Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2=[CH:12][NH:13][N:14]=[C:10]2[C:9]2[CH:8]=[C:7]([C:15](O)=[O:16])[C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[CH:5][C:4]=2[N:3]1[CH2:24][C:25]([F:28])([F:27])[F:26].C(=O)(O)[O-].[NH4+:33].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>N1C=CC=CC=1.CCOC(C)=O>[O:1]=[C:2]1[C:11]2=[CH:12][NH:13][N:14]=[C:10]2[C:9]2[CH:8]=[C:7]([C:15]([NH2:33])=[O:16])[C:6]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)=[CH:5][C:4]=2[N:3]1[CH2:24][C:25]([F:27])([F:26])[F:28]
Reactant: [NH4+]
Reactant: O=C(O)c1cc2c3n[nH]cc3c(=O)n(CC(F)(F)F)c2cc1-c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: NC(=O)c1cc2c3n[nH]cc3c(=O)n(CC(F)(F)F)c2cc1-c1ccncc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.9 %

Procedure:
A mixture of 4-oxo-7-(pyrid-4-yl)-5-(2,2,2-trifluoroethyl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-8-carboxylic acid [Example 11] (38 mg, 010 mmol), ammonium bicarbonate (46 mg, 0.59 mmol) and di-tert-butyl dicarbonate (47 mg, 0.22 mmol) in 1 mL of pyridine/EtOAc (1/1) is stirred at room temperature under nitrogen for 16 hours and then concentrated to dryness. After purification by preparative HPLC on a C18 reverse phase [eluent A: H2O/0.1M CH3COONH4 (90/10); eluent B: CH3CN/0.1M CH3COONH4 (90/10); gradient A/B: 95/5 to 50/50], 3 mg of a white powder are obtained (8%).
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[NH2:10][OH:11]>CCO>[NH2:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1](=[N:10][OH:11])[NH2:9]
Reactant: NO
Reactant: N#Cc1ccccc1N
Solvent: CCO
Product: NC(=NO)c1ccccc1N
Yield: 90.3 %

Procedure:
Anthranilonitrile (1 g, 8,5 mmol) and hydroxylamine (50% in water, 0.57 cm3, 9.3 mmol, 1.1 eq) in EtOH (42.5 cm3) were stirred under reflux for 24 hours, after which the volatiles were removed under reduced pressure and residue was partitioned between water (5 cm3) and CH2Cl2 (100 cm3). The organic phase was evaporated to dryness in the rotary evaporator followed by high vacuum line to give the product 2-amino-N′-hydroxybenzimidamide (1.16 g, 90.3%) as a solid, mp 85-86° C.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=4)[CH:21]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.[Li+].[OH-]>CO>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=4)[CH:21]([CH2:29][C:30]([OH:32])=[O:31])[CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2
Reactant: CCOC(=O)CC1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2cc(Cl)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2cc(Cl)ccc21
Reaction time: 2 h
Yield: 7.3 %

