Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9](O)[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCC>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH:9]([Br:13])[CH3:10])[CH:3]=1
Reactant: CC(O)c1cc(F)cc(Br)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(Br)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (±)-1-(3-bromo-5-fluorophenyl)ethanol (1.0 g, 4.6 mmol) and carbon tetrabromide (1.82 g, 5.48 mmol) in tetrahydrofuran (5 mL) at 0° C. was added triphenylphosphine (1.44 g, 5.48 mmol). The resulting solution was stirred at room temperature for 45 min. The reaction was diluted with several volumes of pentane, and filtered to remove the undissolved solids which were discarded. The organics were concentrated and purified by column chromatography (1% ethyl acetate/hexanes) to give 1.26 g (98%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.35 (s, 1H), 7.17 (m, 1H), 7.09 (m, 1H), 5.06 (q, J=7.0 Hz, 1H), 2.00 (d, J=7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 163.6, 161.6, 147.2 (m), 126.0 (m), 122.8, 122.7, 119.2, 119.0, 113.3, 113.1, 46.5, 26.7.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:11][C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[N+:27]([O-:29])=[O:28]>C(Cl)Cl>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([CH3:1])=[C:3]([O:11][C:12]3[CH:13]=[N:14][CH:15]=[N:16][CH:17]=3)[CH:4]=2)[NH:8][CH:7]=1)[CH2:26][N+:27]([O-:29])=[O:28]
Reactant: Cc1cc2[nH]ccc2cc1Oc1cncnc1
Reactant: O=[N+]([O-])/C=C/c1ccccc1F
Solvent: ClCCl
Product: Cc1cc2[nH]cc(C(C[N+](=O)[O-])c3ccccc3F)c2cc1Oc1cncnc1
Temperature: 130 °C
Yield: 52.9 %

Procedure:
6-Methyl-5-(pyrimidin-5-yloxy)-1H-indole (0.1783 g, 0.792 mmol) and (E)-1-fluoro-2-(2-nitrovinyl)benzene (0.159 g, 0.950 mmol) were dissolved in CH2Cl2, and the solution was concentrated in vacuo. The residue was heated at 130° C. for 4 hr, and the crude product was purified by flash chromatography using an ISCO 40 g column eluting with 0-5% MeOH/CH2Cl2. Appropriate fractions were collected and concentrated in vacuo to give the desired product (0.1644 g, 0.419 mmol, 52.9% yield) as a tan foam.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]5[C:31]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=5)=[CH:20][CH:19]=4)[CH2:13][CH2:12]3)[N:9]=[CH:10][C:3]=12.N[NH:39][C:40]([NH2:42])=[S:41].C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O>[NH2:42][C:40]1[S:41][C:28]([C:27]2[CH:30]=[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:24]([C:21]3[CH:20]=[CH:19][C:18]([CH2:17][N:14]4[CH2:15][CH2:16][CH:11]([N:8]5[C:4]6=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]6[CH:10]=[N:9]5)[CH2:12][CH2:13]4)=[CH:23][CH:22]=3)=[N:25][CH:26]=2)=[N:29][N:39]=1
Reactant: N#Cc1cnc(-c2ccc(CN3CCC(n4ncc5c(N)ncnc54)CC3)cc2)c(-c2ccccc2)c1
Reactant: NNC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(-c2cnc(-c3ccc(CN4CCC(n5ncc6c(N)ncnc65)CC4)cc3)c(-c3ccccc3)c2)s1

