Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:8])=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:20][C:21]2[S:25][CH:24]=[N:23][C:22]=2[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(=O)OCC.[Cl-].[Na+].O>COCCOC.CCO.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:17][C:18]1[C:19]([C:2]2[S:6][C:5]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])=[O:8])=[CH:4][CH:3]=2)=[CH:20][C:21]2[S:25][CH:24]=[N:23][C:22]=2[CH:26]=1
Reactant: O=C(Nc1ccccc1F)c1ccc(Br)s1
Reactant: CC1(C)OB(c2cc3scnc3cc2Cl)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(Nc1ccccc1F)c1ccc(-c2cc3scnc3cc2Cl)s1
Temperature: 110 °C
Yield: 71.6 %

Procedure:
A mixture of (5-bromo(2-thienyl))-N-(2-fluorophenyl)carboxamide (9, 18 mg, 0.06 mmol), 5-chloro-6-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))benzothiazole (20) (17 mg, 0.06 mmol), tetrakis(triphenylphosphine)-palladium(0) (Pd(Ph3P)4, 7 mg) and sodium carbonate (19 mg) in 0.5 ml DME, 0.5 ml EtOH and 0.25 ml water was heated under Ar in microwave reactor at 110° C. for 30 min. The reaction mixture was worked up with EA/brine. Org. phase was concentrated and then subjected to silica gel flash chromatography (0-60% B; A: hexane; B: 50% EA in hexane) to furnish 16.7 mg of [5-(5-chlorobenzothiazol-6-yl)(2-thienyl)]-N-(2-fluorophenyl)carboxamide (23) as white solid (yield: 71.6%; purity>95%). LC-MS: calcd. for C18H10FClN2OS2: 389 (M+1).
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H-].[Na+].[CH2:13]([OH:16])[C:14]#[CH:15].Cl>O1CCCC1>[CH2:13]([O:16][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:14]#[CH:15]
Reactant: C#CCO
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOCC(=O)CC(=O)OCC
Yield: 95.3 %

Procedure:
A solution of ethyl 4-chloroacetoacetate (294 g) in tetrahydrofuran (200 ml) was added over 3 hours to a stirred, ice-cooled suspension of sodium hydride (150 g of a 80% dispersion in mineral oil) in tetrahydrofuran (500 ml) at such a rate than the reaction temperature remained ≤20°. A solution of prop-2-ynol (100 g) in tetrahydrofuran (200 ml) was then added over 2 hours to the above mixture with stirring and ice-cooling at such a rate that the reaction temperature never exceeded +25°. The mixture was then stirred at room temperature for 16 hours, poured into 2M HCl (900 ml) and the layers separated. The organic layer was evaporated and the resulting red oil was separated in a separating funnel from the mineral oil. The red oil was taken up in dichloromethane and the resulting solution was washed several times with water, dried over Na2SO4 and evaporated to give the title compound (313 g) as a dark oil which was used directly in Preparation 3.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:13](CC3C=NC=CC=3)[CH2:12][C@@H:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]([S:28]([C:31]3SC=[CH:34][CH:35]=3)(=[O:30])=[O:29])[CH2:9][C:8]=2[CH:36]=1)#[N:3].[C:37]1(C)[C:38](S(Cl)(=O)=O)=CC=[CH:41][CH:42]=1>>[CH3:41][C:42]1[CH:37]=[CH:38][C:31]([S:28]([N:10]2[CH2:9][C:8]3[CH:36]=[C:4]([C:2]#[N:3])[CH:5]=[CH:6][C:7]=3[NH:13][CH2:12][C@H:11]2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:29])=[O:30])=[CH:35][CH:34]=1
Reactant: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2Cc1cccnc1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: Cl
Product: Cc1ccc(S(=O)(=O)N2Cc3cc(C#N)ccc3NC[C@H]2Cc2ccccc2)cc1