Procedure:
To a solution of (±)-ethyl 2-(1′-((2-adamantyl)carbamoyl)-6-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate (150 mg, 0.3 mmol) in MeOH (3 mL), LiOH (15 mg, 0.6 mmol) was added and the mixture was stirred for 2 h. The solution was concentrated to give the residue, which was purified by preparative HPLC to obtain (±)-2-(1′-((2-adamantyl)carbamoyl)-6-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid (10 mg, 7%). LC-MS Method 5 tR=1.485 min, m/z=457.2; 1H NMR (CD3OD): δ=1.59-1.76 (m, 6H), 1.86-1.99 (m, 8H), 1.99-2.19 (m, 6H), 2.48-2.57 (m, 1H), 2.78 (m, 1H), 2.95 (m, 1H), 3.00-3.09 (m, 1H), 3.11-3.23 (m, 1H), 3.69 (m, 1H), 3.94 (s, 1H), 4.06-4.19 (m, 2H), 7.26 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]([N:22]3[CH2:27][CH2:26][C@:25]([CH2:34][C:35]([OH:38])([CH3:37])[CH3:36])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:24][C:23]3=[O:39])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO.[H][H]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]([N:22]3[CH2:27][CH2:26][C@:25]([CH2:34][C:35]([OH:38])([CH3:37])[CH3:36])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:24][C:23]3=[O:39])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@@H](c1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H](c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
A mixture of 4-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.34 g) and 10% palladium on carbon (60 mg) in methanol (10 mL) was shaken in hydrogen atmosphere (50 psi) for 4 h. Then, the catalyst was separated by filtration and the filtrate was concentrated to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH3:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[O:17][CH3:18])[CH:5]=[CH:4][N:3]=1.[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26]([OH:28])=O)(=[O:22])=[O:21]>>[Cl:1][C:2]1[C:7]([N:8]([CH3:9])[C:26](=[O:28])[C:25]2[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])[CH:24]=2)=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[O:17][CH3:18])[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1c(-c2ccc(F)cc2OC)ccnc1Cl
Product: COc1cc(F)ccc1-c1ccnc(Cl)c1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from [2-chloro-4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-methyl-amine and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) after a reaction time of 66 hours. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50), followed by a second chromatography using preparative HPLC (Gemini NX column) eluting with a gradient of methanol:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless solid (30%). MS (ESI): m/z=517.06 [M+H]+.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:29][C:30](=O)[CH2:31][C:32]1[NH:36][CH:35]=[N:34][N:33]=1)C>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:30](=[O:29])[CH2:31][C:32]1[NH:36][CH:35]=[N:34][N:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1nnc[nH]1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Product: COc1ccc(N2CCN(C(=O)Cc3nnc[nH]3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Yield: 19 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclobutyloxy-4-methoxy-phenyl)-piperazine and (4H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester with heating for 15 days to afford the title compound as a yellow solid (75 mg, 19%). LC/MS (Method B) 3.17 min, [M+1]+ 462.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>C1(C)C=CC=CC=1>[C:19]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)(=[O:22])[CH:20]=[CH2:21]
Reactant: C=CC(=O)Cl
Reactant: Oc1cccc2cccnc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)Oc1cccc2cccnc12
Reaction time: 8 h

Procedure:
8-Hydroxyquinoline (58.0 g: 0.40 mole) was dissolved in a mixture of toluene (500 ml) and triethylamine (41.4 g; 0.41 mole). Acrylyl chloride (38.0 g; 0.42 mole) was added slowly, while stirring, the reaction temperature beting kept under 30° C. When the addition was complete the mixture was stirred for another 1 hour. The solution was then filtered and washed with a solution of sodium hydrogen carbonate in water followed by water only, and finally the toluene layer was dried with anhydrous sodium sulphate. Some toluene was evaporated off using a rotary evaporator under low pressure. The solution was left in a refrigerator overnight and the solid formed was filtered off. This was identified by infra-red and N.M.R. spectroscopy and microanalysis to be 8-quinolinyl acrylate. Yield 48.6 g (61 percent of the theoretical yield).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([F:15])=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([F:15])=[N:10][CH:11]=[C:12]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(Br)cnc1F
Reactant: Brc1cccnc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(-c2cccnc2)cnc1F

Procedure:
By carrying out the operation analogously to example 49, starting from 5-bromo-2-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VIII and 3-bromopyridine, the desired product is obtained in the form of a gray solid (yield=26%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[C:14]4([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[CH2:13][N:12]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[C:11](=[O:38])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[CH:41]=[C:40]1B(O)O>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[O:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[CH:41]=[C:40]1[C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[C:14]4([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[CH2:13][N:12]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[C:11](=[O:38])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)c3[nH]c(-c4ccnc(Cl)n4)cc3C2=O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)c3[nH]c(-c4ccnc(-c5cc6ccccc6o5)n4)cc3C2=O)cc1
Temperature: 140 °C
Reaction time: 0.75 h
Yield: 69.5 %

