Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:16]([CH2:17][CH2:18][O:19][CH3:20])[CH2:15][CH2:14][O:13][CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: COCCNCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COCCN(CCOC)c1ccc([N+](=O)[O-])cc1F
Temperature: 80 °C

Procedure:
1.13 g (7.1 mmol) of 3,4-difluoronitrobenzene (Aldrich, Buchs, Switzerland), 1.04 g (7.81 mmol) of bis(2-methoxyethyl)amine (Fluka, Buchs, Switzerland) and 1.96 g (14.2 mmol) of K2CO3 in 7 ml of DMSO are stirred for 1.5 h at rt and then heated at 80° C. for 4 h. The reaction mixture is quenched with H2O and extracted with EtOAc (2×). The organic layers are washed with brine (3×), dried over MgSO4, filtered and evaporated. The residue is purified by flash chromatography on silica gel (hexane-EtOAc 6:1 to 5:1) to give the title compound as a yellow oil. ES-MS: 273 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH2:11])[CH:3]=1.[CH3:12][C:13]1[S:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[CH3:12][C:13]1[S:17][C:16]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH2:11])[CH:3]=2)=[CH:15][CH:14]=1
Reactant: Nc1cc(Cl)n2nccc2n1
Reactant: Cc1ccc(B(O)O)s1
Product: Cc1ccc(-c2cc(N)nc3ccnn23)s1

Procedure:
The titled compound was prepared using a procedure analogous to that described in connection with Example 15 except that 7-chloropyrazolo[1,5-a]pyrimidin-5-amine (1E) and 5-methylthiophen-2-ylboronic acid were used as starting materials. 1H NMR (400 MHz, CHLOROFORM-d) δ 2.59 (s, 3H), 4.76 (s, 2H), 6.21 (d, J=1.8 Hz, 1H), 6.44 (s, 1H), 6.89 (d, J=3.5 Hz, 1H), 7.99-8.04 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:25]([C:26](=[O:29])[NH:27][CH3:28])=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.Cl.[C:31]1([C:37]2([NH2:40])[CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:25]([C:26]([NH:27][CH3:28])=[O:29])=[C:11]3[CH:12]=[C:13]([C:16]4[CH:24]=[CH:23][CH:22]=[C:18]([C:19](=[O:20])[NH:40][C:37]5([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)[CH2:39][CH2:38]5)[CH:17]=4)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NC1(c2ccccc2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cccc(C(=O)O)c3)cc12
Agent: Cl
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cccc(C(=O)NC4(c5ccccc5)CC4)c3)cc12