Procedure:
A solution of 6-(4-{[4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl]methyl}phenyl)-5-phenylnicotinonitrile (4A-4; 0.035 g, 0.072 mmol) and thiosemicarbazide (0.010 g, 0.108 mmol) in TFA (2 mL) was heated to 60° C. for 16 hr. The reaction was then cooled, poured onto ice, and basified with saturated aqueous sodium bicarbonate. The resulting precipitate was filtered, taken up in DMF and purified by reverse phase HPLC (5% CH3CN: 95% H2O+0.1% TFA to 95% CH3—CN: 5% H2O+0.1% TFA). 1H-NMR (500 MHz, d6 DMSO) δ 9.72 (bs, 1H), 9.07 (d, J=2.19, 1H), 8.93 (bs, 1H), 8.42 (bs, 1H), 8.36 (s, 1H), 8.29 (s, 1H), 8.10 (d, J=1.96, 1H), 7.65 (bs, 2H), 7.22-7.49 (m, 9H), 4.93-5.03 (m, 1H), 4.34 (s, 2H), 3.49 (d, J=12.21, 2H), 3.19-3.35 (m, 2H), 2.32-2.56 (m, 2H), 2.15 (d, J=11.96, 2H). HRMS m/z (M+H) Calcd: 561.2292, found: 561.2256.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[C:18]2[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH:19]=2)=[O:10])=[N:4][C:5](Br)=[CH:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.CC([O-])=O.[K+].Br[C:83]1[C:88]([F:89])=[CH:87][CH:86]=[CH:85][N:84]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.CCOC(C)=O.O.O1CCOCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:83]2[C:88]([F:89])=[CH:87][CH:86]=[CH:85][N:84]=2)=[N:4][C:3]=1[C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[CH:19]=1)=[O:10]
Reactant: Cc1cc(-c2ccncc2NC(=O)c2nc(Br)ccc2N)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Reactant: Fc1cccnc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(-c2ccncc2NC(=O)c2nc(-c3ncccc3F)ccc2N)cc(N)n1
Temperature: 90 °C

Procedure:
To a solution of degassed dioxane (0.03M) was added 3-amino-6-bromo-N-(2′-(di-BOC-amino)-6′-methyl-4,4′-bipyridin-3-yl)picolinamide (1.0 equiv.), bis(pinacolato)diboron (2.0 equiv.), Pd2(dba)3 (0.05 equiv.), PCy3 (0.075 equiv.), and KOAc (3.0 equiv.). The solution was heated to 90° C. for 16 hrs until all starting material was consumed. Filtered the reaction and concentrated the filtrate. The crude was dried under vacuo, then dissolved in DME/2M Na2CO3 (3:1, 0.05M), followed by addition of 2-bromo-3-fluoropyridine (2.0 equiv.) and Pd(dppf)Cl2-DCM (0.10 equiv.). The reaction was heated to 100° C. in an oil bath until consumption of the boronic ester. Cooled to room temperature, added H2O and EtOAc, the organic phase was washed with brine, then dried with Na2SO4, and concentrated. The crude material was purified via SiO2 column chromatography eluting with EtOAc and hexanes (1:1) and the pure product was concentrated and stirred in DCM/TFA (25%) until completion of the deprotection. The reaction was concentrated to dryness and purified via reverse phase HPLC to afford 5-amino-N-(2′-amino-6′-methyl-4,4′-bipyridin-3-yl)-3′-fluoro-2,2′-bipyridine-6-carboxamide. LCMS (m/z): 416.2 (MH+); LC Rt=1.77 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[C:4]([C:10]([OH:12])=O)=[N:3]1.C1N=C[N:15](C(N2C=NC=C2)=O)[CH:14]=1.CN>C1COCC1>[CH3:14][NH:15][C:10]([C:4]1[C:5]([N+:7]([O-:9])=[O:8])=[CH:6][N:2]([CH3:1])[N:3]=1)=[O:12]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1cc([N+](=O)[O-])c(C(=O)O)n1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1nn(C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 1-methyl-4-nitropyrazole-3-carboxylic acid (2.0 g) in THF (30 ml) was charged carbonyl-1,1′-diimidazole (1.9 g) over 1 hour at room temperature. The reaction was stirred overnight before cooling to 0° C. A solution of methylamine in THF (12 ml of a 2M solution) was added and the reaction stirred for 1 hour. The THF layer was separated and concentrated in vacuo. The crude oil was purified by column chromatography on silica (25 g), eluting with 100% EtOAc (500 ml) to give N,1-dimethyl-4-nitropyrazole-3-carboxamide, 976 mg.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C1C(=O)N([Br:22])C(=O)C1>CN(C=O)C.C(OCC)(=O)C>[Br:22][C:5]1[S:1][C:2]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)NCc1cccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(Br)s1
Temperature: 20 °C
Reaction time: 5 h
Yield: 91.3 %

