Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:12]=[C:11]2[N:6]([CH2:7][CH2:8][CH2:9][CH:10]2[OH:13])[C:4](=[O:5])[C:3]=1[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[C:23]3[CH:24]=[CH:25][C:26]([F:31])=[CH:27][C:28]=3[O:29][N:30]=2)[CH2:18][CH2:17]1.[C:32]1(=[O:38])[O:37][C:35](=[O:36])[CH2:34][CH2:33]1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:31][C:26]1[CH:25]=[CH:24][C:23]2[C:22]([CH:19]3[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C:3]4[C:4](=[O:5])[N:6]5[CH2:7][CH2:8][CH2:9][CH:10]([O:13][C:32](=[O:38])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:11]5=[N:12][C:2]=4[CH3:1])[CH2:17][CH2:18]3)=[N:30][O:29][C:28]=2[CH:27]=1
Reactant: O=C1CCC(=O)O1
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2OC(=O)CCC(=O)O
Temperature: 60 °C
Reaction time: 48 h

Procedure:
Paliperidone (10 g, 23.45 mmol) was dissolved in pyridine (100 mL) together with N,N-dimethyl-4-pyridinamine (0.5 g; 4.09 mmol) and succinic anhydride (18.3 g; 182.86 mmol). The mixture was stirred under an argon atmosphere for 4 h at 60° C. and for 48 h at room temperature. The reaction mixture was evaporated and dissolved in dichloromethane/methanol (100 mL/10 mL) and water (100 mL). The aqueous phase was extracted five times with dichloromethane/methanol (100 mL/10 mL). The organic layers were combined, dried over Na2SO4 and evaporated under vacuum. The residue was purified by silica gel chromatography (gradient elution with chloroform/ethanol 80/20 to 70/30). The product was dissolved in isopropanol (50 mL) and the resulting precipitate was filtered and washed with isopropanol (10 mL). The precipitate was dried in vacuo to give the title compound as a white solid. ESI-MS (M+1) 528. 1H NMR: (DMSO-d6, 360 MHz): δ ppm 1.75-2.75 (m, 23H), δ 3.5-4.0 (m, 3H), δ 5.74 (m, 1H), δ 7.28 (td, J=9.15, 2.20 Hz, 1H), δ 7.69 (dd, J=8.96, 2.01 Hz, 1H), δ 8.02 (dd, J=8.78, 5.12 Hz, 1H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1.C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CCCCCCCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCCCCCCCCCBr
Yield: 3476.4 %

Procedure:
This example is a method of synthesis for inventive compound no. 3549 (see above for chemical name and structure). A solution of 11-bromoundecanoic acid (5.70 g, 22 mmol, available from Aldrich) and p-toluenesulfonic acid (0.1 g) in absolute ethanol (100 ml) was refluxed for 3 hours. A saturated aqueous sodium bicarbonate solution (40 ml) was added and the reaction mixture then extracted with three 70 ml aliquots of dichloromethane. The combined extracts were washed with water (50 ml) and saturated aqueous salt solution (50 ml) and the solvent was evaporated, leaving a colorless oil. Ethyl 11-bromoundecanoate (5.92 g, 94% yield) was collected during distillation (2 mm) at 135° C. A solution of this bromoester (5.92 g, 20 mmol) and 1-sodiotheobromine (4.08 g, 20 mmol) in dimethylsulfoxide (80 ml) was stirred for 18 hours at ambient temperature. The mixture was added to water (100 ml) and dichloromethane (100 ml). The aqueous layer was extracted with two 80 ml aliquots of dichloromethane. The combined organic layers were washed with water (80 ml) and saturated aqueous salt solution (80 ml), dried over magnesium sulfate, and the solvent was evaporated under vacuum, leaving a white solid residue. The residue was recrystallized in dichloromethane/ether/hexane, yielding 4.95 g of 1-(ethyl 11-yl-undecanoate)-3,7-dimethylxanthine (62% yield).
Reaction SMILES: CC1C=CC(S(O[N:12]=[C:13]2[CH2:22][CH2:21][CH2:20][C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)(=O)=O)=CC=1.C([O-])(=[O:25])C.[K+]>CCO.O>[N:18]1[C:19]2[CH2:20][CH2:21][CH2:22][C:13](=[O:25])[NH:12][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)ON=C2CCCc3ncccc32)cc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1CCCc2ncccc2N1
Temperature: 25 °C

