Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[CH:11]([CH2:26][NH:27][CH2:28][CH:29]=[CH2:30])[CH2:10]1.[CH3:31][S:32]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)(=[O:34])=[O:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[CH:11]([CH2:26][N:27]([CH2:28][CH:29]=[CH2:30])[S:42]([C:39]2[CH:38]=[CH:37][C:36]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:41][CH:40]=2)(=[O:44])=[O:43])[CH2:10]1
Reactant: CS(=O)(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCNCC1CN(c2c(Cl)cccc2Cl)CCN1Cc1ccc(OC)c(OC)c1
Product: C=CCN(CC1CN(c2c(Cl)cccc2Cl)CCN1Cc1ccc(OC)c(OC)c1)S(=O)(=O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
In a manner similar to Preparation 3, react 4-(2,6-dichlorophenyl)-1-[(3,4-dimethoxyphenyl)methyl]-N-(2-propenyl)-2-piperazinemethanamine with 4-[(methylsulfonyl)amino]benzenesulfonyl chloride to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Cl:9][CH2:10][C:11]([CH2:13]Cl)=O>COCCOC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:13]=[C:11]([CH2:10][Cl:9])[N:1]=2)[CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(CCl)CCl
Solvent: COCCOC
Product: ClCc1cn2cc(Br)ccc2n1
Yield: 10.4 %

Procedure:
A mixture of 2-amino-5-bromopyridine (10.0 g). 1,3-dichloroacetone (7.71 g) and 1,2-dimethoxyethane (40 ml) was stirred at room temperature for 4 hours. The precipitated crystals were collected by filtration, to which ethanol (100 ml) was added and heated under reflux. The reaction mixture was concentrated, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure to give crystals of 6-bromo-2-chloromethylimidazo-[1,2-a]pyridine (1.48 g, 10%). Recrystallization from ethyl acetate-hexane gave colorless needles, mp 129-130° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:14]([CH:16]1[CH:21]2[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]2)[CH2:17]1)=[CH2:15].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:13][C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2](/[CH:15]=[CH:14]/[CH:16]3[CH:21]4[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]4)[CH2:17]3)=[CH:3][CH:4]=2)[N:12]=1
Reactant: Cc1nc(-c2ccc(I)cc2)no1
Reactant: C=CC1CN2CCC1CC2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(/C=C/C3CN4CCC3CC4)cc2)no1
Temperature: 100 °C
Reaction time: 5 h
Yield: 10.2 %

Procedure:
A mixture of 3-(4-iodophenyl)-5-methyl-1,2,4-oxadiazole (1.43 g), 3-vinylquinuclidine (685 mg), bis(triphenylphosphine)palladium (II) chloride (175 mg), copper (I) iodide (90 mg) and triethylamine (5.0 ml) in dry dimethylformamide (10 ml) was stirred under argon at 100° C. for 5 hours. The dimethylformamide and triethylamine were removed by evaporation. The residue was treated with 2M aqueous sodium hydroxide solution (20 ml) and extracted with dichloromethane (3×20 ml). The organic extracts were washed with water (20 ml), dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on silica gel using 5% methanol in dichloromethane containing 0.5% ammonia (density, 0.88 g/cm3) as eluent to give E-3-[2-{4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl}ethenyl]quinuclidine (150 mg) as a solid, m.p. 93°-97° C.; NMR: 1.4(1H,m), 1.65(2H,m), 1.8(2H,m), 2.55(1H,m), 2.65(3H,s), 2.8(4H,m), 3.08(1H,m), 3.45(1H,m), 6.5(1H,d), 6.62(1H,d,d), 7.6(2H,d) and 7.82(2H,d).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[NH:7]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:8]1.Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=1>C(#N)C>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([N:7]2[CH:11]=[CH:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:8]2)=[CH:19][CH:20]=1)[CH3:26]
Reactant: CCOC(=O)c1cc[nH]n1
Reactant: CCOc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1ccn(-c2ccc(OCC)cc2)n1
Temperature: 82 °C
Reaction time: 7 h

