Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:34])[C@@H:10]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([Cl:32])[C:25]=1[CH3:33])[C:11]([NH:13][NH:14][C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>C1COCC1>[Si:1]([O:8][C@H:9]([CH3:34])[C@@H:10]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([Cl:32])[C:25]=1[CH3:33])[C:11]1[S:44][C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:14][N:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccccc3)s2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.8 %

Procedure:
To a 25-mL round bottom flask charged with a solution of N′-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-benzohydrazide (326 mg, 0.65 mmol) in dry THF (10 mL) and equipped with a magnetic stirbar and septum was added Lawesson's reagent (527 mg, 1.3 mmol) under an atmosphere of nitrogen. This was stirred at room temperature for a period of 20 h. The solvent was then blown off under a gentle stream of nitrogen and the residue was directly purified via silica gel chromatography eluted with 30% EtOAc/hexanes to yield the product as a white solid (246 mg, 76%). 1H NMR (500 MHz, CDCl3, δ in ppm) 7.90 (m, 2H), 7.46 (m, 3H), 7.31 (d, J=8.8 Hz, 1H), 6.75 (d, J=8.8 Hz, 1H), 5.19 (d, J=7.9 Hz, 1H), 5.00 (dd, J=3.1, 7.9 Hz, 1H), 4.50 (m, 1H), 2.27 (s, 3H), 1.21 (d, J=6.3 Hz, 3H), 1.02 (s, 9H), 0.24 (s, 3H), 0.17 (s, 3H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@H:15]([C:18](=[O:23])N(OC)C)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[BH4-].[Na+]>C1COCC1.O.[Br-]>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@H:15]([CH:18]([OH:23])[CH2:3][CH:2]=[CH2:1])[CH2:14]1)=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: C=CC[Mg]Br
Reactant: CON(C)C(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC(O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.9 %

Procedure:
Add slowly and dropwise a solution of allylmagnesium bromide (2.0 M in THF, 100.3 mL, 200.5 mmol) to a stirred solution of (S)-3-(methoxy(methyl)carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (37.0 g, 143.2 mmol) in THF (296 mL) kept under nitrogen at 0° C. Allow the reaction to warm to room temperature and continue to stir for 48 hours. Add the mixture over a cold solution (0-5° C.) of sodium borohydride (5.42 g, 143 mmol) and tertabutylammonium bromide (0.74 g, 2.39 mmol) in water (74 mL) and stir for 1 hour. Separate the phases and extract the water phase with t-butylmethylether (2×). Combine the organic phases and wash with water and brine. Concentrate and purify the crude residue by silica gel column chromatography eluting with t-butylmethylether/hexanes (3/7 to 7/3) to obtain (3S)-3-(1-hydroxy-but-3-enyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (S-mix) (29 g, 85%). MS (m/z)=186.1 [M−55].
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9]([NH:12][CH:13]([CH3:15])[CH3:14])([CH3:11])[CH3:10].C(O)C.Cl>O>[CH:9]([N:12]([CH:13]([CH3:15])[CH3:14])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCBr
Reactant: CC(C)NC(C)C
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCN(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
Ethyl 3-diisopropylaminopropionate may be obtained in the following manner: ethyl 3-bromopropionate (18.1 g) is introduced dropwise in the course of 30 minutes into a solution of diisopropylamine (28.5 cc) and ethanol (40 cc) maintained at a temperature of 25° C. The suspension obtained is heated to reflux for 4 hours. After being cooled, the reaction mixture is taken up with water (100 cc) and 4N aqueous hydrochloric acid solution (70 cc). After the mixture is washed with ethyl ether (100 cc), it is alkalinized to a pH in the region of 9 with 4N aqueous sodium hydroxide solution. The oil formed is extracted with methylene chloride (3×150 cc). After being washed with water (2×100 cc) and dried, the methylene chloride solution obtained is concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. Ethyl 3-diisopropylaminopropionate (11.6 g) is thereby obtained in the form of an oil, which is employed in the crude state in the subsequent syntheses.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:10]([C:20]([O-:22])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:10]([C:20]([OH:22])=[O:21])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1C1CN(Cc2ccccc2)CC1C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1C1CN(Cc2ccccc2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 1-Benzyl-4-(2-methylphenyl)pyrrolidine-3-carboxylate (0.685 g, 2.214 mmol) in THF/MeOH/H2O (5 ml) was added 2N NaOH (3.32 ml, 6.64 mmol). The solution was stirred for 12 hours at room temperature and was acidified to pH1-2 with 1N HCl. The crude acid was extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8]Br)=[CH:6][CH:5]=[CH:4][N:3]=1.[C-:10]#[N:11].[Na+].O.C(O)C>ClCCl>[Br:1][C:2]1[C:7]([CH2:8][C:10]#[N:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: BrCc1cccnc1Br
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: N#CCc1cccnc1Br
Yield: 83 %