Procedure:
A mixture of 1.0 eq of 95 and 2.3 eq of potassium acetate in 70 mL of EtOH and 140 mL of H2O was refluxed for 17 hrs. After cooling to rt and rotary evaporation of the EtOH, the solution was made alkaline with 10 N NaOH. The mixture was extracted with chloroform (3×50 mL). The combined organic extracts were dried over MgSO4 and vacuum filtered. The filtrate was rotary evaporated and dried under vacuum to yield 96.
Reaction SMILES: C(O)(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-].[C:13]([C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][C:24]([C:30]([OH:32])=[O:31])=[CH:23][C:22]=1[N+]#N)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.O.O.C([O-])(=O)C.[Na+].C(OCC)C>C(#N)C.O>[C:13]([C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][C:24]([C:30]([OH:32])=[O:31])=[CH:23][C:22]=1[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#[N+]c1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Reactant: O=C(O)C=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: O=C(O)c1cc(C=Cc2ccccc2)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of cinnamic acid (3.1 g) in acetonitrile (200 ml), moist 2-benzoyl-5-carboxy-3-nitrobenzenediazonium chloride (corresponding to about 8 g dry material) is added. To the vigorously stirred suspension, a solution of sodium acetate trihydrate (9.4 g) in water (160 ml) is added, followed immediately by a solution of cupric chloride dihydrate (1 g) in water (10 ml). After stirring at room temperature for a further 2 hours, the vigorous nitrogen-evolution has subsided and the mixture is diluted with water (180 ml) followed by diethyl ether (130 ml). The mixture is filtered, and the organic layer is separated. The aqueous layer is extracted with five portions of diethyl ether, and the combined ether extracts are washed with water and evaporated in vacuo. The residue is crystallized by trituration with aqueous ethanol (50-100 ml). The crude 4-benzoyl-5-nitro-3-styrylbenzoic acid obtained is collected by filtration, washed with aqueous ethanol and dried. The crude acid is dissolved in hot 1 N sodium hydrogen carbonate, and after cooling, the precipitated sodium 4-benzoyl-5-nitro-3-styrylbenzoate is collected by filtration and washed with a small amount of icecold water. After drying, the salt is dissolved in hot water (100 ml) and the solution is clairied by filtration hot in the presence of decolorizing carbon. 4-Benzoyl-5-nitro-3-styrylbenzoic acid is precipitated by acidification with acetic acid. It is collected by filtration and is, after drying, obtained with a melting point of 288°-289° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=2)=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH2:21][C@H:22]([C:24]1[N:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:32](=[O:40])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[Cl:41])[N:25]=1)[CH3:23].[F-].[K+].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=2)=[C:6]([NH:21][C@H:22]([C:24]2[N:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:32](=[O:40])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[Cl:41])[N:25]=2)[CH3:23])[N:5]=[CH:4][N:3]=1
Reactant: C[C@H](N)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: COC(=O)c1ccc(C#Cc2c(N)ncnc2Cl)nc1
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C#Cc2c(N)ncnc2N[C@@H](C)c2nc3cccc(Cl)c3c(=O)n2-c2ccccc2)nc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To methyl 6-((4-amino-6-chloropyrimidin-5-yl)ethynyl)nicotinate (50 mg, 0.17 mmol) (prepared according to the procedure in Example 3 above) in NMP (5 mL) was added (S)-2-(1-aminoethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (62 mg 0.21 mmol) (prepared according to the procedure in Example 2A above), KF (33 mg 0.35 mmol), and Hunig's base (0.15 ml, 0.21 mmol). After stirring overnight at 120° C. the reaction was cooled to rt. Water was added. The precipitate was filtered, and then dissolved in DCM. Purification on silica with 0 to 100% EtOAc in hexanes then 0 to 20% MeOH in EtOAc gave material that required further purification. Purification on a reverse phase system run from 0 to 95% ACN in water (0.1% TFA) gave (S)-methyl 6-((4-amino-6-(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidin-5-yl)ethynyl)nicotinate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:15](=O)([O-])[O-].[Na+].[Na+].CI.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: Cc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1C
Temperature: 60 °C
Yield: 83.5 %

