Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:10]([NH:12][C:13]2[C:14]([CH3:28])=[C:15]([CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:16]=[CH:17][CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[CH:34]1[CH:39]=[C:38]([CH:40]=[O:41])[C:37]([CH:42]=O)=[CH:36][CH:35]=1.O>C(O)(=O)C>[CH:29]1([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:1]3[CH2:42][C:37]4[C:38](=[CH:39][CH:34]=[CH:35][CH:36]=4)[C:40]3=[O:41])=[CH:4][CH:5]=2)[C:10]([NH:12][C:13]2[C:14]([CH3:28])=[C:15]([CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH:16]=[CH:17][CH:18]=2)=[O:11])[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: O=Cc1ccccc1C=O
Reactant: Cc1c(CCC(=O)OC(C)(C)C)cccc1NC(=O)C(c1ccc(CN)cc1)C1CCCC1
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(CCC(=O)OC(C)(C)C)cccc1NC(=O)C(c1ccc(CN2Cc3ccccc3C2=O)cc1)C1CCCC1
Reaction time: 1 h

Procedure:
At RT, 50 mg (0.11 mmol) of (+/−)-tert-butyl 3-[3-({[4-(aminomethyl)phenyl](cyclopentyl)acetyl}amino)-2-methylphenyl]propanoate and 16.4 mg (0.12 mmol) of phthaldialdehyde were dissolved in 2.5 ml of glacial acetic acid, and the mixture was left to stand for 1 h. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by preparative RP-HPLC. This gave 53 mg (85% of theory) of the target compound.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[NH2:5][C:6]1[C:7]2[S:16][CH:15]=[CH:14][C:8]=2[C:9]([CH3:13])=[N:10][C:11]=1[OH:12]>C(O)(=O)C>[OH:12][C:11]1[N:10]=[C:9]([CH3:13])[C:8]2[CH:14]=[CH:15][S:16][C:7]=2[C:6]=1[NH:5][C:2]([NH2:3])=[O:1]
Reactant: Cc1nc(O)c(N)c2sccc12
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nc(O)c(NC(N)=O)c2sccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
Sodium cyanate (0.50 g, 7.69 mmol) was added to a solution of crude 7-amino-4-methylthieno[3,2-c]pyridin-6-ol (1.26 g, 7.00 mmol) in acetic acid (30 ml) and an off-white solid precipitated. This mixture was stirred for one hour at room temperature. The solid was collected by filtration, washed with acetic acid, triturated with refluxing MeOH, then refluxing Et2O, and dried in vacuo to give the urea (0.798 g, 51% yield); mp 294°-297° C. (dec); IR (KBr) 1525, 1620 and 2300-3100 cm-1 ; mass spectrum m/z 223 (M+); 1H NMR (TFA) δ3.02 (s, 3H, 4-CH3), 7.63 and 7.77 each (d, J=6 Hz, 1H, thiophene-H).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li:13])CCC>>[Li:13][C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: [Li]CCCC
Product: [Li]C#Cc1ccccc1

Procedure:
Phenylacetylene is reacted with one equivalent of butyllithium at −78° C. to give lithiophenylacetylene. Two equivalents of lithiophenylacetylene are reacted with 1,7-bis(chlorotetrwrnethyldisiloxyl)-m-carborane to give 1,7-bis(phenylacetylenetetramethyldisiloxyl)-m-carborane. This latter material can be used in the hydrosilation reaction as 1,7-bis(ethynyltetramethyldisiloxyl)-m-carborane above.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:26][C:27]1[CH:28]=[CH:29][C:30](F)=[N:31][CH:32]=1.O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1([C:30]2[CH:29]=[CH:28][C:27]([Br:26])=[CH:32][N:31]=2)[CH2:15][CH2:14][C:9]2([O:10][CH2:11][CH2:12][O:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Fc1ccc(Br)cn1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Reaction time: 1.5 h
Yield: 65.6 %

