Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][C@@H:52]([CH2:66][C:67]1[CH:72]=[C:71]([F:73])[CH:70]=[C:69]([F:74])[CH:68]=1)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=1>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH:51][C@@H:52]([CH2:66][C:67]3[CH:68]=[C:69]([F:74])[CH:70]=[C:71]([F:73])[CH:72]=3)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=3)=[O:16])[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ccc2ccc(C(=O)O)cc21
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCn1ccc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.3 %

Procedure:
To a mixture of 1-butyl-1H-indole-6-carboxylic acid (0.278 g) in methylene chloride (10 mL) was added triethylamine (0.129 g), HOBT (0.175 g) and, HATU (0.486 g). The mixture was stirred at room temperature for 30 minutes at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.408 g) was added. The resulting mixture was stirred at room temperature for 18 h then partitioned between water and methylene chloride. The layers were separated and the organic layer washed with water followed by brine and dried over anhydrous magnesium sulfate. Column chromatography on silica gel (100 mL) using 3% methanol in methylene chloride as eluent to give 0.256 g of the title compound: MS (ESI+) for C32H37F2N3O2 m/z 542.2 (M+H).
Reaction SMILES: [I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:36]([O:38][C:39]([C:41]1([NH2:50])[CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42]1)=[O:40])[CH3:37].C(N(CC)C(C)C)(C)C>CC(O)C.C(Cl)Cl.C(Cl)Cl>[CH2:36]([O:38][C:39]([C:41]1([NH:50][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[I:1])[CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42]1)=[O:40])[CH3:37]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: Cc1cccc(C(=O)O)c1I
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Reaction time: 0.08 h
Yield: 62.1 %

Procedure:
A 100 mL round bottom flask is charged with 2-iodo-3-methylbenzoic acid (1.92 g, 7.31 mmol) and dry DCM (25 mL). A stirring bar is added and stirring is initiated. After 5 min, the HBTU (2.37 g, 7.31 mmol) is added. After 5 min, the 2-amino-indane-2-carboxylic acid ethyl ester (1.5 g, 7.31 mmol) is added followed by N,N-diisopropylethyl-amine (3.2 mL, 18.37 mmol). The reaction is allowed to stir for 118 h. Analysis by tlc of the reaction mixture (silica, 15% iPrOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are transferred to a separatory funnel and diluted with EtOAc (70 mL). This is washed dilute aqueous HCl (3%, 2×30 mL), saturated aqueous NaHCO3 (2×30 mL) and brine (30 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 2.04 g of a white solid. This material is dissolved in 15 mL of DCM. This material is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 10% EtOAc in heptanes over 4 column volumes followed by a linear gradient to 50% EtOAc over 10 column volumes. 27 mL fractions of UV active eluent are collected. Fractions 10 through 15 are combined and evaporated in vacuo. Pumping to constant weight gives 1.04 g a white solid material.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](Cl)=[N:10][N:9]=1>CO>[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([S:5][CH2:2][CH:3]=[CH2:4])=[N:10][N:9]=1
Reactant: C=CCS
Reactant: COc1nnc(Cl)c2ccccc12
Agent: [Na]
Solvent: CO
Product: C=CCSc1nnc(OC)c2ccccc12

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 30 ml of absolute methanol and then mixed with 0.93 ml(0.01 mol) of allylmercaptan. To this mixture was added 1.95 g(0.01 mol) of 1-methoxy-4-chlorophthalazine obtained from Preparation 7. The reaction solution was refluxed for one hour and then treated according to the same manner as Example 1 to obtain the title compound as a freezing pale white crystal.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(N(CC)CC)C.[I-].[K+]>CN(C)C=O.O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: CCOC(=O)CBr
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 59.9 %

