Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:17])[C:13](Br)([F:15])[F:14])[CH3:10].C(OCC)(=O)C>CN(C=O)C>[CH2:9]([O:11][C:12](=[O:17])[C:13]([F:15])([F:14])[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:10]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Fc1ccc(I)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
1-Fluoro-4-iodobenzene (30 g, 135 mmol) and 2-bromo2,2-difluoroacetic acid ethyl ester (29 g, 142.9 mmol) were dissolved in DMF (100 ml) and Cu (21.5 g, 71.2 mmol) was added. The reaction mixture was heated at 90° C. for 18 h. Ethyl acetate (100 ml) was added and the reaction mixture was quenched with a solution of potassium dihydrogen phosphate (20 g) in water (200 ml). The resultant solution was stirred for 30 min, filtered and was washed with ethyl acetate. The organic layer was separated, washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated to give 2,2-difluoro-2-(4-fluorophenyl)acetic acid ethyl ester (26.5 g) as a yellow liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C1(C)C=CC=CC=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[N:21][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[Br:8][C:4]1[N:3]=[C:2]([C:19]2[CH:20]=[N:21][CH:22]=[C:17]([F:16])[CH:18]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: Brc1cccc(Br)n1
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: CCO
Solvent: Cc1ccccc1
Product: Fc1cncc(-c2cccc(Br)n2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Added to a solution of 2.00 g (8.44 mmol) of 2,6-dibromo-pyridine in 80 ml of a 4/1 mixture of toluene and ethanol, are 1.18 g (8.44 mmol) of 5-fluoropyridine-3-boronic acid, 0.48 g (0.42 mmol) of Pd(PPh3)4 and 25 ml of a 1M aqueous solution of sodium carbonate. The mixture is stirred at 90° C. for 2 hours.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:14][NH2:15]>C1COCC1.[Cl-].[Na+].C(OCC)(=O)C>[CH3:14][NH:15][S:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:12])=[O:11]
Reactant: CN
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1cccc([N+](=O)[O-])c1

Procedure:
To a solution of 4.42 g (20.0 mmol) of 3-nitrobenzenesulfonyl chloride in 150 mL of dry THF was added 25.0 mL (50.0 mmol) of methylamine as a 2 M solution in THF under ice cooling and stirring. The resulting cloudy solution was stirred overnight at ambient temperature. After this time period, the reaction mixture was diluted with 150 mL of saturated sodium chloride solution and 50 mL of ethyl acetate, then transferred to a 500 mL separatory funnel, mixed thoroughly, and the organic phase was separated. The aqueous phase was extracted twice with 50 mL of ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by recrytallization from EtOH. The yield of the title compound was 97% (4.20 g, 19.48 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C@H:13]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([NH:12][C@H:13]2[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][CH2:14]2)[CH:6]=[CH:5]3)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.4 %