Procedure:
A 10 mL Schlenk tube was dried under vacuum, filled with nitrogen and consecutively charged with 19.4 mg (0.102 mmol, 0.2 eq) Cul, 332.3 mg (1.020 mmol, 2.0 eq) Cs2CO3, 100.0 mg (0.714 mmol, 1.4 eq) ethyl 1H-pyrazole-3-carboxylate (6), 102.4 mg (73.0 μL, 0.510 mmol, 1.0 eq) p-bromophenetol and 1 mL dry ACN. The light brown suspension was degassed by vaccum/N2 cycles and stirred first at 82° C. for 7 h and than after adding 0.5 mL dry DMF (solubility issue) at 120° C. for further 65 h. The GC-MS analysis showed full conversion. ACN and DMF were removed under high pressure and the brown residue was suspended in 10 mL EtOAc. After filtration of the brown suspension through a pad of silica and flushing with 150 mL EtOAc the colorless filtrate was concentrated under reduced pressure leading to 52.1 mg (39%) crude product as a green-brown oil. Final purification by column chromatography (CH/EtOAc 3:1, size: 15.5×2.0 cm, 20 g silica gel) yielded the pure title compound.
Reaction SMILES: [CH2:1](N)C.Cl[C:5]1[C:14]([C:15]([C:17](=[CH:23][N:24](C)[CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])=[CH:13][C:12]2[C:7](=[CH:8][C:9]([Cl:28])=[C:10]([F:27])[CH:11]=2)[N:6]=1.C1CCN2C(=NCCC2)CC1>C(O)C>[Cl:28][C:9]1[C:10]([F:27])=[CH:11][C:12]2[C:7]([CH:8]=1)=[N:6][C:5]1[N:24]([CH2:25][CH3:1])[CH:23]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15](=[O:16])[C:14]=1[CH:13]=2
Reactant: CCN
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(CC)c2nc3cc(Cl)c(F)cc3cc2c1=O
Reaction time: 2 h
Yield: 85.1 %

