Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3(O)[CH2:21][CH2:20][O:19][CH2:18]3)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1>C(N(CC)CC)C>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:18][O:19][CH2:20][CH:21]=3)[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2ccc3c(c2)CN(Cc2ccccc2)C3)CCOC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: C1=C(c2ccc3c(c2)CN(Cc2ccccc2)C3)COC1

Procedure:
Prepared in analogy to Example A65(a) from 3-(2-benzyl-2,3-dihydro-1H-isoindol-5-yl)-tetrahydro-furan-3-ol (Example A66(a)) and methanesulfonyl chloride, triethylamine, and DBU. Brown solid. MS (m/e): 278.0 ([M+H]+, 100%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:15][C:16]([F:25])([F:26])[O:17][C:18]1[CH:23]=[CH:22][C:21]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1
Yield: 90.9 %

Procedure:
Tert-butyl 4-hydroxypiperidine-1-carboxylate (56.5 g, 0.28 mol), 4-trifluoromethoxyphenol (50 g, 0.28 mol) and triphenylphosphine (108 g, 0.42 mol) were dissolved in THF (500 ml). Diethyl azodicarboxylate (65 ml, 0.42 mol) was added dropwise to this solution under reflux, and the mixture was refluxed for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=5/1) to afford tert-butyl 4-(4-trifluoromethoxyphenoxy)-piperidine-1-carboxylate (92 g, yield 91%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]2[NH:6][C:7]([C:9]3[C:13]([N+:14]([O-])=O)=[CH:12][NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1.[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C(O)C>[Cl:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH2:14])=[CH:12][NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2[nH]c(-c3n[nH]cc3[N+](=O)[O-])nc2cc1Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc2[nH]c(-c3n[nH]cc3N)nc2cc1Cl

Procedure:
A stirred solution of 5-chloro-6-methyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole [0.320 g, Example 249(g)] and tin-chloride (1.10 g) in ethanol (5 ml) was heated in a Smith Creator microwave at 140° C. for 10 minutes. The reaction mixture was basified using saturated sodium hydrogen carbonate solution to pH 8 and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give 3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine as a pale brown solid. LC-MS (METHOD B): RT=2.28 minutes, 248.13 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[O:27][C:28]([F:31])([F:30])[F:29]>>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:22][C:21]=1[O:27][C:28]([F:29])([F:31])[F:30]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccc(F)c(OC(F)(F)F)c1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c(OC(F)(F)F)c1
Yield: 67.8 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 270 mg of 4-fluoro-3-(trifluoromethoxy)aniline in place of the 2,4-difluoroaniline. 270 mg of N-[4-fluoro-3-(trifluoromethoxy)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:8]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: NC1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(CNC2CCCCC2)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of cyclohexylamine (9.34 g) in methanol (300 ml) was added benzaldehyde (10.0 g) followed by activated 3 Å molecular sieves. After 1 h, sodium cyanoborohydride (7.13 g) was added followed by the dropwise addition of acetic acid (9.2 ml), and the reaction was stirred overnight. The reaction mixture was filtered through hiflo, the solvent removed in vacuo and the resulting white solid was heated under reflux in 5M potassium hydroxide solution for 30 mins. The product was extracted into dichloromethane (3×100 ml) and the combined organic layers were washed with brine (100 ml), dried over sodium sulphate and the solvent was removed in vacuo to give a clear oil. The product was purified by column chromatography (eluting with ethyl acetate) then distillation; bpt=137° C. at 1.0 mbarr. 1H NMR (360 MHz, D6 -DMSO) δ0.94-1.24 (5H, m), 1.48-1.88 (5H, m), 2.32 (1H, m), 2.32 (1H, m), 3.10 (2H, s(b)), 3.72 (2H, s), 7.14-7.40 (5H, m).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)=[N:4][C:5]2[NH:6][C:7](=[O:12])[CH2:8][CH2:9][C:10]=2[CH:11]=1.Cl.[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[N:4][C:3]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:31]1[CH2:30][CH2:29][N:28]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=3[Cl:20])[CH2:33][CH2:32]1)[NH:6][C:7](=[O:12])[CH2:8][CH2:9]2
Reactant: O=CCCCOc1nc2c(cc1Br)CCC(=O)N2
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C1CCc2cc(Br)c(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
To a solution of 4-(3-bromo-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.43 g, approx. 1.37 mmol, crude from previous reaction) in DCE (6 mL) was added 1-(2,3-dichloro-phenyl)-piperazine hydrochloride (367 mg, 1.37 mmol) followed by Et3N (0.38 mL, 2.75 mmol). The solution was stirred for 15 min and NaBH(OAc)3 (407 mg, 1.92 mmol) was added as a powder. The reaction was stirred at room temperature for 2 h and quenched with saturated NaHCO3 and H2O. The mixture was extracted with EtOAc. The organic layer was washed with saturated NaHCO3, H2O and brine, dried over Na2SO4 and concentrated. Purification by liquid chromatography (4% MeOH/CH2Cl2) afforded the title compound as a white foam (497 mg, 0.941 mmol, 69%). MS: APCI: M+1: 527.0, 529.0, 531.0 (Exact Mass: 526.05).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:22])[C:5]2=[N:4][C:3]=1[CH3:23].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.CO>[NH2:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:22])[C:13]=1[CH2:12][O:11][C:10]1[C:5]2[N:6]([C:2]([Br:1])=[C:3]([CH3:23])[N:4]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1nc2c(OCc3c(Cl)cccc3[N+](=O)[O-])cccn2c1Br
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nc2c(OCc3c(N)cccc3Cl)cccn2c1Br
Reaction time: 0.5 h
Yield: 14.4 %

