Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C:19]3[N:20]=[CH:21][N:22]([C:24]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:23]=3)([OH:18])[CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)[CH:3]=1.[C:43](OC(=O)C)(=[O:45])[CH3:44].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1>[OH:18][C:14]([C:11]1[CH:10]=[CH:9][C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:43](=[O:45])[CH3:44])[CH:7]=[CH:6][N:5]=2)=[CH:13][CH:12]=1)([C:19]1[N:20]=[CH:21][N:22]([C:24]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:23]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)C(O)(c1ccc(-c2cc(N)ccn2)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccnc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 1-[4-(4-amino-2-pyridyl)phenyl]-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.40 g), acetic anhydride (0.46 ml), triethylamine (0.71 ml) and p-dimethylaminopyridine (20 mg) was stirred in THF (20 ml) at 60° C. for 16 h. The solvent was evaporated and ethyl acetate and water were added to the residue for partitioning. The organic layer was washed with aqueous sodium hydrogen carbonate and brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was dissolved in a mixture of acetonitrile (10 ml)—water (10 ml) and tetrabutylammonium bromide (13 mg) was added. The mixture was stirred at room temperature for 10 h. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer was combined, and the mixture was dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chomatography (eluent; hexane:ethyl acetate=2:1). Recrystallization from ethyl acetate gave the title compound (630 mg) as colorless powder crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCCC1>CO>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])/[C:24]/2=[CH:16]\[C:13]1[NH:12][C:8]2[CH2:9][CH2:10][CH2:11][N:5]([CH2:4][CH2:3][N:2]([CH3:19])[CH3:1])[C:6](=[O:18])[C:7]=2[C:14]=1[CH3:15]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Cl)cc32)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Temperature: 25 °C
Yield: 75.1 %

Procedure:
5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c (53 mg, 0.2 mmol) was dissolved in 1 ml of methanol under stirring, and added with 5-chloro-1,3-dihydro-indol-2-one (34 mg, 0.2 mmol) and piperidine (0.1 ml) to the solution. Upon the completion of the addition, the mixture was stirred to mix well in dark, heated to reflux for 2 hours and lots of precipitate was formed. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled down to room temperature, and filtered. The filter cake was washed with ethanol and dried to obtain the title compound (Z)-2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-dimethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 23 (62 mg, yield 75%) as an orange powder.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]#[N:12])[CH2:7][CH2:6]2)OCC1.[OH:13][NH:14][C:15](=N)[CH2:16][CH2:17][CH3:18]>>[CH2:16]([C:15]1[N:12]=[C:11]([N:8]2[CH2:7][CH2:6][C:5](=[O:1])[CH2:10][CH2:9]2)[O:13][N:14]=1)[CH2:17][CH3:18]
Reactant: CCCC(=N)NO
Reactant: N#CN1CCC2(CC1)OCCO2
Product: CCCc1noc(N2CCC(=O)CC2)n1

Procedure:
The title compound is prepared from 1,4-dioxa-8-aza-spiro[4.5]decane-8-carbonitrile and N-hydroxy-butyramidine following a procedure analogous to that described in Intermediate 5. LC (method 13): tR=1.16 min; Mass spectrum (ESI+): m/z=254 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:10][C:9]=1[F:23])=[O:6].[OH-].[NH4+:26]>>[F:23][C:9]1[CH:10]=[C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH:12]=[CH:13][C:8]=1[NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:26])=[O:2]
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)cc1F
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)cc1F
Yield: 87 %