Procedure:
A mixture of tert-butyl 2′-(2-chloropyrimidin-4-yl)-5′-(4-methoxybenzyl)-4′-oxo-1′,4′,5′,6′-tetrahydrospiro[piperidine-4,7′-pyrrolo[3,2-c]pyridine]-1-carboxylate (A5) (4.5 g, 8.36 mmol), 2-benzofuranboronic acid (4.06 g, 25.09 mmol) and potassium phosphate tribasic heptahydrate (8.49 g, 25.09 mmol) was dissolved in anhydrous dioxane (105 mL). The resulting solution was purged with nitrogen, followed by addition of 1,1′-bis(diphenylphosphino)ferrocene palladium(II)chloride (676 mg, 0.836 mmol). The resulting mixture was again purged with nitrogen and stirred at 140° C. for 45 min in the microwave. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed three times with aqueous NaHCO3, once with brine, dried over Na2SO4, filtered and concentrated under vacuum. The crude product was triturated with toluene which gave tert-butyl 2′-(2-(benzofuran-2-yl)pyrimidin-4-yl)-5′-(4-methoxybenzyl)-4′-oxo-1′,4′,5′,6′-tetrahydrospiro[piperidine-4,7′-pyrrolo[3,2-c]pyridine]-1-carboxylate (A6) as a white solid (3.60 g, 70%). 1H NMR (400 MHz, DMSO-D6, 300K): δ=1.42 (9H, s), 1.55 (2H, br d, J=13.0 Hz), 2.08 (2H, br dt, J=13.4 Hz), 2.65 (2H, br s), 3.56 (2H, br s), 3.74 (3H, s), 3.80 (2H, br s), 4.57 (2H, br s), 6.92 (2H, d, J=8.6 Hz), 7.31 (2H, d, J=8.6 Hz), 7.35 (1H, t, J=7.6 Hz), 7.43 (1H, s), 7.46 (1H, t, J=7.8 Hz), 7.75 (1H, d, J=8.2 Hz), 7.80 (1H, d, J=5.5 Hz), 7.82 (1H, d, J=7.7 Hz), 8.03 (1H, s), 8.77 (1H, d, J=5.4 Hz), 11.75 (1H, s). MS (ES) C36H37N5O5 requires: 619. found: 620.2 [M+H]+.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[N:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)Cl>[C:1]([NH:5][S:13]([C:10]1[CH:11]=[N:12][C:7]([Cl:6])=[CH:8][CH:9]=1)(=[O:15])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a mixture of 17.3 mL (165 mmol) of tert-butylamine and 69 mL (495 mmol) of TEA in 330 mL of DCM are added portionwise, at 0° C., 35 g (165 mmol) of 6-chloropyridine-3-sulfonyl chloride. After stirring for 2 hours at 0° C., the reaction medium is taken up in 600 mL of DCM, washed with water (1 L), saturated NaHCO3 solution (1 L) and brine (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure. 32.4 g of N-tertbutyl-6-chloropyridine-3-sulfonamide are obtained in the form of a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Br:10][CH2:11][CH2:12]Br>>[Br:10][CH2:11][CH2:12][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: BrCCBr
Product: N#Cc1ccc(OCCBr)cc1

Procedure:
The procedure is as for Example 53, Step A, using as substrate 4-hydroxybenzonitrile and 1,2-dibromoethane.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4]([NH2:6])=[S:5])[CH3:2].Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O>[CH2:1]([N:3]([C:4]1[S:5][CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:6]=1)[CH2:7][CH3:8])[CH3:2]
Reactant: CCN(CC)C(N)=S
Reactant: CCOC(=O)C(=O)CBr
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(N(CC)CC)n1
Yield: 140.4 %

Procedure:
A solution of 0.972 g (7.36 mmol) of N,N-diethylthiourea and 1.02 ml (8.1 mmol) of ethyl bromopyruvate in 25 ml of acetone was treated with excess solid MgSO4 and heated at reflux for 1 h. The resulting mixture was filtered, and concentrated in vacuo. Silica gel chromatography using CHCl3 provided 2.36 g (38%) of the desired compound as an oil. Mass spectrum: (M+H)+ =229.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH:7](I)([CH3:9])[CH3:8].CN(C)C=O.[OH:16][C@@H:17]1[CH2:31][C@@H:20]2[S:21][C@@H:22]([CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:23][CH2:24][C@@H:19]2[C@H:18]1/[CH:32]=[CH:33]/[C@@H:34]([OH:43])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(OCC)(=O)C>[OH:16][C@@H:17]1[CH2:31][C@@H:20]2[S:21][C@@H:22]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH:7]([CH3:9])[CH3:8])=[O:29])[CH2:23][CH2:24][C@@H:19]2[C@H:18]1[CH2:32][CH2:33][C@@H:34]([OH:43])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(O)CCC[C@H]1CC[C@@H]2[C@@H](/C=C/[C@@H](O)COc3ccccc3)[C@H](O)C[C@@H]2S1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)CCC[C@H]1CC[C@@H]2[C@@H](CC[C@@H](O)COc3ccccc3)[C@H](O)C[C@@H]2S1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Under the argon atmosphere, cesium carbonate (68 mg) and isopropyl iodide (0.016 mL) were added to a dimethylformamide (0.4 mL) solution of the compound 15 (20) (42.8 mg), and the mixture was stirred at 50° C. for 90 minutes. This was cooled to room temperature, ethyl acetate was then added, and the mixture was washed with water two times, and then with a saturated saline once. The mixture was dried with anhydrous magnesium sulfate, and then concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3→1:1) to obtain a titled compound (34 mg) having the following physical property values.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]([O:14][CH3:15])[O:4]1>CCOC(C)=O.[Rh]>[CH3:1][O:2][CH:3]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH:5]([O:14][CH3:15])[O:4]1
Reactant: COC1C=C(c2ccccc2)C(OC)O1
Agent: [Rh]
Solvent: CCOC(C)=O
Product: COC1CC(c2ccccc2)C(OC)O1
Reaction time: 24 h
Yield: 97.9 %

