Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].[NH:17]1[CH2:31][CH2:30][CH2:29][C@@H:18]1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].Cl.C1C=CC2N(O)N=NC=2C=1.O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([N:17]1[CH2:31][CH2:30][CH2:29][C@@H:18]1[C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])=[O:9])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
Boc-L-Ile-OH 1/2 H2O (1.13 g, 4.7 mmol), H-D-Pro-OBzl HCl (1.14 g, 4.7 mmol) and HOBt H2O (72 mg, 0.47 mmol) were dissolved in DMF (10 ml), and TEA (0.66 ml, 4.7 mmol) and DCC (1.16 g, 5.64 mmol) were added under ice cooling, followed by stirring overnight at room temperature. After filtering and concentrating, the reaction mixture was redissolved in ethyl acetate and washed sequentially with 10% citric acid, 4% NaHCO3 and aqueous saturated sodium chloride. After drying over anhydrous MgSO4 and concentrating, purification was effected by flash silica gel chromatography (1% MeOH/CHCl3) to yield 1.76 g (89%) of the titled compound as an oily material.
Reaction SMILES: B(Br)(Br)Br.C([O:12][C:13]1[CH:14]=[C:15]([C:19]2[N:23]3[CH:24]=[C:25]([Br:28])[CH:26]=[CH:27][C:22]3=[N:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:28][C:25]1[CH:26]=[CH:27][C:22]2[N:23]([C:19]([C:15]3[CH:14]=[C:13]([OH:12])[CH:18]=[CH:17][CH:16]=3)=[N:20][N:21]=2)[CH:24]=1
Reactant: Brc1ccc2nnc(-c3cccc(OCc4ccccc4)c3)n2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cccc(-c2nnc3ccc(Br)cn23)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.9 %

Procedure:
Boron tribromide (1 M in DCM, 13.1 mL, 13.1 mmol) was added slowly to a stirred solution of 3-(3-benzyloxy-phenyl)-6-bromo-[1,2,4]triazolo[4,3-a]pyridine (1 g, 2.63 mmol) in DCM (5 mL) at −78° C. The reaction was allowed to warm up to RT, stirred for 24 h, and treated with sat. NaHCO3 solution until pH>7. The product was extracted with DCM:MeOH 9:1 (mL), dried (MgSO4), and concentrated in vacuo. Purification of the crude residue by FCC (DCM:MeOH, 1:0 to 9:1) afforded the title compound (350 mg, 46%) as a yellow solid. LCMS (Method 2): Rt 2.65 min, m/z 290 and 292 [MH+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.ClC(OCC(C)C)=O.Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][NH:35][CH3:36])[CH3:31]>C(Cl)Cl>[CH2:30]([O:32][C:33](=[O:37])[CH2:34][N:35]([C:11](=[O:13])[CH2:10][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:9])[CH3:36])[CH3:31]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CNC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN(C)C(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
To a stirred solution of (tert-butoxycarbonyl-methyl-amino)-acetic acid (37 g, 0.2 mol) and Et3N (60.6 g, 0.6 mol) in CH2Cl2 (300 mL) was added isobutyl chloroformate (27.3 g, 0.2 mmol) dropwise at −20° C. under argon. After stirring for 0.5 h, methylamino-acetic acid ethyl ester hydrochloride (30.5 g, 129 mmol) was added dropwise at −20° C. The mixture was allowed to warm to room temperature (c.a. 1 h) and quenched with water (500 mL). The organic layer was separated, washed with 10% citric acid solution, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/EtOAc 1:1) to give {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid ethyl ester (12.5 g, 22%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(C(C)C)CC)(C)C.[C:21]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)([OH:23])=[O:22].C([BH3-])#N.[Na+]>CO.O.C(O)(=O)C>[C:8]([O:7][C:5]([CH2:4][CH2:3][NH:2][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=1)=[O:6])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)CCNCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl 3-aminopropanoate hydrochloride (5 g, 27.7 mmol) was dissolved in methanol (150 mL). Diisopropylethylamin (4.73 mL, 27.7 mmol) was added followed by 4-carboxybenzaldehyd. The mixture is heated to reflux for 1 hour. After cooling to room temperature sodium cyanoborohydride (1.77 g, 22.1 mmol) was added under nitrogen and stirred for 1 hour at room temperature. Acetic acid (15 mL) was added and the mixture was stirred for an additional 1 hour. The mixture was poured into water (300 mL) and stirred at room temperature over night. The water solution was washed with ethyl acetate (3×250 mL). The organic phase dried (Na2SO4) and solvent removed in vacuo to yield the crude product as an oil which solidifies by standing. The crude product was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1>Br.C(O)(=O)C>[F:21][C:19]([F:20])([F:22])[C:18]1[C:13]([C:9]2[CH:8]=[C:7]3[C:12]([C:3]([OH:2])=[CH:4][CH:5]=[N:6]3)=[CH:11][CH:10]=2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccnc2cc(-c3ncccc3C(F)(F)F)ccc12
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccnc2cc(-c3ncccc3C(F)(F)F)ccc12

