])[NH:18][C:19]([CH3:28])([CH3:29])[CH2:20]2)[CH2:24][CH2:25][CH2:26][CH3:27])[N:5]=[C:4]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:3]=1)[CH:21]1[CH2:20][C:19]([CH3:29])([CH3:28])[NH:18][C:17]([CH3:30])([CH3:16])[CH2:22]1)[CH2:25][CH2:26][CH3:27]
Reactant: CCOC(=O)CNc1nc(Cl)nc(Cl)n1
Reactant: CCCCNC1CC(C)(C)NC(C)(C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCCCN(c1nc(NCC(=O)OCC)nc(N(CCCC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1
Yield: 96.3 %

Procedure:
2.36 g of ethyl N-(2,4-dichloro-1,3,5-triazin-6-yl)-glycinate [obtained as described in Preparation 4(A)], 4.19 g of 2,2,6,6-tetramethyl-4-(butylamino)piperidine [obtained as described in Preparation I(A)] and 2.77 g of sodium bicarbonate were heated under reflux in 20 ml of xylene for 29 hours. At the end of this time, the xylene was removed by distillation under reduced pressure, and a mixture of methylene chloride and water was added to the resulting residue, after which the mixture was shaken. The methylene chloride layer was separated, dried and concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (using a 20:10:1:1 by volume mixture of hexane, diethyl ether, ethanol and triethylamine as eluent), to yield 5.46 g of the title compound melting at40° C.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].FC(F)(F)S(O[CH2:25][C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])(=O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[F:34][C:26]([F:35])([C:27]([F:32])([F:33])[C:28]([F:29])([F:31])[F:30])[CH2:25][C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: N#CC(C#N)(CC(F)(F)C(F)(F)C(F)(F)F)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 3 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 3.3 g of 2,2,3,3,4,4,4-heptafluorobutyl trifluoromethanesulfonate were dissolved in 10 ml of ethylene glycol dimethyl ether, 0.97 g of potassium carbonate was added, and the mixture was stirred at room temperature for 7 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.07 g of 2-(2,2,3,3,4,4,4-heptafluorobutyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (79)).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36].C(N(CC)CC)C>CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]3[C:30](=[O:31])[C:29]4[C:28](=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:27]3=[O:36])[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN3C(=O)c4ccccc4C3=O)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.9 %

Procedure:
1.45 g of 2-tert-butyl-4-(piperazin-1-yl)-6-cyclobutyl-pyrimidine (5.28 mmol), 1.5 g of N-(4-bromobutyl)phthalimid (5.28 mmol) and 0.8 g of triethylamine (7.9 mmol) were dissolved in 20 ml of dimethylformamide and stirred for 16 h at room temperature. The reaction mixture was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness. The oily residue began to crystallise upon standing, was stirred with acetonitrile, and finally filtered to yield 0.55 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([Cl:24])[CH:3]=1.[S:25]1(=[O:31])(=[O:30])[CH2:29][CH2:28][CH2:27][NH:26]1>>[Cl:24][C:4]1[CH:3]=[C:2]([N:26]2[CH2:27][CH2:28][CH2:29][S:25]2(=[O:31])=[O:30])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3Cl)CC2)c(C)c1
Reactant: O=S1(=O)CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3Cl)CC2)c(C)c1
Yield: 13.2 %

Procedure:
Using (4-bromo-2-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (408 mg) described in Preparation Example 119 and isothiazolidine 1,1-dioxide (121 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (59 mg) was obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:9].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][NH2:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1.S>CN(C)C=O.CO.[Cu]Br>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[NH:31][CH2:30][CH:27]2[CH2:26][CH2:25][N:24]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[CH2:29][CH2:28]2)=[O:9])=[CH:12][CH:13]=1
Reactant: NCC1CCN(c2ccncc2)CC1
Reactant: O=C(Nc1ccc(Cl)cc1)c1ccncc1Cl
Agent: [Cu]Br
Agent: S
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1)c1ccncc1NCC1CCN(c2ccncc2)CC1
Temperature: 110 °C
Reaction time: 18 h
Yield: 14 %