Procedure:
A solution of 1,4-dioxaspiro[4,5]decane-8-carboxylic acid ethyl ester (6.09 g) in tetrahydrofuran (14 ml) was added dropwise to a tetrahydrofuran solution (32 ml) of 1.0M tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (39.8 ml) at −78° C., and stirred at the same temperature for 1.5 hours. Next, a solution of 5-bromo-2-fluoropyridine (5.0 g) in tetrahydrofuran (14 ml) was added dropwise and stirred at the same temperature for 0.5 hour and at room temperature for an hour. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate twice. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4,5]decane-8-carboxylic acid ethyl ester (6.9 g) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[F:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[CH:13]=O>>[F:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[CH2:13][NH:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2]
Reactant: CCOC(CN)OCC
Reactant: O=Cc1ccc(F)cc1F
Product: CCOC(CNCc1ccc(F)cc1F)OCC
Yield: 37.1 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-2, 2,2-diethoxyethanamine (75.6 ml, 520 mmol) was reacted with 2,4-difluorobenzaldehyde (75 g, 520 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=5:1 and 3:1) to obtain the title compound (50.0 g, 36%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH2:11][CH3:12])=[C:4]([CH3:13])[CH:3]=1.[CH2:14]([Sn](CCCC)(CCCC)CCCC)[CH:15]=[CH2:16]>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>[CH2:16]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH2:11][CH3:12])=[C:4]([CH3:13])[CH:3]=1)[CH:15]=[CH2:14]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CCOCOc1ccc(Br)cc1C
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=CCc1ccc(OCOCC)c(C)c1

Procedure:
In a manner similar to Example 1c, by reacting 16 g (65 mmol) of 4-bromo-1-ethoxymethoxy-2-methylbenzene with 30 ml (97 mmol) of allyltributyltin and 1.35 g (2 mmol) of dichlorobis (triphenylphosphino)palladium. A yellow oil is obtained (m=12:1 g, y=89%).
Reaction SMILES: I[C:2](=C)[CH2:3][CH2:4][CH:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[OH:6].[OH-].[Na+].Cl.[CH3:21]N(C)C=O>>[CH3:21][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)([CH2:4][C:3]#[CH:2])[OH:6]
Reactant: CN(C)C=O
Reactant: C=C(I)CCC(O)c1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C#CCC(C)(O)c1cccc2ccccc12

Procedure:
5.00 Grams of 2-iodoallylmethyl-α-naphthylcarbinol were dissolved in 50 g of dimethylformamide, and 1.18 g of sodium hydroxide in a flake form were added. The resultant mixture was stirred at room temperature for 8 hours. After the reaction was completed, the reaction mixture was neutralized with concentrated hydrochloric acid, insolubles were filtered off, and the remaining filtrate was concentrated under reduced pressure. The concentration residue was subjected to extraction with toluene, and washed with a 7% sodium carbonate aqueous solution. Then, the toluene was distilled off under reduced pressure to give 2.77 g of methyl-α-naphthylpropargylcarbinol; nD25 =1.5141, FI-MS m/e 210 (M) (Propargyl compound/allene compound 100.0/0.0).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccccc1
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Solvent: CC#N
Product: Clc1cccnc1N1CCc2c(ncnc2Nc2ccccc2)C1
Temperature: 180 °C
Yield: 32.9 %

Procedure:
4-Chloro-7-(3-chloro-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine (150 mg, 0.54 mmol) was dissolved in acetonitrile (2 mL). To the mixture was added aniline (60 mg). The mixture was heated in a sealed tube at 180° C. for 30 minutes in a Personal Chemistry Microwave (Smith Creator). The solvent was removed under vacuum and the resulting orange residue was purified by flash chromatography over silica gel using a 0-100% ethyl acetate-hexane gradient to give the product as an off white solid (60 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[NH2:20][C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[C:25](OC2C=CC(NC(=O)OC(C)(C)C)=C(F)C=2)[CH:24]=[CH:23][N:22]=1>>[C:15]([O:14][C:13](=[O:19])[NH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][C:25]2[CH:24]=[CH:23][N:22]=[C:21]([NH2:20])[C:26]=2[N+:27]([O-:29])=[O:28])=[CH:3][CH:4]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])cc1F
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])c2ccccc12

Procedure:
The title compound was prepared from tert-butyl 4-hydroxynaphthalen-1-ylcarbamate (Regan, J. et al, J. Med. Chem., 2002, Vol. 45, No. 14, p. 2994) (3.9 g, 15 mmol) by the same method as described for compound (3a).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:19]=4)=[CH:17][C:12]=3[CH:11]=[C:10]([C:31]([O:33]C)=[O:32])[CH2:9][CH2:8]2)=[CH:2]1.[OH-].[Na+].O.Cl>O1CCCC1.CO>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:19]=4)=[CH:17][C:12]=3[CH:11]=[C:10]([C:31]([OH:33])=[O:32])[CH2:9][CH2:8]2)=[CH:2]1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccoc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 87.5 %

