Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:26])[CH2:5][CH2:6][C:7]1[C:8](Cl)=[N:9][C:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:16]=2[Br:24])=[N:11][C:12]=1[CH3:13])C.[CH2:27]([CH:29]([NH2:32])[CH2:30][CH3:31])[CH3:28]>CN1CCCC1=O>[Br:24][C:16]1[CH:17]=[C:18]([CH:21]([CH3:23])[CH3:22])[CH:19]=[CH:20][C:15]=1[NH:14][C:10]1[N:11]=[C:12]([CH3:13])[C:7]2[CH2:6][CH2:5][C:4](=[O:26])[N:32]([CH:29]([CH2:30][CH3:31])[CH2:27][CH3:28])[C:8]=2[N:9]=1
Reactant: CCC(N)CC
Reactant: CCOC(=O)CCc1c(C)nc(Nc2ccc(C(C)C)cc2Br)nc1Cl
Solvent: CN1CCCC1=O
Product: CCC(CC)N1C(=O)CCc2c(C)nc(Nc3ccc(C(C)C)cc3Br)nc21
Temperature: 130 °C
Yield: 49.4 %

Procedure:
A solution of 3-[2-(2-bromo-4-isopropyl-phenylamino)-4-chloro-6-methyl-pyrimidin-5-yl]-propionic acid ethyl ester (XII; 0.22 g, 0.50 mmol) in N-methylpyrrolidinone (2.5 mL) was treated with 1-ethyl-propylamine (0.22 g, 2.5 mmol) and heated to 130° C. in a sealed tube for 130 hours. The cooled reaction mixture was poured onto water (50 mL) and extracted with diethyl ether (3×50 mL). The combined extracts were washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The brown solid was chromatographed over silica gel, eluting with 20% ethyl acetate in hexane, to provide 113 as a white solid (0.11 g, 43%; mp 124-126° C.; ESIMS m/z (M+H) 445).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:14]([NH:17][CH2:18][C:19](O)=[O:20])(=[O:16])[CH3:15]>>[Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[C:5]2[O:10][C:19](=[O:20])[C:18]([NH:17][C:14](=[O:16])[CH3:15])=[CH:7][C:6]=2[CH:9]=1
Reactant: CC(=O)NCC(=O)O
Reactant: O=Cc1cc(Br)cc([N+](=O)[O-])c1O
Product: CC(=O)Nc1cc2cc(Br)cc([N+](=O)[O-])c2oc1=O

Procedure:
The second step was the Erlenmeyer condensation of 5-bromo-2-hydroxy-3-nitrobenzaldehyde (2*) with N-acetyl-glycine to yield N-(6-bromo-8-nitro-2-oxo-2H-1-benzopyran-3-yl)acetamide (3*).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]([CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH2:31][C:32]([OH:34])=O)=[CH:23][CH:22]=1)([OH:19])=O>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:17](=[O:19])[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH2:31][C:32]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:34])=[CH:23][CH:22]=1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: O=C(O)Cc1ccc(CC(=O)O)c2ccccc12
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)Cc1ccc(CC(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)c2ccccc12
Yield: 74.1 %

Procedure:
Using General Procedure A with 200 mg (0.82 mmol) D-Proline benzyl ester hydrochloride and 100 mg (0.41 mmol) (4-carboxymethyl-naphthalen-1-yl)-acetic acid afforded, after flash chromatography (EtOAc), 188 mg (75%) of the title compound as a colorless oil.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl[C:8]1[N:13]2[N:14]=[CH:15][C:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[C:19]=3[CH3:28])=[C:12]2[N:11]=[C:10]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:9]=1.[NH:35]1[CH:39]=[C:38](B(O)O)[CH:37]=[N:36]1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:28][C:19]1[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][C:16]1[CH:15]=[N:14][N:13]2[C:8]([C:38]3[CH:39]=[N:35][NH:36][CH:37]=3)=[CH:9][C:10]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[N:11][C:12]=12
Reactant: Cc1c(Cc2cnn3c(Cl)cc(N4CCOCC4)nc23)cccc1C(F)(F)F
Reactant: OB(O)c1cn[nH]c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1c(Cc2cnn3c(-c4cn[nH]c4)cc(N4CCOCC4)nc23)cccc1C(F)(F)F
Yield: 78.4 %