Procedure:
The title compound was prepared from Compound A of Example 23 and toluenesulfonyl chloride following the procedure of Compound B of Example 23.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])O.[Fe:6].[CH:7]1[CH:8]=[CH:9][C:10]2[C:11](=[C:13]3[N:45]=[C:44]4[N:46]=[C:37]([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][C:43]=54)[N:36]=[C:34]4[NH:35][C:27]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=54)=[N:26][C:24]4=[N:25][C:17]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=54)=[N:16][C:15]=2[NH:14]3)[CH:12]=1>>[S:1]([Fe:6]([S:1]([OH:5])(=[O:4])=[O:3])([S:1]([OH:3])(=[O:5])=[O:4])[S:1]([OH:3])(=[O:5])=[O:4])([OH:3])(=[O:5])=[O:4].[CH:8]1[CH:7]=[CH:12][C:11]2[C:10](=[C:15]3[N:16]=[C:17]4[N:25]=[C:24]([C:23]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=54)[N:26]=[C:27]4[NH:35][C:34]([C:33]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=54)=[N:36][C:37]4=[N:46][C:44]([C:43]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=54)=[N:45][C:13]=2[NH:14]3)[CH:9]=1
Reactant: [Fe]
Reactant: O=S(=O)(O)O
Agent: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Product: O=S(=O)(O)[Fe](S(=O)(=O)O)(S(=O)(=O)O)S(=O)(=O)O
Temperature: 50 °C

Procedure:
Under a nitrogen pad, about 55 g of 20 weight percent of fuming sulfuric acid is added slowly to about 10 g of iron-phthalocyanine. After the fuming sulfuric acid is completely added, the reaction mixture is heated to 50° C. for 2 hours. The reaction mixture is then cooled to room temperature and filtered. The filtrate is then washed with 500 mL of pH 8 water. The resulting solid is then removed and dried in a vacuum oven. The dried solid is then ground to a fine powder with a mortar and pestle. The final product is a dark gray powder having a tetra-sulfo iron-phthalocyanine yield of 70 percent. The material contains 12 percent sulfophthalimide, 25 percent phthalimide, 3 percent phthalic acid, and 0.8 percent sulfophthalic acid. A 1 percent solution of the material in 1:1 methyldiethanolamine:water yields excessive foaming characteristics and is non-filterable using standardized tests.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=O)[O:21][C:19](=[O:20])[C:18]2=[CH:24][CH:25]=1>>[Cl:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:24][CH:25]=1)[C:19](=[O:20])[N:1]([CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5])[C:22]2=[O:21]
Reactant: COC(=O)C(CN)C1(C)OCCO1
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Product: COC(=O)C(CN1C(=O)c2ccc(Cl)cc2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(5-chloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.54 g, 73%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.40 g, 2.11 mmol) and 4-chlorophthalic anhydride (0.50 g, 2.74 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][CH:8]([C:15]1([C:20](OCC)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+].[OH-].[Na+]>CCOCC>[OH:7][CH:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:15]1([CH2:20][OH:21])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)C1(C(O)c2ccccc2)CCCC1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: OCC1(C(O)c2ccccc2)CCCC1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
Under a nitrogen stream, lithium aluminum hydride (0.38 g, 0.01 mol) was suspended in dehydrating ether (8 ml) and ethyl 1-(1-hydroxy-1-phenylmethyl)cyclopentanecarboxylate (2.46 g, 0.01 mol) as 8 ml of a dehydrating ether solution was added dropwise over 30 min while stirring the mixture at room temperature. After the completion of dropwise addition, the mixture was stirred for 30 min while gently refluxing, then 10% aqueous sodium hydrogen carbonate (1 ml) was slowly added dropwise under ice-cooling. Then 20% aqueous sodium hydroxide (2 ml) was added dropwise and the ether layer was taken by decantation. The residue was washed twice with ether (10 ml). The ether layer was combined and the mixture was dehydrated over anhydrous magnesium sulfate and concentrated. The residual solution (2.01 g) was purified by silica gel column chromatography (ethyl acetate/hexane=2/3) to give the title compound (1.8 g) as a colorless oil (yield 87%).
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16](=[O:44])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]1[C@H:27]([CH:28]=[CH:29][Sn](CCCC)(CCCC)CCCC)[CH2:26][CH2:25][C:24]1=[O:43].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[CH3:14][O:15][C:16](=[O:44])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]1[C:24](=[O:43])[CH2:25][CH2:26][C@H:27]1[CH:28]=[CH:29][C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:12]
Reactant: CCCC[Sn](C=C[C@@H]1CCC(=O)[C@H]1CCCCCCC(=O)OC)(CCCC)CCCC
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCC[C@@H]1C(=O)CC[C@H]1C=CC(=O)c1cccc2ccccc12
Temperature: 100 °C