Procedure:
3.3 g (0.01 mol) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid in 50 ml of dimethylformamide are heated at 90° C. with 2.5 g (0.015 mole) of ethyl bromoacetate, 1.2 g (0.02 mole) of triethylamine and 2.5 g of potassium iodide for 5 hours. The reaction mixture is poured into 30 ml of water and the precipitate is filtered off with suction, washed with water and recrystallized from methanol. 2.5 g of 1-cyclopropyl-6-fluoro-7-[4-(ethoxycarbonylmethyl)-1-piperazinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 192° to 194° C. are obtained.
Reaction SMILES: B([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[CH3:26])[CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])(=[O:12])=[O:11])(O)O.C([O-])([O-])=O.[Na+].[Na+].[C:33]1([CH3:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CCO>[CH3:25][C:22]1[C:21]([CH3:26])=[C:20]([N:13]([CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:14]2[N:13]([S:10]([C:5]3[CH:4]=[CH:9][CH:8]=[CH:7][CH:6]=3)(=[O:11])=[O:12])[C:38]3[C:33]([CH:39]=2)=[CH:34][CH:35]=[CH:36][CH:37]=3)(=[O:12])=[O:11])[O:24][N:23]=1
Reactant: Cc1ccccc1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: 85 °C
Yield: 19 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (230 mg; 10 mol %) was added to a degassed solution of the title product of Step (A) (766 mg; 2 mmol) and the title product of Step (B) (900 mg; 2.34 mmol) in 10 ml of toluene and 8.5 ml of EtOH under argon. After adding 7 ml of 2M Na2CO3, the heterogeneous mixture was heated to 85° C. for 5 hrs with vigorous stirring. At this time, an additional amount of the title product of Step (B) (100 mg; 0.26 mmol) was added and the mixture was heated an additional 2 hrs. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (75 ml) and water (50 ml). The organic layer was washed with brine (50 ml), dried (MgSO4), and concentrated to afford a yellow residue which was chromatographed on a 5×20 cm silica gel column, using 4 L EtOAc:Hexanes, 3:7, 2 L EtOAc:hexanes, 4:6 and 1 L EtOAc:Hexanes, 1:1 as the mobile phase. The pure fractions were concentrated to afford 222 mg (19%) of the title product of this step as a light yellow foam.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25]>O1CCCC1>[CH3:28][O:27][C:23](=[O:26])[CH2:24][CH2:25][N:20]1[CH2:21][CH2:22][N:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:8]2[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:9]2)[CH2:18][CH2:19]1
Reactant: CC(C)(C)C1CCC(c2ccccc2N2CCNCC2)CC1
Reactant: C=CC(=O)OC
Solvent: C1CCOC1
Product: COC(=O)CCN1CCN(c2ccccc2C2CCC(C(C)(C)C)CC2)CC1
Temperature: 45 °C
Reaction time: 12 h
Yield: 94.5 %