Procedure:
Heat a solution of 4-methoxy-7-[3-(trifluoromethyl)pyridin-2-yl]quinoline (100 mg), in 33% hydrogen bromide in acetic acid (5 mL) at 100° C. for 18 hours. Evaporate to dryness to give the hydrobromide salt of the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=[O:9])[C:5](=[O:11])[NH:4][NH:3]1.ClOC(C)(C)C.[C:18]([OH:24])(=[O:23])[CH:19]=[CH:20][CH:21]=[CH2:22]>O1CCOCC1>[C:18]([CH:19]1[CH:20]=[CH:21][CH2:22][N:4]2[C:5](=[O:11])[N:6]([CH2:7][C:8]([OH:10])=[O:9])[C:2](=[O:1])[N:3]12)([OH:24])=[O:23]
Reactant: C=CC=CC(=O)O
Reactant: O=C(O)Cn1c(=O)[nH][nH]c1=O
Agent: CC(C)(C)OCl
Solvent: C1COCCO1
Product: O=C(O)Cn1c(=O)n2n(c1=O)C(C(=O)O)C=CC2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 41.7 %

Procedure:
1.69 g (0.011 mol) of 3,5-dioxo-1,2,4-triazolidine-4-acetic acid were suspended in 20 ml of dry dioxan and the suspension was stirred at room temperature under a stream of nitrogen. A solution of 1.32 g (0.012 mol) of tert.butyl hypochlorite in 4 ml of dry dioxan was added dropwise over a period of 15 minutes. Stirring was continued for 45 minutes, the resulting red solution was filtered and the filtrate was evaporated in vacuo to give a red solid. This red solid was dissolved in 30 ml of dioxan and added portionwise to a stirred solution of 1.25 g (0.013 mol) of penta-2,4-dienoic acid in 20 ml of dioxan. The red colour was allowed to fade between the additions. After completion of the addition and when no red colour persisted, the solution was stirred at room temperature for 1 hour and evaporated in vacuo to give a colourless solid. This solid was recrystallized from acetonitrile to give 1.17 g (43%) of 5-carboxy-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo-[1,2-a]pyridazine-2-acetic acid of melting point 209°-211° C. (decomposition).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>CCOC(C)=O.[Pd]>[C:11]1([NH:10][C:5]2[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccnc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
A mixture of (3-nitropyridin-2-yl)phenylamine (2.49 g, 0.0116 mol) and 10% Pd/C (40 mg) in EtOAc (100 mL) was degassed with a stream of nitrogen and then stirred at RT under a hydrogen atmosphere for 16 h. The suspension was then filtered through a pad of Celite® and then the filtrate was concentrated in vacuo affording N2-Phenylpyridine-2,3-diamine as a white solid (2.06 g, 96%). LCMS: RT 1.15 min [M+H]+ 186.0.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH:11]=[O:12])[CH:10]=1)=[O:5])C.[OH-].[K+].O>CO>[CH:11]([C:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[NH:7][CH:8]=1)=[O:12]
Reactant: CCOC(=O)c1cc(C=O)c[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=Cc1c[nH]c(C(=O)O)c1

