Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH-:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li+].[CH3:11]OS(OC)(=O)=O.O>C(OCC)C>[CH3:11][C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]=1
Reactant: c1ccc2[cH-]ccc2c1
Reactant: COS(=O)(=O)OC
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC1=CCc2ccccc21
Yield: 94.6 %

Procedure:
Lithium indenide (9.60 g, 0.0786 moles) in diethylether (100 mL) was added dropwise to a solution of dimethylsulfate (9.91 g, 0.0786 moles) in diethylether (125 mL) over a period of 15 minutes. After the addition was complete, H2O (150 mL) was added to the reaction. The organic layer was then separated and washed with H2O (2×100 mL). Drying over MgSO4 followed by filtration and solvent removal yielded the desired product as a yellow oil (9.68 g, 94.7 percent).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:5]2.[N:27]1([CH2:33][CH2:34][NH2:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl-].[Na+]>CN(C)C=O>[N:27]1([CH2:33][CH2:34][NH:35][C:18]([CH:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:9]3[CH:10]=[C:2]([CH3:1])[CH:3]=[C:4]4[C:8]=3[NH:7][C:6]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:5]4)[CH2:13][CH2:14]2)=[O:20])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: Cc1cc(NC2CCC(C(=O)O)CC2)c2[nH]c(-c3ccccc3)cc2c1
Reactant: NCCN1CCOCC1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(NC2CCC(C(=O)NCCN3CCOCC3)CC2)c2[nH]c(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
The compound obtained in Example 55 (30 mg, 0.09 mmol) was dissolved in N,N-dimethyl formamide 5 ml. 2-Morpholine-4-yl-ethylamine (22 mg, 0.17 mmol), EDC (25 mg, 0.19 mmol) and HOBT (18 mg, 0.19 mmol) were added. The mixture was stirred for 8 hours at room temperature. Saturated 1N aqueous sodium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered. The filtrate was distilled under reduced pressure and purified by column chromatography to give the title compound 40 mg (Yield 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]2=[N:10][CH:11]=[CH:12][C:3]=12.[CH2:13]([NH2:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:13]([NH:19][C:2]1[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]2=[N:10][CH:11]=[CH:12][C:3]=12)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CSc1nc(Cl)c2ccnc-2[nH]1
Reactant: CCCCCCN
Product: CCCCCCNc1nc(SC)[nH]c2nccc1-2

Procedure:
To 200 mg of 4-chloro-2-methylthiopyrrolo[2,3-d]-pyrimidine was added 2 ml of n-hexylamine. The solution was heated at reflux under nitrogen for 2 hours. The resulting dark oil was purified by chromatography on 30 g of Sephadex LH-20, elution with H2O and then with increasing concentrations of ethyl alcohol up to 40% ethyl alcohol. The appropriate fractions were combined and evaporated to dryness and the solid residue was crystallized from ethyl alcohol/water to afford white crystals of product, yield 79 mg (60%), m.p. 117.5° - 118.5°.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1[N:13]=[N:14][C:15]([O:21][CH2:22][CH3:23])=[CH:16][C:17]=1[O:18][CH2:19][CH3:20])=O)C>C1COCC1>[CH2:19]([O:18][C:17]1[CH:16]=[C:15]([O:21][CH2:22][CH3:23])[N:14]=[N:13][C:12]=1[CH2:10][OH:9])[CH3:20]
Reactant: CCOC(=O)c1nnc(OCC)cc1OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1cc(OCC)c(CO)nn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
LiAlH4 (1N solution in THF, 1 mL) is added to a stirred solution of 4,6-diethoxy-pyridazine-3-carboxylic acid ethyl ester (213 mg, 0.8 mmol) in THF (8 mL), cooled to 0° C. The solution is stirred at 0° C. for 3 hours. Excess Na2SO4.10H2O is then added and the mixture is stirred at room temperature for 45 minutes. The solid is filtered and washed with EtOAc. Evaporation of the filtrate in vacuo provides a light yellow oil. This alcohol used in the next step without further purification. LC-MS (M+1) 199.2.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:29]=2)O1.Br[C:32]1[CH:43]=[CH:42][C:35]([C:36]([NH:38][CH2:39][CH2:40][OH:41])=[O:37])=[C:34]([F:44])[CH:33]=1>>[F:44][C:34]1[CH:33]=[C:32]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:29]=2)[CH:43]=[CH:42][C:35]=1[C:36](=[O:37])[NH:38][CH2:39][CH2:40][OH:41]
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Reactant: O=C(NCCO)c1ccc(Br)cc1F
Product: CC(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C(=O)NCCO)c(F)c4)ccc3o2)CC1
Yield: 32.2 %