Procedure:
To a solution of produce tert-butyl thiophen-2-ylmethylcarbamate (1.28 g, 6 mmol, 1.0 equiv.) in DMF (4 mL) was added NBS (1.17 g, 6.6 mmol, 1.1 eq). After stirring at 20° C. for 5 h, the reaction mixture was diluted with ethyl acetate and washed with water for three times. The organic layer was dried (MgSO4) and concentrated in vacua. The residue was purified by silica gel column chromatography (PE/EtOAc=100:1 to 5:1) to afford tert-butyl (5-bromothiophen-2-yl)methylcarbamate (1.6 g, 91%). LC-MS (m/z)=235.9 [M−55]+. 1H NMR (400 MHz, DMSO-d6): δ 1.39 (s, 9H), 4.20 (d, J=6.0 Hz, 2H), 6.76 (d, J=4.0 Hz, 1H), 7.03 (d, J=3.6 Hz, 1H), 7.52 (t, J=5.6 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH2:15][CH:14]=[CH:13][CH2:12][C:11]=1[CH2:16][C:17]([OH:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C.[H][H]>[OH-].[NH4+].[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=1[CH2:16][C:17]([OH:19])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCC1=C(CC(=O)O)CC=CC1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)NCC1=C(CC(=O)O)CCCC1

Procedure:
A solution of α-[2-(t-butoxycarbonylaminomethyl)-1,4-cyclohexadienyl]-acetic acid (1.33 g., 5 mmoles) in 3% ammonium hydroxide (10 ml.) was hydrogenated at 40 psi with palladium or charcoal (10%, 0.2 g.). A theoretical amount of hydrogen was taken up in 3 hours. The catalyst was removed and the filtrate was acidified to pH 2 with dil. HCl and extracted with ethyl acetate (2 × 50 ml.). The combined extracts were washed with water (20 ml.), dried with Na2SO4 and evaporated under reduced pressure to afford an oil (1.34 g.) which solidified on standing for several days. Recrystallization from n-hexane - ethyl acetate gave 1.2 g. title product as colorless prisms melting at 118°-119° C.
Reaction SMILES: [NH2:1]/[C:2](/[CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[C:3](/[C:7]#[N:8])\[C:4](Cl)=O.C([O-])(O)=O.[Na+]>C(#N)C.O>[NH2:1]/[C:2](/[CH:9]([CH2:10][CH3:11])[CH2:12][CH3:13])=[C:3](\[C:7]#[N:8])/[CH3:4]
Reactant: CCC(CC)/C(N)=C(\C#N)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCC(CC)/C(N)=C(\C)C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
3 g (15 mmol) of (2Z)-3-amino-2-cyano-4-ethyl-2-hexenoyl chloride dissolved in acetonitrile were added dropwise to a solution of 2.6 g (30 mmol) NaHCO3 in water. The solution was stirred at 25° C. for 30 min, then concentrated to dryness and the residue was taken up in methanol. The precipitate was seperated and the filtrate concencentrated to dryness again. The residue was dissolved in water and saturated KHSO4-solution was added. Filtration of the precipitate gave 2 g of the title compound (73% of theory) as a colorless solid (m. p. 150° C.)
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=O.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>C(Cl)Cl>[CH2:21]([N:23]([CH2:24][CH3:25])[C:7]([C:6]1[CH:5]=[CH:4][O:3][C:2]=1[CH3:1])=[O:9])[CH3:22]
Reactant: Cc1occc1C(=O)O
Reactant: CCNCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccoc1C
Temperature: 0 °C
Yield: 83.4 %