Procedure:
The title compound is prepared in analogy to example 3 from N-[2-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester and ammonium hydroxide. Yield=87%. Slightly yellow solid. MS: m/e=321.3 (M++H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3ccccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3ccccn3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-pyridin-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester of Step A and benzenesulfonyl chloride following the method described in Example 3, Step B. 1H NMR (400 MHz, CDCl3) δ 8.67 (d, 1H), 7.86 (m, 4H), 7.77-7.51 (m, 5H), 7.24 (m, 1H), 7.11 (m, 3H), 6.76 (dd, 1H), 6.64 (d, 1H), 6.59 (d, 1H), 4.38 (s, 2H), 4.35 (s, 2H), 4.30 (s, 2H), 1.48 (s, 9H); MS 545 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)[C:16](Cl)=[S:17])C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:1]([C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:16]=[S:17]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CCN(CC)C(=S)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(N=C=S)c1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
In 500 ml of toluene was dissolved 82.5 g of ethyl m-aminobenzoate. While stirring the solution at room temperature, 83.4 g of N,N-diethylthiocarbamoyl chloride was added dropwise to the solution over a period of about 1 hour and then the mixture was refluxed for 5 hours. The toluene was distilled off under reduced pressure, the residue thus formed was dissolved in 300 ml of ethyl acetate, and the ethyl acetate solution was washed with water. Then, ethyl acetate was distilled off under reduced pressure and the residue was further subjected to distillation under reduced pressure to provide 80 g of oily ethyl m-isothiocyanatobenzoate having a boiling point of 125° C./0.6 mm Hg at a yield of 77%.
Reaction SMILES: FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[CH3:13][N:14]([CH3:40])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C@@H:21]1[CH2:35][C@H:34]2[C@@H:24]([CH2:25][C:26]3[C:36]4[C:29](=[CH:30][CH:31]=[CH:32][C:33]2=4)[NH:28][CH:27]=3)[N:23]([CH2:37][CH:38]=[CH2:39])[CH2:22]1)=[O:20].C(N(CC)CC)C.[CH2:48]([N:50]=[C:51]=[O:52])[CH3:49].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>ClCCl>[CH3:49][CH2:48][NH:50][C:51]([N:18]([C:19]([C@H:21]1[CH2:22][N:23]([CH2:37][CH:38]=[CH2:39])[C@H:24]2[C@@H:34]([C:33]3[C:36]4[C:26]([CH2:25]2)=[CH:27][NH:28][C:29]=4[CH:30]=[CH:31][CH:32]=3)[CH2:35]1)=[O:20])[CH2:17][CH2:16][CH2:15][N:14]([CH3:13])[CH3:40])=[O:52]
Reactant: C=CCN1C[C@H](C(=O)NCCCN(C)C)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: CCN=C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [F-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN1C[C@H](C(=O)N(CCCN(C)C)C(=O)NCC)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 18 °C
Reaction time: 14 h
Yield: 67.5 %

Procedure:
Trimethylsilyl trifluromethanesulfonate (7.6 g, 34.2 mmol, 1.1 eq) was added dropwise during 2 hours to a stirred mixture of N-[3-(dimethylamino)propyl]-6-allylergoline-8β-carboxamide (11.9 g, 31.5 mmol, 1 eq), triethylamine (3.8 g, 37.6 mmol, 1.2 eq) and dichloromethane (280 g) at −2° C. The mixture was stirred for 14 hours at 18° C. Ethyl isocyanate (11.1 g, 156.2 mmol, 5 eq) was added in one portion to the stirred mixture at 18° C. The obtained mixture was stirred for 48 hours at the same temperature. Tetrabutylammonium fluoride, 1.0 M solution in THF (30.4 g, 34.2 mmol, 1.1 eq) was added dropwise during 2 hours to the stirred mixture at −2° C. The reaction mixture was stirred for 2 hours at the same temperature and evaporated under reduced pressure. A solution of the residue in tert-butyl methyl ether was washed with aqueous solution of sodium bicarbonate and aqueous solution of sodium chloride, dried over sodium sulfate and passed through short silica gel column. The column was washed with acetone and the acetone solution was evaporated under reduced pressure to give 9.6 g (68.2%) of cabergoline as amorphous solid with 98% purity by HPLC. A hot solution of the amorphous cabergoline in tert-butyl methyl ether was kept at 0–5° C. for 60 hours. The precipitated solid was filtered off, washed on the filter with cold tert-butyl methyl ether and dried under reduced pressure at 15–25° C. to give 8.5 g (50%) solvate form A of cabergoline as white crystals with mp 66–70° C. and 99.8% purity by HPLC.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[CH:23][CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[Cl-].[O:38]([C:45]1[C:50]([CH2:51][NH3+:52])=[CH:49][CH:48]=[CH:47][N:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)CC)C.CS(C)=O>C(#N)C>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:23]=[CH:22][C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:52][CH2:51][C:50]4[C:45]([O:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)=[N:46][CH:47]=[CH:48][CH:49]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])=[CH:26][CH:25]=1
Reactant: [NH3+]Cc1cccnc1Oc1ccccc1
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4Oc4ccccc4)n3Cc3ccccc32)cc1
Yield: 26.4 %

