Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[C:9]([CH3:11])=[N:10][C:5]2=[CH:4][CH:3]=1.C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C1(C)C=CC=CC=1>[CH2:26]([O:25][C:23]([C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][NH:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[C:9]([CH3:11])=[N:10][C:5]2=[CH:4][CH:3]=1)=[O:24])[CH3:27]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1nc2ccc(N)nc2n1C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccc2nc(C)n(C)c2n1)C(=O)OCC
Temperature: 0 °C
Yield: 84.3 %

Procedure:
A solution of 5-amino-2,3-dimethyl-3H-imidazo-[4,5-b]pyridine (4.86 g) and 2-ethoxy-1,1-bis-(ethoxycarbonyl)ethene (7.13 g) in toluene (200 ml) was stirred and heated at reflux for 2 hours and then it was evaporated to dryness. The residue was extracted 3 times with boiling petroleum ether (b.p. 80°-100° C.), the extracts were filtered while hot and the filtrate was then cooled to 0° C. The resulting yellow solid was filtered off, to give 1,1-bis(ethoxycarbonyl)-2-(2,3-dimethyl-3H-imidazo-[4,5-b]pyrid-5-ylamino)ethene (8.4 g) in the form of a yellow sold, m.p. 128°-130° C.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].[CH3:31][O:32][CH2:33][CH2:34][CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1>>[CH3:31][O:32][CH2:33][CH2:34][CH2:35][O:36][C:37]1[CH:38]=[CH:39][C:40]([N:43]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][C:17]([F:30])([F:29])[F:16])(=[O:27])=[O:26])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:41][CH:42]=1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: COCCCOc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Product: COCCCOc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4OC(F)(F)F)CC3)C2=O)cc1

Procedure:
Off-white solid. MS (ESI): 543.17 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethoxy-benzenesulfonyl chloride and 4-(3-methoxy-propoxy)-phenylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)=[O:8])=[C:4]([O:11][CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1
Reactant: CN(C)C(=O)COc1cc(Cl)ccc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)COc1cc(Cl)ccc1C(=O)NCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
The product from step (b) (0.7 g) and 1,1′-carbonyldiimidazole (0.62 g) were dissolved in N,N-dimethylformamide (10 ml) and stirred at room temperature for 1 hour. tert-Butyl 4-(2-aminoethyl)-1-piperazinecarboxylate (2.73 g) was added, the solution stirred for 16 hours and then evaporated to leave a gum. Dichloromethane and sodium bicarbonate solution were added, the organic phase was separated, dried and concentrated to a gum which was purified by chromatography (ethyl acetate:triethylamine, 10:1) to give the product as a solid (0.62 g), m.p. 139-140° C.
Reaction SMILES: [CH2:1]([N:19]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:56]([I:68])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67]>CC(=O)CC>[I-:68].[CH2:67]([N+:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH2:57][CH3:56]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCCCCC
Reactant: CCCCCCCCCCCCI
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCCCC[N+](CCCCCCCCCCCC)(CCCCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCCCCC
Product: [I-]
Reaction time: 96 h

Procedure:
N-dodecyl-N,N,N-trioctadecylammonium iodide is prepared according to the following process. 0.14 g (0.18 mmol) trioctadecylamine, 0.20 ml (0.8 mmol) C12H25I (99%, Aldrich), and 4 ml butanone (ACS, Baker) are placed into a dry nitrogen atmosphere with stirring for 4 days. 85 mg (44%) white solid, mp 93°-94° C., is obtained after the solvent is evaporated, and the residue is recrystallized twice in ethanol (anhydrous). IR(KBr) 2920, 2857 (C-H stretching, vvs), 1473, 1381 (C-H bending, w) cm-1. 1HNMR (CDCl3) δ 3.65-2.99 (CH2, m, 8H), 1.91-0.49 (heptadecyl and undecyl groups, m, 134H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[CH3:10].S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([CH2:8][Cl:13])=[CH:6][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(CO)cnc1Cl
Product: Cc1cc(CCl)cnc1Cl