Procedure:
2-(4-fluorophenyl)-N-methyl-5-(3-(1-phenylcyclopropylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide was prepared from 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl)benzoic acid (0.070 g, 0.14 mmol) and 1-phenylcyclopropanamine hydrochloride (0.040 g, 0.20 mmol). 1H NMR (500 MHz, DMSO-D6) δ ppm 9.40 (s, 1H), 8.90 (d, J=7.32 Hz, 1H), 8.35 (s, 1H), 8.11 (d, J=1.22 Hz, 1H), 8.03 (d, J=7.93 Hz, 1H), 7.98 (d, J=7.63 Hz, 2H), 7.90 (dd, J=8.70, 5.65 Hz, 2H), 7.65 (t, J=7.78 Hz, 1H), 7.49 (dd, J=7.32, 1.83 Hz, 1H), 7.28-7.35 (m, 4H), 7.23-7.26 (m, 2H), 7.15-7.20 (m, 1H), 2.81 (d, J=4.58 Hz, 3H), 1.32 (d, J=9.16 Hz, 4H). LCMS: retention time: 3.053 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10u, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 505 (MH+).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:28]([CH3:29])=[CH:27][S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[C:28]([CH3:29])=[CH:27][S:26][C:16]=3[N:17]=2)[CH:21]=1
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Reactant: NCCc1ccc2c(c1)OCO2
Product: Cc1csc2nc(-c3cccnc3)nc(NCCc3ccc4c(c3)OCO4)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-methylenedioxyphenethylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH2:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:14].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:13]([N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:14]
Reactant: CCNc1ccccc1
Reactant: Oc1ccc(OCCCBr)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCCOc1ccc(O)cc1)c1ccccc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
Compound 10a (500 mg, 2.2 mmol) and N-ethylaniline (1 g, 5.5 mmol) were reacted in acetonitrile for 30 mins before diisopropylethylamine (284 mg, 2.2 mmol) was added dropwise. The reaction mixture was then heated and stirred at 70° C. for 12 hours. After cooling to room temperature, the solvent was evaporated and the residue was purified by silica gel column chromatography to provide the compound 10 (170 mg, 0.66 mmol, 24% yield) as a pale yellow solid. MS (ESI, positive) m/z calcd. for C17H21NO2 [M+H]+: 272.16, found: 272.00. 1H NMR (400 MHz, Chloroform-d) δ 7.25 (d, J=7.8 Hz, 2H), 6.88-6.66 (m, 7H), 3.99 (t, J=5.8 Hz, 2H), 3.53 (t, J=7.1 Hz, 2H), 3.41 (q, J=7.2 Hz, 2H), 2.08 (q, J=6.7 Hz, 2H), 1.19 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Mg].[CH2:2]([O:9][CH2:10][C@H:11]1[CH2:16][O:15][CH2:14][C:13](=[O:17])[N:12]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl-].[NH4+].C(OCC)(=O)C.Br[C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[C:36]([F:42])[CH:35]=1>C(OCC)C.O1CCCC1>[CH2:2]([O:9][CH2:10][C@H:11]([NH:12][C:18](=[O:19])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:16][O:15][CH2:14][C:13](=[O:17])[C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[C:36]([F:42])[CH:35]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: CC(C)(C)OC(=O)N1C(=O)COC[C@@H]1COCc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](COCC(=O)c1cc(F)c(F)c(F)c1)COCc1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a suspension of magnesium (249 mg) in diethyl ether (5 mL), 1-bromo-3,4,5-trifluorobenzene (446 μL) was added dropwise at 40° C. over 10 minutes, and the reaction solution was stirred at 40° C. for one hour. This solution was added dropwise to a solution of tert-butyl (S)-3-benzyloxymethyl-5-oxomorpholine-4-carboxylate (1.1 g) in tetrahydrofuran (30 mL) at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. for one hour. A saturated ammonium chloride solution was added to the solution in small portions at −40° C., and the reaction solution was returned to room temperature. Ethyl acetate was added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 952 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl[C:27]1[CH:36]=[CH:35][C:30]([C:31]([NH:33][CH3:34])=[O:32])=[CH:29][N:28]=1>C(O)(C)(C)C>[CH3:34][NH:33][C:31]([C:30]1[CH:35]=[CH:36][C:27]([O:19][C:16]2[CH:17]=[CH:18][C:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14][CH2:13][C:12]=3[CH:15]=2)=[N:28][CH:29]=1)=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Reactant: CNC(=O)c1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7-Hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (PCT Int. Appl. (2002), WO 02/40471) (8.7 g, 33 mmol) was dissolved in tert-butanol and treated with potassium-tert-butoxide (4 g, 36 mmol). After stirring for 30 minutes at room temperature, 6-chloro-N-methyl-nicotinamide (D10) (5.1 g, 30 mmol) was added and the reaction mixture was stirred at reflux for 20 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. Ice/water was added to the crude residue resulting in a precipitate which was collected by filtration. The solid precipitate was dissolved in ethyl acetate, washed with brine and dried (magnesium sulfate). The organic layer was filtered, concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of ethyl acetate:hexane (1:1) to afford the title compound (D39). NMR (CDCl3) 8.52 (1H, d, J=2.4), 8.12 (1H, dd, J=8.8), 7.16 (1H, m), 6.95-6.81 (3H, m), 6.02 (1H, br), 3.57 (4H, br), 3.02 (3H, d, J=2.4), 2.89 (4H, br), 1.49 (9H, s).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12](Cl)[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>>[CH2:1]([O:8][CH2:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH:19][NH2:20])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: Clc1ccc(Cl)c(COCc2ccccc2)n1
Solvent: O
Product: NNc1ccc(Cl)c(COCc2ccccc2)n1
Temperature: 120 °C

