Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][CH2:7][CH2:8][OH:9])([CH3:5])[CH3:4].[CH3:10][C:11]1[CH:16]=[C:15]([C:17]2[NH:26][C:25](=[O:27])[C:24]3[C:19](=[CH:20][C:21](F)=[CH:22][C:23]=3[O:28][CH3:29])[N:18]=2)[CH:14]=[C:13]([CH3:31])[N:12]=1.O>CS(C)=O>[CH3:10][C:11]1[CH:16]=[C:15]([C:17]2[NH:26][C:25](=[O:27])[C:24]3[C:19](=[CH:20][C:21]([O:9][CH2:8][CH2:7][O:6][CH:3]([CH3:5])[CH3:4])=[CH:22][C:23]=3[O:28][CH3:29])[N:18]=2)[CH:14]=[C:13]([CH3:31])[N:12]=1
Reactant: COc1cc(F)cc2nc(-c3cc(C)nc(C)c3)[nH]c(=O)c12
Reactant: CC(C)OCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(OCCOC(C)C)cc2nc(-c3cc(C)nc(C)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of sodium hydride (60% suspension in mineral oil, 0.24 g, 6.00 mmol) in anhydrous DMSO (10 mL) was added 2-isopropoxy-ethanol at room temperature under nitrogen. The mixture was stirred for 20 minutes at room temperature, then 2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-methoxy-3H-quinazolin-4-one (0.30 g, 1.00 mmol) was added and the reaction mixture was stirred at 80° C. for 16 hours, then cooled to room temperature. Water (50 mL) was added, and the mixture was extracted with a mixture of ethyl acetate and THF (4:1, 200 mL). The organic phase was washed with brine and dried over anhydrous sodium sulfate. Solvent was evaporated, and the crude compound was purified by the Simpliflash system (3:15:82 methanol, ethyl acetate and dichloromethane as eluent) to give the title compound as a white solid. Yield: 127 mg (33%). MP 188-189° C. 1H NMR (400 MHz, CDCl3): δ 11.14 (br s, 1H), 7.72 (s, 2H), 6.86 (d, J=2.34 Hz, 1H), 6.59 (d, J=2.34 Hz, 1H), 4.35-4.15 (m, 2H), 3.97 (s, 3H), 3.89-3.79 (m, 2H), 3.78-3.64 (m, 1H), 2.66 (s, 6H), 1.23 (d, J=5.85 Hz, 6H). MS (ES+) m/z: 384.20 (100%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][S:17]([CH3:16])(=[O:19])=[O:18]
Reactant: NCc1ccccn1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a 0° solution of 15 g of 2-(aminomethyl)pyridine, 15.44 g of triethylamine and 150 ml of methylene chloride is added 17.48 g of methanesulfonyl chloride in 100 ml of methylene chloride. The mixture is stirred at 0° C. for 1 hour followed by stirring at room temperature for 3 hours. The reaction is poured into saturated sodium bicarbonate and extracted with methylene chloride. The combined extracts are washed with saturated sodium chloride and concentrated in vacuo. The residue is purified by chromatography (silica gel: 10% methyl alcohol/ethyl acetate) to give 19.84 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[C:11]([NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH:15]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)(O)[O-].[Na+]>C(O)(=O)CC>[N:23]1[CH:24]=[CH:25][C:20]([C:16]2[CH:15]=[C:14]([C:13]3[O:1][C:2]4[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][C:11]=4[N:12]=3)[CH:19]=[CH:18][CH:17]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1cccc(NC(=O)c2cccc(-c3ccncc3)c2)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(=O)O
Product: COC(=O)c1cccc2nc(-c3cccc(-c4ccncc4)c3)oc12
Yield: 14.5 %

Procedure:
A mixture of methyl 2-hydroxy-3-(3-(pyridin-4-yl)benzamido)benzoate (0.9 g, 5 mmol) of propionic acid (50 mL) was stirred at reflux for 3 days. Then the mixture was adjusted to pH=7 by sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate, brine, dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure. The crude products was purified by chromatography (petroleum ether/ethyl acetate=5:1). 240 mg of methyl 2-(3-(pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxylate as a solid was obtained. Yield 28%. LC-MS (ESI) m/z: 331 (M+1)+.
Reaction SMILES: [F:1][C:2]1[C:3]([O:9][CH3:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:19][CH:18]=[CH2:17])[C:3]=1[O:9][CH3:10]
Reactant: COc1c(O)cccc1F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc(F)c1OC
Temperature: 25 °C

