Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[O:10][CH3:11])[C:3]=1[O:12][CH3:13].[Li]CCCC.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C>O1CCCC1>[CH3:13][O:12][C:3]1[C:4](/[CH:8]=[CH:9]/[O:10][CH3:11])=[CH:5][CH:6]=[CH:7][C:2]=1[B:19]([OH:24])[OH:20]
Reactant: CO/C=C/c1cccc(Br)c1OC
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CO/C=C/c1cccc(B(O)O)c1OC
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 1-bromo-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]benzene (D100) (930 mg, 3.83 mmol) in Tetrahydrofuran (THF) (10 mL) was added BuLi (1.989 mL, 4.97 mmol) dropwise at −78° C. under nitrogen. The reaction mixture was stirred at −78° C. for 2 hours. Tris(1-methylethyl) borate (1.319 mL, 5.74 mmol) was added to the reaction mixture by syringe at −78° C. Then the reaction was stirred at −78° C. for 30 min, and then warmed to room temperature slowly. Then the reaction was quenched with water. The mixture was extracted with EA (15 mL×3). The combined organic layers was dried over anhydrous sodium sulphate. After filtration and concentration, the crude {2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}boronic acid (D101) (741 mg) was used directly in the next step. MS (ES): C10H13BO4 requires 208.1. found 209.0 (M+H+)
Reaction SMILES: N1(C([O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:23](=[O:24])[NH:22][C:21]4[C:16]3=[N:17][C:18]([N:25]3[C:29]5[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=5[N:27]=[CH:26]3)=[N:19][CH:20]=4)[CH2:11][CH2:10]2)=O)C=CN=C1.Cl.[OH-].[Na+]>CS(C)=O.CCOC(C)=O>[F:34][C:31]1[CH:32]=[CH:33][C:28]2[N:27]=[CH:26][N:25]([C:18]3[N:17]=[C:16]4[C:21]([NH:22][C:23](=[O:24])[N:15]4[C@H:12]4[CH2:11][CH2:10][C@H:9]([OH:8])[CH2:14][CH2:13]4)=[CH:20][N:19]=3)[C:29]=2[CH:30]=1
Reactant: O=C(O[C@H]1CC[C@H](n2c(=O)[nH]c3cnc(-n4cnc5ccc(F)cc54)nc32)CC1)n1ccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cnc(-n3cnc4ccc(F)cc43)nc2n1[C@H]1CC[C@H](O)CC1
Temperature: 50 °C

Procedure:
A solution of trans-4-(2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-8-oxo-7,8-dihydropurin-9-yl)cyclohexyl 1H-imidazole-1-carboxylate (30 mg) in DMSO (5 ml) was treated with concentrated HCl (1 ml). The mixture was heated at 50° C. for 3 hours. The mixture was diluted with EtOAc and made basic with 3N NaOH (10 ml) The organic layer was washed three times with brine, dried over Na2SO4, filtered, and concentrated to provide 20 mg of the title compound. 1H-NMR (300 MHz, CD3OD) δ 10.5 (s, 1H), 8.8 (dd, 1H), 8.6 (s, 1H), 8.1 (dd, 1H), 7.7 (td, 1H), 4.6 (m, 1H), 4.7 (m, 1H), 4.0 (m, 1H), 2.7 (m, 2H), 2.3 (m, 2H), 2.1 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:26][CH:25]=3)[C@H:8]([C:13]3[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:14]=3[F:23])[CH2:9][O:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:28][CH:29]=3)[C@H:8]([C:13]3[C:14]([F:23])=[C:15]([F:22])[C:16]([F:21])=[C:17]([F:20])[C:18]=3[F:19])[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1c(F)c(F)c(F)c(F)c1F)[C@H]2c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2c(c1)OC[C@@H](c1c(F)c(F)c(F)c(F)c1F)[C@H]2c1ccc(OCCN2CCCC2)cc1