Procedure:
To a solution of methyl 1-(3-furylmethyl)-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (362 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 5 days. Then, to the mixture was added water at −0° C., and 1N hydrochloric acid was further added to make acidic (pH=4), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was washed with hexane to give 1-(3-furylmethyl)-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (307 mg) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.Cl.[NH2:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][SH:15].[OH-].[Na+]>C(OCC)C.C(O)C>[NH2:12][C@@H:13]([CH2:14][S:15][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:16]([OH:18])=[O:17]
Reactant: COc1ccc(CO)cc1
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(CSC[C@H](N)C(=O)O)cc1
Reaction time: 1 h
Yield: 63.8 %

Procedure:
4-Methoxybenzyl alcohol (280 g, 1780 mmol) dissolved in diethylether (400 mL) was added in drops to a mixture of diethylether (400 mL) and conc. hydrochloric acid (400 mL) over 2 h, and the mixture was stirred for 1 h. The organic layer was separated, and added to a solution prepared by dissolving L-cysteine (197 g, 1625 mmol) and 2N aqueous sodium hydroxide solution (980 mL) to ethanol (1890 mL). The mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction mixture was cooled to 0°, and neutralized to pH 7 using 3N aqueous hydrochloric acid solution. The resulting solid was filtered and dried to give the title compound (250 g, Yield 64%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH2:11]C)=[O:9].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17].[NH4+].[Cl-]>CCOC(C)=O>[CH3:15][N:16]([CH3:18])[CH:17]=[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)Cc1ccccn1
Reactant: COC(OC)N(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COC(=O)C(=CN(C)C)c1ccccn1
Temperature: 130 °C

Procedure:
10 g of ethyl 2-(2-pyridinyl)acetate, 39 ml of dimethoxy-N,N-dimethylmethanamine and 1.5 ml of N,N,N′,N′-tetramethylenediamine are mixed and the mixture is heated at 130° C. for 18 hours. The mixture is taken up in 120 ml of a mixture of equal volumes of AcOEt and of a saturated NH4Cl solution. The organic phase is separated by settling, washed with a saturated NaCl solution, dried over Na2SO4 and evaporated to produce the expected product in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[Cl:10].C1C(=O)N(Br)C(=O)C1.[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[K].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Cl:10][C:4]1[CH:5]=[CH:6][C:7]([CH2:9][N:23]2[C:19](=[O:29])[C:20]3[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:22]2=[O:24])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cc(C)ccc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(CN2C(=O)c3ccccc3C2=O)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
To a solution of 2-chloro-5-methylphenyl methyl ether (12.0 g, 76 mmol) dissolved in CCl4 (200 mL) was added NBS (215.0 g, 83.6 mmol) and AIBN (0.63 g, 3.8 mmol). The reaction mixture was placed in an oil bath at 85° C. and stirred for 2-4 h. The reaction was cooled to RT, filtered and the solid washed with CCl4. The filtrate was evaporated and the resulting solid was dissolved in DMF (200 mL) then potassium phthalimide (35.0 g, 192 mmol) was added. The reaction mixture was placed in an oil bath at 60° C. and stirred for 2 h. The reaction mixture was cooled to RT then 10% citric acid (200 mL) was added and the mixture was extracted with EtOAc (3×200 mL). The organic extracts were combined, washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and evaporated. Purification was accomplished by column chromatography (hexane/EtOAc) to afford the title compound (15.0 g, 65%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.78-7.88 (m, 4H), 7.30 (d, 1H), 7.09 (d, 1H), 6.81 (dd, 1H), 4.72 (s, 2H), 3.80 (s, 3H). MS: m/z 324.0 (M+23).
Reaction SMILES: [C:1]([C@:3]([CH3:26])([C@H:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[C:4](O)=[O:5])#[N:2].C(Cl)(=O)C(Cl)=O.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:38]=[C:39]([O:41][CH3:42])[CH:40]=1>C1COCC1.CN(C=O)C.CN(C1C=CN=CC=1)C.ClCCl>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([N:43]2[CH2:44][CH2:45][N:46]([C:4](=[O:5])[C@:3]([C@H:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:11]=[CH:10][CH:9]=3)([CH3:26])[C:1]#[N:2])[CH2:47][CH2:48]2)[CH:38]=[C:39]([O:41][CH3:42])[CH:40]=1
Reactant: COc1ccccc1[C@H](c1cccc2ccccc12)[C@@](C)(C#N)C(=O)O
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(OC)cc(N2CCN(C(=O)[C@](C)(C#N)[C@H](c3ccccc3OC)c3cccc4ccccc34)CC2)c1
Reaction time: 8 h
Yield: 71.4 %