Procedure:
(6-Amino-quinolin-2-yl)-(R)-indan-1-yl-amine (0.05 g, 0.18 mmol) and 4-fluoro-benzenesulfonyl chloride (0.035 g, 0.18 mmol) were dissolved in pyridine (1 mL). The reaction mixture was stirred for 16 h at ambient temperature. Saturated sodium bicarbonate solution was added then and the aqueous phase extracted with ethyl acetate (3×10 mL). The combined organic phases were dried over sodium sulfate, filtered and the filtrate was evaporated. The residual oil was subjected to column chromatography (silica gel, heptane, ethyl acetate; 9:1=>1:1) to yield the title compound as a brown solid (5 mg, 6%); MS 434.7 [(M+H)+].
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH:13]([C:15]2[NH:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]5[N:35]=[C:36]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:54])[CH:45]([NH:49][C:50]([O:52][CH3:53])=[O:51])[CH:46]([CH3:48])[CH3:47])[NH:37][CH:38]=5)=[CH:30][CH:29]=4)=[CH:22][CH:21]=3)[N:19]=2)[N:12]([C:55](=[O:65])[CH:56]([NH:60][C:61]([O:63][CH3:64])=[O:62])[CH:57]([CH3:59])[CH3:58])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:66][Si:67]([CH3:74])([CH3:73])[CH2:68][CH2:69][O:70][CH2:71]Cl>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:14][CH:13]([C:15]2[N:16]([CH2:71][O:70][CH2:69][CH2:68][Si:67]([CH3:74])([CH3:73])[CH3:66])[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]5[N:35]=[C:36]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:54])[CH:45]([NH:49][C:50]([O:52][CH3:53])=[O:51])[CH:46]([CH3:48])[CH3:47])[N:37]([CH2:71][O:70][CH2:69][CH2:68][Si:67]([CH3:74])([CH3:73])[CH3:66])[CH:38]=5)=[CH:30][CH:29]=4)=[CH:22][CH:21]=3)[N:19]=2)[N:12]([C:55](=[O:65])[CH:56]([NH:60][C:61]([O:63][CH3:64])=[O:62])[CH:57]([CH3:58])[CH3:59])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(C#Cc3ccc(-c4c[nH]c(C5CN(C(=O)OC(C)(C)C)CN5C(=O)C(NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(C#Cc3ccc(-c4cn(COCC[Si](C)(C)C)c(C5CN(C(=O)OC(C)(C)C)CN5C(=O)C(NC(=O)OC)C(C)C)n4)cc3)cc2)cn1COCC[Si](C)(C)C)C(C)C
Temperature: 25 °C
Yield: 156.5 %

Procedure:
Sodium hydride (60% in mineral oil, 27 mg, 0.55 mmol) was added to a solution of 3′-(2-methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-phenylethynyl)-phenyl]-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid tert-butyl ester (248 mg, 0.23 mmol) in dimethylformamide (8 mL) under an atmosphere of nitrogen at 0° C. After 15 minutes 2-(trimethylsilyl)ethoxymethyl chloride (107.5 μL, 0.48 mmol) was added and the reaction was allowed to warm to ambient temperature. After 2 hours the solvent was removed under reduced pressure. The residue was taken up in dichloromethane (50 mL) washed with water (20 mL), and dried over sodium sulfate and filtered. The solvent was removed under reduced pressure. The residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to yield 3′-(2-methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl}-phenylethynyl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid tert-butyl ester (410 mg, 0.36 mmol). C58H85N9O10Si2 calculated 1123.6 observed [M+1]+1124.7; rt=3.10 min.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1([C:23]([O:25]C)=O)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[Cl:27][CH2:28]I>>[Cl:27][CH2:28][C:23]([C:10]1([F:9])[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]1)=[O:25]
Reactant: COC(=O)C1(F)CCN(C(=O)OC(C)(C)C)CC1
Reactant: ClCI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1CCC(F)(C(=O)CCl)CC1
Yield: 78.1 %

Procedure:
Prepared according to the method of Example 60, Step A, using lithium diisopropylamide (12.8 mL, 19.1 mmol), 1-tert-butyl 4-methyl 4-fluoropiperidine-1,4-dicarboxylate (1.0 g, 3.83 mmol) and chloroiodomethane (2.70 g, 15.3 mmol). Obtained 0.837 g (78.2% yield) of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=[CH:19][C:14]=2[O:13][C:12]1=[O:23].CO.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[C:17]([NH2:20])[CH:18]=[CH:19][C:14]=2[O:13][C:12]1=[O:23]
Reactant: COC(=O)CCCCCCCn1c(=O)oc2ccc([N+](=O)[O-])cc21
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CCCCCCCn1c(=O)oc2ccc(N)cc21