Procedure:
In an manner analogous to that described in step 5 for Example 10, (±)-cis-7-methoxy-3-(2,3,4,5,6-pentafluorophenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane (0.260 g, 0.50 mmol) was de-methylated by heating with pyridine hydrochloride to give the title compound as an off-white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SC)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH3:31][NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]([CH3:31])[CH2:33][CH2:34][N:35]5[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:29])[F:30])[CH:3]=1
Reactant: CNCCN1CCN(C)CC1
Reactant: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN1CCN(CCN(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-{methyl-[2-(4-methyl-piperazin-1-yl)-ethyl]-amino}-thiazol-4-one one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one and methyl-[2-(4-methyl-piperazin-1-yl)-ethyl]-amine following General Procedure B.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Br:20])=[CH:18][N:17]=[C:16]3[NH:21][C:22]([C:24]4[CH:29]=[CH:28][C:27]([N:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=4)=[N:23][C:15]=23)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Br:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[C:15]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([N:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=3)[NH:21][C:16]2=[N:17][CH:18]=1
Reactant: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(Br)cnc3[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1ccc(-c2nc3c(N4CCNCC4)c(Br)cnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To 4-[6-Bromo-2-(4-dimethylamino-phenyl)-3H-imidazo[4,5-b]pyridin-7-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.380 g, 0.75 mmol) in dichloromethane (20 mL) at 0° C. was added slowly TFA (2 mL) and the reaction mixture was stirred at rt for 30 mins. TFA (1 mL) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and TFA was co-evaporated with CH3CN. The crude product was run trough a 5 g SCX cartridge and eluted with 0.1M NH3 in methanol. The compound was further triturated in ether/methanol 9/1 to give the title compound as a solid (0.228 g, 75%);
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:5]=1[C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7].C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[F:1][C:4]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:5]=1[C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7]
Reactant: [F-]
Reactant: O=C(CNC(=O)c1cc([N+](=O)[O-])ccc1Cl)OCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(CNC(=O)c1cc([N+](=O)[O-])ccc1F)OCc1ccccc1
Temperature: 105 °C
Reaction time: 0.75 h
Yield: 63.6 %

Procedure:
A mixture of spray dried KF (208 mg, 3.58 mmol), intermediate 6 (250 mg, 0.71 mmol) and catalytic amount of 18-crown-6 in dry DMSO (5 mL) was stirred at 100-110° C. for 45 min. Work-up of the reaction mixture as described in example 1 gave the product as a brown color solid (150 mg, 63%), mp 56-58° C. 1H NMR (400 MHz, CDCl3): δ 9.00 (1H, dd, J=6.0, 2.8 Hz), 8.36-8.40 (1H, m), 7.31-7.38 (7H, m), 5.25 (2H, s), 4.34 (2H, d, J=4.4 Hz); LC-MS (negative ion mode): m/z 331 (M−H)−.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1>CC(N(C)C)=O>[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: C1=COCC1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CC(=O)N(C)C
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Yield: 71.5 %

Procedure:
In 20 ml of dimethylacetamide were dissolved 1.3 g of 5-fluorouracil. To this solution were added 1.4 g of 2,3-dihydrofuran and the mixture was reacted in an autoclave for 5 hours at 180° C. After completion of the reaction, the reaction liquid was treated in the same manner as described in Example 1 whereby 0.22 g of the starting 5-fluorouracil was recovered as a substance insoluble in chloroform and 1.43 g of 1-(2-tetrahydrofuryl)-5-fluorouracil were obtained. The yield of the end product was 86.4% based on the consumed 5-fluorouracil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8]Br)=[CH:5][CH:4]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8][N:17]2[C:13](=[O:23])[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16]2=[O:18])=[CH:5][CH:4]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-methoxyphenacyl bromide (5.78 g, 25.23 mmol) in DMF (20 mL) was added potassium phthalimide (5.00 g, 26.99 mmol) and the reaction stirred at rt for 18 h. The reaction mixture was partitioned between dichloromethane (200 mL) and water (100 mL). The layers were separated and the aqueous layer extracted with dichloromethane (3×50 mL). The combined organics were washed with sodium hydroxide (2M, 50 mL), water (50 mL) and brine (50 mL) and dried (MgSO4). Filtration, then concentration in vacuo gave an off white solid. Trituration with diethyl ether followed by collection by filtration gave the title compound as a white solid. δH (CDCl3): 3.86 (3H, s), 5.15 (2H, s), 7.09 (2H, d), 7.81-8.01 (4H, m), 8.05 (2H, d).
Reaction SMILES: [Br:1]Br.[OH:3][CH:4]([CH3:18])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([CH3:17])[CH:8]=1>C(O)(=O)C>[Br:1][C:8]1[C:9]([CH3:17])=[N:10][C:11]2[C:16]([C:7]=1[NH:6][CH2:5][CH:4]([OH:3])[CH3:18])=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: Cc1cc(NCC(C)O)c2ccccc2n1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1nc2ccccc2c(NCC(C)O)c1Br
Reaction time: 1 h