Procedure:
A mixture of 2-bromo-3-bromomethyl-pyridine (840 mg, 3.35 mmol) and sodium cyanide (187.99 mg, 3.68 mmol) is stirred and refluxed for 1 h in a mixture water (10 mL)-ethanol (2 mL). The reaction mixture is diluted with dichloromethane and washed with saturated aqueous solution of sodium bicarbonate. The organic layer is separated, dried over magnesium sulfate and the solvent evaporated in vacuo to give 83% of the title compound that is used without further purification. MS (m/z): 197 (M+1), 199 (M+3).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19](C)([O-:21])C.[K+]>C(OCCCC)(=O)C>[OH:16][C:14]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:19](=[O:21])[CH:18]=1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1cccnc1Nc1ccccc1
Agent: [K+]
Solvent: CCCCOC(C)=O
Product: O=c1cc(O)c2cccnc2n1-c1ccccc1

Procedure:
To a stirred solution of 1 kg. of methyl 2-phenylamino-3-pyridine carboxylate in 3.97 liters of n-butyl acetate there is added portionwise, 1.1 kg. of potassium tertiary butoxide. After the addition of the potassium tertiary butoxide, there is added an additional 1.32 liters of n-butyl acetate. The reaction mixture is heated to reflux for 20 hours during which the internal temperature of the reaction mixture rose from 90° C. to 122° C. During this period, 1.8 liters of liquid is removed from the reaction mixture via a Dean-Stark trap. Xylene (3.0 liters) is added to the reaction mixture and the remainder of the n-butyl acetate is removed via the Dean-Stark trap. The reaction mixture is cooled and the potassium salt is collected by filtration, washed with toluene and air dried. The crude potassium salt is dissolved in 12 liters of water, the aqueous solution is extracted with toluene, acidified to pH 2 and the product filtered and dried; weight 937 g., m.p. 311°-313° C.
Reaction SMILES: [F:1][C:2]1[C:3](/[N:9]=[CH:10]/[N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].C(=S)=S.I[CH2:20][CH3:21]>CN(C=O)C>[CH2:20]([N:6]1[CH:7]=[C:2]([F:1])[C:3](/[N:9]=[CH:10]/[N:11]([CH3:13])[CH3:12])=[N:4][C:5]1=[O:8])[CH3:21]
Reactant: CCI
Reactant: CN(C)/C=N/c1nc(O)ncc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: S=C=S
Product: CCn1cc(F)c(/N=C/N(C)C)nc1=O
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 91.6 %

Procedure:
A 25 mL screw-top vial was charged with (E)-N′-(5-fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformimidamide (99.5 mg, 0.540 mmol), DMF (2 mL), and NaH (60% dispersion in mineral oil; 24.5 mg, 0.613 mmol) and was agitated on a rotary shaker at 50° C. for 40 min. After cooling to room temperature, carbon disulfide (0.036 mL, 0.599 mmol) was added, and the reaction mixture was agitated on a rotary shaker at room temperature for 90 min. At this point, iodoethane (0.052 mL, 0.650 mmol) was added, and the reaction mixture was further agitated at room temperature for 3.5 h, whereupon the crude mixture was concentrated in vacuo. The crude material was purified by normal phase chromatography (gradient, 0 to 30% MeOH/CH2Cl2) to afford (E)-N′-(1-ethyl-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)-N,N-dimethylformimidamide (105 mg, 67%) as a white solid: mp 157-160° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.09 (d, J=6.2 Hz, 1H), 3.70 (q, J=7.1 Hz, 2H), 3.20 (s, 3H), 3.07 (s, 3H), 1.18 (t, J=7.1 Hz, 3H); ESIMS m/z 213 ([M+H]+.
Reaction SMILES: [O:1]([CH:9]([C:39]([F:47])([F:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:10][CH2:11][C@H:12]1[C@H:16]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:15][C@@H:14]([OH:24])[CH:13]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C(Cl)(=O)C(Cl)=O.CS(C)=O>ClCCl.C(N(CC)CC)C>[O:1]([CH:9]([C:39]([F:47])([F:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:10][CH2:11][C@H:12]1[C@H:16]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:15][C:14](=[O:24])[CH:13]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH:36]([CH3:37])[CH3:38])=[O:34])[Si:2]([C:5]([CH3:7])([CH3:8])[CH3:6])([CH3:3])[CH3:4]
Reactant: CCCCCCC(F)(F)C(CC[C@@H]1C(CCCCCCCCC(=O)OC(C)C)[C@H](O)C[C@H]1OC1CCCCO1)O[Si](C)(C)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCCCCC(F)(F)C(CC[C@@H]1C(CCCCCCCCC(=O)OC(C)C)C(=O)C[C@H]1OC1CCCCO1)O[Si](C)(C)C(C)(C)C