Procedure:
A mixture of 3-fluoro-2-methoxyphenol (19.5 g; 0.137 m) potassium carbonate (85 g), allyl bromide (15 ml) and acetone (100 ml) was refluxed for 4 hours. The reaction was cooled to room temperature and evaporated to dryness. The residue was partitioned between water and dichloromethane. The organic layer was separated, dried and evaporated affording 19.0 g of the desired product as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][CH2:11][OH:12]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:12][CH2:11][CH3:10])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: BrCc1ccc(Br)cc1
Product: CCOCc1ccc(Br)cc1

Procedure:
A solution of 1.00 g of 4-bromobenzyl bromide in 20 ml EtOH is stirred 5 h under reflux. The solvent is evaporated to obtain 766 mg of 1-bromo-4-ethoxymethyl-benzene as a yellow oil, MS (ESI) 216.1 (M+H)+.
Reaction SMILES: [CH:1]([CH:4]([CH:8]([CH3:10])[CH3:9])[C:5]([NH2:7])=[O:6])([CH3:3])C.[CH3:11]OC(C)(C)C>>[CH2:1]([C@@H:4]([CH:8]([CH3:9])[CH3:10])[C:5]([NH2:7])=[O:6])[CH2:3][CH3:11]
Reactant: CC(C)C(C(N)=O)C(C)C
Reactant: COC(C)(C)C
Product: CCC[C@H](C(N)=O)C(C)C
Reaction time: 0.01 h

Procedure:
Assay of plasma samples: to test tubes containing 2 μg of the internal standard (diisopropyl acetamide), 0.5 ml of plasma (thawed at room temperature) and 5 ml of tert-butyl methyl ether (TBME) was added. The test tubes were vigorously vortexed for 30 sec and centrifuged at 3000 g for 10 minutes. The organic phase was separated and dried under reduced pressure using a vortex evaporator. Samples were then reconstituted with 150 μl of chloroform and dried under reduced pressure without vortexing. The sample was again reconstituted with 30 μl of chloroform, of which 2 μl were injected into the GC apparatus.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:27](O)[CH3:28]>>[C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([O:21][CH2:27][CH3:28])=[O:20])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCO
Reactant: O=C(O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12

Procedure:
[2-(1-Cyclohexenyl)-4-oxo-4H-[1]-benzopyran-8-yl]acetic acid (2.0 g) was dissolved in ethanol (50 ml) and to the solution was added conc. sulfuric acid (0.5 ml). The mixture was heated under reflux for 5 hours. After dilution with water, the mixture was extracted with ethyl acetate and the extract was washed with water, dried (MgSO4) and concentrated under reduced pressure to obtain the title compound as crystals. The crystals were recrystallized from ethyl acetate to obtain prisms, yield 1.34 g (61.0%), m.p. 126°-127° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N:20]([S:22]([C:25]3[C:33]4[O:32][C:31]([F:35])([F:34])[O:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH3:21])[CH:17]=[CH:16][C:15]=2[O:36][CH3:37])[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Na+].CI.[ClH:42]>C(O)(C)C>[ClH:42].[CH3:21][N:20]([C:18]1[CH:17]=[CH:16][C:15]([O:36][CH3:37])=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=1)[S:22]([C:25]1[C:33]2[O:32][C:31]([F:35])([F:34])[O:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: COc1ccc(N(C)S(=O)(=O)c2cccc3c2OC(F)(F)O3)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CI
Product: COc1ccc(N(C)S(=O)(=O)c2cccc3c2OC(F)(F)O3)cc1N1CCNCC1

Procedure:
The compound was prepared by reaction of 4-{5-[(2,2-difluorobenzo[1,3]dioxole-4-sulfonyl)-methyl-amino]-2-methoxy-phenyl}-piperazine-1-carboxylic acid tert-butyl ester with sodium hydride and methyliodide by analogy to Preparation Example 3, and subsequent deprotection of the tert.butoxycarbonyl group with hydrochloric acid in isopropanol.
Reaction SMILES: C[Al](C)C.[N:5]([Si](C)(C)C)=[N+:6]=[N-:7].[I:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)[N:21]=2)[CH:18]=1.Cl>C1(C)C=CC=CC=1>[I:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]3[CH:29]=[CH:28][C:25]([C:26]4[NH:27][N:7]=[N:6][N:5]=4)=[CH:24][CH:23]=3)[N:21]=2)[CH:18]=1
Reactant: N#Cc1ccc(-c2cn3cc(I)ccc3n2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Ic1ccc2nc(-c3ccc(-c4nnn[nH]4)cc3)cn2c1
Temperature: 80 °C