Procedure:
Bromine (32 g) was added dropwise to a solution of 44 g of N-(2-hydroxypropyl)-2-methyl-4-quinolinamine in 600 ml of acetic acid. The solution was stirred for 1 hour and the HBr salt was filtered and washed with a small amount of acetic acid. It was then dissolved in 500 ml of water and an aqueous KOH solution was added, whereupon the free base precipitated. It was filtered and recrystallized from isopropanol. The yield was 22 g, mp 147°-149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:11]([O:13][C:14](=[O:17])[CH2:15]Br)C>CN(C=O)C>[CH3:11][O:13][C:14](=[O:17])[CH2:15][S:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: Sc1cccc(Cl)c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CSc1cccc(Cl)c1
Reaction time: 2 h
Yield: 94.3 %

Procedure:
In analogy to example 81.1, 4.34 g (0.030 mol) of 3-chloro-benzenethiol in 50 mL of DMF at 0° C. were treated with 1.32 g (0.033 mol, 1.1 eq) of NaH (55% in oil) over 45 min. 4.82 g (0.032 g, 1.05 eq) of bromo-acetic acid ethyl ester were added, and stirring was continued for 2 hours. Workup and purification gave 5.9 g (91%) of (3-chloro-phenylsulfanyl)-acetic acid methyl ester as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2Br)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][C:25]3[O:24][CH2:23][C:22]4=[N:21][NH:20][C:19](=[O:29])[CH:18]([CH3:30])[N:17]4[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC1C(=O)NN=C2COc3cc(-c4ccccc4)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A mixture of 4-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.02 g, 0.042 mmol), phenylboronic acid (0.01 g, 0.083 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloride dichloromethane complex (0.007 g, 0.008 mmol) and K2CO3 (0.012 g, 0.083 mmol) in dioxane (1 mL) and water (0.2 mL) was heated to reflux for 8 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative TLC (eluting with 50% EtOAc in petroleum ether) to give tert-butyl-4-(1-methyl-2-oxo-8-phenyl-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)piperidine-1-carboxylate (0.02 g, 100%) as a pale-white solid. LC/MS (Table 1, Method 3) Rt=1.596 min.; MS m/z: 477 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)[N:6]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCCl>[Br:14][CH2:13][C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([Cl:1])[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cccc(-c2csc(Cl)n2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1nc(-c2cccc(CBr)c2)cs1
Reaction time: 3 h

Procedure:
600 mg of 2-chloro-4-(3-tolyl)thiazole was dissolved in a mixture of 8 ml of carbon tetrachloride and 2 ml of 1,2-dichloroethane. N-bromosuccinimide (511 mg) and 3 mg of benzoyl peroxide were added, and the mixture refluxed with stirring for 3 hours. After cooling, the precipitate was separated from the reaction mixture by filtration. It was washed with an aqueous solution of sodium hydrogen carbonate, and the solvent was evaporated under reduced pressure to give 4-(3-bromomethylphenyl)-2-chlorothiazole as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([O:16][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COc1ccc(O)cc1
Reactant: O=C(O)C1CCCc2ccc([N+](=O)[O-])cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(OC(=O)C2CCCc3ccc([N+](=O)[O-])cc32)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 54.2 %