Procedure:
Refluxing 4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester in 2 equivalents of potassium hydroxide in methanol:water followed by acidification to pH 3 at 0° C. gave 4-formyl-1H-pyrrole-2-carboxylic acid as a solid. MS m/z 140 [M+1].
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1.[CH2:17]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:34][C:33]([CH:35]=O)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)C>CO.ClCCl.[Cl-].[NH4+]>[CH2:17]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:34][C:33]([CH:35]=[C:6]3[S:5][C:4](=[S:7])[N:3]([CH:8]4[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]4)[C:2]3=[O:1])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1ccc(-c2ccc(Cc3ccccc3)cc2)o1
Reactant: O=C(O)C1CCCC(N2C(=O)CSC2=S)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: O=C(O)C1CCCC(N2C(=O)C(=Cc3ccc(-c4ccc(Cc5ccccc5)cc4)o3)SC2=S)C1
Temperature: 25 °C
Reaction time: 65 h
Yield: 64.1 %

Procedure:
3-(4-oxo-2-thioxo-thiazolidin-3-yl)-cyclohexanecarboxylic acid (80 mg, 0.31 mmol), 5-(4-benzyl-phenyl)-furan-2-carbaldehyde (87 mg, 0.33 mmol), and diethylenediamine diacetate (59 mg, 0.33 mmol) were combined in a 20 mL vial with ethanol (5 mL) and stirred at room temperature for 65 h. The reaction mixture was diluted with 10% methanol in dichloromethane (200 mL) and aqueous ammonium chloride (20 mL) and stirred at room temperature for 15 minutes. The layers were separated and the aqueous layer was extracted with 10% methanol in dichloromethane (2×100 mL). The combined organic extracts were washed with 0.6N sodium hydrogensulfite (1×20 mL) and then brine (1×20 mL), dried (sodium sulfate) and concentrated under vacuum. The residue was triturated with dichloromethane/hexanes (1:5, 30 mL), filtered and dried overnight in a vacuum oven at 55° C. to afford 3-{5-[1-[5-(4-benzyl-phenyl)-furan-2-yl]-methylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-cyclohexanecarboxylic acid (100 mg, 64%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 1.25-1.41 (2H, m), 1.67 (1H, m), 1.87-1.92 (3H, m), 2.29-2.45 (3H, m), 4.00 (2H, s), 4.97 (1H, m), 7.18-7.22 (1H, m), 7.26-7.32 (5H, m), 7.36 (1H, d, J=3.6 Hz) 7.43 (2H, m), 7.58 (1H, s), 7.77 (1H, d, J=8.0 Hz), 12.18 (1H, s); APCI-MS: 503.54; HPLC: 95%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]([NH:13][S:14]([C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])(=[O:16])=[O:15])=[O:12])[N:4]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]([NH:13][S:14]([C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])(=[O:16])=[O:15])=[O:12])[N:4]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(CO)n1
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(COC(C)=O)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 0.5 g of the compound from Example 5 was added 1 ml of acetic anhydride and 1 ml of pyridine. After 1 hour at room temperature, ice-water was added, the precipitated oil was triturated, filtered, and washed with water to afford 0.4 g of the title compound, m.p. 145°-150°.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]([NH2:9])=[O:8])[CH:4]([CH3:6])[CH3:5].[C:10](=O)([O-])[OH:11].[Na+].ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.O>C(#N)C>[CH3:5][CH:4]([C@@H:3]1[NH:2][C:10](=[O:11])[NH:9][C:7]1=[O:8])[CH3:6]
Reactant: O=C([O-])O
Reactant: CC(C)[C@H](N)C(N)=O
Agent: Cl
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)[C@@H]1NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To a suspension of L-valinamide hydrochloride (1.0 g) and sodium hydrogen carbonate (3.03 g) in acetonitrile (100 mL) was added p-nitrophenyl chloroformate (1.32 g), and the mixture was stirred at room temperature for 3 hr. Water was added thereto, the resulting mixture was stirred at room temperature overnight, and then acetonitrile was distilled off under reduced pressure. After extraction with ethyl acetate, the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform/methanol) to afford (5S)-5-(propan-2-yl)imidazolidine-2,4-dione (540 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:7]=1[Cl:15])(=[O:5])=[O:4]>Cl>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:7]=1[Cl:15])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Product: CN(C)S(=O)(=O)c1cc(N)ccc1Cl
Temperature: 10 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