Procedure:
In a microwave vial was added Na2CO3 (0.049 mL, 0.097 mmol) was added to a suspension of 7-chloro-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-5-(4-morpholinyl)pyrazolo[1,5-a]pyrimidine (20 mg, 0.049 mmol), 1H-pyrazol-4-ylboronic acid (10.89 mg, 0.097 mmol), and PdCl2(dppf) (3.56 mg, 4.87 μmol) in 1,4-Dioxane (0.6 mL). The reaction mixture was purged with N2, sealed and irradiated with microwave at 150 C for 3 min (temp didn't reach to 150 C until at 7-8 min, total reaction time 10 min). LCMS showed complete reaction. The reaction mixture was concentrated, and the residue was loaded on a biotage column (10 g), which was eluted with 0-6% MeOH in DCM to give 17 mg (75%) of the product as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.51 (s, 3H), 3.72 (m, 4H), 3.87 (m, 4H), 4.11 (s, 2H), 6.60 (s, 1H), 7.21 (t, 1H), 7.52 (t, 2H), 7.75 (s, 1H), 8.67 (s, 2H); LC/MS: MS (ES+) m/e 443.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=3[N:21]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[C:22]([O:25][C@@H:26]([CH3:48])[C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:31][CH2:30]1)=[O:28])(=[O:24])[CH3:23]>>[C:22]([O:25][C@@H:26]([CH3:48])[C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][N:13]2[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=3[N:21]=[C:12]2[S:11][C:3]2[C:2]([Br:1])=[CH:10][C:6]3[O:7][CH2:8][O:9][C:5]=3[CH:4]=2)[CH2:31][CH2:30]1)=[O:28])(=[O:24])[CH3:23]
Reactant: CC(=O)O[C@@H](C)C(=O)N1CCC(CCOS(=O)(=O)c2ccc(C)cc2)CC1
Reactant: Nc1nccc2[nH]c(Sc3cc4c(cc3Br)OCO4)nc12
Product: CC(=O)O[C@@H](C)C(=O)N1CCC(CCn2c(Sc3cc4c(cc3Br)OCO4)nc3c(N)nccc32)CC1

Procedure:
The title compound was prepared by a similar procedure described for step 7 of example 1 using 2-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-1H-imidazo[4,5-c]pyridin-4-amine (350 mg, 0.95 mmol) and (2S)-1-[4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)piperidin-1-yl]-1-oxopropan-2-yl acetate (662 mg, 1.66 mmol). LC-MS [M+H]+ 590.1. This product is used for the next step without further purification.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[S:5]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]1=2.Cl.[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>ClC=CCl>[C:15]([C:11]1[CH:12]=[CH:13][C:6]2[S:5][CH2:9][CH2:8][C:7]=2[CH:10]=1)(=[O:18])[CH2:16][CH3:17]
Reactant: c1ccc2c(c1)CCS2
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC=CCl
Product: CCC(=O)c1ccc2c(c1)CCS2
Temperature: 10 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To 0.3M of aluminum chloride in 500 ml of 1,2-dichloroethylene, 0.21M of propionyl chloride are added, then slowly while stirring 0.2M of 2,3-dihydrobenzo[b]thiophene are added, temperature being maintained at about 10° C. The mixture is then still stirred for 3 hours at room temperature, then decomposed with a mixture of ice and hydrochloric acid. The organic phase is separated and the aqueous phase is extracted with 1,2-dichloroethylene. The combined organic phases are dried on MgSO4, filtered and solvent is evaporated in a vacuum. The residence obtained is solidified by addition of petroleum ether: 25 gr. of 5-propionyl-2,3-dihydrobenzo[b]thiophene are so obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH3:30][NH:31][C:32]([C:34]1[S:35][CH:36]=[CH:37][C:38]=1[NH:39][C:40]1[C:45]([Cl:46])=[CH:44][N:43]=[C:42](Cl)[N:41]=1)=[O:33].C(=O)(O)[O-].[Na+]>C(O)(C)C.O>[CH3:30][NH:31][C:32]([C:34]1[S:35][CH:36]=[CH:37][C:38]=1[NH:39][C:40]1[C:45]([Cl:46])=[CH:44][N:43]=[C:42]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[O:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)[N:41]=1)=[O:33]
Reactant: CCN1CCCOc2ccc(N)cc21
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCN1CCCOc2ccc(Nc3ncc(Cl)c(Nc4ccsc4C(=O)NC)n3)cc21
Yield: 48.7 %