Procedure:
A solution of tetrakis(triphenylphosphine)palladium(0) (97 mg, 0.084 mmol) in dry toluene (10 mL) was evacuated under vacuum and was purged with carbon monoxide (3×). Naphthalene-1-carbonyl chloride (320 mg, 1.68 mmol) was added followed by addition of trans-7-[2-oxo-5-(2-tributylstannanyl-vinyl)-cyclopentyl)-heptanoic acid methyl ester (the compound of Preparation 1, Step D, 1.0 g, 1.85 mmol) and 2,6-di-tert-butyl-4-methylphenol (few crystals). The mixture was heated at 100° C. under an atmosphere of carbon monoxide for 24 h. The mixture was cooled to room temperature, diluted with ethyl acetate, and the insolubles were removed by filtration through a pad of Celite®. The filtrate was washed with 10% aqueous ammonium hydroxide, dried (magnesium sulfate), filtered, and concentrated. Purification by flash chromatography (hexanes to 20% ethyl acetate in hexanes) provided the title compound of Step A (162 mg). 1H NMR (CDCl3, 250 MHz) d 8.31 (m, 1H), 8.00 (d, 1H), 7.91 (m, 1H), 7.70 (dd, 1H), 7.55 (m, 3H), 6.91-6.71 (m, 2H), 3.68 (s, 3H), 2.75 (m, 1H), 2.42-2.11 (m, 5H), 2.00 (m, 1H), 1.81-1.20 (m, 9H), 1.94 (t, 2H); MS 407 (M+1), 424 (M+18).
Reaction SMILES: F[C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4](F)[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.[F:19][C:20]([F:31])([F:30])C1C=CC=CC=1B(O)O>>[F:19][C:20]([F:31])([F:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Product: O=C(O)c1csc(-c2ccccc2C(F)(F)F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (2-(trifluoromethyl)phenyl)boronic acid gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][C@H:15]1[O:20][C@:16]1([CH3:19])[CH2:17][OH:18].C[Si](C)(C)Cl.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@:16]([CH3:19])([OH:20])[CH2:17][OH:18]
Reactant: COc1c(C)c(C)c(OC)c(C[C@H]2O[C@]2(C)CO)c1C
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)CO)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.10 g of (2R,3R)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2,3-epoxy-2-methylbutanol are dissolved in 2 ml of pyridine. 0.5 ml of trimethylchlorosilane is then added and the mixture is left to stand at room temperature for 1 hour. Thereupon, sodium bicarbonate solution is added and the mixture is extracted with toluene. The combined organic phases are dried over anhydrous sodium sulphate and concentrated. The thus-obtained (2R,3R)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2,3-epoxy-2-methyl-1-(trimethylsilyloxy)-butane is dissolved in 10 ml of diethyl ether, treated with 40 mg of lithium aluminum hydride and stirred at room temperature for 16 hours. Ammonium hydrogen difluoride solution is then added and the mixture is subsequently extracted with ethyl acetate. The combined organic phases are dried over anhydrous sodium sulphate and concentrated, and the residue is dried further in a higher vacuum. There are thus obtained 804 mg (73%) of (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1,2-butanediol, m.p. 86°-87° C., [α]D20 +2.53° (c=5.3% in CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:35])[C@H:13]([O:14][Si](C)(C)C)[C@@H:12]([O:19][Si](C)(C)C)[C@H:11]([O:24][Si](C)(C)C)[C@@H:10]([CH2:29][O:30][Si](C)(C)C)[O:9]2)=[CH:4][C:3]=1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]([F:48])([F:47])[F:46])=[CH:39][CH:38]=1.[CH3:49]S(O)(=O)=O.C(=O)(O)[O-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:35][CH3:49])[C@H:13]([OH:14])[C@@H:12]([OH:19])[C@H:11]([OH:24])[C@@H:10]([CH2:29][OH:30])[O:9]2)=[CH:4][C:3]=1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]([F:48])([F:47])[F:46])=[CH:39][CH:38]=1
Reactant: CS(=O)(=O)O
Reactant: C[Si](C)(C)OC[C@H]1O[C@@](O)(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2S,3R,4S,5R,6R)-2-[4-chloro-3-[[4-(2,2,2-trifluoroethoxyl)phenyl]methyl]phenyl]-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-ol 17d (45.0 g, 58.0 mmol) in anhydrous methanol (120 mL) was added methylsulfonic acid (11.3 mL, 174 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate till pH becomes 7 and concentrated in vacuo to remove most of the solvent. The residue was partitioned between water (200 mL) and ethyl acetate (200 mL). The aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by re-crystallization from a toluene/n-hexane mixture (v/v)=1/1 to give the title compound 17e as yellow solid powder (12.5 g, 54.3%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 537.1 [M+HCOO]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=2)[N:11]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:10]=1[CH:27]([CH3:29])[CH3:28])=[O:8].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[N:11]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:10]=1[CH:27]([CH3:29])[CH3:28])=[O:8]
Reactant: COc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccn3)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-(3,4-difluorobenzyl)-2-isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 200, 735 mg, 1.64 mmol) in CH2Cl2 (25 ml) at 0° C. was added BBr3 (1.0 M in CH2Cl2, 6.6 ml, 6.56 mmol) dropwise. The reaction was stirred for 1 h at 0° C. and 1 h at room temperature, quenched with ice, extracted with EtOAc, the organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→85% EtOAc-hexanes) to yield the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[N:7]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:8]=[CH:9][CH:10]=1)=[O:5].[C:21](=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[N:7]([N:11]([CH3:21])[C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:8]=[CH:9][CH:10]=1)=[O:5]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Nn1cccc1C(=O)c1ccccc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)N(C)n1cccc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 78 h
Yield: 65.1 %