Procedure:
To a mixture of 3-bromo-8-(2-chloro-6-nitrobenzyloxy)-2-methylimidazo[1,2-a]pyridine (300 mg), nickel(II) chloride hexahydrate (360 mg) and methanol (9 ml) was added sodium borohydride (114 mg) portionwise under an ice-water bath cooling for 20 minutes. After stirring for 30 minutes, the mixture was concentrated in vacuo and diluted with water. The pH value of the mixture was adjusted to 3 and the separated crystals were collected by filtration. The crystals were dissolved in dichloromethane, and the solution was washed with saturated aqueous solution of sodium hydrogencarbonate, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (3% solution of methanol in dichloromethane) and preparative thin-layer chromatography (3% solution of methanol in dichloromethane) followed by crystallization from diethyl ether to give 8-(2-amino-6-chlorobenzyloxy)-3-bromo-2-methylimidazo[1,2-a]pyridine (40 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:7][C:6]=1[O:18]C)[CH3:2].B(Br)(Br)Br.O>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:7][C:6]=1[OH:18])[CH3:2]
Reactant: CCOC(=O)c1c(C)cc(N2CCOCC2)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(C)cc(N2CCOCC2)cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methoxy-6-methyl-4-morpholin-4-yl-benzoic acid ethyl ester (7.0 g, 25.1 mmol) in dichloromethane (370 ml) is added neat boron tribromide (5.94 ml, 62.7 mmol) at −78° C. The temperature is slowly raised to room temperature over a period of 30 min and stirred for 1 h at room temperature. The reaction mixture is poured onto cold water, extracted with dichloromethane (3×30 ml). Combined organic layers are washed with brine (30 ml), dried over sodium sulfate and evaporated to dryness. The crude material is used in the next step without further purification.
Reaction SMILES: [C@@H:1]1([NH2:7])[CH2:5][CH2:4][CH2:3][C@@H:2]1[NH2:6].[CH3:8][C:9]([CH3:14])=[CH:10][C:11](O)=[O:12]>C1(C)C=CC=CC=1>[CH3:8][C:9]1([CH3:14])[CH2:10][C:11](=[O:12])[NH:7][C@H:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[NH:6]1
Reactant: CC(C)=CC(=O)O
Reactant: N[C@@H]1CCC[C@@H]1N
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)N[C@H]2CCC[C@H]2N1
Temperature: 25 °C
Yield: 24 %