Procedure:
A sealable flask is charged with 2-(benzyloxymethyl)-3,6-dichloropyridine as prepated in Step 2 (950 mg, 3.5 mmol), hydrazine hydrate (1 mL) is added, and the reaction is heated to 120° C. overnight. After cooling the solids are collected by filtration to provide 2-(benzyloxymethyl)-3-chloro-6-hydrazinylpyridine.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([NH:13][C@@H:14]([C:27](=[O:29])[NH2:28])[CH2:15][CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:12])[CH3:10])=O)(C)(C)C.[ClH:30].CCOCC>C(OCC)(=O)C>[ClH:30].[NH2:8][C@H:9]([C:11]([NH:13][C@@H:14]([C:27](=[O:29])[NH2:28])[CH2:15][CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])=[O:12])[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C[C@H](N)C(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Reaction time: 0.17 h

Procedure:
To 0.406 g of benzyl t-butyloxycarbonyl-L-alanyl-D-isoglutaminate (7, n = 2, X1 = L-alanyl) at 22° C there is added 5 ml of a saturated solution of hydrogen chloride in ethyl acetate. After 10 minutes, 40 ml of ether is added and the precipitated salt is collected by centrifugation and carefully dried in vacuo to give 0.325 g of benzyl L-alanyl-D-isoglutaminate hydrochloride (10, n = 2, X1 = L-alanyl).
Reaction SMILES: C(C1C=CC(C=O)=CC=1)CC.C(OCC)(=O)CC(C)=O.[OH-].[Na+].Cl.[CH2:24]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]([CH2:38][C:39]([OH:41])=[O:40])[CH2:34][C:35]([OH:37])=O)=[CH:29][CH:28]=1)[CH2:25][CH3:26]>C(O)C.C(Cl)(=O)C>[CH2:24]([C:27]1[CH:28]=[CH:29][C:30]([CH:33]2[CH2:34][C:35](=[O:37])[O:41][C:39](=[O:40])[CH2:38]2)=[CH:31][CH:32]=1)[CH2:25][CH3:26]
Reactant: CCCc1ccc(C(CC(=O)O)CC(=O)O)cc1
Agent: CCCc1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(=O)CC(C)=O
Solvent: CC(=O)Cl
Solvent: CCO
Product: CCCc1ccc(C2CC(=O)OC(=O)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of commercial 4-propyl-benzaldehyde (5 g) and ethyl acetoacetate (8.77 g) in ethanol (10 ml) piperidine (1 ml) was added with stirring at rt. The yellow solution was kept at rt overnight. The precipitate was collected by suction filtration and washed with ethanol. After drying in vacuo 8.75 g of a faint yellowish solid (the bis-adduct of acetoacetate to the benzaldehyde) was isolated. The finely divided solid was added in portions to 40% NaOH (120 g) with stirring. The resulting yellow slurry was stirred at reflux for 2 h. After cooling in an ice bath the mixture was acidified by portionwise addition of conc. HCl (110 ml) to give a precipitate. The solid was collected by suction filtration and washed with water. After drying in vacuo 3-(4-propylphenyl)glutaric acid (4.89 g) was obtained. The suspension of finely divided 3-(4-propylphenyl)glutaric acid in acetyl chloride (7 ml) was heated to reflux with stirring for 1 h. After cooling to rt precipitation of the product is completed by addition of petrol ether (50 ml). The precipitate is isolated by suction filtration, washed with petrol ether, and recrystallised to give 3-(4-propylphenyl)glutaric anhydride (2.5 g) as colourless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][CH:10]=[C:9]([OH:21])[C:8]=2[C:7]1=[O:22].Cl[CH2:28]Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][CH:10]=[C:9]([O:21][CH3:28])[C:8]=2[C:7]1=[O:22]
Reactant: CCOC(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: ClCCl
Solvent: CO
Product: CCOC(=O)c1ncc(OC)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (208 g, 0.55 mol) in a mixture of dichloromethane (830 mL) and methanol (410 mL) at 10° C., a solution of (trunethyl-silyl)diazomethane (600 mL, 1.2 mol; 2M) in hexanes was added over a period of 1 hour with the reaction temperature maintained below 15° C. The reaction mixture (unstirred) was allowed to stand at 10° C. overnight, and then at 20° C. for additional 4 hours. The reaction mixture was cooled back to 10° C. and quenched with acetic acid (˜75 mL). The product mixture was concentrated under vacuum and the residue recrystallized from boiling methyl tert-butyl ether and heptane. The solid recrystallized was collected by filtration, washed with a mixture of methyl tert-butyl ether and heptane (1:1, v/v), and air dried to afford the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37](=[O:44])(=[O:43])[NH:38]C(C)(C)C)=[CH:27][CH:26]=2)[C:7](=[O:23])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(Cl)Cl>CO>[CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37](=[O:44])(=[O:43])[NH2:38])=[CH:27][CH:26]=2)[C:7](=[O:23])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:19]([F:20])([F:22])[F:21])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: ClCCl
Solvent: CO
Product: CCCCc1nn(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1