Procedure:
A mixture of 3-chloro-N-(4-chlorophenyl)pyridine-4-carboxamide (130 mg, 0.49 mmol), 1-(4-pyridyl)piperidine-4-methylamine (187 mg, 0.98 mmol), and copper(1) bromide (70 mg) in dimethylformamide (1 mL) was heated at 110° C. After 18 h, the mixture was diluted with MeOH, filtered, and concentrated. The residue was treated with 6:1 chloroform:water (10 mL) followed by MeOH until a homogenoeus solution resulted. The solution was treated with hydrogen sulfide(g), heated at reflux for 0.1 h, and filtered through diatomaceous earth. The filtrate was concentrated and the residue taken up in water, 1 N NaOH, and EtOAc. The aqueous layer was washed with EtOAc (3×), the combined extracts were dried (sodium sulfate), filtered and concentrated. The residue was purified by RPHPLC yielding 29 mg (13%) of the title compound as a hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2.[CH3:12][S:13]([CH:16]=[CH2:17])(=[O:15])=[O:14]>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:17][CH2:16][S:13]([CH3:12])(=[O:15])=[O:14])[CH2:7]2
Reactant: C=CS(C)(=O)=O
Reactant: Brc1cccc2c1CCNC2
Solvent: ClCCl
Product: CS(=O)(=O)CCN1CCc2c(Br)cccc2C1
Temperature: 35 °C
Reaction time: 14 h

Procedure:
A mixture containing 5-bromo-1,2,3,4-tetrahydroisoquinoline (212 mg, 1 mmol) and methylsulfonylethene (106 mg, 1 mmol) in dichloromethane is stirred at 35° C. for 14 hours. The solution is concentrated to afford 5-bromo-2-(2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline as a brown oil (LC-MS m/z: 318.1 (M+1)) which is used without further purification in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20](O)=[O:21])[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.Cl.[CH3:31][O:32][C:33](=[O:37])[C@H:34]([CH3:36])[NH2:35]>C(Cl)Cl>[CH3:2][C:1]([CH3:3])([O:5][C:6]([NH:8][CH:9]([C:20]([NH:35][C@@H:34]([C:33]([O:32][CH3:31])=[O:37])[CH3:36])=[O:21])[CH2:10][C:11]1[C:12]([CH3:19])=[CH:13][C:14]([OH:18])=[CH:15][C:16]=1[CH3:17])=[O:7])[CH3:4]
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](C)NC(=O)C(Cc1c(C)cc(O)cc1C)NC(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
Racemic t-butoxycarbonyl 2,6-dimethyltyrosine (3.9 g, 10 mmoles) was dissolved in 30 ml of CH2Cl2 by adding 1.12 ml (10 mmoles) of NMM. After bringing this mixture to reflux it was cooled to -30° C. and 1.32 ml (10 mmoles) of IBCF were added to this stirred solution. The temperature was allowed to rise to -15° C. and then lowered to -50° C. (D) alanine methyl ester hydrochloride (1.54 g, 11 mmoles) was added to the solution followed by 1.3 ml (11 mmoles) of NMM. The mixture was allowed to warm to room temperature and stand for 16 hours. The majority of the CH2Cl2 was removed under reduced pressure. Ethyl acetate (200 ml) was added and this solution was washed twice with 100 ml portions of 0.5 molar KHSO4, once with 100 ml of H2O and dried over MgSO4. Removal of all solvent gave 3.9 g of the mixture of diastereomers. Recrystallization of this material from Skelly B/CH2Cl2 produced 1.6 g (4.2 mmoles) of diastereomer F. Removal of the solvent from the filtrate gave 1.3 g (3.3 mmoles) of diastereomer S contaminated by less than 10% of diastereomer F.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]([CH3:13])([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[O:5].C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][CH:26]1[CH2:28][O:27]1>C(#N)C.CCOC(C)=O>[CH3:13][C:7]([NH:6][C:4](=[O:5])[C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[O:1][CH2:25][CH:26]1[CH2:28][O:27]1)([CH3:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccccc1O
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)C(C)(C)NC(=O)c1ccccc1OCC1CO1
Yield: 5 %

Procedure:
A solution of methyl 2-[(2-hydroxybenzoyl)amino]-2-methylpropanoate, K2CO3 (20 mmol, 2.68 g) and 2-(chloromethyl)oxirane (22 mmol, 2.03 g) in acetonitrile (60 ml) was stirred at reflux temperature overnight. The reaction mixture was diluted with EtOAc and washed with 1.8% HCl/aq (250 ml) and sat. NaCl/aq (250 ml). The organic phase was dried over Na2SO4 and concentrated at reduced pressure. The residue was purified on C18-column (H2O:CH3CN, 0.1M NH4OAc buffer, gradient 10% to 95% CH3CN) to give the subtitle compound (244 mg, 5% yield, two steps).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][C:13]([OH:15])=O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)([Cl:18])=O>>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][C:13]([Cl:18])=[O:15])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](CC(=O)O)CC1
Reactant: O=S(Cl)Cl
Product: CCCCC[C@H]1CC[C@H](CC(=O)Cl)CC1