Procedure:
Following the General Procedure-3, the titled compound (65 mg) was prepared from Intermediate 14 (200 mg, 0.54 mmol) and 4-bromo-2-fluoro-N-(2-hydroxyethyl)benzamide (110 mg, 0.43 mmol) as a brown solid. M.P.: 145-147° C. MS (m/z): 470.4 [M+H]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][S:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[CH3:12][S:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:16][CH:15]=1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CSc1ccc(N)cc1
Product: CSc1ccc(Nc2ccccc2CC(=O)O)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 4-methylmercaptoaniline to yield 2-[(4-methylmercaptophenyl)amino]phenylacetic acid.
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](/[CH:11]=[CH:12]/[C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[CH:6]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>>[N:22]([CH2:2][C@@H:3]([OH:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](/[CH:11]=[CH:12]/[C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[CH:6]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: O[C@H](CCl)Cc1cccc(/C=C/c2c(Cl)cccc2Cl)c1
Agent: [Na+]
Product: [N-]=[N+]=NC[C@@H](O)Cc1cccc(/C=C/c2c(Cl)cccc2Cl)c1

Procedure:
(S,E)-1-Chloro-3-(3-(2,6-dichlorostyryl)phenyl)propan-2-ol was reacted with NaN3 following the method used in Example 74 to give (S,E)-1-azido-3-(3-(2,6-dichlorostyryl)phenyl)propan-2-ol. This material was used in the next synthetic step without purification.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)([CH3:19])[CH3:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:55][C:56]1([CH3:65])[O:60][C@@H:59]([CH2:61][CH2:62][CH2:63]O)[CH2:58][O:57]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:12]([C:9]1[CH:8]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:22]=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]([O:31][CH2:63][CH2:62][CH2:61][C@@H:59]3[CH2:58][O:57][C:56]([CH3:65])([CH3:55])[O:60]3)=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=2)([CH3:18])[CH3:19])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC1(C)OC[C@H](CCCO)O1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](CCCOc2c(C(C)(C)C)cc(SC(C)(C)Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cc2C(C)(C)C)O1
Temperature: 0 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
To a solution of probucol (2.93 g, 5.7 mmole) in 100 ml of THF were added Ph3P (1.63 g, 6.2 mmole) and 3-[2,2-dimethyl-1,3-dioxolane-4(S)-yl]-propanol (1.0 g, 6.2 mmole). The mixture was cooled to 0° C. with an ice bath, and DEAD (1.1 g, 6.2 mmol) was then added dropwise under nitrogen. The mixture was stirred overnight while allowed to warm to room temperature and then heated to reflux. The reaction mixture was cooled and concentrated to an oily residue when HPLC and TLC showed that the new peak ceased to grow. Chromatography on silica gel with gradient solvent from hexanes to 25% EtOAc in hexanes to afford 1.3 g (35.1%) 2,6-di-tert-butyl-4-(1-{3,5-di-tert-butyl-4-[3-(2,2-dimethyl-[1,3]dioxolan-4(R)-yl)-propoxy]-phenylsulfanyl}-1-methyl-ethylsulfanyl)phenol as a white solid. 1H-NMR (CDCl3) δ 7.53 (s, 2H), 7.45 (s, 2H), 5.37(s, 1H), 4.05–4.17 (m, 2H), 3.71–3.77 (m, 2H), 3.35 (t, J=2.5 Hz, 1H), 1.90–2.00 (m, 2H), 1.63–1.73 (m, 2H), 1.42–1.46 (m, 42H). MS m/z: 676.4429 ([M+NH4]+, 25%)
Reaction SMILES: C[O:2]/[CH:3]=[C:4]1\[CH2:5][CH2:6][C:7]2[C:8]([C:13]#[N:14])=[CH:9][CH:10]=[CH:11][C:12]\1=2.B(Br)(Br)Br>C(Cl)Cl>[CH:3]([CH:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:13]#[N:14])[C:7]=2[CH2:6][CH2:5]1)=[O:2]
Reactant: CO/C=C1\CCc2c(C#N)cccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cccc2c1CCC2C=O
Reaction time: 3 h
Yield: 83.4 %