Procedure:
The title compound was prepared from 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-2,4-dihydro-2-[4-nitro-2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step B) according to the procedure of Example 8, Step B, as a cream-colored solid, mp 218°-220° C.; homogeneous by TLC (19:1 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 576 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O:13]CC)=O)=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH:16]1([C:19]2[C:27]3[C:26]([NH2:28])=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)[N:20]=2)[CH2:18][CH2:17]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl-].[NH4+]>C1COCC1.CC(O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:28][C:26]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:27]=3[C:19]([CH:16]3[CH2:18][CH2:17]3)=[N:20][N:21]4[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)=[O:13])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cnc2cc(Br)ccn12
Reactant: Cc1cccc(Cn2nc(C3CC3)c3c(N)cccc32)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(Br)ccn45)cccc32)n1
Temperature: -13 °C
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
A mixture of ethyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate (0.54 g, 2.0 mmol) and 3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (0.56 g, 2.0 mmol; prepared as in Example 65, steps A1-A3) in THF (10 mL) was cooled to −13° C. using an ice/water/MeOH bath. A solution of 1.0M lithium bis(trimethylsilyl)amide (4.4 mL, 4.4 mmol) was added over 5 minutes keeping the internal temperature below −10° C. The mixture was stirred at −10° C. for 10 minutes, warmed to ambient temperature and concentrated to give an oily residue. The residue was dissolved using IPA (10 mL) and treated with a 10% aqueous ammonium chloride solution (20 mL) to give a slurry which was stirred overnight. The slurry was filtered to collect the solid which was dried under vacuum to give the product (0.89 g). MS (ES+APCI) m/z=501.0 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])=[CH:5][C:4]=1C.BrC1C=CC(S(Cl)(=O)=O)=C([C:29]([F:32])([F:31])[F:30])C=1.C([O-])([O-])=O.[Na+].[Na+]>[C-]#N.[C-]#N.[Zn+2].CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:12][C:13]([CH3:14])([CH3:15])[CH3:16])(=[O:10])=[O:11])=[C:7]([C:29]([F:32])([F:31])[F:30])[CH:8]=1
Reactant: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1CN
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(C)NS(=O)(=O)c1ccc(CN)cc1C(F)(F)F
Temperature: 110 °C
Reaction time: 1 h

Procedure:
4-Aminomethyl-N-tert-butyl-2-trifluoromethyl-benzenesulfonamide was synthesized in a manner analogous to 4-Aminomethyl-N-tert-butyl-3-methyl-benzenesulfonamide in Example 4, using 4-bromo-2-(trifluoromethyl)benzene-1-sulfonyl chloride in place of 4-bromo-3-methylbenzene-1-sulfonyl chloride. In the second step, K4-[Fe(CN)6].3H2O was used in place of Zn(CN)2, Pd(OAc)2/dppf was used as the catalyst, Na2CO3 was used as base and the reaction mixture was stirred at 110° C. with microwave irradiation for one hour.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5](#N)[CH2:6][CH2:7][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][CH2:21][CH3:22]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].O>[CH2:21]([C:22]1[NH:3][CH2:2][CH2:1][N:4]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH3:5]
Reactant: CCCCCCCCCCCCCCCCCC#N
Reactant: NCCN
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Product: CCCCCCCCCCCCCCCCCC1=NCCN1
Temperature: 210 °C
Yield: 86.7 %