Procedure:
A toluene (200 mL) suspension of cis-cyclopentane-1,2-diamine (19.7 g, 197 mmol) and 3-methyl-2-butenoic acid (19.7 g, 197 mmol) was stirred under reflux for 24 hours under azeotropic conditions using a Dean-Stark apparatus. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure, and the deposited crystal was collected by filtration. The obtained crystal was washed with ether and then dried to obtain cis -4,4-dimethyloctahydrocyclopenta[b][1,4]diazepin-2-one (8.60 g, 24%) in a light brown powder form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]([CH3:31])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:22]4[CH:27]=[C:26]([NH2:28])[C:25]([F:29])=[CH:24][C:23]=4[Cl:30])[C:15](=[O:21])[N:16]3[CH2:19][CH3:20])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=1[N:42]=[C:43]=[O:44]>N1C=CC=CC=1>[Cl:30][C:23]1[C:22]([C:14]2[C:15](=[O:21])[N:16]([CH2:19][CH3:20])[C:17]3[C:12]([CH:13]=2)=[CH:11][N:10]=[C:9]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:33][CH:32]=2)[CH3:31])[CH:18]=3)=[CH:27][C:26]([NH:28][C:43]([NH:42][C:36]2[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=2[F:34])=[O:44])=[C:25]([F:29])[CH:24]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Reactant: O=C=Nc1cc(F)ccc1F
Solvent: c1ccncc1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(F)ccc3F)c(F)cc2Cl)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A solution of Example A4 (250 mg, 0.535 mmol) in pyridine (2 mL) was treated with 2,5-difluorophenyl isocyanate (91 mg, 0.589 mmol) and stirred at RT overnight. Additional 2,5-difluorophenyl isocyanate (30 μL, 0.256 mmol) was added and stirred at RT for 4 h. The mixture was concentrated to near-dryness, treated with EtOAc and brine and the resulting solid was collected via filtration and dried to afford 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2,5-difluorophenyl)urea (314 mg, 94% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.31 (s, 2H), 8.51 (s, 1H), 8.19 (d, J=8.6 Hz, 1H), 7.98 (m, 1H), 7.78 (s, 1H), 7.56 (d, J=10.9 Hz, 1H), 7.29 (m, 1H), 7.18 (d, J=8.4 Hz, 2H), 6.89-6.78 (m, 3H), 6.33 (s, 1H), 4.85 (s, 2H), 4.19 (q, J=7.1 Hz, 2H), 3.70 (s, 3H), 3.13 (s, 3H), 1.13 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 622.2 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[H-].[Na+]>C1COCC1>[CH2:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCCCCCCCl
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: ClCCCCCCOCc1ccccc1
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a stirred solution of 6-chloro-1-hexanol (15.0 g, 0.110 mol) and benzyl bromide (18.8 g, 0.110 mol) in dry THF (200 ml) at room temperature under argon was slowly added (over 30 min.) sodium hydride powder (2.899 g, 0.121 mol). The solution was left overnight and the solids filtered off. The solvent was removed under reduced pressure, the residues taken up into dichloromethane (100 ml) and washed (2×20 ml water). The solution was dried over MgSO4 and the solvent removed to yield an orange oil which was subsequently distilled (160° C., 0.5 mBar) to yield the title compound (17.5 g, 70%) as a colourless oil. C13H19OCl requires 226. Found DCl: MNH4+, 244. δH (CDCl3) 1.49 (4H, m, (CH2)2(CH2)2Cl), 1.70 (2H, p, CH2CH2O), 1.83 (2H, t, CH2CH2Cl), 3.54, 3.56 (4H, 2×t, CH2CH2O, CH2Cl), 4.56 (2H, s, CH2Ph), 7.40 (5H, m, Ph). δC (CDCl3) 25.3 (1C, CH2(CH2)2Cl), 26.4 (1C, CH2(CH2)3Cl), 29.3 (1C, CH2(CH2)2O), 32.3 (1C, CH2CH2Cl), 44.8 (1C, CH2Cl), 69.9, 72.6 (2C, CH2O), 127.2 (1C, CH(CH2)2C), 127.3 (2C, CHC), 128.1 (2C, CHCHC), 138.4 (1C, CCH2O).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:27][CH2:28][CH2:29][C:30](Cl)=[O:31]>N1C=CC=CC=1.C(Cl)Cl>[C:30]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:19][N:20]=1)(=[O:31])[CH2:29][CH2:28][CH3:27]
Reactant: CCCC(=O)Cl
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccccc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)O[C@@H](C)[C@@H](Nc1ccc(C#N)c(Cl)c1C)c1nnc(-c2ccccc2)o1
Reaction time: 60 h
Yield: 97.5 %