Procedure:
A solution of (S,S)2-cyano-3-(2-methoxy-phenyl)-2-methyl-3-naphthalen-1-yl-propionic acid (0.45 g, 1.30 mmol) in THF (150 mL) is treated with DMF (2 drops). Oxalyl chloride (0.16 mL, 1.84 mmol) is added dropwise in order to control gas evolution; when the gas evolution stopped the solution is heated to reflux for 5 minutes. The solution is cooled, the THF is evaporated in vacuo and the solid is dissolved in dry toluene (15 mL) and evaporated to a solid. This procedure is repeated twice. The acid chloride is dissolved in dichloromethane (10 mL) this is added to a solution of 1-(3,5-dimethoxy-phenyl)-piperazine (305 mg, 1.36 mmol) and a crystal of DMAP in dichloromethane (15 mL). This is followed by the dropwise addition of TEA (0.6 mL, 4.27 mmol). The reaction is stirred overnight. The reaction mixture is diluted with dichloromethane (50 mL), washed with aqueous HCl (10 mL 0.5 N) then saturated NaHCO3 (10 mL) and brine (10 mL). The sample is dried over NaSO4, filtered and concentrated in vacuo. Chromatography on silica gel using 30% ethyl acetate/hexanes provided 510 mg the title compound as a white solid. Recrystallization from ethyl acetate/hexanes yielded colorless needles. mp 186-188° C.; [α]D25=−153.91° (1%, CHCl3);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:27])[N:11]([CH2:13][C:14]2([C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH3:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:28]1([CH:31]=O)[CH2:30][CH2:29]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl.CCOC(C)=O>[CH:28]1([CH2:31][N:17]2[CH2:18][CH2:19][C:14]([CH2:13][N:11]([CH3:12])[C:10]([NH:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)=[O:27])([C:20]3[CH:21]=[CH:22][C:23]([I:26])=[CH:24][CH:25]=3)[CH2:15][CH2:16]2)[CH2:30][CH2:29]1
Reactant: O=CC1CC1
Reactant: CN(CC1(c2ccc(I)cc2)CCNCC1)C(=O)Nc1cc(Cl)cc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(CC1(c2ccc(I)cc2)CCN(CC2CC2)CC1)C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
To a solution of 3-(3,5-dichloro-phenyl)-1-[4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-1-methyl-urea (˜0.10 g, 0.17 mmol) in ClCH2CH2Cl (1 mL) was added cyclopropanecarboxaldehyde (0.016 mL, 0.204 mmol, 1.2 eq.). The mixture was stirred at room temperature for 15 min and then HOAc (0.01 mL, 1% v/v) was added. The reaction was stirred for a further 1 h. Na(OAc)3BH (0.054 g, 0.255 mmol, 1.5 eq.) was added and the reaction was stirred at room temperature for 12 h. It was diluted with EtOAc (10 mL) and washed with saturated NaHCO3 (10 mL) and saturated brine (10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give 1-[1-cyclopropylmethyl-4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-3-(3,5-dichloro-phenyl)-1-methyl-urea (0.094 g, 95%). Crude 1H NMR (CDCl3): δ 7.83 (d, 2H), 7.22 (m, 4H), 7.05 (s, 1H), 6.01 (br.s, 1H), 3.50 (s, 2H), 2.97 (d, 2H), 2.83 (s, 3H), 2.36 (m, 2H), 2.27 (m, 2H), 2.09 (m, 2H), 0.91 (br.m, 1H), 0.58 (d, 2H), 0.15 (d, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[N:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[C:22]([CH:23]=2)=[N:21][N:20]([CH3:24])[CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:35]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>O1CCOCC1.CN(C=O)C.C(=O)([O-])O.[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:24][N:20]1[CH:19]=[C:18]2[C:22]([CH:23]=[C:15]([NH:14][C:12]([C:11]3[C:10]([NH:9][CH2:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:41]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[O:42])[CH:7]=4)=[N:28][CH:27]=[CH:26][CH:25]=3)=[O:13])[CH:16]=[CH:17]2)=[N:21]1
Reactant: Cn1cc2ccc(NC(=O)c3cccnc3NCc3ccnc(Cl)c3)cc2n1
Reactant: NC(=O)N1CCOCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cn1cc2ccc(NC(=O)c3cccnc3NCc3ccnc(NC(=O)N4CCOCC4)c3)cc2n1
Temperature: 110 °C
Reaction time: 11 h
Yield: 48 %