Procedure:
In a 500 ml SUS 316L stainless steel autoclave were charged 60 g of ethylene diamine, 267 g of stearonitrile and 2.5 g of titanium tetraisopropoxide. After addition of 1 g of water, the mixture was heated up to 210° C. with stirring and maintained at that temperature for 4 hours while removing ammonia produced in situ to maintain the pressure within the autoclave at 8-9 kg/cm2G. The resulting mixture was then subjected to vacuum distillation at 0.6 mmHg and at 230°-235° C. to obtain 267 g of 2-heptadecyl-2-imidazoline with a yield of 86%.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])(C)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:6]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cccc(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc(C#N)c1
Yield: 24.3 %

Procedure:
The title compound of Example 17 (9.35 g, 47.0 mmol) and potassium carbonate (32.0 g, 235.0 mmol) was stirred in MeOH (120 mL) at RT for 15 minutes. The reaction was partitioned between water and hexanes. The organic extracts were washed with water, dried over sodium sulphate, filtered and concentrated. The reaction mixture was purified by column chromatography to afford the title product (1.45 g, 56%) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)[C:3]([NH:5][C:6]1[C:11](F)=[CH:10][C:9](F)=[CH:8][C:7]=1F)=[O:4].[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[BH4-].[Na+].OO>C1(C)C=CC=CC=1.C(OCC)(=O)C.CO.O>[CH3:3][CH:2]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH:6]([CH3:11])[CH3:7])[C:6]=1[NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)[CH3:15]
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)Nc1c(F)cc(F)cc1F
Reactant: O=Cc1ccccc1
Agent: OO
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)c1cccc(C(C)C)c1NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.4 %

Procedure:
A solution of (S)-α-amino-4-(phenylmethoxy)-N-(2,4,6-trifluorophenyl)benzenepropanamide (1.0 g, 2.3 mmol) and benzaldehyde (0.25 g, 2.3 mmol) in toluene was heated under reflux with the azeotropic removal of water (1 hr). The resulting solution was cooled (25° C.), then methanol (30 mL) and an excess of sodium borohydride was added, and the resulting slurry was stirred (2h, 25° C.). To the resulting mixture was added 3% aqueous H2O2 (ca. 10 mL), and the resulting mixture was again stirred (1 hr, 25° C.). The resulting mixture was diluted with ethyl acetate (200 mL), washed with water (2×100 mL), washed with brine (1×100 mL), then dried (MgSO4) and concentrated. The resulting oil was triturated with ether:hexane (1:1) and the resulting precipitate was collected by filtration to yield 0.11 g (9.1%) of the title compound, mp 127°-129° C.
Reaction SMILES: FC(F)(F)C(O)=O.N1([C:13]23[O:28][N:27]=[C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:14]2[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18]3)CCCC1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:28]1[C:13]2[CH2:18][CH2:17][NH:16][CH2:15][C:14]=2[C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:27]1
Reactant: CCOC(=O)C1=NOC2(N3CCCC3)CCN(C(=O)OC(C)(C)C)CC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1noc2c1CNCC2
Temperature: 0 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
Trifluoroacetic acid (6.67 ml, 89.9 mmol) was added at 0° C. to a solution of 5-tert-butyl 3-ethyl 7a-(pyrrolidin-1-yl)-3a,4,7,7a-tetrahydroisoxazolo[4,5-c]pyridine-3,5(6H)-dicarboxylate (5.5 g, 14.98 mmol) in DCM (100 ml), and the mixture was stirred for 16 hours under reflux. Cooling to 0° C. was then carried out and NaHCO3 solution was added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. Purification of the crude product was carried out by column chromatography (silica gel, 16% methanol in ethyl acetate). Yield: 62% [Alternatively, ethyl 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-carboxylate A-06 can be synthesised as described in WO2006105945.]