Procedure:
Trimethylaluminum (150 μL) and azidotrimethylsilane (42 μL) were added to a solution (1 mL) of 4-(6-iodoimidazo[1,2-a]pyridin-2-yl)benzonitrile (104 mg) in toluene, followed by heating at 80° C. for 2 hours. The mixture was left to cool to room temperature, and 6N hydrochloric acid solution was added thereto. The precipitated matter was recovered through filtration and dried, to thereby yield the title compound (17 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:25])[NH:4][N:5]=[C:6]([N+:22]([O-])=O)[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][CH3:21])[CH:11]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(O)(=O)C>C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:1][C:2]1[C:3](=[O:25])[NH:4][N:5]=[C:6]([NH2:22])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][CH3:21])[CH:11]=1
Reactant: CCCOc1cc(CNc2c([N+](=O)[O-])n[nH]c(=O)c2Cl)ccc1OC
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCOc1cc(CNc2c(N)n[nH]c(=O)c2Cl)ccc1OC
Temperature: 25 °C

Procedure:
1.00 g of 4-chloro-5-(3-n-propoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 22) prepared in Example 2, was dissolved in a solvent mixture of 20 ml of ethanol and 20 ml of a 10% sodium carbonate aqueous solution, 3.30 g of sodium hydrosulfite was gradually added thereto at room temperature under stirring. The mixture was stirred at room temperature for 1 hour, and was neutralized with glacial acetic acid. Then, ethanol was distilled off under reduced pressure, and water was added to the residue thereby obtained. The mixture was extracted with chloroform. The extract was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. Then, the solvent was distilled off to obtain light yellow crystals This product was crystallized from a solvent mixture of methanol-diethyl ether, to obtain 634 mg of the above identified compound having a melting point of from 187.5° to 189.5° C. as colorless crystals
Reaction SMILES: C([O:5][C:6](=[O:43])[C@H:7]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])[N:12]1[C:23](=[O:35])[CH2:24][CH2:25][S:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[C:27]([S:26][CH2:25][CH2:24][C:23]([N:12]1[CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])[CH2:14][CH2:15][C@H:11]1[C:9]([NH:8][C@H:7]([C:6]([OH:43])=[O:5])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:10])=[O:35])(=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCC(c2ccccc2O)N1C(=O)CCSC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(SCCC(=O)N1C(c2ccccc2O)CC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.8 %

Procedure:
The mixture of 0.7 g of (2S)-N-[[1-(S-benzoyl-3-mercaptopropanoyl)-5-(2-hydroxyphenyl)-2-pyrrolidinyl]carbonyl]-phenylalanine t-butyl ester obtained in Example 15, 2.7 g of trifluoroacetic acid and 0.6 g of anisole is stirred at room temperature for 4 hours. After removing trifluoroacetic acid and anisole from it, the reaction mixture is purified by silica gel column chromatography to give 0.5 g (79%) of the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)[CH3:7])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:8]1([CH:6]([CH3:7])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)CC(C)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC(C)N1CCNCC1
Yield: 60.3 %

Procedure:
A solution of 513 (1.02 g, 3.40 mmol) and TFA (10 ml) in DCM (50 ml) was stirred at rt for 3 h. The reaction mixture was concentrated (azeotropes with DCM), diluted in water, and the pH was adjusted to around 8-9 with a saturated aqueous solution of sodium bicarbonate and 1N NaOH, and extracted with DCM. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to afford the desired product 514 (411 mg, 2.05 mmol, 60% yield) as a yellow sticky oil that was used crude in the next step without any further purification. MS (m/z): 201.3 (M+H).
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:31]([OH:33])=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].CC([C@H]1[C@@H]2[C@@H]3[C@@](C)(CC[C@@]2(CO)CC1)[C@@]1(C)[C@@H]([C@]2(C)[C@@H](CC1)C(C)(C)[C@@H:49]([OH:62])[CH2:48]C2)CC3)=C>>[CH3:3][C:2]([CH:4]1[CH:8]2[CH:9]3[C:22]([CH3:25])([CH2:23][CH2:24][C:7]2([C:31]([OH:33])=[O:32])[CH2:6][CH2:5]1)[C:21]1([CH3:26])[CH:12]([C:13]2([CH3:30])[CH:18]([CH2:19][CH2:20]1)[C:17]([CH3:27])([CH3:28])[CH:16]([O:29][C:49]([CH3:48])=[O:62])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:1]
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)C1CCC2(C(=O)O)CCC3(C)C(CCC4C5(C)CCC(OC(C)=O)C(C)(C)C5CCC43C)C12