Procedure:
6.7 g. of 8-(5-Nitro-2-oxo-benzoxazolin-3-yl)-caprylic acid methyl ester are dissolved in 100 cc. of methanol and the solution is heated to boiling. 20 cc. of water are added to the solution and within 1 hour 13.9 g. of sodium dithionite are added and the mixture is boiled so long until the starting yellow solution is decolourized. Thereafter, the solution is evaporated in a vacuum, the residue is stirred with dilute soda lye and the solid crude product as filtered off with suction. The crude product is washed with water, dried and further purified chromatographically on silicic acid using hexane/ethyl acetate as eluant.
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH2:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[C:10]([CH3:16])[CH:9]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1>O>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:15][C:11]1[C:10]([CH3:16])=[CH:9][C:8]([NH2:7])=[C:13]([CH3:14])[CH:12]=1
Reactant: Cc1cc(O)c(C)cc1N
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60 wt %, 0.36 g) was added to dimethyl sulfoxide (10 ml), and the mixture was stirred at 50° C. for 30 min and was then cooled to room temperature. 4-Amino-2,5-dimethylphenol (1.23 g) was added to the cooled mixture, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added thereto, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel by development with chloroform/acetone (1/1) to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:19]([O:21][C:22]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29](B1OC(C)(C)C(C)(C)O1)=[CH:28][CH:27]=2)=[O:23])[CH3:20]>>[CH2:19]([O:21][C:22]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([C:2]1[CH:7]=[N:6][C:5]([NH2:8])=[C:4]([O:9][CH2:10][C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[CH:3]=1)=[CH:28][CH:27]=2)=[O:23])[CH3:20]
Reactant: CCOC(=O)c1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
Reactant: Nc1ncc(Br)cc1OCc1c(Cl)cccc1Cl
Product: CCOC(=O)c1cc2cc(-c3cnc(N)c(OCc4c(Cl)cccc4Cl)c3)ccc2[nH]1

Procedure:
5-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indole-2-carboxylic acid ethyl ester was prepared from 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine and 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole-2-carboxylic acid ethyl ester following procedure 3.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A159) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3=[CH:19][CH:20]=[CH:21][C:22]([C:23]([O-:25])=[O:24])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].O.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3=[CH:19][CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])c1cccc2c1nc(Nc1cccc(Cl)c1)c1ccncc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc2c1nc(Nc1cccc(Cl)c1)c1ccncc12

Procedure:
5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-7-carboxylate (29 mg) was stirred in ethanol (2 ml) and 6N aqueous NaOH (1 ml) at 60° C. for 30 minutes. Water and HCl were added to reach pH=1. The resulting precipitate was filtered, washed with water and dried to afford 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-7-carboxylic acid as a solid. LCMS (ES): >95% pure, m/z 350 [M+1]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[C:19]2[C:14](=[C:15]([OH:20])[CH:16]=[CH:17][CH:18]=2)[C:13](=[O:21])[C:12]2[C:11]([OH:22])=[CH:10][CH:9]=[CH:8][C:7]1=2>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:19]2[C:14](=[C:15]([O:20][C:15](=[O:20])[CH3:14])[CH:16]=[CH:17][CH:18]=2)[C:13]([O:21][C:13](=[O:21])[CH3:12])=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[C:11]2[O:22][C:11](=[O:22])[CH3:10]
Reactant: O=C1c2c(O)cccc2C(c2cccs2)c2cccc(O)c21
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc2c(-c3cccs3)c3cccc(OC(C)=O)c3c(OC(C)=O)c12
Temperature: 80 °C
Reaction time: 3 h
Yield: 170.3 %