A mixture of 200 g of stannous chloride dihydrate and 250 ml of concentrated hydrochloric acid was cooled to 10° C. To the stirred mixture was added 50 g of N,N-dimethyl-2-chloro-5-nitrobenzenesulfonamide (Example A-2 above) in portions maintaining the temperature of 10° C. After removing the cooling bath, the reaction temperature rose to 55° C. and was held for two hours. The reaction mixture was cooled and filtered to remove the complex of the product with stannic chloride. The product was treated with water to decompose the complex and extracted with methylene chloride. Removal of solvent from the dried extract on a rotary evaporator gave 22 g of the title compound as a solid with a melting point of 125°-126° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[O:18][C:17]([CH3:19])=[N:16][C:15]=3[CH3:20])[OH:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.[Al]>O=[Mn]=O.O1CCOCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[O:18][C:17]([CH3:19])=[N:16][C:15]=3[CH3:20])=[O:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:29]=1
Reactant: COc1nc2ccc(C(O)c3oc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: O=[Mn]=O
Agent: [Al]
Solvent: C1COCCO1
Product: COc1nc2ccc(C(=O)c3oc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a 100 mL flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,4-dimethyloxazol-5-yl)methanol (960 mg, 2.01 mmol, Intermediate 87: step a) was added 1,4-dioxane (50 mL) and activated MnO2 (900 mg, 10.3 mmol) at room temperature. The mixture was heated to 85° C. in an aluminum heating mantle under a nitrogen atmosphere. After 60 minutes, the contents were filtered through Celite® while the solution is still warm and rinsed with THF, and concentrated to give an off white solid. The crude material was triturated with Et2O to give a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]2[C:7]([CH:8]=[C:9]3[C:14](=[CH:15]2)[CH:13]=[C:12]([OH:18])[CH:11]=[CH:10]3)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.O1CCCC1.[P:31]([S:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[CH:41][CH:40]=1)(=[O:37])(Cl)[S:32][CH2:33][CH2:34][CH3:35]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[P:31]([S:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[CH:41][CH:40]=1)(=[O:37])([S:32][CH2:33][CH2:34][CH3:35])[O:18][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][C:16]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:17]=3)[CH:13]=1
Reactant: CCCSP(=O)(Cl)Sc1ccc(C#N)cc1
Reactant: O=[N+]([O-])c1ccc2cc3ccc(O)cc3cc2c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCSP(=O)(Oc1ccc2cc3ccc([N+](=O)[O-])cc3cc2c1)Sc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7-Nitro-2-anthrol (0.01 mole), triethylamine (0.01 mole), tetrahydrofuran (25 ml) and toluene (25 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0° C. and S-(4-cyanophenyl) S-propyl phosphorochloridodithioate (0.01 mole) dissolved in toluene (25 ml) is added with stirring over a period of about 30 minutes. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 16 hours. After this time the reaction mixture is filtered to remove triethylamine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvents leaving a residue. This residue is subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product S-(4-cyanophenyl) O-(7-nitro-2-anthryl) S-propyl phosphorodithioate.
Reaction SMILES: [Cl:1][C:2]([Cl:43])([Cl:42])[C:3]([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:36]([OH:38])=[O:37])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=4Br)=[CH:20][CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:39](=[O:41])[CH3:40])[CH2:13]2)=[O:8])([CH3:5])[CH3:4].[Cl:44]C(Cl)(Cl)C(OC(N1C2C(C(OCC)=O)=C(C3C=CC(OCCOC4C=CC=C(F)C=4Cl)=CC=3)CC1CN(C(=O)C)C2)=O)(C)C.[OH-].[Na+]>CCO>[Cl:1][C:2]([Cl:43])([Cl:42])[C:3]([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:36]([OH:38])=[O:37])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=4[Cl:44])=[CH:20][CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:39](=[O:41])[CH3:40])[CH2:13]2)=[O:8])([CH3:5])[CH3:4]
Reactant: CC(=O)N1CC2CC(c3ccc(OCCOc4cc(F)ccc4Br)cc3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Reactant: CCOC(=O)C1=C(c2ccc(OCCOc3cccc(F)c3Cl)cc2)CC2CN(C(C)=O)CC1N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N1CC2CC(c3ccc(OCCOc4cc(F)ccc4Cl)cc3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C(Cl)(Cl)Cl