Procedure:
To a stirred solution of 5-chloro-2-methyl-3-nitrobenzoic acid (6.75 g, 31.3 mmol) in DMF (33 mL), were added sodium carbonate (13.2 g, 125 mmol) and methyl iodide (17.8 g, 125 mmol). The mixture was heated at 60° C. for 4 h. Water was added to the reaction mixture followed by extraction with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel to afford the title compound (6.0 g, 84%).
Reaction SMILES: C([Mg]Br)C.[O:5]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN(P(N(C)C)(N(C)C)=O)C.[CH2:30]=[O:31].Cl>C(OCC)C.C1(C)C=CC=CC=1>[O:5]([C:12]1[CH:13]=[C:14]([CH:30]=[O:31])[C:15]([OH:18])=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: C=O
Agent: CC[Mg]Br
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: O=Cc1cc(Oc2ccccc2)ccc1O
Temperature: 80 °C
Yield: 41.7 %

Procedure:
Ethyl magnesium bromide (67.5 mL of an approximately 3.0 M solution in diethyl ether, 202.5 mmol) was added to toluene (50 mL). A solution of 4-phenoxyphenol (25.00 g, 134.26 mmol) in diethyl ether (35 mL) was added resulting in the evolution of gas. The reaction was heated to 80° C. causing distillation of the diethyl ether. Toluene (300 mL), HMPA (23.4 mL, 24.059 g, 134.26 mmol), and paraformaldehyde (10.07 g, 335.65 mmol) were added and the reaction was heated to 85° C. for 4 hours. The reaction was cooled to room temperature and was acidified with 2N HCl. The resulting layers were separated and the organic phase collected. The organic phase was washed with brine. The combined aqueous phases were extracted with methylene chloride. The organic phases were combined, dried over MgSO4, filtered and concentrated in vacuo yielding a yellow oil. The oil was purified by silica flash chromatography (hexanes-ethyl acetate, 95:5). Concentration in vacuo of the desired fractions provided the salicylaldehyde as a pale yellow powder (12.0 g, 42%) of suitable purity to use in subsequent steps.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.ClC[C:11]([N:13](CCCC)CCCC)=[O:12].C(N(C(C)C)CC)(C)C.C(COC)[O:32]C>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:11]([NH2:13])=[O:12])[C:3]=1[C:2]([NH2:1])=[O:32]
Reactant: CCCCN(CCCC)C(=O)CCl
Reactant: COCCOC
Reactant: NCc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=O)c1cccnc1C(N)=O

Procedure:
Pyridine diamide 6 was prepared according to the general procedure described in Example 8 using 2-(aminomethyl)pryidine (0.010 mol), 2-chloro-N,N-dibutylacetamide (0.030 mol), diisopropylethylamine (0.030 mol) and dimethoxyethane (30 mL). The product was isolated from the methylene chloride extraction of the acidic aqueous layer. The product was made basic by extraction with aqueous NaOH. The organic solution was concentrated, and the residue was distilled (150°-200° C., 0.10 mm) to afford 3.6 g of product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[Cl:12].Cl.[CH3:14][C@H:15]1[CH2:20][NH:19][CH2:18][CH2:17][N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[CH2:2][N:19]1[CH2:18][CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:15]([CH3:14])[CH2:20]1
Reactant: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2Cl)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.5 %

Procedure:
A mixture of crude 1-(bromomethyl)-2-chloro-4-nitrobenzene (D102) (0.391 g), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate hydrochloride (0.407 g, 1.72 mmol) and Hunig's base (0.625 mL, 3.59 mmol) in dry DMF (3 mL) was stirred at room temperature for 10 minutes. The reaction mixture was concentrated to give an orange oil which was dissolved in DCM and washed with water (33 2) and brine, then dried and concentrated to give an orange oil. Purification by column chromatography eluting with 0-30% EtOAc/pentane gave the title compound as a yellow oil (0.199 g). δH (CDCl3, 400 MHz) 8.24 (1H, d), 8.12 (1H, dd), 7.77 (1H, d), 4.24 (1H, br.s), 3.85 (1H, d), 3.63 (2H, s), 3.14 (1H, td), 2.76 (1H, m), 2.59 (1H, m), 2.33 (1H, dd), 2.18 (1H, m), 1.47 (9H, s), 1.28 (3H, d). MS (ES): MH+ 370/372,
Reaction SMILES: [I:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[CH:18]([Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19].O>CN(C=O)C>[I:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:18]([CH3:20])[CH3:19])[CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2cccc(I)c2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1ccc2cccc(I)c2c1)(C(C)C)C(C)C
Temperature: 40 °C