Procedure:
In a three-necked flask equipped with a magnetic agitator, there are stirred 250 mg of 10-(2-thienyl)-1,8-dihydroxy anthrone, obtained according to example 8, in 5 cm3 of acetic anhydride and several drops of pyridine. The mixture is stirred for 3 hours at 80° C. under an inert atmosphere, then cooled. The expected triester crystallizes and is then filtered and washed with hexane, yielding 300 mg of light yellow crystals having a melting point of 260° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[C:4]([C@@H:6]1[C@@H:11]2[CH2:12][CH2:13][N:8]([CH:9]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]32OCC[O:14]3)[CH2:7]1)=[O:5])[CH3:2]>Cl>[CH2:31]([N:3]([CH2:1][CH3:2])[C:4]([C@@H:6]1[C@@H:11]2[CH2:12][CH2:13][N:8]([CH:9]([CH:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:10]2=[O:14])[CH2:7]1)=[O:5])[CH3:32]
Reactant: CCN(CC)C(=O)[C@H]1CN2CC[C@@H]1C1(OCCO1)C2C(c1ccccc1)c1ccccc1
Agent: Cl
Product: CCN(CC)C(=O)[C@H]1CN2CC[C@@H]1C(=O)C2C(c1ccccc1)c1ccccc1
Yield: 66.7 %

Procedure:
A solution of 22 (6.5 g, 15 mmol) in 6N-HCl aq (100 ml) was heated at reflux for 10 hours. The resulting solution of sodium hydroxide (NaOH) (24 g) in water (100 ml) and extracted with CH2Cl2 (100 ml) four times. The combined extracts were dried over Na2SO4 and concentrated. The clude was purified by recrystallization from EtOH to give 23 (1:1 mixture at 6-position; 10 mmol, 68%).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:30])[C:15]2[C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:17][NH:18][C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:10]([N+:31]([O-:33])=[O:32])[CH:9]=1>ClCCl.[O-2].[Cr+6].[O-2].[O-2]>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:15]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:18][NH:17][C:16]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:30])=[C:10]([N+:31]([O-:33])=[O:32])[CH:9]=1
Reactant: CCOC(=O)c1n[nH]c(C(=O)OCC)c1C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1n[nH]c(C(=O)OCC)c1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Chromium (VI) oxide (17.48 g, 174.8 mmol) was added over 37 minutes to a solution of pyridine (27.6 mL, 349.5 mmol) in dichloromethane (400 mL). Diethyl 4-[(4-chloro-2-nitro-phenyl)hydroxymethyl]-1H-pyrazole-3,5-dicarboxylate (11.56 g, 29.1 mmol) was added as a solid over 9 minutes. The reaction mixture was allowed to stir at room temperature 44 is hours. The solution was filtered and the organic layer was washed with aqueous hydrochloric acid (500 mL, 3N). The aqueous layer was extracted with ethyl acetate (3×250 mL) and dichloromethane (3×250 mL). The resulting organic extracts were combined and concentrated on the rotary evaporator to give a crude solid (10.92 g). The product was purified by chromatography eluting with dichloromethane:2-propanol (98:2, 96:4, and 94:6). The desired product was obtained from the mixed fractions by recrystallization from toluene (250 mL). Clean fractions from chromatography were combined with recrystallized product to give the title compound as a white solid (9.85 g, 86%, mp 168° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Si:17]([O:24][C@H:25]1[CH2:34][C@H:33](O)[C@H:32]2[C:27]([CH:28]=[CH:29][C@H:30]([CH3:53])[C@@H:31]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH2:39]2)=[CH:26]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>>[Si:17]([O:24][C@H:25]1[CH2:34][C@H:33]([O:11][C:10](=[O:12])[C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:16][CH:15]=2)([CH3:14])[CH3:13])[C@H:32]2[C:27]([CH:28]=[CH:29][C@H:30]([CH3:53])[C@@H:31]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48])[CH2:39]2)=[CH:26]1)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CC(C)(Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Product: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C(C)(C)Oc3ccc([N+](=O)[O-])cc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 597 mg of 2-(4-nitrophenoxy)-2-methylpropionic acid and 731 mg of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give880 mg of the title compound as a colorless foam.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[C:11]3[N:16]=[CH:15][S:14][C:12]=3[N:13]=2)[CH2:4]1.[N:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[C:34](O)=[O:35].CCN=C=NCCCN(C)C.CN1C=CN=C1>C(Cl)Cl>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([NH:17][C:10]2[C:11]3[N:16]=[CH:15][S:14][C:12]=3[N:13]=[C:8]([N:5]3[CH2:6][CH2:7][CH:3]([NH:2][C:34]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][N:28]=4)=[O:35])[CH2:4]3)[N:9]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: COc1ccc(Nc2nc(N3CCC(N)C3)nc3scnc23)cc1OC
Reactant: O=C(O)c1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2nc(N3CCC(NC(=O)c4cnccn4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.1 %