Procedure:
[2-(2-Chlorobenzoyl)-1H-pyrrol-1-yl]-carbamic acid, ethyl ester (22 g, 75.1 mmol), sodium carbonate (16.0 g, 0.112 mol) and methyl iodide (13 g, 0.122 mol) were added to 100 ml of dry DMF and the mixture stirred at ambient temperature for 78 hours. The reaction was quenched with 1 liter of H2O and extracted with five 200 ml portions of diethyl ether. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and evaporated to give 15 g of solid. This solid was purified by HPLC (silica gel, DCM) to give 13.1 g (57%) of crystals, m.p. 54°-56°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[N+]=[N-])[C:5](=[O:10])[CH2:6][CH2:7][CH:8]=[CH2:9]>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]12[CH2:9][CH:8]1[CH2:7][CH2:6][C:5]2=[O:10])=[O:13]
Reactant: C=CCCC(=O)C(=[N+]=[N-])C(=O)OC
Solvent: c1ccccc1
Product: COC(=O)C12CC1CCC2=O
Reaction time: 3 h

Procedure:
In an argon atmosphere, the unpurified 2-diazo-3-oxo-6-heptenoic acid methyl ester of Preparation 1 (4.55 g, 25 mmol) was dissolved in 100 ml of benzene. Anhydrous cupric sulfate (2.5 g) was added as a catalyst to the solution. The mixture was stirred for about 3 hours under reflux. After confirming the disappearance of the starting materials by thin layer chromatography, the reaction mixture was filtered through a Celite column. The solvvent was distilled off from the filtrate under reduced pressure and the remaining oily product was distilled under a reduced pressure to obtain 2.92 g of 2-oxo-bicyclo[3.1.0]hexane-1-carboxylic acid methyl ester as an oily product.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]([C:11](O)=O)=[CH:9][C:8]=1[N+:19]([O-:21])=[O:20].S(N)([NH2:25])(=O)=O.O>S1(CCCC1)(=O)=O>[CH3:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]([C:11]#[N:25])=[CH:9][C:8]=1[N+:19]([O-:21])=[O:20]
Reactant: NS(N)(=O)=O
Reactant: Cc1c([N+](=O)[O-])cc(C(=O)O)cc1[N+](=O)[O-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O=S1(=O)CCCC1
Product: Cc1c([N+](=O)[O-])cc(C#N)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 91.2 %