Procedure:
1-Iodo-7-hydroxynaphthalene, as described in Step A, (15.84 g, 58.65 mmol), imidazole (5.59 g, 82.11 mmol) and triisopropylsilyl chloride (17.6 mL, 82.11 mmol) were dissolved in DMF (40 mL) and heated to 40° C. for 18 hours. The reaction was poured into H2O and extracted with hexanes (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo, to yield the above-titled compound.
Reaction SMILES: CNN.[Si:4]([O:11][CH2:12][C@H:13]1[O:17][C@@H:16]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:15][C@@H:14]1[O:27][N:28]1C(=O)C2=CC=CC=C2C1=O)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]>C(Cl)Cl>[NH2:28][O:27][C@@H:14]1[C@@H:13]([CH2:12][O:11][Si:4]([C:7]([CH3:10])([CH3:8])[CH3:9])([CH3:5])[CH3:6])[O:17][C@@H:16]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:15]1
Reactant: Cc1cn([C@H]2C[C@H](ON3C(=O)c4ccccc4C3=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Agent: CNN
Solvent: ClCCl
Product: Cc1cn([C@H]2C[C@H](ON)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
Cold methylhydrazine (1.6 ml, 30 mmol) was added to a stirred solution of 5'-O-(t-butyldimethylsilyl)-3'-O-phthalimidothymidine (2, 4.6 g, 9.18 mmol) in dry CH2Cl2 (60 ml) at 5°-10° C. After 10 minutes white precipitation of 1,2-dihydro-4-hydroxy-2-methyl-1-oxophthalizine occurred. The suspension was stirred at room temperature for 1 h. The suspension was filtered and precipitate washed with CH2 l Cl2 (2×20 ml). The combined filtrates were concentrated and the residue purified by silica gel column chromatography. Elution with CH2Cl2 :MeOH (100:0→97:3, v/v) furnished the title compound (3.40g, 100%) as white solid. Crystallization from CH2Cl2 gave white needles, m.p. 171° C.; 1H NMR (CDCl3)) δ0.05 [s, 6, (CH3)2 ], 0.90 [s, 9, (CH3)3 ], 2.22-2.58 (2m, 2, 2'CH2), 3.9-4.08 (m, 3, 5'CH2, and 3'H) 4.30 (m, 1, 4'H) 5.5 (br s, 2, NH2) 6.2 (m, 1, 1'H) 7.45 (s, 1, C6HH) 8.9 (br s, 1, NH). Anal. Calcd. for C16H29O5Si: C, 51.72; H, 7.87; N, 11.32. found: C, 51.87, H, 7.81; N, 11.32.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Si:14]([O:21][CH2:22][CH2:23][CH2:24][OH:25])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].CN1CCOCC1>C(Cl)Cl>[Si:14]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=1)=[O:10])([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:16])[CH3:15]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
A 0.604 g (3.00 mmol) sample of p-nitrophenoxycarbonylchloride in 3 mL of methylene chloride was added to a solution of 0.570 g (3.00 mmol) of 3-(t-butyldimethylsilyloxy)-1-propanol and 0.329 mL of 4-methylmorpholine in 2 mL of methylene chloride cooled in an ice bath. The solution was stirred for 2 hours. The mixture was diluted with methylene chloride, which was washed with water, dried and concentrated. The crude product was chromatographed on silica gel, eluting with 10% ethyl acetate in hexane. The solvent was removed and the product dried to afford 0.831 g of the title compound, which was taken directly to the next step.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[CH3:8][C:9]1[CH:14]2[C:15]([CH3:17])([CH3:16])[CH:12]([CH2:13]2)[CH2:11][CH:10]=1.[C:18](O)([CH3:21])([CH3:20])[CH3:19].O>S(=O)(=O)(O)O.C1(C)C(C)=CC=CC=1>[CH:14]12[CH2:13][CH:12]([C:15]1([CH3:17])[CH3:16])[CH2:11][CH2:10][C:9]2([S:1][C:2]1[S:3][C:4]([S:7][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:5][N:6]=1)[CH3:8]
Reactant: Sc1nnc(S)s1
Reactant: CC1=CCC2CC1C2(C)C
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)(C)Sc1nnc(SC2(C)CCC3CC2C3(C)C)s1
Temperature: 140 °C