Procedure:
In 20 ml of pyridine were dissolved 1 g of 7-nitro-1,2,3,4-tetrahydro-1-naphthoic acid and 560 mg of p-methoxyphenol. To the solution which had been cooled was added 700 mg of phosphorus oxychloride and the mixture was allowed to stand for 2 days. The reaction mixture was poured into ice water, made slightly alkaline with a 5% sodium hydrogen carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and concentrated under reduced pressure to remove the ethyl acetate. The residue was recrystallized from an ethyl acetate-hexane mixture to obtain 0.8 g of p-methoxyphenyl 7-nitro-1,2,3,4-tetrahydro-1-naphthoate, m.p. 109°-110° C.
Reaction SMILES: [SH-:1].[Na+].Cl[C:4]1[N:9]2[N:10]=[C:11]([CH2:13][O:14][CH3:15])[N:12]=[C:8]2[N:7]=[C:6]([CH3:16])[CH:5]=1>O>[SH:1][C:4]1[N:9]2[N:10]=[C:11]([CH2:13][O:14][CH3:15])[N:12]=[C:8]2[N:7]=[C:6]([CH3:16])[CH:5]=1
Reactant: COCc1nc2nc(C)cc(Cl)n2n1
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Product: COCc1nc2nc(C)cc(S)n2n1
Temperature: 55 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
In 350 ml of water was dissolved 24 g of sodium hydrosulfide and 34.5 g of 7-chloro-2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidine was added thereto, and the mixture was stirred at 55° C. for one hour. After the reaction mixture was filtered, it was ice-cooled and adjusted to pH 1 with addition of a 2N-hydrochloric acid. The precipitates were collected by filtration, washed with water and with isopropanol, and dried to obtain 30.18 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[C:7]([OH:14])[C:6]([CH3:15])=[CH:5][C:3]=1O.[CH:16]([C:18]1([OH:22])[CH2:21][CH2:20][CH2:19]1)=[CH2:17]>O1CCOCC1.C(OCC)(=O)C>[CH3:15][C:6]1[C:7]([OH:14])=[C:8]([CH2:9][CH2:10][CH:11]([CH3:12])[CH3:13])[C:2]([CH3:1])=[C:3]2[C:5]=1[CH2:17][CH2:16][C:18]1([O:22]2)[CH2:21][CH2:20][CH2:19]1
Reactant: Cc1cc(O)c(C)c(CCC(C)C)c1O
Reactant: C=CC1(O)CCC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1c(O)c(CCC(C)C)c(C)c2c1CCC1(CCC1)O2
Yield: 45.1 %

Procedure:
To a solution of 2,5-dimethyl-3-(3-methylbutyl)hydroquinone (208 mg) and BF3-ether (0.25 mL) in dioxane (3 mL) was added 1-vinyl-cyclobutanol (98 mg) in dioxane (3 mL) over 50 min at 110° C. degree under nitrogen. The reaction was refluxed for one additional hour. The solution was diluted with ethyl acetate and washed with water and brine, and dried. After evaporation the residue waschromatographed (silica gel, hexane-ethyl acetate 0% to 3%) gave 5,8-dimethyl-7-(3-methylbutyl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol (130 mg).
Reaction SMILES: [N:1]([CH:4]([CH3:19])[CH2:5][N:6]1[CH:10]=[CH:9][C:8]2[CH2:11][C:12]3[C:17]([C:7]1=2)=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N+:2]=[N-:3].[CH:20](Br)([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:1]([CH:4]([CH3:19])[CH2:5][N:6]1[CH:10]=[CH:9][C:8]2[CH2:11][C:12]3[C:17]([C:7]1=2)=[CH:16][C:15]([O:18][CH:20]([CH3:22])[CH3:21])=[CH:14][CH:13]=3)=[N+:2]=[N-:3]
Reactant: CC(Cn1ccc2c1-c1cc(O)ccc1C2)N=[N+]=[N-]
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Cn1ccc2c1-c1cc(OC(C)C)ccc1C2)N=[N+]=[N-]
Yield: 28 %

Procedure:
A solution of 1.05 g of (RS)-1-(2-azido-propyl)-7-hydroxy-1,4-dihydro-indeno[1,2-b]pyrrole, 0.77 ml of isopropyl bromide and 1.14 g of potassium carbonate in 30 ml of N,N-dimethyl-formamide was heated to 50° for 48 hours. After cooling, the solution was poured into 150 ml of water and extracted twice with 150 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of semi-saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The crude product was purified by column chromatography on silica gel (toluene). 0.35 g (28%) of (RS)-1-(2-azido-propyl)-7-iso-propoxy-1,4-dihydro-indeno[1,2-b]pyrrole was obtained as an orange oil which was used directly in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[C:4](=[N:6][OH:7])Cl.[CH3:13][O:14][C:15](=[O:19])[C:16]#[C:17][CH3:18].C(N(CC)CC)C>C(OCC)C>[CH3:13][O:14][C:15]([C:16]1[C:4]([C:3]2[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=2[F:12])=[N:6][O:7][C:17]=1[CH3:18])=[O:19]
Reactant: ON=C(Cl)c1c(F)cccc1F
Reactant: CC#CC(=O)OC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2c(F)cccc2F)noc1C
Yield: 60.9 %