Procedure:
9-Ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-ylamine (57 mg, 0.30 mmol), 10-Camphorsulfonic acid (72.3 mg, 0.311 mmol) and 3-(2,5-Dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide (9.0E1 mg, 0.30 mmol) in Isopropyl alcohol (2.0 mL) was irradiated in a CEM microwave (120° C., 30 min). The mixture was diluted with satd. sodium bicarbonate (1 mL) and water (6 mL). The flocculent solids were separated from an oily residue on the sides of the vial, filtered and washed with water. Drying in vacuo of the solids furnished 3-[5-Chloro-2-(9-ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-thiophene-2-carboxylic acid methylamide (67 mg, 49%). MP=153-155° C.; LCMS: 459 (M+H); 1H-NMR (CDCl3): 11.27 (s, 1H), 8.31 (d, 1H, J=5.1 Hz), 8.08 (s, 1H), 6.92 (s, 1H), 6.88 (m, 2H), 6.71 (s, 1H), 5.67 (s, 1H), 4.14 (m, 2H), 3.29 (m, 2H), 3.27 (m, 2H), 3.02 (d, 3H, J=4.8 Hz), 2.03 (m, 2H), 1.18 (t, 3H, J=6.4 Hz).
Reaction SMILES: C(OC([NH:11][C:12]1([CH2:25][OH:26])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=O)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].[C].C(O)C>[NH2:11][C:12]1([CH2:25][OH:26])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(NC(=O)OCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N)(CO)CC1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To 10 mL of an ethanol solution containing 0.55 g of tert-butyl 4-(((benzyloxy)carbonyl)amino)-4-(hydroxymethyl)piperidine-1-carboxylate, 0.10 g of 20% palladium hydroxide-carbon was added at room temperature, and the mixture was stirred at 40° C. for 3 hours under a hydrogen atmosphere. The insoluble material filtered off, and the filtration residue thus obtained was washed 3 times with chloroform. The filtrate and the washing solution were combined, and the solvent was removed under reduced pressure to obtain 0.39 g of a dark brown oily substance, tert-butyl 4-amino-4-(hydroxymethyl)piperidine-1-carboxylate.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([N:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH2:8][CH2:9][CH3:10].[C:24]([O-])(=[O:26])C.[Na+]>CN(C)C=O>[CH:24]([C:20]1[CH:21]=[CH:22][C:23]2[N:11]([CH:6]=[CH:7][CH2:8][CH2:9][CH3:10])[C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:26]
Reactant: CCCC=Cn1c2ccccc2c2ccccc21
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCC=Cn1c2ccccc2c2cc(C=O)ccc21
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Phosphorus oxychloride (9.1 g, 60mmol) was added to dimethylformamide (17 mL) at 0° C. with strong stirring over 15 minutes. Upon complete addition, the orange solution was stirred at 0° C. for a further 10 minutes. N-pentenyl-carbazole (10.5 g, 45 mmol) was gradually added to the iminium salt and the mixture was heated at 100° C. for 1.5 hours, then cooled to room temperature and added to ice. The ice slurry was adjusted to a pH of 6 with saturated sodium acetate solution and the crude product was extracted with dichloromethane (2×50 mL), dried (Na2SO4), and concentrated. Traces of dimethylformamide were removed under high vacuum to give 9.6 g of 3-formyl-N-pentenyl-carbazole as a brown oil. The material was used at this level of purity in the next step of the synthesis.
Reaction SMILES: [OH-].[Na+].[CH:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)([CH3:5])[CH3:4]>C(O)C.[Zn]>[NH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[NH:6][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)Nc1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Product: CC(C)Nc1ccccc1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To a mixture of ethanol (600 mL) and 2 M sodium hydroxide solution (320 mL) cooled in an ice bath was added Zn dust (59.5 g) slowly. While stirring the Zn slurry, N-isopropyl-N-(2-nitrophenyl)amine (41 g, 0.228 mol) dissolved in ethanol (50 mL) was added. The mixture was stirred at 0° C. for 30 min, then heated to 85° C. The mixture was stirred at 85° C. for about 12 h until the refluxing solution of the mixture became a colorless solution. The mixture was then cooled to 0° C. and filtered. The collected solid was rinsed with EtOAc (200 mL). The filtrate and rinsed solution were combined, and evaporated in vacuo to remove excess volatile solvents. During the concentration, the mixture became pale brown/yellow. The aqueous concentrate was extracted with EtOAc (800 mL). The organic solution was concentrated to dryness, to provide the title intermediate (33 g) as a brown-pink oil which was used in the next step without further treatment. 1H-NMR (CDCl3, 300 MHz): δ (ppm) 6.73-6.5 (m, 4H), 3.58-3.55 (hept, 1H), 1.2 (d, 6H).