Procedure:
A mixture of 2,5-dihydro-2,5-dimethoxy-3-phenylfuran (590 mg, 2.86 mmol) and 10% Rh/Al2O3 (110 mg) in EtOAc (10 mL) was stirred under H2 atmosphere for 24 hours. The catalyst was filtered onto Celite and rinsed with EtOAc. The filtrate was concentrated in vacuo to afford 583 mg (98%) of 2,5-dimethoxy-3-phenyl-tetrahydrofuran as a colorless oil which was typically used without further purification.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:15]4=[N:16][CH:17]=[N:18][C:19]([NH2:20])=[C:14]4[C:13]([C:21]4[CH:26]=[CH:25][C:24]([O:27][C:28]5[N:33]=[CH:32][CH:31]=[CH:30][N:29]=5)=[CH:23][CH:22]=4)=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>CC(C)=O>[NH2:20][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:11]([CH:8]3[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]3)[N:12]=[C:13]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:25][CH:26]=3)[C:14]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ncccn3)cc1)nn2C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ncccn3)cc1)nn2C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
A slurry of 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-[4-(2-pyrimidinyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (int BB) (1.22 g, 0.00274 mol) in acetone was cooled to 0° C. and 5 N aqueous hydrochloric acid (15 mL) was added dropwise keeping the temperature less than 5° C. After the addition was complete, the mixture was stirred at ambient temperature for three hours. The solution was filtered through celite and neutralized with a saturated aqueous solution of sodium bicarbonate. The precipitate which formed was filtered, washing with water and dried in vacuo overnight to give 4{-4-amino-3-[4-(2-pyrimidinyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-cyclohexanone as a white solid (0.937 g, 0.00243 mol): 1H NMR (DMSO-d6, 400 MHz) 8.68 (d, 2H), 8.29 (s, 1H), 7.56 (d, 2H), 7.37 (d, 2H), 7.31 (t, 1H), 6.30-7.20 (bs, 2H), 5.25-5.30 (m, 1H), 2.67-2.75 (m, 2H), 2.24-2.43 (m, 6H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Br[C:16]1[CH:20]=[CH:19][S:18][CH:17]=1.[Cl-].[NH4+]>C(OCC)C>[CH2:1]([C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC[Mg]Br
Reactant: Brc1ccsc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCCCCCCCCc1ccsc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a freshly prepared dodecylmagnesium bromide (from 45 mmoles of dodecyl bromide and 45 mmoles of magnesium) in anhydrous diethyl ether (100 ml) was added 3-bromothiophene (45 mmoles) in diethyl ether (25 ml) at ambient temperature under argon and then bis-(1,2-diphenylphosphino)ethane nickel (II) chloride (0.25 g) was added. The reaction mixture was stirred overnight at ambient temperature and then hydrolyzed with ice and saturated aqueous ammonium chloride. The aqueous layer was extracted with diethyl ether (3×25 ml) and the organic phases were combined, washed with water (3×25 ml), dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product was purified by distillation in vacuo and then flash chromatography to afford the desired product.
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][C:3]=1[F:13].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>>[Cl:20][CH2:21][CH2:22][CH2:23][N:8]1[C:7]2[C:2]([F:1])=[C:3]([F:13])[CH:4]=[CH:5][C:6]=2[O:11][CH2:10][C:9]1=[O:12]
Reactant: O=C1COc2ccc(F)c(F)c2N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1COc2ccc(F)c(F)c2N1CCCCl
Yield: 72 %