Procedure:
To a mixture of 1-[2-(4-t-butylcyclohexyl)phenyl]piperazine (530 mg, 1.76 mmol) produced in Example (10a) and tetrahydrofuran (2 mL) was added methyl acrylate (0.24 mL, 2.65 mmol), followed by stirring for 12 hours at an external temperature of 45° C. The reaction mixture was concentrated under reduced pressure and the resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 643 mg of the title compound as colorless crystals, as a mixture of diastereomers at the position of t-butylcyclohexyl.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH2:14][CH:13]([C:16]([O:18]CC)=[O:17])[O:12][C:11]=2[CH:21]=1)(=O)C>CO>[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[O:12][C:11]=2[CH:21]=1
Reactant: CCOC(=O)C1COc2ccc(OC(C)=O)cc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1COc2ccc(O)cc2O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
Under a nitrogen atmosphere, slowly add 75 mmol of a 10% aqueous sodium hydroxide solution to a solution of 2 g (7.5 mmol) of ethyl 7-acetoxy-2,3-dihydro-1,4-benzodioxin-2-carboxylate in 20 cm3 of methanol. Stir at room temperature for 6 hours and then, after concentrating under reduced pressure, acidify the mixture with a 2N hydrochloric acid solution. Extract with diethyl ether the acid which precipitates, then, after drying and concentration to dryness, wash the resulting acid with methylene chloride. 7-Hydroxy-2,3-dihydro-1,4-benzodioxin-2-carboxylic acid is thereby obtained in a yield of 85%. Melting point: 204° C. ##STR48##
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[C:25]([O:29][C:30]([NH:32][C:33]1[CH:54]=[CH:53][C:36]([CH2:37][N:38]2[CH2:42][CH2:41][N:40]([C:43]3[S:47][C:46]([C:48](O)=[O:49])=[C:45]([CH3:51])[CH:44]=3)[C:39]2=[O:52])=[CH:35][CH:34]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[NH2:55][CH2:56][C:57]1[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=1>>[CH3:51][C:45]1[CH:44]=[C:43]([N:40]2[CH2:41][CH2:42][N:38]([CH2:37][C:36]3[CH:35]=[CH:34][C:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:28])[CH3:26])=[CH:54][CH:53]=3)[C:39]2=[O:52])[S:47][C:46]=1[C:48](=[O:49])[NH:55][CH2:56][C:57]1[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(NC(=O)OC(C)(C)C)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(NC(=O)OC(C)(C)C)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 75 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-(tert-butoxycarbonylamino)benzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a beige solid in 75% yield: 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.53 (d, J=4.5 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.33 (d, J=8.3 Hz, 2H), 7.27 (dd, J=7.8, 4.5 Hz, 1H), 7.21 (d, J=8.3 Hz, 2H), 6.51 (br s, 1H), 6.08 (br s, 2H), 4.58 (d, J=5.8 Hz, 2H), 4.40 (s, 2H), 3.82-3.73 (m, 2H), 3.45-3.37 (m, 2H), 2.50 (s, 3H), 1.51 (s, 9H); MS (ES+) m/z 522.5 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH3:23])[CH2:9][CH2:10][N:11]1[CH2:14][CH:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:12]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH:13]2[CH2:14][N:11]([CH2:10][CH2:9][C@H:8]([NH2:7])[CH3:23])[CH2:12]2)=[CH:21][CH:20]=1
Reactant: C[C@H](CCN1CC(Oc2ccc(Cl)cc2)C1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)CCN1CC(Oc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of {(R)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-methyl-propyl}-carbamic acid tert-butyl ester (0.019 mg, 0.053 mmol) in DCM (1 ml) is treated with trifluoroacetic acid (0.042 ml) and stirred at room temperature overnight. The solvent is evaporated and the residue partition between DCM and 1M sodium hydroxide solution. The aqueous phase is extracted with more DCM (×3) and the combined organic phases washed with brine, dried over magnesium sulphate and evaporated to afford (R)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-methyl-propylamine. [M+H] 255.22
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[N:32]=[CH:31][N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:29]=4)[CH:26]=3)[N:21](C3CCCCO3)[N:20]=2)[CH:14]=1)=[O:12].Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH:29]1[C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[C:19]3[C:15]2[CH:14]=[C:13]([C:11]([NH:10][CH:2]3[CH2:1][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3]3)=[O:12])[CH:18]=[CH:17][CH:16]=2)=[N:32][CH:31]=[N:30]1
Reactant: O=C(NC1Cc2ccccc2C1)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NC1Cc2ccccc2C1)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 50 °C
Yield: 21.5 %

Procedure:
To a stirred solution of N-indan-2-yl(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide (0.342 g, 0.458 mmol) was added dioxane (4.0 mL) and aqueous 6 N hydrochloric acid (4.0 mL) and the mixture heated at 50° C. for 5.5 h. The mixture was cooled and poured into saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Addition of ethyl acetate (5 mL) initiated crystal growth and the ethyl acetate phase was pipetted off. The crystals were filtered. Purification by preparative HPLC (30-80% acetonitrile/water) followed by washing with saturated sodium bicarbonate and extraction with ethyl acetate gave the title compound (0.0414 g, 22% yield). 1H NMR (CD3OD) δ 8.79 (s, 1H), 8.50 (m, 1H), 8.21 (d, 1H), 8.13 (d, 1H), 7.91 (d, 1H), 7.69 (m, 2H), 7.25 (m, 2H), 7.17 (m, 2H), 4.83 (m, 1H), 3.34 (dd, 2H), 3.07 (dd, 2H). ES-MS (m/z) 421 [M+1]+.
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[C:13](=O)[C:12](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][O:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([NH:25][NH2:26])[CH2:23][CH3:24]>CO>[C:1]1([C:7]2[N:25]([CH2:22][CH2:23][CH3:24])[N:26]=[C:13]3[C:12](=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][O:10][CH2:9][C:8]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C(=Cc2ccccc2)COCC1=Cc1ccccc1
Reactant: CCCNN
Solvent: CO
Product: CCCn1nc2c(c1-c1ccccc1)COCC2=Cc1ccccc1