Procedure:
A solution of (1E)-1-[(methyloxy)methylidene]-2,3-dihydro-1H-indene-4-carbonitrile (250 mg, 1.05 mmol) in DCM (5 mL) was added BBr3 dropwise at −78° C. under N2. Then the mixture was stirred at this temperature for 3 h. It was poured into ice-saturated NaHCO3 solution, and extracted with DCM. The organic layer was washed with brine and dried over Na2SO4. The solvent was removed in vacuo to give crude 1-formyl-2,3-dihydro-1H-indene-4-carbonitrile (150 mg, crude), which is used for next step directly.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([C:16]([OH:18])=[O:17])=[CH:11][CH:10]=[CH:9]2.[CH2:19](O)[CH3:20]>>[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=[CH:9]2
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cccc2cc(O)ccc12
Temperature: 25 °C
Yield: 87 %

Procedure:
Thionyl chloride (2.3 mL, 31.9 mmol) was slowly added to a solution of 6-hydroxy-1-naphthoic acid (3 g, 15.9 mmol) in ethanol (140 mL) and stirred under N2. After addition, the reaction mixture was heated at reflux under nitrogen for 6 days. The reaction mixture was cooled to room temperature and concentrated to give the crude product as an oil. The oil was carefully partitioned between 5% NaHCO3 and EtOAc. The organic phase was separated and washed with brine, dried over MgSO4, filtered and the filtrate was concentrated to give 3 g (87%) of the product as a red amorphous solid. 1H NMR (400 MHz, DMSO-d6): δ 9.92 (s, 1H), 8.57 (m, 1 H), 7.92 (d, J=8 Hz, 1 H), 7.85 (d, J=7 Hz, 1 H), 7.45 (t, J=8, 1H), 7.20-7.18 (m, 2 H), 4.38-4.33 (m, 2 H), 1.34 (t, J=7 Hz, 3 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1.ClCCl>[C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][O:11][S:21]([CH3:20])(=[O:23])=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN(CCO)Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CN(CCOS(C)(=O)=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
The product from Example 1 (10.0 g; 38 mmol) is dissolved in anhydrous pyridine (185 ml), and methanesulphonyl chloride (3.7 ml; 46 mmol) is slowly added dropwise at 0° C. The solution is stirred at room temperature for 6.5 h. Subsequently, the solution is diluted with dichloromethane (740 ml) and extracted twice with a 10% solution of sodium hydrogen carbonate (250 ml on each occasion). The organic phase is dried (magnesium sulphate) and concentrated, and the residue is subsequently distilled repeatedly with toluene. Yield: 10.79 g (85%), brown oil.
Reaction SMILES: [NH:1]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C)[P:17](N(C)C)N(C)C>>[N:1]12[P:17]3[N:11]([CH2:10][CH2:9][CH2:8][N:7]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH2:12][CH2:13][CH2:14]2
Reactant: CN(C)P(N(C)C)N(C)C
Reactant: C1CNCCCNCCNCCNC1
Product: C1CN2CCCN3CCNCCN(C1)P23