Procedure:
5,6-Difluoro-4H-benzo[1,4]oxazin-3-one (0.13 g, 0.69 mmol), Cs2CO3 (0.45 g, 1.4 mmol), and 1-chloro-3-iodopropane (0.15 g, 0.76 mmol) were mixed according to GP2. Purified by column chromatography (SiO2; heptanes/EtOAc, gradient 0 to 30% EtOAc) to give the title compound (0.13 g, 75%). Rf=0.60 (heptanes/EtOAc 1:1); 1H NMR (CDCl3) δ 6.88-6.74 (m, 2H), 4.52 (s, 2H), 4.19-4.14 (m, 2H), 3.58 (t, J=6.4 Hz, 2H), 2.22-2.14 (m, 2H); 13C NMR (CDCl3) δ 165.1, 147.5 (dd, J=242.5 Hz, J=12.7 Hz), 143.8 (t, J=3.0 Hz), 140.7 (dd, J=249.8 Hz, J=17.3 Hz), 119.8 (d, J=4.6 Hz), 111.9 (dd, J=7.4 Hz, J=3.9 Hz), 111.2 (d, J=18.8 Hz), 68.4, 42.4 (d, J=9.7 Hz), 42.1, 31.1 (d, J=3.5 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]#[N:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Se](=O)=[O:15]>O1CCOCC1.O>[CH:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]#[N:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[O:15]
Reactant: O=[Se]=O
Reactant: Cc1ccc2cccc(C#N)c2n1
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cccc2ccc(C=O)nc12
Temperature: 25 °C
Yield: 82.1 %

Procedure:
To a solution of 2-methylquinoline-8-carbonitrile (1.70 g, 10.1 mmol) in 1,4-dioxane (50 mL) and water (1 mL), was added selenium dioxide (2.80 g, 25.3 mmol) and the resulting mixture heated at reflux for 7 hours. After cooling to ambient temperature, the solids formed were removed by filtration through a pad of Celite® and washed with 1:1 mixture of ethyl acetate/dichloromethane (50 mL). The filtrate was concentrated under reduced pressure and the residue obtained purified by column chromatography (Biotage, 40M; 1% MeOH: dichloromethane) to give 2-formylquinoline-8-carbonitrile (1.51 g, 82%).
Reaction SMILES: [CH2:1]([N:5]([CH3:27])[C:6](=[O:26])[CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13](C(OCC2C=CC=CC=2)=O)[CH2:12][CH2:11]1)[CH2:2][CH2:3][CH3:4]>[Pd].C(O)C>[CH2:1]([N:5]([CH3:27])[C:6](=[O:26])[CH2:7][CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C)C(=O)CCCN1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCCN(C)C(=O)CCCN1CCNCC1

Procedure:
A mixture of the N-n-butyl-N-methyl-4-(4- benzyloxycarbonylpiperazin-1-yl)butyramide thus obtained (0.187 g.), a 10% palladium-on-charcoal catalyst (0.1 g.) and ethanol (5 ml.) was stirred at laboratory temperature under an atmosphere of hydrogen for 22 hours and then filtered and the filtrate was evaporated to dryness. There was thus obtained as an oil N-n-butyl-N-methyl-4-(piperazin-1-yl)butyramide.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)O)[CH2:6][CH2:5]1)(=O)C.[ClH:26]>C(O)C>[ClH:26].[Br:25][C:22]1[CH:23]=[CH:24][C:19]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[C:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)=[CH:20][CH:21]=1
Reactant: CC(=O)N1CCC(C(O)(c2ccc(F)cc2)c2ccc(Br)cc2)CC1
Agent: Cl
Solvent: CCO
Product: Fc1ccc(C(=C2CCNCC2)c2ccc(Br)cc2)cc1

Procedure:
A mixture of 75 parts of 1-acetyl-α-(4-bromophenyl)-α-(4-fluorophenyl)-4-piperidinemethanol, 600 parts of concentrate hydrochloric acid and 80 parts of ethanol was stirred and refluxed for 18 hours. The reaction mixture was evaporated. 500 Parts of water were added to the residue. The solution was treated with ammonium hydroxide. The product was extracted twice with 375 parts of trichloromethane. The combined organic layers were washed with 100 parts of water, dried, filtered and evaporated. The oily residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume), saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The whole was evaporated. The residue solidified in 80 parts of acetonitrile. The product was filtered off (filtrate I was set aside) and crystallized from 160 parts of acetonitrile at 0° C. The product was filtered off (filtrate II was set aside) and dried, yielding 36 parts of 4-[(4-bromophenyl)(4-fluorophenyl)methylene]piperidine hydrochloride.