Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]=[CH:5][C:6]1[CH:23]=[CH:22][C:9]2[N:10]([CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]([CH2:13][NH2:14])=[N:12][C:8]=2[CH:7]=1.C(N(CC)C(C)C)(C)C.ClCCl.[CH3:37][C:38]([CH3:43])([CH3:42])[C:39](Cl)=[O:40]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:24])[CH:4]=[CH:5][C:6]1[CH:23]=[CH:22][C:9]2[N:10]([CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]([CH2:13][NH:14][C:39](=[O:40])[C:38]([CH3:43])([CH3:42])[CH3:37])=[N:12][C:8]=2[CH:7]=1
Reactant: CCN(CC)CCn1c(CN)nc2cc(C=CC(=O)OC)ccc21
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)CCn1c(CNC(=O)C(C)(C)C)nc2cc(C=CC(=O)OC)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a pre-stirred solution of 3-[2-aminomethyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-acrylic acid methyl ester (61-6, 0.10 g, 0.23 mmol), N,N-diisopropylethylamine (97 μL, 0.58 mmol) and dichloromethane (1.17 mL) was added 2,2-dimethyl-propionyl chloride (34.6 μL, 0.28 mmol) and the resulting reaction mixture was stirred at room temperature for 1 h. When the reaction has completed, ethyl acetate (20 mL) was added to dilute the mixture. The organic contents were washed with saturated sodium hydrogencarbonate (2×20 mL) and brine (2×20 mL), before drying in Na2SO4. The mixture was filtered and concentrated in vacuo. The product 3-{1-(2-diethylamino-ethyl)-2-[(2,2-dimethyl-propionylamino)-methyl]-1H-benzoimidazol-5-yl}-acrylic acid methyl ester (61-7) was obtained in 76.6% (74.1 mg). LCMS m/z: 415 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][NH2:20])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>CO>[C:21]([NH:20][CH2:19][C:13]1[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Cn1c(CN)nc2c(N)nc3ccccc3c21
Solvent: CO
Product: CC(=O)NCc1nc2c(N)nc3ccccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Amino-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methanamine (1.1 g; 0.004 mol, Example 14) was added to acetic anhydride (3 mL). The mixture was stirred at room temperature for 5 hrs. The solution was then diluted with methanol (50 mL) and refluxed for 1 hr. The solution was concentrated and the residue made basic with aqueous sodium bicarbonate solution. The oily residue was extracted into dichloromethane. The extracts were dried over magnesium sulfate and evaporated to dryness. The residue was recrystallized from ethyl acetate to yield pure product m.p. 214-218° C. Analysis: Calculated: C, 65.6; H, 6.8; N, 22.5. Found: C, 65.1; H, 6.6; N, 22.0.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:6]=1[O:7][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].[Br:24]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:22]=[C:21]([CH2:23][Br:24])[CH:20]=[CH:19][C:6]=1[O:7][CH:8]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:9]([O:11][CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(Oc1ccc(C)cc1C(C)(C)C)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Oc1ccc(CBr)cc1C(C)(C)C)c1ccccc1
Yield: 21.7 %

Procedure:
To a solution of 0.494 g (1.58 mmol) of the product of Step A dissolved in 10 mL of CCl4 was added 0.310 g (1.74 mmol) of N-bromosuccinimide and 15 mg (catalytic amount) of AIBN and the mixture was heated at reflux for 3.5 hours. The reaction was cooled, filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 3% ethyl acetate/hexane to afford 0.134 g (22%) of the title compound.
Reaction SMILES: [C:1]1([N:7]2[C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:9][C:8]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([OH:24])(=[O:23])/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21]>C(OCC)C>[C:17]([OH:24])(=[O:23])/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21].[CH:17]12[CH2:4][CH:3]([N:13]3[CH2:12][CH2:11][C:10]4([N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:8](=[O:16])[CH2:9]4)[CH2:15][CH2:14]3)[CH:2]1[CH2:1][CH2:6][CH2:5][CH2:20][CH2:19][CH2:18]2
Reactant: O=C1CC2(CCNCC2)N1c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Product: O=C1CC2(CCN(C3CC4CCCCCCC43)CC2)N1c1ccccc1