Procedure:
To a solution of 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile (200 mg, 0.54 mmol) in pyridine (1.0 mL) and CH2Cl2 (7.0 mL) was added n-butyryl chloride (84 μL, 0.81 mmol). Upon complete addition the reaction mixture was stirred for 60 h, then quenched with 10% aqueous HCl (10 mL). The mixture was partitioned between H2O (25 mL) and CH2Cl2 (30 mL). The aqueous layer was extracted with CH2Cl2 (25 mL). The combined organic extracts were washed with NaHCO3 (30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide an orange viscous oil, which was purified by flash chromatography over silica gel (15-30% EtOAc in hexanes) to provide the title compound as a colourless solid (231 mg, 97%): 1H NMR (400 MHz, CDCl3, δ in ppm) 7.99 (td, J=1.4, 8.8 Hz, 2H), 7.57-7.47 (m, 3H), 7.38 (d, J=8.6 Hz, 2H), 6.73 (d, J=8.6 Hz, 1H), 5.59 (pentet, J=6.5 Hz, 1H), 5.19 (d, J=8.0 Hz, 1H), 5.03 (dd, J=5.9, 7.8 Hz, 1H), 2.34 (dt, J=2.3, 7.6 Hz, 2H), 2.31 (s, 3H), 1.64 (sextet, J=7.4 Hz, 2H), 1.37 (d, J=6.5 Hz, 3H), 0.92 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10](Cl)=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH2:20])[CH3:19].C1COCC1>C1COCC1>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([NH:20][CH2:18][CH3:19])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CCNc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 65 °C
Yield: 100.4 %

Procedure:
4-Chloro-3-nitrobenzoic acid tert-butyl ester (3.0 g, 11.6 mmol), prepared according to a published procedure [WO 9707101], was cautiously added to a solution of 2.0 M EtNH2/THF (20 mL, 40 mmol) and TEA (2.0 mL, 14 mmol) in anhydrous THF (30 mL). The resulting mixture was heated at 65° C. for 3 h, cooled, concentrated under reduced pressure, diluted with DCM (200 mL), washed with water (2×100 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated to give the title compound (3.1 g, 99%) as a yellow solid, which was used without further purification. 1H-NMR (CDCl3): δ 8.80 (1H, d), 8.24 (1H, br s), 8.02 (1H, dd), 6.84 (1H, d), 3.41 (2H, m), 1.59 (9H, s), 1.40 (3H, t).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:10]([CH2:18][CH3:19])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:20]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)([OH:22])=[O:21].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.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>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][C:20]([OH:22])=[O:21])=[CH:26][CH:27]=2)=[N:3][C:4]=1[C:9]1[N:10]([CH2:18][CH3:19])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]=1
Reactant: CCn1c(-c2nc(Br)cnc2N)nc2cnccc21
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(-c2nc(-c3ccc(CCC(=O)O)cc3)cnc2N)nc2cnccc21
Temperature: 200 °C
Yield: 21.6 %

Procedure:
5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.032 g, 0.10 mmol) (made in example 2), 4-(2-carboxyethyl)benzeneboronic acid (0.039 g, 0.20 mmol), Pd(PPh3)2Cl2 (0.0035 g, 0.005 mmol) and K2CO3 (0.050 g, 0.36 mmol) were combined in 0.5 mL of N,N-dimethylformamide and heated to 200° C. in the SmithSynthesizer microwave for 8 minutes. The reaction mixture was concentrated in vacuo and the residue purified by HPLC to give 0.0084 g of the title compound.
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>COC(C)(C)C>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[N:9][C@@H:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Solvent: COC(C)(C)C
Product: C[C@H](N=Cc1cccc(OCc2ccccc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 115.5 %