Procedure:
A mixture of 5-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine hydrochloride (40 mg, 0.1 mmol), pyrazine-2-carboxylic acid (14 mg, 0.11 mmol), EDCI (38 mg, 0.2 mmol) and N-methylimidazole (25 mg, 0.3 mmol) in 3 mL of DCM was stirred at room temperature for 15 hours. The mixture was washed with water (5 mL), the organic layer was dried over Na2SO4. After filtration and concentration, the residue was purified by preparative TLC (Silica gel, 20 cm×20 cm, separated by EtOAc, eluted by DCM:MeOH=1:20, v/v) to give N-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-yl)pyrazine-2-carboxamide (35 mg, 73%) as white solid. 1H NMR (300 MHz, DMSO): δ 9.56 (s, 1H), 9.18 (s, 1H), 9.12 (d, 1H, J=7.8 Hz), 8.86 (d, 1H, J=2.4 Hz), 8.80 (s, 1H), 8.71 (s, 1H), 7.85 (s, 1H), 7.50-7.27 (m, 1H), 6.90 (d, 1H, J=8.4 Hz), 4.64-4.62 (m, 1H), 3.75-3.64 (m, 10H), 2.27-2.16 (m, 2H). LC-MS: 479 [M+H]+, 477 [M−H]−, tR=1.39 min. HPLC: 97.06% at 214 nm, 96.92% at 254 nm, tR=4.63 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].O>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=2[N+:20]([O-:22])=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: N#Cc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)cc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: N#Cc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
To a suspension of 4-chloro-4′-cyanobenzenesulfonanilide (4.03 g (13.8 mmol)) in 15 ml of acetic anhydride, 97% fuming nitric acid (0.61 ml (14.3 mmol)) was added dropwise with stirring at room temperature. After one hour's stirring at 50° C. the reaction mixture was poured into water to give crystals, which were then collected by filtration and washed with water to give 4.30 g (93%) of 4-chloro-4′-cyano-2′-nitrobenzenesulfonanilide as pale yellow crystals.
Reaction SMILES: [C@@H:1]1([N:9]2[CH2:16][NH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[C:17](O)(=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CO>[C:17]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH2:16][NH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])(=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: NC1=NC(=O)N([C@H]2C[C@H](O)[C@@H](CO)O2)CN1
Solvent: CO
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](N2CNC(N)=NC2=O)C[C@@H]1O
Yield: 107.6 %

Procedure:
To a solution of (9) (0.26 g, 1.13 mmol) in MeOH (50 mL) was added a solution of palmitic acid (0.29 g, 1.13 mmol) in hot MeOH (10 mL) and evaporated. The residue was triturated with ether and filtered giving 0.57 g (quantitative yield) of a colorless product with m.p. 123-124°. MS ES+ 231 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([N:14]=[C:15]=[S:16])=[CH:4][CH:3]=1.[NH3:17]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14][C:15]([NH2:17])=[S:16])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Fc1ccc(N=C=S)c(-c2ccccc2)c1
Reactant: N
Solvent: CCO
Product: NC(=S)Nc1ccc(F)cc1-c1ccccc1

Procedure:
Reaction of 5-fluoro-2-biphenylylisothiocyanate (9.3 g) in ethanol (40 ml) with 28% aqueous ammonia solution (80 ml) at ambient temperature for 24 hours gave N-(5-fluoro-2-biphenylyl)thiourea as a yellow solid (m.p. 188°-190° C.).