Procedure:
A stirred mixture of 6.00 g (30 mmol) of 1,4,7,11-tetraazacyclotetradecane and 4.90 g of hexamethylphosphorous triamide is heated under nitrogen for 3 hr at 120° and then distilled in a short-path apparatus to give 5.50 g (80%) of clear, colorless liquid 1,5,9,12-tetraaza-15-phosphatricyclo[7.5.1.05,15 ]pentadecane, bp 106°-110° (0.30 mm), which solidifies on storing below 0°.
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:15])([C:7]([F:14])([F:13])[C:8]([F:12])([F:11])[CH2:9][OH:10])[CH2:5][OH:6].[CH2:16](I)[CH3:17]>O>[F:3][C:4]([F:15])([C:7]([F:13])([F:14])[C:8]([F:12])([F:11])[CH2:9][O:10][CH2:16][CH3:17])[CH2:5][OH:6]
Reactant: OCC(F)(F)C(F)(F)C(F)(F)CO
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOCC(F)(F)C(F)(F)C(F)(F)CO
Temperature: 90 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
30.8 g potassium hydroxide was dissolved in 400 ml of water, 100 g (0.4715 moles) of 2,2,3,3,4,4-hexafluoropentane-1,5-diol (prepared essentially as described supra) was added, and the resulting mixture was heated to 90° C. Over a period of one hour, 74.9 g (0.480 moles) of ethyl iodide was added to the flask via an addition funnel with rapid stirring. The reaction flask was then heated to reflux for two hours. The reaction mixture was cooled to room temperature, and the bottom product phase (87.1 g) was split away from the aqueous layer. The crude product was distilled at 6.0 mm Hg (6.0 torr) to give 58.8 g of 2,2,3,3,4,4-hexafluoro-5-ethoxypentanol distilling at 85°-91° C. (conversion=68%; yield based on converted material=76%).
Reaction SMILES: [CH2:1]1[CH2:26][O:25][C:3]([C@@H:5]2[C@:22]3([CH3:23])[C@H:8]([C@H:9]4[C@H:19]([C:20](=[O:24])[CH2:21]3)[C@:17]3([CH3:18])[C@H:12]([CH2:13][CH:14]=[CH:15][CH2:16]3)[CH2:11][CH2:10]4)[CH2:7][CH2:6]2)([CH3:4])[O:2]1.[BH4-].[Na+]>C(O)C.O>[CH2:26]1[CH2:1][O:2][C:3]([C@@H:5]2[C@:22]3([CH3:23])[C@H:8]([C@H:9]4[C@H:19]([C@@H:20]([OH:24])[CH2:21]3)[C@:17]3([CH3:18])[C@H:12]([CH2:13][CH:14]=[CH:15][CH2:16]3)[CH2:11][CH2:10]4)[CH2:7][CH2:6]2)([CH3:4])[O:25]1
Reactant: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5CC=CC[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5CC=CC[C@]5(C)[C@H]4[C@@H](O)C[C@]23C)OCCO1
Yield: 96.8 %

Procedure:
20,20-Ethylenedioxy-5α-pregn-2-en-11-one (9.3 g) in hot ethanol (300 ml) was treated with sodium borohydride (5.5 g) in water (30 ml), and the mixture was refluxed on a steam bath for 1 1/2 hours, concentrated by evaporation to about 200 ml, the excess borohydride destroyed by the addition of glacial acetic acid (0.5 ml), and the mixture poured on to ice-water to give a white crystalline precipitate. The precipitate was filtered off, washed with water and dried in vacuo to give title compound (9.05 g), as colourless needles, m.p. 141°-145°, [α]D +64°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][S:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[N:36]=[C:35](Cl)[C:34]([Cl:38])=[CH:33][N:32]=1.O>CN(C)C=O>[Cl:30][C:31]1[N:36]=[C:35]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[CH2:5][S:6][C:7]2[CH:8]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[CH:10]=[CH:11][CH:12]=2)[C:34]([Cl:38])=[CH:33][N:32]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)Nc1cccc(SCc2cccc(N)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(SCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.6 %