Procedure:
A mixture of 2-[(2-chloro-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-nicotinamide (200 mg, 0.51 mmol), Pd2 dba3 (5.2 mg, 0.0051 mmol), xantphos (9.1 mg, 0.0153 mmol), cesium carbonate (169 mg, 0.54 mmol) and morpholine-4-carboxylic acid amide (332 mg, 2.55 mmol) in dioxane (12.1 mL) and DMF (4.1 mL) under nitrogen, was stirred at 110° C. for 11 hours. A second reaction was performed in duplicate. The two reactions were combined, diluted with dilute aqueous sodium hydrogencarbonate solution and extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated in vacuo. Purification was achieved by chromatography on Isolute® flash silica gel (Separtis) to give morpholine-4-carboxylic acid (4-{[3-(2-methyl-2H-indazol-6-ylcarbamoyl)-pyridin-2-ylamino]-methyl}-pyridin-2-yl)-amide (119 mg) which was further purified by recrystallisation from EtOAc; 1H-NMR (300 MHz, d6-DMSO) 10.2 (1H, s), 9.06 (1H, s), 8.45 (1H, t), 8.22 (1H, s), 8.03-8.13 (4H, m), 7.73 (1H, s), 7.62 (1H, d), 7.27 (1H, unresolved dd), 6.89 (1H, unresolved dd), 6.67 (1H, dd), 4.62 (2H, d), 4.10 (3H, s), 3.52 (4H, t), 3.39 (4H, t).
Reaction SMILES: CS(O)(=O)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[CH:13]([CH2:19][C:20]([OH:22])=[O:21])[CH2:12][CH2:11]2.[CH2:23](O)[CH3:24]>>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[CH:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11]2
Reactant: COc1ccc2c(c1)CCC(CC(=O)O)C2=O
Reactant: CCO
Agent: CS(=O)(=O)O
Product: CCOC(=O)CC1CCc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
Methane sulfonic acid (450 mL) was added to a solution of 1B (250 g, 1067 mmol) in ethanol (1.5 L), and the mixture was stirred at room temperature for 16 h. Ethanol was removed from the reaction mixture under reduced pressure, and residue was diluted with ethyl acetate and extracted with brine solution. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under vacuum to afford the title compound (241 g, 81%) as a solid. 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J=8.8 Hz, 1H), 6.82 (dd, J1=2.4 Hz, J2=8.8 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 4.18 (q, J=8.1 Hz, 2H), 3.8 (s, 3H), 3.12-2.85 (m, 4H), 2.39 (q, J=9.0 Hz, 1H), 2.23 (m, 1H), 1.94 (dq, J1=4.5 Hz, J2=12.6 Hz, 1H), 1.28 (t, J=7.5 Hz, 3H). ESI-MS m/z: 263 (M+H)+.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.ClC(OCC)=O.Cl.Cl.[CH2:36]([NH:43][NH2:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[CH2:36]([NH:43][NH:44][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NNCc1ccccc1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)NNCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 7.0 g linoleic acid in 250 ml methylenechloride cooled to -20° is added first 2.5 g triethylamine and then dropwise 2.7 g ethyl chloroformate. The reaction mixture is allowed gradually to come to room temperature and stirred for 2 hours. There is then added 5.0 g triethylamine followed by 4.9 g benzylhydrazine dihydrochloride and the reaction mixture then stirred for 16 hours. Thereafter the reaction mixture is extracted five times with portions of 2 N hydrochloric acid, then once with 2 N aqueous sodium hydroxide solution and washed extensively with saturated aqueous sodium chloride. The organic phase is then dried with anh. sodium sulphate, filtered and the filtrate evaporated i.v. to dryness. The residue is then chromatographed over silica gel, with chloroform as the eluent. The desired fractions* are collected, and evaporated i.v. to dryness to yield the title product as a viscous oil.