Procedure:
To a solution of 2-methyl-3-furoic acid (34.75 g, 0.3469 mol) in dry methylene chloride (200 ml) under an argon atmosphere, were added a catalytic amount of dimethylformamide followed by dropwise addition of oxalyl chloride (45.5 ml, 0.5216 mol). After the addition the reaction mixture was allowed to stir until the effervescence had subsided (4.0 hours). The excess oxalyl chloride/methylene chloride was evaporated and the residue was dissolved in methylene chloride (200 ml). The solution was cooled (ice/acetone) and diethylamine (75.0 ml, 0.725 mol) in methylene chloride (100 ml) was added dropwise. After the addition (1.0 hour) the reaction was poured into ice/water and the solution was acidified to a pH of 3.0. The mixture was extracted with diethyl ether (4×200 ml). The combined extracts were washed with saturated sodium carbonate solution (2×50 ml), water (4×50 ml), brine (2×25 ml), and dried (MgSO4). Solvent evaporation gave 59.75 g of crude product. The oil was distilled to give 52.45 g (83% yield) of product which crystallized upon standing (bp: 91° C./1.2 mmHg; mp 32°-34° C.).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]1[O:15][C:9]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[O:8][CH2:7]1.C(N(CC)CC)C>CCOCC>[CH2:6]1[O:15][C:9]2([CH2:14][CH2:13][N:12]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:11][CH2:10]2)[O:8][CH2:7]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)N1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
Methanesulphonyl chloride (24.8 g, 0.217mol) was added dropwise to a solution of 4-piperidone ethylene ketal (28.2 g, 0.197 mol) and triethylamine (30.2 ml, 0.217 mol) in ether (280 ml), and the reaction stirred at room temperature for 3 hours. The mixture was washed consecutively with water (2×), hydrochloric acid (1N), and saturated sodium bicarbonate solution, dried (MgSO4), filtered and evaporated in vacuo. The residue was triturated with hexane, filtered and dried to give the desired product as an off-white solid (41.6 g, 95%).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=2)[N:14]([CH2:22][C:23]2[CH:28]=[C:27]([Br:29])[C:26]([Br:30])=[C:25]([Br:31])[CH:24]=2)[C:13](=[O:32])[CH:12]=1)C1C=CC=CC=1.C(O)C.Cl>O1CCOCC1.[Pd]>[OH:8][CH2:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=2)[N:14]([CH2:22][C:23]2[CH:28]=[C:27]([Br:29])[C:26]([Br:30])=[C:25]([Br:31])[CH:24]=2)[C:13](=[O:32])[CH:12]=1
Reactant: O=c1cc(CCOCc2ccccc2)c2cc(F)ccc2n1Cc1cc(Br)c(Br)c(Br)c1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: O=c1cc(CCO)c2cc(F)ccc2n1Cc1cc(Br)c(Br)c(Br)c1
Yield: 71 %

Procedure:
A solution of 4-(2-benzyloxyethyl)-6-fluoro-1-(3,4,5-tribromobenzyl)-1,2-dihydro-2-oxoquinoline (6.0g.) in a mixture of dioxan (50ml.), ethanol (50ml.), and concentrated hydrochloric acid (2ml.) was hydrogenated at atmospheric pressure over 5% palladium on carbon (1g.). The theoretical quantity of hydrogen (390ml. at N.T.P.) was absorbed in four minutes. The hydrogenation was stopped and the mixture filtered. Evaporation of the filtrate gave the crude product which was recrystallised twice from methanol to give 4-(2-hydroxyethyl)-6-fluoro-1-(3,4,5-tribromobenzyl)-1,2-dihydro-2-oxoquinoline, m.p. 199°-201° C., in 71% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:6][C@H:5]([CH2:7][O:8][C:9]2[C:10](C)=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14]C)=[O:13])[CH2:4][O:3]1.[OH-].[Li+]>CO.O>[CH3:1][C:2]1([CH3:20])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([OH:14])=[O:13])[CH2:4][O:3]1
Reactant: COC(=O)c1cccc(OC[C@@H]2COC(C)(C)O2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)OC[C@@H](COc2cccc(C(=O)O)c2)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.7 %