Procedure:
16 g of ethylamine are added, in the course of 5 minutes, at between 10° and 15° C., to a stirred suspension of 13.5 g of ethyl 2-(2,7-dichloro-6-fluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate in 135 cm3 of ethanol, the temperature is allowed to rise to about 20° C., 0.5 g of DBU is added and the mixture is heated, with stirring, for 2 hours at a temperature close to 75° C. After cooling to a temperature close to 20° C., the precipitate is drained and washed with twice 100 cm3 of ethanol and twice 100 cm3 of diethyl ether. 10.4 g of 8-chloro-3-ethoxycarbonyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-benzo-[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 300°-301° C.
Reaction SMILES: [CH3:1][N:2]([C@@H:11]([CH2:15][CH:16]=[CH2:17])[C:12]([OH:14])=O)[S:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:5])=[O:4].CCN=C=NCCC[N+](C)(C)C.[I-].ON1C2C=CC=CC=2N=N1.[CH2:41]([O:44][C@H:45]1[C:53]2[C:48](=[CH:49][C:50]([O:54][CH3:55])=[CH:51][CH:52]=2)[C@@H:47]([NH:56][CH2:57][C@@H:58]([OH:70])[C@@H:59]([NH2:69])[CH2:60][C:61]2[CH:66]=[C:65]([Cl:67])[CH:64]=[C:63]([Cl:68])[CH:62]=2)[CH2:46]1)[CH:42]=[CH2:43]>C(N(CC)CC)C.CN(C)C=O>[CH2:41]([O:44][C@H:45]1[C:53]2[C:48](=[CH:49][C:50]([O:54][CH3:55])=[CH:51][CH:52]=2)[C@@H:47]([NH:56][CH2:57][C@@H:58]([OH:70])[C@@H:59]([NH:69][C:12](=[O:14])[C@@H:11]([N:2]([CH3:1])[S:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:4])=[O:5])[CH2:15][CH:16]=[CH2:17])[CH2:60][C:61]2[CH:62]=[C:63]([Cl:68])[CH:64]=[C:65]([Cl:67])[CH:66]=2)[CH2:46]1)[CH:42]=[CH2:43]
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(Cl)cc(Cl)c2)c2cc(OC)ccc21
Reactant: C=CC[C@@H](C(=O)O)N(C)S(=O)(=O)CCCCC
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: On1nnc2ccccc21
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2cc(Cl)cc(Cl)c2)NC(=O)[C@H](CC=C)N(C)S(=O)(=O)CCCCC)c2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
Step DL (1): A mixture of 28.7 mg (S)-2-(N-methylpentylsulfonamido)pent-4-enoic acid (0.11 mmol, from Preparation J), 24.8 mg 1-[3-(dimethyamino)propyl]-3-ethyl carbodiimide methiodide (0.083 mmol), 18 mg 1-hydroxybenzotriazole, 3 drops triethylamine and 1 mL dimethyl-formamide was stirred for 15 minutes at rt. The mixture was then added to 21 mg (2R,3S)-1-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-amino-4-(3,5-dichloro-phenyl)butan-2-ol (0.046 mmoles, from Preparation BG) and the reaction mixture was allowed to stand at rt overnight. The reaction mixture was subjected to preparative HPLC, with the peak at 9.8 min collected to yield 14.1 mg (S)-N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-yl-amino)-1-(3,5-dichlorophenyl)-3-hydroxybutan-2-yl)-2-(N-methylpentyl-sulfon-amido)pent-4-enamide as a clear oil. LC-MS Rt 2.18 min (method A), (M+H)+=696.0, 698.0; HRMS (M+H)+=696.2653; 1H NMR (500 MHz, CDCl3) δ 7.31 (d, J=8.2, 1H) 7.19 (s, 1H) 7.14 (s, 2H) 6.94 (d, J=2.1, 1H) 6.84 (d of d, J=8.2, 2.4, 1H) 6.68 (d, J=9.1, 1H) 5.95 (m, 1H) 5.69 (m, 1H) 5.31 (d, J=17, 1H) 5.2-5.08 (m, 3H) 4.77 (t, J=5.5, 1H) 4.17 (d of d, J=9.5, 5.7, 1H) 4.10 (m, 1H) 3.80 (s, 3H) 3.51 (m, 1H) 3.12 (d of d, J=14.3, 3.7, 1H) 2.90 (m, 4H) 2.67 (m, 4H) 2.54 (s, 3H) 2.31 (m, 2H) 1.93 (d, J=13.4 of t, J=4.6, 1H) 1.75 (m, 2H) 1.33 (m, 4H) 0.90 (t, J=7, 3H).
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@:8]2([O:10][CH2:9]2)[C@H:7](/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[O:6][CH2:5][C@@H:4]1[CH3:20].[CH:21]1[N-:25][CH:24]=[N:23][CH:22]=1.[Na+]>CN(C)C=O.O>[N:23]1([CH2:9][C@:8]2([OH:10])[C@@H:3]([O:2][CH3:1])[C@@H:4]([CH3:20])[CH2:5][O:6][C@H:7]2/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:22]=[CH:21][N:25]=[CH:24]1
Reactant: CCCCCCC/C=C/[C@@H]1OC[C@H](C)[C@H](OC)[C@@]12CO2
Reactant: c1c[n-]cn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCC/C=C/[C@@H]1OC[C@H](C)[C@H](OC)[C@@]1(O)Cn1ccnc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.7 %