Procedure:
Reaction of (1RS,8RS)-bicyclo[6.2.0]dec-9-one and 1-phenyl-1,7-diaza-spiro[3.5]nonan-2 -one in accordance with the general method of example 1 and treatment of the base with fumaric acid in diethyl ether yielded the title compound, white solid, m.p. 203° C. and MS: m/e=353.4 (M+H+).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=O)[NH:14][C:12]2=[O:13])[CH2:8][C@:7]1([F:21])O)(=[O:3])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:23]>N1C=CC=CC=1>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[S:23])[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[F:21])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@]1(O)F
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=S)[nH]c2=O)C[C@@H]1F

Procedure:
5'-O-Acetyl-3'-fluorothymidine (400 mg, 1.4 mmoles) are heated under reflux for 24 hours with 933 mg of phosphorus pentasulfide in 32 mL of pyridine. After the solvent is driven off, the residue is fractionated by column chromatography on Kieselgel 40 and yields the desired compound as a yellow oil.
Reaction SMILES: [S:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[C:2]#N.[BH4-].[Na+].CS(OC[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)=O>CN(C)C=O>[CH2:2]([S:1][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Reactant: CS(=O)(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(SCc2ccccc2)cc1[N+](=O)[O-]

Procedure:
To a solution of 19.5 g (0.1 mol) 4-thiocyano-2-nitroaniline in 130 ml dimethylformamide is added 3.78 g (0.1 mol) sodium borohydride, all at once. The mixture is stirred for one-half hour, then 15.2 g (0.1 mol) benzyl methanesulfonate in 70 ml dimethylformamide is added. The solution is stirred at 30° for 3 hours, cooled and partitioned between water and dichloromethane. The layers are separated and the aqueous phase reextracted with dichloromethane. The organic phases are combined, washed with aqueous K2CO3, water and saturated NaCl, dried, filtered and stripped to yield 4-(benzyl)sulfenyl-2-nitroaniline.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:10][S:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(O)(C)C>[N:5]1[C:4]2[CH2:8][S:9][CH2:10][C:3]=2[C:2]([N:21]2[CH2:20][CH2:19][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:23][CH2:22]2)=[N:7][CH:6]=1
Reactant: Clc1ncnc2c1CSC2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2CSC3)CC1
Yield: 88.2 %