Procedure:
A solution of tert-butyl {3-[(3-aminobenzyl)thio]phenyl}carbamate (0.55 g, 1.7 mmol) in N,N-dimethylformamide (5.0 mL) was treated with potassium carbonate (0.30 g, 2.2 mmol) and stirred at 25° C. for 5 min. The reaction mixture was treated with 2,4,5-trichloropyrimidine (0.25 mL, 2.2 mmol) and stirred at 25° C. for 16 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated and washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude gum. This material was purified by flash column chromatography to give the desired product (0.67 g, 84%) as a solid. LCMS for C22H22Cl2N4O2SNa (M+Na)+: m/z=499.0, 501.0.
Reaction SMILES: O[CH:2]=[C:3]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]([CH3:16])([C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1.Cl.[NH2:18]O>C(O)C.O>[CH3:16][C:5]1([C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][C:3]2[CH:2]=[N:18][O:9][C:8]=2[CH:7]=[CH:6]1
Reactant: NO
Reactant: CC1(C#C[Si](C)(C)C)C=CC(=O)C(=CO)C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1(C#C[Si](C)(C)C)C=Cc2oncc2C1
Yield: 99.5 %

Procedure:
To a solution of 6-(hydroxymethylene)-4-methyl-4-((trimethylsilyl)ethynyl)-cyclohex-2-enone (147 mg, 0.63 mmol) in ethanol (15 mL) was added a solution of hydroxylamine hydrochloride (452 mg) in water (0.65 mL). The mixture was heated under reflux for 1 h. To the mixture was added water (50 mL). The aqueous mixture was extracted with methylene chloride/ether (1:2, 50 mL ×3). The extract was washed with saturated aqueous sodium bicarbonate solution (50 mL ×1) and brine (50 mL ×1), dried over MgSO4, and filtered. The filtrate was evaporated in vacuo to give 9 as a crystalline solid (145 mg, quantitative yield): 1H NMR (CDCl3) δ 8.06 (1H, s), 6.47 (1H, d, J=9.9 Hz), 6.03 (1H, d, J=9.9 Hz), 3.07 (1H, d, J=16.1 Hz), 2.77 (1H, d, J=16.1 Hz), 1.37 (3H, s), 0.14 (9H, s). This material was used without further purification for the next step.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1.C(N(CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[O:40]=[C:41]1[CH2:46][S:45][C:44]2[CH:47]=[CH:48][C:49]([C:51](O)=[O:52])=[N:50][C:43]=2[NH:42]1>CN(C=O)C>[CH3:1][N:2]([CH2:3][CH:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1)[C:51]([C:49]1[CH:48]=[CH:47][C:44]2[S:45][CH2:46][C:41](=[O:40])[NH:42][C:43]=2[N:50]=1)=[O:52]
Reactant: CNCC1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(CC1CCN(C(=O)OC(C)(C)C)C1)C(=O)c1ccc2c(n1)NC(=O)CS2
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.7 %