Procedure:
The method of claim 12 wherein the overall yield of the α-isomer of betulinic acid from betulin is greater than 50%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([NH:22][C:21]2[CH:23]=[CH:24][C:18]([O:17][C:16]([F:15])([F:25])[F:26])=[CH:19][CH:20]=2)=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)CCC(=O)c1cccc(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCC(=O)c1cccc(F)c1)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.1 %

Procedure:
Stir 4-(3-fluoro-phenyl)-4-oxo-butyric acid [C.A. 69797-46-2] (J. Med. Chem. (1983) 26 381) (1.96 g, 10 mmol), 4-trifluoromethoxyaniline (1.77 g, 10 mmol) and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (3.5 g, 11 mmol) in dimethylformamide (30 mL). Add triethylamine (2.02 g, 20 mmol). Stir at room temperature for 48 hours. Pour into dilute aqueous HCl (250 mL) and extract into ethyl acetate. Wash the organic phase three times with water, dry over anhydrous magnesium sulfate, evaporate and purify on a silica gel column (dichloromethane-ethyl acetate) to give the titled compound (3.13 g, 88% yield) MS (m/z): 356 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O.CN(C=O)C>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCCCCBr
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCCCCCCBr
Reaction time: 16 h
Yield: 94.9 %

Procedure:
8-Bromooctanoic acid (2 g, 8.90 mmol, 1 equiv) was stirred in CH2Cl2 (15 mL) under N2 atmosphere and thionyl chloride (784 μL, 10.68 mmol, 1.2 equiv) added followed by DMF (few drops). The solution was stirred for 16 h and concentrated in vacuo to give 8-bromooctanoyl chloride (2.04 g, 95%) as a yellow oil which was used without further purification. Thiourea 4 (600 mg, 1.84 mmol, 1 equiv.) was stirred in CH2Cl2 (15 mL) under N2 atmosphere. 8-Bromooctanoyl chloride (532 mg, 2.02 mmol, 1.2 equiv.) was added, followed by triethylamine (256 μL, 1.84 mmol, 1 equiv.). The beige suspension was stirred at rt for 16 h and diluted with CH2Cl2 (20 mL). The organic solution was washed with 1 M aqueous hydrochloric acid (1×20 mL), 10% aqueous sodium hydroxide (1×20 mL), and saturated brine (1×20 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The resulting yellow foam was purified by flash chromatography on silica (50% ethyl acetate/petroleum ether) to give 8-bromo-octanoic acid {4-[3-(4-tert-butyl-benzoyl)-thioureido]-phenyl}-amide (579 mg, 59%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:14]([O-])=O)=[C:4]([CH2:8][C:9](OCC)=[O:10])[CH:5]=[CH:6][CH:7]=1>[Fe].CC(O)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:14][C:9](=[O:10])[CH2:8]2
Reactant: CCOC(=O)Cc1cccc(F)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Cc2cccc(F)c2N1
Temperature: 60 °C
Yield: 56.7 %

Procedure:
To a 250 mL round bottom flask was added ethyl 2-(3-fluoro-2-nitrophenyl)acetate (3.1 g, 14 mmol), iron (3.8 g, 68 mmol), and 50 mL of AcOH. The reaction mixture was heated at 60° C. for 1 hour. The reaction mixture was concentrated and dissolved in 100 mL of EtOAc, filtered, and washed with 50 mL of a saturated NaHCO3 solution. The organic layer was concentrated and purified with silica gel column chromatography, eluting with 40% EtOAc/hexane to give 7-fluoroindolin-2-one (1.2 g, 58% yield) as a white solid. MS m/z: 152 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 3.58 (s, 2H), 6.94-7.04 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:4]([CH3:30])[CH:5]=[C:6]([CH2:8][N:9]2[CH2:29][CH2:28][C:12]3([O:16][C:15](=[O:17])[N:14]([C:18]4[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=4)[CH2:13]3)[CH2:11][CH2:10]2)[CH:7]=1.[OH-].[K+].C(O)(=O)C>C(O)C>[CH3:1][C:2]1[C:3]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:4]([CH3:30])[CH:5]=[C:6]([CH2:8][N:9]2[CH2:29][CH2:28][C:12]3([O:16][C:15](=[O:17])[N:14]([C:18]4[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=4)[CH2:13]3)[CH2:11][CH2:10]2)[CH:7]=1
Reactant: COC(=O)c1ccc(N2CC3(CCN(Cc4cc(C)c(-c5ccc(F)cc5)c(C)c4)CC3)OC2=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(CN2CCC3(CC2)CN(c2ccc(C(=O)O)cc2)C(=O)O3)cc(C)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17 %