Procedure:
A mixture of tetrahydro-3,5-bis-(phenylmethylene)-4H-pyran-4-one (3.6 g, 13 mmole) and propylhydrazine (1.1 g, 14 mmole) in methanol (250 ml) is heated at reflux temperature for 3-4 hours. MeOH is then removed in vacuo. The residue is dissolved in CHCl3 and washed with dilute HCl and water, then dried (anhydrous MgSO4) and concentrated in vacuo to give a yellow oil. When this crude oil is triturated with a small amount of acetonitrile the major product of this reaction precipitates out. The filtrate is concentrated and the residue is applied to a dry-packed Al2O3 (Activity I, neutral) column. The fractions eluted with ether are combined and recrystallized first from ether/hexane, then from cyclohexane until a constant m.p. (126.5°-128.5° C.) is reached, giving the product in crystalline form (99% pure).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][CH:7]=1.[H-].[Na+].C(OC([N:24]1[CH2:29][C@@H:28]([CH3:30])[N:27]([C:31](Cl)=[O:32])[C@@H:26]([CH3:34])[CH2:25]1)=O)(C)(C)C>>[CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][O:13][C:31]([N:27]2[C@H:28]([CH3:30])[CH2:29][NH:24][CH2:25][C@@H:26]2[CH3:34])=[O:32])=[CH:8][CH:7]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Reactant: CC(C)CCOc1ccc(CO)cn1
Agent: [H-]
Agent: [Na+]
Product: CC(C)CCOc1ccc(COC(=O)N2[C@H](C)CNC[C@@H]2C)cn1

Procedure:
cis-2,6-Dimethyl-piperazine-1-carboxylic acid 6-(3-methyl-butoxy)-pyridin-3-ylmethyl ester was prepared from [6-(3-Methyl-butoxy)-pyridin-3-yl]-methanol (0.19 g), sodium hydride (60%, 0.048 g) and 4-tert-butoxycarbonyl-1-chlorocarbonyl-cis-2,6-dimethylpiperazine (0.25 g) according to the method described in Example 54 to give the product as a pale oil (0.052 g, 13%): δH (400 MHz, CDCl3) 8.15 (1H, d, J 2.5 Hz), 7.58 (1H, dd, J 8.5, 2.5 Hz), 6.71 (1H, d, J 8.5 Hz), 5.07 (2H, s), 4.32 (2H, t, J 7 Hz), 4.18 (2H, m), 3.95 (2H, m), 2.95 (2H, m), 1.81 (1H, nonet, J 7 Hz), 1.67 (2H, q, J 7 Hz), 1.47 (9H, s), 1.22 (6H, d, J 7 Hz) and 0.96 (6H, d, J 6.5 Hz); HPLC (XTERRA, 50/80, 235 nm) 91% (7.19 min).
Reaction SMILES: C1(C[O:8][C:9](=[O:59])[CH2:10][N:11]([CH2:48][C:49](=[O:58])[O:50]CC2C=CC=CC=2)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:14]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:13]=2)C=CC=CC=1.[H][H]>[Pd].C1COCC1.C(OCC)(=O)C>[C:9]([CH2:10][N:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:14]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:13]=1)[CH2:48][C:49]([OH:58])=[O:50])([OH:59])=[O:8]
Reactant: CCCCCCCCCCCCCCOc1ccc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)cc1OCCCCCCCCCCCCCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(N(CC(=O)O)CC(=O)O)cc1OCCCCCCCCCCCCCC
Yield: 56 %

Procedure:
A mixture of N-[2-oxo-2-(phenylmethoxy)ethyl]-N-[3,4-bis(tetradecyloxy)phenyl]glycine phenylmethyl ester and 0.5 g of 10% palladium on carbon in 40 ml of THF and 20 ml of ethyl acetate was stirred in a hydrogen atmosphere at room temperature for 2.5 hours when uptake ceased. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was triturated with hexane and filtered to give 1.4 g (56% yield, mp 89°-93°) of pure N-(carboxymethyl)-N-[3,4-bis(tetradecyloxy)phenyl]glycine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]3[NH:21][C:22]([CH3:27])=[C:23]([Cl:26])[C:24]=3[Cl:25])=[O:19])[CH2:13][CH2:12]2)[N:3]=1.Cl.[O:29]([NH2:31])[CH3:30]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:31][O:29][CH3:30])=[O:10])[CH:5]=[C:4]([N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18]([C:20]3[NH:21][C:22]([CH3:27])=[C:23]([Cl:26])[C:24]=3[Cl:25])=[O:19])[CH2:15][CH2:16]2)[N:3]=1
Reactant: CON
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(Cl)n3)CC2)c(Cl)c1Cl
Agent: Cl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(Cl)n1