Procedure:
The mixture of 4-chloro-5,7-dihydrothieno[3,4-d]pyrimidine (2.0 g, 11.6 mmol) and 1-Boc-piperazine (5.0 g, 26.8 mmol) in isopropanol (50 mL) was refluxed for 12 hours. The solvent was removed and the residue was subject to silica gel chromatography, eluting with hexane/ethyl acetate (1:1) to give tert-butyl 4-(5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (3.3 g, 89%). 1H NMR (CDCl3, 400 MHz) δ 8.49 (s, 1H), 4.68 (m, 1H), 4.25 (s, 2H), 4.16 (s, 2H), 1.49 (s, 9H). MS (APCI+) [M+H]+ 323.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]2[N:19]=[C:20]([S:22](Cl)(=[O:24])=[O:23])[N:21]=[C:14]2[N:13]=1>CCCCCC.C1COCC1>[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]2[N:19]=[C:20]([S:22]([NH:4][C:3]3[C:2]([Cl:1])=[CH:8][C:7]([Cl:9])=[CH:6][C:5]=3[Cl:10])(=[O:23])=[O:24])[N:21]=[C:14]2[N:13]=1
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Cl)nc2n1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C)n2nc(S(=O)(=O)Nc3c(Cl)cc(Cl)cc3Cl)nc2n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
A solution (10.7 ml, 17.1 mmol) of 1.60M N-butyl-lithium in hexane was added to a solution of 3.20 g (16.3 mmol) of 2,4,6-trichloroaniline in 20 ml of dry THF cooled to -78° C. The resultant solution was then allowed to warm to room temperature. This solution was added to a solution of 2.00 g (8.11 mmol) of 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonyl chloride in 30 ml of dry THF cooled to --10° C. The temperature of the reaction mixture was maintained between -13° C. and -9° C. during to course of the addition. After the addition was complete, the reaction mixture was stirred for 30 minutes and warmed to room temperature. After 1 hour at room temperature, THF was removed from the reaction mixture by evaporation. The residue was triturated with H2O and filtered. The filtrate was treated with charcoal and filtered through celite. The filtrate was washed with Et2O, and the aqueous phase was separated and acidified with 3N HCl to precipitate a solid. The solid was collected by filtration, washed with water and dried in vacuo to yield 0.70 g (21%) of the desired product as a tan solid, m.p. >200° C. (decomp.) 1H NMR and IR spectra were consistent with the assigned structure.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][C:5]=1[C:16]([OH:18])=[O:17].C(N(C(C)C)CC)(C)C.[C:28](OC(=O)C)(=[O:30])[CH3:29].[OH-].[Na+].Cl>O1CCCC1>[C:28]([NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][C:5]=1[C:16]([OH:18])=[O:17])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(CCN)c(C(=O)O)[nH]c2cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(CCNC(C)=O)c(C(=O)O)[nH]c2cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(2-aminoethyl)-6-fluoro-5-methoxy-1H-indole-2-carboxylic acid (1.90 g) and tetrahydrofuran (38.0 mL) were added diisopropylethylamine (6.45 mL) and acetic anhydride (1.42 mL), followed by stirring at room temperature overnight. To the reaction mixture was added a 1 M aqueous sodium hydroxide solution (50.0 mL), followed by stirring for 1 hour and acidifying by the addition of 1 M hydrochloric acid (90.0 mL). This mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The insoluble materials were separated by filtration and the filtrate was concentrated under reduced pressure to obtain 3-(2-acetamidoethyl)-6-fluoro-5-methoxy-1H-indole-2-carboxylic acid (2.21 g) as a pale yellow solid.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7].C(N(CC)CC)C.[CH3:20][C:21]1([CH3:31])[CH:23]([CH:24]=[C:25]([Cl:27])[Cl:26])[CH:22]1[C:28](Cl)=[O:29].O>C1(C)C=CC=CC=1>[CH3:20][C:21]1([CH3:31])[CH:23]([CH:24]=[C:25]([Cl:26])[Cl:27])[CH:22]1[C:28]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[O:3][CH:2]([F:12])[F:1])=[O:29]
Reactant: OCc1ccccc1OC(F)F
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OCc1ccccc1OC(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
6.09 g (0.035 mol) of 2-difluoromethoxybenzyl alcohol and 3.5 g (0.035 mol) of triethylamine were dissolved in 50 ml of toluene and the solution was added dropwise to a mixture of 7.95 g (0.35 mol) of 2,2-dimethyl-3-(2',2'-dichloro-vinyl)-cyclopropanecarboxylic acid chloride in 100 ml of toluene at 20°-25° C. The reaction mixture was subsequently stirred at room temperature for 3 hours and poured into 150 ml of water, the toluene phase was filtered off, washed with 100 ml of water and dried with sodium sulphate and the toluene was distilled off in vacuo. Last residues of solvent were removed by incipient distillation at a bath temperature of 60° C./0.2 to 1.0 mm Hg. 10.9 g (81% of theory) of 2-difluoromethoxybenzyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropanecarboxylate were obtained as a viscous oil with the refractive index nD20 =1.5190.
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=O)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH2:25]([O:32][C:33](=[O:41])[CH2:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([O:32][C:33](=[O:41])[CH2:34][N:35]1[CH2:36][CH2:37][N:38]([C:12](=[O:14])[C:11]([CH3:16])([CH3:15])[CH:10]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:9][C:7](=[O:8])[C:6]2[CH:23]=[CH:24][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:39][CH2:40]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(CN1CCNCC1)OCc1ccccc1
Reactant: CC(C)(C(=O)O)C(NC(=O)c1ccc(C#N)cc1)c1ccccc1
Product: CC(C)(C(=O)N1CCN(CC(=O)OCc2ccccc2)CC1)C(NC(=O)c1ccc(C#N)cc1)c1ccccc1
Yield: 71.9 %

Procedure:
The same procedure as in Example 2-(6-2) was performed with N-4-cyanobenzoyl-β-phenyl-α,α-dimethyl-β-alanine (0.4 g, 1.24 mmol) and piperazineacetic acid benzyl ester (0.87 g, 3.72 mmol) to yield an oil of N-4-cyanobenzoyl-β-phenyl-α,α-dimethyl-β-alanyl-4-piperazineacetic acid benzyl ester (0.48 g, 70.0%).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[F:9][C:10]1[CH:11]=[C:12]([C:19](=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17]>C1(C)C=CC=CC=1>[F:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:19]([C:20](=[CH:3][N:4]([CH3:5])[CH3:6])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:26]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 50 °C
Yield: 99.7 %