Procedure:
The title compound was prepared according to the procedure of Example 6, Step D, from 2,2,2-trichloro-1-{10-[(2′-methoxy-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone (0.20 g, 0.379 mmol), 2-phenoxy-pyridin-3-ylmethyl-ammonium chloride (0.192 g, 0.78 mmol), triethylamine (0.112 g, 0.8 mmol), dimethylsulfoxide (0.131 mL, 1.85 mmol), and acetonitrile (5 mL). The crude material was purified by hplc using the following conditions: solvent system, 65:35 acetonitrile:water (0.1% trifluoroacetic acid); Primesphere 10 C18, 250 by 50 mm column; flow rate 100 mL/min) to provide the title compound (0.062 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10]C)[CH:5]=[C:6]([O:8]C)[CH:7]=1.[I-].[Na+].C[Si](Cl)(C)C>C(#N)C.O>[Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:10])[CH:3]=1
Reactant: COc1cc(Br)cc(OC)c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Oc1cc(O)cc(Br)c1
Temperature: 25 °C
Yield: 72.9 %

Procedure:
To a suspension of 5-bromo-1,3-dimethoxy-benzene (15 g, 67.02 mmol) and sodium iodide (100.5 g, 670.2 mmol) in acetonitrile (577 mL) was added trimethylsilyl chloride (42.39 mL, 335.1 mmol) at room temperature. Then, the resulting light yellow suspension was heated to reflux for 48 h. Then, it was cooled to room temperature and diluted with water (150 mL). The organic compound was extracted into ethyl acetate (2×150 mL) and the combined ethyl acetate extracts were washed with saturated sodium thiosulfate solution (300 mL) to remove the iodine color and was also washed with brine solution (300 mL). Then, the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by using an ISCO 330 g column, eluting with 5-30% ethyl acetate in hexanes to obtain 5-bromo-benzene-1,3-diol (9.24 g, 73%) as a light brown solid: ES(+)-HRMS m/e calcd for C6H5BrO2 (M+H)+ 189.2341. found 189.2346.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16]2)[CH:12]=[CH:11][C:10]=1[N:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25](=[O:30])[C:24]([C:31](O)=[O:32])=[N:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:35][NH:36][O:37][CH3:38].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.C(N(CC)CC)C.C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19]2)[CH:12]=[CH:11][C:10]=1[N:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25](=[O:30])[C:24]([C:31]([N:36]([O:37][CH3:38])[CH3:35])=[O:32])=[N:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: COc1cn(-c2ccc(-n3cc(F)c(F)c3)cc2OCc2ccccc2)nc(C(=O)O)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cn(-c2ccc(-n3cc(F)c(F)c3)cc2OCc2ccccc2)nc(C(=O)N(C)OC)c1=O