Reaction SMILES: C(N[C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[C:12](O)=[O:13])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:4][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[CH2:12][OH:13]
Reactant: CCNC(=O)N1CCCC[C@@H]1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCCC[C@@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
The product of Step 1 (0.60 g, 0.003 mole) in dry tetrahydrofuran (10 ml) was added dropwise to a suspension of lithium aluminium hydride (0.57 g, 0.015 mole) in dry tetrahydrofuran (20 ml). The mixture was heated under reflux for 2 hours and stirred at room temperature overnight. The reaction mixture was cooled to 0° C. and water (0.5 ml) was added dropwise, followed by 10% sodium hydroxide solution (0.9 ml) and water (1.4 ml). The mixture was stirred for 1 hour, filtered through Celite and the filtrate evaporated in vacuo to afford the title compound 0.31 g (80%) as a pale yellow oil; 1H NMR (CDCl3) 1.17-2.00 (8H, m), 2.14 (1H, dt, J 13 and 2 Hz), 2.30 (3H, s), 2.76-2.96 (1H, m), 3.40 (1H, dd, J 13 and 1 Hz), 3.88 (1H, dd, J 12 and 5 Hz); MS (+ve ion electrospray) m/z 130 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[C:7]3[CH:13]=[C:12]([C:14]4[CH:15]=[C:16]([CH2:20][NH2:21])[CH:17]=[CH:18][CH:19]=4)[NH:11][C:8]3=[N:9][CH:10]=[C:5]2[CH:4]=[N:3]1.CCN(C(C)C)C(C)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>CN(C=O)C>[CH3:1][N:2]1[C:6]2=[C:7]3[CH:13]=[C:12]([C:14]4[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=4)[CH2:20][NH:21][S:32]([CH3:31])(=[O:34])=[O:33])[NH:11][C:8]3=[N:9][CH:10]=[C:5]2[CH:4]=[N:3]1
Reactant: Cn1ncc2cnc3[nH]c(-c4cccc(CN)c4)cc3c21
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc2cnc3[nH]c(-c4cccc(CNS(C)(=O)=O)c4)cc3c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
To a flask was added (3-(1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)phenyl)methanamine (0.075 g, 0.27 mmol, Example #T.3.1), DMF (2.7 mL), DIEA (0.118 mL, 0.676 mmol) and MsCl (0.025 mL, 0.325 mmol). The mixture was stirred at rt for about 10 min. The mixture was purified directly by flash chromatography (25 g silica gel column, DCM/MeOH 1:0 to 10:1 with 2% 2.0 M NH3 in EtOH). The solid was dried under reduced pressure at about 60° C. for about 1 h to give N-(3-(1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)benzyl)methanesulfonamide (0.057 g, 58%): LC/MS (Table 2, Method a) Rt=1.84 min; MS m/z 356 (M+H)+. Syk IC50=B.
Reaction SMILES: [CH2:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:3](=[O:4])[CH2:2]1.O.[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[N+:13]([C:8]1[CH:7]=[C:1]2[C:11](=[CH:10][CH:9]=1)[CH2:6][NH:5][C:3](=[O:4])[CH2:2]2)([O-:15])=[O:14]
Reactant: O=C1CCc2ccccc2N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1Cc2cc([N+](=O)[O-])ccc2CN1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To a solution of hydrocarbostyril (9.00 g, 61.2 mmol) in conc. H2SO4 (180 mL) cooled to −10° C. was slowly added H2O (45 mL), followed by HNO3 (65%, 4.5 mL). The yellow solution was stirred at −10° C. for 10 min and then carefully quenched at −10° C. with H2O (500 mL). The precipitated yellow solid was filtered off, washed with H2O and dried in vacuo to yield 1,2-dihydro-6-nitroisoquinolin-3(4H)-one (10.3 g, 88% yield). 1H NMR (400 MHz, CDCl3): δ 9.35 (brs, 1H), 8.12-8.09 (m, 2H), 6.95-6.92 (m, 1H), 3.10 (t, J=7.6 Hz, 2H), 2.73 (t, J=7.8 Hz, 2H); MS (ESI) m/z: 193.0 (M+H+).
Reaction SMILES: II.Br[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1.[Mg].Cl[Si:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=1)([CH3:25])[CH3:24]>O1CCCC1.C(OCC)C>[CH2:33]([O:32][C:29]1[CH:30]=[CH:31][C:26]([Si:23]([CH2:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=2)([CH3:24])[CH3:25])=[CH:27][CH:28]=1)[CH3:34]
Reactant: CCOc1ccc([Si](C)(C)Cl)cc1
Reactant: Fc1ccc(CCCBr)cc1Oc1ccccc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1ccc([Si](C)(C)CCCc2ccc(F)c(Oc3ccccc3)c2)cc1
Temperature: 10 °C