Procedure:
2,5-Dimercapto-1,3,4-thiadiazole (35 g, 0.23 mol) and alpha-pinene (35 g, 0.26 mol) were charged to a reaction vessel and heated cautiously to 140° C. (exothermic reaction). The reaction was maintained at 135°-155° C. for 15 min. The reaction was fitted with a Dean Stark trap filled with xylene. Xylene (15 ml) was charged to the reaction. The reaction was fitted with an addition funnel containing t-butanol (25 g, 0.34 mol). The alcohol was added slowly with the reaction refluxing. Sulfuric acid (3 drops) was added to accelerate the water removal. The reaction product was isolated after approximately 5 ml (about 0.25 mol) of water were collected. Solvent was stripped by rotary evaporation. The product was mixed with calcium hydroxide (1 g), hexane (about 100 ml), and sufficient acetone (about 50 ml) to maintain one liquid layer. The product was filtered using a filter aid and the solvent removed by rotary evaporation. This afforded the final product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:24][CH2:23]2)=[C:18]([F:33])[CH:17]=1.BrC1C=C2C(=CC=1)[C:41](=[O:45])NC(=O)C2=CNC1C=CC(N2CC(C)NC(C)C2)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/[O:45][CH3:41].[F:33][C:18]1[CH:17]=[C:16]([NH2:15])[CH:21]=[CH:20][C:19]=1[N:22]1[CH2:27][CH2:26][CH:25]([N:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:24][CH2:23]1
Reactant: O=C1NC(=O)c2ccc(Br)cc2/C1=C/Nc1ccc(N2CCC(N3CCCC3)CC2)c(F)c1
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Product: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Product: Nc1ccc(N2CCC(N3CCCC3)CC2)c(F)c1

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione, 0.18 g (40.0% yield) of brown solid is obtained from 0.25 g (0.89 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione, and 0.25 g (1.07 mmol) of [3-fluoro-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl]amine: mp 204-205° C.; MS (ESI) m/z 513.0 (M+H)+1
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1.[CH2:9]([OH:12])[CH2:10]O.O.[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:12]1[CH2:9][CH2:10][O:8][CH:7]1[C:4]1[CH:3]=[C:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:6][CH:5]=1
Reactant: c1ccccc1
Reactant: O=Cc1csc(Br)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: c1ccc(-c2cc(C3OCCO3)cs2)cc1

Procedure:
A solution of 5-bromo-3-thiophenecarboxaldehyde (32.5 g) in benzene (500 ml) was treated with p-toluenesulphonic acid monohydrate (0.323 g) and ethylene glycol (21.1 g), and the mixture heated under reflux in a Dean and Stark apparatus until the theoretical volume of water had been removed. After cooling the mixture was washed with water, (2 x) then brine, dried, filtered and concentrated, and the residue distilled (b.p. 96°-100° at 0.4 mm) to give the title compound as an oil (24 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17]CC3C=CC=CC=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:7])[CH3:6])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[C:5]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:7])[CH3:6])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(C)(C)n1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(C)n1ccc2cc(O)ccc21
Yield: 96.2 %

Procedure:
A mixture of 2-(5-benzyloxy-indol-1-yl)-2-methyl-propionic acid ethyl ester (15.6 g) and Pd/C (5%, 1.93 g) in ethanol (190 mL) is stirred under 60 PSI of hydrogen overnight. Filtration and concentration yields the title compound (11 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](I)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].C([Mg]Cl)(C)C.[CH2:19]([Sn:23]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])Cl)[CH2:20][CH2:21][CH3:22]>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn:23]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH3:22])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(I)n[nH]c2c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a round-bottomed flask, 6-chloro-3-iodo-1H-indazole (250 mg, 0.85 mmol) was dissolved in THF (5 ml) and sodium hydride (60% dispersion in mineral oil, 41 mg, 1.03 mmol) was added. The reaction mixture was stirred at room temperature for 10 min then cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride (2.0 M in THF, 0.52 ml, 1.04 mmol) was added dropwise. The reaction mixture was stirred at −16° C. for 30 min then additional isopropylmagnesium chloride (2.0 M in THF (0.14 ml, 0.28 mmol) was added. The reaction mixture was stirred at −16° C. for 10 min then tributylchlorostannane (0.28 ml, 1.03 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature over 2.5 h then quenched with saturated NH4Cl-solution and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered, concentrated to give 6-chloro-3-tributylstannanyl-1H-indazole as a yellow oil which was used without further purification.