Procedure:
A solution of the compound (12-10) (1.09 g) in dichloromethane (2 ml) was subjected to Swan oxydation using oxalyl chloride (2.0M, CH2Cl2 solution, 1.58 ml), a solution of DMSO (0.45 ml) in dichloromethane (10 ml) and triethylamine (0.88 ml). The crude product obtained by the conventional treatment was purified by silica gel chromatography (n-hexane/ethyl acetate=8/2) to give the titled compound (12-11).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N+:7]([O-])=[CH:6][C:5]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([O-])=O>CO.O1CCCC1.[Ni]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][C:5]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1c(N2CCCCC2)c[n+]([O-])c2ccccc12
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1c(N2CCCCC2)cnc2ccccc12

Procedure:
The 4-nitro-3-piperidinoquinoline-N-oxide (4 g, 0.015 mol) was dissolved in a mixed solvent of methanol and tetrahydrofuran (50 ml) and subjected to catalytic reduction in the presence of purified Raney nickel (2 ml). Upon isolation and purification by chromatography on an alumina column (developing solvent: CHCl3), 4-amino-3-piperidinoquinoline was obtained in an amount of 2.1 g (yield, 63%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([NH:32][CH2:33][C:34]4[CH:35]=[C:36]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42](C=O)[CH:41]=5)[CH:37]=[CH:38][CH:39]=4)=[O:31])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][N:51]1[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.[C:58](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([NH:32][CH2:33][C:34]4[CH:35]=[C:36]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:50][N:51]6[CH2:57][CH2:56][CH2:55][N:54]([CH3:58])[CH2:53][CH2:52]6)[CH:41]=5)[CH:37]=[CH:38][CH:39]=4)=[O:31])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CN1CCCNCC1
Reactant: CC(=O)O
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2cccc(-c3cccc(CN4CCCN(C)CC4)c3)c2)c1
Yield: 28 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-3-biphenylyl)methyl]-5-methyl-1,3-benzenedicarboxamide (30 mg, 0.046 mmol), 1-methylhexahydro-1H-1,4-diazepine (52 mg, 0.46 mmol, 10 eq) and acetic acid (2.61 μL, 0.046 mmol, 1 eq) were dissolved in DMSO (1.5 mL). The mixture was stirred in VX-2500 Multi-Tube Vortexer for overnight at room temperature. MP-triacetoxyborohydride (137 mg, 0.319 mmol, 7 eq) was then added and the mixture was stirred again in VX-2500 Multi-Tube Vortexer for overnight at room temperature. The reaction mixture was filtered through a polypropylene cartridge (10 mL tube) on Bohdan Miniblock in a reaction tube and concentrated in a Glas-Col evaporator. The reaction mixture was then purified using a Gilson HPLC with a water-acetonitrile with 0.1% TFA buffer. The desired product fractions were combined, filtered through amine cartouche (500 mg) on Bohdan Miniblock and concentrated in a Glas-Col evaporator, giving 9.74 mg (25.4%) of the title compound. LC-MS m/z 757.4 (M+H)+, 1.26 min (ret time).
Reaction SMILES: Cl.N([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)C1C=CC=CC=1.[Cl:23][C:24]1[C:25]([O:33][CH3:34])=[CH:26][C:27]([O:31][CH3:32])=[C:28]([CH:30]=1)[NH2:29]>C(O)C>[OH2:31].[ClH:23].[Cl:23][C:24]1[C:25]([O:33][CH3:34])=[CH:26][C:27]([O:31][CH3:32])=[C:28]([CH:30]=1)[NH:29][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1
Reactant: COc1cc(OC)c(Cl)cc1N
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Solvent: CCO
Product: COc1cc(OC)c(Nc2cc(C)nc3ccc4nc[nH]c4c23)cc1Cl
Product: O
Reaction time: 8 h