Procedure:
A small crystal of iodine was added to a mixture of 0.75 g (0.0024 mole) of 1-bromo-3-(4-fluoro-3-phenoxyphenyl)propane and 0.11 g (0.0045 mole) of magnesium powder in 1 ml of tetrahydrofuran. This mixture was heated in a water bath for about three hours. After heating, the clear solution was light grey-brown in color. The solution was cooled to 10° C., and 0.51 g (0.0022 mole) of chloro(4-ethoxyphenyl)dimethylsilane was added. This mixture was stirred for one-half hour and was then heated for an hour. Following dilution with diethyl ether, the reaction mixture was washed successively with 10% hydrochloric acid and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, leaving a colorless oil weighing 0.95 g as the residue. This oil was purified using a Chromatotron (eluant=ethyl acetate/hexane (2:98)), producing (4-ethoxyphenyl)[3-(4-fluoro-3-phenoxyphenyl)propyl]dimethylsilane as a colorless oil. The proton and 13C nmr spectra were consistent with the proposed structure.
Reaction SMILES: [CH3:1][CH:2]1[C:6]([N:7]2[CH2:11][CH2:10][C:9]3([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:8]2=[O:24])=[C:5]([CH3:25])[C:4](=[O:26])[O:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][CH:2]1[C:6]([N:7]2[CH2:11][CH2:10][C:9]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:8]2=[O:24])=[C:5]([CH3:25])[C:4](=[O:26])[O:3]1
Reactant: CC1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)C(C)OC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1=C(N2CCC3(CCNCC3)C2=O)C(C)OC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(2,4-dimethyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (195 mg, 0.535 mmol) in methylene chloride (1 mL) was added trifluoroacetic acid (2.06 mL, 26.8 mmol) and the resulting solution was stirred at rt for 1 h. After removing the volatiles the residue was dissolved in methylene chloride (1 mL) and treated with hydrogen chloride (4 mL, 1N in diethyl ether) and concentrated to give 2-(2,4-dimethyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one. LCMS: (M+1)+: 265.19.
Reaction SMILES: C([NH:4][C:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:20][CH:19]=1)(C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=O)C.[ClH:32]>C(O)C>[ClH:32].[NH2:4][CH:5]([CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:23]=1)[C:6]([OH:8])=[O:7]
Reactant: CCCCCCCCc1ccc(CCC(NC(C)=O)(C(=O)OCC)C(=O)OCC)cc1
Agent: Cl
Solvent: CCO
Product: CCCCCCCCc1ccc(CCC(N)C(=O)O)cc1