Procedure:
The preparation is carried out analogously to Example 6A from 1.00 g (6.35 mmol) (6-chloro-5-methylpyridin-3-yl)methanol and 5 ml thionyl chloride. 1.26 g of the title compound, which is reacted without further purification, are obtained.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=3)[C:28]([CH3:38])=[C:27]2[CH3:39])=[CH:21][CH:20]=1)=[O:12])(C)(C)C>>[CH:1]1([NH:5][C:35]([C:31]2[CH:30]=[C:29]3[C:34](=[CH:33][CH:32]=2)[N:26]([CH2:25][C:22]2[CH:21]=[CH:20][C:19]([C:14]4[C:13]([C:11]([OH:12])=[O:10])=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:24][CH:23]=2)[C:27]([CH3:39])=[C:28]3[CH3:38])=[O:36])[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NC3CCC3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using cyclobutylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]([O:14][Si](C)(C)C)([CH3:13])[C:3]#[C:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:6].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[OH:14][C:2]([CH3:13])([CH3:1])[C:3]#[C:4][C:5]([C:7]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: CC(C)(C#CC(=O)c1ccncc1)O[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)C#CC(=O)c1ccncc1
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a stirred solution of 4-methyl-1-(pyridin-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-one (3.0 g, 11.0 mmol) in DCM (60 mL) was added PTSA (2.62 g, 13.0 mmol) at RT and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with water (10 mL), the organic layer was washed with a saturated NaHCO3 solution, water, dried over Na2SO4, filtered and then concentrated in vacuo to afford 4-hydroxy-4-methyl-1-(pyridin-4-yl)pent-2-yn-1-one (1.5 g, 69%) as an oil.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[Cl:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)=[N:8][C:9]=1Cl)(=O)[CH3:2].[NH2:29][NH2:30]>CC(O)C.O>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([C:7]2[N:8]=[C:9]3[NH:29][N:30]=[C:1]([CH3:2])[C:4]3=[N:5][CH:6]=2)=[CH:12][CH:13]=1)(=[O:20])=[O:19]
Reactant: NN
Reactant: CC(=O)c1ncc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)cc2)nc1Cl
Solvent: CC(C)O
Solvent: O
Product: Cc1n[nH]c2nc(-c3ccc(NS(=O)(=O)c4cccc(Cl)c4Cl)cc3)cnc12
Temperature: 120 °C

Procedure:
N-[4-(5-acetyl-6-chloro-pyrazin-2-yl)-phenyl]-2,3-dichloro-benzenesulfonamide (230 mg) was suspended in a mixture of 2 ml iPrOH and 2 ml 35% hydrazine in water at RT and heated to 120° C. by microwave irradiation (Biotage Initiator™ apparatus) for 20 min under stirring in a sealed vessel. The reaction mixture was left to cool to RT, quenched with a saturated aqueous sodium bicarbonate solution (10 ml) and extracted with EtOAc (3×30 ml). The combined organic phases were dried over sodium sulfate, filtered and evaporated to afford the crude product. Purification by recrystallisation from an acetone-water mixture afforded the title compound as a pale yellow solid after drying under vacuum. Yield: 81.6 mg (38%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:19]=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[C:15]([C:16]#[N:17])=[CH:14][N:13]=1.N1C=CC=CC=1>C1COCC1>[C:5]1([O:4][C:2](=[O:3])[NH:11][C:12]2[CH:19]=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)Oc1cc(N)ncc1C#N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)Oc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Phenyl chloroformate (3.89 ml, 31.0 mmol) was added drop wise to a mixture of 6-amino-4-isopropoxynicotinonitrile (intermediate 97, 2.5 g, 14.11 mmol) and pyridine (2.51 ml, 31.0 mmol) in THF (100 ml) at room temperature. The reaction mixture was stirred for 12 h at room temperature, additional pyridine (2.51 ml, 31.0 mmol) added, before stirring for an additional 12 h and then partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic layer was washed with saturated brine, dried over MgSO4 and evaporated. The residue was triturated with Et2O and the product obtained by filtration as a beige solid. (UPLC-MS 7) tR 1.09; ESI-MS 298.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:13]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)[N:16]=[CH:15][N:14]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N-:29]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CS(C)=O.O.C1(C)C=CC=CC=1>[F:26][C:25]([F:28])([F:27])[C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:16]=[CH:15][N:14]=[C:13]([NH:12][C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[N:3]=[C:2]([NH2:29])[CH:11]=[CH:10]4)[CH:18]=2)=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Nc3cccc4ccc(Cl)nc34)ncn2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc2cccc(Nc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2n1
Temperature: 105 °C
Reaction time: 96 h

Procedure:
To a round-bottomed flask containing (2-chloroquinolin-8-yl)-[6-(4-trifluoromethyl-phenyl)pyrimidin-4-yl]amine, Example 32(e), (0.090 g, 0.22 mmol) in DMSO (10 mL) was added NaN3 (0.53 g, 8.1 mmol, Aldrich). The reaction mixture was stirred at 105° C. for 4 days and then at 115° C. for 1 day. The reaction mixture was cooled to room temperature and then diluted with H2O and extracted with EtOAc. The combined extracts were washed with H2O (3×), brine, dried over Na2SO4, and concentrated in vacuo to afford a tan solid. The tan solid was dissolved in toluene (5 mL), triphenylphosphine (0.12 g, 0.44 mmol, Aldrich) was added with stirring at room temperature and the mixture was stirred at reflux for 8 h. After cooling to room temperature, the mixture was concentrated in vacuo to remove the toluene. To the residue was added AcOH/H2O (2:1, 7 mL) and the mixture was stirred at 55° C. for 1 day. The reaction mixture was cooled to room temperature and then diluted with satd NaHCO3 (75 mL) and extracted with EtOAc (2×75 mL). The combined extracts were washed with brine, dried over K2CO3 and concentrated in vacuo. The residue was dissolved in EtOAc and concentrated in vacuo onto silica gel. Purification by silica gel chromatography with gradient from 20% to 60% EtOAc in hexane afforded the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 382 (M+1). MP: 211-213° C.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:4]=1)[CH3:2].C1C(=O)N([Cl:19])C(=O)C1>CC#N>[Cl:19][C:4]1[C:5]([C:8]([F:10])([F:11])[F:9])=[N:6][NH:7][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cc(C(F)(F)F)n[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCc1[nH]nc(C(F)(F)F)c1Cl