Procedure:
To a mixture of half of the crude methyl 4-{8-[(4′-fluoro-2,6-dimethylbiphen-4-yl)methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl}benzoate from Step 3 (˜0.065 mmol) in ethanol (1 mL) was added excess aqueous potassium hydroxide and the reaction was stirred at room temperature for 24 hours. The mixture was then acidified with acetic acid and the title product (5.4 mg) was isolated by mass directed reverse phase (C18) chromatography (0.1% ammonium hydroxide) and evaporation of the product fractions.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1>O>[CH:1]([O:4][C:8]1[CH:13]=[C:12]([CH:11]=[CH:10][N:9]=1)[C:14]#[N:15])([CH3:3])[CH3:2]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1cc(C#N)ccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 53 %

Procedure:
To isopropanol (30.0 mL) was added sodium hydride (0.606 g of 60% dispersion, 15.2 mmol) in small portions over 5 minutes. The resulting gel-like suspension was stirred for an additional 5 minutes at room temperature. 2-Chloro-4-cyanopyridine (2.00 g, 14.4 mmol) was then added in one portion and the resulting solution was heated to reflux. After 1 hour, the reaction mixture was allowed to cool to room temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried (magnesium sulfate) and concentrated to provide a yellow oil. Flash chromatography over silica (hexanes/ethyl acetate) afforded 1.25 g (53%) of product as a colorless oil: 1H NMR (CDCl3) δ 8.27 (d, J=5.2 Hz, 1H), 7.01 (dd, J=5.2, 1.4 Hz, 1H), 6.91 (d, J=1.4 Hz, 1H), 5.31 (sept, J=6.2 Hz, 1H), 3.33 (d, J=6.2 Hz, 6H) ppm.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=O.CC[N:15](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[Si](N[Si](C)(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([NH2:15])=[O:12]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C1Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-indancarboxylic acid (1.4 g, 8.63 mmol) was dissolved in anhydrous DMF (20 mL), and the following was added sequentially: DIPEA (3.02 mL, 17.26 mmol), HATU (3.94 g, 10.36 mmol), and HMDS (2.17 mL, 10.36 mmol) after 30 min of stirring at rt. After stirring for 20 h at rt, the solution was taken up in EtOAc and washed with 0.5M HCl (3×), water (3×), and 10% aq. sodium carbonate (3×). The organic phase was collected and dried over magnesium sulfate, and concentrated in vacuo. The solid residue was recrystallized from EtOH to afford the title compound as sharp, colorless crystals. (Yield: 861 mg, 5.06 mmol, 59%) 1H NMR (400 MHz, CDCl3) 7.34-7.12, 5.52, 3.41-3.08
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH:13][CH3:14].O>CCO>[CH3:12][N:13]([CH3:14])[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: CNC
Solvent: CCO
Solvent: O
Product: CN(C)c1ccc(N)cc1[N+](=O)[O-]
Yield: 98.3 %

Procedure:
In an alternative preparation: 4-Fluoro-3-nitro-aniline (20 g, 128 mmol) was dissolved in EtOH (300 mL) and dimethylamine (5.6 M solution in EtOH, 360 mL, 2.02 mol) was added in a steady stream. After refluxing for 18 h, the reaction mixture was cooled and 100 mL water was added. EtOH was removed by evaporation and the residue was extracted with Et2O (3×100 mL). The combined organics were washed with brine, filtered, and the solvent was evaporated to afford 22.8 g of 4-(dimethylamino)-3-nitroaniline as a black oil. This was dissolved in EtOH (80 mL) and HNO3 (69% aq, 18.5 mL, 22.1 mmol) added dropwise followed by cyanamide (50% wt in water, 37 mL, 476 mmol). The mixture was heated at reflux for 18 h. Once cooled, the mixture was poured into Et2I (1 L). The ethereal supernatant was decanted and the residue was treated with propan-2-ol, followed by Et2O to give 19.0 g of the corresponding guanidine nitrate as a tan solid. This was stirred with K2CO3 (15.04 g, 108.8 mmol) in 2-methoxyethanol (250 mL) for 10 min before adding 3-dimethylamino-1-(2,4-dimethylthiazol-5-yl)-propenone (9.53 g, 45.33 mmol). The mixture was heated at 125° C. for 18 h. The reaction mixture was concentrated and diluted with EtOAc, filtered through a pad of silica and evaporated to give a dark oil, which was purified by chromatography, using EtOAc to elute the title product as a reddish solid. Recrystallisation from toluene yielded 7.3 g pure title compounds.