Procedure:
N,N-Dimethylformamide dimethyl acetal (100 g, 810 mmol) was added dropwise (10 min) to a cooled (0° C.) solution of ethyl 3-(3-fluoro-4-nitrophenyl)-3-oxopropanoate (138 g, 540 mmol) in toluene (540 mL). The reaction was warmed (50° C.) for 2.5 h and then the volatiles were evaporated under reduced pressure to afford the desired product (167 g, 100%), which was sufficiently pure (>95% by NMR) to proceed without further purification. 1H NMR (300 MHz, DMSO-d6) δ 8.24-8.29 (m, 1H), 7.92 (s, 1H), 7.60-7.74 (m, 1H), 7.58-7.62 (m, 1H), 3.97 (q, J=7.0 Hz, 2H), 3.44 (s, 3H), 2.81 (s, 3H), 0.99 (t, J=7.0 Hz, 3H); ES-MS m/z 310.9 (MH)+; HPLC RT (Method B) 2.87 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C@@H:11]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[N:20]=[CH:19]4)[C@@H:12]([NH2:14])[CH3:13])[CH:9]=[CH:10][C:2]1=2.CCN(C(C)C)C(C)C.[CH:41]1([S:44](Cl)(=[O:46])=[O:45])[CH2:43][CH2:42]1>CN1C(=O)CCC1.O>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C@@H:11]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[N:20]=[CH:19]4)[C@@H:12]([NH:14][S:44]([CH:41]3[CH2:43][CH2:42]3)(=[O:46])=[O:45])[CH3:13])[CH:9]=[CH:10][C:2]1=2
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2c(c1)OCCO2
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NS(=O)(=O)C1CC1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine (43a, 102 mg, 0.24 mmol) and DIPEA (170 μL, 0.97 mmol) was dissolved in NMP (2 mL). cyclopropanesulfonyl chloride (40 μL, 0.39 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×10 mL), the organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give an oily residue (NMP residues). The crude material was further purified by HPLC. Yield 80 mg (62%)
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([N:16]([CH3:18])[CH3:17])[CH:11]=1.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[SH:37])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O.C(OCC)(=O)C>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[S:37][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]([CH3:18])[CH3:17])[CH:11]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccccc2S)cc1
Reactant: CN(C)c1cc(CCl)ccn1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)c1cc(CSc2ccccc2C(=O)Nc2ccc(C(C)(C)C)cc2)ccn1
Reaction time: 68 h
Yield: 34.8 %

Procedure:
Triethylamine (6 μL, 0.44 mmol) was added to a solution of 4-chloromethyl-2-dimethylaminopyridine (36 mg, 0.21 mmol) and N-(4-tert-butylphenyl)-2-mercaptobenzamide (36 mg, 0.13 mmol) in N,N-dimethylformamide (1.0 mL) at room temperature, and the mixture was stirred for 68 hours. The mixture was diluted with ethyl acetate (30 mL), the whole was washed with saturated aqueous sodium hydrogen carbonate solution (30 mL) and brine (30 mL) successively, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 19 mg of the target compound as a pale yellow oil. (Yield 22%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=[CH:18][C:13]=3[S:12][N:11]=2)=[CH:5][CH:4]=1.C(O)(=O)C>[Fe].C(OCC)(=O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[S:12][N:11]=[C:10]([C:6]3[CH:7]=[C:8]([CH3:9])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:14]=2[CH:15]=1
Reactant: COc1ccc(-c2nsc3ccc([N+](=O)[O-])cc23)cc1C
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nsc3ccc(N)cc23)cc1C
Temperature: 65 °C
Yield: 98.1 %

Procedure:
A mixture of 3-(6-methoxy-m-tolyl)-5-nitro-1,2-benzisothiazole (63.0 g, 0.210 mol), 5% acetic acid (1.52 L, 1.21 mol) and ethyl acetate (975 mL) is heated to 65° C., treated portionwise with iron powder (58.6 g, 1.05 mol), stirred at 65° C., and filtered through quartz filter paper. The filtrate phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phase and extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title product as an orange oil (55.7 g, 98.1%) which is identified by NMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([O:16]C(C)CCCCC)=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl>O>[CH:5]1[CH:6]=[N:7][C:8]2[C:3](=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=2[O:12][CH2:13][C:14]([OH:16])=[O:15])[CH:4]=1
Reactant: CCCCCC(C)OC(=O)COc1ccc(Cl)c2cccnc12
Agent: Cl
Solvent: O
Product: O=C(O)COc1ccc(Cl)c2cccnc12
Temperature: 100 °C
Yield: 71.1 %