Procedure:
Methyl 3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)-2-methylbenzoate (4.2 g, 15 mmol) was dissolved in 20 mL of methanol and 1 mL of water. To the above solution was added lithium hydroxide (2.4 g, Seq.). After stirring the reaction mixture at room temperature for 4 h, the volatile was removed under vacuo and the residue was partitioned between EtOAc and H2O. The aqueous layer was separated, cooled with an ice bath, and then acidified with 10% aq. HCl. The acidic aqueous layer was extracted with EtOAc. The EtOAc layer was washed with NaCl (sat.), dried over Na2SO4, and concentrated to give 3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)benzoic acid as a white solid (4 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH2:11][CH3:12])=[N:9][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1)=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC.C1COCC1>[CH2:11]([C:10]1[C:6]([CH2:4][OH:3])=[N:7][N:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:9]=1)[CH3:12]
Reactant: CCOC(=O)c1nn(-c2ccccc2)nc1CC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1nn(-c2ccccc2)nc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
11.55 g of ethyl-5-ethyl-2-phenyl-1,2,3-triazole-4-carboxylate dissolved in a mixed solvent of 150 ml of ether and 30 ml of THF was added dropwise at 3-8° C. to LiAIH4 suspended in 100 ml of ether. After stirring overnight at room temperature, a small amount of saturated sodium sulfate solution was added thereto. Insoluble materials were filtered off, and the filtrate was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 9.40 g of the aimed compound.
Reaction SMILES: NC1C=CC=C(C)C=1.[CH2:9]([C:11]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:14]([NH:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[C:13]([N+:26]([O-:28])=[O:27])[C:12]=1[CH2:29]OC)[CH3:10]>>[CH2:9]([C:11]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:14]([NH:15][CH:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[C:13]([N+:26]([O-:28])=[O:27])[C:12]=1[CH3:29])[CH3:10]
Reactant: CCc1cc([N+](=O)[O-])c(NC(CC)CC)c([N+](=O)[O-])c1COC
Solvent: Cc1cccc(N)c1
Product: CCc1cc([N+](=O)[O-])c(NC(CC)CC)c([N+](=O)[O-])c1C

Procedure:
The preceding m-toluidine was dinitrated in a manner similar to that used for 4-ethyl-N-(1-ethylpropyl)-α-methoxy-2,6-dinitro-m-toluidine to give the product after purification by chromatography with m.p. 51°-53°.
Reaction SMILES: [CH3:1][Ge:2]([CH3:17])([CH3:16])[C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([Ge:9]([CH3:12])([CH3:11])[CH3:10])[CH:8]=1.[CH:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)=O.[OH-].[K+].Cl>C(O)(C)C.O1CCCC1>[CH3:11][Ge:9]([CH3:10])([CH3:12])[C:7]1[CH:6]=[C:5]([C:13](=[O:15])[CH:14]=[CH:18][C:20]2[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH:4]=[C:3]([Ge:2]([CH3:16])([CH3:1])[CH3:17])[CH:8]=1
Reactant: CC(=O)c1cc([Ge](C)(C)C)cc([Ge](C)(C)C)c1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C[Ge](C)(C)c1cc(C(=O)C=Cc2ccc(C(=O)O)cc2)cc([Ge](C)(C)C)c1
Yield: 53.7 %

Procedure:
3',5'-Bis(trimethylgermyl)acetophenone 163 mg (0.46 mmol) and 96 mg (0.58 mmol) of methyl 4-formylbenzoate was dissolved in 4 ml of a mixture of isopropanol and tetrahydrofuran (1:1). To the mixture was added 2.5 ml of 0.75N aqueous potassium hydroxide solution with stirring and the mixture was stirred at room temperature overnight. The reaction mixture was adjusted to pH3.8 with 0.2N hydrochloric acid and extracted with AcOEt. The extract was evaporated. The residue was purified by column chromatography on silicagel [eluent: methylene chloride-MeOH (10:1)] and recrystallized from a mixture of methylene chloride, MeOH and n-hexane to give 120 mg of yellow prisms, m.p. 194°-195.5° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[O:16][CH3:15])=[O:11]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: COc1ccccc1N
Product: COc1ccccc1NC(=O)c1cc(C(N)=O)ccc1OC

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-methoxyaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[CH:8]=[C:7]([NH:11][CH3:12])[N:6]([C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=3[F:20])[C:5]2=[O:21])[CH2:3][CH2:2]1.[CH3:22][CH:23]([C:27]([OH:29])=O)[C:24]([OH:26])=O.C(OC(=O)C)(=O)C>>[CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:27]([OH:29])=[C:23]([CH3:22])[C:24](=[O:26])[N:11]([CH3:12])[C:7]=3[N:6]([C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=3[F:20])[C:5]2=[O:21])[CH2:2][CH2:3]1
Reactant: CNc1cc(=O)n(C2CC2)c(=O)n1-c1ccc(I)cc1F
Reactant: CC(C(=O)O)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1c(O)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(I)cc3F)c2n(C)c1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 36.2 %