Procedure:
A suspension of 1-[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (0.5 THF solvate, 4.67 g), N,O-dimethylhydroxylamine hydrochloride (1.11 g), WSC (2.19 g), HOBt (1.54 g) and triethylamine (1.59 mL) in DMF (75 mL) was stirred at room temperature for 6 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, THF), and recrystallized from hexane/THF to give the title compound (4.51 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:21])[C:10]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:5]([OH:7])=O.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[F:21][C:9]1[CH:8]=[C:4]([C:5]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[O:7])[CH:3]=[C:2]([F:1])[C:10]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: COc1ccc(CNc2c(F)cc(C(=O)O)cc2F)cc1
Reactant: CN1CCNCC1
Product: COc1ccc(CNc2c(F)cc(C(=O)N3CCN(C)CC3)cc2F)cc1

Procedure:
Using 3,5-difluoro-4-(4-methoxy-benzylamino)-benzoic acid (95.4 mg) obtained in Step B in Example 1-D-24 and 1-methyl-piperazine (43.3 μl) instead of 1-ethyl-piperazine, in the same manner as Step C in Example 1-D-24, the desired compound was obtained as a crude product (82 mg, 67%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:26]1[CH:27]=[C:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:29]=[CH:30][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CN(C=O)C.CCOCC>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][O:5][C:30]1[CH:29]=[C:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:26][CH:31]=1
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: Cc1cccc(C)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)Cc1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2,6-Dimethylbenzyl alcohol (5.25 g, 38.6 mmol) and diisopropyl azodicarboxylate (DIAD, 8.49 g, 42 mmol) in THF (30 ml) and DMF (13 ml) was added drop wise to a solution of Ethyl 3-hydroxyphenylacetate (Step A, 6.66 g, 37 mmol) and triphenylphosphine (11 g, 42 mmol) in THF (100 ml). The reaction mixture was stirred at room temperature for 4 hours, diluted with ether and washed with water. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 1:1) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[CH3:28][C:26]1[NH:25][N:24]=[C:23]([NH:22][C:12]2[N:11]=[C:10]([O:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:19]3[C:14]([CH:13]=2)=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[CH:27]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Cc1ccc(O)cc1
Product: COc1ccc2c(Oc3ccc(C)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-methyl-phenol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-(1-p-tolyloxy-6-methoxy-isoquinolin-3-yl)-amine. LC-MS m/e 361(MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:5]=[CH:4][C:3]=1[C:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(O)(=O)C>[Pd].CO>[CH2:22]([C:3]1[CH:4]=[CH:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:7][C:2]=1[OH:1])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCc1ccc(C(=O)CCCCC)c(O)c1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCc1ccc(CCCCCC)c(O)c1
Reaction time: 24 h
Yield: 93.4 %

Procedure:
A mixture of 16.99 g of 1-(2-hydroxy-4-tetradecylphenyl)-1-hexanone, 4 g of 5% palladium on carbon catalyst, 100 ml of glacial acetic acid and 50 ml of methanol was hydrogenated in a Parr apparatus for 24 hours. The mixture was filtered, the solvents removed and the residue dissolved in ether, washed with water and dried. This crude material was chromatographed on silica gel, eluting with hexane:ethyl acetate (10:1), giving 15.3 g of the desired product, mp 43°-45° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]Br)=[CH:12][CH:11]=1.[P:18]([O:23]C)([O:21][CH3:22])[O:19][CH3:20]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][P:18]([O:21][CH3:22])([O:19][CH3:20])=[O:23])=[CH:12][CH:11]=1
Reactant: BrCc1ccc(-c2nc3ccccc3s2)cc1
Reactant: COP(OC)OC
Product: COP(=O)(Cc1ccc(-c2nc3ccccc3s2)cc1)OC
Temperature: 25 °C