Procedure:
A mixture of 40 g. (0.184 m.) of the compound of Example I, C., 346 g. (0.184 m.) of 5-chloro-2,4-dimethoxyaniline and 500 ml. of ethanol was refluxed with stirring overnight. The solvents were removed by distillation and the crude product dissolved in 3000 ml. of MeOH. The MeOH filtrate was concentrated to one-half its volume, chilled and filtered to yield 13 g. m.p. 400°.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=2[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:6](=[O:9])[CH2:7][N:8]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+].[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O.CCCCCCC.CCOC(C)=O>[Cl:23][C:21]1[CH:20]=[CH:19][C:4]2[N:5]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:6](=[O:9])[CH2:7][N:8]=[C:2]([C:41]3[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][CH:40]=3)[C:3]=2[CH:22]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1ccc(CN2C(=O)CN=C(Cl)c3cc(Cl)ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(CN2C(=O)CN=C(c3ccc(OC)cc3)c3cc(Cl)ccc32)cc1
Temperature: 85 °C
Reaction time: 0.08 h
Yield: 33.3 %

Procedure:
In a 1 L 3 neck RBF equipped with magnetic stir bar, condenser, thermocouple, and N2 inlet, crude (E)-5,7-dichloro-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (54 g) was dissolved into 360 mL of DME. To this was added a solution of Na2CO3 (23 g, 0.15 mol, in 250 mL of H2O) followed by the addition of 4-methoxyphenyl boronic acid (22.7 g, 0.15 mol) and Pd(PPh3)4 (1.4 g, 1.2 mmol). The reaction mixture was heated in a 85° C. oil bath for 2 h and then cooled (RT). To this was added 200 mL of EtOAc and the mixture stirred for 5 min. Organic layer was separated and washed with 200 mL H2O and then brine. Organic layer was concentrated to dryness to give 68 g of crude product. This was subjected to column chromatography using 550 g of silica gel and 25/75 to 60/40 EtOAc/heptane. Fractions containing pure product were combined to give 21 g of pure product and other fractions containing a small amount of impurity (by TLC) gave another 20 g of product, albeit less pure. However NMR of both lots was identical. Total of 41 g of product was obtained. Yield 72% over two steps. 1H NMR (300 MHz, CDCl3) δ 3.7 (s, 3H), 3.80 (d, 1H), 3.85 (s, 3H), 4.57 (d, 1H), 4.85 (d, 1H), 5.57 (d, 1H), 6.63 (d, 2H), 6.85-6.95 (m, 4H), 7.16 (d, 1H), 7.3-7.44 (m, 4H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:40])=[C:9]([CH2:11][O:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][O:18][C:19]3[C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][N:22]=[C:21]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:38][CH3:39])[N:10]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:40])=[C:9]([CH2:11][O:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][O:18][C:19]3[C:24]([C:25]([OH:27])=[O:26])=[CH:23][N:22]=[C:21]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:20]=3)=[CH:15][C:14]=2[O:38][CH3:39])[N:10]=1
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(COc2nc(-c3ccccc3)ncc2C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a mixture of ethyl 4-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-2-phenylpyrimidine-5-carboxylate (0.47 g), tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was poured into water, 2N hydrochloric acid was added to acidify the solution, and the precipitated crystals were collected by filtration. Recrystallized from methanol-ethyl acetate gave 4-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-2-phenylpyrimidine-5-carboxylic acid as pale-yellow needle crystals (0.18 g, yield 40%). melting point: 163-164° C.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH:11](O)=[O:12]>C(OCC)C>[CH:11]([N:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1)[NH2:10])=[O:12]
Reactant: O=CO
Reactant: NNC(=O)c1cccnc1
Solvent: CCOCC
Product: NN(C=O)C(=O)c1cccnc1

Procedure:
25 g (182 mmol) of nicotinic acid hydrazide were stirred in 50 ml (1325 mmol) of formic acid for 16 h, 500 ml of diethyl ether were added and the precipitate formed was filtered off with suction. The filter residue was washed with diethyl ether and dried.
Reaction SMILES: [CH3:1][C:2]1[NH:20][C:5]2=[N:6][C:7]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=1.Br[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[CH3:1][C:2]1[N:20]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:5]2=[N:6][C:7]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=1
Reactant: COC(=O)c1cc(N2CCOCC2)nc2[nH]c(C)nc12
Reactant: BrCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)nc2c1nc(C)n2Cc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 5 h
Yield: 68.7 %