Procedure:
A suspension of 70.70 g of cloquintocet-mexyl (96.9% strength) in 205 g of demineralised water was stirred at 100° C. in a 1 L jacketed glass vessel. 27.5 g of aqueous hydrochloric acid [32%] was slowly added, and the reaction mixture was stirred under reflux for 6 hours. The biphasic solution was then cooled down to 20° C. over 4 hours and the resulting suspension was filtered and the solid was wash with 2×50 mL of demineralised water and dried. Cloquintocet acid hydrochloride (35.55 g) was isolated as a light brown solid.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C@H:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:10])=[O:7])=[CH:4][N:3]=1.[CH:17]1([NH:20][C:21]([C:23]2[CH:24]=[C:25]([F:33])[C:26]([CH3:32])=[C:27](B(O)O)[CH:28]=2)=[O:22])[CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>CC(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>[CH:17]1([NH:20][C:21]([C:23]2[CH:24]=[C:25]([F:33])[C:26]([CH3:32])=[C:27]([C:2]3[N:3]=[CH:4][C:5]([C:6]([NH:8][C@@H:9]([CH3:10])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])=[CH:15][CH:16]=3)[CH:28]=2)=[O:22])[CH2:19][CH2:18]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B(O)O
Reactant: C[C@H](NC(=O)c1ccc(Cl)nc1)C(C)(C)C
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: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@@H](C)C(C)(C)C)cn1
Temperature: 90 °C

Procedure:
6-Chloro-N-[(S)-3,3-dimethyl-2-butyl]nicotinamide (Intermediate 16, 100 mg), {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (Intermediate 6, 100 mg), tetrakis(triphenylphosphine)palladium (10 mg) and aqueous sodiumhydrogen carbonate (4 ml) were mixed in propan-2-ol (8 ml) and heated at 90° C. under nitrogen for 18 hrs. The solvents were evaporated from the cooled reaction under vacuum and the residue dissolved as far as possible in ethylacetate. The solution was applied to an SPE (SCX, 10 g) and washed with ethyl acetate. The product was eluted from the column with methanol/0.880 ammonia, and the solvents evaporated in vacuo. The residue was redissolved in ethyl acetate and filtered through an SPE (silica, 0.5 g). The filtrate was reduced to dryness under vacuum and triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1,2,2-trimethylpropyl]-3-pyridinecarboxamide.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][S:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])(=[O:44])=[O:43])[C@@:22]([OH:33])([CH2:30][CH2:31][CH3:32])[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][S:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])(=[O:44])=[O:43])[C@@:22]([OH:33])([CH2:30][CH2:31][CH3:32])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCNS(=O)(=O)CCCCCCCC)[C@@](O)(CCC)C(=O)OC(C)(C)C)C(=O)OC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCNS(=O)(=O)CCCCCCCC)[C@@](O)(CCC)C(=O)O)C(=O)OC)cc1
Reaction time: 1.25 h
Yield: 89.9 %

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-10-(octane-1-sulfonylamino)-2-propyl-dec-4-enoate (35.0 mg, 0.0467 mmol) was dissolved in dichloromethane (1.0 mL), and trifluoroacetic acid (1.0 mL, 13.6 mmol) was then added at room temperature. The mixture was stirred for 75 minutes, and then concentrated under reduced pressure. The resulting crude product was purified by preparative HPLC to obtain 29.1 mg (0.0420 mmol, 90% yield) of the title compound.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O.[OH-].[Li+:23]>O>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Li+:23]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
A suspension prepared from 55.0 g of granulated stearic acid (An 198, titer 66° C., particle size 100-300μ) and 8.1 g lithium hydroxide monohydrate in 550 ml of water is heated to 80° C. within 10-15 minutes. The remaining free fatty acid at this point is only 12.1%. Stirring is continued at 80° C. for the duration of one more hour and the resultant hollow granulate, which now contains only 0.4% free fatty acid, is filtered and dried.