Procedure:
6.08 g (0.2 mol) of 4-(benzothiazol-2-yl) bromomethylbenzene was reacted with 10 ml of trimethyl phosphite in nitrogen gas at 130°-160° C. for 15 minutes. The reaction mixture was allowed to cool down to room temperature and the resulting crystals were crystallized from n-hexane to give 3.9 g (83%) of colorless flakes of 1-(benzothiazol-2-yl)-4-dimethoxyphosphinylmethylbenzene melting at 129.5°-130.5° C.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH:6]=[CH:7][Cl:8].CC(N=NC(C#N)(C)C)(C#N)C.N#N.CCCC[SnH](CCCC)CCCC>C1(C)C=CC=CC=1>[C:12]([O:11][C:9]([N:4]1[C:3]2[C:16](=[CH:17][CH:18]=[CH:19][CH:2]=2)[CH:6]([CH2:7][Cl:8])[CH2:5]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N(CC=CCl)c1ccccc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Agent: N#N
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(CCl)c2ccccc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
A solution of 3.3 (110 mg, 0.318 mmol) and AIBN (21 mg, 0.127 mmol) in dry toluene (10 ml) was degassed for 15 mins with N2 and then heated to 90° C. Bu3SnH (84 μl, 0.318 mmol) was added to the mixture in four portions over an hour and the resulting mixture was stirred at 90° C. for a further 2 h. The mixture was then concentrated and purified by flash chromatography (SiO2, 0–10% EtOAc in hexane) to afford 3.4 (50 mg, 59%) as a colourless oil.FAB MS: (NBA/NaI) 267, (M+H+, expected 267) 292 (M+Na+, expected 292).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:4][CH2:5]1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Clc1cccnc1Cl
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncccc2Cl)CC1
Temperature: 100 °C

Procedure:
A mixture of benzyl 4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1) (1 g, 4.03 mmol) and 2,3-dichloropyridine (0.25 g) was heated to 100° C. for 12 h. The reaction mixture was cooled and partitioned between EtOAc and pH5.2 citrate buffer. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent evaporated to give a crude product. Purification by flash column chromatography (5–50% EtOAc hexane) afforded the title compound. M.S (M+1): 360.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:31]#[N:32])=[C:14]([NH:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=1>CN(C=O)C>[Cl:1][C:11]1[C:10]([Cl:9])=[CH:15][C:14]([NH:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[C:13]([C:31]#[N:32])[CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1Nc1cc(Cl)ccc1C#N
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1Nc1cc(Cl)c(Cl)cc1C#N
Temperature: 80 °C
Reaction time: 5 h

Procedure:
1-Chloro-2,5-pyrrolidinedione (NCS) was added at room temperature to a DMF solution of tert-butyl {(1R,2R)-2-[(5-chloro-2-cyanophenyl)amino]cyclohexyl}carbamate, followed by stirring at 80° C. for 5 hours. By post-treating the reaction liquid, tert-butyl {(1R,2R)-2-[(4,5-dichloro-2-cyanophenyl)amino]cyclohexyl}carbamate was obtained.
Reaction SMILES: C1(C(=[N:14][CH:15]([C@H:21]([CH2:29][CH3:30])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C2C=CC=CC=2)C=CC=CC=1.[ClH:31]>C(OCC)C>[ClH:31].[NH2:14][CH:15]([C@H:21]([CH2:29][CH3:30])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: C=CCCC(C)C[C@@H](CC)C(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Agent: Cl
Solvent: CCOCC
Product: C=CCCC(C)C[C@@H](CC)C(N)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A solution of (3R)-ethyl 2-(diphenylmethyleneamino)-3-ethyl-5-methylnon-8-enoate (7.00 g, 17.3 mmole) in diethyl ether (20 mL) was added aqueous 1.5 N HCl solutions (100 mL) and the reaction mass was stirred at room temperature overnight. The reaction mass was washed with diethyl ether (100 mL). The aqueous solution was basified using saturated sodium bicarbonate solution and extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4; filtered; then concentrated under reduced pressure to get crude compound (2.6 g, 62.4%). The crude compound was taken to the next step without further purification. MS: MS m/z 242.4 (M++1).