Procedure:
To a solution of 1,1-dimethylethyl 3-[(methylamino)methyl]-1-pyrrolidinecarboxylate (153 mg, 0714 mmol) in DMF (2 mL) were added triethylamine (0.1 mL, 0.714 mmol) followed by DPPA (0.154 mL, 0.714 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (150 mg, 0.714 mmol). After stirring at room temperature for 24 h, the solution was partitioned between ethyl acetate and K CO solution (5% in H O). The aqueous layer was extracted several times with ethyl acetate. The organic fractions were combined, dried over MgSO, concentrated and purified with column chromatography (silica, 0-5% MeOH in DCM) to provide the title compound as an off-white solid (240 mg, 83%): LC/MS (ES) m/e 407 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([O:18]CC)=[O:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.[OH-].[K+].Cl>C(O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1
Reactant: CCOC(=O)c1cnn2c(-c3cccnc3)ccnc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 0.10 mole of ethyl 7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate and 0.50 mole of potassium hydroxide in 50 ml. of ethanol-water (9:1) is heated at reflux temperature for 4 hours. The mixture is brought to pH 7 with concentrated hydrochloric acid, concentrated and filtered to give 7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid. The preceding product in tetrahydrofuran is added dropwise to a solution of 0.2 mole of diborane in tetrahydrofuran chilled in an ice bath. The mixture is stirred for one hour and the bath removed. After standing 16 hours at room temperature the mixture is poured onto ice to give the product of the example.
Reaction SMILES: B(Br)(Br)Br.[CH:5]([C:8]1[C:9]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:27]C)=[CH:24][CH:25]=3)[C:20]([CH:29]=[O:30])=[C:19]([CH3:31])[N:18]=2)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[CH:11]2)([CH3:7])[CH3:6]>C(Cl)Cl>[OH:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[C:17]([C:9]1[C:8]([CH:5]([CH3:7])[CH3:6])=[CH:16][CH:15]=[C:14]3[C:10]=1[CH:11]=[N:12][NH:13]3)=[N:18][C:19]([CH3:31])=[C:20]2[CH:29]=[O:30]
Reactant: COc1ccc2c(-c3c(C(C)C)ccc4[nH]ncc34)nc(C)c(C=O)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nc(-c2c(C(C)C)ccc3[nH]ncc23)c2ccc(O)cc2c1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
BBr3 (8.8 g, 35 mmol) is added slowly to a solution of 1-(5-Isopropyl-1H-indazol-4-yl)-6-methoxy-3-methyl-isoquinoline-4-carbaldehyde (842 mg, 2.3 mmol) in DCM (15 ml) at −78° C. The cold bath is removed and the mixture is warmed to room temperature, and then stirred for a further 1 h. The reaction mixture is poured into ice-water mixture and treated with NH4OH (6 ml). The layers are separated and the aqueous layer is extracted with DCM. The combined organic layers are dried (Na2SO4) and evaporated. The residue is chromatographed on silica gel eluting with EtOAc/MeOH (20:1) to give 490 mg of starting material and 276 mg of 6-hydroxy-1-(5-isopropyl-1H-indazol-4-yl)-3-methyl-isoquinoline-4-carbaldehyde. 1H NMR (CDCl3) 10.9 (s, 1H), 8.87 (s, 1H), 7.62-7.42 (m, 4H), 6.99 (d, 1H), 3.09 (s, 3H), 2.73-2.67 (m, 1H), 1.23 (d, 3H), 1.12 (d, 3H).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.C(OC(=O)C)C>[C:1]([N:5]([C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:6][C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC(=O)NNC(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCC(=O)NN(C(=O)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 1-t-butyl-2-valerylhydrazine (4 g, 0.023M) in toluene (40 ml) at 5° C. was added benzoyl chloride (3.4 g, 0.024M) and 50% aq. sodium hydroxide (0.98 g, 0.024M). After addition, the mixture was warmed to room temperature and stirred 2.5 hour. The mixture was diluted with ethylacetate (50 ml) and washed with water (2×25 ml) and brine (1×25 ml). The organic layer was dried over magnesium sulfate and concentrated under vacuum to afford N'-t-butyl-N-valeryl-N'-benzoylhydrazine as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[N:10][C:9]2[C:8](=O)[N:7]=[CH:6][NH:5][C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.P(Cl)(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[Cl:24][C:8]1[C:9]2[N:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc[nH]c2cc(Cl)cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Clc1cnc2c(Cl)ncnc2c1
Temperature: 25 °C

Procedure:
To a mixture of 7-chloropyrido[3,2-d]pyrimidin-4(1H)-one (250 mg, 1.377 mmol) in toluene (12 mL) were added DIPEA (0.73 mL, 4.20 mmol) and phosphorus oxychloride (0.391 mL, 4.27 mmol), and the reaction was stirred at reflux for 1 hour. After cooling to RT, the reaction mixture was concentrated to provide the title compound. LC/MS (ESI+) m/z=200 (M+H).