Procedure:
To a 2:1 mixture (34.6 g) of 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6-methylamino-1H-pyrimidine-2,4-dione 52 and 1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)6-methylamino-1H-pyrimidine-2,4-dione 53 obtained in Step 4, and 2-methylmalonic acid 54 (10.2 g) was added acetic anhydride (173 ml), and the mixture was stirred at 100° C. for 2 hrs. After allowing to cool to room temperature, the reaction mixture was concentrated under reduced pressure. Acetone (104 ml) was added to the residue, and the mixture was stirred with heating under reflux for 30 min. After allowing to cool to room temperature, the precipitated crystals were collected by filtration and dried to give 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 55 (15.1 g, yield from 48, 21%) as colorless crystals.
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([NH:15][C@H:16]([C:21](=[O:49])[NH:22][C@@H:23]([C:36](=[O:48])[NH:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[N:44]=[CH:43][CH:42]=[CH:41]2)[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)[CH2:17][C:18](O)=[O:19])=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:50]([O:54][C:55]([NH:57][CH2:58][CH2:59][NH:60][CH2:61][CH2:62][NH:63][C:64](=[O:70])[O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:56])([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl>[C:50]([O:54][C:55]([NH:57][CH2:58][CH2:59][N:60]([CH2:61][CH2:62][NH:63][C:64]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:70])[C:18]([CH2:17][C@H:16]([NH:15][C:13](=[O:14])[O:12][C:8]([CH3:10])([CH3:9])[CH3:11])[C:21](=[O:49])[NH:22][C@@H:23]([C:36](=[O:48])[NH:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[N:44]=[CH:43][CH:42]=[CH:41]2)[CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1)=[O:19])=[O:56])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)OC(=O)NCCNCCNC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2ncccc2c1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(CCNC(=O)OC(C)(C)C)C(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2ncccc2c1
Yield: 72 %

Procedure:
To a solution of CDMT (37 mg, 0.20 mmol) in DCM (10 mL) and cooled to 0° C. was added N-methylmorpholine (0.023 mL, 0.20 mmol). The mixture was stirred for min before adding (3S)-3-{[(tert-butoxy)carbonyl]amino}-3-{[(1R)-1-[(quinolin-6-yl)carbamoyl]-3-[4-(trifluoromethyl)phenyl]propyl]carbamoyl}propanoic acid (110 mg, 0.18 mmol). The solution was stirred for 60 min at 0° C. The tert-butyl N-{2-[(2-{[(tert-butoxy)carbonyl]amino}ethyl)amino]ethyl}carbamate X was then added and the mixture stirred at r.t. overnight. The solution was washed with 1 M aq. K2CO3, 1 M aq. HCl, brine and dried over anhydrous MgSO4. The crude product was then purified on a silica gel column (100:1 CHCl3/MeOH) and finally crystallized from ethyl ether/hexane to give tert-butyl N-[(1S)-2-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-1-{[(1R)-1-[(quinolin-6-yl)carbamoyl]-3-[4-(trifluoromethyl)phenyl]propyl]carbamoyl}ethyl]carbamate XI (110 mg, 0.13 mmol, 72% yield). 1H NMR (CDCl3) 1.43 (s, 18H), 1.50 (s, 9H), 1.69 (brs, 2H), 2.03 (brs, 2H), 2.78 (brs, 2H), 3.23 (brs, 2H), 3.46 (brs, 4H), 4.60 (brs, 4H), 4.96-5.11 (m, 1H), 5.98-6.14 (m, 1H), 6.91-7.01 (m, 1H), 7.28-7.38 (m, 3H), 7.47-7.58 (m, 3H), 7.88-8.03 (m, 2H), 8.12 (d, J=7 Hz, 1H), 8.52 (s, 1H), 8.81 (brs, 1H), 9.31 (brs, 1H); 19F NMR (DMSO-d6) −61.75 (s, 3F); ESIMS found for C43H58F3N7O9 m/z 874 (M+H).