Procedure:
As described for compound BN2, but from bicyclononene BM10 (2.82 g, 3.94 mmol), aq. 1M NaOH (30 mL) and EtOH (70 mL). The crude title compound (1.90 g, 74%) was used ftther without purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[N:14][N:15]2[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)=[N+]=[N-]>O1CCCC1>[NH2:7][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[N:14][N:15]2[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1
Reactant: [N-]=[N+]=NCc1cccc2c1cnn2C1CCCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cccc2c1cnn2C1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
A solution of lithium aluminum hydride in tetrahydrofuran (1.0 M; 0.51 mL, 0.51 mmol) was added dropwise over 12 min to a cooled (0° C.) solution of 4-azidomethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (130 mg, 0.505 mmol) in dry tetrahydrofuran (1.5 mL). The solution was stirred at ˜0° C. for 1 h and then quenched with 1 M sodium hydroxide (75 μL) over approx. 1 min. The cooling bath was removed and the mixture was stirred for 1 h. The mixture was diluted with ethyl acetate (3 mL), dried (Na2SO4), filtered through Celite (which was washed with ethyl acetate), and concentrated to give 4-aminomethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (106 mg, 91%) as a yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34]([OH:36])=O)[CH2:31][N:32]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:60][O:61][CH2:62][CH2:63][NH2:64]>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O>[CH3:60][O:61][CH2:62][CH2:63][NH:64][C:34](=[O:36])[CH2:33][CH:30]1[S:29][C:28]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:11][C:8]2[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:20][C:19]=3[O:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:32][CH2:31]1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Reactant: COCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: COCCNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.4 %

Procedure:
To a solution of {2-[5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (150 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (65 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg), and 2-methoxyethylamine (42 mg), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio), and crystallized from hexane to give the title compound (102 mg, yield 60%) as a pale-yellow amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][S:14][CH3:15])[C:3]=1[C:4]#[N:5].[S:16](Cl)(=[O:19])(=[O:18])[NH2:17]>>[S:16]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][S:14][CH3:15])[C:3]=1[C:4]#[N:5])(=[O:19])(=[O:18])[NH2:17]
Reactant: NS(=O)(=O)Cl
Reactant: CSCCCOc1cccc(N)c1C#N
Product: CSCCCOc1cccc(NS(N)(=O)=O)c1C#N
Yield: 69 %

Procedure:
Prepared as in Example 197a from 2-amino-6-(3-(methylthio)propoxy)benzonitrile (Example 234b) and sulfamoyl chloride in 69% yield. MS 302 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:31])[CH2:17][C:18]([S:21]CC2C=CC(OC)=CC=2)([CH3:20])[CH3:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[C:12]([C:9]1[CH:8]=[C:7]([C:16](=[O:31])[CH2:17][C:18]([SH:21])([CH3:20])[CH3:19])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: COc1ccc(CSC(C)(C)CC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(S)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 3 h

Procedure:
To a stirred, ice-cold solution of 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(4-methoxyphenylmethylthio)-3-methyl-butan-1-one (70 mg) in CHCl3 (1 mL), under argon, is added CF3COOH (0.02 mL) via syringe. The reaction mixture is kept at 0° C. for 3 hours, and then solvent is evaporated under reduced pressure to give a brown oil. The crude material is purified twice by preparative silica gel thin layer chromatography (hexane:ethyl acetate, 9:1), to give 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-sulfhydryl-3-methyl-butan-1-one as a colorless oil.