Procedure:
Diethyl 2-acetamido-2-[2-(4-octylphenyl)ethyl]malonate (20 g) was added to a 5N aqueous hydrochloric acid solution (350 ml) and the mixture was refluxed under heating for 6.5 hours. Ethanol (45 ml) was added to the mixture and the whole mixture was further refluxed under heating for 1.5 hours. The reaction mixture was concentrated under reduced pressure to give the subject compound (20 g).
Reaction SMILES: CC(C)=[O:3].Br[CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13](=[O:17])[O:14]2)=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>O>[OH:3][CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13](=[O:17])[O:14]2)=[CH:9][CH:8]=1
Reactant: O=c1ccc2ccc(CBr)cc2o1
Reactant: CC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=c1ccc2ccc(CO)cc2o1

Procedure:
To a 1:1 mixture of acetone and water (560 ml) was added 7-bromomethy1coumarin (7.0 g, 29.3 mmol). The resulting suspension was refluxed for 48 hrs at which time the reaction mixture became a clear solution. The solution was then cooled and neutralized with sodium bicarbonate (2.4 g, 29.3 mmol) and concentrated in vacuo to about 65 ml. A thick mass of crystals resulted. The crystals were collected by filtration to yield 5.27 g of product after drying in vacuo (100% of theory). The melting point was 116°-117° C.
Reaction SMILES: C[Mg]Br.[CH2:4](N(CC)CC)C.[CH3:11][C:12]1[CH:13]=[C:14]([N:18]2[N:22]=[N:21][C:20]([C:23]([O:25]CC)=O)=[N:19]2)[CH:15]=[CH:16][CH:17]=1.Cl>C1(C)C=CC=CC=1.O>[CH3:11][C:12]1[CH:13]=[C:14]([N:18]2[N:22]=[N:21][C:20]([C:23](=[O:25])[CH3:4])=[N:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1nnn(-c2cccc(C)c2)n1
Reactant: CCN(CC)CC
Agent: C[Mg]Br
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1nnn(-c2cccc(C)c2)n1
Temperature: -10 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
Methylmagnesium bromide (1070 mL, 1.50 mol, 1.4 M in tetrahydrofuran/toluene) in triethylamine (520 mL, 3.74 mol) was added via an addition funnel to a stirred solution of ethyl 2-(3-methylphenyl)-2H-tetrazole-5-carboxylate in dry toluene (1000 mL) at −10° C. for 5 hours. The mixture was continued to stir at −10° C. overnight. A cooled (+3° C.) solution of hydrochloric acid (37%, 500 mL) and water (500 mL) was added over 2 hours 20 minutes. The layers were separated and the organic layer was washed with water (500 mL) and brine (2×250 mL). The aqueous layer was extracted with toluene (3×500 mL) and the toluene was washed with brine (2×250 mL). The combined organic extracts were concentrated and purified on silica using dichloromethane as eluent. The concentrated product residue was triturated with petroleum ether, filtrated and dried under reduced pressure at room temperature to give the title product (90.86 g, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH2:21][NH2:22])[CH2:15][CH2:14]1>CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([NH:22][CH2:21][CH2:20][CH2:19][CH:16]2[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: CN1CCC(CCCN)CC1
Solvent: CO
Product: COC(=O)c1cnc(NCCCC2CCN(C)CC2)cn1
Temperature: 25 °C

Procedure:
A solution of 5-chloro-pyrazine-2-carboxylic acid methyl ester (1 equiv.) and 3-(1-methyl-piperidin-4-yl)-propylamine (1.1 equiv.) in MeOH (0.25 M) heated at 100° C. in a sealed tube for 4 h. The mixture was cooled to rt and concentrated to give a crude product which was purified by FCC.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@@H:17]2[O:35][C@H:18]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:36]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@H:17]([OH:35])[C@@H:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:20]=2)[NH2:36])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc([C@@H]2O[C@H]2c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Reactant: N
Product: COc1ccc([C@@H](N)[C@@H](O)c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1

Procedure:
Mixture: 1.0 g (2.1 mmol) of rel-(S,S)-3,3'-dibenzyloxy-4,4'-dimethoxystilbene oxide, 15 ml of EtoH, abs., 15 ml of ammonia.