Procedure:
Following protocol L, 5-ethyl-3-trifluoromethyl-1H-pyrazole was treated with NCS in CH3CN to yield title compound
Reaction SMILES: [Cl:1][CH2:2][C:3](/[N:5]=[C:6](\OCC)/[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=O.[C:17]1([NH:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][CH2:2][C:3]1[N:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[N:5]=1
Reactant: CCO/C(=N\C(=O)CCl)c1cccc(F)c1
Reactant: NNc1ccccc1
Product: Fc1cccc(-c2nc(CCl)n(-c3ccccc3)n2)c1

Procedure:
The product was obtained starting from (Z)-ethyl N-2-chloroacetyl-3-fluorobenzimidate (535 mg, 1.98 mmol) and phenylhydrazine (270 mg, 246 μL, 2.37 mmol) according to the method described in example 57, step 2 as orange solid (448 mg, 1.56 mmol, 78.8%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[N:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18](=[O:23])[C:17]([C:24](O)=[O:25])=[N:16]1.Cl.[CH3:28][NH:29][O:30][CH3:31].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[CH:5]=[CH:4][C:3]=1[N:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18](=[O:23])[C:17]([C:24]([N:29]([O:30][CH3:31])[CH3:28])=[O:25])=[N:16]1
Reactant: COc1cn(-c2ccc(N3CCOCC3)c(F)c2F)nc(C(=O)O)c1=O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cn(-c2ccc(N3CCOCC3)c(F)c2F)nc(C(=O)N(C)OC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A mixture of 1-(2,3-difluoro-4-morpholin-4-ylphenyl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (3.8 g, 10 mmol), N,O-dimethylhydroxylamine hydrochloride (1.1 g, 11 mmol), HOBt (1.5 g, 11 mmol), triethylamine (2.9 mL, 21 mmol) and WSC (2.2 g, 11 mmol) in DMF (20 mL) was stirred at room temperature overnight. The mixture was diluted with AcOEt, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure to give the title compound (3.3 g, 77% yield) as a brown solid: 1H NMR (300 MHz, DMSO-d6): δ ppm 3.05-3.18 (4H, m), 3.24 (3H, s), 3.57 (3H, s), 3.68-4.02 (7H, m), 7.03 (1H, td, J=8.8, 2.1 Hz), 7.27-7.81 (1H, m), 8.50 (1H, s). LC-MS (ESI) m/z 411 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][NH:16][CH3:17].C(O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][N:16]([CH3:17])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C)C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 72 h

Procedure:
Crude N-t-butyloxycarbonyl-(S)-prolinal (2.34 g, 11.7 mmol) was dissolved in dichloromethane (90 ml). A 5.6 M solution of dimethylamine in ethanol (4.19 ml, 23.5 mmol) was added. 0.4 nm Mol sieves (10.0 g) was added. Sodium triacetoxyborohydride 7.47 g, 35.2 mmol) and glacial acetic acid (1.34 ml, 23.5 mmol) were added successively. The reaction mixture was stirred for 3 days. It was filtered through a plug of celite. The celite was washed with methanol (150 ml). An 1N aqueous solution of sodium hydroxide (150 ml) and tert-butyl methyl ether (150 ml) were added. The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (3×100 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 1.29 g of (2S)-2-((dimethylamino)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:11]1[CH2:12][NH:13][CH2:14][CH:15]=1)([CH3:10])=[CH2:9].CO>[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([CH:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)([CH3:10])[CH3:9]
Reactant: C=C(C)C1=CCNC1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1CCNC1
Reaction time: 3 h