Procedure:
A mixture of (3S,4S,7S,8S)-8-methoxy-7-methyl-4-[(E)-1-nonenyl]-1,5-dioxaspiro[2,5]octane (4.2 mg) and imidazole sodium derivative (14.0 mg) in dry N,N-dimethylformamide(0.5 ml) was stirred for 15 hours at room temperature. The reaction mixture was diluted with water. The mixture was extracted with dietyl ether, the combined ethereal extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by preparative thin layer chromatography (ethyl acetate as an eluent) gave (2S,3S,4S,5S)-3-(1H-imidazol-1-ylmethyl)-4-methoxy-5-methyl-2-[(E)-1-nonenyl]tetrahydro-2H-pyran-3-ol (4.1 mg, y. 79%) as colorless oil; EI-MS: m/z 351 (M+); 1H-NMR (CDCl3)d: 0.88 (3H,t,J=8 Hz), 1.10 (3H,d,J=7 Hz), 1.2-1.5 (10H,m), 2.1 (3H,m), 2.39 (1H,br.s, --OH), 2.93 (1H,d,J=5 Hz), 3.39 (3H,s), 3.40 (1H, dd, J=3 & 12 Hz), 3.61 (1H,d,J=8 Hz), 3.76 (1H,dd,J=4 & 12 Hz), 3.96 (1H,d,J=14 Hz), 4.13 (1H,d,J=14 Hz), 5.87 (2H,m), 6.91 (1H, s), 7.14 (1H,s), 7.46 (1H,s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27]S(C)=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.NCC1C(=O)NC(C)=CC=1CC>O>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH2:24][CH3:27])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CS(C)=O
Agent: CCc1cc(C)[nH]c(=O)c1CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Product: CCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)nc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) in DMSO (3 mL for 1 mmol), PyBOP (1.5 equiv.) was added and reaction stirred at room temperature for 15 min. Then 3-(aminomethyl)-4-ethyl-6-methylpyridin-2(1H)-one (2 equiv.) was added and reaction stirred overnight. On completion, water was added and solid that precipitates out was filtered and washed with water. Then this solid was stirred with acetonitrile for 10 min and filtered again to obtain the desired intermediate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)C(N)C1CCCCC1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C1CCCCC1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-cyclohexylacetate hydrochloride (prepared from cyclohexylglycine (Advanced Chemtech) using General Procedure H), the title compound was prepared as a solid (mp=146-150° C.). The reaction was monitored by tlc (Rf=0.3 in 3% MeOH/CHCl3) and the product was purified by silica gel chromatography using 3% MeOH/CHCl3 as the eluent.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>ClCCl.N1C=CC=CC=1>[Cl:19][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(CCl)cc1
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a stirred solution of tert-butyl 4-(hydroxymethyl)phenylcarbamate (0.50 g, 2.24 mmol) in dichloromethane was added pyridine (3 drops), followed by the dropwise addition of thionyl chloride (0.35 mL, 4.98 mmol). The resulting reaction mixture was stirred for 30 minutes, and then quenched with water (25 mL). The aqueous layer was extracted with dichloromethane (50 mL), and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford tert-butyl 4-(chloromethyl)phenylcarbamate as an orange solid in 50% yield (0.27 g, 50%): 1H NMR (300 MHz, CDCl3) δ 7.38-7.28 (m, 4H), 6.51 (br s, 1H), 4.55 (s, 2H), 1.52 (s, 9H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccncc1
Reactant: CNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccncc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 126.6 %

Procedure:
To a solution of N-methyl-4-nitroaniline (5 g, 32.9 mmol) in DMF (75 ml) was slowly added NaH (60% in mineral oil, 4.21 g, 105 mmol) at RT (Warning: important gaz evolution occurred!). The suspension was vigorously stirred at RT for 15 min then cooled to 0° C. (ice bath). 4-(Chloromethyl)pyridine hydrochloride (8.09 g, 49.3 mmol) was added carefully then the slurry was allowed to warm to RT and further stirred for 45 min. The reaction mixture was poured into water and extracted with Et2O (3×). The combined organic phases were dried over Na2SO4, filtered and evaporated to dryness to yield the crude title compound (10.13 g) as an orange solid, which was used in the next step without further purification. HPLC: AtRet=1.01 min; LC-MS: m/z 244.5 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 3.23 (s, 3H), 4.82 (s, 2H), 6.77-6.83 (m, 2H), 7.17-7.22 (m, 2H), 8.02-8.08 (m, 2H), 8.49-8.54 (m, 2H).
Reaction SMILES: CS(O[CH:6]([C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=O)=O.[C:33]([C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)([CH3:36])([CH3:35])[CH3:34].C(OCC)(=O)C.Cl>CN(C=O)C>[C:33]([C:37]1[CH:38]=[CH:39][C:40]([N:41]2[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[CH2:8][CH2:7][CH:6]2[C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[CH:42][CH:43]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(N2C(c3ccc([N+](=O)[O-])cc3)CCC2c2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.17 h

Procedure:
The product from Example 1C (3.67 g, 7.51 mmol) and 4-tert-butylaniline (11.86 ml, 75 mmol) in DMF (40 ml) was stirred under nitrogen at 50° C. for 4 h. The resulting mixture was diluted into ethyl acetate, treated with 1M HCl, stirred for 10 minutes and filtered to remove solids. The filtrate organic layer was washed twice with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (5% to 30%) to give a solid. The solid was triturated in a minimal volume of 1:9 ethyl acetate/hexane to give a light yellow solid as a mixture of trans and cis isomers (1.21 g, 36%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:35])[C:5]2=[C:6]([CH2:8][C@H:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[N:28]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[N:7]=1.[CH3:36][N:37]1CCOC[CH2:38]1.ClC(OCC(C)C)=O.CNC.CO>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([CH3:35])[C:5]2=[C:6]([CH2:8][C@H:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[N:28]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][CH2:15][CH2:16][C:17]([N:37]([CH3:38])[CH3:36])=[O:19])[N:7]=1
Reactant: CN1CCOCC1
Reactant: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCCCC(=O)O)N2)n1
Agent: CC(C)COC(=O)Cl
Agent: CNC
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCCCC(=O)N(C)C)N2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.3 %