Procedure:
For conversion into the acid chloride, trans-4-pentylcyclohexylacetic acid (12.0 g, 0.0566 mol) was reacted for about 1 hour on an oil bath at 80° C. with thionyl chloride (50 ml). The solution obtained was evaporated under reduced pressure, treated with absolute toluene (50 ml) and once more evaporated under reduced pressure.
Reaction SMILES: [CH:1]1([CH:4]([CH:12]2[CH2:14][CH2:13]2)[N:5]([CH2:9][CH2:10][CH3:11])[C:6]([NH2:8])=[S:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH:23]([CH3:34])[C:24]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33])=O>C(O)C>[Cl:33][C:27]1[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:26]=1[C:24]1[N:8]=[C:6]([N:5]([CH:4]([CH:1]2[CH2:3][CH2:2]2)[CH:12]2[CH2:13][CH2:14]2)[CH2:9][CH2:10][CH3:11])[S:7][C:23]=1[CH3:34]
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Reactant: CCCN(C(N)=S)C(C1CC1)C1CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(C1CC1)C1CC1
Yield: 88 %

Procedure:
To 1 g of N-(dicyclopropylmethyl)-N-propylthiourea (Compound 88) dissolved in 25 ml of anhydrous ethanol, add 0.54 ml of triethylamine, then slowly 1 g of 2-bromo-1-(2,4-dichlorophenyl)-1-propanone (Compound 15). After two hours of heating under reflux of the ethanol, evaporate to dryness. Take up the residue in methylene chloride and wash with water until bromide ions have been removed completely. Dry the organic phase over anhydrous sodium sulphate and then evaporate to dryness. Purify the residue on a silica column, using a mixture of cyclohexane and ethyl acetate (20:1 V/V) as eluent, to obtain the expected product in the form of an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[NH:7][C:8]2[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.Cl[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[C:8]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COCCCc1nc2cccc(C(=O)OC)c2[nH]1
Product: COCCCc1nc2c(C(=O)OC)cccc2n1COCC[Si](C)(C)C

Procedure:
Analogously to Example 228e, 4.3 g of methyl 2-(3-methoxypropyl)-3H-benzoimidazole-4-carboxylate and 3.54 ml of (2-chloromethoxyethyl)trimethylsilane are reacted. The title compound is obtained as a brown solid. Rf=0.33 (95:5 dichloromethane-methanol); Rt=4.26.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)O1.[CH:16]([N:20]1[CH:24]=[C:23](I)[C:22]([C:26]2[S:27][CH:28]=[C:29]([Cl:31])[CH:30]=2)=[N:21]1)([CH2:18][CH3:19])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH:16]([N:20]1[CH:24]=[C:23]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[C:22]([C:26]2[S:27][CH:28]=[C:29]([Cl:31])[CH:30]=2)=[N:21]1)([CH2:18][CH3:19])[CH3:17]
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: CCC(C)n1cc(I)c(-c2cc(Cl)cs2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCC(C)n1cc(-c2ccncc2)c(-c2cc(Cl)cs2)n1
Temperature: 25 °C
Yield: 26.7 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.48 mmol) and bis(tricyclohexylphosphine)palladium(II) chloride (0.04 mmol) were weighed into a microwave vial (reaction volume 2-5 mL). A solution of 1-sec-butyl-3-(4-chloro-2-thienyl)-4-iodo-1H-pyrazole (0.40 mmol) in 3.0 mL degassed dioxane and 1.0 mL of a degassed 2 M aqueous sodium carbonate solution were added. The reaction mixture was purged with argon, the microwave vial was capped with a septum and transferred to a laboratory microwave oven. The reaction mixture was irradiated to a reaction temperature of 120° C. for 12 min. After cooling to room temperature, the reaction mixture was diluted with dioxane and filtered through a short pad of silica. The filtered solid was washed thoroughly with dioxane, ethyl acetate and dichloromethane. The combined filtrates were concentrated in vacuum. The residue was purified by chromatography on silica gel (cyclohexane:ethyl acetate 97:3 to 0:100) to afford 34 mg 4-[1-sec-butyl-3-(4-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (27% yield).