Procedure:
To a solution of 3-isopropenyl-2,5-dihydro-1H-pyrrole trifluoroacetate (2.09 g, 0.00936 mol) in methanol (100.0 mL, 2.469 mol) was added 1.3 g of Pd (10% wt. on activated carbon), then the mixture was hydrogenated on par shaker at 43 psi for 3 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dried under high vacuum to afford the product as a white solid. LC-MS (M+H) 114.2 (base) [M+H) 130.1 base, for the corresponding alcohol].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][NH:13][CH3:14].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][N:13]([CH2:12][CH2:11][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:14])[CH3:21]
Reactant: CNCCc1c(Cl)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN(C)CCc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
A solution of [2-(2-chloro-6-nitro-phenyl)-ethyl]-methylamine (11.0 g, 0.051 mole) and ethyl bromoacetate (8.56 g, 0.051 mole) in acetonitrile (200 mL) containing potassium carbonate (3.54 g, 0.026 mole) was stirred at room temperature overnight. The mixture was evaporated in vacuo, water was added to the residue, this mixture was made basic with sodium carbonate and then extracted with dichloromethane (2×300 mL), the combined organic layers were washed with saturated sodium chloride (300 mL), dried and concentrated. Purification by flash column chromatography (silica gel, methylene chloride:hexanes 1:1) provided 9.0 g of the title compound as a light brown oil. 1H NMR (CDCl3): 7.70 δ (d, 1H); 7.60 δ (d, 1H); 7.35 δ (t, 1H); 4.20 δ (m, 2H); 3.35 δ (s, 2H); 3.15 δ (t, 2H); 2.90 δ (t, 2H); 2.50 δ (s, 3H); 1.30 δ (t, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]2)[C:3]1=[O:23].CCN(C(C)C)C(C)C.CN(C(ON1N=[N:48][C:43]2C=[CH:45][CH:46]=[N:47][C:42]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N1CCNCC1)(OC(C)(C)C)=O.OS(O)(=O)=O>CN(C=O)C.C(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([N:47]3[CH2:42][CH2:43][NH:48][CH2:45][CH2:46]3)=[O:22])[CH2:16][CH2:15]2)[C:3]1=[O:23]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cn1c(=O)n(C[C@H]2CC[C@H](C(=O)O)CC2)c(=O)c2ccccc21
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(=O)n(C[C@H]2CC[C@H](C(=O)N3CCNCC3)CC2)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
trans-4-(1-Methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-cyclohexanecarboxylic acid (1.0 g, 3.2 mmol), DIPEA (560 μL, 3.2 mmol), HATU (1.2 g, 0.32 mmol) were dissolved in 20 ml of DMF. The mixture was stirred at room temperature for 2 hours and then 14 ml of the solution were transferred in a different flask. To this solution Boc-piperazine (411 mg, 2.2 mmol) was added and the mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue dissolved in DCM and washed with 0.4 M solution of Na2CO3. The organic phase was separated and the solvent removed under reduced pressure to give 900 mg of crude boc protected intermediate. The compound was dissolved in 10 ml of DCM, 255 μL of H2SO4 were added and the mixture was left stirring at room temperature for 18 hours. The solution was washed with a solution of NaOH (10% W/W), the organic phase was separated and concentrated under reduced pressure to give 570 mg (yield 80%) of the titled compound.
Reaction SMILES: C/C(/CC/C=C(\C)/CCC=C(C)C)=C\[CH2:4][CH2:5][C:6](OC(C)(C)C)=[O:7].Cl[CH2:25][CH:26]=[C:27]([CH3:39])[CH2:28][CH2:29][CH:30]=[C:31]([CH3:38])[CH2:32][CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.C(OCC)C>[CH3:39][C:27]([CH2:28][CH2:29][CH:30]=[C:31]([CH3:38])[CH2:32][CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36])=[CH:26][CH2:25][CH2:4][CH2:5][CH2:6][OH:7]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCl
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC(=O)OC(C)(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)=CCCC(C)=CCCC(C)=CCCCCO
Reaction time: 1 h

Procedure:
A solution of 37.5 mL (20.3 mmol, 5.1 eq.) of a 0.54M solution of Grignard reagent (Part (2)) in tetrahydrofuran and 9 mL of hexamethylphosphoramide at room temperature under argon was treated over 10 minutes with a solution of 955.5 mg (3.97 mmol) of farnesyl chloride (Part (1)) in 5 mL of tetrahydrofuran. After one hour, the reaction mixture was diluted with a mixture of 1:1 diethyl ether:hexane and quenched with 1M HCl. The organic phase was washed with three 25 mL portions of saturated NaHCO3, three 25 mL portions of H2O, and 25 mL of brine, dried over MgSO4 and evaporated to obtain 995.0 mg of crude product. Purification required two chromatographies. The first was run on 70 g of silica gel, eluting with 1:99 ethyl acetate:CH2Cl2 to provide 484.3 mg of impure material and 307.7 mg of pure title compound. The second chromatography, of the impure fractions, on 50 g of silica gel eluted with 0.75:99.25 ethyl acetate:CH2Cl2 gave 117.2 mg of slightly impure material and 302.8 mg of pure title compound. Combination of pure material from both columns gave a yield of 610.5 mg (58%) of pure desired title isomer.