Procedure:
A mixture of methyl 2-methyl-5-morpholino-3H-imidazo[4,5-b]pyridine-7-carboxylate (138 mg, 0.5 mmol), 1-(bromomethyl)naphthalene (166 mg, 0.75 mmol) and Na2CO3 (138 mg, 1 mmol) in DMF (10 mL) was stirred at 80° C. for 5 h. It was cooled to room temperature and poured into water (50 mL). It was extracted with EA (100 mL×2). The combined organic layers were washed with brine (100 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with 100% EA to afford the desired product as a black solid (143 mg, 69%); LC/MS: MS (ES+) m/e 417 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.42 (s, 3H), 3.42 (t, J=4.5 Hz, 4H), 3.67 (t, J=4.5 Hz, 4H), 3.93 (s, 3H), 5.92 (s, 2H), 6.70 (d, J=7.2 Hz, 1H), 7.09 (s, 1H), 7.39 (t, J=7.5 Hz, 1H), 7.57-7.65 (m, 2H), 7.87 (d, J=9.0 Hz, 1H), 7.90 (d, J=9.0 Hz, 1H), 8.34 (d, J=7.2 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17](Br)=[CH:18][N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=2[CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:30]1C2C(=O)N(COCC[Si](C)(C)C)N=CC=2N(COCC[Si](C)(C)C)C=1.CB(O)O>>[CH2:1]([O:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17]([CH3:30])=[CH:18][N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=2[CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(=O)n(COCc3ccccc3)ncc21
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(Br)cn2COCC[Si](C)(C)C)c1=O
Agent: CB(O)O
Product: Cc1cn(COCC[Si](C)(C)C)c2cnn(COCc3ccccc3)c(=O)c12
Yield: 96 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference example 20-(b) except for using 30.8 g (66.3 mmol) of 5-benzyloxymethyl-3-bromo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 24-(b) in place of 3-bromo-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, and using 12.0 g (200 mmol) of methylboronic acid in place of propylboronic acid, respectively, whereby 25.3 g of the title compound was obtained as a brownish oil. (Yield: 96%)
Reaction SMILES: CO[C:3]1[CH:10]=[C:9]([C:11]#[C:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:8]([O:23][CH2:24][CH3:25])=[CH:7][C:4]=1[CH:5]=O.[CH2:26]([O:28][C:29]1[CH:43]=[C:42]([I:44])[C:41]([O:45][CH3:46])=[CH:40][C:30]=1[CH2:31]P(=O)(OCC)OCC)[CH3:27].[H-].[Na+].O1CCC[CH2:50]1>>[CH2:26]([O:28][C:29]1[CH:43]=[C:42]([I:44])[C:41]([O:45][CH3:46])=[CH:40][C:30]=1[CH:31]=[CH:5][C:4]1[C:3]([CH3:50])=[CH:10][C:9]([C:11]#[C:12][Si:13]([CH:14]([CH3:16])[CH3:15])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[C:8]([O:23][CH2:24][CH3:25])[CH:7]=1)[CH3:27]
Reactant: C1CCOC1
Reactant: CCOc1cc(I)c(OC)cc1CP(=O)(OCC)OCC
Reactant: CCOc1cc(C=O)c(OC)cc1C#C[Si](C(C)C)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Product: CCOc1cc(C=Cc2cc(OC)c(I)cc2OCC)c(C)cc1C#C[Si](C(C)C)(C(C)C)C(C)C

Procedure:
The 2-methoxy-5-ethoxy-4-((tri-iso-propylsilyl)ethynyl)benzaldehyde and diethyl 2-ethoxy-4-iodo-5-methoxybenzylphosphonate can be added to a solution containing sodium hydride (NaH) dissolved in tetrahydrofuran (THF), yielding (E)-((4-(2-ethoxy-4-iodo-5-methoxystyryl)-(2-ethoxy-5-methylphenyl)ethynyl)tri-iso-propylsilane.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1)=[O:4].[N-:17]=[N+:18]=[N-:19].[Na+]>>[N:17]([CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1)=[O:4])=[N+:18]=[N-:19]
Reactant: COc1cc(C(=O)CBr)cc(OC)c1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: COc1cc(C(=O)CN=[N+]=[N-])cc(OC)c1OC

Procedure:
In a manner similar to Preparation 3 react 2-bromo-1-(3,4,5-trimethoxyphenyl)ethanone with NaN3 to obtain the title compound.