Procedure:
In a fashion similar to that for preparation 15, 2,6-difluorobenzoylchloride oxime (1.00 g, 5.19 mmol), methyl-2-butynoate (1.01 g, 10.4 mmol), triethyl amine (0.94 ml, 6.8 mmol) in diethyl ether (3 ml), and diethyl ether (25 ml) afforded 4-methoxycarbonyl-5-methyl-3-(2,6-difluorophenyl)isoxazole (0.80 g, 61%) after purification by column chromatography (silica gel, hexanes/diethyl ether gradient).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][CH2:37][N:38]4C(=O)C5=CC=CC=C5C4=O)[CH:31]=3)[C:15](=[O:29])[N:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=3[Cl:28])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:38][CH2:37][CH2:36][C:32]1[CH:31]=[C:30]([N:14]2[C:12]3=[N:13][C:8]([NH:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:9][CH:10]=[C:11]3[CH2:17][N:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=3[Cl:28])[C:15]2=[O:29])[CH:35]=[CH:34][CH:33]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1cccc(N2C(=O)N(c3ccc(C(F)(F)F)cc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCc1cccc(N2C(=O)N(c3ccc(C(F)(F)F)cc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Yield: 32.3 %

Procedure:
A solution of 155 mg (0.23 mmol) of 7-anilino-3-(2-chloro-4-trifluoromethylphenyl)-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one in 20 ml of ethanol was treated with 0.3 ml of hydrazine hydrate. After 18 hours the mixture was evaporated and the product purified by column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, evaporated and the residue evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. Trituration of the residue with hexane followed by filtration afforded 40 mg (32%) of 1-[3-(2-aminoethyl)phenyl]-7-anilino-3-(2-chloro-4-trifluoromethylphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 102° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6](=[O:25])[NH:5]1)([CH3:3])[CH3:2].CC([O:29][CH2:30][C@H:31]1[O:36][C@H:35](Br)[C@H:34]([O:38]C(C)=O)[C@@H:33]([O:42]C(C)=O)[C@@H:32]1[O:46]C(C)=O)=O.[OH-].[Na+]>ClCCl>[CH:1]([N:4]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:7]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:6]([O:25][C@@H:35]2[O:36][C@H:31]([CH2:30][OH:29])[C@@H:32]([OH:46])[C@H:33]([OH:42])[C@H:34]2[OH:38])=[N:5]1)([CH3:2])[CH3:3]
Reactant: COc1ccc(Cc2c(Oc3ccccc3)n(C(C)C)[nH]c2=O)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(C(C)C)c2Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
To a suspension of 1-isopropyl-4-(4-methoxybenzyl)-5-phenoxy-1,2-dihydro-3H-pyrazol-3-one (10 mg), acetobromo-α-D-glucose (40 mg) and benzyl(n-tributyl)ammonium chloride (30 mg) in dichloromethane (3 mL) was added sodium hydroxide aqueous solution (2 mol/L, 0.1 mL) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent: tetrahydrofuran). The obtained semi-purified 1-isopropyl-4-(4-methoxybenzyl)-5-phenoxy-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy-1H-pyrazole was dissolved in methanol (5 mL) and sodium methoxide (28% methanol solution, 0.2 mL) was added to the solution. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and to the residue was added 10% citric acid aqueous solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELLPAC C18 UG80, 5 μm, 20×50 mm, flowrate 30 mL/min linear gradient, water/methanol=70/30-10/90) to give 10 mg of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH:13]=O)[O:8][N:7]=1.[C:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:15]1([N:21]2[CH2:26][CH2:25][N:24]([CH2:13][CH2:12][CH2:11][C:9]3[O:8][N:7]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2cccs2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(N2CCN(CCCc3cc(-c4cccs4)no3)CC2)cc1
Yield: 74.7 %

Procedure:
About 2 min after dissolving 3-[3-(2-thienyl)isoxazol-5-yl]propanal (20 mg, 0.1 mmol), 1-phenylpiperazine (14.7, 0.1 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (61.4 mg, 0.3 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 3.5 hr and followed the same processes as in Example 1 to obtain 26.4 mg (77.4%) of the target compound.