Procedure:
A solution of (R,Z)-4-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)butanoic acid (101a, 26 mg, 0.054 mmol) in anhydrous THF was chilled in an ice bath and N-methylmorpholine (9 μL, 0.081 mmol) and isobutyl chloroformate (7.7 μL, 0.060 mmol) were added sequentially. The mixture was stirred under an N2 atmosphere for 20 min. A 33 wt % solution of dimethylamine in methanol (54 μL, 0.11 mmol) was added to the reaction which was subsequently allowed to warm to room temperature with stirring overnight. The THF was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with H2O×2 and dried over anhydrous Na2SO4. The ethyl acetate was removed in vacuo and the residue was purified via preparative HPLC to yield (R,Z)-4-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N,N-dimethylbutanamide (98, 6.4 mg, 0.0126 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([O-:11])([OH:10])=[O:9].[N:12]#[C:13][NH2:14]>C(O)C>[N+:8]([O-:11])([OH:10])=[O:9].[C:2]1([NH:1][C:13]([NH2:14])=[NH:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CN
Reactant: Nc1ccccc1
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: N=C(N)Nc1ccccc1
Temperature: 0 °C

Procedure:
Phenyl guanidine nitrate is prepared from a mixture of 12.8 g (0.1 mole) of aniline, 9.0 g of concentrated nitric acid (equivalent to 0.1 mole of HNO3), 12.6 g of a 50 percent aqueous cyanamide solution (equivalent to 0.15 mole of cyanamide) and 100 ml of ethyl alcohol which is heated under reflux for 20 hours. The reaction mixture is then cooled to 0°C for 5 hours and the precipitated product is collected on a filter. The product is purified by recrystallization from ethyl alcohol. The purified white crystalline solid melts at 125°-7°C. The infrared spectrum was consistent with the assigned structure.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.Cl.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35]([N:37]1[CH2:38][CH2:39][N:40]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:41][CH2:42]1)=[O:36]
Reactant: O=C(c1ccco1)N1CCNCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCN(C(=O)c5ccco5)CC4)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.5 %

Procedure:
In DMF (3 ml) was dissolved N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the solution were added 1-(2-furoyl)piperazine hydrochloride (109 mg) and potassium carbonate (268 mg). The mixture was stirred at room temperature for 18 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with ethyl acetate-diisopropylether to give N-[4-[1-(2-furoyl)-4-piperazinylmethyl]phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 44) (112 mg) as colorless amorphous.
Reaction SMILES: [CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14].C=CCCCC.CCCCC=CCCCC.[C:32](OCCCCCCCCC=C)(=[O:34])[CH3:33]>>[C:32]([O:15][CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:34])[CH3:33]
Reactant: CCCCC=CCCCCCCCCO
Reactant: C=CCCCCCCCCOC(C)=O
Agent: CCCCC=CCCCC
Solvent: C=CCCCC
Product: CCCCCCCCCCCCC=COC(C)=O

Procedure:
A process for preparing 9-tetradecenyl alcohol by reacting 1-hexene or 5-decene with 9-decenyl acetate in accordance with the method of claim 7 to obtain tetradecenyl acetate and then reacting the acetate with water to obtain said alcohol.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:28][CH2:27][CH:26]([N:29]([CH3:31])[CH3:30])[CH2:25]2)=[CH:20][CH:19]=1>>[CH3:30][N:29]([CH3:31])[CH:26]1[CH2:27][CH2:28][N:24]([C:21]2[CH:22]=[CH:23][C:18]([NH:17][C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:16])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Product: CN(C)C1CCN(c2ccc(NC(=O)C3CCNCC3)cc2)C1

Procedure:
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E, and the product was then treated by method G. This resulted in the product with the molecular weight of 316.45 (C18H28N4O); MS (ESI): 317 (M+H+).