Procedure:
0.12 g (0.97 mmol) of (S)-α-methylbenzylamine and 0.25 g (1.19 mmol) of 3-benzyloxybenzaldehyde are mixed in 4 ml of t-butyl methyl ether and stirred for three days at room temperature, and then evaporated under reduced pressure to give 0.35 g (1.12 mmol) of (S)-N-(3-benzyloxybenzylidene)-α-methylbenzylamine (Yield: 115%, purity 85%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([Si:21]([CH2:36][CH2:37][CH2:38][Si:39](Cl)(Cl)Cl)([CH2:29][CH2:30][CH2:31][Si:32](Cl)(Cl)Cl)[CH2:22][CH2:23][CH2:24][Si:25](Cl)(Cl)Cl)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl>O1CCCC1>[CH2:13]([Si:21]([CH2:36][CH2:37][CH2:38][SiH2:39][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:7][CH2:8][CH3:9])([CH2:29][CH2:30][CH2:31][SiH2:32][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:4][CH2:5][CH3:6])[CH2:22][CH2:23][CH2:24][SiH2:25][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:1][CH2:2][CH3:3])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCC[Mg]Br
Reactant: CCCCCCCC[Si](CCC[Si](Cl)(Cl)Cl)(CCC[Si](Cl)(Cl)Cl)CCC[Si](Cl)(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC[SiH2]CCC[Si](CCCCCCCC)(CCC[SiH2]CCCCCCCCCCCCC)CCC[SiH2]CCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 81 %

Procedure:
Under a strong nitrogen flow, into a 2 L three-neck round bottom flask equipped with rubber septum, reflux condenser, nitrogen bypass inlet, and magnetic stirring bar was introduced, via a flex-needle, a tetrahydrofuran solution of n-decylmagnesium bromide (114.7 g, 467 mmol). In an inert atmosphere enclosure, into a 50 Ml addition funnel was added n-octyl-tris-[3-(trichlorosilyl)propyl]silane (27.85 g, 41.5 mmol, prepared by the procedure described in Example 1, Step (b)). The addition funnel was attached to the flask containing the n-decylmagnesium bromide solution, and n-octyl-tris-[3-(trichlorosilyl)propyl]silane was added over a period of 40 minutes. The reaction mixture was kept at 50° C. for 15 hours, then allowed to cool to room temperature, and an additional solution of n-decylmagnesium bromide (114.6 g, 467 mmol) in tetrahydrofuran was added into the reaction flask. The reaction mixture was then heated at reflux temperature for 164 hours. After cooling in an ice-water bath, hydrochloric acid (500 Ml, 1.2N) was cautiously added. The reaction mixture separated into two layers on standing. These were separated, and the aqueous layer was extracted with diethyl ether (2×200 Ml). The organic layers were combined, washed with water (200 Ml), and dried over magnesium sulfate, and the solvent removed under reduced pressure. Purification by silica gel column chromatography yielded 54.5 g (81.0%) of n-octyl-tris-[3-(tridecylsilyl)propyl]silane. This tetrasilahydrocarbon had a kinematic viscosity of 89.7 centistokes at 40° C., a kinematic viscosity of 15.4 centistokes at 100° C., and a viscosity index of 182. Onset of volatilization under 0.44 mm Hg pressure, based on thermogravimetric analysis, was at 285° C.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.Cl.Cl.[Cl:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:13][N:14]1[CH2:19][CH2:18][O:17][C@@H:16]([CH2:20][NH:21][C:22]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])[CH2:15]1.C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]1([C:4]([N:29]2[CH2:30][CH2:31][CH:26]([CH2:25][NH:24][C:22]([NH:21][CH2:20][C@@H:16]3[O:17][CH2:18][CH2:19][N:14]([CH2:13][C:12]4[CH:32]=[CH:33][C:34]([Cl:35])=[C:10]([Cl:9])[CH:11]=4)[CH2:15]3)=[O:23])[CH2:27][CH2:28]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(NCC1CCNCC1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCN(C(=O)C2CC2)CC1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
Cyclopropanecarbonyl chloride (0.014 ml) was added to a solution of Intermediate 18 (0.54 g) and N,N-diisopropylethylamine (0.063 ml) in dichloromethane (2 ml). The solution was stirred for 3 h at 23° C. The solvent was removed in vacuo and the residue purified by solid phase extraction (Isolute SCX sulphonic acid column) eluting with methanol followed by 10% 0.880 ammonia solution in methanol. The basic fraction was concentrated in vacuo and the residue was further purified using a silica gel solid phase extraction cartridge (1 g Varian Bond Elut) eluting with 0–1% methanol in ethyl acetate, to give the title compound as a clear gum (0.023 g).