Procedure:
Phosphorus oxychloride (27.2 kg) is added over 30 minutes to a mixture of 4-methyl-3,5-dinitrobenzoic acid (3) (20.7 kg) and sulfamide (19.9 kg) in sulfolane (118 kg). The mixture is heated to about 120° C. and aged for about 8 hours. After cooling to ambient temperature, water (104 L) is added and the mixture is cooled to about 5° C. to crystallize the product. After aging at least 1.5 hours, the product is isolated via centrifugation, and washed with water (142 L). The product is then removed from the centrifuge and dried in a convection tray dryer at about 60° C. until drying is complete to provide 4-methyl-3,5-dinitrobenzonitrile (4) (17.3 kg, 91% yield) as a tan solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH2:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].N([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[N+]=[N-].C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+].[Na+].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O.CCOCC>[C:32]([O:31][C:29]([NH:16][C@H:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Dissolve N5 -benzyloxycarbonyl-ornithine, t-butyl ester (3.22 g, 10 mmol) in 50/50 dioxane/water (25 mL) and buffer to pH 10 with 1N sodium hydroxide. Add, by dropwise addition, an ether solution of t-butyl azidoformate (1.58 g, 11 mmol) at 10° C. Allow to warm to room temperature and buffer occasionally to retain pH 10. Acidify with a sodium citrate/citric acid buffer to pH 5, extract with ether (3×), dry (MgSO4) and blow to a residue with a stream of nitrogen to give N-t-butyloxycarbonyl-N5 -benzyloxycarbonyl-ornithine, t-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:5]2[C:21]([F:24])([F:23])[F:22].P(Cl)(Cl)([Cl:27])=O.C(N(C(C)C)CC)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:27])[C:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:5]2[C:21]([F:24])([F:23])[F:22]
Reactant: O=c1[nH]c2ccc(Br)cc2c(C(F)(F)F)c1Oc1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1c(Oc2ccc(Cl)cc2)c(Cl)nc2ccc(Br)cc12
Temperature: 120 °C

Procedure:
To a suspension of 6-bromo-3-(4-chlorophenoxy)-4-(trifluoromethyl)quinolin-2(1H)-one (1.08 g, 2.58 mmol, Intermediate 7, step c) in phosphoryl trichloride (7.2 mL, 77.3 mmol) was added diisopropylethylamine (1.33 mL, 7.74 mmol). The resulting mixture was heated at 120° C. for 8 hours. The solution was concentrated in vacuo at room temperature and the resulting residue was cooled to 0° C. with an ice bath. To the cold residue was added ice in small portions to quench excess phosphoryl trichloride. After cessation of bubbling, the solid suspension was diluted with dichloromethane. The organic phase was separated out, dried (MgSO4), filtered and concentrated to yield the title compound.
Reaction SMILES: C(S[C:4]1[N:5]=[CH:6][C:7]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=[O:16])=[CH:11][N:10]([CH:18]3[CH2:20][CH2:19]3)[C:8]=2[N:9]=1)C.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:4]2[N:5]=[CH:6][C:7]3[C:13](=[O:14])[C:12]([C:15]([OH:17])=[O:16])=[CH:11][N:10]([CH:18]4[CH2:19][CH2:20]4)[C:8]=3[N:9]=2)[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: CCSc1ncc2c(=O)c(C(=O)O)cn(C3CC3)c2n1
Product: CN1CCN(c2ncc3c(=O)c(C(=O)O)cn(C4CC4)c3n2)CC1

Procedure:
A solution of 2.91 g of 2-ethylmercapto-8-cyclopropyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid and 2.2 l g of N-methylpiperazine in 30 ml of N-dimethylformamide is heated at 110° for 2.5 hours. The solvent is distilled off in vacuo and the residue is recrystallised from ethanol. 2.4 g (73% of the theoretical yield) of 2-(4-methyl-piperazino-8-cyclopropyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid with a melting point of 209°-210° C. are obtained.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[N:9]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1.CI>C1COCC1>[CH3:1][C:11]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][N:9]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:10]1
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Temperature: -50 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a cold (−78° C.) solution of lithium diisopropylamide (LDA) (23.3 mmol) in THF (10 mL) under an argon atmosphere was added dropwise a solution of 1-tert-butyl 3-ethyl 1,3-piperidinedicarboxylate (3.0 g, 11.6 mmol) in THF (5 mL), then stirred at −50° C. for 2 hrs. To the resulting mixture was added a solution of MeI (1.98 g, 14 mmol) in THF at −50° C. The reaction mixture was allowed to warm to room temperature, and quenched with saturated aqueous NH4Cl solution. The mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (hexane:ethyl acetate, 9:1) to give 1-tert-butyl 3-ethyl 3-methyl-1,3-piperidinedicarboxylate as a pale yellow oil (2.27 g, yield; 72%).