Procedure:
The title compound was synthesised by an analogous method to Example 8 starting from 2-chloro-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)pyrimidine-4-carboxylic acid (Example 32) and methoxylamine hydrochloride.
Reaction SMILES: F[B-](F)(F)F.[H+].[F:7][C:8]1[C:9]([CH3:15])=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11].[N:16]([O-])=O.[Na+]>O>[F:7][C:8]1[CH:14]=[CH:13][CH:12]=[C:10]2[C:9]=1[CH:15]=[N:16][NH:11]2
Reactant: O=N[O-]
Reactant: Cc1c(N)cccc1F
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Fc1cccc2[nH]ncc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To tetrafluoroboric acid (8.2 ml, 48 wt % in water) was added 3-fluoro-2-methylaniline (2.27 ml). The mixture was cooled to 0° C. when a precipitate formed which was redissolved by the addition of water (8 ml). A solution of sodium nitrite (1.38 g) in water (2.7 ml) was then added dropwise and the mixture was then allowed to warm to ambient temperature and then stirred for a further 1 hour. The precipitated solid was filtered, then washed with diethyl ether, and then dried under suction for 30 minutes. The resulting tetrafluoroborate salt was added to a suspension of potassium acetate (3.92 g) and 18-crown-6 (0.264 g) in chloroform (45 ml). After stirring for 3 hours at ambient temperature the bright orange mixture was filtered and the insoluble material was washed with dichloromethane, then subjected to flash column chromatography on silica eluting with a mixture of 40/60 petrol and ethyl acetate (3:1 v/v) to give 4-fluoro-1H-indazole (0.675 g) as an off-white solid. LC-MS (METHOD B): RT=2.70 minutes; 137 (M+H)+.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[N:10][CH:11]=1>CS(C)=O.[Cl-].[Na+].O>[CH3:13][O:12][C:9]1[N:10]=[CH:11][C:6]([CH2:5][C:1]#[N:2])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCl)cn1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CC#N)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.9 %

Procedure:
Sodium cyanide (1.25 g, 25.4 mmol) was added to a solution of 5-(chloromethyl)-2-methoxypyridine (1.00 g, 6.34 mmol) in DMSO (10 ml) and stirred for 18 h at room temperature. After completion of reaction, the reaction mixture was diluted with brine and the compound was extracted with DCM (3×35 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated. The crude compound was purified by column chromatography using 100-200 silica gel, 10% ethyl acetate in petroleum ether as eluent to afford 0.6 g (63.8%) of 2-(6-methoxypyridin-3-yl)acetonitrile as white color solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([CH3:21])([O:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18]([OH:20])=O)[CH:14]=[CH:15][CH:16]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(Cl)(Cl)Cl>ClCCl>[CH:28]1([NH:34][C:18]([CH2:17][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[O:10][C:8]([CH3:9])([CH3:21])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:20])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCCCC1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CC(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CC(=O)NC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(1-tert-Butoxycarbonyl-1-methylethoxy)phenylacetic acid (250 mg, 0.849 mmol) was dissolved in solvent mixture of dimethylformamide (10 μL)-dichloromethane (6 mL). Subsequently, oxalyl chloride [(COCl)2 (148 μL, 1.70 mmol)] was added at 0° C., the mixture was stirred for one hour at room temperature. The reaction mixture was added to a solution obtained by dissolving cyclohexylamine (0.97 mL, 8.49 mmol) in dichloromethane (1 mL) at 0° C., the mixture was stirred for one hour at room temperature. Chloroform was added to the reaction mixture. Washing was performed sequentially with 1M hydrochloric acid, water, and saturated brine, followed by drying over sodium sulfate. The mixture was subjected to concentration under reduced pressure and purification by silica gel column chromatography (chloroform/methanol=50/1), whereby the target compound was obtained (280 mg, 0.746 mmol, 87.8%).